In Focus

Introduction

Gastroesophageal reflux disease (GERD) is a frequently encountered condition, and rising annually.¹ A recent meta-analysis suggests nearly 14% (1.03 billion) of the population are affected worldwide. Differences may range by region from 12% in Latin America to 20% in North America, and by country from 4% in China to 23% in Turkey.¹ In the United States, 21% of the population are afflicted with weekly GERD symptoms.² Novel medical therapies and endoscopic options provide clinicians with opportunities to help patients with GERD.³Herein, we review diagnostics as well as the evolution of medical, endoscopic and basic surgical management for GERD.

Diagnosis

Definition

courtesy University of Southern California

GERD was originally defined by the Montreal consensus as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications.⁴ Heartburn and regurgitation are common symptoms of GERD, with a sensitivity of 30%-76% and specificity of 62%-96% for erosive esophagitis (EE), which occurs when the reflux of stomach content causes esophageal mucosal breaks.⁵ The presence of characteristic mucosal injury observed during an upper endoscopy or abnormal esophageal acid exposure on ambulatory reflux monitoring are objective evidence of GERD. A trial of a proton pump inhibitor (PPI) may function as a diagnostic test for patients exhibiting the typical symptoms of GERD without any alarm symptoms.^3,6

Endoscopic Evaluation and Confirmation

The 2022 American Gastroenterological Association (AGA) clinical practice update recommends diagnostic endoscopy, after PPIs are stopped for 2-4 weeks, in patients whose GERD symptoms do not respond adequately to an empiric trial of a PPI.³ Those with GERD and alarm symptoms such as dysphagia, weight loss, bleeding, and vomiting should undergo endoscopy as soon as possible. Endoscopic findings of EE (Los Angeles Grade B or more severe) and long-segment Barrett’s esophagus (> 3-cm segment with intestinal metaplasia on biopsy) are diagnostic of GERD.³

Reflux Monitoring

courtesy University of Southern California

With ambulatory reflux monitoring (pH or impedance-pH), esophageal acid exposure (or neutral refluxate in impedance testing) can be measured to confirm GERD diagnosis and to correlate symptoms with reflux episodes. Patients with atypical GERD symptoms or patients with a confirmed diagnosis of GERD whose symptoms have not improved sufficiently with twice-daily PPI therapy should have esophageal impedance-pH monitoring while on PPIs.^6,7

Esophageal Manometry

High-resolution esophageal manometry can be used to assess motility abnormalities associated with GERD.

Although no manometric abnormality is unique to GERD, weak lower esophageal sphincter (LES) resting pressure and ineffective esophageal motility frequently coexist with severe GERD.⁶

Manometry is particularly useful in patients considering surgical or endoscopic anti-reflux procedures to evaluate for achalasia,³ an important contraindication to surgery.
 

Medical Management

courtesy University of Southern California

Management of GERD requires a multidisciplinary and personalized approach based on symptom presentation, body mass index, endoscopic findings (e.g., presence of EE, Barrett’s esophagus, hiatal hernia), and physiological abnormalities (e.g., gastroparesis or ineffective motility).³

Lifestyle Modifications

Recommended lifestyle modifications include weight loss for patients with obesity, stress reduction, tobacco and alcohol cessation, elevating the head of the bed, staying upright during and after meals, avoidance of food intake < 3 hours before bedtime, and cessation of foods that potentially aggravate reflux symptoms such as coffee, chocolate, carbonated beverages, spicy foods, acidic foods, and foods with high fat content.^6,8

Medications

Pharmacologic therapy for GERD includes medications that primarily aim to neutralize or reduce gastric acid -- we summarize options in Table 1.^3,8

MDedge News

Proton Pump Inhibitors

Most guidelines suggest a trial of 4-8 weeks of once-daily enteric-coated PPI before meals in patients with typical GERD symptoms and no alarm symptoms. Escalation to double-dose PPI may be considered in the case of persistent symptoms. The relative potencies of standard-dose pantoprazole, lansoprazole, esomeprazole, and rabeprazole are presented in Table 1.⁹ When a PPI switch is needed, rabeprazole may be considered as it is a PPI that does not rely on CYP2C19 for primary metabolism.⁹

Acid suppression should be weaned down to the lowest effective dose or converted to H2RAs or other antacids once symptoms are sufficiently controlled unless patients have EE, Barrett’s esophagus, or peptic stricture.³ Patients with severe GERD may require long-term PPI therapy or an invasive anti-reflux procedure.

Recent studies have shown that potassium-competitive acid blockers (PCAB) like vonoprazan may offer more effective gastric acid inhibition. While not included in the latest clinical practice update, vonoprazan is thought to be superior to lansoprazole for those with LA Grade C/D esophagitis for both symptom relief and healing at 2 weeks.¹⁰

Adjunctive Therapies

Alginates can function as a physical barrier to even neutral reflux and may be helpful for patients with postprandial or nighttime symptoms as well as those with hiatal hernia.³ H2RAs can also help mitigate nighttime symptoms.³ Baclofen is a gamma-aminobutyric acid–B agonist which inhibits transient lower esophageal sphincter relaxation (TLESR) and may be effective for patients with belching.³ Prokinetics may be helpful for GERD with concomitant gastroparesis^.3 Sucralfate is a mucosal protective agent, but there is a lack of data supporting its efficacy in GERD treatment. Consider referral to a behavioral therapist for supplemental therapies, hypnotherapy, cognitive-behavior therapy, diaphragmatic breathing, and relaxation strategies for functional heartburn or reflux-associated esophageal hypervigilance or reflux hypersensitivity.³

When to Refer to Higher Level of Care

For patients who do not wish to remain on longer-term pharmacologic therapy or would benefit from anatomic repair, clinicians should have a discussion of risks and benefits prior to consideration of referral for anti-reflux procedures.^3,6,8 We advise this conversation should include review of patient health status, postsurgical side effects such as increased flatus, bloating and dysphagia as well as the potential need to still resume PPI post operation.⁸

Endoscopic Management

Patient Selection And Evaluation

For the groups indicated for a higher level of care, we agree with AGA recommendations, multi-society guidelines, and expert review,^3,7,11,12 and highlight potential options in Table 2. Step-up options should be based on patient characteristics and reviewed carefully with patients. Endoscopic therapies are less invasive than surgery and may be considered for those who do not require anatomic repair of hiatal hernia, do not want surgery, or are not suitable for surgery.

MDedge News

The pathophysiology of GERD is from a loss of the anti-reflux barrier of the esophageal gastric junction (EGJ) at the lower esophageal sphincter (LES) leading to unintended retrograde movement of gastric contents.⁶ Anatomically, the LES is composed of muscles of the distal esophagus and sling fibers of the proximal stomach, the “external valve” from the diaphragmatic crura, and the “internal valve” from the gastroesophageal flap valve (GEFV). GERD occurs from mechanical failure of the LES. First, there may be disproportional dilation of the diaphragmatic crura as categorized by Hill Grade of the GEFV as seen by a retroflexed view of EGJ after 30-45 seconds of insufflation.¹³ Second, there may be a migration of the LES away from the diaphragmatic crura as in the case of a hiatal hernia. Provocative maneuvers may reveal a sliding hernia by gentle retraction of the endoscope while under retroflexed view.¹³ Third, there may be more frequent TLESR associated with GERD.¹²

The aim of most interventions is to restore competency of the LES by reconstruction of the GEFV via suture or staple-based approximation of tissue.^11,12 Intraluminal therapy may only target the GEFV at the internal valve. Therefore, most endoscopic interventions are limited to patients with intact diaphragmatic crura (ie, small to no hiatal hernia and GEFV Hill Grade 1 to 2). Contraindications for endoscopic therapy are moderate to severe reflux (ie, LA Grade C/ D), hiatus hernia 2 cm or larger, strictures, or long-segment Barrett’s esophagus.
 

Utility, Safety, and Outcomes of TIF

Historically, endoscopic therapy targeting endoscopic fundoplication started with EndoLuminal gastro-gastric fundoplication (ELF, 2005) which was a proof of concept of safe manipulation and suture for gastro-gastric plication to below the Z-line. Transoral incisionless fundoplication (TIF) 1.0 was suggested in 2007 for clinical application by proposing a longitudinal oriented esophago-gastric plication 1 cm above the Z-line.

In 2009, TIF2.0 was proposed as a rotational 270° wrap of the cardia and fundus to a full-thickness esophago-gastric fundoplication around 2-4 cm of the distal esophagus. Like a surgical fundoplication, this reinforces sling fibers, increases the Angle of His and improves the cardiac notch. TIF 2.0 is indicated for those with small (< 2 cm) or no hiatal hernia and a GEFV Hill Grade 1 or 2. The present iteration of TIF2.0 uses EsophyX-Z (EndoGastric Solutions; Redmond, Washington) which features dual fastener deployment and a simplified firing mechanism. Plication is secured via nonresorbable polypropylene T-fasteners with strength equivalence of 3-0 sutures.

Compared with the original, TIF2.0 represents a decrease of severe adverse events from 2%-2.5% to 0.4%-1%.^11,14 Based on longitudinal TEMPO data, patient satisfaction ranges between 70% and 90% and rates of patients reverting to daily PPI use are 17% and 34% at 1 and 5 years. A 5% reintervention rate was noted to be comparable with surgical reoperation for fundoplication.¹⁵ One retrospective evaluation of patients with failed TIF followed by successful cTIF noted that in all failures there was a documented underestimation of a much larger crura defect at time of index procedure.¹⁶ Chest pain is common post procedure and patients and collaborating providers should be counseled on the expected course. In our practice, we admit patients for at least 1 postprocedure day and consider scheduling symptom control medications for those with significant pain.
 

TIF2.0 for Special Populations

Indications for TIF2.0 continue to evolve. In 2017, concomitant TIF2.0 with hiatal hernia repair (cTIF or HH-TIF) for hernia > 2 cm was accepted for expanded use. In one study, cTIF has been shown to have similar outcomes for postprocedural PPI use, dysphagia, wrap disruption, and hiatal hernia recurrence, compared with hiatal hernia repair paired with laparoscopic Nissen fundoplication with possibly shorter postadmission stay, serious adverse events, and bloating.¹⁷ A cTIF may be performed in a single general anesthetic session typically with a surgical hiatal hernia repair followed by TIF2.0.

Other Endoscopic Procedures

Several other endoscopic interventions have been proposed for GERD management. The following procedures are under continuous study and should be considered only by those with expertise.
 

Stretta

The Stretta device (Restech; Houston, Texas) was approved in 2000 for use of a radiofrequency (RF) generator and catheter applied to the squamocolumnar junction under irrigation. Ideal candidates for this nonablative procedure may include patients with confirmed GERD, low-grade EE, without Barrett’s esophagus, small hiatal hernia, and a competent LES with pressure > 5 mmHg. Meta-analysis has yielded conflicting results in terms of its efficacy, compared with TIF2.0, and recent multi-society guidance suggests fundoplication over Stretta.⁷

ARM, MASE, and RAP

Anti-reflux mucosectomy (ARM) has been proposed based on the observation that patients undergoing mucosectomy for neoplasms in the cardia had improvement of reflux symptoms.^11,12 Systematic review has suggested a clinical response of 80% of either PPI discontinuation or reduction, but 17% of adverse events include development of strictures. Iterations of ARM continue to be studied including ARM with band ligation (L-ARM) and endoscopic submucosal dissection for GERD (ESD-G).¹²

Experts have proposed incorporating endoscopic suturing of the EGJ to modulate the LES. Mucosal ablation and suturing of the EG junction (MASE) has been proposed by first priming tissue via argon plasma coagulation (APC) prior to endoscopic overstitch of two to three interrupted sutures below the EGJ to narrow and elongate the EGJ. The resection and plication (RAP) procedure performs a mucosal resection prior to full-thickness plication of the LES and cardia.^11,12 Expert opinion has suggested that RAP may be used in patients with altered anatomy whereas MASE may be used when resection is not possible (eg, prior scarring, resection or ablation).¹²
 

Surgical Management

We agree with a recent multi-society guideline recommending that an interdisciplinary consultation with surgery for indicated patients with refractory GERD and underlying hiatal hernia, or who do not want lifelong medical therapy.

Fundoplication creates a surgical wrap to reinforce the LES and may be performed laparoscopically. Contraindications include body mass index (BMI) >35 kg/m2 and significantly impaired dysmotility. Fundoplication of 180°, 270°, and 360° may achieve comparable outcomes, but a laparoscopic toupet fundoplication (LTF 270°) may have fewer postsurgical issues of dysphagia and bloating. Advantages for both anterior and posterior partial fundoplications have been demonstrated by network meta-analysis. Therefore, a multi-society guideline for GERD suggests partial over complete fundoplication.⁷ Compared with posterior techniques, anterior fundoplication (Watson fundoplication) led to more recurrent reflux symptoms but less dysphagia and other side effects.¹⁹

Magnetic sphincter augmentation (MSA) is a surgical option that strengthens the LES with magnets to improve sphincter competence. In addition to listed contraindications of fundoplication, patients with an allergy to nickel and/or titanium are also contraindicated to receive MSA.⁷ MSA has been suggested to be equivalent to LNF although there may be less gas bloat and greater ability to belch on follow up.²⁰
 

Surgical Options for Special Populations

Patients with medically refractory GERD and a BMI ≥ 35 kg/m² may benefit from either Roux-en-Y gastric bypass (RYGB) or fundoplication, however sleeve gastrectomy is not advised.⁷ In patients with BMI > 50 kg/m2, RYGB may provide an optimal choice. We agree with consultation with a bariatric surgeon when reviewing these situations.

Conclusion

Patients with GERD are commonly encountered worldwide. Empiric PPI are effective mainstays for medical treatment of GERD. Novel PCABs (e.g., vonoprazan) may present new options for GERD with LA Grade C/D esophagitis EE and merit more study. In refractory cases or for patients who do not want long term medical therapy, step-up therapy may be considered via endoscopic or surgical interventions. Patient anatomy and comorbidities should be considered by the clinician to inform treatment options. Surgery may have the most durable outcomes for those requiring step-up therapy. Improvements in technique, devices and patient selection have allowed TIF2.0 to grow as a viable offering with excellent 5-year outcomes for indicated patients.

Dr. Chang, Dr. Tintara, and Dr. Phan are based in the Division of Gastrointestinal and Liver Disease at the University of Southern California in Los Angeles. They have no conflicts of interest to declare.

References

1. Richter JE andRubenstein JH. Gastroenterology. 2018 Jan. doi: 10.1053/j.gastro.2017.07.045.

2. El-Serag HB et al. Gut. 2014 Jun. doi: 10.1136/gutjnl-2012-304269.

3. Yadlapati R et al. Clin Gastroenterol Hepatol. 2022 May. doi: 10.1016/j.cgh.2022.01.025.

4. Vakil N et al. Am J Gastroenterol. 2006 Aug. doi: 10.1111/j.1572-0241.2006.00630.x.

5. Numans ME et al. Ann Intern Med. 2004 Apr. doi: 10.7326/0003-4819-140-7-200404060-00011.

6. Kahrilas PJ et al. Gastroenterology. 2008 Oct. doi: 10.1053/j.gastro.2008.08.045.

7. Slater BJ et al. Surg Endosc. 2023 Feb. doi: 10.1007/s00464-022-09817-3.

8. Gyawali CP et al. Gut. 2018 Jul. doi:10.1136/gutjnl-2017-314722.

9. Graham DY and Tansel A. Clin Gastroenterol Hepatol. 2018 Jun. doi: 10.1016/j.cgh.2017.09.033.

10. Graham DY and Dore MP. Gastroenterology. 2018 Feb. doi:10.1053/j.gastro.2018.01.018.

11. Haseeb M and Thompson CC. Curr Opin Gastroenterol. 2023 Sep. doi: 10.1097/MOG.0000000000000968.

12. Kolb JM and Chang KJ. Curr Opin Gastroenterol. 2023 Jul. doi:10.1097/MOG.0000000000000944.

13. Nguyen NT et al. Foregut. 2022 Sep. doi: 10.1177/26345161221126961.

14. Mazzoleni G et al. Endosc Int Open. 2021 Feb. doi: 10.1055/a-1322-2209.

15. Trad KS et al. Surg Innov. 2018 Apr. doi: 10.1177/1553350618755214.

16. Kolb JM et al. Gastroenterology. 2021 May. doi: 10.1016/S0016-5085(21)02953-X.

17. Jaruvongvanich VK et al. Endosc Int Open. 2023 Jan. doi: 10.1055/a-1972-9190.

18. Lee Y et al. Surg Endosc. 2023 Jul. doi: 10.1007/s00464-023-10151-5.

19. Andreou A et al. Surg Endosc. 2020 Feb. doi: 10.1007/s00464-019-07208-9.

20. Guidozzi N et al. Dis Esophagus. 2019 Nov. doi: 10.1093/dote/doz031.

Introduction

Gastroesophageal reflux disease (GERD) is a frequently encountered condition, and rising annually.¹ A recent meta-analysis suggests nearly 14% (1.03 billion) of the population are affected worldwide. Differences may range by region from 12% in Latin America to 20% in North America, and by country from 4% in China to 23% in Turkey.¹ In the United States, 21% of the population are afflicted with weekly GERD symptoms.² Novel medical therapies and endoscopic options provide clinicians with opportunities to help patients with GERD.³Herein, we review diagnostics as well as the evolution of medical, endoscopic and basic surgical management for GERD.

Diagnosis

Definition

courtesy University of Southern California

GERD was originally defined by the Montreal consensus as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications.⁴ Heartburn and regurgitation are common symptoms of GERD, with a sensitivity of 30%-76% and specificity of 62%-96% for erosive esophagitis (EE), which occurs when the reflux of stomach content causes esophageal mucosal breaks.⁵ The presence of characteristic mucosal injury observed during an upper endoscopy or abnormal esophageal acid exposure on ambulatory reflux monitoring are objective evidence of GERD. A trial of a proton pump inhibitor (PPI) may function as a diagnostic test for patients exhibiting the typical symptoms of GERD without any alarm symptoms.^3,6

Endoscopic Evaluation and Confirmation

The 2022 American Gastroenterological Association (AGA) clinical practice update recommends diagnostic endoscopy, after PPIs are stopped for 2-4 weeks, in patients whose GERD symptoms do not respond adequately to an empiric trial of a PPI.³ Those with GERD and alarm symptoms such as dysphagia, weight loss, bleeding, and vomiting should undergo endoscopy as soon as possible. Endoscopic findings of EE (Los Angeles Grade B or more severe) and long-segment Barrett’s esophagus (> 3-cm segment with intestinal metaplasia on biopsy) are diagnostic of GERD.³

Reflux Monitoring

courtesy University of Southern California

With ambulatory reflux monitoring (pH or impedance-pH), esophageal acid exposure (or neutral refluxate in impedance testing) can be measured to confirm GERD diagnosis and to correlate symptoms with reflux episodes. Patients with atypical GERD symptoms or patients with a confirmed diagnosis of GERD whose symptoms have not improved sufficiently with twice-daily PPI therapy should have esophageal impedance-pH monitoring while on PPIs.^6,7

Esophageal Manometry

High-resolution esophageal manometry can be used to assess motility abnormalities associated with GERD.

Although no manometric abnormality is unique to GERD, weak lower esophageal sphincter (LES) resting pressure and ineffective esophageal motility frequently coexist with severe GERD.⁶

Manometry is particularly useful in patients considering surgical or endoscopic anti-reflux procedures to evaluate for achalasia,³ an important contraindication to surgery.
 

Medical Management

courtesy University of Southern California

Management of GERD requires a multidisciplinary and personalized approach based on symptom presentation, body mass index, endoscopic findings (e.g., presence of EE, Barrett’s esophagus, hiatal hernia), and physiological abnormalities (e.g., gastroparesis or ineffective motility).³

Lifestyle Modifications

Recommended lifestyle modifications include weight loss for patients with obesity, stress reduction, tobacco and alcohol cessation, elevating the head of the bed, staying upright during and after meals, avoidance of food intake < 3 hours before bedtime, and cessation of foods that potentially aggravate reflux symptoms such as coffee, chocolate, carbonated beverages, spicy foods, acidic foods, and foods with high fat content.^6,8

Medications

Pharmacologic therapy for GERD includes medications that primarily aim to neutralize or reduce gastric acid -- we summarize options in Table 1.^3,8

MDedge News

Proton Pump Inhibitors

Most guidelines suggest a trial of 4-8 weeks of once-daily enteric-coated PPI before meals in patients with typical GERD symptoms and no alarm symptoms. Escalation to double-dose PPI may be considered in the case of persistent symptoms. The relative potencies of standard-dose pantoprazole, lansoprazole, esomeprazole, and rabeprazole are presented in Table 1.⁹ When a PPI switch is needed, rabeprazole may be considered as it is a PPI that does not rely on CYP2C19 for primary metabolism.⁹

Acid suppression should be weaned down to the lowest effective dose or converted to H2RAs or other antacids once symptoms are sufficiently controlled unless patients have EE, Barrett’s esophagus, or peptic stricture.³ Patients with severe GERD may require long-term PPI therapy or an invasive anti-reflux procedure.

Recent studies have shown that potassium-competitive acid blockers (PCAB) like vonoprazan may offer more effective gastric acid inhibition. While not included in the latest clinical practice update, vonoprazan is thought to be superior to lansoprazole for those with LA Grade C/D esophagitis for both symptom relief and healing at 2 weeks.¹⁰

Adjunctive Therapies

Alginates can function as a physical barrier to even neutral reflux and may be helpful for patients with postprandial or nighttime symptoms as well as those with hiatal hernia.³ H2RAs can also help mitigate nighttime symptoms.³ Baclofen is a gamma-aminobutyric acid–B agonist which inhibits transient lower esophageal sphincter relaxation (TLESR) and may be effective for patients with belching.³ Prokinetics may be helpful for GERD with concomitant gastroparesis^.3 Sucralfate is a mucosal protective agent, but there is a lack of data supporting its efficacy in GERD treatment. Consider referral to a behavioral therapist for supplemental therapies, hypnotherapy, cognitive-behavior therapy, diaphragmatic breathing, and relaxation strategies for functional heartburn or reflux-associated esophageal hypervigilance or reflux hypersensitivity.³

When to Refer to Higher Level of Care

For patients who do not wish to remain on longer-term pharmacologic therapy or would benefit from anatomic repair, clinicians should have a discussion of risks and benefits prior to consideration of referral for anti-reflux procedures.^3,6,8 We advise this conversation should include review of patient health status, postsurgical side effects such as increased flatus, bloating and dysphagia as well as the potential need to still resume PPI post operation.⁸

Endoscopic Management

Patient Selection And Evaluation

For the groups indicated for a higher level of care, we agree with AGA recommendations, multi-society guidelines, and expert review,^3,7,11,12 and highlight potential options in Table 2. Step-up options should be based on patient characteristics and reviewed carefully with patients. Endoscopic therapies are less invasive than surgery and may be considered for those who do not require anatomic repair of hiatal hernia, do not want surgery, or are not suitable for surgery.

MDedge News

The pathophysiology of GERD is from a loss of the anti-reflux barrier of the esophageal gastric junction (EGJ) at the lower esophageal sphincter (LES) leading to unintended retrograde movement of gastric contents.⁶ Anatomically, the LES is composed of muscles of the distal esophagus and sling fibers of the proximal stomach, the “external valve” from the diaphragmatic crura, and the “internal valve” from the gastroesophageal flap valve (GEFV). GERD occurs from mechanical failure of the LES. First, there may be disproportional dilation of the diaphragmatic crura as categorized by Hill Grade of the GEFV as seen by a retroflexed view of EGJ after 30-45 seconds of insufflation.¹³ Second, there may be a migration of the LES away from the diaphragmatic crura as in the case of a hiatal hernia. Provocative maneuvers may reveal a sliding hernia by gentle retraction of the endoscope while under retroflexed view.¹³ Third, there may be more frequent TLESR associated with GERD.¹²

The aim of most interventions is to restore competency of the LES by reconstruction of the GEFV via suture or staple-based approximation of tissue.^11,12 Intraluminal therapy may only target the GEFV at the internal valve. Therefore, most endoscopic interventions are limited to patients with intact diaphragmatic crura (ie, small to no hiatal hernia and GEFV Hill Grade 1 to 2). Contraindications for endoscopic therapy are moderate to severe reflux (ie, LA Grade C/ D), hiatus hernia 2 cm or larger, strictures, or long-segment Barrett’s esophagus.
 

Utility, Safety, and Outcomes of TIF

Historically, endoscopic therapy targeting endoscopic fundoplication started with EndoLuminal gastro-gastric fundoplication (ELF, 2005) which was a proof of concept of safe manipulation and suture for gastro-gastric plication to below the Z-line. Transoral incisionless fundoplication (TIF) 1.0 was suggested in 2007 for clinical application by proposing a longitudinal oriented esophago-gastric plication 1 cm above the Z-line.

In 2009, TIF2.0 was proposed as a rotational 270° wrap of the cardia and fundus to a full-thickness esophago-gastric fundoplication around 2-4 cm of the distal esophagus. Like a surgical fundoplication, this reinforces sling fibers, increases the Angle of His and improves the cardiac notch. TIF 2.0 is indicated for those with small (< 2 cm) or no hiatal hernia and a GEFV Hill Grade 1 or 2. The present iteration of TIF2.0 uses EsophyX-Z (EndoGastric Solutions; Redmond, Washington) which features dual fastener deployment and a simplified firing mechanism. Plication is secured via nonresorbable polypropylene T-fasteners with strength equivalence of 3-0 sutures.

Compared with the original, TIF2.0 represents a decrease of severe adverse events from 2%-2.5% to 0.4%-1%.^11,14 Based on longitudinal TEMPO data, patient satisfaction ranges between 70% and 90% and rates of patients reverting to daily PPI use are 17% and 34% at 1 and 5 years. A 5% reintervention rate was noted to be comparable with surgical reoperation for fundoplication.¹⁵ One retrospective evaluation of patients with failed TIF followed by successful cTIF noted that in all failures there was a documented underestimation of a much larger crura defect at time of index procedure.¹⁶ Chest pain is common post procedure and patients and collaborating providers should be counseled on the expected course. In our practice, we admit patients for at least 1 postprocedure day and consider scheduling symptom control medications for those with significant pain.
 

TIF2.0 for Special Populations

Indications for TIF2.0 continue to evolve. In 2017, concomitant TIF2.0 with hiatal hernia repair (cTIF or HH-TIF) for hernia > 2 cm was accepted for expanded use. In one study, cTIF has been shown to have similar outcomes for postprocedural PPI use, dysphagia, wrap disruption, and hiatal hernia recurrence, compared with hiatal hernia repair paired with laparoscopic Nissen fundoplication with possibly shorter postadmission stay, serious adverse events, and bloating.¹⁷ A cTIF may be performed in a single general anesthetic session typically with a surgical hiatal hernia repair followed by TIF2.0.

Other Endoscopic Procedures

Several other endoscopic interventions have been proposed for GERD management. The following procedures are under continuous study and should be considered only by those with expertise.
 

Stretta

The Stretta device (Restech; Houston, Texas) was approved in 2000 for use of a radiofrequency (RF) generator and catheter applied to the squamocolumnar junction under irrigation. Ideal candidates for this nonablative procedure may include patients with confirmed GERD, low-grade EE, without Barrett’s esophagus, small hiatal hernia, and a competent LES with pressure > 5 mmHg. Meta-analysis has yielded conflicting results in terms of its efficacy, compared with TIF2.0, and recent multi-society guidance suggests fundoplication over Stretta.⁷

ARM, MASE, and RAP

Anti-reflux mucosectomy (ARM) has been proposed based on the observation that patients undergoing mucosectomy for neoplasms in the cardia had improvement of reflux symptoms.^11,12 Systematic review has suggested a clinical response of 80% of either PPI discontinuation or reduction, but 17% of adverse events include development of strictures. Iterations of ARM continue to be studied including ARM with band ligation (L-ARM) and endoscopic submucosal dissection for GERD (ESD-G).¹²

Experts have proposed incorporating endoscopic suturing of the EGJ to modulate the LES. Mucosal ablation and suturing of the EG junction (MASE) has been proposed by first priming tissue via argon plasma coagulation (APC) prior to endoscopic overstitch of two to three interrupted sutures below the EGJ to narrow and elongate the EGJ. The resection and plication (RAP) procedure performs a mucosal resection prior to full-thickness plication of the LES and cardia.^11,12 Expert opinion has suggested that RAP may be used in patients with altered anatomy whereas MASE may be used when resection is not possible (eg, prior scarring, resection or ablation).¹²
 

Surgical Management

We agree with a recent multi-society guideline recommending that an interdisciplinary consultation with surgery for indicated patients with refractory GERD and underlying hiatal hernia, or who do not want lifelong medical therapy.

Fundoplication creates a surgical wrap to reinforce the LES and may be performed laparoscopically. Contraindications include body mass index (BMI) >35 kg/m2 and significantly impaired dysmotility. Fundoplication of 180°, 270°, and 360° may achieve comparable outcomes, but a laparoscopic toupet fundoplication (LTF 270°) may have fewer postsurgical issues of dysphagia and bloating. Advantages for both anterior and posterior partial fundoplications have been demonstrated by network meta-analysis. Therefore, a multi-society guideline for GERD suggests partial over complete fundoplication.⁷ Compared with posterior techniques, anterior fundoplication (Watson fundoplication) led to more recurrent reflux symptoms but less dysphagia and other side effects.¹⁹

Magnetic sphincter augmentation (MSA) is a surgical option that strengthens the LES with magnets to improve sphincter competence. In addition to listed contraindications of fundoplication, patients with an allergy to nickel and/or titanium are also contraindicated to receive MSA.⁷ MSA has been suggested to be equivalent to LNF although there may be less gas bloat and greater ability to belch on follow up.²⁰
 

Surgical Options for Special Populations

Patients with medically refractory GERD and a BMI ≥ 35 kg/m² may benefit from either Roux-en-Y gastric bypass (RYGB) or fundoplication, however sleeve gastrectomy is not advised.⁷ In patients with BMI > 50 kg/m2, RYGB may provide an optimal choice. We agree with consultation with a bariatric surgeon when reviewing these situations.

Conclusion

Patients with GERD are commonly encountered worldwide. Empiric PPI are effective mainstays for medical treatment of GERD. Novel PCABs (e.g., vonoprazan) may present new options for GERD with LA Grade C/D esophagitis EE and merit more study. In refractory cases or for patients who do not want long term medical therapy, step-up therapy may be considered via endoscopic or surgical interventions. Patient anatomy and comorbidities should be considered by the clinician to inform treatment options. Surgery may have the most durable outcomes for those requiring step-up therapy. Improvements in technique, devices and patient selection have allowed TIF2.0 to grow as a viable offering with excellent 5-year outcomes for indicated patients.

Dr. Chang, Dr. Tintara, and Dr. Phan are based in the Division of Gastrointestinal and Liver Disease at the University of Southern California in Los Angeles. They have no conflicts of interest to declare.

References

1. Richter JE andRubenstein JH. Gastroenterology. 2018 Jan. doi: 10.1053/j.gastro.2017.07.045.

2. El-Serag HB et al. Gut. 2014 Jun. doi: 10.1136/gutjnl-2012-304269.

3. Yadlapati R et al. Clin Gastroenterol Hepatol. 2022 May. doi: 10.1016/j.cgh.2022.01.025.

4. Vakil N et al. Am J Gastroenterol. 2006 Aug. doi: 10.1111/j.1572-0241.2006.00630.x.

5. Numans ME et al. Ann Intern Med. 2004 Apr. doi: 10.7326/0003-4819-140-7-200404060-00011.

6. Kahrilas PJ et al. Gastroenterology. 2008 Oct. doi: 10.1053/j.gastro.2008.08.045.

7. Slater BJ et al. Surg Endosc. 2023 Feb. doi: 10.1007/s00464-022-09817-3.

8. Gyawali CP et al. Gut. 2018 Jul. doi:10.1136/gutjnl-2017-314722.

9. Graham DY and Tansel A. Clin Gastroenterol Hepatol. 2018 Jun. doi: 10.1016/j.cgh.2017.09.033.

10. Graham DY and Dore MP. Gastroenterology. 2018 Feb. doi:10.1053/j.gastro.2018.01.018.

11. Haseeb M and Thompson CC. Curr Opin Gastroenterol. 2023 Sep. doi: 10.1097/MOG.0000000000000968.

12. Kolb JM and Chang KJ. Curr Opin Gastroenterol. 2023 Jul. doi:10.1097/MOG.0000000000000944.

13. Nguyen NT et al. Foregut. 2022 Sep. doi: 10.1177/26345161221126961.

14. Mazzoleni G et al. Endosc Int Open. 2021 Feb. doi: 10.1055/a-1322-2209.

15. Trad KS et al. Surg Innov. 2018 Apr. doi: 10.1177/1553350618755214.

16. Kolb JM et al. Gastroenterology. 2021 May. doi: 10.1016/S0016-5085(21)02953-X.

17. Jaruvongvanich VK et al. Endosc Int Open. 2023 Jan. doi: 10.1055/a-1972-9190.

18. Lee Y et al. Surg Endosc. 2023 Jul. doi: 10.1007/s00464-023-10151-5.

19. Andreou A et al. Surg Endosc. 2020 Feb. doi: 10.1007/s00464-019-07208-9.

20. Guidozzi N et al. Dis Esophagus. 2019 Nov. doi: 10.1093/dote/doz031.

Introduction

Gastroesophageal reflux disease (GERD) is a frequently encountered condition, and rising annually.¹ A recent meta-analysis suggests nearly 14% (1.03 billion) of the population are affected worldwide. Differences may range by region from 12% in Latin America to 20% in North America, and by country from 4% in China to 23% in Turkey.¹ In the United States, 21% of the population are afflicted with weekly GERD symptoms.² Novel medical therapies and endoscopic options provide clinicians with opportunities to help patients with GERD.³Herein, we review diagnostics as well as the evolution of medical, endoscopic and basic surgical management for GERD.

Diagnosis

Definition

courtesy University of Southern California

GERD was originally defined by the Montreal consensus as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications.⁴ Heartburn and regurgitation are common symptoms of GERD, with a sensitivity of 30%-76% and specificity of 62%-96% for erosive esophagitis (EE), which occurs when the reflux of stomach content causes esophageal mucosal breaks.⁵ The presence of characteristic mucosal injury observed during an upper endoscopy or abnormal esophageal acid exposure on ambulatory reflux monitoring are objective evidence of GERD. A trial of a proton pump inhibitor (PPI) may function as a diagnostic test for patients exhibiting the typical symptoms of GERD without any alarm symptoms.^3,6

Endoscopic Evaluation and Confirmation

The 2022 American Gastroenterological Association (AGA) clinical practice update recommends diagnostic endoscopy, after PPIs are stopped for 2-4 weeks, in patients whose GERD symptoms do not respond adequately to an empiric trial of a PPI.³ Those with GERD and alarm symptoms such as dysphagia, weight loss, bleeding, and vomiting should undergo endoscopy as soon as possible. Endoscopic findings of EE (Los Angeles Grade B or more severe) and long-segment Barrett’s esophagus (> 3-cm segment with intestinal metaplasia on biopsy) are diagnostic of GERD.³

Reflux Monitoring

courtesy University of Southern California

With ambulatory reflux monitoring (pH or impedance-pH), esophageal acid exposure (or neutral refluxate in impedance testing) can be measured to confirm GERD diagnosis and to correlate symptoms with reflux episodes. Patients with atypical GERD symptoms or patients with a confirmed diagnosis of GERD whose symptoms have not improved sufficiently with twice-daily PPI therapy should have esophageal impedance-pH monitoring while on PPIs.^6,7

Esophageal Manometry

High-resolution esophageal manometry can be used to assess motility abnormalities associated with GERD.

Although no manometric abnormality is unique to GERD, weak lower esophageal sphincter (LES) resting pressure and ineffective esophageal motility frequently coexist with severe GERD.⁶

Manometry is particularly useful in patients considering surgical or endoscopic anti-reflux procedures to evaluate for achalasia,³ an important contraindication to surgery.
 

Medical Management

courtesy University of Southern California

Management of GERD requires a multidisciplinary and personalized approach based on symptom presentation, body mass index, endoscopic findings (e.g., presence of EE, Barrett’s esophagus, hiatal hernia), and physiological abnormalities (e.g., gastroparesis or ineffective motility).³

Lifestyle Modifications

Recommended lifestyle modifications include weight loss for patients with obesity, stress reduction, tobacco and alcohol cessation, elevating the head of the bed, staying upright during and after meals, avoidance of food intake < 3 hours before bedtime, and cessation of foods that potentially aggravate reflux symptoms such as coffee, chocolate, carbonated beverages, spicy foods, acidic foods, and foods with high fat content.^6,8

Medications

Pharmacologic therapy for GERD includes medications that primarily aim to neutralize or reduce gastric acid -- we summarize options in Table 1.^3,8

MDedge News

Proton Pump Inhibitors

Most guidelines suggest a trial of 4-8 weeks of once-daily enteric-coated PPI before meals in patients with typical GERD symptoms and no alarm symptoms. Escalation to double-dose PPI may be considered in the case of persistent symptoms. The relative potencies of standard-dose pantoprazole, lansoprazole, esomeprazole, and rabeprazole are presented in Table 1.⁹ When a PPI switch is needed, rabeprazole may be considered as it is a PPI that does not rely on CYP2C19 for primary metabolism.⁹

Acid suppression should be weaned down to the lowest effective dose or converted to H2RAs or other antacids once symptoms are sufficiently controlled unless patients have EE, Barrett’s esophagus, or peptic stricture.³ Patients with severe GERD may require long-term PPI therapy or an invasive anti-reflux procedure.

Recent studies have shown that potassium-competitive acid blockers (PCAB) like vonoprazan may offer more effective gastric acid inhibition. While not included in the latest clinical practice update, vonoprazan is thought to be superior to lansoprazole for those with LA Grade C/D esophagitis for both symptom relief and healing at 2 weeks.¹⁰

Adjunctive Therapies

Alginates can function as a physical barrier to even neutral reflux and may be helpful for patients with postprandial or nighttime symptoms as well as those with hiatal hernia.³ H2RAs can also help mitigate nighttime symptoms.³ Baclofen is a gamma-aminobutyric acid–B agonist which inhibits transient lower esophageal sphincter relaxation (TLESR) and may be effective for patients with belching.³ Prokinetics may be helpful for GERD with concomitant gastroparesis^.3 Sucralfate is a mucosal protective agent, but there is a lack of data supporting its efficacy in GERD treatment. Consider referral to a behavioral therapist for supplemental therapies, hypnotherapy, cognitive-behavior therapy, diaphragmatic breathing, and relaxation strategies for functional heartburn or reflux-associated esophageal hypervigilance or reflux hypersensitivity.³

When to Refer to Higher Level of Care

For patients who do not wish to remain on longer-term pharmacologic therapy or would benefit from anatomic repair, clinicians should have a discussion of risks and benefits prior to consideration of referral for anti-reflux procedures.^3,6,8 We advise this conversation should include review of patient health status, postsurgical side effects such as increased flatus, bloating and dysphagia as well as the potential need to still resume PPI post operation.⁸

Endoscopic Management

Patient Selection And Evaluation

For the groups indicated for a higher level of care, we agree with AGA recommendations, multi-society guidelines, and expert review,^3,7,11,12 and highlight potential options in Table 2. Step-up options should be based on patient characteristics and reviewed carefully with patients. Endoscopic therapies are less invasive than surgery and may be considered for those who do not require anatomic repair of hiatal hernia, do not want surgery, or are not suitable for surgery.

MDedge News

The pathophysiology of GERD is from a loss of the anti-reflux barrier of the esophageal gastric junction (EGJ) at the lower esophageal sphincter (LES) leading to unintended retrograde movement of gastric contents.⁶ Anatomically, the LES is composed of muscles of the distal esophagus and sling fibers of the proximal stomach, the “external valve” from the diaphragmatic crura, and the “internal valve” from the gastroesophageal flap valve (GEFV). GERD occurs from mechanical failure of the LES. First, there may be disproportional dilation of the diaphragmatic crura as categorized by Hill Grade of the GEFV as seen by a retroflexed view of EGJ after 30-45 seconds of insufflation.¹³ Second, there may be a migration of the LES away from the diaphragmatic crura as in the case of a hiatal hernia. Provocative maneuvers may reveal a sliding hernia by gentle retraction of the endoscope while under retroflexed view.¹³ Third, there may be more frequent TLESR associated with GERD.¹²

The aim of most interventions is to restore competency of the LES by reconstruction of the GEFV via suture or staple-based approximation of tissue.^11,12 Intraluminal therapy may only target the GEFV at the internal valve. Therefore, most endoscopic interventions are limited to patients with intact diaphragmatic crura (ie, small to no hiatal hernia and GEFV Hill Grade 1 to 2). Contraindications for endoscopic therapy are moderate to severe reflux (ie, LA Grade C/ D), hiatus hernia 2 cm or larger, strictures, or long-segment Barrett’s esophagus.
 

Utility, Safety, and Outcomes of TIF

Historically, endoscopic therapy targeting endoscopic fundoplication started with EndoLuminal gastro-gastric fundoplication (ELF, 2005) which was a proof of concept of safe manipulation and suture for gastro-gastric plication to below the Z-line. Transoral incisionless fundoplication (TIF) 1.0 was suggested in 2007 for clinical application by proposing a longitudinal oriented esophago-gastric plication 1 cm above the Z-line.

In 2009, TIF2.0 was proposed as a rotational 270° wrap of the cardia and fundus to a full-thickness esophago-gastric fundoplication around 2-4 cm of the distal esophagus. Like a surgical fundoplication, this reinforces sling fibers, increases the Angle of His and improves the cardiac notch. TIF 2.0 is indicated for those with small (< 2 cm) or no hiatal hernia and a GEFV Hill Grade 1 or 2. The present iteration of TIF2.0 uses EsophyX-Z (EndoGastric Solutions; Redmond, Washington) which features dual fastener deployment and a simplified firing mechanism. Plication is secured via nonresorbable polypropylene T-fasteners with strength equivalence of 3-0 sutures.

Compared with the original, TIF2.0 represents a decrease of severe adverse events from 2%-2.5% to 0.4%-1%.^11,14 Based on longitudinal TEMPO data, patient satisfaction ranges between 70% and 90% and rates of patients reverting to daily PPI use are 17% and 34% at 1 and 5 years. A 5% reintervention rate was noted to be comparable with surgical reoperation for fundoplication.¹⁵ One retrospective evaluation of patients with failed TIF followed by successful cTIF noted that in all failures there was a documented underestimation of a much larger crura defect at time of index procedure.¹⁶ Chest pain is common post procedure and patients and collaborating providers should be counseled on the expected course. In our practice, we admit patients for at least 1 postprocedure day and consider scheduling symptom control medications for those with significant pain.
 

TIF2.0 for Special Populations

Indications for TIF2.0 continue to evolve. In 2017, concomitant TIF2.0 with hiatal hernia repair (cTIF or HH-TIF) for hernia > 2 cm was accepted for expanded use. In one study, cTIF has been shown to have similar outcomes for postprocedural PPI use, dysphagia, wrap disruption, and hiatal hernia recurrence, compared with hiatal hernia repair paired with laparoscopic Nissen fundoplication with possibly shorter postadmission stay, serious adverse events, and bloating.¹⁷ A cTIF may be performed in a single general anesthetic session typically with a surgical hiatal hernia repair followed by TIF2.0.

Other Endoscopic Procedures

Several other endoscopic interventions have been proposed for GERD management. The following procedures are under continuous study and should be considered only by those with expertise.
 

Stretta

The Stretta device (Restech; Houston, Texas) was approved in 2000 for use of a radiofrequency (RF) generator and catheter applied to the squamocolumnar junction under irrigation. Ideal candidates for this nonablative procedure may include patients with confirmed GERD, low-grade EE, without Barrett’s esophagus, small hiatal hernia, and a competent LES with pressure > 5 mmHg. Meta-analysis has yielded conflicting results in terms of its efficacy, compared with TIF2.0, and recent multi-society guidance suggests fundoplication over Stretta.⁷

ARM, MASE, and RAP

Anti-reflux mucosectomy (ARM) has been proposed based on the observation that patients undergoing mucosectomy for neoplasms in the cardia had improvement of reflux symptoms.^11,12 Systematic review has suggested a clinical response of 80% of either PPI discontinuation or reduction, but 17% of adverse events include development of strictures. Iterations of ARM continue to be studied including ARM with band ligation (L-ARM) and endoscopic submucosal dissection for GERD (ESD-G).¹²

Experts have proposed incorporating endoscopic suturing of the EGJ to modulate the LES. Mucosal ablation and suturing of the EG junction (MASE) has been proposed by first priming tissue via argon plasma coagulation (APC) prior to endoscopic overstitch of two to three interrupted sutures below the EGJ to narrow and elongate the EGJ. The resection and plication (RAP) procedure performs a mucosal resection prior to full-thickness plication of the LES and cardia.^11,12 Expert opinion has suggested that RAP may be used in patients with altered anatomy whereas MASE may be used when resection is not possible (eg, prior scarring, resection or ablation).¹²
 

Surgical Management

We agree with a recent multi-society guideline recommending that an interdisciplinary consultation with surgery for indicated patients with refractory GERD and underlying hiatal hernia, or who do not want lifelong medical therapy.

Fundoplication creates a surgical wrap to reinforce the LES and may be performed laparoscopically. Contraindications include body mass index (BMI) >35 kg/m2 and significantly impaired dysmotility. Fundoplication of 180°, 270°, and 360° may achieve comparable outcomes, but a laparoscopic toupet fundoplication (LTF 270°) may have fewer postsurgical issues of dysphagia and bloating. Advantages for both anterior and posterior partial fundoplications have been demonstrated by network meta-analysis. Therefore, a multi-society guideline for GERD suggests partial over complete fundoplication.⁷ Compared with posterior techniques, anterior fundoplication (Watson fundoplication) led to more recurrent reflux symptoms but less dysphagia and other side effects.¹⁹

Magnetic sphincter augmentation (MSA) is a surgical option that strengthens the LES with magnets to improve sphincter competence. In addition to listed contraindications of fundoplication, patients with an allergy to nickel and/or titanium are also contraindicated to receive MSA.⁷ MSA has been suggested to be equivalent to LNF although there may be less gas bloat and greater ability to belch on follow up.²⁰
 

Surgical Options for Special Populations

Patients with medically refractory GERD and a BMI ≥ 35 kg/m² may benefit from either Roux-en-Y gastric bypass (RYGB) or fundoplication, however sleeve gastrectomy is not advised.⁷ In patients with BMI > 50 kg/m2, RYGB may provide an optimal choice. We agree with consultation with a bariatric surgeon when reviewing these situations.

Conclusion

Patients with GERD are commonly encountered worldwide. Empiric PPI are effective mainstays for medical treatment of GERD. Novel PCABs (e.g., vonoprazan) may present new options for GERD with LA Grade C/D esophagitis EE and merit more study. In refractory cases or for patients who do not want long term medical therapy, step-up therapy may be considered via endoscopic or surgical interventions. Patient anatomy and comorbidities should be considered by the clinician to inform treatment options. Surgery may have the most durable outcomes for those requiring step-up therapy. Improvements in technique, devices and patient selection have allowed TIF2.0 to grow as a viable offering with excellent 5-year outcomes for indicated patients.

Dr. Chang, Dr. Tintara, and Dr. Phan are based in the Division of Gastrointestinal and Liver Disease at the University of Southern California in Los Angeles. They have no conflicts of interest to declare.

References

1. Richter JE andRubenstein JH. Gastroenterology. 2018 Jan. doi: 10.1053/j.gastro.2017.07.045.

2. El-Serag HB et al. Gut. 2014 Jun. doi: 10.1136/gutjnl-2012-304269.

3. Yadlapati R et al. Clin Gastroenterol Hepatol. 2022 May. doi: 10.1016/j.cgh.2022.01.025.

4. Vakil N et al. Am J Gastroenterol. 2006 Aug. doi: 10.1111/j.1572-0241.2006.00630.x.

5. Numans ME et al. Ann Intern Med. 2004 Apr. doi: 10.7326/0003-4819-140-7-200404060-00011.

6. Kahrilas PJ et al. Gastroenterology. 2008 Oct. doi: 10.1053/j.gastro.2008.08.045.

7. Slater BJ et al. Surg Endosc. 2023 Feb. doi: 10.1007/s00464-022-09817-3.

8. Gyawali CP et al. Gut. 2018 Jul. doi:10.1136/gutjnl-2017-314722.

9. Graham DY and Tansel A. Clin Gastroenterol Hepatol. 2018 Jun. doi: 10.1016/j.cgh.2017.09.033.

10. Graham DY and Dore MP. Gastroenterology. 2018 Feb. doi:10.1053/j.gastro.2018.01.018.

11. Haseeb M and Thompson CC. Curr Opin Gastroenterol. 2023 Sep. doi: 10.1097/MOG.0000000000000968.

12. Kolb JM and Chang KJ. Curr Opin Gastroenterol. 2023 Jul. doi:10.1097/MOG.0000000000000944.

13. Nguyen NT et al. Foregut. 2022 Sep. doi: 10.1177/26345161221126961.

14. Mazzoleni G et al. Endosc Int Open. 2021 Feb. doi: 10.1055/a-1322-2209.

15. Trad KS et al. Surg Innov. 2018 Apr. doi: 10.1177/1553350618755214.

16. Kolb JM et al. Gastroenterology. 2021 May. doi: 10.1016/S0016-5085(21)02953-X.

17. Jaruvongvanich VK et al. Endosc Int Open. 2023 Jan. doi: 10.1055/a-1972-9190.

18. Lee Y et al. Surg Endosc. 2023 Jul. doi: 10.1007/s00464-023-10151-5.

19. Andreou A et al. Surg Endosc. 2020 Feb. doi: 10.1007/s00464-019-07208-9.

20. Guidozzi N et al. Dis Esophagus. 2019 Nov. doi: 10.1093/dote/doz031.

Introduction

Abdominal bloating is a common condition affecting up to 3.5% of people globally (4.6% in women and 2.4% in men),¹ with 13.9% of the US population reporting bloating in the past 7 days.² The prevalence of bloating and distention exceeds 50% when linked to disorders of gut-brain interaction (DGBIs) such as irritable bowel syndrome (IBS), constipation, gastroparesis, and functional dyspepsia (FD).^3,4 According to the Rome IV criteria, functional bloating and distention (FABD) patients are characterized by recurrent symptoms of abdominal fullness or pressure (bloating), or a visible increase in abdominal girth (distention) occurring at least 1 day per week for 3 consecutive months with an onset of 6 months and without predominant pain or altered bowel habits.⁵

Prolonged abdominal bloating and distention (ABD) can significantly impact quality of life and work productivity and can lead to increased medical consultations.² Multiple pathophysiological mechanisms are involved in ABD that complicate the clinical management.⁴ There is an unmet need to understand the underlying mechanisms that lead to the development of ABD such as, food intolerance, abnormal viscerosomatic reflex, visceral hypersensitivity, and gut microbial dysbiosis. Recent advancements and acceptance of a multidisciplinary management of ABD have shifted the paradigm from merely treating symptoms to subtyping the condition and identifying overlaps with other DGBIs in order to individualize treatment that addresses the underlying pathophysiological mechanism. The recent American Gastroenterological Association (AGA) clinical update provided insights into the best practice advice for evaluating and managing ABD based on a review of current literature and on expert opinion of coauthors.⁶ This article aims to deliberate a practical approach to diagnostic strategies and treatment options based on etiology to refine clinical care of patients with ABD.

University of Nevada, Reno

Pathophysiological Mechanisms

ABD can result from various pathophysiological mechanisms. This section highlights the major causes (illustrated in Figure 1).

Food intolerances

Understanding food intolerances is crucial for diagnosing and managing patients with ABD. Disaccharidase deficiency is common (e.g., lactase deficiency is found in 35%-40% of adults).⁷ It can be undiagnosed in patients presenting with IBS symptoms, given the overlap in presentation with a prevalence of 9% of pan-disaccharidase deficiency. Sucrase-deficient patients must often adjust sugar and carbohydrate/starch intake to relieve symptoms.⁷ Deficiencies in lactase and sucrase activity, along with the consumption of some artificial sweeteners (e.g., sugar alcohols and sorbitol) and fructans can lead to bloating and distention. These substances increase osmotic load, fluid retention, microbial fermentation, and visceral hypersensitivity, leading to gas production and abdominal distention. One prospective study of symptomatic patients with various DGBIs (n = 1372) reported a prevalence of lactose intolerance and malabsorption at 51% and 32%, respectively.⁸ Furthermore, fructose intolerance and malabsorption prevalence were 60% and 45%, respectively.⁸ Notably, lactase deficiency does not always cause ABD, as not all individuals with lactase deficiency experience these symptoms after consuming lactose. Patients with celiac disease (CD), non-celiac gluten sensitivity (NCGS), and gluten intolerance can also experience bloating and distention, with or without changes in bowel habits.⁹ In some patients with self-reported NCGS, symptoms may be due to fructans in gluten-rich foods rather than gluten itself, thus recommending the elimination of fructans may help improve symptoms.⁹

Visceral hypersensitivity

Visceral hypersensitivity is explained by an increased perception of gut mechano-chemical stimulation, which typically manifests in an aggravated feeling of pain, nausea, distension, and ABD.¹⁰ In the gut, food particles and gut bacteria and their derived molecules interact with neuroimmune and enteroendocrine cells causing visceral sensitivity by the proximity of gut’s neurons to immune cells activated by them and leading to inflammatory reactions (Figure 1).

Dr. Singh and Dr. Moshiree

Pelvic floor dysfunction

Patients with anorectal motor dysfunction often experience difficulty in effectively evacuating both gas and stool, leading to ABD.¹² Impaired ability to expel gas and stool results in prolonged balloon expulsion times, which correlates with symptoms of distention in patients with constipation.

Atrium Health

Abdominophrenic dyssynergia

Abdominophrenic dyssynergia is characterized as a paradoxical viscerosomatic reflex response to minimal gaseous distention in individuals with FABD.¹³ In this condition, the diaphragm contracts (descends), and the anterior abdominal wall muscles relax in response to the presence of gas. This response is opposite to the normal physiological response to increased intraluminal gas, where the diaphragm relaxes and the anterior abdominal muscles contract to increase the craniocaudal capacity of the abdominal cavity without causing abdominal protrusion.¹³ Patients with FABD exhibit significant abdominal wall protrusion and diaphragmatic descent even with relatively small increases in intraluminal gas.¹¹ Understanding the role of abdominophrenic dyssynergia in abdominal bloating and distention is essential for effective diagnosis and management of the patients.

Gut dysmotility

Gut dysmotility is a crucial factor that can contribute to FABD. Gut dysmotility affects the movement of contents through the GI tract, accumulating gas and stool, directly contributing to bloating and distention. A prospective study involving over 2000 patients with functional constipation and constipation predominant-IBS (IBS-C) found that more than 90% of these patients reported symptoms of bloating.¹⁴ Furthermore, in IBS-C patients, those with prolonged colonic transit exhibited greater abdominal distention compared to those with normal gut transit times. In patients with gastroparesis, delayed gastric emptying resulting in prolonged retention of stomach contents is the main factor in the generation of bloating symptoms.⁴

Small intestinal bacterial overgrowth (SIBO)

SIBO is overrepresented in various conditions, including IBS, FD, diabetes, gastrointestinal (GI) surgery patients and obesity, and can play an important role in generating ABD. Excess bacteria in the small intestine ferment carbohydrates, producing gas that stretches and distends the small intestine, leading to these symptoms. Additionally, altered sensation and abnormal viscerosomatic reflexes may contribute to SIBO-related bloating.⁴ One recent study noted decreased duodenal phylogenetic diversity in individuals who developed postprandial bloating.¹⁵ Increased methane levels caused by intestinal methanogen overgrowth, primarily the archaea Methanobrevibacter smithii, is possibly responsible for ABD in patients with IBS-C.¹⁶ Testing for SIBO in patients with ABD is generally only recommended if there are clear risk factors or severe symptoms warranting a test-and-treat approach.

Practical Diagnosis

Diagnosing ABD typically does not require extensive laboratory testing, imaging, or endoscopy unless there are alarm features or significant changes in symptoms. Here is the AGA clinical update on best practice advice⁶ for when to conduct further testing:

Diagnostic tests should be considered if patients exhibit:

• Recent onset or worsening of dyspepsia or abdominal pain
• Vomiting
• GI bleeding
• Unintentional weight loss exceeding 10% of body weight
• Chronic diarrhea
• Family history of GI malignancy, celiac disease, or inflammatory bowel disease

Physical examination

If visible abdominal distention is present, a thorough abdominal examination can help identify potential issues:

• Tympany to percussion suggests bowel dilation.
• Abnormal bowel sounds may indicate obstruction or ileus.
• A succussion splash could indicate the presence of ascites and obstruction.
• Any abnormalities discovered during the physical exam should prompt further investigation with imaging, such as a computed tomography (CT) scan or ultrasound, to evaluate for ascites, masses, or increased bowel gas due to ileus, obstruction, or pseudo-obstruction.

Radiologic imaging, laboratory testing and endoscopy

• An abdominal x-ray may reveal an increased stool burden, suggesting the need for further evaluation of slow transit constipation or a pelvic floor disorder, particularly in patients with functional constipation, IBS-mixed, or IBS-C.
• Hyperglycemia, weight gain, and bloating can be a presenting sign of ovarian cancer therefore all women should continue pelvic exams as dictated by the gynecologic societies. The need for an annual pelvic exam should be discussed with health care professionals especially in those with family history of ovarian cancer.
• An upper endoscopy may be warranted for patients over 40 years old with dyspeptic symptoms and abdominal bloating or distention, especially in regions with a high prevalence of Helicobacter pylori.
• Chronic pancreatitis, indicated by bloating and pain, may necessitate fecal elastase testing to assess pancreatic function.

The expert review in the AGA clinical update provides step-by-step advice regarding the best practices⁶ for diagnosis and identifying who to test for ABD.
 

Treatment Options

The following sections highlight recent best practice advice on therapeutic approaches for treating ABD.

Dietary interventions

Specific foods may trigger bloating and abdominal distention, especially in patients with overlapping DGBIs. However, only a few studies have evaluated dietary restriction specifically for patients with primary ABD. Restricting non-absorbable sugars led to symptomatic improvement in 81% of patients with FABD who had documented sugar malabsorption.¹⁷ Two studies have shown that IBS patients treated with a low-fermentable, oligo-, di-, and monosaccharides (FODMAP) diet noted improvement in ABD and that restricting fructans initially may be the most optimal.¹⁸ A recent study showed that the Mediterranean diet improved IBS symptoms, including abdominal pain and bloating.¹⁹ It should be noted restrictive diets are efficacious but come with short- and long-term challenges. If empiric treatment and/or therapeutic testing do not resolve symptoms, a referral to a dietitian can be useful. Dietitians can provide tailored dietary advice, ensuring patients avoid trigger foods while maintaining a balanced and nutritious diet.

Prokinetics and laxatives

Prokinetic agents are used to treat symptoms of FD, gastroparesis, chronic idiopathic constipation (CIC), and IBS. A meta-analysis of 13 trials found all constipation medications superior to placebo for treating abdominal bloating in patients with IBS-C.²⁰

Probiotics

Treatment with probiotics is recommended for bloating or distention. One double-blind placebo-controlled trial with two separate probiotics, Bifidobacterium lactis and Lactobacillus acidophilus, showed improvements in global GI symptoms of patients with DGBI at 8 weeks versus placebo, with improvements in bloating symptoms.²¹

Antibiotics

The most commonly studied antibiotic for treating bloating is rifaximin.²² Global symptomatic improvement in IBS patients treated with antibiotics has correlated with the normalization of hydrogen levels in lactulose hydrogen breath tests.²² Patients with non-constipation IBS randomized to rifaximin 550 mg three times daily for 14 days had a greater proportion of relief of IBS-related bloating compared to placebo for at least 2 of the first 4 weeks after treatment.²² Future research warrants use of narrow-spectrum antibiotics study for FABD as the use of broad-spectrum antibiotics may deplete commensals forever, resulting in metabolic disorders.

Biofeedback therapy

Anorectal biofeedback therapy may help with ABD, particularly in patients with IBS-C and chronic constipation. One study noted that post-biofeedback therapy, myoelectric activity of the intercostals and diaphragm decreased, and internal oblique myoelectric activity increased.²³ This study also showed ascent of the diaphragm and decreased girth, improving distention.

Central neuromodulators

As bloating results from multiple disturbed mechanisms, including altered gut-brain interaction, these symptoms can be amplified by psychological states such as anxiety, depression, or somatization. Central neuromodulators reduce the perception of visceral signals, re-regulate brain-gut control mechanisms, and improve psychological comorbidities.⁶ A large study of FD patients demonstrated that both amitriptyline (50 mg daily) and escitalopram (10 mg daily) significantly improved postprandial bloating compared to placebo.²⁴ Antidepressants that activate noradrenergic and serotonergic pathways, including tricyclic antidepressants (e.g., amitriptyline) and serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and venlafaxine), show the greatest benefit in reducing visceral sensations.⁶

Brain-gut behavioral therapies

A recent multidisciplinary consensus report supports a myriad of potential brain-gut behavioral therapies (BGBTs) for treating DGBI.²⁵ These therapies, including hypnotherapy, cognitive behavioral therapy (CBT), and other modalities, may be combined with central neuromodulators and other GI treatments in a safe, noninvasive, and complementary fashion. BGBTs do not need to be symptom-specific, as they improve overall quality of life, anxiety, stress, and the burden associated with DGBIs. To date, none of the BGBTs have focused exclusively on FABD; however, prescription-based psychological therapies are now FDA-approved for use on smart apps, improving global symptoms that include bloating in IBS and FD.

Recent AGA clinical update best practices should be considered for the clinical care of patients with ABD.⁶

Conclusion and Future Perspectives

ABD are highly prevalent and significantly impact patients with various GI and metabolic disorders. Although our understanding of these symptoms is still evolving, evidence increasingly points to the dysregulation of the gut-brain axis and supports the application of the biopsychosocial model in treatment. This model addresses diet, motility, visceral sensitivity, pelvic floor disorders and psychosocial factors, providing a comprehensive approach to patient care.

Physician-scientists around the globe face numerous challenges when evaluating patients with these symptoms. However, the recent AGA clinical update on the best practice guidelines offers step-by-step diagnostic tests and treatment options to assist physicians in making informed decisions. A multidisciplinary approach and a patient-centered model are essential for effectively managing treatment in patients with ABD. More comprehensive, large-scale, and longitudinal studies using metabolomics, capsule technologies for discovery of dysbiosis, mass spectrometry, and imaging data are needed to identify the exact contributors to disease pathogenesis, particularly those that can be targeted with pharmacologic agents. Collaborative work between gastroenterologists, dietitians, gut-brain behavioral therapists, endocrinologists, is crucial for clinical care of patients with ABD.

Careful attention to the patient’s primary symptoms and physical examination, combined with advancements in targeted diagnostics like the analysis of microbial markers, metabolites, and molecular signals, can significantly enhance patient clinical outcomes. Additionally, education and effective communication using a patient-centered care model are essential for guiding practical evaluation and individualized treatment.

Dr. Singh is assistant professor (research) at the University of Nevada, Reno, School of Medicine. Dr. Moshiree is director of motility at Atrium Health, and clinical professor of medicine, Wake Forest Medical University, Charlotte, North Carolina.

References

1. Ballou S et al. Prevalence and associated factors of bloating: Results from the Rome Foundation Global Epidemiology Study. Gastroenterology. 2023 June. doi: 10.1053/j.gastro.2023.05.049.

2. Oh JE et al. Abdominal bloating in the United States: Results of a survey of 88,795 Americans examining prevalence and healthcare seeking. Clin Gastroenterol Hepatol. 2023 Aug. doi: 10.1016/j.cgh.2022.10.031.

3. Drossman DA et al. Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): A Rome Foundation Working Team Report. Gastroenterology. 2018 Mar. doi: 10.1053/j.gastro.2017.11.279.

4. Lacy BE et al. Management of chronic abdominal distension and bloating. Clin Gastroenterol Hepatol. 2021 Feb. doi: 10.1016/j.cgh.2020.03.056.

5. Mearin F et al. Bowel disorders. Gastroenterology. 2016 Feb. doi: 10.1053/j.gastro.2016.02.031.

6. Moshiree B et al. AGA Clinical Practice Update on evaluation and management of belching, abdominal bloating, and distention: expert review. Gastroenterology. 2023 Sep. doi: 10.1053/j.gastro.2023.04.039.

7. Viswanathan L and Rao SS. Intestinal disaccharidase deficiency in adults: evaluation and treatment. Curr Gastroenterol Rep 2023 May. doi: 10.1007/s11894-023-00870-z.

8. Wilder-Smith CH et al. Fructose and lactose intolerance and malabsorption testing: the relationship with symptoms in functional gastrointestinal disorders. Aliment Pharmacol Ther. 2013 Jun. doi: 10.1111/apt.12306.

9. Skodje GI et al. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity. Gastroenterology. 2018 Feb. doi: 10.1053/j.gastro.2017.10.040.

10. Singh R et al. Current treatment options and therapeutic insights for gastrointestinal dysmotility and functional gastrointestinal disorders. Front Pharmacol. 2022 Jan. doi: 10.3389/fphar.2022.808195.

11. Accarino A et al. Abdominal distention results from caudo-ventral redistribution of contents. Gastroenterology 2009 May. doi: 10.1053/j.gastro.2009.01.067.

12. Shim L et al. Prolonged balloon expulsion is predictive of abdominal distension in bloating. Am J Gastroenterol. 2010 Apr. doi: 10.1038/ajg.2010.54.

13. Villoria A et al. Abdomino-phrenic dyssynergia in patients with abdominal bloating and distension. Am J Gastroenterol. 2011 May. doi: 10.1038/ajg.2010.408.

14. Neri L and Iovino P. Laxative Inadequate Relief Survey Group. Bloating is associated with worse quality of life, treatment satisfaction, and treatment responsiveness among patients with constipation-predominant irritable bowel syndrome and functional constipation. Neurogastroenterol Motil. 2016 Apr. doi: 10.1111/nmo.12758.

15. Saffouri GB et al. Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders. Nat Commun. 2019 May. doi: 10.1038/s41467-019-09964-7.

16. Villanueva-Millan MJ et al. Methanogens and hydrogen sulfide producing bacteria guide distinct gut microbe profiles and irritable bowel syndrome subtypes. Am J Gastroenterol. 2022 Dec. doi: 10.14309/ajg.0000000000001997.

17. Fernández-Bañares F et al. Sugar malabsorption in functional abdominal bloating: a pilot study on the long-term effect of dietary treatment. Clin Nutr. 2006 Oct. doi: 10.1016/j.clnu.2005.11.010.

18. Böhn L et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial. Gastroenterology. 2015 Nov. doi: 10.1053/j.gastro.2015.07.054.

19. Staudacher HM et al. Clinical trial: A Mediterranean diet is feasible and improves gastrointestinal and psychological symptoms in irritable bowel syndrome. Aliment Pharmacol Ther. 2024 Feb. doi: 10.1111/apt.17791.

20. Nelson AD et al. Systematic review and network meta-analysis: efficacy of licensed drugs for abdominal bloating in irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2021 Jul. doi: 10.1111/apt.16437.

21. Ringel-Kulka T et al. Probiotic bacteria Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 versus placebo for the symptoms of bloating in patients with functional bowel disorders: a double-blind study. J Clin Gastroenterol. 2011 Jul. doi: 10.1097/MCG.0b013e31820ca4d6.

22. Pimentel M et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011 Jan. doi: 10.1056/NEJMoa1004409.

23. Iovino P et al. Pelvic floor biofeedback is an effective treatment for severe bloating in disorders of gut-brain interaction with outlet dysfunction. Neurogastroenterol Motil 2022 May. doi: 10.1111/nmo.14264.

24. Talley NJ et al. Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study. Gastroenterology. 2015 Aug. doi: 10.1053/j.gastro.2015.04.020.

25. Keefer L et al. A Rome Working Team Report on brain-gut behavior therapies for disorders of gut-brain interaction. Gastroenterology. 2022 Jan. doi: 10.1053/j.gastro.2021.09.015.

Introduction

Abdominal bloating is a common condition affecting up to 3.5% of people globally (4.6% in women and 2.4% in men),¹ with 13.9% of the US population reporting bloating in the past 7 days.² The prevalence of bloating and distention exceeds 50% when linked to disorders of gut-brain interaction (DGBIs) such as irritable bowel syndrome (IBS), constipation, gastroparesis, and functional dyspepsia (FD).^3,4 According to the Rome IV criteria, functional bloating and distention (FABD) patients are characterized by recurrent symptoms of abdominal fullness or pressure (bloating), or a visible increase in abdominal girth (distention) occurring at least 1 day per week for 3 consecutive months with an onset of 6 months and without predominant pain or altered bowel habits.⁵

Prolonged abdominal bloating and distention (ABD) can significantly impact quality of life and work productivity and can lead to increased medical consultations.² Multiple pathophysiological mechanisms are involved in ABD that complicate the clinical management.⁴ There is an unmet need to understand the underlying mechanisms that lead to the development of ABD such as, food intolerance, abnormal viscerosomatic reflex, visceral hypersensitivity, and gut microbial dysbiosis. Recent advancements and acceptance of a multidisciplinary management of ABD have shifted the paradigm from merely treating symptoms to subtyping the condition and identifying overlaps with other DGBIs in order to individualize treatment that addresses the underlying pathophysiological mechanism. The recent American Gastroenterological Association (AGA) clinical update provided insights into the best practice advice for evaluating and managing ABD based on a review of current literature and on expert opinion of coauthors.⁶ This article aims to deliberate a practical approach to diagnostic strategies and treatment options based on etiology to refine clinical care of patients with ABD.

University of Nevada, Reno

Pathophysiological Mechanisms

ABD can result from various pathophysiological mechanisms. This section highlights the major causes (illustrated in Figure 1).

Food intolerances

Understanding food intolerances is crucial for diagnosing and managing patients with ABD. Disaccharidase deficiency is common (e.g., lactase deficiency is found in 35%-40% of adults).⁷ It can be undiagnosed in patients presenting with IBS symptoms, given the overlap in presentation with a prevalence of 9% of pan-disaccharidase deficiency. Sucrase-deficient patients must often adjust sugar and carbohydrate/starch intake to relieve symptoms.⁷ Deficiencies in lactase and sucrase activity, along with the consumption of some artificial sweeteners (e.g., sugar alcohols and sorbitol) and fructans can lead to bloating and distention. These substances increase osmotic load, fluid retention, microbial fermentation, and visceral hypersensitivity, leading to gas production and abdominal distention. One prospective study of symptomatic patients with various DGBIs (n = 1372) reported a prevalence of lactose intolerance and malabsorption at 51% and 32%, respectively.⁸ Furthermore, fructose intolerance and malabsorption prevalence were 60% and 45%, respectively.⁸ Notably, lactase deficiency does not always cause ABD, as not all individuals with lactase deficiency experience these symptoms after consuming lactose. Patients with celiac disease (CD), non-celiac gluten sensitivity (NCGS), and gluten intolerance can also experience bloating and distention, with or without changes in bowel habits.⁹ In some patients with self-reported NCGS, symptoms may be due to fructans in gluten-rich foods rather than gluten itself, thus recommending the elimination of fructans may help improve symptoms.⁹

Visceral hypersensitivity

Visceral hypersensitivity is explained by an increased perception of gut mechano-chemical stimulation, which typically manifests in an aggravated feeling of pain, nausea, distension, and ABD.¹⁰ In the gut, food particles and gut bacteria and their derived molecules interact with neuroimmune and enteroendocrine cells causing visceral sensitivity by the proximity of gut’s neurons to immune cells activated by them and leading to inflammatory reactions (Figure 1).

Dr. Singh and Dr. Moshiree

Pelvic floor dysfunction

Patients with anorectal motor dysfunction often experience difficulty in effectively evacuating both gas and stool, leading to ABD.¹² Impaired ability to expel gas and stool results in prolonged balloon expulsion times, which correlates with symptoms of distention in patients with constipation.

Atrium Health

Abdominophrenic dyssynergia

Abdominophrenic dyssynergia is characterized as a paradoxical viscerosomatic reflex response to minimal gaseous distention in individuals with FABD.¹³ In this condition, the diaphragm contracts (descends), and the anterior abdominal wall muscles relax in response to the presence of gas. This response is opposite to the normal physiological response to increased intraluminal gas, where the diaphragm relaxes and the anterior abdominal muscles contract to increase the craniocaudal capacity of the abdominal cavity without causing abdominal protrusion.¹³ Patients with FABD exhibit significant abdominal wall protrusion and diaphragmatic descent even with relatively small increases in intraluminal gas.¹¹ Understanding the role of abdominophrenic dyssynergia in abdominal bloating and distention is essential for effective diagnosis and management of the patients.

Gut dysmotility

Gut dysmotility is a crucial factor that can contribute to FABD. Gut dysmotility affects the movement of contents through the GI tract, accumulating gas and stool, directly contributing to bloating and distention. A prospective study involving over 2000 patients with functional constipation and constipation predominant-IBS (IBS-C) found that more than 90% of these patients reported symptoms of bloating.¹⁴ Furthermore, in IBS-C patients, those with prolonged colonic transit exhibited greater abdominal distention compared to those with normal gut transit times. In patients with gastroparesis, delayed gastric emptying resulting in prolonged retention of stomach contents is the main factor in the generation of bloating symptoms.⁴

Small intestinal bacterial overgrowth (SIBO)

SIBO is overrepresented in various conditions, including IBS, FD, diabetes, gastrointestinal (GI) surgery patients and obesity, and can play an important role in generating ABD. Excess bacteria in the small intestine ferment carbohydrates, producing gas that stretches and distends the small intestine, leading to these symptoms. Additionally, altered sensation and abnormal viscerosomatic reflexes may contribute to SIBO-related bloating.⁴ One recent study noted decreased duodenal phylogenetic diversity in individuals who developed postprandial bloating.¹⁵ Increased methane levels caused by intestinal methanogen overgrowth, primarily the archaea Methanobrevibacter smithii, is possibly responsible for ABD in patients with IBS-C.¹⁶ Testing for SIBO in patients with ABD is generally only recommended if there are clear risk factors or severe symptoms warranting a test-and-treat approach.

Practical Diagnosis

Diagnosing ABD typically does not require extensive laboratory testing, imaging, or endoscopy unless there are alarm features or significant changes in symptoms. Here is the AGA clinical update on best practice advice⁶ for when to conduct further testing:

Diagnostic tests should be considered if patients exhibit:

• Recent onset or worsening of dyspepsia or abdominal pain
• Vomiting
• GI bleeding
• Unintentional weight loss exceeding 10% of body weight
• Chronic diarrhea
• Family history of GI malignancy, celiac disease, or inflammatory bowel disease

Physical examination

If visible abdominal distention is present, a thorough abdominal examination can help identify potential issues:

• Tympany to percussion suggests bowel dilation.
• Abnormal bowel sounds may indicate obstruction or ileus.
• A succussion splash could indicate the presence of ascites and obstruction.
• Any abnormalities discovered during the physical exam should prompt further investigation with imaging, such as a computed tomography (CT) scan or ultrasound, to evaluate for ascites, masses, or increased bowel gas due to ileus, obstruction, or pseudo-obstruction.

Radiologic imaging, laboratory testing and endoscopy

• An abdominal x-ray may reveal an increased stool burden, suggesting the need for further evaluation of slow transit constipation or a pelvic floor disorder, particularly in patients with functional constipation, IBS-mixed, or IBS-C.
• Hyperglycemia, weight gain, and bloating can be a presenting sign of ovarian cancer therefore all women should continue pelvic exams as dictated by the gynecologic societies. The need for an annual pelvic exam should be discussed with health care professionals especially in those with family history of ovarian cancer.
• An upper endoscopy may be warranted for patients over 40 years old with dyspeptic symptoms and abdominal bloating or distention, especially in regions with a high prevalence of Helicobacter pylori.
• Chronic pancreatitis, indicated by bloating and pain, may necessitate fecal elastase testing to assess pancreatic function.

The expert review in the AGA clinical update provides step-by-step advice regarding the best practices⁶ for diagnosis and identifying who to test for ABD.
 

Treatment Options

The following sections highlight recent best practice advice on therapeutic approaches for treating ABD.

Dietary interventions

Specific foods may trigger bloating and abdominal distention, especially in patients with overlapping DGBIs. However, only a few studies have evaluated dietary restriction specifically for patients with primary ABD. Restricting non-absorbable sugars led to symptomatic improvement in 81% of patients with FABD who had documented sugar malabsorption.¹⁷ Two studies have shown that IBS patients treated with a low-fermentable, oligo-, di-, and monosaccharides (FODMAP) diet noted improvement in ABD and that restricting fructans initially may be the most optimal.¹⁸ A recent study showed that the Mediterranean diet improved IBS symptoms, including abdominal pain and bloating.¹⁹ It should be noted restrictive diets are efficacious but come with short- and long-term challenges. If empiric treatment and/or therapeutic testing do not resolve symptoms, a referral to a dietitian can be useful. Dietitians can provide tailored dietary advice, ensuring patients avoid trigger foods while maintaining a balanced and nutritious diet.

Prokinetics and laxatives

Prokinetic agents are used to treat symptoms of FD, gastroparesis, chronic idiopathic constipation (CIC), and IBS. A meta-analysis of 13 trials found all constipation medications superior to placebo for treating abdominal bloating in patients with IBS-C.²⁰

Probiotics

Treatment with probiotics is recommended for bloating or distention. One double-blind placebo-controlled trial with two separate probiotics, Bifidobacterium lactis and Lactobacillus acidophilus, showed improvements in global GI symptoms of patients with DGBI at 8 weeks versus placebo, with improvements in bloating symptoms.²¹

Antibiotics

The most commonly studied antibiotic for treating bloating is rifaximin.²² Global symptomatic improvement in IBS patients treated with antibiotics has correlated with the normalization of hydrogen levels in lactulose hydrogen breath tests.²² Patients with non-constipation IBS randomized to rifaximin 550 mg three times daily for 14 days had a greater proportion of relief of IBS-related bloating compared to placebo for at least 2 of the first 4 weeks after treatment.²² Future research warrants use of narrow-spectrum antibiotics study for FABD as the use of broad-spectrum antibiotics may deplete commensals forever, resulting in metabolic disorders.

Biofeedback therapy

Anorectal biofeedback therapy may help with ABD, particularly in patients with IBS-C and chronic constipation. One study noted that post-biofeedback therapy, myoelectric activity of the intercostals and diaphragm decreased, and internal oblique myoelectric activity increased.²³ This study also showed ascent of the diaphragm and decreased girth, improving distention.

Central neuromodulators

As bloating results from multiple disturbed mechanisms, including altered gut-brain interaction, these symptoms can be amplified by psychological states such as anxiety, depression, or somatization. Central neuromodulators reduce the perception of visceral signals, re-regulate brain-gut control mechanisms, and improve psychological comorbidities.⁶ A large study of FD patients demonstrated that both amitriptyline (50 mg daily) and escitalopram (10 mg daily) significantly improved postprandial bloating compared to placebo.²⁴ Antidepressants that activate noradrenergic and serotonergic pathways, including tricyclic antidepressants (e.g., amitriptyline) and serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and venlafaxine), show the greatest benefit in reducing visceral sensations.⁶

Brain-gut behavioral therapies

A recent multidisciplinary consensus report supports a myriad of potential brain-gut behavioral therapies (BGBTs) for treating DGBI.²⁵ These therapies, including hypnotherapy, cognitive behavioral therapy (CBT), and other modalities, may be combined with central neuromodulators and other GI treatments in a safe, noninvasive, and complementary fashion. BGBTs do not need to be symptom-specific, as they improve overall quality of life, anxiety, stress, and the burden associated with DGBIs. To date, none of the BGBTs have focused exclusively on FABD; however, prescription-based psychological therapies are now FDA-approved for use on smart apps, improving global symptoms that include bloating in IBS and FD.

Recent AGA clinical update best practices should be considered for the clinical care of patients with ABD.⁶

Conclusion and Future Perspectives

ABD are highly prevalent and significantly impact patients with various GI and metabolic disorders. Although our understanding of these symptoms is still evolving, evidence increasingly points to the dysregulation of the gut-brain axis and supports the application of the biopsychosocial model in treatment. This model addresses diet, motility, visceral sensitivity, pelvic floor disorders and psychosocial factors, providing a comprehensive approach to patient care.

Physician-scientists around the globe face numerous challenges when evaluating patients with these symptoms. However, the recent AGA clinical update on the best practice guidelines offers step-by-step diagnostic tests and treatment options to assist physicians in making informed decisions. A multidisciplinary approach and a patient-centered model are essential for effectively managing treatment in patients with ABD. More comprehensive, large-scale, and longitudinal studies using metabolomics, capsule technologies for discovery of dysbiosis, mass spectrometry, and imaging data are needed to identify the exact contributors to disease pathogenesis, particularly those that can be targeted with pharmacologic agents. Collaborative work between gastroenterologists, dietitians, gut-brain behavioral therapists, endocrinologists, is crucial for clinical care of patients with ABD.

Careful attention to the patient’s primary symptoms and physical examination, combined with advancements in targeted diagnostics like the analysis of microbial markers, metabolites, and molecular signals, can significantly enhance patient clinical outcomes. Additionally, education and effective communication using a patient-centered care model are essential for guiding practical evaluation and individualized treatment.

Dr. Singh is assistant professor (research) at the University of Nevada, Reno, School of Medicine. Dr. Moshiree is director of motility at Atrium Health, and clinical professor of medicine, Wake Forest Medical University, Charlotte, North Carolina.

References

1. Ballou S et al. Prevalence and associated factors of bloating: Results from the Rome Foundation Global Epidemiology Study. Gastroenterology. 2023 June. doi: 10.1053/j.gastro.2023.05.049.

2. Oh JE et al. Abdominal bloating in the United States: Results of a survey of 88,795 Americans examining prevalence and healthcare seeking. Clin Gastroenterol Hepatol. 2023 Aug. doi: 10.1016/j.cgh.2022.10.031.

3. Drossman DA et al. Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): A Rome Foundation Working Team Report. Gastroenterology. 2018 Mar. doi: 10.1053/j.gastro.2017.11.279.

4. Lacy BE et al. Management of chronic abdominal distension and bloating. Clin Gastroenterol Hepatol. 2021 Feb. doi: 10.1016/j.cgh.2020.03.056.

5. Mearin F et al. Bowel disorders. Gastroenterology. 2016 Feb. doi: 10.1053/j.gastro.2016.02.031.

6. Moshiree B et al. AGA Clinical Practice Update on evaluation and management of belching, abdominal bloating, and distention: expert review. Gastroenterology. 2023 Sep. doi: 10.1053/j.gastro.2023.04.039.

7. Viswanathan L and Rao SS. Intestinal disaccharidase deficiency in adults: evaluation and treatment. Curr Gastroenterol Rep 2023 May. doi: 10.1007/s11894-023-00870-z.

8. Wilder-Smith CH et al. Fructose and lactose intolerance and malabsorption testing: the relationship with symptoms in functional gastrointestinal disorders. Aliment Pharmacol Ther. 2013 Jun. doi: 10.1111/apt.12306.

9. Skodje GI et al. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity. Gastroenterology. 2018 Feb. doi: 10.1053/j.gastro.2017.10.040.

10. Singh R et al. Current treatment options and therapeutic insights for gastrointestinal dysmotility and functional gastrointestinal disorders. Front Pharmacol. 2022 Jan. doi: 10.3389/fphar.2022.808195.

11. Accarino A et al. Abdominal distention results from caudo-ventral redistribution of contents. Gastroenterology 2009 May. doi: 10.1053/j.gastro.2009.01.067.

12. Shim L et al. Prolonged balloon expulsion is predictive of abdominal distension in bloating. Am J Gastroenterol. 2010 Apr. doi: 10.1038/ajg.2010.54.

13. Villoria A et al. Abdomino-phrenic dyssynergia in patients with abdominal bloating and distension. Am J Gastroenterol. 2011 May. doi: 10.1038/ajg.2010.408.

14. Neri L and Iovino P. Laxative Inadequate Relief Survey Group. Bloating is associated with worse quality of life, treatment satisfaction, and treatment responsiveness among patients with constipation-predominant irritable bowel syndrome and functional constipation. Neurogastroenterol Motil. 2016 Apr. doi: 10.1111/nmo.12758.

15. Saffouri GB et al. Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders. Nat Commun. 2019 May. doi: 10.1038/s41467-019-09964-7.

16. Villanueva-Millan MJ et al. Methanogens and hydrogen sulfide producing bacteria guide distinct gut microbe profiles and irritable bowel syndrome subtypes. Am J Gastroenterol. 2022 Dec. doi: 10.14309/ajg.0000000000001997.

17. Fernández-Bañares F et al. Sugar malabsorption in functional abdominal bloating: a pilot study on the long-term effect of dietary treatment. Clin Nutr. 2006 Oct. doi: 10.1016/j.clnu.2005.11.010.

18. Böhn L et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial. Gastroenterology. 2015 Nov. doi: 10.1053/j.gastro.2015.07.054.

19. Staudacher HM et al. Clinical trial: A Mediterranean diet is feasible and improves gastrointestinal and psychological symptoms in irritable bowel syndrome. Aliment Pharmacol Ther. 2024 Feb. doi: 10.1111/apt.17791.

20. Nelson AD et al. Systematic review and network meta-analysis: efficacy of licensed drugs for abdominal bloating in irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2021 Jul. doi: 10.1111/apt.16437.

21. Ringel-Kulka T et al. Probiotic bacteria Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 versus placebo for the symptoms of bloating in patients with functional bowel disorders: a double-blind study. J Clin Gastroenterol. 2011 Jul. doi: 10.1097/MCG.0b013e31820ca4d6.

22. Pimentel M et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011 Jan. doi: 10.1056/NEJMoa1004409.

23. Iovino P et al. Pelvic floor biofeedback is an effective treatment for severe bloating in disorders of gut-brain interaction with outlet dysfunction. Neurogastroenterol Motil 2022 May. doi: 10.1111/nmo.14264.

24. Talley NJ et al. Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study. Gastroenterology. 2015 Aug. doi: 10.1053/j.gastro.2015.04.020.

25. Keefer L et al. A Rome Working Team Report on brain-gut behavior therapies for disorders of gut-brain interaction. Gastroenterology. 2022 Jan. doi: 10.1053/j.gastro.2021.09.015.

Introduction

Abdominal bloating is a common condition affecting up to 3.5% of people globally (4.6% in women and 2.4% in men),¹ with 13.9% of the US population reporting bloating in the past 7 days.² The prevalence of bloating and distention exceeds 50% when linked to disorders of gut-brain interaction (DGBIs) such as irritable bowel syndrome (IBS), constipation, gastroparesis, and functional dyspepsia (FD).^3,4 According to the Rome IV criteria, functional bloating and distention (FABD) patients are characterized by recurrent symptoms of abdominal fullness or pressure (bloating), or a visible increase in abdominal girth (distention) occurring at least 1 day per week for 3 consecutive months with an onset of 6 months and without predominant pain or altered bowel habits.⁵

Prolonged abdominal bloating and distention (ABD) can significantly impact quality of life and work productivity and can lead to increased medical consultations.² Multiple pathophysiological mechanisms are involved in ABD that complicate the clinical management.⁴ There is an unmet need to understand the underlying mechanisms that lead to the development of ABD such as, food intolerance, abnormal viscerosomatic reflex, visceral hypersensitivity, and gut microbial dysbiosis. Recent advancements and acceptance of a multidisciplinary management of ABD have shifted the paradigm from merely treating symptoms to subtyping the condition and identifying overlaps with other DGBIs in order to individualize treatment that addresses the underlying pathophysiological mechanism. The recent American Gastroenterological Association (AGA) clinical update provided insights into the best practice advice for evaluating and managing ABD based on a review of current literature and on expert opinion of coauthors.⁶ This article aims to deliberate a practical approach to diagnostic strategies and treatment options based on etiology to refine clinical care of patients with ABD.

University of Nevada, Reno

Pathophysiological Mechanisms

ABD can result from various pathophysiological mechanisms. This section highlights the major causes (illustrated in Figure 1).

Food intolerances

Understanding food intolerances is crucial for diagnosing and managing patients with ABD. Disaccharidase deficiency is common (e.g., lactase deficiency is found in 35%-40% of adults).⁷ It can be undiagnosed in patients presenting with IBS symptoms, given the overlap in presentation with a prevalence of 9% of pan-disaccharidase deficiency. Sucrase-deficient patients must often adjust sugar and carbohydrate/starch intake to relieve symptoms.⁷ Deficiencies in lactase and sucrase activity, along with the consumption of some artificial sweeteners (e.g., sugar alcohols and sorbitol) and fructans can lead to bloating and distention. These substances increase osmotic load, fluid retention, microbial fermentation, and visceral hypersensitivity, leading to gas production and abdominal distention. One prospective study of symptomatic patients with various DGBIs (n = 1372) reported a prevalence of lactose intolerance and malabsorption at 51% and 32%, respectively.⁸ Furthermore, fructose intolerance and malabsorption prevalence were 60% and 45%, respectively.⁸ Notably, lactase deficiency does not always cause ABD, as not all individuals with lactase deficiency experience these symptoms after consuming lactose. Patients with celiac disease (CD), non-celiac gluten sensitivity (NCGS), and gluten intolerance can also experience bloating and distention, with or without changes in bowel habits.⁹ In some patients with self-reported NCGS, symptoms may be due to fructans in gluten-rich foods rather than gluten itself, thus recommending the elimination of fructans may help improve symptoms.⁹

Visceral hypersensitivity

Visceral hypersensitivity is explained by an increased perception of gut mechano-chemical stimulation, which typically manifests in an aggravated feeling of pain, nausea, distension, and ABD.¹⁰ In the gut, food particles and gut bacteria and their derived molecules interact with neuroimmune and enteroendocrine cells causing visceral sensitivity by the proximity of gut’s neurons to immune cells activated by them and leading to inflammatory reactions (Figure 1).

Dr. Singh and Dr. Moshiree

Pelvic floor dysfunction

Patients with anorectal motor dysfunction often experience difficulty in effectively evacuating both gas and stool, leading to ABD.¹² Impaired ability to expel gas and stool results in prolonged balloon expulsion times, which correlates with symptoms of distention in patients with constipation.

Atrium Health

Abdominophrenic dyssynergia

Abdominophrenic dyssynergia is characterized as a paradoxical viscerosomatic reflex response to minimal gaseous distention in individuals with FABD.¹³ In this condition, the diaphragm contracts (descends), and the anterior abdominal wall muscles relax in response to the presence of gas. This response is opposite to the normal physiological response to increased intraluminal gas, where the diaphragm relaxes and the anterior abdominal muscles contract to increase the craniocaudal capacity of the abdominal cavity without causing abdominal protrusion.¹³ Patients with FABD exhibit significant abdominal wall protrusion and diaphragmatic descent even with relatively small increases in intraluminal gas.¹¹ Understanding the role of abdominophrenic dyssynergia in abdominal bloating and distention is essential for effective diagnosis and management of the patients.

Gut dysmotility

Gut dysmotility is a crucial factor that can contribute to FABD. Gut dysmotility affects the movement of contents through the GI tract, accumulating gas and stool, directly contributing to bloating and distention. A prospective study involving over 2000 patients with functional constipation and constipation predominant-IBS (IBS-C) found that more than 90% of these patients reported symptoms of bloating.¹⁴ Furthermore, in IBS-C patients, those with prolonged colonic transit exhibited greater abdominal distention compared to those with normal gut transit times. In patients with gastroparesis, delayed gastric emptying resulting in prolonged retention of stomach contents is the main factor in the generation of bloating symptoms.⁴

Small intestinal bacterial overgrowth (SIBO)

SIBO is overrepresented in various conditions, including IBS, FD, diabetes, gastrointestinal (GI) surgery patients and obesity, and can play an important role in generating ABD. Excess bacteria in the small intestine ferment carbohydrates, producing gas that stretches and distends the small intestine, leading to these symptoms. Additionally, altered sensation and abnormal viscerosomatic reflexes may contribute to SIBO-related bloating.⁴ One recent study noted decreased duodenal phylogenetic diversity in individuals who developed postprandial bloating.¹⁵ Increased methane levels caused by intestinal methanogen overgrowth, primarily the archaea Methanobrevibacter smithii, is possibly responsible for ABD in patients with IBS-C.¹⁶ Testing for SIBO in patients with ABD is generally only recommended if there are clear risk factors or severe symptoms warranting a test-and-treat approach.

Practical Diagnosis

Diagnosing ABD typically does not require extensive laboratory testing, imaging, or endoscopy unless there are alarm features or significant changes in symptoms. Here is the AGA clinical update on best practice advice⁶ for when to conduct further testing:

Diagnostic tests should be considered if patients exhibit:

• Recent onset or worsening of dyspepsia or abdominal pain
• Vomiting
• GI bleeding
• Unintentional weight loss exceeding 10% of body weight
• Chronic diarrhea
• Family history of GI malignancy, celiac disease, or inflammatory bowel disease

Physical examination

If visible abdominal distention is present, a thorough abdominal examination can help identify potential issues:

• Tympany to percussion suggests bowel dilation.
• Abnormal bowel sounds may indicate obstruction or ileus.
• A succussion splash could indicate the presence of ascites and obstruction.
• Any abnormalities discovered during the physical exam should prompt further investigation with imaging, such as a computed tomography (CT) scan or ultrasound, to evaluate for ascites, masses, or increased bowel gas due to ileus, obstruction, or pseudo-obstruction.

Radiologic imaging, laboratory testing and endoscopy

• An abdominal x-ray may reveal an increased stool burden, suggesting the need for further evaluation of slow transit constipation or a pelvic floor disorder, particularly in patients with functional constipation, IBS-mixed, or IBS-C.
• Hyperglycemia, weight gain, and bloating can be a presenting sign of ovarian cancer therefore all women should continue pelvic exams as dictated by the gynecologic societies. The need for an annual pelvic exam should be discussed with health care professionals especially in those with family history of ovarian cancer.
• An upper endoscopy may be warranted for patients over 40 years old with dyspeptic symptoms and abdominal bloating or distention, especially in regions with a high prevalence of Helicobacter pylori.
• Chronic pancreatitis, indicated by bloating and pain, may necessitate fecal elastase testing to assess pancreatic function.

The expert review in the AGA clinical update provides step-by-step advice regarding the best practices⁶ for diagnosis and identifying who to test for ABD.
 

Treatment Options

The following sections highlight recent best practice advice on therapeutic approaches for treating ABD.

Dietary interventions

Specific foods may trigger bloating and abdominal distention, especially in patients with overlapping DGBIs. However, only a few studies have evaluated dietary restriction specifically for patients with primary ABD. Restricting non-absorbable sugars led to symptomatic improvement in 81% of patients with FABD who had documented sugar malabsorption.¹⁷ Two studies have shown that IBS patients treated with a low-fermentable, oligo-, di-, and monosaccharides (FODMAP) diet noted improvement in ABD and that restricting fructans initially may be the most optimal.¹⁸ A recent study showed that the Mediterranean diet improved IBS symptoms, including abdominal pain and bloating.¹⁹ It should be noted restrictive diets are efficacious but come with short- and long-term challenges. If empiric treatment and/or therapeutic testing do not resolve symptoms, a referral to a dietitian can be useful. Dietitians can provide tailored dietary advice, ensuring patients avoid trigger foods while maintaining a balanced and nutritious diet.

Prokinetics and laxatives

Prokinetic agents are used to treat symptoms of FD, gastroparesis, chronic idiopathic constipation (CIC), and IBS. A meta-analysis of 13 trials found all constipation medications superior to placebo for treating abdominal bloating in patients with IBS-C.²⁰

Probiotics

Treatment with probiotics is recommended for bloating or distention. One double-blind placebo-controlled trial with two separate probiotics, Bifidobacterium lactis and Lactobacillus acidophilus, showed improvements in global GI symptoms of patients with DGBI at 8 weeks versus placebo, with improvements in bloating symptoms.²¹

Antibiotics

The most commonly studied antibiotic for treating bloating is rifaximin.²² Global symptomatic improvement in IBS patients treated with antibiotics has correlated with the normalization of hydrogen levels in lactulose hydrogen breath tests.²² Patients with non-constipation IBS randomized to rifaximin 550 mg three times daily for 14 days had a greater proportion of relief of IBS-related bloating compared to placebo for at least 2 of the first 4 weeks after treatment.²² Future research warrants use of narrow-spectrum antibiotics study for FABD as the use of broad-spectrum antibiotics may deplete commensals forever, resulting in metabolic disorders.

Biofeedback therapy

Anorectal biofeedback therapy may help with ABD, particularly in patients with IBS-C and chronic constipation. One study noted that post-biofeedback therapy, myoelectric activity of the intercostals and diaphragm decreased, and internal oblique myoelectric activity increased.²³ This study also showed ascent of the diaphragm and decreased girth, improving distention.

Central neuromodulators

As bloating results from multiple disturbed mechanisms, including altered gut-brain interaction, these symptoms can be amplified by psychological states such as anxiety, depression, or somatization. Central neuromodulators reduce the perception of visceral signals, re-regulate brain-gut control mechanisms, and improve psychological comorbidities.⁶ A large study of FD patients demonstrated that both amitriptyline (50 mg daily) and escitalopram (10 mg daily) significantly improved postprandial bloating compared to placebo.²⁴ Antidepressants that activate noradrenergic and serotonergic pathways, including tricyclic antidepressants (e.g., amitriptyline) and serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and venlafaxine), show the greatest benefit in reducing visceral sensations.⁶

Brain-gut behavioral therapies

A recent multidisciplinary consensus report supports a myriad of potential brain-gut behavioral therapies (BGBTs) for treating DGBI.²⁵ These therapies, including hypnotherapy, cognitive behavioral therapy (CBT), and other modalities, may be combined with central neuromodulators and other GI treatments in a safe, noninvasive, and complementary fashion. BGBTs do not need to be symptom-specific, as they improve overall quality of life, anxiety, stress, and the burden associated with DGBIs. To date, none of the BGBTs have focused exclusively on FABD; however, prescription-based psychological therapies are now FDA-approved for use on smart apps, improving global symptoms that include bloating in IBS and FD.

Recent AGA clinical update best practices should be considered for the clinical care of patients with ABD.⁶

Conclusion and Future Perspectives

ABD are highly prevalent and significantly impact patients with various GI and metabolic disorders. Although our understanding of these symptoms is still evolving, evidence increasingly points to the dysregulation of the gut-brain axis and supports the application of the biopsychosocial model in treatment. This model addresses diet, motility, visceral sensitivity, pelvic floor disorders and psychosocial factors, providing a comprehensive approach to patient care.

Physician-scientists around the globe face numerous challenges when evaluating patients with these symptoms. However, the recent AGA clinical update on the best practice guidelines offers step-by-step diagnostic tests and treatment options to assist physicians in making informed decisions. A multidisciplinary approach and a patient-centered model are essential for effectively managing treatment in patients with ABD. More comprehensive, large-scale, and longitudinal studies using metabolomics, capsule technologies for discovery of dysbiosis, mass spectrometry, and imaging data are needed to identify the exact contributors to disease pathogenesis, particularly those that can be targeted with pharmacologic agents. Collaborative work between gastroenterologists, dietitians, gut-brain behavioral therapists, endocrinologists, is crucial for clinical care of patients with ABD.

Careful attention to the patient’s primary symptoms and physical examination, combined with advancements in targeted diagnostics like the analysis of microbial markers, metabolites, and molecular signals, can significantly enhance patient clinical outcomes. Additionally, education and effective communication using a patient-centered care model are essential for guiding practical evaluation and individualized treatment.

Dr. Singh is assistant professor (research) at the University of Nevada, Reno, School of Medicine. Dr. Moshiree is director of motility at Atrium Health, and clinical professor of medicine, Wake Forest Medical University, Charlotte, North Carolina.

References

1. Ballou S et al. Prevalence and associated factors of bloating: Results from the Rome Foundation Global Epidemiology Study. Gastroenterology. 2023 June. doi: 10.1053/j.gastro.2023.05.049.

2. Oh JE et al. Abdominal bloating in the United States: Results of a survey of 88,795 Americans examining prevalence and healthcare seeking. Clin Gastroenterol Hepatol. 2023 Aug. doi: 10.1016/j.cgh.2022.10.031.

3. Drossman DA et al. Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): A Rome Foundation Working Team Report. Gastroenterology. 2018 Mar. doi: 10.1053/j.gastro.2017.11.279.

4. Lacy BE et al. Management of chronic abdominal distension and bloating. Clin Gastroenterol Hepatol. 2021 Feb. doi: 10.1016/j.cgh.2020.03.056.

5. Mearin F et al. Bowel disorders. Gastroenterology. 2016 Feb. doi: 10.1053/j.gastro.2016.02.031.

6. Moshiree B et al. AGA Clinical Practice Update on evaluation and management of belching, abdominal bloating, and distention: expert review. Gastroenterology. 2023 Sep. doi: 10.1053/j.gastro.2023.04.039.

7. Viswanathan L and Rao SS. Intestinal disaccharidase deficiency in adults: evaluation and treatment. Curr Gastroenterol Rep 2023 May. doi: 10.1007/s11894-023-00870-z.

8. Wilder-Smith CH et al. Fructose and lactose intolerance and malabsorption testing: the relationship with symptoms in functional gastrointestinal disorders. Aliment Pharmacol Ther. 2013 Jun. doi: 10.1111/apt.12306.

9. Skodje GI et al. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity. Gastroenterology. 2018 Feb. doi: 10.1053/j.gastro.2017.10.040.

10. Singh R et al. Current treatment options and therapeutic insights for gastrointestinal dysmotility and functional gastrointestinal disorders. Front Pharmacol. 2022 Jan. doi: 10.3389/fphar.2022.808195.

11. Accarino A et al. Abdominal distention results from caudo-ventral redistribution of contents. Gastroenterology 2009 May. doi: 10.1053/j.gastro.2009.01.067.

12. Shim L et al. Prolonged balloon expulsion is predictive of abdominal distension in bloating. Am J Gastroenterol. 2010 Apr. doi: 10.1038/ajg.2010.54.

13. Villoria A et al. Abdomino-phrenic dyssynergia in patients with abdominal bloating and distension. Am J Gastroenterol. 2011 May. doi: 10.1038/ajg.2010.408.

14. Neri L and Iovino P. Laxative Inadequate Relief Survey Group. Bloating is associated with worse quality of life, treatment satisfaction, and treatment responsiveness among patients with constipation-predominant irritable bowel syndrome and functional constipation. Neurogastroenterol Motil. 2016 Apr. doi: 10.1111/nmo.12758.

15. Saffouri GB et al. Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders. Nat Commun. 2019 May. doi: 10.1038/s41467-019-09964-7.

16. Villanueva-Millan MJ et al. Methanogens and hydrogen sulfide producing bacteria guide distinct gut microbe profiles and irritable bowel syndrome subtypes. Am J Gastroenterol. 2022 Dec. doi: 10.14309/ajg.0000000000001997.

17. Fernández-Bañares F et al. Sugar malabsorption in functional abdominal bloating: a pilot study on the long-term effect of dietary treatment. Clin Nutr. 2006 Oct. doi: 10.1016/j.clnu.2005.11.010.

18. Böhn L et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial. Gastroenterology. 2015 Nov. doi: 10.1053/j.gastro.2015.07.054.

19. Staudacher HM et al. Clinical trial: A Mediterranean diet is feasible and improves gastrointestinal and psychological symptoms in irritable bowel syndrome. Aliment Pharmacol Ther. 2024 Feb. doi: 10.1111/apt.17791.

20. Nelson AD et al. Systematic review and network meta-analysis: efficacy of licensed drugs for abdominal bloating in irritable bowel syndrome with constipation. Aliment Pharmacol Ther. 2021 Jul. doi: 10.1111/apt.16437.

21. Ringel-Kulka T et al. Probiotic bacteria Lactobacillus acidophilus NCFM and Bifidobacterium lactis Bi-07 versus placebo for the symptoms of bloating in patients with functional bowel disorders: a double-blind study. J Clin Gastroenterol. 2011 Jul. doi: 10.1097/MCG.0b013e31820ca4d6.

22. Pimentel M et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011 Jan. doi: 10.1056/NEJMoa1004409.

23. Iovino P et al. Pelvic floor biofeedback is an effective treatment for severe bloating in disorders of gut-brain interaction with outlet dysfunction. Neurogastroenterol Motil 2022 May. doi: 10.1111/nmo.14264.

24. Talley NJ et al. Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study. Gastroenterology. 2015 Aug. doi: 10.1053/j.gastro.2015.04.020.

25. Keefer L et al. A Rome Working Team Report on brain-gut behavior therapies for disorders of gut-brain interaction. Gastroenterology. 2022 Jan. doi: 10.1053/j.gastro.2021.09.015.

Introduction

Barrett’s esophagus (BE) is characterized by the replacement of squamous epithelium by columnar metaplasia of the distal esophagus (>1 cm length). It is a precancerous condition, with 3%-5% of patients with BE developing esophageal adenocarcinoma (EAC) in their lifetime. EAC is one of the cancers with high morbidity and mortality (5-year survival < 20%), and its incidence has been on the rise. Studies examining the natural history of BE have demonstrated that the progression happens through a metaplasia-dysplasia-neoplasia sequence. Therefore, early detection of BE and timely management to prevent progression to EAC is crucial.

Grades of Dysplasia

The current gold standard for the diagnosis of BE neoplasia includes a high-quality endoscopic evaluation and biopsies. Biopsies should be obtained from any visible lesions (nodules, ulcers) followed by a random 4-quadrant fashion (Seattle protocol) interval of the entire length of the BE segment. It is essential to pay attention to the results of the biopsy that have been obtained since it will not only determine the surveillance interval but is crucial in planning any necessary endoscopic therapy. The possible results of the biopsy and its implications are:

• No intestinal metaplasia (IM): This would rule out Barrett’s esophagus and no further surveillance would be necessary. A recent population-based study of over 1 million patients showed a 55% and 61% reduced risk of upper gastrointestinal (UGI) cancer and deaths respectively after a negative endoscopy.¹
• Intestinal metaplasia with no dysplasia (non-dysplastic BE): Biopsies confirm presence of intestinal metaplasia in the biopsies without any evidence of dysplasia. While the rate of progression to EAC is low (0.07%-0.25%), it is not absent and thus surveillance would be indicated. Current guidelines suggest repeating an endoscopy with biopsy in 5 years if the length of BE is < 3 cm or 3 years if length of BE ≥ 3 cm.²
• Indeterminate for dysplasia (BE-IND): Biopsies confirm IM but are not able to definitively rule out dysplasia. This can be seen in about 4%-8% of the biopsies obtained. The progression rates to EAC are reported to be comparable or lower to low-grade dysplasia (LGD), so the current recommendation is to intensify acid reduction therapy and repeat endoscopy in 6 months. If repeat endoscopy downgrades to non-dysplastic, then can follow surveillance according to NDBE protocol; otherwise recommend continuing surveillance every 12 months.
• Low-grade dysplasia (BE-LGD): Biopsies confirm IM but also show tightly packed overlapping basal nuclei with hyperchromasia and irregular contours, basal stratification of nuclei, and diminished goblet and columnar cell mucus. There is significant inter-observer variability reported,³ and thus the slides must be reviewed by a second pathologist with experience in BE to confirm the findings. Once confirmed, based on risk factors such as presence of multifocal LGD, persistence of LGD, presence of visible lesions, etc., the patient can be offered Barrett’s endoscopic therapy (BET) or undergo continued surveillance. The decision of pursuing one or the other would be dependent on patient preference and shared decision-making between the patient and the provider.
• High-grade dysplasia (BE-HGD): Biopsies confirm IM with cells showing greater degree of cytologic and architectural alterations of dysplasia than LGD but without overt neoplastic features. Over 40% of the patients would progress to EAC and thus the current recommendations would be to recommend BET in these patients.⁴
• Esophageal adenocarcinoma (EAC): Biopsies demonstrate neoplasia. If the neoplastic changes are limited to the mucosa (T1a) on endoscopic ultrasound or cross-sectional imaging, then BET is suggested. If there is involvement of submucosa, then depending on the depth of invasion, absence of high-risk features (poor differentiation, lymphovascular invasion), BET can be considered as an alternative to esophagectomy.

Lesion Detection on Endoscopy

Data from large population-based studies with at least 3 years of follow-up reported that 58%-66% of EAC detected during endoscopy were diagnosed within 1 year of an index Barrett’s esophagus screening endoscopy, or post-endoscopy Barrett’s neoplasia, and were considered likely to have been missed during index endoscopy.⁵ This underscores the importance of careful and systematic endoscopic examination during an upper endoscopy.

Studies have also demonstrated that longer examination time was associated with significantly higher detection of HGD/EAC.^6,7 Careful examination of the tubular esophagus and gastroesophageal junction (GEJ) should be performed in forward and retroflexed views looking for any subtle areas of nodularity, loop distortion, variability in vascular patterns, mucosal changes concerning for dysplasia or neoplasia. Use of high-definition white light endoscopy (HD-WLE) and virtual chromoendoscopy techniques such as narrow banding imaging (NBI) or blue laser imaging (BLI) are currently recommended in the guidelines.² Spray chromoendoscopy using acetic acid can also be utilized. Another exciting development is the use of artificial intelligence (AI) in detecting and diagnosing BE associated lesions and neoplasia.
 

Barrett’s Endoscopic Therapy (BET)

Patients with visible lesions, dysplasia, or early EAC are candidates for BET (Table 1).

BET involves resective and ablative modalities. The resective modalities include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) and are the modalities of choice for nodular or raised lesions.

EMR involves endoscopic resection of abnormal mucosa using either lift-assisted technique or multi-band ligation (Figure 1).

ESD, on the other hand, involves submucosal dissection and perimeter resection of the lesion, thus providing the advantage of an en-bloc resection. In a recent randomized controlled trial (RCT) of 40 patients undergoing ESD vs EMR for HGD/EAC, ESD was better for curative resection (R0) (58%) compared with EMR (12%); however, the remission rates at 3 months were comparable with two perforations reported in the ESD group while there were no complications in the EMR group.⁸

There is an apparent learning curve when it comes to these advanced techniques, and with more experience, we are seeing comparable results for both these modalities. However, given the complexity and time required for the procedure, current practices typically involve preserving ESD for lesions > 2 cm, those having a likelihood of cancer in the superficial submucosa, or those that EMR cannot remove due to underlying fibrosis or post-EMR recurrence.

University of Kansas Health System

Barrett’s Refractory to Endoscopic Therapy

Failure of BET is defined as persistent columnar lined epithelium (intestinal metaplasia) with inadequate response, after adequate attempts at endoscopic ablation therapy (after resection) with at least four ablation sessions.¹³ If encountered, special attention must be given to check compliance with proton pump inhibitors (PPIs), previous incomplete resection, and presence of large hiatal hernia. If CE-IM is not achieved after multiple sessions, change of ablative modality is typically considered. In addition, careful examination for visible lesions should be performed and even if a small one is noted, this should be first resected prior to application of any ablative therapy.

University of Kansas Health System

Currently there are no guideline recommendations regarding the preference of one endoscopic modality over another or consideration of potential endoscopic or surgical fundoplication. These modalities primarily rely on technologies available at an institution and the preference of a provider based on their training and experience. Most studies indicate 1-3 sessions (~ 3 months apart) of ablative treatment before achieving CE-IM.
 

Success and Adverse Events of BET

In a recent real-world study of over 27,000 patients with dysplastic BE, 5295 underwent BET. Analysis showed that patients with HGD/EAC who had BET had a significantly lower 3-year mortality (HGD: RR, 0.59; 95%CI, 0.49-0.71; EAC: RR, 0.53; 95% CI, 0.44-0.65) compared with those who did not undergo BET. Esophageal strictures were the most common adverse event and were noted in 6.5%, followed by chest pain (1.8%), upper GI bleeding (0.47%), and esophageal perforation (0.2%).¹⁴

In general, adverse events can be divided into immediate and delayed adverse events. Immediate adverse events typically involve bleeding and perforation that can occur during or shortly after the procedure. These are reported at higher rates with resective modalities compared with ablative therapies. Standard endoscopic techniques involving coagulation grasper or clips can be used to achieve hemostasis. Endoscopic suturing devices offer the ability to contain any perforation. The need for surgical intervention is small and limited to adverse events not detected during the procedure.

Delayed adverse events such as stricture and stenosis are higher for resective modalities (up to 30%), especially when involving more significant than 75% of the esophageal circumference. Post-procedural pain/dysphagia is most common after ablative therapies. Dysphagia reported after any endoscopic therapy should be promptly evaluated, and sequential dilation until the goal esophageal lumen is achieved should be performed every 2-4 weeks.
 

Recurrences and Surveillance After BET

What is established is that recurrences can occur and may be subtle, therefore detailed endoscopic surveillance is required. In a prospective study, recurrence rates of 15%-16% for IM and 3%-5% for any dysplasia were reported, with the majority being in the first 2 years after achieving CE-IM.¹⁵ A systematic review of 21 studies looking at the location of recurrences suggested that the majority (56%) occur in the distal esophagus. Of those that occur in the esophagus, about 80% of them were in the distal 2 cm of the esophagus and only 50% of the recurrences were visible recurrences, thus reiterating the importance of meticulous examination and systematic biopsies.¹⁶

On the contrary, a recent single-center study of 217 patients who had achieved CE-IM with 5.5 years of follow-up demonstrated a 26% and 8% recurrence of IM and dysplasia, respectively. One hundred percent of the recurrence in the esophagus was reported as visible.¹⁷ Therefore, follow-up endoscopy surveillance protocol after CE-IM should still involve meticulous examination, biopsy of visible lesions, and systematic biopsies for non-visible lesions from the original BE segment, similar to those patients who have not needed BET.

Current guidelines based on expert consensus and evidence recommend surveillance after CE-IM based on original most advanced histology:²

1. LGD: 1 year, 3 years, and every 2 years after that.

2. HGD/EAC: 3 months, 6 months, 12 months, and annually after that.

There is no clear guideline on when to stop surveillance since the longest available follow-up is around 10 years, and recurrences are still detected. A potential surveillance endpoint may be based on age and comorbidities, especially those that would preclude a patient from being a candidate for BET.
 

When Should a Patient Be Referred?

BE patients with visible lesions and/or dysplastic changes in the biopsy who would require BET should be considered for referral to high-volume centers. Studies have shown higher success for CE-IM and lower rates of adverse events and recurrences in these patients managed at expert centers. The presence of a multidisciplinary team involving pathologists, surgeons, and oncologists is critical and offers a timely opportunity in case of need for a high-risk patient.

Conclusion

BE is a precursor to EAC, with rising incidence and poor 5-year survival. Endoscopic diagnosis is the gold standard and requires a high-quality examination and biopsies. Based on histopathology, a systematic surveillance and BET plan should be performed to achieve CE-IM in patients with dysplasia. Once CE-IM is achieved, regular surveillance should be performed with careful attention to recurrences and complications from the BET modalities.

Dr. Srinivasan and Dr. Sharma are based at the University of Kansas Medical Center, Kansas City, Kansas, and the Kansas City Veterans Affairs Medical Center, Kansas City, Missouri. Dr. Srinivasan has no relevant disclosures. Dr. Sharma disclosed research grants from ERBE, Ironwood Pharmaceuticals, Olympus, and Medtronic. He has served as a consultant for Takeda, Samsung Bioepis, Olympus, and Lumendi, and reports other funding from Medtronic, Fujifilm Medical Systems USA, and Salix.

References

1. Holmberg D, et al. Incidence and mortality in upper gastrointestinal cancer after negative endoscopy for gastroesophageal reflux disease. Gastroenterology. 2022;162(2):431-438.e4.

2. Shaheen NJ, et al. Diagnosis and management of Barrett’s esophagus: An updated ACG guideline. Am J Gastroenterol. 2022 Apr;117(4):559-587.

3. Pech O, et al. Inter-observer variability in the diagnosis of low-grade dysplasia in pathologists: A comparison between experienced and inexperienced pathologists. Gastrointest Endosc. 2006 Apr;63(5):AB130.

4. Krishnamoorthi R, et al. Factors associated with progression of Barrett’s esophagus: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018 Jul;16(7):1046-1055.e8.

5. Visrodia K, et al. Magnitude of missed esophageal adenocarcinoma after Barrett’s esophagus diagnosis: A systematic review and meta-analysis. Gastroenterology. 2016 Mar;150(3):599-607.e7; quiz e14-5.

6. Perisetti A, Sharma P. Tips for improving the identification of neoplastic visible lesions in Barrett’s esophagus. Gastrointest Endosc. 2023 Feb;97(2):248-250.

7. Gupta N, et al. Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett’s esophagus. Gastrointest Endosc. 2012 Sep;76(3):531-538.

8. Terheggen G, et al. A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett’s neoplasia. Gut. 2017 May;66(5):783-793.

9. Wolfson P, et al. Endoscopic eradication therapy for Barrett’s esophagus-related neoplasia: A final 10-year report from the UK National HALO Radiofrequency Ablation Registry. Gastrointest Endosc. 2022 Aug;96(2):223-233.

10. Rösch T, et al. 1151 Multicenter feasibility study of combined injection and argon plasma coagulation (hybrid-APC) in the ablation therapy of neoplastic Barrett esophagus. Gastrointest Endosc. 2017;85(5):AB154.

11. Knabe M, et al. Radiofrequency ablation versus hybrid argon plasma coagulation in Barrett’s esophagus: A prospective randomised trial. Surg Endosc. 2023;37(10):7803-7811.

12. Van Munster SN, et al. Radiofrequency vapor ablation for Barrett’s esophagus: Feasibility, safety, and proof of concept in a stepwise study with in vitro, animal, and the first in-human application. Endoscopy. 2021 Nov;53(11):1162-1168.

13. Emura F, et al. Rio de Janeiro global consensus on landmarks, definitions, and classifications in Barrett’s esophagus: World Endoscopy Organization Delphi study. Gastroenterology. 2022 Jul;163(1):84-96.e2.

14. Singh RR, et al. Real-world evidence of safety and effectiveness of Barrett’s endoscopic therapy. Gastrointest Endosc. 2023 Aug;98(2):155-161.e1.

15. Wani S, et al. Recurrence Is rare following complete eradication of intestinal metaplasia in patients with Barrett’s esophagus and peaks at 18 months. Clin Gastroenterol Hepatol. 2020 Oct;18(11):2609-2617.e2.

16. Duvvuri A, et al. Mo1273 Location and pattern of recurrences in patients with Barrett’s esophagus after endoscopic therapy: A systematic review and critical analysis of the published literature. Gastrointest Endosc. 2020;91(6):AB410-1.

17. He T, et al. Location and appearance of dysplastic Barrett’s esophagus recurrence after endoscopic eradication therapy: No additional yield from random biopsy sampling neosquamous mucosa. Gastrointest Endosc. 2023 Nov;98(5):722-732.

Introduction

Barrett’s esophagus (BE) is characterized by the replacement of squamous epithelium by columnar metaplasia of the distal esophagus (>1 cm length). It is a precancerous condition, with 3%-5% of patients with BE developing esophageal adenocarcinoma (EAC) in their lifetime. EAC is one of the cancers with high morbidity and mortality (5-year survival < 20%), and its incidence has been on the rise. Studies examining the natural history of BE have demonstrated that the progression happens through a metaplasia-dysplasia-neoplasia sequence. Therefore, early detection of BE and timely management to prevent progression to EAC is crucial.

Grades of Dysplasia

The current gold standard for the diagnosis of BE neoplasia includes a high-quality endoscopic evaluation and biopsies. Biopsies should be obtained from any visible lesions (nodules, ulcers) followed by a random 4-quadrant fashion (Seattle protocol) interval of the entire length of the BE segment. It is essential to pay attention to the results of the biopsy that have been obtained since it will not only determine the surveillance interval but is crucial in planning any necessary endoscopic therapy. The possible results of the biopsy and its implications are:

• No intestinal metaplasia (IM): This would rule out Barrett’s esophagus and no further surveillance would be necessary. A recent population-based study of over 1 million patients showed a 55% and 61% reduced risk of upper gastrointestinal (UGI) cancer and deaths respectively after a negative endoscopy.¹
• Intestinal metaplasia with no dysplasia (non-dysplastic BE): Biopsies confirm presence of intestinal metaplasia in the biopsies without any evidence of dysplasia. While the rate of progression to EAC is low (0.07%-0.25%), it is not absent and thus surveillance would be indicated. Current guidelines suggest repeating an endoscopy with biopsy in 5 years if the length of BE is < 3 cm or 3 years if length of BE ≥ 3 cm.²
• Indeterminate for dysplasia (BE-IND): Biopsies confirm IM but are not able to definitively rule out dysplasia. This can be seen in about 4%-8% of the biopsies obtained. The progression rates to EAC are reported to be comparable or lower to low-grade dysplasia (LGD), so the current recommendation is to intensify acid reduction therapy and repeat endoscopy in 6 months. If repeat endoscopy downgrades to non-dysplastic, then can follow surveillance according to NDBE protocol; otherwise recommend continuing surveillance every 12 months.
• Low-grade dysplasia (BE-LGD): Biopsies confirm IM but also show tightly packed overlapping basal nuclei with hyperchromasia and irregular contours, basal stratification of nuclei, and diminished goblet and columnar cell mucus. There is significant inter-observer variability reported,³ and thus the slides must be reviewed by a second pathologist with experience in BE to confirm the findings. Once confirmed, based on risk factors such as presence of multifocal LGD, persistence of LGD, presence of visible lesions, etc., the patient can be offered Barrett’s endoscopic therapy (BET) or undergo continued surveillance. The decision of pursuing one or the other would be dependent on patient preference and shared decision-making between the patient and the provider.
• High-grade dysplasia (BE-HGD): Biopsies confirm IM with cells showing greater degree of cytologic and architectural alterations of dysplasia than LGD but without overt neoplastic features. Over 40% of the patients would progress to EAC and thus the current recommendations would be to recommend BET in these patients.⁴
• Esophageal adenocarcinoma (EAC): Biopsies demonstrate neoplasia. If the neoplastic changes are limited to the mucosa (T1a) on endoscopic ultrasound or cross-sectional imaging, then BET is suggested. If there is involvement of submucosa, then depending on the depth of invasion, absence of high-risk features (poor differentiation, lymphovascular invasion), BET can be considered as an alternative to esophagectomy.

Lesion Detection on Endoscopy

Data from large population-based studies with at least 3 years of follow-up reported that 58%-66% of EAC detected during endoscopy were diagnosed within 1 year of an index Barrett’s esophagus screening endoscopy, or post-endoscopy Barrett’s neoplasia, and were considered likely to have been missed during index endoscopy.⁵ This underscores the importance of careful and systematic endoscopic examination during an upper endoscopy.

Studies have also demonstrated that longer examination time was associated with significantly higher detection of HGD/EAC.^6,7 Careful examination of the tubular esophagus and gastroesophageal junction (GEJ) should be performed in forward and retroflexed views looking for any subtle areas of nodularity, loop distortion, variability in vascular patterns, mucosal changes concerning for dysplasia or neoplasia. Use of high-definition white light endoscopy (HD-WLE) and virtual chromoendoscopy techniques such as narrow banding imaging (NBI) or blue laser imaging (BLI) are currently recommended in the guidelines.² Spray chromoendoscopy using acetic acid can also be utilized. Another exciting development is the use of artificial intelligence (AI) in detecting and diagnosing BE associated lesions and neoplasia.
 

Barrett’s Endoscopic Therapy (BET)

Patients with visible lesions, dysplasia, or early EAC are candidates for BET (Table 1).

BET involves resective and ablative modalities. The resective modalities include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) and are the modalities of choice for nodular or raised lesions.

EMR involves endoscopic resection of abnormal mucosa using either lift-assisted technique or multi-band ligation (Figure 1).

ESD, on the other hand, involves submucosal dissection and perimeter resection of the lesion, thus providing the advantage of an en-bloc resection. In a recent randomized controlled trial (RCT) of 40 patients undergoing ESD vs EMR for HGD/EAC, ESD was better for curative resection (R0) (58%) compared with EMR (12%); however, the remission rates at 3 months were comparable with two perforations reported in the ESD group while there were no complications in the EMR group.⁸

There is an apparent learning curve when it comes to these advanced techniques, and with more experience, we are seeing comparable results for both these modalities. However, given the complexity and time required for the procedure, current practices typically involve preserving ESD for lesions > 2 cm, those having a likelihood of cancer in the superficial submucosa, or those that EMR cannot remove due to underlying fibrosis or post-EMR recurrence.

University of Kansas Health System

Barrett’s Refractory to Endoscopic Therapy

Failure of BET is defined as persistent columnar lined epithelium (intestinal metaplasia) with inadequate response, after adequate attempts at endoscopic ablation therapy (after resection) with at least four ablation sessions.¹³ If encountered, special attention must be given to check compliance with proton pump inhibitors (PPIs), previous incomplete resection, and presence of large hiatal hernia. If CE-IM is not achieved after multiple sessions, change of ablative modality is typically considered. In addition, careful examination for visible lesions should be performed and even if a small one is noted, this should be first resected prior to application of any ablative therapy.

University of Kansas Health System

Currently there are no guideline recommendations regarding the preference of one endoscopic modality over another or consideration of potential endoscopic or surgical fundoplication. These modalities primarily rely on technologies available at an institution and the preference of a provider based on their training and experience. Most studies indicate 1-3 sessions (~ 3 months apart) of ablative treatment before achieving CE-IM.
 

Success and Adverse Events of BET

In a recent real-world study of over 27,000 patients with dysplastic BE, 5295 underwent BET. Analysis showed that patients with HGD/EAC who had BET had a significantly lower 3-year mortality (HGD: RR, 0.59; 95%CI, 0.49-0.71; EAC: RR, 0.53; 95% CI, 0.44-0.65) compared with those who did not undergo BET. Esophageal strictures were the most common adverse event and were noted in 6.5%, followed by chest pain (1.8%), upper GI bleeding (0.47%), and esophageal perforation (0.2%).¹⁴

In general, adverse events can be divided into immediate and delayed adverse events. Immediate adverse events typically involve bleeding and perforation that can occur during or shortly after the procedure. These are reported at higher rates with resective modalities compared with ablative therapies. Standard endoscopic techniques involving coagulation grasper or clips can be used to achieve hemostasis. Endoscopic suturing devices offer the ability to contain any perforation. The need for surgical intervention is small and limited to adverse events not detected during the procedure.

Delayed adverse events such as stricture and stenosis are higher for resective modalities (up to 30%), especially when involving more significant than 75% of the esophageal circumference. Post-procedural pain/dysphagia is most common after ablative therapies. Dysphagia reported after any endoscopic therapy should be promptly evaluated, and sequential dilation until the goal esophageal lumen is achieved should be performed every 2-4 weeks.
 

Recurrences and Surveillance After BET

What is established is that recurrences can occur and may be subtle, therefore detailed endoscopic surveillance is required. In a prospective study, recurrence rates of 15%-16% for IM and 3%-5% for any dysplasia were reported, with the majority being in the first 2 years after achieving CE-IM.¹⁵ A systematic review of 21 studies looking at the location of recurrences suggested that the majority (56%) occur in the distal esophagus. Of those that occur in the esophagus, about 80% of them were in the distal 2 cm of the esophagus and only 50% of the recurrences were visible recurrences, thus reiterating the importance of meticulous examination and systematic biopsies.¹⁶

On the contrary, a recent single-center study of 217 patients who had achieved CE-IM with 5.5 years of follow-up demonstrated a 26% and 8% recurrence of IM and dysplasia, respectively. One hundred percent of the recurrence in the esophagus was reported as visible.¹⁷ Therefore, follow-up endoscopy surveillance protocol after CE-IM should still involve meticulous examination, biopsy of visible lesions, and systematic biopsies for non-visible lesions from the original BE segment, similar to those patients who have not needed BET.

Current guidelines based on expert consensus and evidence recommend surveillance after CE-IM based on original most advanced histology:²

1. LGD: 1 year, 3 years, and every 2 years after that.

2. HGD/EAC: 3 months, 6 months, 12 months, and annually after that.

There is no clear guideline on when to stop surveillance since the longest available follow-up is around 10 years, and recurrences are still detected. A potential surveillance endpoint may be based on age and comorbidities, especially those that would preclude a patient from being a candidate for BET.
 

When Should a Patient Be Referred?

BE patients with visible lesions and/or dysplastic changes in the biopsy who would require BET should be considered for referral to high-volume centers. Studies have shown higher success for CE-IM and lower rates of adverse events and recurrences in these patients managed at expert centers. The presence of a multidisciplinary team involving pathologists, surgeons, and oncologists is critical and offers a timely opportunity in case of need for a high-risk patient.

Conclusion

BE is a precursor to EAC, with rising incidence and poor 5-year survival. Endoscopic diagnosis is the gold standard and requires a high-quality examination and biopsies. Based on histopathology, a systematic surveillance and BET plan should be performed to achieve CE-IM in patients with dysplasia. Once CE-IM is achieved, regular surveillance should be performed with careful attention to recurrences and complications from the BET modalities.

Dr. Srinivasan and Dr. Sharma are based at the University of Kansas Medical Center, Kansas City, Kansas, and the Kansas City Veterans Affairs Medical Center, Kansas City, Missouri. Dr. Srinivasan has no relevant disclosures. Dr. Sharma disclosed research grants from ERBE, Ironwood Pharmaceuticals, Olympus, and Medtronic. He has served as a consultant for Takeda, Samsung Bioepis, Olympus, and Lumendi, and reports other funding from Medtronic, Fujifilm Medical Systems USA, and Salix.

References

1. Holmberg D, et al. Incidence and mortality in upper gastrointestinal cancer after negative endoscopy for gastroesophageal reflux disease. Gastroenterology. 2022;162(2):431-438.e4.

2. Shaheen NJ, et al. Diagnosis and management of Barrett’s esophagus: An updated ACG guideline. Am J Gastroenterol. 2022 Apr;117(4):559-587.

3. Pech O, et al. Inter-observer variability in the diagnosis of low-grade dysplasia in pathologists: A comparison between experienced and inexperienced pathologists. Gastrointest Endosc. 2006 Apr;63(5):AB130.

4. Krishnamoorthi R, et al. Factors associated with progression of Barrett’s esophagus: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018 Jul;16(7):1046-1055.e8.

5. Visrodia K, et al. Magnitude of missed esophageal adenocarcinoma after Barrett’s esophagus diagnosis: A systematic review and meta-analysis. Gastroenterology. 2016 Mar;150(3):599-607.e7; quiz e14-5.

6. Perisetti A, Sharma P. Tips for improving the identification of neoplastic visible lesions in Barrett’s esophagus. Gastrointest Endosc. 2023 Feb;97(2):248-250.

7. Gupta N, et al. Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett’s esophagus. Gastrointest Endosc. 2012 Sep;76(3):531-538.

8. Terheggen G, et al. A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett’s neoplasia. Gut. 2017 May;66(5):783-793.

9. Wolfson P, et al. Endoscopic eradication therapy for Barrett’s esophagus-related neoplasia: A final 10-year report from the UK National HALO Radiofrequency Ablation Registry. Gastrointest Endosc. 2022 Aug;96(2):223-233.

10. Rösch T, et al. 1151 Multicenter feasibility study of combined injection and argon plasma coagulation (hybrid-APC) in the ablation therapy of neoplastic Barrett esophagus. Gastrointest Endosc. 2017;85(5):AB154.

11. Knabe M, et al. Radiofrequency ablation versus hybrid argon plasma coagulation in Barrett’s esophagus: A prospective randomised trial. Surg Endosc. 2023;37(10):7803-7811.

12. Van Munster SN, et al. Radiofrequency vapor ablation for Barrett’s esophagus: Feasibility, safety, and proof of concept in a stepwise study with in vitro, animal, and the first in-human application. Endoscopy. 2021 Nov;53(11):1162-1168.

13. Emura F, et al. Rio de Janeiro global consensus on landmarks, definitions, and classifications in Barrett’s esophagus: World Endoscopy Organization Delphi study. Gastroenterology. 2022 Jul;163(1):84-96.e2.

14. Singh RR, et al. Real-world evidence of safety and effectiveness of Barrett’s endoscopic therapy. Gastrointest Endosc. 2023 Aug;98(2):155-161.e1.

15. Wani S, et al. Recurrence Is rare following complete eradication of intestinal metaplasia in patients with Barrett’s esophagus and peaks at 18 months. Clin Gastroenterol Hepatol. 2020 Oct;18(11):2609-2617.e2.

16. Duvvuri A, et al. Mo1273 Location and pattern of recurrences in patients with Barrett’s esophagus after endoscopic therapy: A systematic review and critical analysis of the published literature. Gastrointest Endosc. 2020;91(6):AB410-1.

17. He T, et al. Location and appearance of dysplastic Barrett’s esophagus recurrence after endoscopic eradication therapy: No additional yield from random biopsy sampling neosquamous mucosa. Gastrointest Endosc. 2023 Nov;98(5):722-732.

Introduction

Barrett’s esophagus (BE) is characterized by the replacement of squamous epithelium by columnar metaplasia of the distal esophagus (>1 cm length). It is a precancerous condition, with 3%-5% of patients with BE developing esophageal adenocarcinoma (EAC) in their lifetime. EAC is one of the cancers with high morbidity and mortality (5-year survival < 20%), and its incidence has been on the rise. Studies examining the natural history of BE have demonstrated that the progression happens through a metaplasia-dysplasia-neoplasia sequence. Therefore, early detection of BE and timely management to prevent progression to EAC is crucial.

Grades of Dysplasia

The current gold standard for the diagnosis of BE neoplasia includes a high-quality endoscopic evaluation and biopsies. Biopsies should be obtained from any visible lesions (nodules, ulcers) followed by a random 4-quadrant fashion (Seattle protocol) interval of the entire length of the BE segment. It is essential to pay attention to the results of the biopsy that have been obtained since it will not only determine the surveillance interval but is crucial in planning any necessary endoscopic therapy. The possible results of the biopsy and its implications are:

• No intestinal metaplasia (IM): This would rule out Barrett’s esophagus and no further surveillance would be necessary. A recent population-based study of over 1 million patients showed a 55% and 61% reduced risk of upper gastrointestinal (UGI) cancer and deaths respectively after a negative endoscopy.¹
• Intestinal metaplasia with no dysplasia (non-dysplastic BE): Biopsies confirm presence of intestinal metaplasia in the biopsies without any evidence of dysplasia. While the rate of progression to EAC is low (0.07%-0.25%), it is not absent and thus surveillance would be indicated. Current guidelines suggest repeating an endoscopy with biopsy in 5 years if the length of BE is < 3 cm or 3 years if length of BE ≥ 3 cm.²
• Indeterminate for dysplasia (BE-IND): Biopsies confirm IM but are not able to definitively rule out dysplasia. This can be seen in about 4%-8% of the biopsies obtained. The progression rates to EAC are reported to be comparable or lower to low-grade dysplasia (LGD), so the current recommendation is to intensify acid reduction therapy and repeat endoscopy in 6 months. If repeat endoscopy downgrades to non-dysplastic, then can follow surveillance according to NDBE protocol; otherwise recommend continuing surveillance every 12 months.
• Low-grade dysplasia (BE-LGD): Biopsies confirm IM but also show tightly packed overlapping basal nuclei with hyperchromasia and irregular contours, basal stratification of nuclei, and diminished goblet and columnar cell mucus. There is significant inter-observer variability reported,³ and thus the slides must be reviewed by a second pathologist with experience in BE to confirm the findings. Once confirmed, based on risk factors such as presence of multifocal LGD, persistence of LGD, presence of visible lesions, etc., the patient can be offered Barrett’s endoscopic therapy (BET) or undergo continued surveillance. The decision of pursuing one or the other would be dependent on patient preference and shared decision-making between the patient and the provider.
• High-grade dysplasia (BE-HGD): Biopsies confirm IM with cells showing greater degree of cytologic and architectural alterations of dysplasia than LGD but without overt neoplastic features. Over 40% of the patients would progress to EAC and thus the current recommendations would be to recommend BET in these patients.⁴
• Esophageal adenocarcinoma (EAC): Biopsies demonstrate neoplasia. If the neoplastic changes are limited to the mucosa (T1a) on endoscopic ultrasound or cross-sectional imaging, then BET is suggested. If there is involvement of submucosa, then depending on the depth of invasion, absence of high-risk features (poor differentiation, lymphovascular invasion), BET can be considered as an alternative to esophagectomy.

Lesion Detection on Endoscopy

Data from large population-based studies with at least 3 years of follow-up reported that 58%-66% of EAC detected during endoscopy were diagnosed within 1 year of an index Barrett’s esophagus screening endoscopy, or post-endoscopy Barrett’s neoplasia, and were considered likely to have been missed during index endoscopy.⁵ This underscores the importance of careful and systematic endoscopic examination during an upper endoscopy.

Studies have also demonstrated that longer examination time was associated with significantly higher detection of HGD/EAC.^6,7 Careful examination of the tubular esophagus and gastroesophageal junction (GEJ) should be performed in forward and retroflexed views looking for any subtle areas of nodularity, loop distortion, variability in vascular patterns, mucosal changes concerning for dysplasia or neoplasia. Use of high-definition white light endoscopy (HD-WLE) and virtual chromoendoscopy techniques such as narrow banding imaging (NBI) or blue laser imaging (BLI) are currently recommended in the guidelines.² Spray chromoendoscopy using acetic acid can also be utilized. Another exciting development is the use of artificial intelligence (AI) in detecting and diagnosing BE associated lesions and neoplasia.
 

Barrett’s Endoscopic Therapy (BET)

Patients with visible lesions, dysplasia, or early EAC are candidates for BET (Table 1).

BET involves resective and ablative modalities. The resective modalities include endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) and are the modalities of choice for nodular or raised lesions.

EMR involves endoscopic resection of abnormal mucosa using either lift-assisted technique or multi-band ligation (Figure 1).

ESD, on the other hand, involves submucosal dissection and perimeter resection of the lesion, thus providing the advantage of an en-bloc resection. In a recent randomized controlled trial (RCT) of 40 patients undergoing ESD vs EMR for HGD/EAC, ESD was better for curative resection (R0) (58%) compared with EMR (12%); however, the remission rates at 3 months were comparable with two perforations reported in the ESD group while there were no complications in the EMR group.⁸

There is an apparent learning curve when it comes to these advanced techniques, and with more experience, we are seeing comparable results for both these modalities. However, given the complexity and time required for the procedure, current practices typically involve preserving ESD for lesions > 2 cm, those having a likelihood of cancer in the superficial submucosa, or those that EMR cannot remove due to underlying fibrosis or post-EMR recurrence.

University of Kansas Health System

Barrett’s Refractory to Endoscopic Therapy

Failure of BET is defined as persistent columnar lined epithelium (intestinal metaplasia) with inadequate response, after adequate attempts at endoscopic ablation therapy (after resection) with at least four ablation sessions.¹³ If encountered, special attention must be given to check compliance with proton pump inhibitors (PPIs), previous incomplete resection, and presence of large hiatal hernia. If CE-IM is not achieved after multiple sessions, change of ablative modality is typically considered. In addition, careful examination for visible lesions should be performed and even if a small one is noted, this should be first resected prior to application of any ablative therapy.

University of Kansas Health System

Currently there are no guideline recommendations regarding the preference of one endoscopic modality over another or consideration of potential endoscopic or surgical fundoplication. These modalities primarily rely on technologies available at an institution and the preference of a provider based on their training and experience. Most studies indicate 1-3 sessions (~ 3 months apart) of ablative treatment before achieving CE-IM.
 

Success and Adverse Events of BET

In a recent real-world study of over 27,000 patients with dysplastic BE, 5295 underwent BET. Analysis showed that patients with HGD/EAC who had BET had a significantly lower 3-year mortality (HGD: RR, 0.59; 95%CI, 0.49-0.71; EAC: RR, 0.53; 95% CI, 0.44-0.65) compared with those who did not undergo BET. Esophageal strictures were the most common adverse event and were noted in 6.5%, followed by chest pain (1.8%), upper GI bleeding (0.47%), and esophageal perforation (0.2%).¹⁴

In general, adverse events can be divided into immediate and delayed adverse events. Immediate adverse events typically involve bleeding and perforation that can occur during or shortly after the procedure. These are reported at higher rates with resective modalities compared with ablative therapies. Standard endoscopic techniques involving coagulation grasper or clips can be used to achieve hemostasis. Endoscopic suturing devices offer the ability to contain any perforation. The need for surgical intervention is small and limited to adverse events not detected during the procedure.

Delayed adverse events such as stricture and stenosis are higher for resective modalities (up to 30%), especially when involving more significant than 75% of the esophageal circumference. Post-procedural pain/dysphagia is most common after ablative therapies. Dysphagia reported after any endoscopic therapy should be promptly evaluated, and sequential dilation until the goal esophageal lumen is achieved should be performed every 2-4 weeks.
 

Recurrences and Surveillance After BET

What is established is that recurrences can occur and may be subtle, therefore detailed endoscopic surveillance is required. In a prospective study, recurrence rates of 15%-16% for IM and 3%-5% for any dysplasia were reported, with the majority being in the first 2 years after achieving CE-IM.¹⁵ A systematic review of 21 studies looking at the location of recurrences suggested that the majority (56%) occur in the distal esophagus. Of those that occur in the esophagus, about 80% of them were in the distal 2 cm of the esophagus and only 50% of the recurrences were visible recurrences, thus reiterating the importance of meticulous examination and systematic biopsies.¹⁶

On the contrary, a recent single-center study of 217 patients who had achieved CE-IM with 5.5 years of follow-up demonstrated a 26% and 8% recurrence of IM and dysplasia, respectively. One hundred percent of the recurrence in the esophagus was reported as visible.¹⁷ Therefore, follow-up endoscopy surveillance protocol after CE-IM should still involve meticulous examination, biopsy of visible lesions, and systematic biopsies for non-visible lesions from the original BE segment, similar to those patients who have not needed BET.

Current guidelines based on expert consensus and evidence recommend surveillance after CE-IM based on original most advanced histology:²

1. LGD: 1 year, 3 years, and every 2 years after that.

2. HGD/EAC: 3 months, 6 months, 12 months, and annually after that.

There is no clear guideline on when to stop surveillance since the longest available follow-up is around 10 years, and recurrences are still detected. A potential surveillance endpoint may be based on age and comorbidities, especially those that would preclude a patient from being a candidate for BET.
 

When Should a Patient Be Referred?

BE patients with visible lesions and/or dysplastic changes in the biopsy who would require BET should be considered for referral to high-volume centers. Studies have shown higher success for CE-IM and lower rates of adverse events and recurrences in these patients managed at expert centers. The presence of a multidisciplinary team involving pathologists, surgeons, and oncologists is critical and offers a timely opportunity in case of need for a high-risk patient.

Conclusion

BE is a precursor to EAC, with rising incidence and poor 5-year survival. Endoscopic diagnosis is the gold standard and requires a high-quality examination and biopsies. Based on histopathology, a systematic surveillance and BET plan should be performed to achieve CE-IM in patients with dysplasia. Once CE-IM is achieved, regular surveillance should be performed with careful attention to recurrences and complications from the BET modalities.

Dr. Srinivasan and Dr. Sharma are based at the University of Kansas Medical Center, Kansas City, Kansas, and the Kansas City Veterans Affairs Medical Center, Kansas City, Missouri. Dr. Srinivasan has no relevant disclosures. Dr. Sharma disclosed research grants from ERBE, Ironwood Pharmaceuticals, Olympus, and Medtronic. He has served as a consultant for Takeda, Samsung Bioepis, Olympus, and Lumendi, and reports other funding from Medtronic, Fujifilm Medical Systems USA, and Salix.

References

1. Holmberg D, et al. Incidence and mortality in upper gastrointestinal cancer after negative endoscopy for gastroesophageal reflux disease. Gastroenterology. 2022;162(2):431-438.e4.

2. Shaheen NJ, et al. Diagnosis and management of Barrett’s esophagus: An updated ACG guideline. Am J Gastroenterol. 2022 Apr;117(4):559-587.

3. Pech O, et al. Inter-observer variability in the diagnosis of low-grade dysplasia in pathologists: A comparison between experienced and inexperienced pathologists. Gastrointest Endosc. 2006 Apr;63(5):AB130.

4. Krishnamoorthi R, et al. Factors associated with progression of Barrett’s esophagus: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018 Jul;16(7):1046-1055.e8.

5. Visrodia K, et al. Magnitude of missed esophageal adenocarcinoma after Barrett’s esophagus diagnosis: A systematic review and meta-analysis. Gastroenterology. 2016 Mar;150(3):599-607.e7; quiz e14-5.

6. Perisetti A, Sharma P. Tips for improving the identification of neoplastic visible lesions in Barrett’s esophagus. Gastrointest Endosc. 2023 Feb;97(2):248-250.

7. Gupta N, et al. Longer inspection time is associated with increased detection of high-grade dysplasia and esophageal adenocarcinoma in Barrett’s esophagus. Gastrointest Endosc. 2012 Sep;76(3):531-538.

8. Terheggen G, et al. A randomised trial of endoscopic submucosal dissection versus endoscopic mucosal resection for early Barrett’s neoplasia. Gut. 2017 May;66(5):783-793.

9. Wolfson P, et al. Endoscopic eradication therapy for Barrett’s esophagus-related neoplasia: A final 10-year report from the UK National HALO Radiofrequency Ablation Registry. Gastrointest Endosc. 2022 Aug;96(2):223-233.

10. Rösch T, et al. 1151 Multicenter feasibility study of combined injection and argon plasma coagulation (hybrid-APC) in the ablation therapy of neoplastic Barrett esophagus. Gastrointest Endosc. 2017;85(5):AB154.

11. Knabe M, et al. Radiofrequency ablation versus hybrid argon plasma coagulation in Barrett’s esophagus: A prospective randomised trial. Surg Endosc. 2023;37(10):7803-7811.

12. Van Munster SN, et al. Radiofrequency vapor ablation for Barrett’s esophagus: Feasibility, safety, and proof of concept in a stepwise study with in vitro, animal, and the first in-human application. Endoscopy. 2021 Nov;53(11):1162-1168.

13. Emura F, et al. Rio de Janeiro global consensus on landmarks, definitions, and classifications in Barrett’s esophagus: World Endoscopy Organization Delphi study. Gastroenterology. 2022 Jul;163(1):84-96.e2.

14. Singh RR, et al. Real-world evidence of safety and effectiveness of Barrett’s endoscopic therapy. Gastrointest Endosc. 2023 Aug;98(2):155-161.e1.

15. Wani S, et al. Recurrence Is rare following complete eradication of intestinal metaplasia in patients with Barrett’s esophagus and peaks at 18 months. Clin Gastroenterol Hepatol. 2020 Oct;18(11):2609-2617.e2.

16. Duvvuri A, et al. Mo1273 Location and pattern of recurrences in patients with Barrett’s esophagus after endoscopic therapy: A systematic review and critical analysis of the published literature. Gastrointest Endosc. 2020;91(6):AB410-1.

17. He T, et al. Location and appearance of dysplastic Barrett’s esophagus recurrence after endoscopic eradication therapy: No additional yield from random biopsy sampling neosquamous mucosa. Gastrointest Endosc. 2023 Nov;98(5):722-732.

Introduction

The treatment of benign gallbladder disease has changed substantially in the past decade, but this represents only a snapshot in the evolutionary history of the management of this organ. What began as a problem managed exclusively by open cholecystectomy (CCY) transitioned into a race toward minimally invasive approaches in the 1980s, with advances from gastroenterology, surgery, and radiology.

The opening strides were made in 1980 with the first description of percutaneous cholecystostomy (PC) by Dr. R.W. Radder.¹ Shortly thereafter, in 1984, Dr. Richard Kozarek first reported the feasibility of selective cystic duct cannulation during endoscopic retrograde cholangiopancreatography (ERCP).² Subsequent stenting for the treatment of acute cholecystitis (endoscopic transpapillary gallbladder drainage, ET-GBD) was then reported by Tamada et. al. in 1991.³ Not to be outdone, the first laparoscopic cholecystectomy (LC) was completed by Dr. Med Erich Mühe of Germany in 1985.⁴ More recently, with the expansion of interventional endoscopic ultrasound (EUS), the first transmural EUS-guided gallbladder drainage (EUS-GBD) was described by Dr. Baron and Dr. Topazian in 2007.⁵

Techniques & Tips

ET-GBD

• During ERCP, after successful cannulation of the bile duct, attempted wire cannulation of the cystic duct is performed.

A cholangiogram, which clearly delineates the insertion of the cystic duct into the main bile duct, can enhance cannulation success. Rotatable fluoroscopy can facilitate identification.

• After anatomy is clear, wire access is often best achieved using a sphincterotome or stone retrieval (occlusion) balloon.

The balloon, once inflated, can be pulled downward to establish traction on the main bile duct, which can straighten the approach.

• After superficial wire engagement into the cystic duct, the accessory used can be slowly advanced into the cystic duct to stabilize the catheter and then navigate the valves of Heister to reach the gallbladder lumen.

Use of a sphincterotome, which directs toward the patient’s right (most often direction of cystic duct takeoff), is helpful. Angled guidewires are preferable. We often use a 0.035-inch, 260-cm angled hydrophilic wire (GLIDEWIRE; Terumo, Somerset, NJ) to overcome this challenging portion of ET-GBD.

If despite the above maneuvers the guidewire has failed to enter the cystic duct, cholangioscopy can be used to identify the orifice and/or stabilize deep wire cannulation. This is often cumbersome, time consuming, does not always produce success, and requires additional expertise.

• If a stone is encountered that cannot be extracted or traversed by a guidewire, cholangioscopy with electrohydraulic lithotripsy can be pursued.
• After the guidewire has entered the gallbladder, a 5 French or 7 French plastic double pigtail stent is placed. Typical lengths are 9-15 cm.

Some authors prefer to use two side-by-side plastic stents.¹² This has been shown retrospectively to enhance the long term clinical success of ET-GBD but with additional technical difficulty.

• This stent can remain in place indefinitely and need not be exchanged, though it should be removed just prior to CCY if pursued. Alternatively, the surgeon can be alerted to its presence and, if comfortable, it can be removed intraoperatively.

EUS-GBD

• Use of fluoroscopy is optional but can enhance technical success in selected situations.
• Conversion, or internalization, of PC is reasonable and can enhance patient quality of life.¹³
• If the gallbladder wall is not in close apposition to the duodenal (or gastric) wall, consider measuring the distance.

We preferentially use 10-mm diameter by 10-mm saddle length LAMS for EUS-GBD, unless the above distance warrants use of a 15-mm by 15-mm LAMS (AXIOS, Boston Scientific, Marlborough, MA). If the distance is greater than 15 mm, consider searching for an alternative site, using a traditional biliary fully covered self-expandable metal stent (FCSEMS) for longer length, or converting to ET-GBD. Smaller diameter (8 mm) with an 8-mm saddle length can be used as well. The optimal diameter is unknown and also dependent on whether transluminal endoscopic diagnosis or therapy is a consideration.

• If there is difficulty locating the gallbladder, it may be decompressed or small (particularly if PC or a partial CCY has already been performed).

If a cholecystostomy tube is in place, instillation of sterile water via the tube can sometimes improve the target for LAMS placement, though caution should be made to not over-distend the gallbladder. ERCP with placement of a nasobiliary tube into the gallbladder can also serve this purpose and has been previously described.¹⁴

The gallbladder can be punctured with a 19-gauge FNA needle to instill sterile water and distend the gallbladder with the added benefit of being able to pass a guidewire, which may enhance procedural safety in difficult cases. However, success of this technique is contingent on fluid remaining within the gallbladder and not transiting out via the cystic duct. Expedient exchange of the FNA needle for the LAMS device may be necessary.

• Attempt to confirm location within the duodenum prior to puncture, as gastric origins can pose unique ramifications (i.e. potential for partial gastric outlet obstruction, obstruction of LAMS with food debris, etc.).

It can be easy to mistake an unintentional pre-pyloric position for a position within the duodenum since the working channel is behind (proximal to) the echoprobe.

• Turning off Doppler flow prior to advancement of the cautery enhanced LAMS can reduce obscurement of views on entry into the gallbladder. Lack of certainty about entry or misdeployment after presumed entry herald the most challenging aspect of EUS-GBD.

Utilization of a previously placed guidewire or advancement of one preloaded into the LAMS can aid in both enhancing confidence in location and assist with salvage maneuvers, if needed.

• After successful deployment of the LAMS we routinely place a double pigtail plastic stent through it (typically 7 French by 4 cm) to maintain patency. This may also prevent bleeding from the LAMS flange abrading the wall of either lumen.
• We routinely exchange the LAMS for two double pigtail plastic stents (typically 7 French by 4 cm) 4 weeks after initial placement especially when there is a more than modest residual stone burden (data in press). These plastic stents can remain in place indefinitely.

This exchange can be deferred if the patient is not expected to survive until the one-year anniversary of LAMS deployment. After one year the LAMS plastic covering may degrade and pose additional problems.¹⁵

LAMS Misdeployment Salvage Tips

• Salvage techniques can vary from simple to complex.
• If a wire is in place, it can be used to balloon or catheter dilate the tract and place a FCSEMS traversing the gallbladder and duodenal/gastric lumens. A similar approach can be used if the LAMS deployed on only one side (gallbladder or duodenum/stomach) and the other flange is within the peritoneum.
• The most challenging scenario to salvage is if the LAMS is misdeployed or becomes dislodged and no wire is present. This is why the use of a guidewire, even if preloaded into the LAMS and placement is freehand, is essential for EUS-GBD. A potential technique is to balloon dilate the duodenal/gastric defect and drive the endoscope into the peritoneum to reconnect that lumen to the gallbladder defect or LAMS, depending on the site of misdeployment. Doing so requires a high degree of commitment and skill and should not be done casually.
• If uncertainty remains or if misdeployment has occurred and salvage attempts have failed, consider closure of the duodenal/gastric defect and conversion to ET-GBD.

This may both treat the initial procedural indication and assist with what is essentially a large bile leak, which might also require percutaneous therapy for non-surgical management.

• For endoscopists with limited experience at salvage techniques, it is reasonable for the threshold for conversion to be low, assuming experience with and confidence in ET-GBD is high.
• If salvage is successful but ambiguity remains, consider obtaining a cholangiogram via the LAMS to confirm positioning and absence of leak.

Adverse Events

Both ET-GBD and EUS-GBD should be performed by an endoscopist comfortable with their techniques and the management of their adverse events (AEs). Rates for EUS-GBD AEs in patients at high risk for LC were reported in one international multicenter registry to be 15.3% with a 30-day mortality of 9.2%, with a significant predictor of AE being endoscopist experience less than 25 procedures.¹⁶ A meta-analysis also found an overall AE rate of 18.31%, with rates for perforation and stent related AEs (i.e. migration, occlusion, pneumoperitoneum) being 6.71% and 8.16%, respectively.¹⁷ For this reason, we recommend that patients with cholecystitis who are deemed to be poor surgical candidates be transferred to a tertiary referral center with expertise in these approaches. Rates of AEs for ET-GBD are similar to that for standard ERCP, with reported ranges of 5%-10.3%.¹⁰
 

Comparisons Between Techniques

The decision on which technique to utilize for endoscopic management of cholecystitis or symptomatic cholelithiasis depends first and foremost on the expertise and comfort level of the endoscopist. Given the additional training that an advanced endoscopist needs to perform EUS-GBD, combined with the perhaps slightly higher AE rate and permanency of endoscopic cholecystostomy, it is reasonable to proceed with a trial of ET-GBD if confidence is insufficient. However, ET-GBD can certainly be more technically challenging and less effective than EUS-GBD, with lower reported technical and clinical success rates (technical 85.3% vs 93.0%, clinical 95.2% vs 97.3%).¹⁸ Despite this, the rate of recurrence of cholecystitis is similar between ET-GBD and EUS-GBD (4.6% vs 4.2%).¹⁹ As stated above in the Techniques & Tips section, some authors utilize two plastic stents for ET-GBD for this purpose, though with increased technical difficulty. It is important to remember that these numbers, when paired with AE rates, represent the achievements of expert endoscopists.

Discussion with your surgery team is important when deciding modality. If the patient is felt to be a potential candidate for CCY, and EUS-GBD is not being used as a destination therapy, the surgeon may prefer ET-GBD. EUS-GBD may enhance the difficulty of CCY, though at least one study demonstrated that this was no different than PC with similar rates of conversion from LC to open CCY.²⁰ This conversation is most critical for patients who are potential liver transplant candidates. For patients where this is not a consideration there is some evidence to suggest equivalency between LC and EUS-GBD, though certainly EUS-GBD has not yet supplanted LC as the treatment of choice.²¹

While there may eventually be a shift towards EUS-GBD instead of LC in certain patient groups, what is clearer are the advantages of EUS-GBD over PC. One recent meta-analysis revealed that EUS-GBD has significantly favorable odds of overall adverse events (OR 0.43, 95% CI 0.18-1.00), shorter hospital stay (2.76 less days, 95% CI 0.31-5.20 less days), reinterventions (OR 0.15, 95% CI 0.02-0.98), and unplanned readmissions (OR 0.14, 95% CI 0.03-0.70) compared to PC.²² Beyond the data, though, are the emotional and psychological impacts an external drain can have on a patient.
 

Conclusion

When expertise is available, endoscopic treatment of benign gallbladder disease has a definite role but should be undertaken only by those with the experience and skill to safely do so. Decision to proceed, especially with EUS-GBD, should be accompanied by conversation and collaboration with surgical teams. If a patient is under consideration for PC instead of LC, it may be worthwhile to seek consultation with a local center with expertise in EUS-GBD or ET-GBD. The adoption of these techniques is part of the paradigm shift, seen broadly throughout medicine, towards minimally invasive interventions, particularly in advanced endoscopy.
 

Dr. Gilman (X @a_gilman) and Dr. Baron (X @EndoTx) are with the University of North Carolina, Chapel Hill, Division of Gastroenterology & Hepatology. Dr. Gilman has no relevant financial disclosures. Dr. Baron is a consultant and speaker for Ambu, Boston Scientific, Cook Endoscopy, Medtronic, Olympus America, and W.L. Gore.

References

1. Radder RW. Ultrasonically guided percutaneous catheter drainage for gallbladder empyema. Diagn Imaging. 1980;49:330-333.

2. Kozarek RA. Selective cannulation of the cystic duct at time of ERCP. J Clin Gastroenterol. 1984;6:37-40.

3. Tamada K et al. Efficacy of endoscopic retrograde cholecystoendoprosthesis (ERCCE) for cholecystitis. Endoscopy. 1991;23:2-3.

4. Reynolds W. The first laparoscopic cholecystectomy. JSLS. 2001;5:89-94.

5. Baron TH, Topazian MD. Endoscopic transduodenal drainage of the gallbladder: Implications for endoluminal treatment of gallbladder disease. Gastrointest Endosc. 2007 Apr;65(4):735-7. doi: 10.1016/j.gie.2006.07.041.

6. Irani SS et al. Endoscopic ultrasound-guided transluminal gallbladder drainage in patients with acute cholecystitis: A prospective multicenter trial. Ann Surg. 2023 Sep 1;278(3):e556-e562. doi: 10.1097/SLA.0000000000005784.

7. Shen Y et al. Endoscopic ultrasound-guided cholecystostomy for resection of gallbladder polyps with lumen-apposing metal stent. Medicine (Baltimore). 2020 Oct 23;99(43):e22903. doi: 10.1097/MD.0000000000022903.

8. Pang H et al. Endoscopic ultrasound-guided gallbladder endoscopic mucosal resection: A pilot porcine study. Minim Invasive Ther Allied Technol. 2023 Feb;32(1):24-32. doi: 10.1080/13645706.2022.2153228.

9. Imai H et al. EUS-guided gallbladder drainage for rescue treatment of malignant distal biliary obstruction after unsuccessful ERCP. Gastrointest Endosc. 2016 Jul;84(1):147-51. doi: 10.1016/j.gie.2015.12.024.

10. Saumoy M et al. Endoscopic therapies for gallbladder drainage. Gastrointest Endosc. 2021 Oct;94(4):671-84. doi: 10.1016/j.gie.2021.05.031.

11. Van der Merwe SW et al. Therapeutic endoscopic ultrasound: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2022 Feb;54(2):185-205. doi: 10.1055/a-1717-1391.

12. Storm AC et al. Transpapillary gallbladder stent placement for long-term therapy of acute cholecystitis. Gastrointest Endosc. 2021 Oct;94(4):742-8 e1. doi: 10.1016/j.gie.2021.03.025.

13. James TW, Baron TH. Converting percutaneous gallbladder drainage to internal drainage using EUS-guided therapy: A review of current practices and procedures. Endosc Ultrasound. 2018 Mar-Apr;7(2):93-6. doi: 10.4103/eus.eus_110_17.

14. James TW, Baron TH. Transpapillary nasocystic tube placement to allow gallbladder distention for EUS-guided cholecystoduodenostomy. VideoGIE. 2019 Dec;4(12):561-2. doi: 10.1016/j.vgie.2019.08.009.

15. Gilman AJ, Baron TH. Delamination of a lumen-apposing metal stent with tissue ingrowth and stent-in-stent removal. Gastrointest Endosc. 2023 Sep;98(3):451-3. doi: 10.1016/j.gie.2023.04.2087.

16. Teoh AY et al. Outcomes of an international multicenter registry on EUS-guided gallbladder drainage in patients at high risk for cholecystectomy. Endosc Int Open. 2019 Aug;7(8):E964-E973. doi: 10.1055/a-0915-2098.

17. Kalva NR et al. Efficacy and safety of lumen apposing self-expandable metal stents for EUS guided cholecystostomy: A meta-analysis and systematic review. Can J Gastroenterol Hepatol. 2018;2018:7070961. doi: 10.1155/2018/7070961.

18. Khan MA et al. Efficacy and safety of endoscopic gallbladder drainage in acute cholecystitis: Is it better than percutaneous gallbladder drainage? Gastrointest Endosc. 2017 Jan;85(1):76-87 e3. doi: 10.1016/j.gie.2016.06.032.

19. Mohan BP et al. Endoscopic ultrasound-guided gallbladder drainage, transpapillary drainage, or percutaneous drainage in high risk acute cholecystitis patients: a systematic review and comparative meta-analysis. Endoscopy. 2020 Feb;52(2):96-106. doi: 10.1055/a-1020-3932.

20. Jang JW et al. Endoscopic ultrasound-guided transmural and percutaneous transhepatic gallbladder drainage are comparable for acute cholecystitis. Gastroenterology. 2012 Apr;142(4):805-11. doi: 10.1053/j.gastro.2011.12.051.

21. Teoh AYB et al. EUS-guided gallbladder drainage versus laparoscopic cholecystectomy for acute cholecystitis: a propensity score analysis with 1-year follow-up data. Gastrointest Endosc. 2021 Mar;93(3):577-83. doi: 10.1016/j.gie.2020.06.066.

22. Luk SW et al. Endoscopic ultrasound-guided gallbladder drainage versus percutaneous cholecystostomy for high risk surgical patients with acute cholecystitis: a systematic review and meta-analysis. Endoscopy. 2019 Aug;51(8):722-32. doi: 10.1055/a-0929-6603.

Introduction

The treatment of benign gallbladder disease has changed substantially in the past decade, but this represents only a snapshot in the evolutionary history of the management of this organ. What began as a problem managed exclusively by open cholecystectomy (CCY) transitioned into a race toward minimally invasive approaches in the 1980s, with advances from gastroenterology, surgery, and radiology.

The opening strides were made in 1980 with the first description of percutaneous cholecystostomy (PC) by Dr. R.W. Radder.¹ Shortly thereafter, in 1984, Dr. Richard Kozarek first reported the feasibility of selective cystic duct cannulation during endoscopic retrograde cholangiopancreatography (ERCP).² Subsequent stenting for the treatment of acute cholecystitis (endoscopic transpapillary gallbladder drainage, ET-GBD) was then reported by Tamada et. al. in 1991.³ Not to be outdone, the first laparoscopic cholecystectomy (LC) was completed by Dr. Med Erich Mühe of Germany in 1985.⁴ More recently, with the expansion of interventional endoscopic ultrasound (EUS), the first transmural EUS-guided gallbladder drainage (EUS-GBD) was described by Dr. Baron and Dr. Topazian in 2007.⁵

Techniques & Tips

ET-GBD

• During ERCP, after successful cannulation of the bile duct, attempted wire cannulation of the cystic duct is performed.

A cholangiogram, which clearly delineates the insertion of the cystic duct into the main bile duct, can enhance cannulation success. Rotatable fluoroscopy can facilitate identification.

• After anatomy is clear, wire access is often best achieved using a sphincterotome or stone retrieval (occlusion) balloon.

The balloon, once inflated, can be pulled downward to establish traction on the main bile duct, which can straighten the approach.

• After superficial wire engagement into the cystic duct, the accessory used can be slowly advanced into the cystic duct to stabilize the catheter and then navigate the valves of Heister to reach the gallbladder lumen.

Use of a sphincterotome, which directs toward the patient’s right (most often direction of cystic duct takeoff), is helpful. Angled guidewires are preferable. We often use a 0.035-inch, 260-cm angled hydrophilic wire (GLIDEWIRE; Terumo, Somerset, NJ) to overcome this challenging portion of ET-GBD.

If despite the above maneuvers the guidewire has failed to enter the cystic duct, cholangioscopy can be used to identify the orifice and/or stabilize deep wire cannulation. This is often cumbersome, time consuming, does not always produce success, and requires additional expertise.

• If a stone is encountered that cannot be extracted or traversed by a guidewire, cholangioscopy with electrohydraulic lithotripsy can be pursued.
• After the guidewire has entered the gallbladder, a 5 French or 7 French plastic double pigtail stent is placed. Typical lengths are 9-15 cm.

Some authors prefer to use two side-by-side plastic stents.¹² This has been shown retrospectively to enhance the long term clinical success of ET-GBD but with additional technical difficulty.

• This stent can remain in place indefinitely and need not be exchanged, though it should be removed just prior to CCY if pursued. Alternatively, the surgeon can be alerted to its presence and, if comfortable, it can be removed intraoperatively.

EUS-GBD

• Use of fluoroscopy is optional but can enhance technical success in selected situations.
• Conversion, or internalization, of PC is reasonable and can enhance patient quality of life.¹³
• If the gallbladder wall is not in close apposition to the duodenal (or gastric) wall, consider measuring the distance.

We preferentially use 10-mm diameter by 10-mm saddle length LAMS for EUS-GBD, unless the above distance warrants use of a 15-mm by 15-mm LAMS (AXIOS, Boston Scientific, Marlborough, MA). If the distance is greater than 15 mm, consider searching for an alternative site, using a traditional biliary fully covered self-expandable metal stent (FCSEMS) for longer length, or converting to ET-GBD. Smaller diameter (8 mm) with an 8-mm saddle length can be used as well. The optimal diameter is unknown and also dependent on whether transluminal endoscopic diagnosis or therapy is a consideration.

• If there is difficulty locating the gallbladder, it may be decompressed or small (particularly if PC or a partial CCY has already been performed).

If a cholecystostomy tube is in place, instillation of sterile water via the tube can sometimes improve the target for LAMS placement, though caution should be made to not over-distend the gallbladder. ERCP with placement of a nasobiliary tube into the gallbladder can also serve this purpose and has been previously described.¹⁴

The gallbladder can be punctured with a 19-gauge FNA needle to instill sterile water and distend the gallbladder with the added benefit of being able to pass a guidewire, which may enhance procedural safety in difficult cases. However, success of this technique is contingent on fluid remaining within the gallbladder and not transiting out via the cystic duct. Expedient exchange of the FNA needle for the LAMS device may be necessary.

• Attempt to confirm location within the duodenum prior to puncture, as gastric origins can pose unique ramifications (i.e. potential for partial gastric outlet obstruction, obstruction of LAMS with food debris, etc.).

It can be easy to mistake an unintentional pre-pyloric position for a position within the duodenum since the working channel is behind (proximal to) the echoprobe.

• Turning off Doppler flow prior to advancement of the cautery enhanced LAMS can reduce obscurement of views on entry into the gallbladder. Lack of certainty about entry or misdeployment after presumed entry herald the most challenging aspect of EUS-GBD.

Utilization of a previously placed guidewire or advancement of one preloaded into the LAMS can aid in both enhancing confidence in location and assist with salvage maneuvers, if needed.

• After successful deployment of the LAMS we routinely place a double pigtail plastic stent through it (typically 7 French by 4 cm) to maintain patency. This may also prevent bleeding from the LAMS flange abrading the wall of either lumen.
• We routinely exchange the LAMS for two double pigtail plastic stents (typically 7 French by 4 cm) 4 weeks after initial placement especially when there is a more than modest residual stone burden (data in press). These plastic stents can remain in place indefinitely.

This exchange can be deferred if the patient is not expected to survive until the one-year anniversary of LAMS deployment. After one year the LAMS plastic covering may degrade and pose additional problems.¹⁵

LAMS Misdeployment Salvage Tips

• Salvage techniques can vary from simple to complex.
• If a wire is in place, it can be used to balloon or catheter dilate the tract and place a FCSEMS traversing the gallbladder and duodenal/gastric lumens. A similar approach can be used if the LAMS deployed on only one side (gallbladder or duodenum/stomach) and the other flange is within the peritoneum.
• The most challenging scenario to salvage is if the LAMS is misdeployed or becomes dislodged and no wire is present. This is why the use of a guidewire, even if preloaded into the LAMS and placement is freehand, is essential for EUS-GBD. A potential technique is to balloon dilate the duodenal/gastric defect and drive the endoscope into the peritoneum to reconnect that lumen to the gallbladder defect or LAMS, depending on the site of misdeployment. Doing so requires a high degree of commitment and skill and should not be done casually.
• If uncertainty remains or if misdeployment has occurred and salvage attempts have failed, consider closure of the duodenal/gastric defect and conversion to ET-GBD.

This may both treat the initial procedural indication and assist with what is essentially a large bile leak, which might also require percutaneous therapy for non-surgical management.

• For endoscopists with limited experience at salvage techniques, it is reasonable for the threshold for conversion to be low, assuming experience with and confidence in ET-GBD is high.
• If salvage is successful but ambiguity remains, consider obtaining a cholangiogram via the LAMS to confirm positioning and absence of leak.

Adverse Events

Both ET-GBD and EUS-GBD should be performed by an endoscopist comfortable with their techniques and the management of their adverse events (AEs). Rates for EUS-GBD AEs in patients at high risk for LC were reported in one international multicenter registry to be 15.3% with a 30-day mortality of 9.2%, with a significant predictor of AE being endoscopist experience less than 25 procedures.¹⁶ A meta-analysis also found an overall AE rate of 18.31%, with rates for perforation and stent related AEs (i.e. migration, occlusion, pneumoperitoneum) being 6.71% and 8.16%, respectively.¹⁷ For this reason, we recommend that patients with cholecystitis who are deemed to be poor surgical candidates be transferred to a tertiary referral center with expertise in these approaches. Rates of AEs for ET-GBD are similar to that for standard ERCP, with reported ranges of 5%-10.3%.¹⁰
 

Comparisons Between Techniques

The decision on which technique to utilize for endoscopic management of cholecystitis or symptomatic cholelithiasis depends first and foremost on the expertise and comfort level of the endoscopist. Given the additional training that an advanced endoscopist needs to perform EUS-GBD, combined with the perhaps slightly higher AE rate and permanency of endoscopic cholecystostomy, it is reasonable to proceed with a trial of ET-GBD if confidence is insufficient. However, ET-GBD can certainly be more technically challenging and less effective than EUS-GBD, with lower reported technical and clinical success rates (technical 85.3% vs 93.0%, clinical 95.2% vs 97.3%).¹⁸ Despite this, the rate of recurrence of cholecystitis is similar between ET-GBD and EUS-GBD (4.6% vs 4.2%).¹⁹ As stated above in the Techniques & Tips section, some authors utilize two plastic stents for ET-GBD for this purpose, though with increased technical difficulty. It is important to remember that these numbers, when paired with AE rates, represent the achievements of expert endoscopists.

Discussion with your surgery team is important when deciding modality. If the patient is felt to be a potential candidate for CCY, and EUS-GBD is not being used as a destination therapy, the surgeon may prefer ET-GBD. EUS-GBD may enhance the difficulty of CCY, though at least one study demonstrated that this was no different than PC with similar rates of conversion from LC to open CCY.²⁰ This conversation is most critical for patients who are potential liver transplant candidates. For patients where this is not a consideration there is some evidence to suggest equivalency between LC and EUS-GBD, though certainly EUS-GBD has not yet supplanted LC as the treatment of choice.²¹

While there may eventually be a shift towards EUS-GBD instead of LC in certain patient groups, what is clearer are the advantages of EUS-GBD over PC. One recent meta-analysis revealed that EUS-GBD has significantly favorable odds of overall adverse events (OR 0.43, 95% CI 0.18-1.00), shorter hospital stay (2.76 less days, 95% CI 0.31-5.20 less days), reinterventions (OR 0.15, 95% CI 0.02-0.98), and unplanned readmissions (OR 0.14, 95% CI 0.03-0.70) compared to PC.²² Beyond the data, though, are the emotional and psychological impacts an external drain can have on a patient.
 

Conclusion

When expertise is available, endoscopic treatment of benign gallbladder disease has a definite role but should be undertaken only by those with the experience and skill to safely do so. Decision to proceed, especially with EUS-GBD, should be accompanied by conversation and collaboration with surgical teams. If a patient is under consideration for PC instead of LC, it may be worthwhile to seek consultation with a local center with expertise in EUS-GBD or ET-GBD. The adoption of these techniques is part of the paradigm shift, seen broadly throughout medicine, towards minimally invasive interventions, particularly in advanced endoscopy.
 

Dr. Gilman (X @a_gilman) and Dr. Baron (X @EndoTx) are with the University of North Carolina, Chapel Hill, Division of Gastroenterology & Hepatology. Dr. Gilman has no relevant financial disclosures. Dr. Baron is a consultant and speaker for Ambu, Boston Scientific, Cook Endoscopy, Medtronic, Olympus America, and W.L. Gore.

References

1. Radder RW. Ultrasonically guided percutaneous catheter drainage for gallbladder empyema. Diagn Imaging. 1980;49:330-333.

2. Kozarek RA. Selective cannulation of the cystic duct at time of ERCP. J Clin Gastroenterol. 1984;6:37-40.

3. Tamada K et al. Efficacy of endoscopic retrograde cholecystoendoprosthesis (ERCCE) for cholecystitis. Endoscopy. 1991;23:2-3.

4. Reynolds W. The first laparoscopic cholecystectomy. JSLS. 2001;5:89-94.

5. Baron TH, Topazian MD. Endoscopic transduodenal drainage of the gallbladder: Implications for endoluminal treatment of gallbladder disease. Gastrointest Endosc. 2007 Apr;65(4):735-7. doi: 10.1016/j.gie.2006.07.041.

6. Irani SS et al. Endoscopic ultrasound-guided transluminal gallbladder drainage in patients with acute cholecystitis: A prospective multicenter trial. Ann Surg. 2023 Sep 1;278(3):e556-e562. doi: 10.1097/SLA.0000000000005784.

7. Shen Y et al. Endoscopic ultrasound-guided cholecystostomy for resection of gallbladder polyps with lumen-apposing metal stent. Medicine (Baltimore). 2020 Oct 23;99(43):e22903. doi: 10.1097/MD.0000000000022903.

8. Pang H et al. Endoscopic ultrasound-guided gallbladder endoscopic mucosal resection: A pilot porcine study. Minim Invasive Ther Allied Technol. 2023 Feb;32(1):24-32. doi: 10.1080/13645706.2022.2153228.

9. Imai H et al. EUS-guided gallbladder drainage for rescue treatment of malignant distal biliary obstruction after unsuccessful ERCP. Gastrointest Endosc. 2016 Jul;84(1):147-51. doi: 10.1016/j.gie.2015.12.024.

10. Saumoy M et al. Endoscopic therapies for gallbladder drainage. Gastrointest Endosc. 2021 Oct;94(4):671-84. doi: 10.1016/j.gie.2021.05.031.

11. Van der Merwe SW et al. Therapeutic endoscopic ultrasound: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2022 Feb;54(2):185-205. doi: 10.1055/a-1717-1391.

12. Storm AC et al. Transpapillary gallbladder stent placement for long-term therapy of acute cholecystitis. Gastrointest Endosc. 2021 Oct;94(4):742-8 e1. doi: 10.1016/j.gie.2021.03.025.

13. James TW, Baron TH. Converting percutaneous gallbladder drainage to internal drainage using EUS-guided therapy: A review of current practices and procedures. Endosc Ultrasound. 2018 Mar-Apr;7(2):93-6. doi: 10.4103/eus.eus_110_17.

14. James TW, Baron TH. Transpapillary nasocystic tube placement to allow gallbladder distention for EUS-guided cholecystoduodenostomy. VideoGIE. 2019 Dec;4(12):561-2. doi: 10.1016/j.vgie.2019.08.009.

15. Gilman AJ, Baron TH. Delamination of a lumen-apposing metal stent with tissue ingrowth and stent-in-stent removal. Gastrointest Endosc. 2023 Sep;98(3):451-3. doi: 10.1016/j.gie.2023.04.2087.

16. Teoh AY et al. Outcomes of an international multicenter registry on EUS-guided gallbladder drainage in patients at high risk for cholecystectomy. Endosc Int Open. 2019 Aug;7(8):E964-E973. doi: 10.1055/a-0915-2098.

17. Kalva NR et al. Efficacy and safety of lumen apposing self-expandable metal stents for EUS guided cholecystostomy: A meta-analysis and systematic review. Can J Gastroenterol Hepatol. 2018;2018:7070961. doi: 10.1155/2018/7070961.

18. Khan MA et al. Efficacy and safety of endoscopic gallbladder drainage in acute cholecystitis: Is it better than percutaneous gallbladder drainage? Gastrointest Endosc. 2017 Jan;85(1):76-87 e3. doi: 10.1016/j.gie.2016.06.032.

19. Mohan BP et al. Endoscopic ultrasound-guided gallbladder drainage, transpapillary drainage, or percutaneous drainage in high risk acute cholecystitis patients: a systematic review and comparative meta-analysis. Endoscopy. 2020 Feb;52(2):96-106. doi: 10.1055/a-1020-3932.

20. Jang JW et al. Endoscopic ultrasound-guided transmural and percutaneous transhepatic gallbladder drainage are comparable for acute cholecystitis. Gastroenterology. 2012 Apr;142(4):805-11. doi: 10.1053/j.gastro.2011.12.051.

21. Teoh AYB et al. EUS-guided gallbladder drainage versus laparoscopic cholecystectomy for acute cholecystitis: a propensity score analysis with 1-year follow-up data. Gastrointest Endosc. 2021 Mar;93(3):577-83. doi: 10.1016/j.gie.2020.06.066.

22. Luk SW et al. Endoscopic ultrasound-guided gallbladder drainage versus percutaneous cholecystostomy for high risk surgical patients with acute cholecystitis: a systematic review and meta-analysis. Endoscopy. 2019 Aug;51(8):722-32. doi: 10.1055/a-0929-6603.

Introduction

The treatment of benign gallbladder disease has changed substantially in the past decade, but this represents only a snapshot in the evolutionary history of the management of this organ. What began as a problem managed exclusively by open cholecystectomy (CCY) transitioned into a race toward minimally invasive approaches in the 1980s, with advances from gastroenterology, surgery, and radiology.

The opening strides were made in 1980 with the first description of percutaneous cholecystostomy (PC) by Dr. R.W. Radder.¹ Shortly thereafter, in 1984, Dr. Richard Kozarek first reported the feasibility of selective cystic duct cannulation during endoscopic retrograde cholangiopancreatography (ERCP).² Subsequent stenting for the treatment of acute cholecystitis (endoscopic transpapillary gallbladder drainage, ET-GBD) was then reported by Tamada et. al. in 1991.³ Not to be outdone, the first laparoscopic cholecystectomy (LC) was completed by Dr. Med Erich Mühe of Germany in 1985.⁴ More recently, with the expansion of interventional endoscopic ultrasound (EUS), the first transmural EUS-guided gallbladder drainage (EUS-GBD) was described by Dr. Baron and Dr. Topazian in 2007.⁵

Techniques & Tips

ET-GBD

• During ERCP, after successful cannulation of the bile duct, attempted wire cannulation of the cystic duct is performed.

A cholangiogram, which clearly delineates the insertion of the cystic duct into the main bile duct, can enhance cannulation success. Rotatable fluoroscopy can facilitate identification.

• After anatomy is clear, wire access is often best achieved using a sphincterotome or stone retrieval (occlusion) balloon.

The balloon, once inflated, can be pulled downward to establish traction on the main bile duct, which can straighten the approach.

• After superficial wire engagement into the cystic duct, the accessory used can be slowly advanced into the cystic duct to stabilize the catheter and then navigate the valves of Heister to reach the gallbladder lumen.

Use of a sphincterotome, which directs toward the patient’s right (most often direction of cystic duct takeoff), is helpful. Angled guidewires are preferable. We often use a 0.035-inch, 260-cm angled hydrophilic wire (GLIDEWIRE; Terumo, Somerset, NJ) to overcome this challenging portion of ET-GBD.

If despite the above maneuvers the guidewire has failed to enter the cystic duct, cholangioscopy can be used to identify the orifice and/or stabilize deep wire cannulation. This is often cumbersome, time consuming, does not always produce success, and requires additional expertise.

• If a stone is encountered that cannot be extracted or traversed by a guidewire, cholangioscopy with electrohydraulic lithotripsy can be pursued.
• After the guidewire has entered the gallbladder, a 5 French or 7 French plastic double pigtail stent is placed. Typical lengths are 9-15 cm.

Some authors prefer to use two side-by-side plastic stents.¹² This has been shown retrospectively to enhance the long term clinical success of ET-GBD but with additional technical difficulty.

• This stent can remain in place indefinitely and need not be exchanged, though it should be removed just prior to CCY if pursued. Alternatively, the surgeon can be alerted to its presence and, if comfortable, it can be removed intraoperatively.

EUS-GBD

• Use of fluoroscopy is optional but can enhance technical success in selected situations.
• Conversion, or internalization, of PC is reasonable and can enhance patient quality of life.¹³
• If the gallbladder wall is not in close apposition to the duodenal (or gastric) wall, consider measuring the distance.

We preferentially use 10-mm diameter by 10-mm saddle length LAMS for EUS-GBD, unless the above distance warrants use of a 15-mm by 15-mm LAMS (AXIOS, Boston Scientific, Marlborough, MA). If the distance is greater than 15 mm, consider searching for an alternative site, using a traditional biliary fully covered self-expandable metal stent (FCSEMS) for longer length, or converting to ET-GBD. Smaller diameter (8 mm) with an 8-mm saddle length can be used as well. The optimal diameter is unknown and also dependent on whether transluminal endoscopic diagnosis or therapy is a consideration.

• If there is difficulty locating the gallbladder, it may be decompressed or small (particularly if PC or a partial CCY has already been performed).

If a cholecystostomy tube is in place, instillation of sterile water via the tube can sometimes improve the target for LAMS placement, though caution should be made to not over-distend the gallbladder. ERCP with placement of a nasobiliary tube into the gallbladder can also serve this purpose and has been previously described.¹⁴

The gallbladder can be punctured with a 19-gauge FNA needle to instill sterile water and distend the gallbladder with the added benefit of being able to pass a guidewire, which may enhance procedural safety in difficult cases. However, success of this technique is contingent on fluid remaining within the gallbladder and not transiting out via the cystic duct. Expedient exchange of the FNA needle for the LAMS device may be necessary.

• Attempt to confirm location within the duodenum prior to puncture, as gastric origins can pose unique ramifications (i.e. potential for partial gastric outlet obstruction, obstruction of LAMS with food debris, etc.).

It can be easy to mistake an unintentional pre-pyloric position for a position within the duodenum since the working channel is behind (proximal to) the echoprobe.

• Turning off Doppler flow prior to advancement of the cautery enhanced LAMS can reduce obscurement of views on entry into the gallbladder. Lack of certainty about entry or misdeployment after presumed entry herald the most challenging aspect of EUS-GBD.

Utilization of a previously placed guidewire or advancement of one preloaded into the LAMS can aid in both enhancing confidence in location and assist with salvage maneuvers, if needed.

• After successful deployment of the LAMS we routinely place a double pigtail plastic stent through it (typically 7 French by 4 cm) to maintain patency. This may also prevent bleeding from the LAMS flange abrading the wall of either lumen.
• We routinely exchange the LAMS for two double pigtail plastic stents (typically 7 French by 4 cm) 4 weeks after initial placement especially when there is a more than modest residual stone burden (data in press). These plastic stents can remain in place indefinitely.

This exchange can be deferred if the patient is not expected to survive until the one-year anniversary of LAMS deployment. After one year the LAMS plastic covering may degrade and pose additional problems.¹⁵

LAMS Misdeployment Salvage Tips

• Salvage techniques can vary from simple to complex.
• If a wire is in place, it can be used to balloon or catheter dilate the tract and place a FCSEMS traversing the gallbladder and duodenal/gastric lumens. A similar approach can be used if the LAMS deployed on only one side (gallbladder or duodenum/stomach) and the other flange is within the peritoneum.
• The most challenging scenario to salvage is if the LAMS is misdeployed or becomes dislodged and no wire is present. This is why the use of a guidewire, even if preloaded into the LAMS and placement is freehand, is essential for EUS-GBD. A potential technique is to balloon dilate the duodenal/gastric defect and drive the endoscope into the peritoneum to reconnect that lumen to the gallbladder defect or LAMS, depending on the site of misdeployment. Doing so requires a high degree of commitment and skill and should not be done casually.
• If uncertainty remains or if misdeployment has occurred and salvage attempts have failed, consider closure of the duodenal/gastric defect and conversion to ET-GBD.

This may both treat the initial procedural indication and assist with what is essentially a large bile leak, which might also require percutaneous therapy for non-surgical management.

• For endoscopists with limited experience at salvage techniques, it is reasonable for the threshold for conversion to be low, assuming experience with and confidence in ET-GBD is high.
• If salvage is successful but ambiguity remains, consider obtaining a cholangiogram via the LAMS to confirm positioning and absence of leak.

Adverse Events

Both ET-GBD and EUS-GBD should be performed by an endoscopist comfortable with their techniques and the management of their adverse events (AEs). Rates for EUS-GBD AEs in patients at high risk for LC were reported in one international multicenter registry to be 15.3% with a 30-day mortality of 9.2%, with a significant predictor of AE being endoscopist experience less than 25 procedures.¹⁶ A meta-analysis also found an overall AE rate of 18.31%, with rates for perforation and stent related AEs (i.e. migration, occlusion, pneumoperitoneum) being 6.71% and 8.16%, respectively.¹⁷ For this reason, we recommend that patients with cholecystitis who are deemed to be poor surgical candidates be transferred to a tertiary referral center with expertise in these approaches. Rates of AEs for ET-GBD are similar to that for standard ERCP, with reported ranges of 5%-10.3%.¹⁰
 

Comparisons Between Techniques

The decision on which technique to utilize for endoscopic management of cholecystitis or symptomatic cholelithiasis depends first and foremost on the expertise and comfort level of the endoscopist. Given the additional training that an advanced endoscopist needs to perform EUS-GBD, combined with the perhaps slightly higher AE rate and permanency of endoscopic cholecystostomy, it is reasonable to proceed with a trial of ET-GBD if confidence is insufficient. However, ET-GBD can certainly be more technically challenging and less effective than EUS-GBD, with lower reported technical and clinical success rates (technical 85.3% vs 93.0%, clinical 95.2% vs 97.3%).¹⁸ Despite this, the rate of recurrence of cholecystitis is similar between ET-GBD and EUS-GBD (4.6% vs 4.2%).¹⁹ As stated above in the Techniques & Tips section, some authors utilize two plastic stents for ET-GBD for this purpose, though with increased technical difficulty. It is important to remember that these numbers, when paired with AE rates, represent the achievements of expert endoscopists.

Discussion with your surgery team is important when deciding modality. If the patient is felt to be a potential candidate for CCY, and EUS-GBD is not being used as a destination therapy, the surgeon may prefer ET-GBD. EUS-GBD may enhance the difficulty of CCY, though at least one study demonstrated that this was no different than PC with similar rates of conversion from LC to open CCY.²⁰ This conversation is most critical for patients who are potential liver transplant candidates. For patients where this is not a consideration there is some evidence to suggest equivalency between LC and EUS-GBD, though certainly EUS-GBD has not yet supplanted LC as the treatment of choice.²¹

While there may eventually be a shift towards EUS-GBD instead of LC in certain patient groups, what is clearer are the advantages of EUS-GBD over PC. One recent meta-analysis revealed that EUS-GBD has significantly favorable odds of overall adverse events (OR 0.43, 95% CI 0.18-1.00), shorter hospital stay (2.76 less days, 95% CI 0.31-5.20 less days), reinterventions (OR 0.15, 95% CI 0.02-0.98), and unplanned readmissions (OR 0.14, 95% CI 0.03-0.70) compared to PC.²² Beyond the data, though, are the emotional and psychological impacts an external drain can have on a patient.
 

Conclusion

When expertise is available, endoscopic treatment of benign gallbladder disease has a definite role but should be undertaken only by those with the experience and skill to safely do so. Decision to proceed, especially with EUS-GBD, should be accompanied by conversation and collaboration with surgical teams. If a patient is under consideration for PC instead of LC, it may be worthwhile to seek consultation with a local center with expertise in EUS-GBD or ET-GBD. The adoption of these techniques is part of the paradigm shift, seen broadly throughout medicine, towards minimally invasive interventions, particularly in advanced endoscopy.
 

Dr. Gilman (X @a_gilman) and Dr. Baron (X @EndoTx) are with the University of North Carolina, Chapel Hill, Division of Gastroenterology & Hepatology. Dr. Gilman has no relevant financial disclosures. Dr. Baron is a consultant and speaker for Ambu, Boston Scientific, Cook Endoscopy, Medtronic, Olympus America, and W.L. Gore.

References

1. Radder RW. Ultrasonically guided percutaneous catheter drainage for gallbladder empyema. Diagn Imaging. 1980;49:330-333.

2. Kozarek RA. Selective cannulation of the cystic duct at time of ERCP. J Clin Gastroenterol. 1984;6:37-40.

3. Tamada K et al. Efficacy of endoscopic retrograde cholecystoendoprosthesis (ERCCE) for cholecystitis. Endoscopy. 1991;23:2-3.

4. Reynolds W. The first laparoscopic cholecystectomy. JSLS. 2001;5:89-94.

5. Baron TH, Topazian MD. Endoscopic transduodenal drainage of the gallbladder: Implications for endoluminal treatment of gallbladder disease. Gastrointest Endosc. 2007 Apr;65(4):735-7. doi: 10.1016/j.gie.2006.07.041.

6. Irani SS et al. Endoscopic ultrasound-guided transluminal gallbladder drainage in patients with acute cholecystitis: A prospective multicenter trial. Ann Surg. 2023 Sep 1;278(3):e556-e562. doi: 10.1097/SLA.0000000000005784.

7. Shen Y et al. Endoscopic ultrasound-guided cholecystostomy for resection of gallbladder polyps with lumen-apposing metal stent. Medicine (Baltimore). 2020 Oct 23;99(43):e22903. doi: 10.1097/MD.0000000000022903.

8. Pang H et al. Endoscopic ultrasound-guided gallbladder endoscopic mucosal resection: A pilot porcine study. Minim Invasive Ther Allied Technol. 2023 Feb;32(1):24-32. doi: 10.1080/13645706.2022.2153228.

9. Imai H et al. EUS-guided gallbladder drainage for rescue treatment of malignant distal biliary obstruction after unsuccessful ERCP. Gastrointest Endosc. 2016 Jul;84(1):147-51. doi: 10.1016/j.gie.2015.12.024.

10. Saumoy M et al. Endoscopic therapies for gallbladder drainage. Gastrointest Endosc. 2021 Oct;94(4):671-84. doi: 10.1016/j.gie.2021.05.031.

11. Van der Merwe SW et al. Therapeutic endoscopic ultrasound: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2022 Feb;54(2):185-205. doi: 10.1055/a-1717-1391.

12. Storm AC et al. Transpapillary gallbladder stent placement for long-term therapy of acute cholecystitis. Gastrointest Endosc. 2021 Oct;94(4):742-8 e1. doi: 10.1016/j.gie.2021.03.025.

13. James TW, Baron TH. Converting percutaneous gallbladder drainage to internal drainage using EUS-guided therapy: A review of current practices and procedures. Endosc Ultrasound. 2018 Mar-Apr;7(2):93-6. doi: 10.4103/eus.eus_110_17.

14. James TW, Baron TH. Transpapillary nasocystic tube placement to allow gallbladder distention for EUS-guided cholecystoduodenostomy. VideoGIE. 2019 Dec;4(12):561-2. doi: 10.1016/j.vgie.2019.08.009.

15. Gilman AJ, Baron TH. Delamination of a lumen-apposing metal stent with tissue ingrowth and stent-in-stent removal. Gastrointest Endosc. 2023 Sep;98(3):451-3. doi: 10.1016/j.gie.2023.04.2087.

16. Teoh AY et al. Outcomes of an international multicenter registry on EUS-guided gallbladder drainage in patients at high risk for cholecystectomy. Endosc Int Open. 2019 Aug;7(8):E964-E973. doi: 10.1055/a-0915-2098.

17. Kalva NR et al. Efficacy and safety of lumen apposing self-expandable metal stents for EUS guided cholecystostomy: A meta-analysis and systematic review. Can J Gastroenterol Hepatol. 2018;2018:7070961. doi: 10.1155/2018/7070961.

18. Khan MA et al. Efficacy and safety of endoscopic gallbladder drainage in acute cholecystitis: Is it better than percutaneous gallbladder drainage? Gastrointest Endosc. 2017 Jan;85(1):76-87 e3. doi: 10.1016/j.gie.2016.06.032.

19. Mohan BP et al. Endoscopic ultrasound-guided gallbladder drainage, transpapillary drainage, or percutaneous drainage in high risk acute cholecystitis patients: a systematic review and comparative meta-analysis. Endoscopy. 2020 Feb;52(2):96-106. doi: 10.1055/a-1020-3932.

20. Jang JW et al. Endoscopic ultrasound-guided transmural and percutaneous transhepatic gallbladder drainage are comparable for acute cholecystitis. Gastroenterology. 2012 Apr;142(4):805-11. doi: 10.1053/j.gastro.2011.12.051.

21. Teoh AYB et al. EUS-guided gallbladder drainage versus laparoscopic cholecystectomy for acute cholecystitis: a propensity score analysis with 1-year follow-up data. Gastrointest Endosc. 2021 Mar;93(3):577-83. doi: 10.1016/j.gie.2020.06.066.

22. Luk SW et al. Endoscopic ultrasound-guided gallbladder drainage versus percutaneous cholecystostomy for high risk surgical patients with acute cholecystitis: a systematic review and meta-analysis. Endoscopy. 2019 Aug;51(8):722-32. doi: 10.1055/a-0929-6603.

With an expanding armamentarium of biologics and small molecules, selecting therapies in the treatment of inflammatory bowel disease (IBD) has become increasingly complex. Despite new advances in treatment, head to head clinical trials, which are considered the gold standard when comparing therapies, remain limited. Other comparative effectiveness studies and network meta-analyses are the currently available substitutes to guide decision making.¹

While efficacy is often considered first when choosing a drug, other critical factors play a role in tailoring a treatment plan. This article focuses on key considerations to help guide clinical decision making when treating patients with moderate to severe IBD (Figure 1).

Disease activity versus severity

Both disease activity and disease severity should be considered when evaluating a patient for treatment. Disease activity is a cross-sectional view of one’s signs and symptoms which can vary visit to visit. Standardized indices measure disease activity in both Crohn’s disease (CD) and ulcerative colitis (UC).^2,3 Disease severity encompasses the overall prognosis of disease over time and includes factors such as the presence or absence of high risk features, prior medication exposure, history of surgery, hospitalizations and the impact on quality of life.⁴

NYU Langone Health

To prevent disease complications, the goals of treatment should be aimed at both reducing active symptoms (disease activity) but also healing mucosal inflammation, preventing disease progression (disease severity) and downstream sequelae including cancer, hospitalization or surgery.⁵ Determining the best treatment option takes disease activity and severity into account, in addition to the other key factors listed below (Figure 2).

Extraintestinal manifestations

Inflammation of organs outside of the gastrointestinal tract is common and can occur in up to 50% of patients with IBD.⁶ The most prevalent extraintestinal manifestations (EIMs) involve the skin and joints, which will be the primary focus in this article. We will also focus on treatment options with the most evidence supporting their use. Peripheral arthritis is often associated with intestinal inflammation, and treatment of underlying IBD can simultaneously improve joint symptoms. Conversely, axial spondyloarthritis does not commonly parallel intestinal inflammation. Anti–tumor necrosis factor (TNF) agents including infliximab and adalimumab are effective for the treatment of both peripheral and axial disease.⁶

Ustekinumab, an interleukin (IL)-12/23 inhibitor, may be effective for peripheral arthritis, however is ineffective for the treatment of axial spondyloarthritis.⁶ Janus kinase (JAK) inhibitors which include tofacitinib and upadacitinib are oral small molecules used to treat peripheral and axial spondyloarthritis and have more recently been approved for moderate to severe IBD.^6,7

NYU Langone Health

Erythema nodosum (EN) and pyoderma gangrenosum (PG) are skin manifestations seen in patients with IBD. EN appears as subcutaneous nodules and parallels intestinal inflammation, while PG consists of violaceous, ulcerated plaques, and presents with more significant pain. Anti-TNFs are effective for both EN and PG, with infliximab being the only biologic studied in a randomized control trial of patients with PG.⁸ In addition, small case reports have described some benefit from ustekinumab and upadacitinib in the treatment of PG.^9,10

Safety

The safety of IBD therapies is a key consideration and often the most important factor to patients when choosing a treatment option. It is important to note that untreated disease is associated with significant morbidity, and should be weighed when discussing risks of medications with patients. In general, anti-TNFs and JAK inhibitors may be associated with an increased risk of infection and malignancy, while ustekinumab, vedolizumab, risankizumab and ozanimod offer a more favorable safety profile.¹¹ In large registries and observational studies, infliximab was associated with up to a two times greater risk of serious infection as compared to nonbiologic medications, with the most common infections being pneumonia, sepsis and herpes zoster.¹² JAK inhibitors are associated with an increased risk of herpes zoster infection, with a dose dependent effect seen in the maintenance clinical trials with tofacitinib.⁷

Ozanimod may be associated with atrioventricular conduction delays and bradycardia, however long-term safety data has reported a low incidence of serious cardiac related adverse events.¹³ Overall, though risks of infection may vary with different therapies, other consistent risk factors associated with greater rates of serious infection include prolonged corticosteroid use, combination therapy with thiopurines, and disease severity. Anti-TNFs have also been associated with a somewhat increased risk of lymphoma, increased when used in combination with thiopurines. Reassuringly, however, in patients with a prior history of cancer, anti-TNFs and non-TNF biologics have not been found to increase the risk of new or recurrent cancer.¹⁴

NYU Langone Health

Ultimately, in patients with a prior history of cancer, the choice of biologic or small molecule should be made in collaboration with a patient’s oncologist.
 

Anti-TNF exposure

Anti-TNFs were the first available biologics for the treatment of IBD. After the approval of vedolizumab in 2014, the first non-TNF biologic, many patients enrolled in clinical trials thereafter had already tried and failed anti-TNFs. In general, exposure to anti-TNFs may reduce the efficacy of a future biologic. In patients treated with vedolizumab, endoscopic and clinical outcomes were negatively impacted by prior anti-TNF exposure.¹⁵ However, in VARSITY, a head-to-head clinical trial where 20% of patients with UC were previously exposed to anti-TNFs other than adalimumab, vedolizumab had significantly higher rates of clinical remission and endoscopic improvement compared to adalimumab.¹⁶ Clinical remission rates with tofacitinib were not impacted by exposure to anti-TNF treatment, and similar findings were observed with ustekinumab.^7,17 Risankizumab, a newly approved selective anti-IL23, also does not appear to be impacted by prior anti-TNF exposure by demonstrating similar rates of clinical remission regardless of biologic exposure status.¹⁸ Therefore, in patients with prior history of anti-TNF use, consideration of ustekinumab, risankizumab or JAK inhibitors as second line agents may be more favorable as compared to vedolizumab.

Perianal fistulizing disease

Perianal fistulizing disease can affect up to one-third of patients with CD and significantly impact a patient’s quality of life.¹⁹ The most robust data for the treatment of perianal fistulizing disease includes the use of infliximab with up to one-third of patients on maintenance therapy achieving complete resolution of fistula drainage. While no head-to-head trials compare combination therapy with infliximab plus immunomodulators versus infliximab alone for this indication specifically, one observational study demonstrated higher rates of fistula closure with combination therapy as compared to infliximab mono-therapy.¹⁹ In a post hoc analysis, higher infliximab concentrations at week 14 were associated with greater fistula response and remission rates.²⁰ In patients with perianal disease, ustekinumab and vedolizumab may also be an effective treatment option by promoting resolution of fistula drainage.²¹

More recently, emerging data demonstrate that upadacitinib may be an excellent option as a second-line treatment for perianal disease in patients who have failed anti-TNF therapy. Use of upadacitinib was associated with greater rates of complete resolution of fistula drainage and higher rates of external fistula closure (Figure 2).²² Lastly, as an alternative to medical therapy, mesenchymal stem cell therapy has also shown to improve fistula drainage and improve external fistula openings in patients with CD.²³ Stem cell therapy is only available through clinical trials at this time.
 

Patient preferences

Overall, data are lacking for evaluating patient preferences in treatment options for IBD especially with the recent increase in therapeutic options. One survey demonstrated that patient preferences were most impacted by the possibility of improving abdominal pain, with patients accepting additional risk of treatment side effects in order to reduce their abdominal pain.²⁴ An oral route of administration and improving fatigue and bowel urgency were similarly important to patients. Patient preferences can also be highly variable with some valuing avoidance of corticosteroid use while others valuing avoidance of symptoms or risks of medication side effects and surgery. It is important to tailor the discussion on treatment strategies to each individual patient and inquire about the patient’s lifestyle, medical history, and value system, which may impact their treatment preferences utilizing shared decision making.

Access to treatment including the role of social determinants of health

The expanded therapeutic armamentarium has the potential to help patients achieve the current goals of care in IBD. However, these medications are not available to all patients due to numerous barriers including step therapy payer policies, prohibitive costs, insurance prior authorizations, and the role of social determinants of health and proximity to IBD expertise.²⁵ While clinicians work with patients to determine the best treatment option, more often than not, the decision lies with the insurance payer. Step therapy is the protocol used by insurance companies that requires patients to try a lower-cost medication and fail to respond before they approve the originally requested treatment. This can lead to treatment delays, progression of disease, and disease complications. The option to incorporate the use of biosimilars, currently available for anti-TNFs, and other biologics in the near future, will reduce cost and potentially increase access.²⁶ Additionally, working with a clinical pharmacist to navigate access and utilize patient assistance programs may help overcome cost related barriers to treatment and prevent delays in care.

Socioeconomic status has been shown to impact IBD disease outcomes, and compliance rates in treatment vary depending on race and ethnicity.²⁷ Certain racial and ethnic groups remain vulnerable and may require additional support to achieve treatment goals. For example, disparities in health literacy in patients with IBD have been demonstrated with older black men at risk.²⁸ Additionally, the patient’s proximity to their health care facility may impact treatment options. Most IBD centers are located in metropolitan areas and numerous “IBD deserts” exist, potentially limiting therapies for patients from more remote/rural settings.²⁹ Access to treatment and the interplay of social determinants of health can have a large role in therapy selection.
 

Special considerations: Pregnancy and older adults

Certain patient populations warrant special consideration when approaching treatment strategies. Pregnancy in IBD will not be addressed in full depth in this article, however a key takeaway is that planning is critical and providers should emphasize the importance of steroid-free clinical remission for at least 3 months before conception.³⁰ Additionally, biologic use during pregnancy has not been shown to increase adverse fetal outcomes, thus should be continued to minimize disease flare. Newer novel small molecules are generally avoided during pregnancy due to limited available safety data.

Older adults are the largest growing patient population with IBD. Frailty, or a state of decreased reserve, is more commonly observed in older patients and has been shown to increase adverse events including hospitalization and mortaility.³¹ Ultimately reducing polypharmacy, ensuring adequate nutrition, minimizing corticosteroid exposure and avoiding undertreatment of active IBD are all key in optimizing outcomes in an older patient with IBD.
 

Conclusion

When discussing treatment options with patients with IBD, it is important to individualize care and share the decision-making process with patients. Goals include improving symptoms and quality of life while working to achieve the goal of healing intestinal inflammation. In summary, this article can serve as a guide to clinicians for key factors in decision making when selecting therapies in moderate to severe IBD.

Dr. Holmer is a gastroenterologist with NYU Langone Health specializing in inflammatory bowel disease. Dr. Chang is director of clinical operations for the NYU Langone Health Inflammatory Bowel Disease Center. Dr. Malter is director of education for the Inflammatory Bowel Disease Center at NYU Langone Health and director of the inflammatory bowel disease program at Bellevue Hospital Center. Follow Dr. Holmer on X (formerly Twitter) at @HolmerMd and Dr. Chang @shannonchangmd. Dr. Holmer disclosed affiliations with Pfizer, Bristol Myers Squibb, and AvevoRx. Dr. Chang disclosed affiliations with Pfizer and Bristol Myers Squibb. Dr. Malter disclosed receiving educational grants form Abbvie, Janssen, Pfizer and Takeda, and serving on the advisory boards of AbbVie, Bristol Myers Squibb, Celltrion, Janssen, Merck, and Takeda.

References

1. Chang S et al. Am J Gastroenterol. 2023 Aug 24. doi: 10.14309/ajg.0000000000002485.

2. Harvey RF et al. The Lancet. 1980;1:514.

3. Lewis JD et al. Inflammatory Bowel Diseases. 2008;14:1660-1666.

4. Siegel CA et al. Gut. 2018;67(2):244-54.

5. Peyrin-Biroulet L et al. Am J Gastroenterol. 2015;110:1324-38

6. Rogler G et al. Gastroenterology. 2021;161:1118-32.

7. Sandborn WJ et al. N Engl J Med. 2017;376:1723-36.

8. Brooklyn TN et al. Gut. 2006;55:505-9.

9. Fahmy M et al. Am J Gastroenterol. 2012;107:794-5.

10. Van Eycken L et al. JAAD Case Rep. 2023;37:89-91.

11. Lasa JS et al. Lancet Gastroenterol Hepatol. 2022;7:161-70.

12. Lichtenstein GR et al. Inflamm Bowel Dis. 2018;24:490-501.

13. Long MD et al. Gastroenterology. 2022;162:S-5-S-6.

14. Holmer AK et al. Clin Gastroenterol Hepatol.2023;21:1598-1606.e5.

15. Sands BE et al. Gastroenterology. 2014;147:618-27.e3.

16. Sands BE et al. N Engl J Med. 2019;381:1215-26.

17. Sands BE et al. N Engl J Med. 2019;381:1201-14.

18. D’Haens G et al. Lancet. 2022;399:2015-30.

19. Bouguen G et al. Clin Gastroenterol Hepatol. 2013;11:975-81.e1-4.

20. Papamichael K et al. Am J Gastroenterol. 2021;116:1007-14.

21. Shehab M et al. Inflamm Bowel Dis. 2023;29:367-75.

22. Colombel JF et al. J Crohns Colitis. 2023;17:i620-i623.

23. Garcia-Olmo D et al. Dis Colon Rectum. 2022;65:713-20.

24. Louis E et al. J Crohns Colitis. 2023;17:231-9.

25. Rubin DT et al. Inflamm Bowel Dis. 2017;23:224-32.

26. Gulacsi L et al. Curr Med Chem. 2019;26:259-69.

27. Cai Q et al. BMC Gastroenterol. 2022;22:545.

28. Dos Santos Marques IC et al. Crohns Colitis 360. 2020 Oct;2(4):otaa076.

29. Deepak P et al. Gastroenterology. 2023;165:11-15.

30. Mahadevan U et al. Gastroenterology. 2019;156:1508-24.

31. Faye AS et al. Inflamm Bowel Dis. 2022;28:126-32.

32. Berinstein JA et al. Clin Gastroenterol Hepatol. 2021;19:2112-20.e1.

33. Levine J et al. Gastroenterology. 2023;164:S103-S104.

With an expanding armamentarium of biologics and small molecules, selecting therapies in the treatment of inflammatory bowel disease (IBD) has become increasingly complex. Despite new advances in treatment, head to head clinical trials, which are considered the gold standard when comparing therapies, remain limited. Other comparative effectiveness studies and network meta-analyses are the currently available substitutes to guide decision making.¹

While efficacy is often considered first when choosing a drug, other critical factors play a role in tailoring a treatment plan. This article focuses on key considerations to help guide clinical decision making when treating patients with moderate to severe IBD (Figure 1).

Disease activity versus severity

Both disease activity and disease severity should be considered when evaluating a patient for treatment. Disease activity is a cross-sectional view of one’s signs and symptoms which can vary visit to visit. Standardized indices measure disease activity in both Crohn’s disease (CD) and ulcerative colitis (UC).^2,3 Disease severity encompasses the overall prognosis of disease over time and includes factors such as the presence or absence of high risk features, prior medication exposure, history of surgery, hospitalizations and the impact on quality of life.⁴

NYU Langone Health

To prevent disease complications, the goals of treatment should be aimed at both reducing active symptoms (disease activity) but also healing mucosal inflammation, preventing disease progression (disease severity) and downstream sequelae including cancer, hospitalization or surgery.⁵ Determining the best treatment option takes disease activity and severity into account, in addition to the other key factors listed below (Figure 2).

Extraintestinal manifestations

Inflammation of organs outside of the gastrointestinal tract is common and can occur in up to 50% of patients with IBD.⁶ The most prevalent extraintestinal manifestations (EIMs) involve the skin and joints, which will be the primary focus in this article. We will also focus on treatment options with the most evidence supporting their use. Peripheral arthritis is often associated with intestinal inflammation, and treatment of underlying IBD can simultaneously improve joint symptoms. Conversely, axial spondyloarthritis does not commonly parallel intestinal inflammation. Anti–tumor necrosis factor (TNF) agents including infliximab and adalimumab are effective for the treatment of both peripheral and axial disease.⁶

Ustekinumab, an interleukin (IL)-12/23 inhibitor, may be effective for peripheral arthritis, however is ineffective for the treatment of axial spondyloarthritis.⁶ Janus kinase (JAK) inhibitors which include tofacitinib and upadacitinib are oral small molecules used to treat peripheral and axial spondyloarthritis and have more recently been approved for moderate to severe IBD.^6,7

NYU Langone Health

Erythema nodosum (EN) and pyoderma gangrenosum (PG) are skin manifestations seen in patients with IBD. EN appears as subcutaneous nodules and parallels intestinal inflammation, while PG consists of violaceous, ulcerated plaques, and presents with more significant pain. Anti-TNFs are effective for both EN and PG, with infliximab being the only biologic studied in a randomized control trial of patients with PG.⁸ In addition, small case reports have described some benefit from ustekinumab and upadacitinib in the treatment of PG.^9,10

Safety

The safety of IBD therapies is a key consideration and often the most important factor to patients when choosing a treatment option. It is important to note that untreated disease is associated with significant morbidity, and should be weighed when discussing risks of medications with patients. In general, anti-TNFs and JAK inhibitors may be associated with an increased risk of infection and malignancy, while ustekinumab, vedolizumab, risankizumab and ozanimod offer a more favorable safety profile.¹¹ In large registries and observational studies, infliximab was associated with up to a two times greater risk of serious infection as compared to nonbiologic medications, with the most common infections being pneumonia, sepsis and herpes zoster.¹² JAK inhibitors are associated with an increased risk of herpes zoster infection, with a dose dependent effect seen in the maintenance clinical trials with tofacitinib.⁷

Ozanimod may be associated with atrioventricular conduction delays and bradycardia, however long-term safety data has reported a low incidence of serious cardiac related adverse events.¹³ Overall, though risks of infection may vary with different therapies, other consistent risk factors associated with greater rates of serious infection include prolonged corticosteroid use, combination therapy with thiopurines, and disease severity. Anti-TNFs have also been associated with a somewhat increased risk of lymphoma, increased when used in combination with thiopurines. Reassuringly, however, in patients with a prior history of cancer, anti-TNFs and non-TNF biologics have not been found to increase the risk of new or recurrent cancer.¹⁴

NYU Langone Health

Ultimately, in patients with a prior history of cancer, the choice of biologic or small molecule should be made in collaboration with a patient’s oncologist.
 

Anti-TNF exposure

Anti-TNFs were the first available biologics for the treatment of IBD. After the approval of vedolizumab in 2014, the first non-TNF biologic, many patients enrolled in clinical trials thereafter had already tried and failed anti-TNFs. In general, exposure to anti-TNFs may reduce the efficacy of a future biologic. In patients treated with vedolizumab, endoscopic and clinical outcomes were negatively impacted by prior anti-TNF exposure.¹⁵ However, in VARSITY, a head-to-head clinical trial where 20% of patients with UC were previously exposed to anti-TNFs other than adalimumab, vedolizumab had significantly higher rates of clinical remission and endoscopic improvement compared to adalimumab.¹⁶ Clinical remission rates with tofacitinib were not impacted by exposure to anti-TNF treatment, and similar findings were observed with ustekinumab.^7,17 Risankizumab, a newly approved selective anti-IL23, also does not appear to be impacted by prior anti-TNF exposure by demonstrating similar rates of clinical remission regardless of biologic exposure status.¹⁸ Therefore, in patients with prior history of anti-TNF use, consideration of ustekinumab, risankizumab or JAK inhibitors as second line agents may be more favorable as compared to vedolizumab.

Perianal fistulizing disease

Perianal fistulizing disease can affect up to one-third of patients with CD and significantly impact a patient’s quality of life.¹⁹ The most robust data for the treatment of perianal fistulizing disease includes the use of infliximab with up to one-third of patients on maintenance therapy achieving complete resolution of fistula drainage. While no head-to-head trials compare combination therapy with infliximab plus immunomodulators versus infliximab alone for this indication specifically, one observational study demonstrated higher rates of fistula closure with combination therapy as compared to infliximab mono-therapy.¹⁹ In a post hoc analysis, higher infliximab concentrations at week 14 were associated with greater fistula response and remission rates.²⁰ In patients with perianal disease, ustekinumab and vedolizumab may also be an effective treatment option by promoting resolution of fistula drainage.²¹

More recently, emerging data demonstrate that upadacitinib may be an excellent option as a second-line treatment for perianal disease in patients who have failed anti-TNF therapy. Use of upadacitinib was associated with greater rates of complete resolution of fistula drainage and higher rates of external fistula closure (Figure 2).²² Lastly, as an alternative to medical therapy, mesenchymal stem cell therapy has also shown to improve fistula drainage and improve external fistula openings in patients with CD.²³ Stem cell therapy is only available through clinical trials at this time.
 

Patient preferences

Overall, data are lacking for evaluating patient preferences in treatment options for IBD especially with the recent increase in therapeutic options. One survey demonstrated that patient preferences were most impacted by the possibility of improving abdominal pain, with patients accepting additional risk of treatment side effects in order to reduce their abdominal pain.²⁴ An oral route of administration and improving fatigue and bowel urgency were similarly important to patients. Patient preferences can also be highly variable with some valuing avoidance of corticosteroid use while others valuing avoidance of symptoms or risks of medication side effects and surgery. It is important to tailor the discussion on treatment strategies to each individual patient and inquire about the patient’s lifestyle, medical history, and value system, which may impact their treatment preferences utilizing shared decision making.

Access to treatment including the role of social determinants of health

The expanded therapeutic armamentarium has the potential to help patients achieve the current goals of care in IBD. However, these medications are not available to all patients due to numerous barriers including step therapy payer policies, prohibitive costs, insurance prior authorizations, and the role of social determinants of health and proximity to IBD expertise.²⁵ While clinicians work with patients to determine the best treatment option, more often than not, the decision lies with the insurance payer. Step therapy is the protocol used by insurance companies that requires patients to try a lower-cost medication and fail to respond before they approve the originally requested treatment. This can lead to treatment delays, progression of disease, and disease complications. The option to incorporate the use of biosimilars, currently available for anti-TNFs, and other biologics in the near future, will reduce cost and potentially increase access.²⁶ Additionally, working with a clinical pharmacist to navigate access and utilize patient assistance programs may help overcome cost related barriers to treatment and prevent delays in care.

Socioeconomic status has been shown to impact IBD disease outcomes, and compliance rates in treatment vary depending on race and ethnicity.²⁷ Certain racial and ethnic groups remain vulnerable and may require additional support to achieve treatment goals. For example, disparities in health literacy in patients with IBD have been demonstrated with older black men at risk.²⁸ Additionally, the patient’s proximity to their health care facility may impact treatment options. Most IBD centers are located in metropolitan areas and numerous “IBD deserts” exist, potentially limiting therapies for patients from more remote/rural settings.²⁹ Access to treatment and the interplay of social determinants of health can have a large role in therapy selection.
 

Special considerations: Pregnancy and older adults

Certain patient populations warrant special consideration when approaching treatment strategies. Pregnancy in IBD will not be addressed in full depth in this article, however a key takeaway is that planning is critical and providers should emphasize the importance of steroid-free clinical remission for at least 3 months before conception.³⁰ Additionally, biologic use during pregnancy has not been shown to increase adverse fetal outcomes, thus should be continued to minimize disease flare. Newer novel small molecules are generally avoided during pregnancy due to limited available safety data.

Older adults are the largest growing patient population with IBD. Frailty, or a state of decreased reserve, is more commonly observed in older patients and has been shown to increase adverse events including hospitalization and mortaility.³¹ Ultimately reducing polypharmacy, ensuring adequate nutrition, minimizing corticosteroid exposure and avoiding undertreatment of active IBD are all key in optimizing outcomes in an older patient with IBD.
 

Conclusion

When discussing treatment options with patients with IBD, it is important to individualize care and share the decision-making process with patients. Goals include improving symptoms and quality of life while working to achieve the goal of healing intestinal inflammation. In summary, this article can serve as a guide to clinicians for key factors in decision making when selecting therapies in moderate to severe IBD.

Dr. Holmer is a gastroenterologist with NYU Langone Health specializing in inflammatory bowel disease. Dr. Chang is director of clinical operations for the NYU Langone Health Inflammatory Bowel Disease Center. Dr. Malter is director of education for the Inflammatory Bowel Disease Center at NYU Langone Health and director of the inflammatory bowel disease program at Bellevue Hospital Center. Follow Dr. Holmer on X (formerly Twitter) at @HolmerMd and Dr. Chang @shannonchangmd. Dr. Holmer disclosed affiliations with Pfizer, Bristol Myers Squibb, and AvevoRx. Dr. Chang disclosed affiliations with Pfizer and Bristol Myers Squibb. Dr. Malter disclosed receiving educational grants form Abbvie, Janssen, Pfizer and Takeda, and serving on the advisory boards of AbbVie, Bristol Myers Squibb, Celltrion, Janssen, Merck, and Takeda.

References

1. Chang S et al. Am J Gastroenterol. 2023 Aug 24. doi: 10.14309/ajg.0000000000002485.

2. Harvey RF et al. The Lancet. 1980;1:514.

3. Lewis JD et al. Inflammatory Bowel Diseases. 2008;14:1660-1666.

4. Siegel CA et al. Gut. 2018;67(2):244-54.

5. Peyrin-Biroulet L et al. Am J Gastroenterol. 2015;110:1324-38

6. Rogler G et al. Gastroenterology. 2021;161:1118-32.

7. Sandborn WJ et al. N Engl J Med. 2017;376:1723-36.

8. Brooklyn TN et al. Gut. 2006;55:505-9.

9. Fahmy M et al. Am J Gastroenterol. 2012;107:794-5.

10. Van Eycken L et al. JAAD Case Rep. 2023;37:89-91.

11. Lasa JS et al. Lancet Gastroenterol Hepatol. 2022;7:161-70.

12. Lichtenstein GR et al. Inflamm Bowel Dis. 2018;24:490-501.

13. Long MD et al. Gastroenterology. 2022;162:S-5-S-6.

14. Holmer AK et al. Clin Gastroenterol Hepatol.2023;21:1598-1606.e5.

15. Sands BE et al. Gastroenterology. 2014;147:618-27.e3.

16. Sands BE et al. N Engl J Med. 2019;381:1215-26.

17. Sands BE et al. N Engl J Med. 2019;381:1201-14.

18. D’Haens G et al. Lancet. 2022;399:2015-30.

19. Bouguen G et al. Clin Gastroenterol Hepatol. 2013;11:975-81.e1-4.

20. Papamichael K et al. Am J Gastroenterol. 2021;116:1007-14.

21. Shehab M et al. Inflamm Bowel Dis. 2023;29:367-75.

22. Colombel JF et al. J Crohns Colitis. 2023;17:i620-i623.

23. Garcia-Olmo D et al. Dis Colon Rectum. 2022;65:713-20.

24. Louis E et al. J Crohns Colitis. 2023;17:231-9.

25. Rubin DT et al. Inflamm Bowel Dis. 2017;23:224-32.

26. Gulacsi L et al. Curr Med Chem. 2019;26:259-69.

27. Cai Q et al. BMC Gastroenterol. 2022;22:545.

28. Dos Santos Marques IC et al. Crohns Colitis 360. 2020 Oct;2(4):otaa076.

29. Deepak P et al. Gastroenterology. 2023;165:11-15.

30. Mahadevan U et al. Gastroenterology. 2019;156:1508-24.

31. Faye AS et al. Inflamm Bowel Dis. 2022;28:126-32.

32. Berinstein JA et al. Clin Gastroenterol Hepatol. 2021;19:2112-20.e1.

33. Levine J et al. Gastroenterology. 2023;164:S103-S104.

With an expanding armamentarium of biologics and small molecules, selecting therapies in the treatment of inflammatory bowel disease (IBD) has become increasingly complex. Despite new advances in treatment, head to head clinical trials, which are considered the gold standard when comparing therapies, remain limited. Other comparative effectiveness studies and network meta-analyses are the currently available substitutes to guide decision making.¹

While efficacy is often considered first when choosing a drug, other critical factors play a role in tailoring a treatment plan. This article focuses on key considerations to help guide clinical decision making when treating patients with moderate to severe IBD (Figure 1).

Disease activity versus severity

Both disease activity and disease severity should be considered when evaluating a patient for treatment. Disease activity is a cross-sectional view of one’s signs and symptoms which can vary visit to visit. Standardized indices measure disease activity in both Crohn’s disease (CD) and ulcerative colitis (UC).^2,3 Disease severity encompasses the overall prognosis of disease over time and includes factors such as the presence or absence of high risk features, prior medication exposure, history of surgery, hospitalizations and the impact on quality of life.⁴

NYU Langone Health

To prevent disease complications, the goals of treatment should be aimed at both reducing active symptoms (disease activity) but also healing mucosal inflammation, preventing disease progression (disease severity) and downstream sequelae including cancer, hospitalization or surgery.⁵ Determining the best treatment option takes disease activity and severity into account, in addition to the other key factors listed below (Figure 2).

Extraintestinal manifestations

Inflammation of organs outside of the gastrointestinal tract is common and can occur in up to 50% of patients with IBD.⁶ The most prevalent extraintestinal manifestations (EIMs) involve the skin and joints, which will be the primary focus in this article. We will also focus on treatment options with the most evidence supporting their use. Peripheral arthritis is often associated with intestinal inflammation, and treatment of underlying IBD can simultaneously improve joint symptoms. Conversely, axial spondyloarthritis does not commonly parallel intestinal inflammation. Anti–tumor necrosis factor (TNF) agents including infliximab and adalimumab are effective for the treatment of both peripheral and axial disease.⁶

Ustekinumab, an interleukin (IL)-12/23 inhibitor, may be effective for peripheral arthritis, however is ineffective for the treatment of axial spondyloarthritis.⁶ Janus kinase (JAK) inhibitors which include tofacitinib and upadacitinib are oral small molecules used to treat peripheral and axial spondyloarthritis and have more recently been approved for moderate to severe IBD.^6,7

NYU Langone Health

Erythema nodosum (EN) and pyoderma gangrenosum (PG) are skin manifestations seen in patients with IBD. EN appears as subcutaneous nodules and parallels intestinal inflammation, while PG consists of violaceous, ulcerated plaques, and presents with more significant pain. Anti-TNFs are effective for both EN and PG, with infliximab being the only biologic studied in a randomized control trial of patients with PG.⁸ In addition, small case reports have described some benefit from ustekinumab and upadacitinib in the treatment of PG.^9,10

Safety

The safety of IBD therapies is a key consideration and often the most important factor to patients when choosing a treatment option. It is important to note that untreated disease is associated with significant morbidity, and should be weighed when discussing risks of medications with patients. In general, anti-TNFs and JAK inhibitors may be associated with an increased risk of infection and malignancy, while ustekinumab, vedolizumab, risankizumab and ozanimod offer a more favorable safety profile.¹¹ In large registries and observational studies, infliximab was associated with up to a two times greater risk of serious infection as compared to nonbiologic medications, with the most common infections being pneumonia, sepsis and herpes zoster.¹² JAK inhibitors are associated with an increased risk of herpes zoster infection, with a dose dependent effect seen in the maintenance clinical trials with tofacitinib.⁷

Ozanimod may be associated with atrioventricular conduction delays and bradycardia, however long-term safety data has reported a low incidence of serious cardiac related adverse events.¹³ Overall, though risks of infection may vary with different therapies, other consistent risk factors associated with greater rates of serious infection include prolonged corticosteroid use, combination therapy with thiopurines, and disease severity. Anti-TNFs have also been associated with a somewhat increased risk of lymphoma, increased when used in combination with thiopurines. Reassuringly, however, in patients with a prior history of cancer, anti-TNFs and non-TNF biologics have not been found to increase the risk of new or recurrent cancer.¹⁴

NYU Langone Health

Ultimately, in patients with a prior history of cancer, the choice of biologic or small molecule should be made in collaboration with a patient’s oncologist.
 

Anti-TNF exposure

Anti-TNFs were the first available biologics for the treatment of IBD. After the approval of vedolizumab in 2014, the first non-TNF biologic, many patients enrolled in clinical trials thereafter had already tried and failed anti-TNFs. In general, exposure to anti-TNFs may reduce the efficacy of a future biologic. In patients treated with vedolizumab, endoscopic and clinical outcomes were negatively impacted by prior anti-TNF exposure.¹⁵ However, in VARSITY, a head-to-head clinical trial where 20% of patients with UC were previously exposed to anti-TNFs other than adalimumab, vedolizumab had significantly higher rates of clinical remission and endoscopic improvement compared to adalimumab.¹⁶ Clinical remission rates with tofacitinib were not impacted by exposure to anti-TNF treatment, and similar findings were observed with ustekinumab.^7,17 Risankizumab, a newly approved selective anti-IL23, also does not appear to be impacted by prior anti-TNF exposure by demonstrating similar rates of clinical remission regardless of biologic exposure status.¹⁸ Therefore, in patients with prior history of anti-TNF use, consideration of ustekinumab, risankizumab or JAK inhibitors as second line agents may be more favorable as compared to vedolizumab.

Perianal fistulizing disease

Perianal fistulizing disease can affect up to one-third of patients with CD and significantly impact a patient’s quality of life.¹⁹ The most robust data for the treatment of perianal fistulizing disease includes the use of infliximab with up to one-third of patients on maintenance therapy achieving complete resolution of fistula drainage. While no head-to-head trials compare combination therapy with infliximab plus immunomodulators versus infliximab alone for this indication specifically, one observational study demonstrated higher rates of fistula closure with combination therapy as compared to infliximab mono-therapy.¹⁹ In a post hoc analysis, higher infliximab concentrations at week 14 were associated with greater fistula response and remission rates.²⁰ In patients with perianal disease, ustekinumab and vedolizumab may also be an effective treatment option by promoting resolution of fistula drainage.²¹

More recently, emerging data demonstrate that upadacitinib may be an excellent option as a second-line treatment for perianal disease in patients who have failed anti-TNF therapy. Use of upadacitinib was associated with greater rates of complete resolution of fistula drainage and higher rates of external fistula closure (Figure 2).²² Lastly, as an alternative to medical therapy, mesenchymal stem cell therapy has also shown to improve fistula drainage and improve external fistula openings in patients with CD.²³ Stem cell therapy is only available through clinical trials at this time.
 

Patient preferences

Overall, data are lacking for evaluating patient preferences in treatment options for IBD especially with the recent increase in therapeutic options. One survey demonstrated that patient preferences were most impacted by the possibility of improving abdominal pain, with patients accepting additional risk of treatment side effects in order to reduce their abdominal pain.²⁴ An oral route of administration and improving fatigue and bowel urgency were similarly important to patients. Patient preferences can also be highly variable with some valuing avoidance of corticosteroid use while others valuing avoidance of symptoms or risks of medication side effects and surgery. It is important to tailor the discussion on treatment strategies to each individual patient and inquire about the patient’s lifestyle, medical history, and value system, which may impact their treatment preferences utilizing shared decision making.

Access to treatment including the role of social determinants of health

The expanded therapeutic armamentarium has the potential to help patients achieve the current goals of care in IBD. However, these medications are not available to all patients due to numerous barriers including step therapy payer policies, prohibitive costs, insurance prior authorizations, and the role of social determinants of health and proximity to IBD expertise.²⁵ While clinicians work with patients to determine the best treatment option, more often than not, the decision lies with the insurance payer. Step therapy is the protocol used by insurance companies that requires patients to try a lower-cost medication and fail to respond before they approve the originally requested treatment. This can lead to treatment delays, progression of disease, and disease complications. The option to incorporate the use of biosimilars, currently available for anti-TNFs, and other biologics in the near future, will reduce cost and potentially increase access.²⁶ Additionally, working with a clinical pharmacist to navigate access and utilize patient assistance programs may help overcome cost related barriers to treatment and prevent delays in care.

Socioeconomic status has been shown to impact IBD disease outcomes, and compliance rates in treatment vary depending on race and ethnicity.²⁷ Certain racial and ethnic groups remain vulnerable and may require additional support to achieve treatment goals. For example, disparities in health literacy in patients with IBD have been demonstrated with older black men at risk.²⁸ Additionally, the patient’s proximity to their health care facility may impact treatment options. Most IBD centers are located in metropolitan areas and numerous “IBD deserts” exist, potentially limiting therapies for patients from more remote/rural settings.²⁹ Access to treatment and the interplay of social determinants of health can have a large role in therapy selection.
 

Special considerations: Pregnancy and older adults

Certain patient populations warrant special consideration when approaching treatment strategies. Pregnancy in IBD will not be addressed in full depth in this article, however a key takeaway is that planning is critical and providers should emphasize the importance of steroid-free clinical remission for at least 3 months before conception.³⁰ Additionally, biologic use during pregnancy has not been shown to increase adverse fetal outcomes, thus should be continued to minimize disease flare. Newer novel small molecules are generally avoided during pregnancy due to limited available safety data.

Older adults are the largest growing patient population with IBD. Frailty, or a state of decreased reserve, is more commonly observed in older patients and has been shown to increase adverse events including hospitalization and mortaility.³¹ Ultimately reducing polypharmacy, ensuring adequate nutrition, minimizing corticosteroid exposure and avoiding undertreatment of active IBD are all key in optimizing outcomes in an older patient with IBD.
 

Conclusion

When discussing treatment options with patients with IBD, it is important to individualize care and share the decision-making process with patients. Goals include improving symptoms and quality of life while working to achieve the goal of healing intestinal inflammation. In summary, this article can serve as a guide to clinicians for key factors in decision making when selecting therapies in moderate to severe IBD.

Dr. Holmer is a gastroenterologist with NYU Langone Health specializing in inflammatory bowel disease. Dr. Chang is director of clinical operations for the NYU Langone Health Inflammatory Bowel Disease Center. Dr. Malter is director of education for the Inflammatory Bowel Disease Center at NYU Langone Health and director of the inflammatory bowel disease program at Bellevue Hospital Center. Follow Dr. Holmer on X (formerly Twitter) at @HolmerMd and Dr. Chang @shannonchangmd. Dr. Holmer disclosed affiliations with Pfizer, Bristol Myers Squibb, and AvevoRx. Dr. Chang disclosed affiliations with Pfizer and Bristol Myers Squibb. Dr. Malter disclosed receiving educational grants form Abbvie, Janssen, Pfizer and Takeda, and serving on the advisory boards of AbbVie, Bristol Myers Squibb, Celltrion, Janssen, Merck, and Takeda.

References

1. Chang S et al. Am J Gastroenterol. 2023 Aug 24. doi: 10.14309/ajg.0000000000002485.

2. Harvey RF et al. The Lancet. 1980;1:514.

3. Lewis JD et al. Inflammatory Bowel Diseases. 2008;14:1660-1666.

4. Siegel CA et al. Gut. 2018;67(2):244-54.

5. Peyrin-Biroulet L et al. Am J Gastroenterol. 2015;110:1324-38

6. Rogler G et al. Gastroenterology. 2021;161:1118-32.

7. Sandborn WJ et al. N Engl J Med. 2017;376:1723-36.

8. Brooklyn TN et al. Gut. 2006;55:505-9.

9. Fahmy M et al. Am J Gastroenterol. 2012;107:794-5.

10. Van Eycken L et al. JAAD Case Rep. 2023;37:89-91.

11. Lasa JS et al. Lancet Gastroenterol Hepatol. 2022;7:161-70.

12. Lichtenstein GR et al. Inflamm Bowel Dis. 2018;24:490-501.

13. Long MD et al. Gastroenterology. 2022;162:S-5-S-6.

14. Holmer AK et al. Clin Gastroenterol Hepatol.2023;21:1598-1606.e5.

15. Sands BE et al. Gastroenterology. 2014;147:618-27.e3.

16. Sands BE et al. N Engl J Med. 2019;381:1215-26.

17. Sands BE et al. N Engl J Med. 2019;381:1201-14.

18. D’Haens G et al. Lancet. 2022;399:2015-30.

19. Bouguen G et al. Clin Gastroenterol Hepatol. 2013;11:975-81.e1-4.

20. Papamichael K et al. Am J Gastroenterol. 2021;116:1007-14.

21. Shehab M et al. Inflamm Bowel Dis. 2023;29:367-75.

22. Colombel JF et al. J Crohns Colitis. 2023;17:i620-i623.

23. Garcia-Olmo D et al. Dis Colon Rectum. 2022;65:713-20.

24. Louis E et al. J Crohns Colitis. 2023;17:231-9.

25. Rubin DT et al. Inflamm Bowel Dis. 2017;23:224-32.

26. Gulacsi L et al. Curr Med Chem. 2019;26:259-69.

27. Cai Q et al. BMC Gastroenterol. 2022;22:545.

28. Dos Santos Marques IC et al. Crohns Colitis 360. 2020 Oct;2(4):otaa076.

29. Deepak P et al. Gastroenterology. 2023;165:11-15.

30. Mahadevan U et al. Gastroenterology. 2019;156:1508-24.

31. Faye AS et al. Inflamm Bowel Dis. 2022;28:126-32.

32. Berinstein JA et al. Clin Gastroenterol Hepatol. 2021;19:2112-20.e1.

33. Levine J et al. Gastroenterology. 2023;164:S103-S104.

Burden of NAFLD in the U.S.

Nonalcoholic fatty liver disease (NAFLD) has become a rapidly increasing public health burden in the U.S. and elsewhere. NAFLD is a manifestation of systemic metabolic abnormalities, including insulin resistance, dyslipidemia, central obesity, and hypertension. In this short review, we summarize data on the burden of NAFLD in the U.S. and its prognostic determinants and review what clinical and public health approaches may be needed to mitigating its impact.

Epidemiology of NAFLD

Worldwide, the prevalence of NAFLD is estimated at 6% to 35%, with biopsy-based studies reporting NASH in 3% to 5%.¹ U.S. estimates for the prevalence of NAFLD range from 10% to 46%.² In our own analysis of the National Health and Nutrition Examination Survey (NHANES) data, transient elastography-detected steatosis was found in 36%, which projected to a minimum of 73 million American adults.³

Dr. Mai Sedki

NAFLD represents a spectrum of disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the latter leading, in some cases, to progressive hepatic fibrosis and cirrhosis.⁴ Out of a large number of subjects with NAFLD, the proportions of NASH patients that develop severe liver problems such as end-stage liver disease (ESLD) or hepatocellular carcinoma (HCC) are progressively smaller. For example, we recently reported that less than 2,000 liver-related deaths are attributable to NAFLD in the U.S. per annum, which corresponds to a crude case fatality rate of < 0.005% per year.⁵

According to the Centers for Disease Control and Prevention (CDC), there have been substantial increases in liver-related deaths over the last 2 decades. Mortality from liver disease including hepatobiliary cancers more than doubled from 41,966 deaths (including 15,321 women and 26,645 men) in 2000 to 85,884 deaths (33,000 women and 52,884 men) in 2020. The proportion of deaths specifically attributed to NAFLD among liver-related deaths was miniscule in 2000, accounting for 1.1% in women and 0.7% in men. By 2020, the proportions increased several folds in both sexes (7.4% in women and 2.7% in men).⁶ Moreover, it is likely that a substantial portion of deaths from chronic liver disease from unknown causes (“cryptogenic”) are likely end-stage NAFLD, making these figures underestimates of the true impact of NAFLD in the U.S.

From a comparative epidemiologic perspective, there are significant racial and ethnic and socioeconomic disparities in NAFLD prevalence, wherein Hispanic persons and individuals experiencing food insecurity – independent of poverty status, education level, race and ethnicity – are disproportionately more affected by NAFLD.^7,8 Furthermore, these disparities persist when examining long-term complications of NAFLD, such as developing HCC.
 

Prognosis in NAFLD: NASH versus fibrosis

Given the enormous prevalence and increasing public health burden of NAFLD, systematic interventions to mitigate its impact are urgently needed. Clearly, patients who already have developed advanced liver disease need to be directed to specialty care so the disease progression may be halted and complications of ESLD may be prevented or managed. On the other hand, in order to mitigate the future impact of ESLD, prompt identification of at-risk patients and proactive interventions to improve liver health are needed.

Stanford University

In the assessment of disease progression, prior data have shown that the presence of NASH and increasing stages of liver fibrosis are important predictors of disease progression. Fibrosis is a component of NASH, while NASH is thought to be a prerequisite for fibrosis. In a prospective, multicenter follow-up study of NAFLD evaluated by liver biopsies (n = 1,773), over a median follow-up of 4 years, 37 (2%) developed hepatic decompensation, while 47 (3%) died from any cause, which included ESLD (n = 12), cardiovascular complications (n = 4), and malignancies (n = 12), including HCC (n = 9).⁹ It is not entirely surprising that advanced fibrosis and cirrhosis was highly associated with the development of hepatic decompensation. In their multivariable analysis, patients with F3-4 had a 13.8-fold (95% confidence interval [CI]: 4.6, 41.0) increase in the hazard of reaching a MELD score of 15 compared to those with F0-2. In addition, all-cause mortality was 17.2-fold (95% CI: 5.2, 56.6) higher with F3-4 compared to F0-2.

These data have been borne out by a larger body of literature on the topic. In a recent meta-analysis assessing the relation between liver fibrosis and future mortality, which included 17,301 subjects with NAFLD, patients with at least stage 2 fibrosis experience a significantly increased risk of liver-related and overall mortality, a trend that accelerates at higher fibrosis stages.¹⁰ These point to liver fibrosis as the singular determinant of long-term prognosis, in comparison, for example, with the diagnosis of NASH. Hagström conducted a retrospective cohort study of patients with biopsy-proven NAFLD in Sweden. When fibrosis stage and histological diagnosis of NASH were considered together, NASH did not have an impact on overall mortality (hazard ratio [HR] = 0.83, P = .29) or liver morbidity (HR = 0.62, P = .25).¹¹

On an individual level, factors that affect fibrosis progression are not as well studied. It is commonly believed that demographic factors (e.g., age, sex and race), genetic polymorphisms (e.g., PNPLA3, TM6SF2), clinical comorbidities (e.g., obesity, DM, and sleep apnea), and environmental factors (e.g., smoking) may accelerate fibrosis and disease outcomes, although prospective data are sparse to estimate the extent these individual variables affect progression.¹² Recent guidelines remain silent about whether and how these data may be incorporated in screening for NAFLD in the population.
 

Assessment of liver fibrosis

The traditional means to detect liver fibrosis is liver histology, which also assesses steatosis, individual components of NASH and, often importantly, other concomitant liver pathology. In reality, however, liver biopsies have several limitations including the risk of complications, patient discomfort, economic costs, and sampling variability. Increasingly, “noninvasive” methods have been used to estimate liver fibrosis in patients with NAFLD. Liver elastography estimates the physical stiffness of the organ, which may be measured by MRI or ultrasound. Among ultrasound-based technologies, vibration-controlled transient elastography (VCTE) is more widely accepted and affordable although it may not be as accurate as MR elastography.¹³

In general, these elastographic tests are not readily accessible to most physicians outside hepatology specialty practices. Instead, blood test-based markers have been developed and widely recommended as the initial modality to assess liver fibrosis. Figure 1 represents a partial list of blood test-based markers. Traditionally, FIB-4 and NFS have been considered the most widely recommended by society guidelines. The AGA Pathway for evaluation of patients with NAFLD recommends first to apply the FIB-4 score and, in patients considered to be at intermediate risk of fibrosis for advanced fibrosis (stage 3 or 4, FIB-4 = 1.3-2.67), to assess liver stiffness by VCTE.¹⁴

More recently, the accumulating natural history data have highlighted the inflection in the risk of future outcomes coinciding with F2 and therapeutic trials that target patients with “at risk NASH,” thus more attention has been paid to the identification of patients with stage 2 (or higher). The steatosis-associated fibrosis estimator (SAFE) was developed for this specific purpose. The score has been validated in multiple data sets, in all of which SAFE outperformed FIB-4 and NFS (Figure 1). When the score was applied to assess overall survival in participants of the NHANES, patients with NAFLD deemed to be high risk (SAFE > 100) had significantly lower survival (37% Kaplan-Meier survival at 20 years), compared to those with intermediate (SAFE 0-100, 61% survival) and low (SAFE < 0, 86% survival). In comparison, the 20-year survival of subjects without NAFLD survival was 79%.¹⁵

Mai Sedki, MD, MPH and W. Ray Kim, MD

Mai Sedki, MD, MPH and W. Ray Kim, MD

Partnership between primary care and specialty

The insights expressed in Figure 2 can be utilized to guide management decisions. In patients without evidence of liver fibrosis, emphasis may primarily be on screening, stratification and management of metabolic syndrome. For patients with evidence of incipient liver fibrosis, medical management of NAFLD needs to be implemented including lifestyle changes and pharmacological interventions as appropriate. For patients unresponsive to medical therapy, an endoscopic or surgical bariatric procedure should be considered. Management of patients with evidence of cirrhosis includes screening for portal hypertension, surveillance for HCC, medical management of cirrhosis, and finally, in suitable cases, referral for liver transplant evaluation. The reader is referred to the latest treatment guidelines for detailed discussion of these individual management modalities [ref, AGA and AASLD guidelines].^14,17

Given the spectrum of management modalities needed to successfully manage patients with NAFLD, it is unrealistic to expect that hepatologists and gastroenterologists are able to manage the large number of patients with NAFLD. In general, clinical activities on the left side of the figure are in the domain of primary care providers, whereas management of patients with progressive liver fibrosis is conducted by the specialist. An important aspect of the overall management of these patients is risk management in terms of the metabolic syndrome, including cardiovascular risk reduction and diabetes management, as appropriate. Many patients with NAFLD are burdened with several comorbidities and likely to benefit from a multidisciplinary team consisting of primary care, endocrinology, preventive cardiology, pharmacy, nutrition/dietetics, social services, and addiction specialists, as well as hepatology and gastroenterology. Prospective, high-quality data to define these teams and their function are yet to be generated.
 

Conclusion

NAFLD is an important and increasing public health concern in the U.S. Once diagnosed, assessing liver fibrosis and evaluating the presence of the components of metabolic syndrome in these patients, constitute the key components in the care in terms of risk stratification, medical management, and referral decisions. Noninvasive tests have been increasingly utilized including liver stiffness measurements and various blood test-based indicators. For patients in specialty GI/hepatology care, transient elastography is a widely accepted tool, with which standardized recommendations may be made for screening, stratification, and medical and surgical interventions in patients with NAFLD.

Mai Sedki, MD, MPH, is a doctoral candidate at the University of California, San Francisco. W. Ray Kim, MD, is professor of medicine (gastroenterology and hepatology) at Stanford (Calif.) University. Address correspondence to: wrkim@stanford.edu. The authors disclosed no conflicts of interest. Twitter: @SedkiMD and @WRayKimMD.

References

1. Younossi ZM et al. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. 2020 Mar;69(3):564-8.

2. Lazo M et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013 Jul 1;178(1):38-45.

3. Kim D et al. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013 Apr;57:1357-65.

4. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002 Apr 18;346:1221-31.

5. Kim D et al. Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016. Gastroenterology. 2018;155(4):1154-63.e3.

6. FastStats. Chronic Liver Disease and Cirrhosis. Centers for Disease Control and Prevention.

7. Rich NE et al. Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(2):198-210. e2.

8. Coleman-Jensen A et al. Household food security in the United States in 2020 (ERR-298). Washington, DC: U.S. Department of Agriculture; Sep 2021.

9. Sanyal AJ et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med. 2021 Oct 21;385(17):1559-69.

10. Ng CH et al. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023 Apr;21(4):931-9.e5.

11. Hagström H et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265-73.

12. Rinella ME et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-835.

13. Singh S et al. Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: A systematic review and meta-analysis of individual participant data. Clin Gastroenterol Hepatol. 2015 Mar;13(3):440-51.e6.

14. Kanwal F et al. Clinical Care Pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease. Gastroenterology. 2021 Nov;161(5):1657-69.

15. Sripongpun P et al. The steatosis-associated fibrosis estimator (SAFE) score: A tool to detect low-risk NAFLD in primary care. .

16. de Franchis R et al. Baveno VII: Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-74.

17. Rinella ME et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-835.

Burden of NAFLD in the U.S.

Nonalcoholic fatty liver disease (NAFLD) has become a rapidly increasing public health burden in the U.S. and elsewhere. NAFLD is a manifestation of systemic metabolic abnormalities, including insulin resistance, dyslipidemia, central obesity, and hypertension. In this short review, we summarize data on the burden of NAFLD in the U.S. and its prognostic determinants and review what clinical and public health approaches may be needed to mitigating its impact.

Epidemiology of NAFLD

Worldwide, the prevalence of NAFLD is estimated at 6% to 35%, with biopsy-based studies reporting NASH in 3% to 5%.¹ U.S. estimates for the prevalence of NAFLD range from 10% to 46%.² In our own analysis of the National Health and Nutrition Examination Survey (NHANES) data, transient elastography-detected steatosis was found in 36%, which projected to a minimum of 73 million American adults.³

Dr. Mai Sedki

NAFLD represents a spectrum of disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the latter leading, in some cases, to progressive hepatic fibrosis and cirrhosis.⁴ Out of a large number of subjects with NAFLD, the proportions of NASH patients that develop severe liver problems such as end-stage liver disease (ESLD) or hepatocellular carcinoma (HCC) are progressively smaller. For example, we recently reported that less than 2,000 liver-related deaths are attributable to NAFLD in the U.S. per annum, which corresponds to a crude case fatality rate of < 0.005% per year.⁵

According to the Centers for Disease Control and Prevention (CDC), there have been substantial increases in liver-related deaths over the last 2 decades. Mortality from liver disease including hepatobiliary cancers more than doubled from 41,966 deaths (including 15,321 women and 26,645 men) in 2000 to 85,884 deaths (33,000 women and 52,884 men) in 2020. The proportion of deaths specifically attributed to NAFLD among liver-related deaths was miniscule in 2000, accounting for 1.1% in women and 0.7% in men. By 2020, the proportions increased several folds in both sexes (7.4% in women and 2.7% in men).⁶ Moreover, it is likely that a substantial portion of deaths from chronic liver disease from unknown causes (“cryptogenic”) are likely end-stage NAFLD, making these figures underestimates of the true impact of NAFLD in the U.S.

From a comparative epidemiologic perspective, there are significant racial and ethnic and socioeconomic disparities in NAFLD prevalence, wherein Hispanic persons and individuals experiencing food insecurity – independent of poverty status, education level, race and ethnicity – are disproportionately more affected by NAFLD.^7,8 Furthermore, these disparities persist when examining long-term complications of NAFLD, such as developing HCC.
 

Prognosis in NAFLD: NASH versus fibrosis

Given the enormous prevalence and increasing public health burden of NAFLD, systematic interventions to mitigate its impact are urgently needed. Clearly, patients who already have developed advanced liver disease need to be directed to specialty care so the disease progression may be halted and complications of ESLD may be prevented or managed. On the other hand, in order to mitigate the future impact of ESLD, prompt identification of at-risk patients and proactive interventions to improve liver health are needed.

Stanford University

In the assessment of disease progression, prior data have shown that the presence of NASH and increasing stages of liver fibrosis are important predictors of disease progression. Fibrosis is a component of NASH, while NASH is thought to be a prerequisite for fibrosis. In a prospective, multicenter follow-up study of NAFLD evaluated by liver biopsies (n = 1,773), over a median follow-up of 4 years, 37 (2%) developed hepatic decompensation, while 47 (3%) died from any cause, which included ESLD (n = 12), cardiovascular complications (n = 4), and malignancies (n = 12), including HCC (n = 9).⁹ It is not entirely surprising that advanced fibrosis and cirrhosis was highly associated with the development of hepatic decompensation. In their multivariable analysis, patients with F3-4 had a 13.8-fold (95% confidence interval [CI]: 4.6, 41.0) increase in the hazard of reaching a MELD score of 15 compared to those with F0-2. In addition, all-cause mortality was 17.2-fold (95% CI: 5.2, 56.6) higher with F3-4 compared to F0-2.

These data have been borne out by a larger body of literature on the topic. In a recent meta-analysis assessing the relation between liver fibrosis and future mortality, which included 17,301 subjects with NAFLD, patients with at least stage 2 fibrosis experience a significantly increased risk of liver-related and overall mortality, a trend that accelerates at higher fibrosis stages.¹⁰ These point to liver fibrosis as the singular determinant of long-term prognosis, in comparison, for example, with the diagnosis of NASH. Hagström conducted a retrospective cohort study of patients with biopsy-proven NAFLD in Sweden. When fibrosis stage and histological diagnosis of NASH were considered together, NASH did not have an impact on overall mortality (hazard ratio [HR] = 0.83, P = .29) or liver morbidity (HR = 0.62, P = .25).¹¹

On an individual level, factors that affect fibrosis progression are not as well studied. It is commonly believed that demographic factors (e.g., age, sex and race), genetic polymorphisms (e.g., PNPLA3, TM6SF2), clinical comorbidities (e.g., obesity, DM, and sleep apnea), and environmental factors (e.g., smoking) may accelerate fibrosis and disease outcomes, although prospective data are sparse to estimate the extent these individual variables affect progression.¹² Recent guidelines remain silent about whether and how these data may be incorporated in screening for NAFLD in the population.
 

Assessment of liver fibrosis

The traditional means to detect liver fibrosis is liver histology, which also assesses steatosis, individual components of NASH and, often importantly, other concomitant liver pathology. In reality, however, liver biopsies have several limitations including the risk of complications, patient discomfort, economic costs, and sampling variability. Increasingly, “noninvasive” methods have been used to estimate liver fibrosis in patients with NAFLD. Liver elastography estimates the physical stiffness of the organ, which may be measured by MRI or ultrasound. Among ultrasound-based technologies, vibration-controlled transient elastography (VCTE) is more widely accepted and affordable although it may not be as accurate as MR elastography.¹³

In general, these elastographic tests are not readily accessible to most physicians outside hepatology specialty practices. Instead, blood test-based markers have been developed and widely recommended as the initial modality to assess liver fibrosis. Figure 1 represents a partial list of blood test-based markers. Traditionally, FIB-4 and NFS have been considered the most widely recommended by society guidelines. The AGA Pathway for evaluation of patients with NAFLD recommends first to apply the FIB-4 score and, in patients considered to be at intermediate risk of fibrosis for advanced fibrosis (stage 3 or 4, FIB-4 = 1.3-2.67), to assess liver stiffness by VCTE.¹⁴

More recently, the accumulating natural history data have highlighted the inflection in the risk of future outcomes coinciding with F2 and therapeutic trials that target patients with “at risk NASH,” thus more attention has been paid to the identification of patients with stage 2 (or higher). The steatosis-associated fibrosis estimator (SAFE) was developed for this specific purpose. The score has been validated in multiple data sets, in all of which SAFE outperformed FIB-4 and NFS (Figure 1). When the score was applied to assess overall survival in participants of the NHANES, patients with NAFLD deemed to be high risk (SAFE > 100) had significantly lower survival (37% Kaplan-Meier survival at 20 years), compared to those with intermediate (SAFE 0-100, 61% survival) and low (SAFE < 0, 86% survival). In comparison, the 20-year survival of subjects without NAFLD survival was 79%.¹⁵

Mai Sedki, MD, MPH and W. Ray Kim, MD

Mai Sedki, MD, MPH and W. Ray Kim, MD

Partnership between primary care and specialty

The insights expressed in Figure 2 can be utilized to guide management decisions. In patients without evidence of liver fibrosis, emphasis may primarily be on screening, stratification and management of metabolic syndrome. For patients with evidence of incipient liver fibrosis, medical management of NAFLD needs to be implemented including lifestyle changes and pharmacological interventions as appropriate. For patients unresponsive to medical therapy, an endoscopic or surgical bariatric procedure should be considered. Management of patients with evidence of cirrhosis includes screening for portal hypertension, surveillance for HCC, medical management of cirrhosis, and finally, in suitable cases, referral for liver transplant evaluation. The reader is referred to the latest treatment guidelines for detailed discussion of these individual management modalities [ref, AGA and AASLD guidelines].^14,17

Given the spectrum of management modalities needed to successfully manage patients with NAFLD, it is unrealistic to expect that hepatologists and gastroenterologists are able to manage the large number of patients with NAFLD. In general, clinical activities on the left side of the figure are in the domain of primary care providers, whereas management of patients with progressive liver fibrosis is conducted by the specialist. An important aspect of the overall management of these patients is risk management in terms of the metabolic syndrome, including cardiovascular risk reduction and diabetes management, as appropriate. Many patients with NAFLD are burdened with several comorbidities and likely to benefit from a multidisciplinary team consisting of primary care, endocrinology, preventive cardiology, pharmacy, nutrition/dietetics, social services, and addiction specialists, as well as hepatology and gastroenterology. Prospective, high-quality data to define these teams and their function are yet to be generated.
 

Conclusion

NAFLD is an important and increasing public health concern in the U.S. Once diagnosed, assessing liver fibrosis and evaluating the presence of the components of metabolic syndrome in these patients, constitute the key components in the care in terms of risk stratification, medical management, and referral decisions. Noninvasive tests have been increasingly utilized including liver stiffness measurements and various blood test-based indicators. For patients in specialty GI/hepatology care, transient elastography is a widely accepted tool, with which standardized recommendations may be made for screening, stratification, and medical and surgical interventions in patients with NAFLD.

Mai Sedki, MD, MPH, is a doctoral candidate at the University of California, San Francisco. W. Ray Kim, MD, is professor of medicine (gastroenterology and hepatology) at Stanford (Calif.) University. Address correspondence to: wrkim@stanford.edu. The authors disclosed no conflicts of interest. Twitter: @SedkiMD and @WRayKimMD.

References

1. Younossi ZM et al. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. 2020 Mar;69(3):564-8.

2. Lazo M et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013 Jul 1;178(1):38-45.

3. Kim D et al. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013 Apr;57:1357-65.

4. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002 Apr 18;346:1221-31.

5. Kim D et al. Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016. Gastroenterology. 2018;155(4):1154-63.e3.

6. FastStats. Chronic Liver Disease and Cirrhosis. Centers for Disease Control and Prevention.

7. Rich NE et al. Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(2):198-210. e2.

8. Coleman-Jensen A et al. Household food security in the United States in 2020 (ERR-298). Washington, DC: U.S. Department of Agriculture; Sep 2021.

9. Sanyal AJ et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med. 2021 Oct 21;385(17):1559-69.

10. Ng CH et al. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023 Apr;21(4):931-9.e5.

11. Hagström H et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265-73.

12. Rinella ME et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-835.

13. Singh S et al. Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: A systematic review and meta-analysis of individual participant data. Clin Gastroenterol Hepatol. 2015 Mar;13(3):440-51.e6.

14. Kanwal F et al. Clinical Care Pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease. Gastroenterology. 2021 Nov;161(5):1657-69.

15. Sripongpun P et al. The steatosis-associated fibrosis estimator (SAFE) score: A tool to detect low-risk NAFLD in primary care. .

16. de Franchis R et al. Baveno VII: Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-74.

17. Rinella ME et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-835.

Burden of NAFLD in the U.S.

Nonalcoholic fatty liver disease (NAFLD) has become a rapidly increasing public health burden in the U.S. and elsewhere. NAFLD is a manifestation of systemic metabolic abnormalities, including insulin resistance, dyslipidemia, central obesity, and hypertension. In this short review, we summarize data on the burden of NAFLD in the U.S. and its prognostic determinants and review what clinical and public health approaches may be needed to mitigating its impact.

Epidemiology of NAFLD

Worldwide, the prevalence of NAFLD is estimated at 6% to 35%, with biopsy-based studies reporting NASH in 3% to 5%.¹ U.S. estimates for the prevalence of NAFLD range from 10% to 46%.² In our own analysis of the National Health and Nutrition Examination Survey (NHANES) data, transient elastography-detected steatosis was found in 36%, which projected to a minimum of 73 million American adults.³

Dr. Mai Sedki

NAFLD represents a spectrum of disorders ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), the latter leading, in some cases, to progressive hepatic fibrosis and cirrhosis.⁴ Out of a large number of subjects with NAFLD, the proportions of NASH patients that develop severe liver problems such as end-stage liver disease (ESLD) or hepatocellular carcinoma (HCC) are progressively smaller. For example, we recently reported that less than 2,000 liver-related deaths are attributable to NAFLD in the U.S. per annum, which corresponds to a crude case fatality rate of < 0.005% per year.⁵

According to the Centers for Disease Control and Prevention (CDC), there have been substantial increases in liver-related deaths over the last 2 decades. Mortality from liver disease including hepatobiliary cancers more than doubled from 41,966 deaths (including 15,321 women and 26,645 men) in 2000 to 85,884 deaths (33,000 women and 52,884 men) in 2020. The proportion of deaths specifically attributed to NAFLD among liver-related deaths was miniscule in 2000, accounting for 1.1% in women and 0.7% in men. By 2020, the proportions increased several folds in both sexes (7.4% in women and 2.7% in men).⁶ Moreover, it is likely that a substantial portion of deaths from chronic liver disease from unknown causes (“cryptogenic”) are likely end-stage NAFLD, making these figures underestimates of the true impact of NAFLD in the U.S.

From a comparative epidemiologic perspective, there are significant racial and ethnic and socioeconomic disparities in NAFLD prevalence, wherein Hispanic persons and individuals experiencing food insecurity – independent of poverty status, education level, race and ethnicity – are disproportionately more affected by NAFLD.^7,8 Furthermore, these disparities persist when examining long-term complications of NAFLD, such as developing HCC.
 

Prognosis in NAFLD: NASH versus fibrosis

Given the enormous prevalence and increasing public health burden of NAFLD, systematic interventions to mitigate its impact are urgently needed. Clearly, patients who already have developed advanced liver disease need to be directed to specialty care so the disease progression may be halted and complications of ESLD may be prevented or managed. On the other hand, in order to mitigate the future impact of ESLD, prompt identification of at-risk patients and proactive interventions to improve liver health are needed.

Stanford University

In the assessment of disease progression, prior data have shown that the presence of NASH and increasing stages of liver fibrosis are important predictors of disease progression. Fibrosis is a component of NASH, while NASH is thought to be a prerequisite for fibrosis. In a prospective, multicenter follow-up study of NAFLD evaluated by liver biopsies (n = 1,773), over a median follow-up of 4 years, 37 (2%) developed hepatic decompensation, while 47 (3%) died from any cause, which included ESLD (n = 12), cardiovascular complications (n = 4), and malignancies (n = 12), including HCC (n = 9).⁹ It is not entirely surprising that advanced fibrosis and cirrhosis was highly associated with the development of hepatic decompensation. In their multivariable analysis, patients with F3-4 had a 13.8-fold (95% confidence interval [CI]: 4.6, 41.0) increase in the hazard of reaching a MELD score of 15 compared to those with F0-2. In addition, all-cause mortality was 17.2-fold (95% CI: 5.2, 56.6) higher with F3-4 compared to F0-2.

These data have been borne out by a larger body of literature on the topic. In a recent meta-analysis assessing the relation between liver fibrosis and future mortality, which included 17,301 subjects with NAFLD, patients with at least stage 2 fibrosis experience a significantly increased risk of liver-related and overall mortality, a trend that accelerates at higher fibrosis stages.¹⁰ These point to liver fibrosis as the singular determinant of long-term prognosis, in comparison, for example, with the diagnosis of NASH. Hagström conducted a retrospective cohort study of patients with biopsy-proven NAFLD in Sweden. When fibrosis stage and histological diagnosis of NASH were considered together, NASH did not have an impact on overall mortality (hazard ratio [HR] = 0.83, P = .29) or liver morbidity (HR = 0.62, P = .25).¹¹

On an individual level, factors that affect fibrosis progression are not as well studied. It is commonly believed that demographic factors (e.g., age, sex and race), genetic polymorphisms (e.g., PNPLA3, TM6SF2), clinical comorbidities (e.g., obesity, DM, and sleep apnea), and environmental factors (e.g., smoking) may accelerate fibrosis and disease outcomes, although prospective data are sparse to estimate the extent these individual variables affect progression.¹² Recent guidelines remain silent about whether and how these data may be incorporated in screening for NAFLD in the population.
 

Assessment of liver fibrosis

The traditional means to detect liver fibrosis is liver histology, which also assesses steatosis, individual components of NASH and, often importantly, other concomitant liver pathology. In reality, however, liver biopsies have several limitations including the risk of complications, patient discomfort, economic costs, and sampling variability. Increasingly, “noninvasive” methods have been used to estimate liver fibrosis in patients with NAFLD. Liver elastography estimates the physical stiffness of the organ, which may be measured by MRI or ultrasound. Among ultrasound-based technologies, vibration-controlled transient elastography (VCTE) is more widely accepted and affordable although it may not be as accurate as MR elastography.¹³

In general, these elastographic tests are not readily accessible to most physicians outside hepatology specialty practices. Instead, blood test-based markers have been developed and widely recommended as the initial modality to assess liver fibrosis. Figure 1 represents a partial list of blood test-based markers. Traditionally, FIB-4 and NFS have been considered the most widely recommended by society guidelines. The AGA Pathway for evaluation of patients with NAFLD recommends first to apply the FIB-4 score and, in patients considered to be at intermediate risk of fibrosis for advanced fibrosis (stage 3 or 4, FIB-4 = 1.3-2.67), to assess liver stiffness by VCTE.¹⁴

More recently, the accumulating natural history data have highlighted the inflection in the risk of future outcomes coinciding with F2 and therapeutic trials that target patients with “at risk NASH,” thus more attention has been paid to the identification of patients with stage 2 (or higher). The steatosis-associated fibrosis estimator (SAFE) was developed for this specific purpose. The score has been validated in multiple data sets, in all of which SAFE outperformed FIB-4 and NFS (Figure 1). When the score was applied to assess overall survival in participants of the NHANES, patients with NAFLD deemed to be high risk (SAFE > 100) had significantly lower survival (37% Kaplan-Meier survival at 20 years), compared to those with intermediate (SAFE 0-100, 61% survival) and low (SAFE < 0, 86% survival). In comparison, the 20-year survival of subjects without NAFLD survival was 79%.¹⁵

Mai Sedki, MD, MPH and W. Ray Kim, MD

Mai Sedki, MD, MPH and W. Ray Kim, MD

Partnership between primary care and specialty

The insights expressed in Figure 2 can be utilized to guide management decisions. In patients without evidence of liver fibrosis, emphasis may primarily be on screening, stratification and management of metabolic syndrome. For patients with evidence of incipient liver fibrosis, medical management of NAFLD needs to be implemented including lifestyle changes and pharmacological interventions as appropriate. For patients unresponsive to medical therapy, an endoscopic or surgical bariatric procedure should be considered. Management of patients with evidence of cirrhosis includes screening for portal hypertension, surveillance for HCC, medical management of cirrhosis, and finally, in suitable cases, referral for liver transplant evaluation. The reader is referred to the latest treatment guidelines for detailed discussion of these individual management modalities [ref, AGA and AASLD guidelines].^14,17

Given the spectrum of management modalities needed to successfully manage patients with NAFLD, it is unrealistic to expect that hepatologists and gastroenterologists are able to manage the large number of patients with NAFLD. In general, clinical activities on the left side of the figure are in the domain of primary care providers, whereas management of patients with progressive liver fibrosis is conducted by the specialist. An important aspect of the overall management of these patients is risk management in terms of the metabolic syndrome, including cardiovascular risk reduction and diabetes management, as appropriate. Many patients with NAFLD are burdened with several comorbidities and likely to benefit from a multidisciplinary team consisting of primary care, endocrinology, preventive cardiology, pharmacy, nutrition/dietetics, social services, and addiction specialists, as well as hepatology and gastroenterology. Prospective, high-quality data to define these teams and their function are yet to be generated.
 

Conclusion

NAFLD is an important and increasing public health concern in the U.S. Once diagnosed, assessing liver fibrosis and evaluating the presence of the components of metabolic syndrome in these patients, constitute the key components in the care in terms of risk stratification, medical management, and referral decisions. Noninvasive tests have been increasingly utilized including liver stiffness measurements and various blood test-based indicators. For patients in specialty GI/hepatology care, transient elastography is a widely accepted tool, with which standardized recommendations may be made for screening, stratification, and medical and surgical interventions in patients with NAFLD.

Mai Sedki, MD, MPH, is a doctoral candidate at the University of California, San Francisco. W. Ray Kim, MD, is professor of medicine (gastroenterology and hepatology) at Stanford (Calif.) University. Address correspondence to: wrkim@stanford.edu. The authors disclosed no conflicts of interest. Twitter: @SedkiMD and @WRayKimMD.

References

1. Younossi ZM et al. Epidemiology of chronic liver diseases in the USA in the past three decades. Gut. 2020 Mar;69(3):564-8.

2. Lazo M et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013 Jul 1;178(1):38-45.

3. Kim D et al. Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States. Hepatology. 2013 Apr;57:1357-65.

4. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002 Apr 18;346:1221-31.

5. Kim D et al. Changing trends in etiology-based annual mortality from chronic liver disease, from 2007 through 2016. Gastroenterology. 2018;155(4):1154-63.e3.

6. FastStats. Chronic Liver Disease and Cirrhosis. Centers for Disease Control and Prevention.

7. Rich NE et al. Racial and ethnic disparities in nonalcoholic fatty liver disease prevalence, severity, and outcomes in the United States: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(2):198-210. e2.

8. Coleman-Jensen A et al. Household food security in the United States in 2020 (ERR-298). Washington, DC: U.S. Department of Agriculture; Sep 2021.

9. Sanyal AJ et al. Prospective study of outcomes in adults with nonalcoholic fatty liver disease. N Engl J Med. 2021 Oct 21;385(17):1559-69.

10. Ng CH et al. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023 Apr;21(4):931-9.e5.

11. Hagström H et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265-73.

12. Rinella ME et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-835.

13. Singh S et al. Diagnostic performance of magnetic resonance elastography in staging liver fibrosis: A systematic review and meta-analysis of individual participant data. Clin Gastroenterol Hepatol. 2015 Mar;13(3):440-51.e6.

14. Kanwal F et al. Clinical Care Pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease. Gastroenterology. 2021 Nov;161(5):1657-69.

15. Sripongpun P et al. The steatosis-associated fibrosis estimator (SAFE) score: A tool to detect low-risk NAFLD in primary care. .

16. de Franchis R et al. Baveno VII: Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-74.

17. Rinella ME et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 May 1;77(5):1797-835.

Introduction

Dysphagia is the sensation of difficulty swallowing food or liquid in the acute or chronic setting. The prevalence of dysphagia ranges based on the type and etiology but may impact up to one in six adults.^1,2 Dysphagia can cause a significant impact on a patient’s health and overall quality of life. A recent study found that only 50% of symptomatic adults seek medical care despite modifying their eating habits by either eating slowly or changing to softer foods or liquids.¹ The most common, serious complications of dysphagia include aspiration pneumonia, malnutrition, and dehydration.³ According to the Agency for Healthcare Research and Quality, dysphagia may be responsible for up to 60,000 deaths annually.³

History

The diagnosis of dysphagia begins with a thorough history. Questions about the timing, onset, progression, localization of symptoms, and types of food that are difficult to swallow are essential in differentiating oropharyngeal and esophageal dysphagia.^3,4 Further history taking must include medication and allergy review, smoking history, and review of prior radiation or surgical therapies to the head and neck.

Briefly, oropharyngeal dysphagia is difficulty initiating a swallow or passing food from the mouth or throat and can be caused by structural or functional etiologies.⁵ Clinical presentations include a sensation of food stuck in the back of the throat, coughing or choking while eating, or drooling. Structural causes include head and neck cancer, Zenker diverticulum, Killian Jamieson diverticula, prolonged intubation, or changes secondary to prior surgery or radiation.³ Functional causes may include neurologic, rheumatologic, or muscular disorders.⁶

Esophageal dysphagia refers to difficulty transporting food or liquid down the esophagus and can be caused by structural, inflammatory, or functional disorders.⁵ Patients typically localize symptoms of heartburn, regurgitation, nausea, vomiting, cough, or chest pain along the sternum or epigastric region. Alarm signs concerning for malignancy include unintentional weight loss, fevers, or night sweats.^3,7 Aside from symptoms, medication review is essential, as dysphagia is a common side effect of antipsychotics, anticholinergics, antimuscarinics, narcotics, and immunosuppressant drugs.⁸ Larger pills such as NSAIDs, antibiotics, bisphosphonates, potassium supplements, and methylxanthines can cause drug-induced esophagitis, which can initially present as dysphagia.⁸ Inflammatory causes can be elucidated by obtaining a history about allergies, tobacco use, and recent infections such as thrush or pneumonia. Patients with a history of recurrent pneumonias may be silently aspirating, a complication of dysphagia.³ Once esophageal dysphagia is clinically suspected based on history, workup can begin. 

Differentiating etiologies of esophageal dysphagia 

The next step in diagnosing esophageal dysphagia is differentiating between structural, inflammatory, or dysmotility etiology (Figure 1). 

Courtesy Tanisha Ronnie, MD, Lauren Bloomberg, MD, and Mukund Venu, MD

Patients with a structural cause typically have difficulty swallowing solids but are able to swallow liquids unless the disease progresses. Symptoms can rapidly worsen and lead to odynophagia, weight loss, and vomiting. In comparison, patients with motility disorders typically have difficulty swallowing both solids and liquids initially, and symptoms can be constant or intermittent.⁵ 

Prior to diagnostic studies, a 4-week trial of a proton pump inhibitor (PPI) is appropriate for patients with reflux symptoms who are younger than 50 with no alarm features concerning for malignancy.^7,9 If symptoms persist after a PPI trial, then an upper endoscopy (EGD) is indicated. An EGD allows for visualization of structural etiologies, obtaining biopsies to rule out inflammatory etiologies, and the option to therapeutically treat reduced luminal diameter with dilatation.¹⁰ The most common structural and inflammatory etiologies noted on EGD include strictures, webs, carcinomas, Schatzki rings, and gastroesophageal reflux or eosinophilic esophagitis.⁴

If upper endoscopy is normal and clinical suspicion for an obstructive cause remains high, barium esophagram can be utilized as an adjunctive study. Previously, barium esophagram was the initial test to distinguish between structural and motility disorders. The benefits of endoscopy over barium esophagram as the first diagnostic study include higher diagnostic yield, higher sensitivity and specificity, and lower costs.⁷ However, barium studies may be more sensitive for lower esophageal rings or extrinsic esophageal compression.3 

 

Evaluation of esophageal motility disorder

If a structural or inflammatory etiology of dysphagia is not identified, investigation for an esophageal motility disorder (EMD) is warranted. Examples of motility disorders include achalasia, ineffective esophageal motility, hypercontractility, spasticity, or esophagogastric junction outflow obstruction (EGJOO).^10,11 High-resolution esophageal manometry (HRM) remains the gold standard in diagnosis of EMD.¹² An HRM catheter utilizes 36 sensors placed two centimeters apart and is placed in the esophagus to evaluate pressure and peristalsis between the upper and lower esophageal sphincters.¹³ In 2009, the Chicago Classification System was developed to provide a diagnostic algorithm that categorizes EMD based on HRM testing, with the most recent version (4.0) being published in 2020.^12,14 Motility diagnoses are divided into two general classifications of disorders of body peristalsis and disorders of EGJ outflow. The most recent updates also include changes in swallow protocols, patient positioning, targeted symptoms, addition of impedance sensors, and consideration of supplemental testing when HRM is inconclusive based on the clinical context.¹² There are some limitations of HRM to highlight. One of the main diagnostic values used with HRM is the integrated relaxation pressure (IRP). Despite standardization, IRP measurements vary based on the recorder and patient position. A minority of patients with achalasia may have IRP that does not approach the accepted cutoff and, therefore, the EGJ is not accurately assessed on HRM.^15,16 In addition, some swallow protocols have lower sensitivity and specificity for certain motility disorders, and the test can result as inconclusive.14 In these scenarios, supplemental testing with timed barium esophagram or functional luminal imaging probe (EndoFLIP) is indicated.^10,11

Loyola University Chicago

Over the past decade, EndoFLIP has emerged as a novel diagnostic tool in evaluating EMD. EndoFLIP is usually completed during an upper endoscopy and utilizes impedance planimetry to measure cross-sectional area and esophageal distensibility and evaluate contractile patterns.¹⁶ During the procedure, a small catheter with an inflatable balloon is inserted into the esophagus with the distal end in the stomach, traversing the esophagogastric junction (EGJ). The pressure transducer has electrodes every centimeter to allow for a three-dimensional construction of the esophagus and EGJ.¹⁷ EndoFLIP has been shown to accurately measure pyloric diameter, pressure, and distensibility at certain balloon volumes.¹⁸ In addition, FLIP is being used to further identify aspects of esophageal dysmotility in patients with eosinophilic esophagitis, thought primarily to be an inflammatory disorder.¹⁹ However, limitations include minimal accessibility of EndoFLIP within clinical practice and a specific computer program needed to generate the topographic plots.²⁰ 

When used in conjunction with HRM, EndoFLIP provides complementary data that can be used to better detect major motility disorders.^15,20,21 Each study adds unique information about the different physiologic events comprising the esophageal response to distention. Overall, the benefits of EndoFLIP include expediting workup during index endoscopy, patient comfort with sedation, and real-time diagnostic data that supplement results obtained during HRM.^{10,16,20,2223}

Of note, if the diagnostic evaluation for structural, inflammatory, and motility disorders are unrevealing, investigating for atypical reflux symptoms can be pursued for patients with persistent dysphagia. Studies investigating pH, or acidity in the esophagus, in relation to symptoms, can be conducted wirelessly via a capsule fixed to the mucosa or with a nasal catheter.³

Normal workup – hypervigilance

In a subset of patients, all diagnostic testing for structural, inflammatory, or motility disorders is normal. These patients are classified as having a functional esophageal disorder. Despite normal testing, patients still have significant symptoms including epigastric pain, chest pain, globus sensation, or difficulty swallowing. It is theorized that a degree of visceral hypersensitivity between the brain-gut axis contributes to ongoing symptoms.²⁴ Studies for effective treatments are ongoing but typically include cognitive-behavioral therapy, brain-gut behavioral therapy, swallow therapy antidepressants, or short courses of proton pump inhibitors.⁹

Conclusion

In this review article, we discussed the diagnostic approach for esophageal dysphagia. Initial assessment requires a thorough history, differentiation between oropharyngeal and esophageal dysphagia, and determination of who warrants an upper endoscopy. Upper endoscopy may reveal structural or inflammatory causes of dysphagia, including strictures, masses, or esophagitis, to name a few. If a structural or inflammatory cause is ruled out, this warrants investigation for esophageal motility disorders. The current gold standard for diagnosing EMD is manometry, and supplemental studies, including EndoFLIP, barium esophagram, and pH studies, may provide complimentary data. If workup for dysphagia is normal, evaluation for esophageal hypervigilance causing increased sensitivity to normal or mild sensations may be warranted. In conclusion, the diagnosis of dysphagia is challenging and requires investigation with a systematic approach to ensure timely diagnosis and treatment

Dr. Ronnie and Dr. Bloomberg are in the department of internal medicine at Loyola University Chicago, Maywood, Ill. Dr. Venu is in the division of gastroenterology at Loyola. He is on the speakers bureau at Medtronic.

References 

1. Adkins C et al. Clin Gastroenterol Hepatol. 2020;18(9):1970-9.e2. 

2. Bhattacharyya N. Otolaryngol Head Neck Surg. 2014;151(5):765-9. 

3. McCarty EB and Chao TN. Med Clin North Am. 2021;105(5):939-54. 

4. Thiyagalingam S et al. Mayo Clin Proc. 2021;96(2):488-97. 

5. Malagelada JR et al. J Clin Gastroenterol. 2015;49(5):370-8.

6. Rommel, N and Hamdy S. Nat Rev Gastroenterol Hepatol. 2016;13(1):49-59. 

7. Liu LWC et al. J Can Assoc Gastroenterol. 2018;1(1):5-19. 

8. Schwemmle C et al. HNO. 2015;63(7):504-10. 

9. Moayyedi P et al. Am J Gastroenterol. 2017;112(7):988-1013. 

10. Triggs J and Pandolfino J. F1000Res. 2019 Aug 29. doi: 10.12688/f1000research.18900.1. 

11. Yadlapati R et al. Neurogastroenterol Motil. 2021;33(1):e14058. 

12. Yadlapati R et al. Neurogastroenterol Motil. 2021;33(1):e14053. 

13. Fox M et al. Neurogastroenterol Motil. 2004;16(5):533-42. 

14. Sweis R and Fox M. Curr Gastroenterol Rep. 2020;22(10):49. 

15. Carlson DA et al. Gastroenterology. 2015;149(7):1742-51. 

16. Donnan EN and Pandolfino JE. Gastroenterol Clin North Am. 2020;49(3):427-35. 

17. Carlson DA. Curr Opin Gastroenterol. 2016;32(4):310-8.
 

18. Zheng T et al. Neurogastroenterol Motil. 2022;34(10):e14386.

19. Carlson DA et al. Clin Gastroenterol Hepatol. 2022;20(8):1719-28.e3.

20. Carlson DA et al. Am J Gastroenterol. 2016;111(12):1726-35.

21. Carlson DA et al. Neurogastroenterol Motil. 2021;33(10):e14116.

22. Carlson DA et al. Gastrointest Endosc. 2019;90(6):915-923.e1.

23. Fox MR et al. Neurogastroenterol Motil. 2021;33(4):e14120.

24. Aziz Q et al. Gastroenterology. 2016 Feb 15. doi: 10.1053/j.gastro.2016.02.012.

Introduction

Dysphagia is the sensation of difficulty swallowing food or liquid in the acute or chronic setting. The prevalence of dysphagia ranges based on the type and etiology but may impact up to one in six adults.^1,2 Dysphagia can cause a significant impact on a patient’s health and overall quality of life. A recent study found that only 50% of symptomatic adults seek medical care despite modifying their eating habits by either eating slowly or changing to softer foods or liquids.¹ The most common, serious complications of dysphagia include aspiration pneumonia, malnutrition, and dehydration.³ According to the Agency for Healthcare Research and Quality, dysphagia may be responsible for up to 60,000 deaths annually.³

History

The diagnosis of dysphagia begins with a thorough history. Questions about the timing, onset, progression, localization of symptoms, and types of food that are difficult to swallow are essential in differentiating oropharyngeal and esophageal dysphagia.^3,4 Further history taking must include medication and allergy review, smoking history, and review of prior radiation or surgical therapies to the head and neck.

Briefly, oropharyngeal dysphagia is difficulty initiating a swallow or passing food from the mouth or throat and can be caused by structural or functional etiologies.⁵ Clinical presentations include a sensation of food stuck in the back of the throat, coughing or choking while eating, or drooling. Structural causes include head and neck cancer, Zenker diverticulum, Killian Jamieson diverticula, prolonged intubation, or changes secondary to prior surgery or radiation.³ Functional causes may include neurologic, rheumatologic, or muscular disorders.⁶

Esophageal dysphagia refers to difficulty transporting food or liquid down the esophagus and can be caused by structural, inflammatory, or functional disorders.⁵ Patients typically localize symptoms of heartburn, regurgitation, nausea, vomiting, cough, or chest pain along the sternum or epigastric region. Alarm signs concerning for malignancy include unintentional weight loss, fevers, or night sweats.^3,7 Aside from symptoms, medication review is essential, as dysphagia is a common side effect of antipsychotics, anticholinergics, antimuscarinics, narcotics, and immunosuppressant drugs.⁸ Larger pills such as NSAIDs, antibiotics, bisphosphonates, potassium supplements, and methylxanthines can cause drug-induced esophagitis, which can initially present as dysphagia.⁸ Inflammatory causes can be elucidated by obtaining a history about allergies, tobacco use, and recent infections such as thrush or pneumonia. Patients with a history of recurrent pneumonias may be silently aspirating, a complication of dysphagia.³ Once esophageal dysphagia is clinically suspected based on history, workup can begin. 

Differentiating etiologies of esophageal dysphagia 

The next step in diagnosing esophageal dysphagia is differentiating between structural, inflammatory, or dysmotility etiology (Figure 1). 

Courtesy Tanisha Ronnie, MD, Lauren Bloomberg, MD, and Mukund Venu, MD

Patients with a structural cause typically have difficulty swallowing solids but are able to swallow liquids unless the disease progresses. Symptoms can rapidly worsen and lead to odynophagia, weight loss, and vomiting. In comparison, patients with motility disorders typically have difficulty swallowing both solids and liquids initially, and symptoms can be constant or intermittent.⁵ 

Prior to diagnostic studies, a 4-week trial of a proton pump inhibitor (PPI) is appropriate for patients with reflux symptoms who are younger than 50 with no alarm features concerning for malignancy.^7,9 If symptoms persist after a PPI trial, then an upper endoscopy (EGD) is indicated. An EGD allows for visualization of structural etiologies, obtaining biopsies to rule out inflammatory etiologies, and the option to therapeutically treat reduced luminal diameter with dilatation.¹⁰ The most common structural and inflammatory etiologies noted on EGD include strictures, webs, carcinomas, Schatzki rings, and gastroesophageal reflux or eosinophilic esophagitis.⁴

If upper endoscopy is normal and clinical suspicion for an obstructive cause remains high, barium esophagram can be utilized as an adjunctive study. Previously, barium esophagram was the initial test to distinguish between structural and motility disorders. The benefits of endoscopy over barium esophagram as the first diagnostic study include higher diagnostic yield, higher sensitivity and specificity, and lower costs.⁷ However, barium studies may be more sensitive for lower esophageal rings or extrinsic esophageal compression.3 

 

Evaluation of esophageal motility disorder

If a structural or inflammatory etiology of dysphagia is not identified, investigation for an esophageal motility disorder (EMD) is warranted. Examples of motility disorders include achalasia, ineffective esophageal motility, hypercontractility, spasticity, or esophagogastric junction outflow obstruction (EGJOO).^10,11 High-resolution esophageal manometry (HRM) remains the gold standard in diagnosis of EMD.¹² An HRM catheter utilizes 36 sensors placed two centimeters apart and is placed in the esophagus to evaluate pressure and peristalsis between the upper and lower esophageal sphincters.¹³ In 2009, the Chicago Classification System was developed to provide a diagnostic algorithm that categorizes EMD based on HRM testing, with the most recent version (4.0) being published in 2020.^12,14 Motility diagnoses are divided into two general classifications of disorders of body peristalsis and disorders of EGJ outflow. The most recent updates also include changes in swallow protocols, patient positioning, targeted symptoms, addition of impedance sensors, and consideration of supplemental testing when HRM is inconclusive based on the clinical context.¹² There are some limitations of HRM to highlight. One of the main diagnostic values used with HRM is the integrated relaxation pressure (IRP). Despite standardization, IRP measurements vary based on the recorder and patient position. A minority of patients with achalasia may have IRP that does not approach the accepted cutoff and, therefore, the EGJ is not accurately assessed on HRM.^15,16 In addition, some swallow protocols have lower sensitivity and specificity for certain motility disorders, and the test can result as inconclusive.14 In these scenarios, supplemental testing with timed barium esophagram or functional luminal imaging probe (EndoFLIP) is indicated.^10,11

Loyola University Chicago

Over the past decade, EndoFLIP has emerged as a novel diagnostic tool in evaluating EMD. EndoFLIP is usually completed during an upper endoscopy and utilizes impedance planimetry to measure cross-sectional area and esophageal distensibility and evaluate contractile patterns.¹⁶ During the procedure, a small catheter with an inflatable balloon is inserted into the esophagus with the distal end in the stomach, traversing the esophagogastric junction (EGJ). The pressure transducer has electrodes every centimeter to allow for a three-dimensional construction of the esophagus and EGJ.¹⁷ EndoFLIP has been shown to accurately measure pyloric diameter, pressure, and distensibility at certain balloon volumes.¹⁸ In addition, FLIP is being used to further identify aspects of esophageal dysmotility in patients with eosinophilic esophagitis, thought primarily to be an inflammatory disorder.¹⁹ However, limitations include minimal accessibility of EndoFLIP within clinical practice and a specific computer program needed to generate the topographic plots.²⁰ 

When used in conjunction with HRM, EndoFLIP provides complementary data that can be used to better detect major motility disorders.^15,20,21 Each study adds unique information about the different physiologic events comprising the esophageal response to distention. Overall, the benefits of EndoFLIP include expediting workup during index endoscopy, patient comfort with sedation, and real-time diagnostic data that supplement results obtained during HRM.^{10,16,20,2223}

Of note, if the diagnostic evaluation for structural, inflammatory, and motility disorders are unrevealing, investigating for atypical reflux symptoms can be pursued for patients with persistent dysphagia. Studies investigating pH, or acidity in the esophagus, in relation to symptoms, can be conducted wirelessly via a capsule fixed to the mucosa or with a nasal catheter.³

Normal workup – hypervigilance

In a subset of patients, all diagnostic testing for structural, inflammatory, or motility disorders is normal. These patients are classified as having a functional esophageal disorder. Despite normal testing, patients still have significant symptoms including epigastric pain, chest pain, globus sensation, or difficulty swallowing. It is theorized that a degree of visceral hypersensitivity between the brain-gut axis contributes to ongoing symptoms.²⁴ Studies for effective treatments are ongoing but typically include cognitive-behavioral therapy, brain-gut behavioral therapy, swallow therapy antidepressants, or short courses of proton pump inhibitors.⁹

Conclusion

In this review article, we discussed the diagnostic approach for esophageal dysphagia. Initial assessment requires a thorough history, differentiation between oropharyngeal and esophageal dysphagia, and determination of who warrants an upper endoscopy. Upper endoscopy may reveal structural or inflammatory causes of dysphagia, including strictures, masses, or esophagitis, to name a few. If a structural or inflammatory cause is ruled out, this warrants investigation for esophageal motility disorders. The current gold standard for diagnosing EMD is manometry, and supplemental studies, including EndoFLIP, barium esophagram, and pH studies, may provide complimentary data. If workup for dysphagia is normal, evaluation for esophageal hypervigilance causing increased sensitivity to normal or mild sensations may be warranted. In conclusion, the diagnosis of dysphagia is challenging and requires investigation with a systematic approach to ensure timely diagnosis and treatment

Dr. Ronnie and Dr. Bloomberg are in the department of internal medicine at Loyola University Chicago, Maywood, Ill. Dr. Venu is in the division of gastroenterology at Loyola. He is on the speakers bureau at Medtronic.

References 

1. Adkins C et al. Clin Gastroenterol Hepatol. 2020;18(9):1970-9.e2. 

2. Bhattacharyya N. Otolaryngol Head Neck Surg. 2014;151(5):765-9. 

3. McCarty EB and Chao TN. Med Clin North Am. 2021;105(5):939-54. 

4. Thiyagalingam S et al. Mayo Clin Proc. 2021;96(2):488-97. 

5. Malagelada JR et al. J Clin Gastroenterol. 2015;49(5):370-8.

6. Rommel, N and Hamdy S. Nat Rev Gastroenterol Hepatol. 2016;13(1):49-59. 

7. Liu LWC et al. J Can Assoc Gastroenterol. 2018;1(1):5-19. 

8. Schwemmle C et al. HNO. 2015;63(7):504-10. 

9. Moayyedi P et al. Am J Gastroenterol. 2017;112(7):988-1013. 

10. Triggs J and Pandolfino J. F1000Res. 2019 Aug 29. doi: 10.12688/f1000research.18900.1. 

11. Yadlapati R et al. Neurogastroenterol Motil. 2021;33(1):e14058. 

12. Yadlapati R et al. Neurogastroenterol Motil. 2021;33(1):e14053. 

13. Fox M et al. Neurogastroenterol Motil. 2004;16(5):533-42. 

14. Sweis R and Fox M. Curr Gastroenterol Rep. 2020;22(10):49. 

15. Carlson DA et al. Gastroenterology. 2015;149(7):1742-51. 

16. Donnan EN and Pandolfino JE. Gastroenterol Clin North Am. 2020;49(3):427-35. 

17. Carlson DA. Curr Opin Gastroenterol. 2016;32(4):310-8.
 

18. Zheng T et al. Neurogastroenterol Motil. 2022;34(10):e14386.

19. Carlson DA et al. Clin Gastroenterol Hepatol. 2022;20(8):1719-28.e3.

20. Carlson DA et al. Am J Gastroenterol. 2016;111(12):1726-35.

21. Carlson DA et al. Neurogastroenterol Motil. 2021;33(10):e14116.

22. Carlson DA et al. Gastrointest Endosc. 2019;90(6):915-923.e1.

23. Fox MR et al. Neurogastroenterol Motil. 2021;33(4):e14120.

24. Aziz Q et al. Gastroenterology. 2016 Feb 15. doi: 10.1053/j.gastro.2016.02.012.

Introduction

Dysphagia is the sensation of difficulty swallowing food or liquid in the acute or chronic setting. The prevalence of dysphagia ranges based on the type and etiology but may impact up to one in six adults.^1,2 Dysphagia can cause a significant impact on a patient’s health and overall quality of life. A recent study found that only 50% of symptomatic adults seek medical care despite modifying their eating habits by either eating slowly or changing to softer foods or liquids.¹ The most common, serious complications of dysphagia include aspiration pneumonia, malnutrition, and dehydration.³ According to the Agency for Healthcare Research and Quality, dysphagia may be responsible for up to 60,000 deaths annually.³

History

The diagnosis of dysphagia begins with a thorough history. Questions about the timing, onset, progression, localization of symptoms, and types of food that are difficult to swallow are essential in differentiating oropharyngeal and esophageal dysphagia.^3,4 Further history taking must include medication and allergy review, smoking history, and review of prior radiation or surgical therapies to the head and neck.

Briefly, oropharyngeal dysphagia is difficulty initiating a swallow or passing food from the mouth or throat and can be caused by structural or functional etiologies.⁵ Clinical presentations include a sensation of food stuck in the back of the throat, coughing or choking while eating, or drooling. Structural causes include head and neck cancer, Zenker diverticulum, Killian Jamieson diverticula, prolonged intubation, or changes secondary to prior surgery or radiation.³ Functional causes may include neurologic, rheumatologic, or muscular disorders.⁶

Esophageal dysphagia refers to difficulty transporting food or liquid down the esophagus and can be caused by structural, inflammatory, or functional disorders.⁵ Patients typically localize symptoms of heartburn, regurgitation, nausea, vomiting, cough, or chest pain along the sternum or epigastric region. Alarm signs concerning for malignancy include unintentional weight loss, fevers, or night sweats.^3,7 Aside from symptoms, medication review is essential, as dysphagia is a common side effect of antipsychotics, anticholinergics, antimuscarinics, narcotics, and immunosuppressant drugs.⁸ Larger pills such as NSAIDs, antibiotics, bisphosphonates, potassium supplements, and methylxanthines can cause drug-induced esophagitis, which can initially present as dysphagia.⁸ Inflammatory causes can be elucidated by obtaining a history about allergies, tobacco use, and recent infections such as thrush or pneumonia. Patients with a history of recurrent pneumonias may be silently aspirating, a complication of dysphagia.³ Once esophageal dysphagia is clinically suspected based on history, workup can begin. 

Differentiating etiologies of esophageal dysphagia 

The next step in diagnosing esophageal dysphagia is differentiating between structural, inflammatory, or dysmotility etiology (Figure 1). 

Courtesy Tanisha Ronnie, MD, Lauren Bloomberg, MD, and Mukund Venu, MD

Patients with a structural cause typically have difficulty swallowing solids but are able to swallow liquids unless the disease progresses. Symptoms can rapidly worsen and lead to odynophagia, weight loss, and vomiting. In comparison, patients with motility disorders typically have difficulty swallowing both solids and liquids initially, and symptoms can be constant or intermittent.⁵ 

Prior to diagnostic studies, a 4-week trial of a proton pump inhibitor (PPI) is appropriate for patients with reflux symptoms who are younger than 50 with no alarm features concerning for malignancy.^7,9 If symptoms persist after a PPI trial, then an upper endoscopy (EGD) is indicated. An EGD allows for visualization of structural etiologies, obtaining biopsies to rule out inflammatory etiologies, and the option to therapeutically treat reduced luminal diameter with dilatation.¹⁰ The most common structural and inflammatory etiologies noted on EGD include strictures, webs, carcinomas, Schatzki rings, and gastroesophageal reflux or eosinophilic esophagitis.⁴

If upper endoscopy is normal and clinical suspicion for an obstructive cause remains high, barium esophagram can be utilized as an adjunctive study. Previously, barium esophagram was the initial test to distinguish between structural and motility disorders. The benefits of endoscopy over barium esophagram as the first diagnostic study include higher diagnostic yield, higher sensitivity and specificity, and lower costs.⁷ However, barium studies may be more sensitive for lower esophageal rings or extrinsic esophageal compression.3 

 

Evaluation of esophageal motility disorder

If a structural or inflammatory etiology of dysphagia is not identified, investigation for an esophageal motility disorder (EMD) is warranted. Examples of motility disorders include achalasia, ineffective esophageal motility, hypercontractility, spasticity, or esophagogastric junction outflow obstruction (EGJOO).^10,11 High-resolution esophageal manometry (HRM) remains the gold standard in diagnosis of EMD.¹² An HRM catheter utilizes 36 sensors placed two centimeters apart and is placed in the esophagus to evaluate pressure and peristalsis between the upper and lower esophageal sphincters.¹³ In 2009, the Chicago Classification System was developed to provide a diagnostic algorithm that categorizes EMD based on HRM testing, with the most recent version (4.0) being published in 2020.^12,14 Motility diagnoses are divided into two general classifications of disorders of body peristalsis and disorders of EGJ outflow. The most recent updates also include changes in swallow protocols, patient positioning, targeted symptoms, addition of impedance sensors, and consideration of supplemental testing when HRM is inconclusive based on the clinical context.¹² There are some limitations of HRM to highlight. One of the main diagnostic values used with HRM is the integrated relaxation pressure (IRP). Despite standardization, IRP measurements vary based on the recorder and patient position. A minority of patients with achalasia may have IRP that does not approach the accepted cutoff and, therefore, the EGJ is not accurately assessed on HRM.^15,16 In addition, some swallow protocols have lower sensitivity and specificity for certain motility disorders, and the test can result as inconclusive.14 In these scenarios, supplemental testing with timed barium esophagram or functional luminal imaging probe (EndoFLIP) is indicated.^10,11

Loyola University Chicago

Over the past decade, EndoFLIP has emerged as a novel diagnostic tool in evaluating EMD. EndoFLIP is usually completed during an upper endoscopy and utilizes impedance planimetry to measure cross-sectional area and esophageal distensibility and evaluate contractile patterns.¹⁶ During the procedure, a small catheter with an inflatable balloon is inserted into the esophagus with the distal end in the stomach, traversing the esophagogastric junction (EGJ). The pressure transducer has electrodes every centimeter to allow for a three-dimensional construction of the esophagus and EGJ.¹⁷ EndoFLIP has been shown to accurately measure pyloric diameter, pressure, and distensibility at certain balloon volumes.¹⁸ In addition, FLIP is being used to further identify aspects of esophageal dysmotility in patients with eosinophilic esophagitis, thought primarily to be an inflammatory disorder.¹⁹ However, limitations include minimal accessibility of EndoFLIP within clinical practice and a specific computer program needed to generate the topographic plots.²⁰ 

When used in conjunction with HRM, EndoFLIP provides complementary data that can be used to better detect major motility disorders.^15,20,21 Each study adds unique information about the different physiologic events comprising the esophageal response to distention. Overall, the benefits of EndoFLIP include expediting workup during index endoscopy, patient comfort with sedation, and real-time diagnostic data that supplement results obtained during HRM.^{10,16,20,2223}

Of note, if the diagnostic evaluation for structural, inflammatory, and motility disorders are unrevealing, investigating for atypical reflux symptoms can be pursued for patients with persistent dysphagia. Studies investigating pH, or acidity in the esophagus, in relation to symptoms, can be conducted wirelessly via a capsule fixed to the mucosa or with a nasal catheter.³

Normal workup – hypervigilance

In a subset of patients, all diagnostic testing for structural, inflammatory, or motility disorders is normal. These patients are classified as having a functional esophageal disorder. Despite normal testing, patients still have significant symptoms including epigastric pain, chest pain, globus sensation, or difficulty swallowing. It is theorized that a degree of visceral hypersensitivity between the brain-gut axis contributes to ongoing symptoms.²⁴ Studies for effective treatments are ongoing but typically include cognitive-behavioral therapy, brain-gut behavioral therapy, swallow therapy antidepressants, or short courses of proton pump inhibitors.⁹

Conclusion

In this review article, we discussed the diagnostic approach for esophageal dysphagia. Initial assessment requires a thorough history, differentiation between oropharyngeal and esophageal dysphagia, and determination of who warrants an upper endoscopy. Upper endoscopy may reveal structural or inflammatory causes of dysphagia, including strictures, masses, or esophagitis, to name a few. If a structural or inflammatory cause is ruled out, this warrants investigation for esophageal motility disorders. The current gold standard for diagnosing EMD is manometry, and supplemental studies, including EndoFLIP, barium esophagram, and pH studies, may provide complimentary data. If workup for dysphagia is normal, evaluation for esophageal hypervigilance causing increased sensitivity to normal or mild sensations may be warranted. In conclusion, the diagnosis of dysphagia is challenging and requires investigation with a systematic approach to ensure timely diagnosis and treatment

Dr. Ronnie and Dr. Bloomberg are in the department of internal medicine at Loyola University Chicago, Maywood, Ill. Dr. Venu is in the division of gastroenterology at Loyola. He is on the speakers bureau at Medtronic.

References 

1. Adkins C et al. Clin Gastroenterol Hepatol. 2020;18(9):1970-9.e2. 

2. Bhattacharyya N. Otolaryngol Head Neck Surg. 2014;151(5):765-9. 

3. McCarty EB and Chao TN. Med Clin North Am. 2021;105(5):939-54. 

4. Thiyagalingam S et al. Mayo Clin Proc. 2021;96(2):488-97. 

5. Malagelada JR et al. J Clin Gastroenterol. 2015;49(5):370-8.

6. Rommel, N and Hamdy S. Nat Rev Gastroenterol Hepatol. 2016;13(1):49-59. 

7. Liu LWC et al. J Can Assoc Gastroenterol. 2018;1(1):5-19. 

8. Schwemmle C et al. HNO. 2015;63(7):504-10. 

9. Moayyedi P et al. Am J Gastroenterol. 2017;112(7):988-1013. 

10. Triggs J and Pandolfino J. F1000Res. 2019 Aug 29. doi: 10.12688/f1000research.18900.1. 

11. Yadlapati R et al. Neurogastroenterol Motil. 2021;33(1):e14058. 

12. Yadlapati R et al. Neurogastroenterol Motil. 2021;33(1):e14053. 

13. Fox M et al. Neurogastroenterol Motil. 2004;16(5):533-42. 

14. Sweis R and Fox M. Curr Gastroenterol Rep. 2020;22(10):49. 

15. Carlson DA et al. Gastroenterology. 2015;149(7):1742-51. 

16. Donnan EN and Pandolfino JE. Gastroenterol Clin North Am. 2020;49(3):427-35. 

17. Carlson DA. Curr Opin Gastroenterol. 2016;32(4):310-8.
 

18. Zheng T et al. Neurogastroenterol Motil. 2022;34(10):e14386.

19. Carlson DA et al. Clin Gastroenterol Hepatol. 2022;20(8):1719-28.e3.

20. Carlson DA et al. Am J Gastroenterol. 2016;111(12):1726-35.

21. Carlson DA et al. Neurogastroenterol Motil. 2021;33(10):e14116.

22. Carlson DA et al. Gastrointest Endosc. 2019;90(6):915-923.e1.

23. Fox MR et al. Neurogastroenterol Motil. 2021;33(4):e14120.

24. Aziz Q et al. Gastroenterology. 2016 Feb 15. doi: 10.1053/j.gastro.2016.02.012.

Considerable advances in artificial intelligence (AI) and machine-learning (ML) methodologies have led to the emergence of promising tools in the field of gastrointestinal endoscopy. Computer vision is an application of AI/ML that has been successfully applied for the computer-aided detection (CADe) and computer-aided diagnosis (CADx) of colon polyps and numerous other conditions encountered during GI endoscopy. Outside of computer vision, a wide variety of other AI applications have been applied to gastroenterology, ranging from natural language processing (NLP) to optimize clinical documentation and endoscopy quality reporting to ML techniques that predict disease severity/treatment response and augment clinical decision-making. This article focuses on opportunities for AI applications in colonoscopy, reviews the existing data, describes the challenges limiting widespread adoption, and explores future directions.

In the United States, colonoscopy is the standard for colon cancer screening and prevention; however, precancerous polyps can be missed for various reasons, ranging from subtle surface appearance of the polyp or location behind a colonic fold to operator-dependent reasons such as inadequate mucosal inspection. Though clinical practice guidelines have set adenoma detection rate (ADR) thresholds at 20% for women and 30% for men, studies have shown a 4- to 10-fold variation in ADR among physicians in clinical practice settings^,1 with an estimated adenoma miss rate (AMR) of 25% and a false-negative colonoscopy rate of 12%.² Variability in adenoma detection affects the risk of interval colorectal cancer post colonoscopy.^3,4

AI provides an opportunity for mitigating this risk. Advances in deep learning and computer vision have led to the development of CADe systems that automatically detect polyps in real time during colonoscopy, resulting in reduced adenoma miss rates (Table 1). In addition to polyp detection, deep-learning technologies are also being used in CADx systems for polyp diagnosis and characterization of malignancy risk. This could aid therapeutic decision-making: Unnecessary resection or histopathologic analysis could be obviated for benign hyperplastic polyps. On the other end of the polyp spectrum, an AI tool that could predict the presence or absence of submucosal invasion could be a powerful tool when evaluating early colon cancers for consideration of endoscopic submucosal dissection vs. surgery. Examples of CADe polyp detection and CADx polyp characterization are shown in Figure 1.

Other potential computer vision applications that may improve colonoscopy quality include tools that help measure adequacy of mucosal exposure, segmental inspection time, and a variety of other parameters associated with polyp detection performance. These are promising areas for future research. Beyond improving colonoscopy technique, natural language processing tools already are being used to optimize clinical documentation as well as extract information from colonoscopy and pathology reports that can facilitate reporting of colonoscopy quality metrics such as ADR, cecal intubation rate, withdrawal time, and bowel preparation adequacy. AI-powered analytics may help unlock large-scale reporting of colonoscopy quality metrics on a health-systems level⁵ or population-level,⁶ helping to ensure optimal performance and identifying avenues for colonoscopy quality improvement.

In comparison, the data landscape for CADx is nascent and currently limited to several retrospective studies dating back to 2009 and a few prospective studies that have shown promising results.^10,11 There is an expectation that integrated CADx also may support the adoption of “resect and discard” or “diagnose and leave” strategies for low-risk polyps. About two-thirds of polyps identified on average-risk screening colonoscopies are diminutive polyps (less than 5 mm in size), which rarely have advanced histologic features (about 0.5%) and are sometimes non-neoplastic (30%). Malignancy risk is even lower in the distal colon.¹² As routine histopathologic assessment of such polyps is mostly of limited clinical utility and comes with added pathology costs, CADx technologies may offer a more cost-effective approach where polyps that are characterized in real-time as low-risk adenomas or non-neoplastic are “resected and discarded” or “left in” respectively. In 2011, prior to the development of current AI tools, the American Society for Gastrointestinal Endoscopy set performance thresholds for technologies supporting real-time endoscopic assessment of the histology of diminutive colorectal polyps. The ASGE recommended 90% histopathologic concordance for “resect and discard” tools and 90% negative predictive value for adenomatous histology for “diagnose and leave,” tools.¹³ Narrow-band imaging (NBI), for example, has been shown to meet these benchmarks^14,15 with a modeling study suggesting that implementing “resect and discard” strategies with such tools could result in annual savings of $33 million without adversely affecting efficacy, although practical adoption has been limited.¹⁶ More recent work has directly explored the feasibility of leveraging CADx to support “leave-in-situ” and “resect-and-discard” strategies.¹⁷

Similarly, while CADe use in colonoscopy is associated with additional up-front costs, a modeling study suggests that its associated gains in ADR (as detailed in Table 1) make it a cost-saving strategy for colorectal cancer prevention in the long term.¹⁸ There is still uncertainty on whether the incremental CADe-associated gains in adenoma detection will necessarily translate to significant reductions in interval colorectal cancer risk, particularly for endoscopists who are already high-performing polyp detectors. A recent study suggests that, although higher ADRs were associated with lower rates of interval colorectal cancer, the gains in interval colorectal cancer risk reduction appeared to level off with ADRs above 35%-40% (this finding may be limited by statistical power).¹⁹ Further, most of the data from CADe trials suggest that gains in adenoma detection are not driven by increased detection of advanced lesions with high malignancy risk but by small polyps with long latency periods of about 5-10 years, which may not significantly alter interval cancer risk. It remains to be determined whether adoption of CADe will have an impact on hard outcomes, most importantly interval colorectal cancer risk, or merely result in increased resource utilization without moving the needle on colorectal cancer prevention. To answer this question, the OperA study – a large-scale randomized clinical trial of 200,000 patients across 18 centers from 13 countries – was launched in 2022. It will investigate the effect of colonoscopy with CADe on a number of critical measures, including long-term interval colon cancer risk.²⁰

Despite commercial availability of regulatory-approved CADe systems and data supporting use for adenoma detection in colonoscopy, mainstream adoption in clinical practice has been sluggish. Physician survey studies have shown that, although there is considerable interest in integrating CADe into clinical practice, there are concerns about access, cost and reimbursement, integration into clinical work-flow, increased procedural times, over-reliance on AI, and algorithmic bias leading to errors.^21,22 In addition, without mandatory requirements for ADR reporting or clinical practice guideline recommendations for CADe use, these systems may not be perceived as valuable or ready for prime time even though the evidence suggests otherwise.^23,24 For CADe systems to see widespread adoption in clinical practice, it is important that future research studies rigorously investigate and characterize these potential barriers to better inform strategies to address AI hesitancy and implementation challenges. Such efforts can provide an integration framework for future AI applications in gastroenterology beyond colonoscopy, such as CADe of esophageal and gastric premalignant lesions in upper endoscopy, CADx for pancreatic cysts and liver lesions on imaging, NLP tools to optimizing efficient clinical documentation and reporting, and many others.

Dr. Uche-Anya is in the division of gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston. Dr. Berzin is with the Center for Advanced Endoscopy, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. Dr. Berzin is a consultant for Wision AI, Medtronic, Magentiq Eye, RSIP Vision, and Docbot.

Corresponding Author: Eugenia Uche-Anya eucheanya@mgh.harvard.edu Twitter: @UcheAnyaMD @tberzin

References

1. Corley DA et al. Can we improve adenoma detection rates? A systematic review of intervention studies. Gastrointest Endosc. Sep 2011;74(3):656-65. doi: 10.1016/j.gie.2011.04.017.

2. Zhao S et al. Magnitude, risk factors, and factors associated with adenoma miss rate of tandem colonoscopy: A systematic review and meta-analysis. Gastroenterology. 05 2019;156(6):1661-74.e11. doi: 10.1053/j.gastro.2019.01.260.

3. Kaminski MF et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med. May 13 2010;362(19):1795-803. doi: 10.1056/NEJMoa0907667.

4. Corley DA et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. Apr 03 2014;370(14):1298-306. doi: 10.1056/NEJMoa1309086.

5. Laique SN et al. Application of optical character recognition with natural language processing for large-scale quality metric data extraction in colonoscopy reports. Gastrointest Endosc. 03 2021;93(3):750-7. doi: 10.1016/j.gie.2020.08.038.

6. Tinmouth J et al. Validation of a natural language processing algorithm to identify adenomas and measure adenoma detection rates across a health system: a population-level study. Gastrointest Endosc. Jul 14 2022. doi: 10.1016/j.gie.2022.07.009.

7. Glissen Brown JR et al. Deep learning computer-aided polyp detection reduces adenoma miss rate: A United States multi-center randomized tandem colonoscopy study (CADeT-CS Trial). Clin Gastroenterol Hepatol. 07 2022;20(7):1499-1507.e4. doi: 10.1016/j.cgh.2021.09.009.

8. Wallace MB et al. Impact of artificial intelligence on miss rate of colorectal neoplasia. Gastroenterology. 07 2022;163(1):295-304.e5. doi: 10.1053/j.gastro.2022.03.007.

9. Hassan C et al. Performance of artificial intelligence in colonoscopy for adenoma and polyp detection: a systematic review and meta-analysis. Gastrointest Endosc. 01 2021;93(1):77-85.e6. doi: 10.1016/j.gie.2020.06.059.

10. Glissen Brown JR and Berzin TM. Adoption of new technologies: Artificial intelligence. Gastrointest Endosc Clin N Am. Oct 2021;31(4):743-58. doi: 10.1016/j.giec.2021.05.010.

11. Larsen SLV and Mori Y. Artificial intelligence in colonoscopy: A review on the current status. DEN open. Apr 2022;2(1):e109. doi: 10.1002/deo2.109.

12. Gupta N et al. Prevalence of advanced histological features in diminutive and small colon polyps. Gastrointest Endosc. May 2012;75(5):1022-30. doi: 10.1016/j.gie.2012.01.020.

13. Rex DK et al. The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2011;73(3):419-22. doi: 10.1016/j.gie.2011.01.023.

14. Abu Dayyeh BK et al. ASGE Technology Committee systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2015;81(3):502.e1-16. doi: 10.1016/j.gie.2014.12.022.

15. Mori Y et al. Real-time use of artificial intelligence in identification of diminutive polyps during colonoscopy: A prospective study. Ann Intern Med. Sep 18 2018;169(6):357-66. doi: 10.7326/M18-0249.

16. Hassan C et al.. A resect and discard strategy would improve cost-effectiveness of colorectal cancer screening. Clin Gastroenterol Hepatol. Oct 2010;8(10):865-9, 869.e1-3. doi: 10.1016/j.cgh.2010.05.018.

17. Hassan C et al. Artificial intelligence allows leaving-in-situ colorectal polyps. Clin Gastroenterol Hepatol. Nov 2022;20(11):2505-13.e4. doi: 10.1016/j.cgh.2022.04.045.

18. Areia M et al. Cost-effectiveness of artificial intelligence for screening colonoscopy: a modelling study. Lancet Digit Health. 06 2022;4(6):e436-44. doi: 10.1016/S2589-7500(22)00042-5.

19. Schottinger JE et al. Association of physician adenoma detection rates with postcolonoscopy colorectal cancer. JAMA. 2022 Jun 7;327(21):2114-22. doi: 10.1001/jama.2022.6644.

20. Oslo Uo. Optimising colorectal cancer prevention through personalised treatment with artificial intelligence. 2022.

21. Wadhwa V et al. Physician sentiment toward artificial intelligence (AI) in colonoscopic practice: a survey of US gastroenterologists. Endosc Int Open. Oct 2020;8(10):E1379-84. doi: 10.1055/a-1223-1926.

22. Kader R et al. Survey on the perceptions of UK gastroenterologists and endoscopists to artificial intelligence. Frontline Gastroenterol. 2022;13(5):423-9. doi: 10.1136/flgastro-2021-101994.

23. Rex DKet al. Artificial intelligence improves detection at colonoscopy: Why aren’t we all already using it? Gastroenterology. 07 2022;163(1):35-7. doi: 10.1053/j.gastro.2022.04.042.

24. Ahmad OF et al. Establishing key research questions for the implementation of artificial intelligence in colonoscopy: A modified Delphi method. Endoscopy. 09 2021;53(9):893-901. doi: 10.1055/a-1306-7590

Considerable advances in artificial intelligence (AI) and machine-learning (ML) methodologies have led to the emergence of promising tools in the field of gastrointestinal endoscopy. Computer vision is an application of AI/ML that has been successfully applied for the computer-aided detection (CADe) and computer-aided diagnosis (CADx) of colon polyps and numerous other conditions encountered during GI endoscopy. Outside of computer vision, a wide variety of other AI applications have been applied to gastroenterology, ranging from natural language processing (NLP) to optimize clinical documentation and endoscopy quality reporting to ML techniques that predict disease severity/treatment response and augment clinical decision-making. This article focuses on opportunities for AI applications in colonoscopy, reviews the existing data, describes the challenges limiting widespread adoption, and explores future directions.

In the United States, colonoscopy is the standard for colon cancer screening and prevention; however, precancerous polyps can be missed for various reasons, ranging from subtle surface appearance of the polyp or location behind a colonic fold to operator-dependent reasons such as inadequate mucosal inspection. Though clinical practice guidelines have set adenoma detection rate (ADR) thresholds at 20% for women and 30% for men, studies have shown a 4- to 10-fold variation in ADR among physicians in clinical practice settings^,1 with an estimated adenoma miss rate (AMR) of 25% and a false-negative colonoscopy rate of 12%.² Variability in adenoma detection affects the risk of interval colorectal cancer post colonoscopy.^3,4

AI provides an opportunity for mitigating this risk. Advances in deep learning and computer vision have led to the development of CADe systems that automatically detect polyps in real time during colonoscopy, resulting in reduced adenoma miss rates (Table 1). In addition to polyp detection, deep-learning technologies are also being used in CADx systems for polyp diagnosis and characterization of malignancy risk. This could aid therapeutic decision-making: Unnecessary resection or histopathologic analysis could be obviated for benign hyperplastic polyps. On the other end of the polyp spectrum, an AI tool that could predict the presence or absence of submucosal invasion could be a powerful tool when evaluating early colon cancers for consideration of endoscopic submucosal dissection vs. surgery. Examples of CADe polyp detection and CADx polyp characterization are shown in Figure 1.

Other potential computer vision applications that may improve colonoscopy quality include tools that help measure adequacy of mucosal exposure, segmental inspection time, and a variety of other parameters associated with polyp detection performance. These are promising areas for future research. Beyond improving colonoscopy technique, natural language processing tools already are being used to optimize clinical documentation as well as extract information from colonoscopy and pathology reports that can facilitate reporting of colonoscopy quality metrics such as ADR, cecal intubation rate, withdrawal time, and bowel preparation adequacy. AI-powered analytics may help unlock large-scale reporting of colonoscopy quality metrics on a health-systems level⁵ or population-level,⁶ helping to ensure optimal performance and identifying avenues for colonoscopy quality improvement.

In comparison, the data landscape for CADx is nascent and currently limited to several retrospective studies dating back to 2009 and a few prospective studies that have shown promising results.^10,11 There is an expectation that integrated CADx also may support the adoption of “resect and discard” or “diagnose and leave” strategies for low-risk polyps. About two-thirds of polyps identified on average-risk screening colonoscopies are diminutive polyps (less than 5 mm in size), which rarely have advanced histologic features (about 0.5%) and are sometimes non-neoplastic (30%). Malignancy risk is even lower in the distal colon.¹² As routine histopathologic assessment of such polyps is mostly of limited clinical utility and comes with added pathology costs, CADx technologies may offer a more cost-effective approach where polyps that are characterized in real-time as low-risk adenomas or non-neoplastic are “resected and discarded” or “left in” respectively. In 2011, prior to the development of current AI tools, the American Society for Gastrointestinal Endoscopy set performance thresholds for technologies supporting real-time endoscopic assessment of the histology of diminutive colorectal polyps. The ASGE recommended 90% histopathologic concordance for “resect and discard” tools and 90% negative predictive value for adenomatous histology for “diagnose and leave,” tools.¹³ Narrow-band imaging (NBI), for example, has been shown to meet these benchmarks^14,15 with a modeling study suggesting that implementing “resect and discard” strategies with such tools could result in annual savings of $33 million without adversely affecting efficacy, although practical adoption has been limited.¹⁶ More recent work has directly explored the feasibility of leveraging CADx to support “leave-in-situ” and “resect-and-discard” strategies.¹⁷

Similarly, while CADe use in colonoscopy is associated with additional up-front costs, a modeling study suggests that its associated gains in ADR (as detailed in Table 1) make it a cost-saving strategy for colorectal cancer prevention in the long term.¹⁸ There is still uncertainty on whether the incremental CADe-associated gains in adenoma detection will necessarily translate to significant reductions in interval colorectal cancer risk, particularly for endoscopists who are already high-performing polyp detectors. A recent study suggests that, although higher ADRs were associated with lower rates of interval colorectal cancer, the gains in interval colorectal cancer risk reduction appeared to level off with ADRs above 35%-40% (this finding may be limited by statistical power).¹⁹ Further, most of the data from CADe trials suggest that gains in adenoma detection are not driven by increased detection of advanced lesions with high malignancy risk but by small polyps with long latency periods of about 5-10 years, which may not significantly alter interval cancer risk. It remains to be determined whether adoption of CADe will have an impact on hard outcomes, most importantly interval colorectal cancer risk, or merely result in increased resource utilization without moving the needle on colorectal cancer prevention. To answer this question, the OperA study – a large-scale randomized clinical trial of 200,000 patients across 18 centers from 13 countries – was launched in 2022. It will investigate the effect of colonoscopy with CADe on a number of critical measures, including long-term interval colon cancer risk.²⁰

Despite commercial availability of regulatory-approved CADe systems and data supporting use for adenoma detection in colonoscopy, mainstream adoption in clinical practice has been sluggish. Physician survey studies have shown that, although there is considerable interest in integrating CADe into clinical practice, there are concerns about access, cost and reimbursement, integration into clinical work-flow, increased procedural times, over-reliance on AI, and algorithmic bias leading to errors.^21,22 In addition, without mandatory requirements for ADR reporting or clinical practice guideline recommendations for CADe use, these systems may not be perceived as valuable or ready for prime time even though the evidence suggests otherwise.^23,24 For CADe systems to see widespread adoption in clinical practice, it is important that future research studies rigorously investigate and characterize these potential barriers to better inform strategies to address AI hesitancy and implementation challenges. Such efforts can provide an integration framework for future AI applications in gastroenterology beyond colonoscopy, such as CADe of esophageal and gastric premalignant lesions in upper endoscopy, CADx for pancreatic cysts and liver lesions on imaging, NLP tools to optimizing efficient clinical documentation and reporting, and many others.

Dr. Uche-Anya is in the division of gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston. Dr. Berzin is with the Center for Advanced Endoscopy, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. Dr. Berzin is a consultant for Wision AI, Medtronic, Magentiq Eye, RSIP Vision, and Docbot.

Corresponding Author: Eugenia Uche-Anya eucheanya@mgh.harvard.edu Twitter: @UcheAnyaMD @tberzin

References

1. Corley DA et al. Can we improve adenoma detection rates? A systematic review of intervention studies. Gastrointest Endosc. Sep 2011;74(3):656-65. doi: 10.1016/j.gie.2011.04.017.

2. Zhao S et al. Magnitude, risk factors, and factors associated with adenoma miss rate of tandem colonoscopy: A systematic review and meta-analysis. Gastroenterology. 05 2019;156(6):1661-74.e11. doi: 10.1053/j.gastro.2019.01.260.

3. Kaminski MF et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med. May 13 2010;362(19):1795-803. doi: 10.1056/NEJMoa0907667.

4. Corley DA et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. Apr 03 2014;370(14):1298-306. doi: 10.1056/NEJMoa1309086.

5. Laique SN et al. Application of optical character recognition with natural language processing for large-scale quality metric data extraction in colonoscopy reports. Gastrointest Endosc. 03 2021;93(3):750-7. doi: 10.1016/j.gie.2020.08.038.

6. Tinmouth J et al. Validation of a natural language processing algorithm to identify adenomas and measure adenoma detection rates across a health system: a population-level study. Gastrointest Endosc. Jul 14 2022. doi: 10.1016/j.gie.2022.07.009.

7. Glissen Brown JR et al. Deep learning computer-aided polyp detection reduces adenoma miss rate: A United States multi-center randomized tandem colonoscopy study (CADeT-CS Trial). Clin Gastroenterol Hepatol. 07 2022;20(7):1499-1507.e4. doi: 10.1016/j.cgh.2021.09.009.

8. Wallace MB et al. Impact of artificial intelligence on miss rate of colorectal neoplasia. Gastroenterology. 07 2022;163(1):295-304.e5. doi: 10.1053/j.gastro.2022.03.007.

9. Hassan C et al. Performance of artificial intelligence in colonoscopy for adenoma and polyp detection: a systematic review and meta-analysis. Gastrointest Endosc. 01 2021;93(1):77-85.e6. doi: 10.1016/j.gie.2020.06.059.

10. Glissen Brown JR and Berzin TM. Adoption of new technologies: Artificial intelligence. Gastrointest Endosc Clin N Am. Oct 2021;31(4):743-58. doi: 10.1016/j.giec.2021.05.010.

11. Larsen SLV and Mori Y. Artificial intelligence in colonoscopy: A review on the current status. DEN open. Apr 2022;2(1):e109. doi: 10.1002/deo2.109.

12. Gupta N et al. Prevalence of advanced histological features in diminutive and small colon polyps. Gastrointest Endosc. May 2012;75(5):1022-30. doi: 10.1016/j.gie.2012.01.020.

13. Rex DK et al. The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2011;73(3):419-22. doi: 10.1016/j.gie.2011.01.023.

14. Abu Dayyeh BK et al. ASGE Technology Committee systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2015;81(3):502.e1-16. doi: 10.1016/j.gie.2014.12.022.

15. Mori Y et al. Real-time use of artificial intelligence in identification of diminutive polyps during colonoscopy: A prospective study. Ann Intern Med. Sep 18 2018;169(6):357-66. doi: 10.7326/M18-0249.

16. Hassan C et al.. A resect and discard strategy would improve cost-effectiveness of colorectal cancer screening. Clin Gastroenterol Hepatol. Oct 2010;8(10):865-9, 869.e1-3. doi: 10.1016/j.cgh.2010.05.018.

17. Hassan C et al. Artificial intelligence allows leaving-in-situ colorectal polyps. Clin Gastroenterol Hepatol. Nov 2022;20(11):2505-13.e4. doi: 10.1016/j.cgh.2022.04.045.

18. Areia M et al. Cost-effectiveness of artificial intelligence for screening colonoscopy: a modelling study. Lancet Digit Health. 06 2022;4(6):e436-44. doi: 10.1016/S2589-7500(22)00042-5.

19. Schottinger JE et al. Association of physician adenoma detection rates with postcolonoscopy colorectal cancer. JAMA. 2022 Jun 7;327(21):2114-22. doi: 10.1001/jama.2022.6644.

20. Oslo Uo. Optimising colorectal cancer prevention through personalised treatment with artificial intelligence. 2022.

21. Wadhwa V et al. Physician sentiment toward artificial intelligence (AI) in colonoscopic practice: a survey of US gastroenterologists. Endosc Int Open. Oct 2020;8(10):E1379-84. doi: 10.1055/a-1223-1926.

22. Kader R et al. Survey on the perceptions of UK gastroenterologists and endoscopists to artificial intelligence. Frontline Gastroenterol. 2022;13(5):423-9. doi: 10.1136/flgastro-2021-101994.

23. Rex DKet al. Artificial intelligence improves detection at colonoscopy: Why aren’t we all already using it? Gastroenterology. 07 2022;163(1):35-7. doi: 10.1053/j.gastro.2022.04.042.

24. Ahmad OF et al. Establishing key research questions for the implementation of artificial intelligence in colonoscopy: A modified Delphi method. Endoscopy. 09 2021;53(9):893-901. doi: 10.1055/a-1306-7590

Considerable advances in artificial intelligence (AI) and machine-learning (ML) methodologies have led to the emergence of promising tools in the field of gastrointestinal endoscopy. Computer vision is an application of AI/ML that has been successfully applied for the computer-aided detection (CADe) and computer-aided diagnosis (CADx) of colon polyps and numerous other conditions encountered during GI endoscopy. Outside of computer vision, a wide variety of other AI applications have been applied to gastroenterology, ranging from natural language processing (NLP) to optimize clinical documentation and endoscopy quality reporting to ML techniques that predict disease severity/treatment response and augment clinical decision-making. This article focuses on opportunities for AI applications in colonoscopy, reviews the existing data, describes the challenges limiting widespread adoption, and explores future directions.

In the United States, colonoscopy is the standard for colon cancer screening and prevention; however, precancerous polyps can be missed for various reasons, ranging from subtle surface appearance of the polyp or location behind a colonic fold to operator-dependent reasons such as inadequate mucosal inspection. Though clinical practice guidelines have set adenoma detection rate (ADR) thresholds at 20% for women and 30% for men, studies have shown a 4- to 10-fold variation in ADR among physicians in clinical practice settings^,1 with an estimated adenoma miss rate (AMR) of 25% and a false-negative colonoscopy rate of 12%.² Variability in adenoma detection affects the risk of interval colorectal cancer post colonoscopy.^3,4

AI provides an opportunity for mitigating this risk. Advances in deep learning and computer vision have led to the development of CADe systems that automatically detect polyps in real time during colonoscopy, resulting in reduced adenoma miss rates (Table 1). In addition to polyp detection, deep-learning technologies are also being used in CADx systems for polyp diagnosis and characterization of malignancy risk. This could aid therapeutic decision-making: Unnecessary resection or histopathologic analysis could be obviated for benign hyperplastic polyps. On the other end of the polyp spectrum, an AI tool that could predict the presence or absence of submucosal invasion could be a powerful tool when evaluating early colon cancers for consideration of endoscopic submucosal dissection vs. surgery. Examples of CADe polyp detection and CADx polyp characterization are shown in Figure 1.

Other potential computer vision applications that may improve colonoscopy quality include tools that help measure adequacy of mucosal exposure, segmental inspection time, and a variety of other parameters associated with polyp detection performance. These are promising areas for future research. Beyond improving colonoscopy technique, natural language processing tools already are being used to optimize clinical documentation as well as extract information from colonoscopy and pathology reports that can facilitate reporting of colonoscopy quality metrics such as ADR, cecal intubation rate, withdrawal time, and bowel preparation adequacy. AI-powered analytics may help unlock large-scale reporting of colonoscopy quality metrics on a health-systems level⁵ or population-level,⁶ helping to ensure optimal performance and identifying avenues for colonoscopy quality improvement.

In comparison, the data landscape for CADx is nascent and currently limited to several retrospective studies dating back to 2009 and a few prospective studies that have shown promising results.^10,11 There is an expectation that integrated CADx also may support the adoption of “resect and discard” or “diagnose and leave” strategies for low-risk polyps. About two-thirds of polyps identified on average-risk screening colonoscopies are diminutive polyps (less than 5 mm in size), which rarely have advanced histologic features (about 0.5%) and are sometimes non-neoplastic (30%). Malignancy risk is even lower in the distal colon.¹² As routine histopathologic assessment of such polyps is mostly of limited clinical utility and comes with added pathology costs, CADx technologies may offer a more cost-effective approach where polyps that are characterized in real-time as low-risk adenomas or non-neoplastic are “resected and discarded” or “left in” respectively. In 2011, prior to the development of current AI tools, the American Society for Gastrointestinal Endoscopy set performance thresholds for technologies supporting real-time endoscopic assessment of the histology of diminutive colorectal polyps. The ASGE recommended 90% histopathologic concordance for “resect and discard” tools and 90% negative predictive value for adenomatous histology for “diagnose and leave,” tools.¹³ Narrow-band imaging (NBI), for example, has been shown to meet these benchmarks^14,15 with a modeling study suggesting that implementing “resect and discard” strategies with such tools could result in annual savings of $33 million without adversely affecting efficacy, although practical adoption has been limited.¹⁶ More recent work has directly explored the feasibility of leveraging CADx to support “leave-in-situ” and “resect-and-discard” strategies.¹⁷

Similarly, while CADe use in colonoscopy is associated with additional up-front costs, a modeling study suggests that its associated gains in ADR (as detailed in Table 1) make it a cost-saving strategy for colorectal cancer prevention in the long term.¹⁸ There is still uncertainty on whether the incremental CADe-associated gains in adenoma detection will necessarily translate to significant reductions in interval colorectal cancer risk, particularly for endoscopists who are already high-performing polyp detectors. A recent study suggests that, although higher ADRs were associated with lower rates of interval colorectal cancer, the gains in interval colorectal cancer risk reduction appeared to level off with ADRs above 35%-40% (this finding may be limited by statistical power).¹⁹ Further, most of the data from CADe trials suggest that gains in adenoma detection are not driven by increased detection of advanced lesions with high malignancy risk but by small polyps with long latency periods of about 5-10 years, which may not significantly alter interval cancer risk. It remains to be determined whether adoption of CADe will have an impact on hard outcomes, most importantly interval colorectal cancer risk, or merely result in increased resource utilization without moving the needle on colorectal cancer prevention. To answer this question, the OperA study – a large-scale randomized clinical trial of 200,000 patients across 18 centers from 13 countries – was launched in 2022. It will investigate the effect of colonoscopy with CADe on a number of critical measures, including long-term interval colon cancer risk.²⁰

Despite commercial availability of regulatory-approved CADe systems and data supporting use for adenoma detection in colonoscopy, mainstream adoption in clinical practice has been sluggish. Physician survey studies have shown that, although there is considerable interest in integrating CADe into clinical practice, there are concerns about access, cost and reimbursement, integration into clinical work-flow, increased procedural times, over-reliance on AI, and algorithmic bias leading to errors.^21,22 In addition, without mandatory requirements for ADR reporting or clinical practice guideline recommendations for CADe use, these systems may not be perceived as valuable or ready for prime time even though the evidence suggests otherwise.^23,24 For CADe systems to see widespread adoption in clinical practice, it is important that future research studies rigorously investigate and characterize these potential barriers to better inform strategies to address AI hesitancy and implementation challenges. Such efforts can provide an integration framework for future AI applications in gastroenterology beyond colonoscopy, such as CADe of esophageal and gastric premalignant lesions in upper endoscopy, CADx for pancreatic cysts and liver lesions on imaging, NLP tools to optimizing efficient clinical documentation and reporting, and many others.

Dr. Uche-Anya is in the division of gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston. Dr. Berzin is with the Center for Advanced Endoscopy, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. Dr. Berzin is a consultant for Wision AI, Medtronic, Magentiq Eye, RSIP Vision, and Docbot.

Corresponding Author: Eugenia Uche-Anya eucheanya@mgh.harvard.edu Twitter: @UcheAnyaMD @tberzin

References

1. Corley DA et al. Can we improve adenoma detection rates? A systematic review of intervention studies. Gastrointest Endosc. Sep 2011;74(3):656-65. doi: 10.1016/j.gie.2011.04.017.

2. Zhao S et al. Magnitude, risk factors, and factors associated with adenoma miss rate of tandem colonoscopy: A systematic review and meta-analysis. Gastroenterology. 05 2019;156(6):1661-74.e11. doi: 10.1053/j.gastro.2019.01.260.

3. Kaminski MF et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med. May 13 2010;362(19):1795-803. doi: 10.1056/NEJMoa0907667.

4. Corley DA et al. Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med. Apr 03 2014;370(14):1298-306. doi: 10.1056/NEJMoa1309086.

5. Laique SN et al. Application of optical character recognition with natural language processing for large-scale quality metric data extraction in colonoscopy reports. Gastrointest Endosc. 03 2021;93(3):750-7. doi: 10.1016/j.gie.2020.08.038.

6. Tinmouth J et al. Validation of a natural language processing algorithm to identify adenomas and measure adenoma detection rates across a health system: a population-level study. Gastrointest Endosc. Jul 14 2022. doi: 10.1016/j.gie.2022.07.009.

7. Glissen Brown JR et al. Deep learning computer-aided polyp detection reduces adenoma miss rate: A United States multi-center randomized tandem colonoscopy study (CADeT-CS Trial). Clin Gastroenterol Hepatol. 07 2022;20(7):1499-1507.e4. doi: 10.1016/j.cgh.2021.09.009.

8. Wallace MB et al. Impact of artificial intelligence on miss rate of colorectal neoplasia. Gastroenterology. 07 2022;163(1):295-304.e5. doi: 10.1053/j.gastro.2022.03.007.

9. Hassan C et al. Performance of artificial intelligence in colonoscopy for adenoma and polyp detection: a systematic review and meta-analysis. Gastrointest Endosc. 01 2021;93(1):77-85.e6. doi: 10.1016/j.gie.2020.06.059.

10. Glissen Brown JR and Berzin TM. Adoption of new technologies: Artificial intelligence. Gastrointest Endosc Clin N Am. Oct 2021;31(4):743-58. doi: 10.1016/j.giec.2021.05.010.

11. Larsen SLV and Mori Y. Artificial intelligence in colonoscopy: A review on the current status. DEN open. Apr 2022;2(1):e109. doi: 10.1002/deo2.109.

12. Gupta N et al. Prevalence of advanced histological features in diminutive and small colon polyps. Gastrointest Endosc. May 2012;75(5):1022-30. doi: 10.1016/j.gie.2012.01.020.

13. Rex DK et al. The American Society for Gastrointestinal Endoscopy PIVI (Preservation and Incorporation of Valuable Endoscopic Innovations) on real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2011;73(3):419-22. doi: 10.1016/j.gie.2011.01.023.

14. Abu Dayyeh BK et al. ASGE Technology Committee systematic review and meta-analysis assessing the ASGE PIVI thresholds for adopting real-time endoscopic assessment of the histology of diminutive colorectal polyps. Gastrointest Endosc. Mar 2015;81(3):502.e1-16. doi: 10.1016/j.gie.2014.12.022.

15. Mori Y et al. Real-time use of artificial intelligence in identification of diminutive polyps during colonoscopy: A prospective study. Ann Intern Med. Sep 18 2018;169(6):357-66. doi: 10.7326/M18-0249.

16. Hassan C et al.. A resect and discard strategy would improve cost-effectiveness of colorectal cancer screening. Clin Gastroenterol Hepatol. Oct 2010;8(10):865-9, 869.e1-3. doi: 10.1016/j.cgh.2010.05.018.

17. Hassan C et al. Artificial intelligence allows leaving-in-situ colorectal polyps. Clin Gastroenterol Hepatol. Nov 2022;20(11):2505-13.e4. doi: 10.1016/j.cgh.2022.04.045.

18. Areia M et al. Cost-effectiveness of artificial intelligence for screening colonoscopy: a modelling study. Lancet Digit Health. 06 2022;4(6):e436-44. doi: 10.1016/S2589-7500(22)00042-5.

19. Schottinger JE et al. Association of physician adenoma detection rates with postcolonoscopy colorectal cancer. JAMA. 2022 Jun 7;327(21):2114-22. doi: 10.1001/jama.2022.6644.

20. Oslo Uo. Optimising colorectal cancer prevention through personalised treatment with artificial intelligence. 2022.

21. Wadhwa V et al. Physician sentiment toward artificial intelligence (AI) in colonoscopic practice: a survey of US gastroenterologists. Endosc Int Open. Oct 2020;8(10):E1379-84. doi: 10.1055/a-1223-1926.

22. Kader R et al. Survey on the perceptions of UK gastroenterologists and endoscopists to artificial intelligence. Frontline Gastroenterol. 2022;13(5):423-9. doi: 10.1136/flgastro-2021-101994.

23. Rex DKet al. Artificial intelligence improves detection at colonoscopy: Why aren’t we all already using it? Gastroenterology. 07 2022;163(1):35-7. doi: 10.1053/j.gastro.2022.04.042.

24. Ahmad OF et al. Establishing key research questions for the implementation of artificial intelligence in colonoscopy: A modified Delphi method. Endoscopy. 09 2021;53(9):893-901. doi: 10.1055/a-1306-7590

Antithrombotic therapy is increasingly used to either reduce the risk of or treat thromboembolic episodes in patients with various medical conditions such as ischemic and valvular heart disease, atrial fibrillation (AF), cerebrovascular disease, peripheral arterial disease, venous thromboembolism (VTE) and hypercoagulable diseases. Antithrombotics include medications classified as anticoagulants or antiplatelets. Anticoagulants work by interfering with the native clotting cascade and consist of four main classes: vitamin K antagonists (VKA), heparin derivatives, direct factor Xa inhibitors, and direct thrombin inhibitors. Direct oral anticoagulants (DOACs) refer to dabigatran (a direct thrombin inhibitor) and the factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban).

Antiplatelets, on the other hand, work by decreasing platelet aggregation and thus preventing thrombus formation; they include P2Y12 receptor inhibitors, protease-activated receptor-1 inhibitors, glycoprotein IIb/IIIa receptor inhibitors, acetylsalicylic acid (ASA), and nonsteroidal anti-inflammatory drugs. All of these agents may directly cause or increase the risk of gastrointestinal (GI) bleeding from luminal sources such as ulcers or diverticula, as well as after endoscopic interventions such as polypectomy. However, there is also a risk of thromboembolic consequences if some of these agents are withheld. Thus, the management of patients receiving antithrombotic agents and undergoing GI endoscopy represents an important clinical challenge and something that every GI physician has to deal with routinely.

The goal of this review is to discuss the optimal strategy for managing antithrombotics in patients undergoing elective endoscopy based on current available evidence and published clinical guidelines.^1-4 Much of our discussion will review recommendations from the recently published joint American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) guidelines on management of anticoagulants and antiplatelets in the periendoscopic period by Abraham et al.⁴

Factors that guide decision-making

The two most vital factors to consider prior to performing endoscopic procedures in patients receiving antithrombotic therapy are to assess the risk of bleeding associated with the procedure and to assess the risk of thromboembolism associated with the underlying medical condition for which the antithrombotic agents are being used. In addition, it is also important to keep in mind the individual characteristics of the antithrombotic agent(s) used when making these decisions.

Estimating procedure-related bleeding risk

Various endoscopic procedures have different risks of associated bleeding. Although guidelines from GI societies may differ when classifying procedures into low or high risk, it is important to know that most of the original data on postprocedural bleeding risks are from studies conducted in patients who are not on complex antithrombotic regimens and thus may not accurately reflect the bleeding risk of patients using newer antithrombotic therapies.^1,4-7

Traditionally, some of the common low-risk procedures have included diagnostic EGD and colonoscopy with or without biopsy, ERCP without sphincterotomy, biliary stent placement, and push or balloon-assisted enteroscopy. On the other hand, endoscopic procedures associated with interventions are known to have higher bleeding risk, and other procedural factors can influence this risk as well.⁸ For example, polypectomy, one of the most common interventions during endoscopy, is associated with bleeding risk ranging from 0.3% to 10% depending on multiple factors including polyp size, location, morphology (nonpolypoid, sessile, pedunculated), resection technique (cold or hot forceps, cold or hot snare), and type of cautery used.⁹ For some procedures, such as routine screening colonoscopy, however, the preprocedure estimate of bleeding risk can be uncertain because it is unclear if a high risk intervention (e.g., polypectomy of large polyp) will be necessary. For example, in the most recent ACG/CAG guidelines, colonoscopy with polypectomy < 1cm is considered a low/moderate risk bleeding procedure, whereas polypectomy > 1cm is considered high risk for bleeding.⁴ In these situations, the management of antithrombotic medications may depend on the individual patient’s risk of thrombosis and the specific antithrombotic agent. In the example of a patient undergoing colonoscopy while on antithrombotic medications, the bleeding risk associated with polypectomy can potentially be reduced by procedural techniques such as preferential use of cold snare polypectomy. Further high-quality data on the optimal procedural technique to reduce postpolypectomy bleeding in patients on antithrombotic medications is needed to help guide management.
 

Estimating thromboembolic risk

The risk of thromboembolic events in patients who are withholding their antithrombotic therapy for an endoscopic procedure depends on their underlying condition and individual characteristics. In patients who are on antithrombotic therapy for stroke prevention in non-valvular AF, the risk of cerebral thromboembolism in these patients is predictable using the CHA₂DS₂Vasc index.¹⁰ This scoring index includes heart failure, hypertension, age 75 years or older, diabetes mellitus, prior stroke or transient ischemic attack (TIA), vascular disease, age 65-74 years, and sex categories.

Patients with previous VTE on anticoagulation or those who have mechanical heart valves may have different risk factors for thromboembolic episodes. Among patients with VTE, time from initial VTE, history of recurrent VTE with antithrombotic interruption, and presence of underlying thrombophilia are most predictive of future thromboembolic risk. And for patients with mechanical heart valves, presence of a mitral valve prosthesis, and the presence or absence of associated heart failure and AF determine the annual risk of thromboembolic events. Bioprosthetic valves are generally considered low risk.

In patients with coronary artery disease (CAD), high thrombosis risk scenarios with holding antiplatelets include patients within 3 months of an acute coronary syndrome (ACS) event, within 6 months of a drug-eluting stent (DES) placement, or within 1 month of a bare metal coronary stent (BMS) placement. In addition, patients with ACS that occurred within the past 12 months of DES placement or within 2 months of BMS placement are also considered high risk.^11,12 Even beyond these periods, certain patients may still be at high risk of stent occlusion. In particular, patients with a prior history of stent occlusion, ACS or ST elevation myocardial infection, prior multivessel percutaneous coronary intervention, diabetes, renal failure, or diffuse CAD are at higher risk of stent occlusion or ACS events with alteration of antithrombotic therapy.¹³ Thus, modification of antithrombotic regimens in these patients should be cautiously approached.
 

Management of antithrombotics prior to elective endoscopy

In patients who need elective endoscopic procedures, if the indication for antithrombotic therapy is short-term, the procedure is probably best delayed until after that period.¹³ For patients on long-term or lifelong antithrombotic treatment, the decision to temporarily hold the treatment for endoscopy should occur after a discussion with the patient and all of the involved providers. In some high-risk patients, these agents cannot be interrupted; therefore, clinicians must carefully weigh the risks and benefits of the procedure before proceeding with endoscopy. For patients who are known to be undergoing an elective endoscopic procedure, antithrombotic medications may or may not need to be held prior to the procedure depending on the type of therapy. For example, according to the recent ACG/CAG guidelines, warfarin should be continued, whereas DOACs should be temporarily stopped for patients who are undergoing elective/planned endoscopic GI procedures.

Unfractionated heparin (UFH) administered as a continuous intravenous infusion can generally be held 3-4 hours before the procedure, given its short half-life. Low molecular weight heparin (LMWH), including enoxaparin and dalteparin, should be stopped 24 hours prior to the procedure.^2,14 Fondaparinux is a synthetic X-a inhibitor that requires discontinuation at least 36 hours preceding a high risk procedure. For patients on warfarin who are undergoing elective endoscopic procedures that are low risk for inducing bleeding, warfarin can be continued, as opposed to temporarily interrupted, although the dose should be omitted the morning of the procedure.⁴ For those who are undergoing high-risk endoscopic procedures (including colonoscopy with possible polypectomy > 1 cm), 5 days of temporary interruption without periprocedural bridging is appropriate in most patients. This is contrary to previous guidelines, which had recommended bridging for patients with a CHA2DS2Vasc score ≥ 2. Recent impactful randomized trials (BRIDGE and PERIOP-2) have called into question the benefit of periprocedural bridging with LMWH. Avoiding bridging anticoagulation was generally found to be similar to bridging in regard to prevention of thromboembolic complications, but importantly was associated with a decreased risk of major bleeding.^15,16 Of note, periprocedural bridging may still be appropriate in a small subset of patients, including those with mechanical valves, AF with CHADS2 score > 5, and previous thromboembolism during temporary interruption of VKAs. The decision to bridge or not should ideally be made in a multidisciplinary fashion.^15-20

Data are lacking on the ideal strategy for periendoscopic DOAC management. As mentioned above, for patients on DOACs who are undergoing elective endoscopic GI procedures, temporarily interrupting DOACs rather than continuing them is recommended. Currently, there are no randomized controlled trials addressing the management of DOACs in the periendoscopic period. However, based on five cohort studies, the ideal duration of DOAC interruption before endoscopic procedures may be between 1 and 2 days, excluding the day of the procedure.^21-25 This strategy allows for a short preprocedural duration of DOAC interruption and likely provides a balance between bleeding and thromboembolism risk. Importantly, there are no reliable laboratory assays to assess the anticoagulant effect of DOACs, and an individual patient’s degree of renal dysfunction may impact how long the DOAC should be held. In general, the anti-Xa drugs should be held for 1-2 days if the creatinine clearance (CrCl) is ≥ 60 mL/min, for 3 days if the CrCl is between 30 mL/min and 59 mL/min, and for 4 days if the CrCl is less than 30 mL/min.²⁶ For edoxaban, the recommendation is to hold at least 24 hours before high-risk procedures. The recommendation for stopping dabigatran is 2-3 days before a high-risk procedure in patients with CrCl more than 80 mL/min, 3-4 days prior if between 30 and 49 mL/min, and 4-6 days prior if less than 30 mL/min respectively.²⁷

In regard to antiplatelet management, ASA and the P2Y₁₂ receptor inhibitors (e.g. clopidogrel, prasugrel, and ticagrelor) are the most commonly utilized antiplatelets in patients undergoing endoscopic procedures. For patients who are on ASA monotherapy, whether 81 mg or 325 mg daily, for secondary cardiovascular prevention, no interruption of ASA therapy is necessary for elective procedures. The benefit of ASA for secondary cardiovascular prevention and the possible reduction in thrombotic events seen in RCTs of nonendoscopic surgical procedures is well known. However, there may be certain exceptions in which aspirin should be temporarily held. For example, short-term interruption of ASA could be considered in high risk procedures such as biliary or pancreatic sphincterotomy, ampullectomy, and peroral endoscopic myotomy. For patients on single antiplatelet therapy with a P2Y₁₂ receptor inhibitor who are undergoing elective endoscopic GI procedures, the recent CAG/ACG guidelines did not provide a clear recommendation for or against temporary interruption of the P2Y₁₂ receptor inhibitor. Although interruption of a P2Y₁₂ receptor inhibitor should theoretically decrease a patient’s risk of bleeding, the available evidence reported a nonsignificant increased bleeding risk in patients who stop a P2Y₁₂ receptor inhibitor for an elective endoscopic procedure compared with those who continue the medication.^28,29 Therefore, until further data are available, for patients on P2Y₁₂ receptor monotherapy, a reasonable strategy would be to temporarily hold therapy prior to high risk endoscopic procedures, assuming the patients are not at high cardiovascular risk. Clopidogrel and prasugrel have to be stopped 5-7 days prior to allow normal platelet aggregation to resume as opposed to ticagrelor, a reversible P2Y₁₂ receptor inhibitor that can be stopped 3-5 days prior.³⁰

Lastly, for patients who are on dual antiplatelet therapy (DAPT) for secondary prevention, continuation of ASA and temporary interruption of the P2Y₁₂ receptor inhibitor is recommended while undergoing elective endoscopy. Studies have shown that those who discontinued both had a much higher incidence of stent thrombosis compared with those who remained on aspirin alone.^4,28,31

Resumption of antithrombotic therapy after endoscopy

In general, antithrombotic therapy should be resumed upon completion of the procedure unless there remains a persistent risk of major bleeding.^1,14 This consensus is based on studies available on warfarin and heparin products, with minimal literature available regarding the resumption of DOACs. The benefits of immediate re-initiation of antithrombotic therapy for the prevention of thromboembolic events should be weighed against the risk of hemorrhage associated with the specific agent, the time to onset of the medication, and procedure-specific circumstances. For the small subset of patients on warfarin with a high risk of thromboembolism (e.g., mechanical heart valve), bridging with LMWH should be started at the earliest possible time when there is no risk of major bleeding and continued until the international normalized ratio (INR) reaches a therapeutic level with warfarin. For patients at a lower risk of thromboembolism, warfarin should be restarted within 24 hours of the procedure. In addition, because of the shorter duration of DOACs, if treatment with these agents cannot resume within 24 hours of a high-risk procedure, bridge therapy should be considered with UFH or LMWH in patients with a high risk of thrombosis.¹⁸ In patients receiving DOACs for stroke prophylaxis in AF, the DOACS can be safely resumed 1 day after low-risk procedures and 2-3 days after high-risk procedures without the need for bridging.²⁵ All antiplatelet agents should be resumed as soon as hemostasis is achieved.

Conclusion

Antithrombotic therapy is increasingly used given the aging population, widespread burden of cardiovascular comorbidities, and expanding indications for classes of medications such as direct oral anticoagulants. Given the association with antithrombotic medications and gastrointestinal bleeding, it is essential for gastroenterologists to understand the importance, necessity, and timing when holding these medications for endoscopic procedures. Even with the practice guidelines available today to help clinicians navigate certain situations, each patient’s antithrombotic management may be different, and communication with the prescribing physicians and including patients in the decision-making process is essential before planned procedures.

Dr. Wang is a gastroenterology fellow at the University of Chicago. Dr. Sengupta is an associate professor at the University of Chicago. They reported no funding or conflicts of interest.

References

1. ASGE Standards of Practice Committee, Acosta RD et al. The management of antithrombotic agents for patients undergoing GI endoscopy. Gastrointest Endosc. 2016;83(1):3-16.

2. Veitch AM et al. Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines. Endoscopy. 2016;48(4):c1. doi: 10.1055/s-0042-122686.

3. Chan FKL et al. Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: Joint Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) practice guidelines. Gut. 2018;67(3):405-17.

4. Abraham NS et al. American College of Gastroenterology – Canadian Association of Gastroenterology clinical practice guideline: Management of anticoagulants and antiplatelets during acute gastrointestinal bleeding and the periendoscopic period. Am J Gastroenterol. 2022;117(4):542-58.

5. Boustière C et al. Endoscopy and antiplatelet agents. European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2011;43(5):445-61.

6. Fujimoto K et al. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig Endosc. 2014;26(1):1-14.

7. Wilke T et al. Patient preferences for oral anticoagulation therapy in atrial fibrillation: A systematic literature review. Patient 2017;10(1):17-37.

8. Gerson LB et al. Adverse events associated with anticoagulation therapy in the periendoscopic period. Gastrointest Endosc. 2010 Jun;71(7):1211-17.e2.

9. Horiuchi A et al. Removal of small colorectal polyps in anticoagulated patients: A prospective randomized comparison of cold snare and conventional polypectomy. Gastrointest Endosc 2014;79(3):417-23.

10. Lip GYH et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-72.

11. 2012 Writing Committee Members, Jneid H et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (Updating the 2007 guideline and replacing the 2011 focused update): A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2012;126(7):875-910.

12. Douketis JD et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e326S-e350S.

13. Becker RC et al. Management of platelet-directed pharmacotherapy in patients with atherosclerotic coronary artery disease undergoing elective endoscopic gastrointestinal procedures. J Am Coll Cardiol. 2009;54(24):2261-76.

14. Kwok A and Faigel DO. Management of anticoagulation before and after gastrointestinal endoscopy. Am J Gastroenterol. 2009;104(12):3085-97; quiz 3098.

15. Douketis JD et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823-33.

16. Kovacs MJ et al. Postoperative low molecular weight heparin bridging treatment for patients at high risk of arterial thromboembolism (PERIOP2): Double blind randomised controlled trial. BMJ 2021;373:n1205.

17. Tafur A and Douketis J. Perioperative management of anticoagulant and antiplatelet therapy. Heart 2018;104(17):1461-7.

18. Kato M et al. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment: 2017 appendix on anticoagulants including direct oral anticoagulants. Dig Endosc. 2018;30(4):433-40.

19. Inoue T et al. Clinical features of postpolypectomy bleeding associated with heparin bridge therapy. Dig Endosc. 2014;26(2):243-9.

20. Takeuchi Y et al. Continuous anticoagulation and cold snare polypectomy versus heparin bridging and hot snare polypectomy in patients on anticoagulants with subcentimeter polyps: A randomized controlled trial. Ann Intern Med. 2019;171(4):229-37.

21. Ara N et al. Prospective analysis of risk for bleeding after endoscopic biopsy without cessation of antithrombotics in Japan. Dig Endosc. 2015;27(4):458-64.

22. Yanagisawa N et al. Postpolypectomy bleeding and thromboembolism risks associated with warfarin vs. direct oral anticoagulants. World J Gastroenterol. 2018;24(14):1540-9.

23. Arimoto J et al. Safety of cold snare polypectomy in patients receiving treatment with antithrombotic agents. Dig Dis Sci. 2019;64(11):3247-55.

24. Heublein V et al. Gastrointestinal endoscopy in patients receiving novel direct oral anticoagulants: Results from the prospective Dresden NOAC registry. J Gastroenterol. 2018;53(2):236-46.

25. Douketis JD et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med. 2019;179(11):1469-78.

26. Dubois V et al. Perioperative management of patients on direct oral anticoagulants. Thromb J. 2017;15:14.

27. Weitz JI et al. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation. 2012 Nov 13;126(20):2428-32.

28. Chan FKL et al. Risk of postpolypectomy bleeding with uninterrupted clopidogrel therapy in an industry-independent, double-blind, randomized trial. Gastroenterology. 2019;156(4):918-25.

29. Watanabe K et al. Effect of antiplatelet agent number, types, and pre-endoscopic management on postpolypectomy bleeding: Validation of endoscopy guidelines. Surg Endosc. 2021;35(1):317-25.

30. Gurbel PA et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET/OFFSET study. Circulation. 2009;120(25):2577-85.

31. Eisenberg MJ et al. Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents. Circulation. 2009;119(12):1634-42.
 

Antithrombotic therapy is increasingly used to either reduce the risk of or treat thromboembolic episodes in patients with various medical conditions such as ischemic and valvular heart disease, atrial fibrillation (AF), cerebrovascular disease, peripheral arterial disease, venous thromboembolism (VTE) and hypercoagulable diseases. Antithrombotics include medications classified as anticoagulants or antiplatelets. Anticoagulants work by interfering with the native clotting cascade and consist of four main classes: vitamin K antagonists (VKA), heparin derivatives, direct factor Xa inhibitors, and direct thrombin inhibitors. Direct oral anticoagulants (DOACs) refer to dabigatran (a direct thrombin inhibitor) and the factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban).

Antiplatelets, on the other hand, work by decreasing platelet aggregation and thus preventing thrombus formation; they include P2Y12 receptor inhibitors, protease-activated receptor-1 inhibitors, glycoprotein IIb/IIIa receptor inhibitors, acetylsalicylic acid (ASA), and nonsteroidal anti-inflammatory drugs. All of these agents may directly cause or increase the risk of gastrointestinal (GI) bleeding from luminal sources such as ulcers or diverticula, as well as after endoscopic interventions such as polypectomy. However, there is also a risk of thromboembolic consequences if some of these agents are withheld. Thus, the management of patients receiving antithrombotic agents and undergoing GI endoscopy represents an important clinical challenge and something that every GI physician has to deal with routinely.

The goal of this review is to discuss the optimal strategy for managing antithrombotics in patients undergoing elective endoscopy based on current available evidence and published clinical guidelines.^1-4 Much of our discussion will review recommendations from the recently published joint American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) guidelines on management of anticoagulants and antiplatelets in the periendoscopic period by Abraham et al.⁴

Factors that guide decision-making

The two most vital factors to consider prior to performing endoscopic procedures in patients receiving antithrombotic therapy are to assess the risk of bleeding associated with the procedure and to assess the risk of thromboembolism associated with the underlying medical condition for which the antithrombotic agents are being used. In addition, it is also important to keep in mind the individual characteristics of the antithrombotic agent(s) used when making these decisions.

Estimating procedure-related bleeding risk

Various endoscopic procedures have different risks of associated bleeding. Although guidelines from GI societies may differ when classifying procedures into low or high risk, it is important to know that most of the original data on postprocedural bleeding risks are from studies conducted in patients who are not on complex antithrombotic regimens and thus may not accurately reflect the bleeding risk of patients using newer antithrombotic therapies.^1,4-7

Traditionally, some of the common low-risk procedures have included diagnostic EGD and colonoscopy with or without biopsy, ERCP without sphincterotomy, biliary stent placement, and push or balloon-assisted enteroscopy. On the other hand, endoscopic procedures associated with interventions are known to have higher bleeding risk, and other procedural factors can influence this risk as well.⁸ For example, polypectomy, one of the most common interventions during endoscopy, is associated with bleeding risk ranging from 0.3% to 10% depending on multiple factors including polyp size, location, morphology (nonpolypoid, sessile, pedunculated), resection technique (cold or hot forceps, cold or hot snare), and type of cautery used.⁹ For some procedures, such as routine screening colonoscopy, however, the preprocedure estimate of bleeding risk can be uncertain because it is unclear if a high risk intervention (e.g., polypectomy of large polyp) will be necessary. For example, in the most recent ACG/CAG guidelines, colonoscopy with polypectomy < 1cm is considered a low/moderate risk bleeding procedure, whereas polypectomy > 1cm is considered high risk for bleeding.⁴ In these situations, the management of antithrombotic medications may depend on the individual patient’s risk of thrombosis and the specific antithrombotic agent. In the example of a patient undergoing colonoscopy while on antithrombotic medications, the bleeding risk associated with polypectomy can potentially be reduced by procedural techniques such as preferential use of cold snare polypectomy. Further high-quality data on the optimal procedural technique to reduce postpolypectomy bleeding in patients on antithrombotic medications is needed to help guide management.
 

Estimating thromboembolic risk

The risk of thromboembolic events in patients who are withholding their antithrombotic therapy for an endoscopic procedure depends on their underlying condition and individual characteristics. In patients who are on antithrombotic therapy for stroke prevention in non-valvular AF, the risk of cerebral thromboembolism in these patients is predictable using the CHA₂DS₂Vasc index.¹⁰ This scoring index includes heart failure, hypertension, age 75 years or older, diabetes mellitus, prior stroke or transient ischemic attack (TIA), vascular disease, age 65-74 years, and sex categories.

Patients with previous VTE on anticoagulation or those who have mechanical heart valves may have different risk factors for thromboembolic episodes. Among patients with VTE, time from initial VTE, history of recurrent VTE with antithrombotic interruption, and presence of underlying thrombophilia are most predictive of future thromboembolic risk. And for patients with mechanical heart valves, presence of a mitral valve prosthesis, and the presence or absence of associated heart failure and AF determine the annual risk of thromboembolic events. Bioprosthetic valves are generally considered low risk.

In patients with coronary artery disease (CAD), high thrombosis risk scenarios with holding antiplatelets include patients within 3 months of an acute coronary syndrome (ACS) event, within 6 months of a drug-eluting stent (DES) placement, or within 1 month of a bare metal coronary stent (BMS) placement. In addition, patients with ACS that occurred within the past 12 months of DES placement or within 2 months of BMS placement are also considered high risk.^11,12 Even beyond these periods, certain patients may still be at high risk of stent occlusion. In particular, patients with a prior history of stent occlusion, ACS or ST elevation myocardial infection, prior multivessel percutaneous coronary intervention, diabetes, renal failure, or diffuse CAD are at higher risk of stent occlusion or ACS events with alteration of antithrombotic therapy.¹³ Thus, modification of antithrombotic regimens in these patients should be cautiously approached.
 

Management of antithrombotics prior to elective endoscopy

In patients who need elective endoscopic procedures, if the indication for antithrombotic therapy is short-term, the procedure is probably best delayed until after that period.¹³ For patients on long-term or lifelong antithrombotic treatment, the decision to temporarily hold the treatment for endoscopy should occur after a discussion with the patient and all of the involved providers. In some high-risk patients, these agents cannot be interrupted; therefore, clinicians must carefully weigh the risks and benefits of the procedure before proceeding with endoscopy. For patients who are known to be undergoing an elective endoscopic procedure, antithrombotic medications may or may not need to be held prior to the procedure depending on the type of therapy. For example, according to the recent ACG/CAG guidelines, warfarin should be continued, whereas DOACs should be temporarily stopped for patients who are undergoing elective/planned endoscopic GI procedures.

Unfractionated heparin (UFH) administered as a continuous intravenous infusion can generally be held 3-4 hours before the procedure, given its short half-life. Low molecular weight heparin (LMWH), including enoxaparin and dalteparin, should be stopped 24 hours prior to the procedure.^2,14 Fondaparinux is a synthetic X-a inhibitor that requires discontinuation at least 36 hours preceding a high risk procedure. For patients on warfarin who are undergoing elective endoscopic procedures that are low risk for inducing bleeding, warfarin can be continued, as opposed to temporarily interrupted, although the dose should be omitted the morning of the procedure.⁴ For those who are undergoing high-risk endoscopic procedures (including colonoscopy with possible polypectomy > 1 cm), 5 days of temporary interruption without periprocedural bridging is appropriate in most patients. This is contrary to previous guidelines, which had recommended bridging for patients with a CHA2DS2Vasc score ≥ 2. Recent impactful randomized trials (BRIDGE and PERIOP-2) have called into question the benefit of periprocedural bridging with LMWH. Avoiding bridging anticoagulation was generally found to be similar to bridging in regard to prevention of thromboembolic complications, but importantly was associated with a decreased risk of major bleeding.^15,16 Of note, periprocedural bridging may still be appropriate in a small subset of patients, including those with mechanical valves, AF with CHADS2 score > 5, and previous thromboembolism during temporary interruption of VKAs. The decision to bridge or not should ideally be made in a multidisciplinary fashion.^15-20

Data are lacking on the ideal strategy for periendoscopic DOAC management. As mentioned above, for patients on DOACs who are undergoing elective endoscopic GI procedures, temporarily interrupting DOACs rather than continuing them is recommended. Currently, there are no randomized controlled trials addressing the management of DOACs in the periendoscopic period. However, based on five cohort studies, the ideal duration of DOAC interruption before endoscopic procedures may be between 1 and 2 days, excluding the day of the procedure.^21-25 This strategy allows for a short preprocedural duration of DOAC interruption and likely provides a balance between bleeding and thromboembolism risk. Importantly, there are no reliable laboratory assays to assess the anticoagulant effect of DOACs, and an individual patient’s degree of renal dysfunction may impact how long the DOAC should be held. In general, the anti-Xa drugs should be held for 1-2 days if the creatinine clearance (CrCl) is ≥ 60 mL/min, for 3 days if the CrCl is between 30 mL/min and 59 mL/min, and for 4 days if the CrCl is less than 30 mL/min.²⁶ For edoxaban, the recommendation is to hold at least 24 hours before high-risk procedures. The recommendation for stopping dabigatran is 2-3 days before a high-risk procedure in patients with CrCl more than 80 mL/min, 3-4 days prior if between 30 and 49 mL/min, and 4-6 days prior if less than 30 mL/min respectively.²⁷

In regard to antiplatelet management, ASA and the P2Y₁₂ receptor inhibitors (e.g. clopidogrel, prasugrel, and ticagrelor) are the most commonly utilized antiplatelets in patients undergoing endoscopic procedures. For patients who are on ASA monotherapy, whether 81 mg or 325 mg daily, for secondary cardiovascular prevention, no interruption of ASA therapy is necessary for elective procedures. The benefit of ASA for secondary cardiovascular prevention and the possible reduction in thrombotic events seen in RCTs of nonendoscopic surgical procedures is well known. However, there may be certain exceptions in which aspirin should be temporarily held. For example, short-term interruption of ASA could be considered in high risk procedures such as biliary or pancreatic sphincterotomy, ampullectomy, and peroral endoscopic myotomy. For patients on single antiplatelet therapy with a P2Y₁₂ receptor inhibitor who are undergoing elective endoscopic GI procedures, the recent CAG/ACG guidelines did not provide a clear recommendation for or against temporary interruption of the P2Y₁₂ receptor inhibitor. Although interruption of a P2Y₁₂ receptor inhibitor should theoretically decrease a patient’s risk of bleeding, the available evidence reported a nonsignificant increased bleeding risk in patients who stop a P2Y₁₂ receptor inhibitor for an elective endoscopic procedure compared with those who continue the medication.^28,29 Therefore, until further data are available, for patients on P2Y₁₂ receptor monotherapy, a reasonable strategy would be to temporarily hold therapy prior to high risk endoscopic procedures, assuming the patients are not at high cardiovascular risk. Clopidogrel and prasugrel have to be stopped 5-7 days prior to allow normal platelet aggregation to resume as opposed to ticagrelor, a reversible P2Y₁₂ receptor inhibitor that can be stopped 3-5 days prior.³⁰

Lastly, for patients who are on dual antiplatelet therapy (DAPT) for secondary prevention, continuation of ASA and temporary interruption of the P2Y₁₂ receptor inhibitor is recommended while undergoing elective endoscopy. Studies have shown that those who discontinued both had a much higher incidence of stent thrombosis compared with those who remained on aspirin alone.^4,28,31

Resumption of antithrombotic therapy after endoscopy

In general, antithrombotic therapy should be resumed upon completion of the procedure unless there remains a persistent risk of major bleeding.^1,14 This consensus is based on studies available on warfarin and heparin products, with minimal literature available regarding the resumption of DOACs. The benefits of immediate re-initiation of antithrombotic therapy for the prevention of thromboembolic events should be weighed against the risk of hemorrhage associated with the specific agent, the time to onset of the medication, and procedure-specific circumstances. For the small subset of patients on warfarin with a high risk of thromboembolism (e.g., mechanical heart valve), bridging with LMWH should be started at the earliest possible time when there is no risk of major bleeding and continued until the international normalized ratio (INR) reaches a therapeutic level with warfarin. For patients at a lower risk of thromboembolism, warfarin should be restarted within 24 hours of the procedure. In addition, because of the shorter duration of DOACs, if treatment with these agents cannot resume within 24 hours of a high-risk procedure, bridge therapy should be considered with UFH or LMWH in patients with a high risk of thrombosis.¹⁸ In patients receiving DOACs for stroke prophylaxis in AF, the DOACS can be safely resumed 1 day after low-risk procedures and 2-3 days after high-risk procedures without the need for bridging.²⁵ All antiplatelet agents should be resumed as soon as hemostasis is achieved.

Conclusion

Antithrombotic therapy is increasingly used given the aging population, widespread burden of cardiovascular comorbidities, and expanding indications for classes of medications such as direct oral anticoagulants. Given the association with antithrombotic medications and gastrointestinal bleeding, it is essential for gastroenterologists to understand the importance, necessity, and timing when holding these medications for endoscopic procedures. Even with the practice guidelines available today to help clinicians navigate certain situations, each patient’s antithrombotic management may be different, and communication with the prescribing physicians and including patients in the decision-making process is essential before planned procedures.

Dr. Wang is a gastroenterology fellow at the University of Chicago. Dr. Sengupta is an associate professor at the University of Chicago. They reported no funding or conflicts of interest.

References

1. ASGE Standards of Practice Committee, Acosta RD et al. The management of antithrombotic agents for patients undergoing GI endoscopy. Gastrointest Endosc. 2016;83(1):3-16.

2. Veitch AM et al. Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines. Endoscopy. 2016;48(4):c1. doi: 10.1055/s-0042-122686.

3. Chan FKL et al. Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: Joint Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) practice guidelines. Gut. 2018;67(3):405-17.

4. Abraham NS et al. American College of Gastroenterology – Canadian Association of Gastroenterology clinical practice guideline: Management of anticoagulants and antiplatelets during acute gastrointestinal bleeding and the periendoscopic period. Am J Gastroenterol. 2022;117(4):542-58.

5. Boustière C et al. Endoscopy and antiplatelet agents. European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2011;43(5):445-61.

6. Fujimoto K et al. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig Endosc. 2014;26(1):1-14.

7. Wilke T et al. Patient preferences for oral anticoagulation therapy in atrial fibrillation: A systematic literature review. Patient 2017;10(1):17-37.

8. Gerson LB et al. Adverse events associated with anticoagulation therapy in the periendoscopic period. Gastrointest Endosc. 2010 Jun;71(7):1211-17.e2.

9. Horiuchi A et al. Removal of small colorectal polyps in anticoagulated patients: A prospective randomized comparison of cold snare and conventional polypectomy. Gastrointest Endosc 2014;79(3):417-23.

10. Lip GYH et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-72.

11. 2012 Writing Committee Members, Jneid H et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (Updating the 2007 guideline and replacing the 2011 focused update): A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2012;126(7):875-910.

12. Douketis JD et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e326S-e350S.

13. Becker RC et al. Management of platelet-directed pharmacotherapy in patients with atherosclerotic coronary artery disease undergoing elective endoscopic gastrointestinal procedures. J Am Coll Cardiol. 2009;54(24):2261-76.

14. Kwok A and Faigel DO. Management of anticoagulation before and after gastrointestinal endoscopy. Am J Gastroenterol. 2009;104(12):3085-97; quiz 3098.

15. Douketis JD et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823-33.

16. Kovacs MJ et al. Postoperative low molecular weight heparin bridging treatment for patients at high risk of arterial thromboembolism (PERIOP2): Double blind randomised controlled trial. BMJ 2021;373:n1205.

17. Tafur A and Douketis J. Perioperative management of anticoagulant and antiplatelet therapy. Heart 2018;104(17):1461-7.

18. Kato M et al. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment: 2017 appendix on anticoagulants including direct oral anticoagulants. Dig Endosc. 2018;30(4):433-40.

19. Inoue T et al. Clinical features of postpolypectomy bleeding associated with heparin bridge therapy. Dig Endosc. 2014;26(2):243-9.

20. Takeuchi Y et al. Continuous anticoagulation and cold snare polypectomy versus heparin bridging and hot snare polypectomy in patients on anticoagulants with subcentimeter polyps: A randomized controlled trial. Ann Intern Med. 2019;171(4):229-37.

21. Ara N et al. Prospective analysis of risk for bleeding after endoscopic biopsy without cessation of antithrombotics in Japan. Dig Endosc. 2015;27(4):458-64.

22. Yanagisawa N et al. Postpolypectomy bleeding and thromboembolism risks associated with warfarin vs. direct oral anticoagulants. World J Gastroenterol. 2018;24(14):1540-9.

23. Arimoto J et al. Safety of cold snare polypectomy in patients receiving treatment with antithrombotic agents. Dig Dis Sci. 2019;64(11):3247-55.

24. Heublein V et al. Gastrointestinal endoscopy in patients receiving novel direct oral anticoagulants: Results from the prospective Dresden NOAC registry. J Gastroenterol. 2018;53(2):236-46.

25. Douketis JD et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med. 2019;179(11):1469-78.

26. Dubois V et al. Perioperative management of patients on direct oral anticoagulants. Thromb J. 2017;15:14.

27. Weitz JI et al. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation. 2012 Nov 13;126(20):2428-32.

28. Chan FKL et al. Risk of postpolypectomy bleeding with uninterrupted clopidogrel therapy in an industry-independent, double-blind, randomized trial. Gastroenterology. 2019;156(4):918-25.

29. Watanabe K et al. Effect of antiplatelet agent number, types, and pre-endoscopic management on postpolypectomy bleeding: Validation of endoscopy guidelines. Surg Endosc. 2021;35(1):317-25.

30. Gurbel PA et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET/OFFSET study. Circulation. 2009;120(25):2577-85.

31. Eisenberg MJ et al. Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents. Circulation. 2009;119(12):1634-42.
 

Antithrombotic therapy is increasingly used to either reduce the risk of or treat thromboembolic episodes in patients with various medical conditions such as ischemic and valvular heart disease, atrial fibrillation (AF), cerebrovascular disease, peripheral arterial disease, venous thromboembolism (VTE) and hypercoagulable diseases. Antithrombotics include medications classified as anticoagulants or antiplatelets. Anticoagulants work by interfering with the native clotting cascade and consist of four main classes: vitamin K antagonists (VKA), heparin derivatives, direct factor Xa inhibitors, and direct thrombin inhibitors. Direct oral anticoagulants (DOACs) refer to dabigatran (a direct thrombin inhibitor) and the factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban).

Antiplatelets, on the other hand, work by decreasing platelet aggregation and thus preventing thrombus formation; they include P2Y12 receptor inhibitors, protease-activated receptor-1 inhibitors, glycoprotein IIb/IIIa receptor inhibitors, acetylsalicylic acid (ASA), and nonsteroidal anti-inflammatory drugs. All of these agents may directly cause or increase the risk of gastrointestinal (GI) bleeding from luminal sources such as ulcers or diverticula, as well as after endoscopic interventions such as polypectomy. However, there is also a risk of thromboembolic consequences if some of these agents are withheld. Thus, the management of patients receiving antithrombotic agents and undergoing GI endoscopy represents an important clinical challenge and something that every GI physician has to deal with routinely.

The goal of this review is to discuss the optimal strategy for managing antithrombotics in patients undergoing elective endoscopy based on current available evidence and published clinical guidelines.^1-4 Much of our discussion will review recommendations from the recently published joint American College of Gastroenterology (ACG) and Canadian Association of Gastroenterology (CAG) guidelines on management of anticoagulants and antiplatelets in the periendoscopic period by Abraham et al.⁴

Factors that guide decision-making

The two most vital factors to consider prior to performing endoscopic procedures in patients receiving antithrombotic therapy are to assess the risk of bleeding associated with the procedure and to assess the risk of thromboembolism associated with the underlying medical condition for which the antithrombotic agents are being used. In addition, it is also important to keep in mind the individual characteristics of the antithrombotic agent(s) used when making these decisions.

Estimating procedure-related bleeding risk

Various endoscopic procedures have different risks of associated bleeding. Although guidelines from GI societies may differ when classifying procedures into low or high risk, it is important to know that most of the original data on postprocedural bleeding risks are from studies conducted in patients who are not on complex antithrombotic regimens and thus may not accurately reflect the bleeding risk of patients using newer antithrombotic therapies.^1,4-7

Traditionally, some of the common low-risk procedures have included diagnostic EGD and colonoscopy with or without biopsy, ERCP without sphincterotomy, biliary stent placement, and push or balloon-assisted enteroscopy. On the other hand, endoscopic procedures associated with interventions are known to have higher bleeding risk, and other procedural factors can influence this risk as well.⁸ For example, polypectomy, one of the most common interventions during endoscopy, is associated with bleeding risk ranging from 0.3% to 10% depending on multiple factors including polyp size, location, morphology (nonpolypoid, sessile, pedunculated), resection technique (cold or hot forceps, cold or hot snare), and type of cautery used.⁹ For some procedures, such as routine screening colonoscopy, however, the preprocedure estimate of bleeding risk can be uncertain because it is unclear if a high risk intervention (e.g., polypectomy of large polyp) will be necessary. For example, in the most recent ACG/CAG guidelines, colonoscopy with polypectomy < 1cm is considered a low/moderate risk bleeding procedure, whereas polypectomy > 1cm is considered high risk for bleeding.⁴ In these situations, the management of antithrombotic medications may depend on the individual patient’s risk of thrombosis and the specific antithrombotic agent. In the example of a patient undergoing colonoscopy while on antithrombotic medications, the bleeding risk associated with polypectomy can potentially be reduced by procedural techniques such as preferential use of cold snare polypectomy. Further high-quality data on the optimal procedural technique to reduce postpolypectomy bleeding in patients on antithrombotic medications is needed to help guide management.
 

Estimating thromboembolic risk

The risk of thromboembolic events in patients who are withholding their antithrombotic therapy for an endoscopic procedure depends on their underlying condition and individual characteristics. In patients who are on antithrombotic therapy for stroke prevention in non-valvular AF, the risk of cerebral thromboembolism in these patients is predictable using the CHA₂DS₂Vasc index.¹⁰ This scoring index includes heart failure, hypertension, age 75 years or older, diabetes mellitus, prior stroke or transient ischemic attack (TIA), vascular disease, age 65-74 years, and sex categories.

Patients with previous VTE on anticoagulation or those who have mechanical heart valves may have different risk factors for thromboembolic episodes. Among patients with VTE, time from initial VTE, history of recurrent VTE with antithrombotic interruption, and presence of underlying thrombophilia are most predictive of future thromboembolic risk. And for patients with mechanical heart valves, presence of a mitral valve prosthesis, and the presence or absence of associated heart failure and AF determine the annual risk of thromboembolic events. Bioprosthetic valves are generally considered low risk.

In patients with coronary artery disease (CAD), high thrombosis risk scenarios with holding antiplatelets include patients within 3 months of an acute coronary syndrome (ACS) event, within 6 months of a drug-eluting stent (DES) placement, or within 1 month of a bare metal coronary stent (BMS) placement. In addition, patients with ACS that occurred within the past 12 months of DES placement or within 2 months of BMS placement are also considered high risk.^11,12 Even beyond these periods, certain patients may still be at high risk of stent occlusion. In particular, patients with a prior history of stent occlusion, ACS or ST elevation myocardial infection, prior multivessel percutaneous coronary intervention, diabetes, renal failure, or diffuse CAD are at higher risk of stent occlusion or ACS events with alteration of antithrombotic therapy.¹³ Thus, modification of antithrombotic regimens in these patients should be cautiously approached.
 

Management of antithrombotics prior to elective endoscopy

In patients who need elective endoscopic procedures, if the indication for antithrombotic therapy is short-term, the procedure is probably best delayed until after that period.¹³ For patients on long-term or lifelong antithrombotic treatment, the decision to temporarily hold the treatment for endoscopy should occur after a discussion with the patient and all of the involved providers. In some high-risk patients, these agents cannot be interrupted; therefore, clinicians must carefully weigh the risks and benefits of the procedure before proceeding with endoscopy. For patients who are known to be undergoing an elective endoscopic procedure, antithrombotic medications may or may not need to be held prior to the procedure depending on the type of therapy. For example, according to the recent ACG/CAG guidelines, warfarin should be continued, whereas DOACs should be temporarily stopped for patients who are undergoing elective/planned endoscopic GI procedures.

Unfractionated heparin (UFH) administered as a continuous intravenous infusion can generally be held 3-4 hours before the procedure, given its short half-life. Low molecular weight heparin (LMWH), including enoxaparin and dalteparin, should be stopped 24 hours prior to the procedure.^2,14 Fondaparinux is a synthetic X-a inhibitor that requires discontinuation at least 36 hours preceding a high risk procedure. For patients on warfarin who are undergoing elective endoscopic procedures that are low risk for inducing bleeding, warfarin can be continued, as opposed to temporarily interrupted, although the dose should be omitted the morning of the procedure.⁴ For those who are undergoing high-risk endoscopic procedures (including colonoscopy with possible polypectomy > 1 cm), 5 days of temporary interruption without periprocedural bridging is appropriate in most patients. This is contrary to previous guidelines, which had recommended bridging for patients with a CHA2DS2Vasc score ≥ 2. Recent impactful randomized trials (BRIDGE and PERIOP-2) have called into question the benefit of periprocedural bridging with LMWH. Avoiding bridging anticoagulation was generally found to be similar to bridging in regard to prevention of thromboembolic complications, but importantly was associated with a decreased risk of major bleeding.^15,16 Of note, periprocedural bridging may still be appropriate in a small subset of patients, including those with mechanical valves, AF with CHADS2 score > 5, and previous thromboembolism during temporary interruption of VKAs. The decision to bridge or not should ideally be made in a multidisciplinary fashion.^15-20

Data are lacking on the ideal strategy for periendoscopic DOAC management. As mentioned above, for patients on DOACs who are undergoing elective endoscopic GI procedures, temporarily interrupting DOACs rather than continuing them is recommended. Currently, there are no randomized controlled trials addressing the management of DOACs in the periendoscopic period. However, based on five cohort studies, the ideal duration of DOAC interruption before endoscopic procedures may be between 1 and 2 days, excluding the day of the procedure.^21-25 This strategy allows for a short preprocedural duration of DOAC interruption and likely provides a balance between bleeding and thromboembolism risk. Importantly, there are no reliable laboratory assays to assess the anticoagulant effect of DOACs, and an individual patient’s degree of renal dysfunction may impact how long the DOAC should be held. In general, the anti-Xa drugs should be held for 1-2 days if the creatinine clearance (CrCl) is ≥ 60 mL/min, for 3 days if the CrCl is between 30 mL/min and 59 mL/min, and for 4 days if the CrCl is less than 30 mL/min.²⁶ For edoxaban, the recommendation is to hold at least 24 hours before high-risk procedures. The recommendation for stopping dabigatran is 2-3 days before a high-risk procedure in patients with CrCl more than 80 mL/min, 3-4 days prior if between 30 and 49 mL/min, and 4-6 days prior if less than 30 mL/min respectively.²⁷

In regard to antiplatelet management, ASA and the P2Y₁₂ receptor inhibitors (e.g. clopidogrel, prasugrel, and ticagrelor) are the most commonly utilized antiplatelets in patients undergoing endoscopic procedures. For patients who are on ASA monotherapy, whether 81 mg or 325 mg daily, for secondary cardiovascular prevention, no interruption of ASA therapy is necessary for elective procedures. The benefit of ASA for secondary cardiovascular prevention and the possible reduction in thrombotic events seen in RCTs of nonendoscopic surgical procedures is well known. However, there may be certain exceptions in which aspirin should be temporarily held. For example, short-term interruption of ASA could be considered in high risk procedures such as biliary or pancreatic sphincterotomy, ampullectomy, and peroral endoscopic myotomy. For patients on single antiplatelet therapy with a P2Y₁₂ receptor inhibitor who are undergoing elective endoscopic GI procedures, the recent CAG/ACG guidelines did not provide a clear recommendation for or against temporary interruption of the P2Y₁₂ receptor inhibitor. Although interruption of a P2Y₁₂ receptor inhibitor should theoretically decrease a patient’s risk of bleeding, the available evidence reported a nonsignificant increased bleeding risk in patients who stop a P2Y₁₂ receptor inhibitor for an elective endoscopic procedure compared with those who continue the medication.^28,29 Therefore, until further data are available, for patients on P2Y₁₂ receptor monotherapy, a reasonable strategy would be to temporarily hold therapy prior to high risk endoscopic procedures, assuming the patients are not at high cardiovascular risk. Clopidogrel and prasugrel have to be stopped 5-7 days prior to allow normal platelet aggregation to resume as opposed to ticagrelor, a reversible P2Y₁₂ receptor inhibitor that can be stopped 3-5 days prior.³⁰

Lastly, for patients who are on dual antiplatelet therapy (DAPT) for secondary prevention, continuation of ASA and temporary interruption of the P2Y₁₂ receptor inhibitor is recommended while undergoing elective endoscopy. Studies have shown that those who discontinued both had a much higher incidence of stent thrombosis compared with those who remained on aspirin alone.^4,28,31

Resumption of antithrombotic therapy after endoscopy

In general, antithrombotic therapy should be resumed upon completion of the procedure unless there remains a persistent risk of major bleeding.^1,14 This consensus is based on studies available on warfarin and heparin products, with minimal literature available regarding the resumption of DOACs. The benefits of immediate re-initiation of antithrombotic therapy for the prevention of thromboembolic events should be weighed against the risk of hemorrhage associated with the specific agent, the time to onset of the medication, and procedure-specific circumstances. For the small subset of patients on warfarin with a high risk of thromboembolism (e.g., mechanical heart valve), bridging with LMWH should be started at the earliest possible time when there is no risk of major bleeding and continued until the international normalized ratio (INR) reaches a therapeutic level with warfarin. For patients at a lower risk of thromboembolism, warfarin should be restarted within 24 hours of the procedure. In addition, because of the shorter duration of DOACs, if treatment with these agents cannot resume within 24 hours of a high-risk procedure, bridge therapy should be considered with UFH or LMWH in patients with a high risk of thrombosis.¹⁸ In patients receiving DOACs for stroke prophylaxis in AF, the DOACS can be safely resumed 1 day after low-risk procedures and 2-3 days after high-risk procedures without the need for bridging.²⁵ All antiplatelet agents should be resumed as soon as hemostasis is achieved.

Conclusion

Antithrombotic therapy is increasingly used given the aging population, widespread burden of cardiovascular comorbidities, and expanding indications for classes of medications such as direct oral anticoagulants. Given the association with antithrombotic medications and gastrointestinal bleeding, it is essential for gastroenterologists to understand the importance, necessity, and timing when holding these medications for endoscopic procedures. Even with the practice guidelines available today to help clinicians navigate certain situations, each patient’s antithrombotic management may be different, and communication with the prescribing physicians and including patients in the decision-making process is essential before planned procedures.

Dr. Wang is a gastroenterology fellow at the University of Chicago. Dr. Sengupta is an associate professor at the University of Chicago. They reported no funding or conflicts of interest.

References

1. ASGE Standards of Practice Committee, Acosta RD et al. The management of antithrombotic agents for patients undergoing GI endoscopy. Gastrointest Endosc. 2016;83(1):3-16.

2. Veitch AM et al. Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines. Endoscopy. 2016;48(4):c1. doi: 10.1055/s-0042-122686.

3. Chan FKL et al. Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: Joint Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) practice guidelines. Gut. 2018;67(3):405-17.

4. Abraham NS et al. American College of Gastroenterology – Canadian Association of Gastroenterology clinical practice guideline: Management of anticoagulants and antiplatelets during acute gastrointestinal bleeding and the periendoscopic period. Am J Gastroenterol. 2022;117(4):542-58.

5. Boustière C et al. Endoscopy and antiplatelet agents. European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2011;43(5):445-61.

6. Fujimoto K et al. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. Dig Endosc. 2014;26(1):1-14.

7. Wilke T et al. Patient preferences for oral anticoagulation therapy in atrial fibrillation: A systematic literature review. Patient 2017;10(1):17-37.

8. Gerson LB et al. Adverse events associated with anticoagulation therapy in the periendoscopic period. Gastrointest Endosc. 2010 Jun;71(7):1211-17.e2.

9. Horiuchi A et al. Removal of small colorectal polyps in anticoagulated patients: A prospective randomized comparison of cold snare and conventional polypectomy. Gastrointest Endosc 2014;79(3):417-23.

10. Lip GYH et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-72.

11. 2012 Writing Committee Members, Jneid H et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (Updating the 2007 guideline and replacing the 2011 focused update): A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2012;126(7):875-910.

12. Douketis JD et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012 Feb;141(2 Suppl):e326S-e350S.

13. Becker RC et al. Management of platelet-directed pharmacotherapy in patients with atherosclerotic coronary artery disease undergoing elective endoscopic gastrointestinal procedures. J Am Coll Cardiol. 2009;54(24):2261-76.

14. Kwok A and Faigel DO. Management of anticoagulation before and after gastrointestinal endoscopy. Am J Gastroenterol. 2009;104(12):3085-97; quiz 3098.

15. Douketis JD et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823-33.

16. Kovacs MJ et al. Postoperative low molecular weight heparin bridging treatment for patients at high risk of arterial thromboembolism (PERIOP2): Double blind randomised controlled trial. BMJ 2021;373:n1205.

17. Tafur A and Douketis J. Perioperative management of anticoagulant and antiplatelet therapy. Heart 2018;104(17):1461-7.

18. Kato M et al. Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment: 2017 appendix on anticoagulants including direct oral anticoagulants. Dig Endosc. 2018;30(4):433-40.

19. Inoue T et al. Clinical features of postpolypectomy bleeding associated with heparin bridge therapy. Dig Endosc. 2014;26(2):243-9.

20. Takeuchi Y et al. Continuous anticoagulation and cold snare polypectomy versus heparin bridging and hot snare polypectomy in patients on anticoagulants with subcentimeter polyps: A randomized controlled trial. Ann Intern Med. 2019;171(4):229-37.

21. Ara N et al. Prospective analysis of risk for bleeding after endoscopic biopsy without cessation of antithrombotics in Japan. Dig Endosc. 2015;27(4):458-64.

22. Yanagisawa N et al. Postpolypectomy bleeding and thromboembolism risks associated with warfarin vs. direct oral anticoagulants. World J Gastroenterol. 2018;24(14):1540-9.

23. Arimoto J et al. Safety of cold snare polypectomy in patients receiving treatment with antithrombotic agents. Dig Dis Sci. 2019;64(11):3247-55.

24. Heublein V et al. Gastrointestinal endoscopy in patients receiving novel direct oral anticoagulants: Results from the prospective Dresden NOAC registry. J Gastroenterol. 2018;53(2):236-46.

25. Douketis JD et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med. 2019;179(11):1469-78.

26. Dubois V et al. Perioperative management of patients on direct oral anticoagulants. Thromb J. 2017;15:14.

27. Weitz JI et al. Periprocedural management and approach to bleeding in patients taking dabigatran. Circulation. 2012 Nov 13;126(20):2428-32.

28. Chan FKL et al. Risk of postpolypectomy bleeding with uninterrupted clopidogrel therapy in an industry-independent, double-blind, randomized trial. Gastroenterology. 2019;156(4):918-25.

29. Watanabe K et al. Effect of antiplatelet agent number, types, and pre-endoscopic management on postpolypectomy bleeding: Validation of endoscopy guidelines. Surg Endosc. 2021;35(1):317-25.

30. Gurbel PA et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: The ONSET/OFFSET study. Circulation. 2009;120(25):2577-85.

31. Eisenberg MJ et al. Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents. Circulation. 2009;119(12):1634-42.
 

Nonalcoholic fatty liver disease (NAFLD) is defined by the presence of hepatic steatosis detected on either imaging or histology in the absence of secondary causes of fatty liver (e.g., excessive alcohol consumption) or other chronic liver diseases.¹ For practical NAFLD diagnosis purposes, excessive alcohol intake can be defined as an active or recent history of more than 21 standard drinks per week in men and more than¹⁴ standard drinks per week in women. For the sake of terminology, NAFLD is characterized by fatty liver infiltration, affecting at least 5% of hepatocytes, with no evidence of hepatocyte injury, whereas nonalcoholic steatohepatitis (NASH) is defined as the presence of necroinflammation with or without fibrosis in a background of fatty liver.¹

Natural history

NASH and the degree of fibrosis are the two most important determinants of the natural history of NAFLD. NASH can evolve into fibrosis and cirrhosis, whereas advanced fibrosis and cirrhosis (stages 3 or 4 of fibrosis) significantly increase the risk of liver-related decompensation and mortality. NAFLD, per se, has been associated with an increased risk of overall mortality, compared with that of the general population.² The three most common causes of mortality for patients with NAFLD are cardiovascular diseases (CVD), extrahepatic malignancies, and liver-related deaths. Mortality and liver-related events, including hepatic decompensation and hepatocellular carcinoma (HCC), may significantly increase in a dose-dependent manner with increasing fibrosis stages, and stages 3 or 4 of fibrosis may display the highest rates of all-cause mortality and liver-related events.^3,4 It is important to note, however, that almost 15% of HCCs occur in patients with NAFLD who do not have cirrhosis.⁵ The presence of commonly associated comorbidities such as obesity, insulin resistance or diabetes, dyslipidemia, hypothyroidism, polycystic ovary syndrome, and sleep apnea may contribute to an increased risk of NASH and advanced fibrosis and, therefore, an accelerated clinical course of NAFLD.

Nonpharmacological interventions

Lifestyle modification

Lifestyle modification to achieve weight loss remains a first-line intervention in patients with NAFLD. Weight loss achieved either by hypocaloric diet alone or in conjunction with increased physical activity can be beneficial for all patients with NAFLD. The benefits extend not only to those who are overweight and obese but also to those within normal body weight (lean NAFLD).^1,6,7 Weight loss of approximately 3%-5% is necessary to improve hepatic steatosis, but a greater weight loss (7%-10%) is required to improve other histopathological features like necroinflammatory lesions and fibrosis.^8-10 Individuals with higher BMI and/or type 2 diabetes (T2D) will require a larger weight reduction to achieve a similar benefit on NAFLD-related features.^7,8 Weight loss via lifestyle changes can also decrease hepatic venous pressure gradient (HVPG), with greater declines reported among those with more than 10% weight loss.¹¹

Weight loss can be achieved through a variety of modalities, but long-term maintenance of lost weight is much more challenging. A combination of a hypocaloric diet with a caloric deficit of 500-1,000 kcal/d, alongside moderate-intensity exercise and intensive on-site behavioral treatment, will likely increase the possibility of a sustained weight loss over time.^1,12 A growing body of scientific evidence indicates that a healthy diet that includes a reduction of high-glycemic-index foods and refined carbohydrates; increased consumption of monounsaturated fatty acids, omega-3 fatty acids, and fibers; and high intakes of olive oil, nuts, vegetables, fruits, legumes, whole grains, and fish can have beneficial effects on NAFLD and its severity.^13-16 Adherence to these healthy dietary patterns has been associated with a marked reduction in CVD morbidity and mortality and is, thus, a strategic lifestyle recommendation for patients with NAFLD in whom the leading cause of morbidity and death is CVD.^1,3

Exercise alone in adults with NAFLD may reduce hepatic steatosis, but its ability to improve inflammation and fibrosis has not been proven in well-designed RCTs.^17,18 Physical activity and exercise have been shown to curb both the development and the progression of NAFLD, and beneficial effects could be achieved independent of weight loss.^17,19,20 Most importantly, moderate-to-vigorous physical activity is likely associated with lower all-cause and cardiovascular mortality in patients with NAFLD.²¹

Heavy alcohol intake should be avoided by patients with NAFLD or NASH, and those with cirrhotic NASH should avoid any alcohol consumption given the risk of HCC and hepatic decompensation.^1,4,22 Limiting light-to-moderate alcohol intake among patients without cirrhosis is still under debate.¹ People with NAFLD may be advised to drink an equivalent of two to three 8-oz cups of regular brewed coffee daily as it has shown certain antifibrotic effects in NAFLD patients.²³
 

Bariatric surgery

Bariatric surgery is an attractive therapeutic option for eligible obese patients with NAFLD. Bariatric surgery has the potential for inducing great weight loss and, therefore, reverses not only the steatosis, inflammation, and fibrosis among NAFLD individuals but also important comorbid conditions like T2D. A recent systematic review and meta-analysis examining data on the effects of bariatric surgery on histologic features of NAFLD from 32 cohort studies (no RCTs included) showed that bariatric surgery was associated with significant improvements in steatosis (66%), lobular inflammation (50%), ballooning degeneration (76%), and fibrosis (40%), and the benefits were significantly higher in those who underwent Roux-en-Y gastric bypass (RYGB). Of note, worsening of liver histology, including fibrosis, could be seen in up to 12% of patients who underwent bariatric surgery.²⁴ The postsurgical weight regained after RYGB could explain partly the lack of fibrosis improvement or even worsening of fibrosis, although further research is needed to clarify these controversial findings.

RYGB and sleeve gastrectomy (SG) are the most commonly performed bariatric surgeries worldwide. Patients who undergo RYGB achieve higher weight loss when compared with those treated with SG.²⁵ Among all bariatric procedures, RYGB could result in a higher proportion of complete resolution of NAFLD than SG, although evidence is inconclusive on fibrosis improvement rates.^24,26 Most recently, a single-center RCT has compared the effects of RYGB vs. SG on liver fat content and fibrosis in patients with severe obesity and T2D.²⁷ Data showed that both surgical procedures were highly and equally effective in reducing fatty liver content (quantified by magnetic resonance imaging), with an almost complete resolution of the fatty liver at 1 year of both surgical interventions. The beneficial effects of both GB and SG on fibrosis (assessed by enhanced liver test [ELF]) were less evident with no substantial difference between the two groups. Importantly, 69% of participants had an increase in their ELF scores during the study, despite the majority of participants achieving significant reductions in their body weights and better glycemic control at the end of the study. These findings might be considered with caution as several factors, such as the duration of the study (only 1 year) and lack of a liver biopsy to confirm fibrosis changes over time, could be influencing the study results.

Among all NAFLD phenotypes, those with cirrhosis and, most importantly, hepatic decompensation appear to be at increased risk of perioperative mortality and inpatient hospital stays than those without cirrhosis.^28-29 Bariatric surgery is an absolute contraindication in patients with decompensated cirrhosis (Child B and Child C). Among compensated -Child A- cirrhotics, those with portal hypertension are at increased risk of morbidity and perioperative mortality.³⁰ A recent analysis of National Inpatient Sample data suggested that the rates of complications in those with cirrhosis have decreased with time, which could be due to a better selection process and the use of more restrictive bariatric surgery in those with cirrhosis. Low volume centers (defined as less than 50 procedures per year) and nonrestrictive bariatric surgery were associated with a higher mortality rate. These data may suggest that patients with cirrhosis should undergo bariatric surgery only in high-volume centers after a multidisciplinary evaluation.³¹ Bariatric endoscopy is emerging as a new treatment for obesity, but the long-term durability of its effects remains to be determined.

A recent retrospective cohort study, including 1,158 adult patients with biopsy-proven NASH, has investigated the benefits of bariatric surgery on the occurrence of major adverse liver and cardiovascular outcomes in 650 patients who underwent bariatric surgery, compared with 508 patients who received nonsurgical usual care. This study showed that bariatric surgery was associated with 88% lower risk of progression of fatty liver to cirrhosis, liver cancer, or liver-related death, and 70% lower risk of serious CVD events during a follow-up period of 10 years.³² Within 1 year after surgery, 0.6% of patients died from surgical complications. The potential benefits of bariatric surgery in patients with NAFLD must be balanced against surgical risk, especially in eligible obese individuals with established cirrhosis. Data from a retrospective cohort study have shown that bariatric surgery in obese cirrhotic patients does not seem to associate with excessive mortality, compared with noncirrhotic obese patients.³³ More data on immediate complication rates and long-term outcomes in patients with NAFLD by type of bariatric surgery is also required.

NAFLD as a standalone is not an indication for bariatric surgery. However, it could be considered in NAFLD patients who have a BMI of 40 kg/m² or more without coexisting comorbidities or with a BMI of 35 kg/m² or more and one or more severe obesity-related comorbidities, including T2D, hypertension, hyperlipidemia, or obstructive sleep apnea. Bariatric surgery must always be offered in centers with an experienced bariatric surgery program.¹
 

Management of comorbidities

Given the multiple comorbidities associated with NAFLD and the potential to influence its severity, a comprehensive and multidisciplinary approach is needed to ameliorate not only the progression of liver disease but also those complications related to metabolic syndrome, hyperlipidemia, hypertension, diabetes, and other related conditions. Of note, all patients with NAFLD should receive aggressive management of comorbidities regardless of the severity of NAFLD. Ideally, a multidisciplinary team – including a primary care provider, an endocrinologist for patients with T2D, and a gastroenterologist/hepatologist – is needed to successfully manage patients with NAFLD.

It is well recognized that individuals with biopsy-proven NAFLD are at a higher risk of coronary heart disease, stroke, congestive heart failure, and death resulting from CVD when compared with the non-NAFLD population, and excess in CVD morbidity and mortality is evident across all stages of NAFLD and increases with worsening disease severity.³⁴ The strong association between CVD and NAFLD has important clinical implications that may influence the decision to initiate treatment for primary prevention, including lipid-lowering, antihypertensive, or antiplatelet therapies.³⁵ Statins are widely used to reduce LDL cholesterol and have been proven to be safe in NAFLD, including for those with elevated liver enzymes and even in compensated cirrhosis, in several studies conducted during the last 15 years.³⁶ Statins are characterized by anti-inflammatory, anti-oxidative, antifibrotic, and plaque-stabilizing effects, whereby they may improve vascular and hepatic function among patients with NAFLD and reduce cardiovascular risk.³⁷ Statin use for the treatment of NAFLD is still controversial and off-label and is not specifically recommended to treat NASH, but positive results have been shown for reductions in liver enzymes.¹ A recent meta-analysis of 13 studies showed that continued use of statin in cirrhosis was associated with a 46% and 44% risk reduction in hepatic decompensation and mortality, respectively.³⁸

The Food and Drug Administration has approved omega-3 (n-3) fatty acid agents and fibrates for the treatment of very high triglycerides (500 mg/dL or higher); however, no specific indications exist to treat NAFLD.¹ Fenofibrate is related to mild aminotransferase elevations and, in some cases, severe liver injury, so caution must be paid, especially within 2 days of taking the drug.^39-40

NAFLD phenotypes that need liver pharmacotherapy

There are still no FDA-approved drugs or biological treatments for NASH. Pharmacological interventions aiming primarily at improving liver disease should generally be limited to those with biopsy-proven NASH and clinically significant fibrosis (fibrosis stages of 2 or greater).^1,4 For FDA approval, medications used for treating NAFLD with fibrosis need to meet one of the following endpoint criteria: resolution of NASH without worsening of fibrosis, improvement in fibrosis without worsening of NASH, or both. In addition to those criteria, a new medication might improve the metabolic profile and have a tolerable safety profile. Table 1 displays those NAFLD phenotypes that will likely benefit from liver-directed therapy.

Obeticholic acid as an experimental therapy for NASH

A planned month-18 interim analysis of a multicentre, phase III RCT examined the efficacy and safety of obeticholic acid (OCA), a farnesoid X receptor agonist, in patients with NASH and stages 1-3 of fibrosis. The primary endpoint (fibrosis reduction 1 stage or more with no worsening of NASH) was met by 12% of patients in the placebo group, 18% of patients receiving OCA 10 mg (P = .045), and 23% of those receiving OCA 25 mg (P = .0002). An alternative primary endpoint of NASH resolution with no worsening of fibrosis was not met. OCA 25 mg led to the highest rates of pruritus and hyperlipidemia, compared with OCA 10 mg.⁴² These side effects seem to be related to the activation of the farnesoid X receptor.⁴³
 

Currently available but off label medications

Vitamin E, an antioxidant, administered at a daily dose of 800 IU/day improves steatosis, inflammation, and ballooning, but not fibrosis in nondiabetic adults with biopsy-proven NASH.⁴⁴ Vitamin E for 96 weeks was associated with a significantly higher rate of improvement in NASH (43% vs. 19%, P less than .01), compared with placebo.⁴⁴ In the Treatment of Nonalcoholic Fatty Liver Disease in Children trial (TONIC), which examined vitamin E (800 IU/day) or metformin (500 mg twice daily) against placebo in children with biopsy-proven NAFLD, resolution of NASH was significantly greater in children treated with vitamin E than in children treated with placebo (58% vs. 28%, P less than .01). Metformin did not significantly improve the NASH resolution rates, compared with placebo (41% vs. 28%, P = .23). Vitamin E could be recommended for nondiabetic adults or children if lifestyle modifications do not produce the expected results as a result of noncompliance or ineffectiveness. Since continued use of vitamin E has been suggested to be associated with a very small increase in the risk for prostate cancer (an absolute increase of 1.6 per 1,000 person-years of vitamin E use) in men, risks and benefits should be discussed with each patient before starting therapy. A meta-analysis of nine placebo-controlled trials including roughly 119,000 patients reported that vitamin E supplementation increases the risk of hemorrhagic stroke by 20% while reducing ischemic stroke by 10%. It was estimated that vitamin E supplementation would prevent one ischemic stroke per 476 treated patients while inducing one hemorrhagic stroke for every 1,250 patients. It is noteworthy that the combination of vitamin E with anticoagulant and/or antiplatelet therapy was not examined in this trial, so we could not determine how combination therapy might affect the risk of ischemic or hemorrhagic stroke.⁴⁵

Thiazolidinediones drugs have been reported to be effective in improving NAFLD in many human studies. Evidence from RCTs suggests that pioglitazone could significantly improve glucose metabolism, alanine aminotransferase, and liver histology – such as hepatic steatosis, lobular inflammation, and ballooning degeneration – among patients with or without T2D. However, the beneficial effects on improving fibrosis remain to be verified.^1,46 Because of safety concerns, the risk/benefit balance of using pioglitazone to treat NASH should be discussed with each patient.^47-48 Pioglitazone has been associated with long-term risk of bladder cancer,⁴⁹ congestive heart failure,⁵⁰ and bone fractures.⁵¹ Data from the Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis (PIVENS) trial showed that pioglitazone was significantly associated with weight gain but with no other serious adverse events. However, this study was not powered to test any safety-related hypotheses.⁴⁴

Glucagon-like peptide 1 analogs have been reported to induce weight loss and reduce insulin resistance, which may lead to improvements in NAFLD. Phase II RCTs of glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide) for the treatment of biopsy-proven NASH showed significant improvements in serum liver enzymes, steatosis, and inflammation, as well as NASH resolution without worsening liver fibrosis, although no direct benefit was observed in reversing fibrosis.^52-53 One of these studies explores the efficacy and safety of different doses of daily subcutaneous semaglutide vs. placebo on the rates of resolution of NASH with no worsening of fibrosis. The highest dose (0.4 mg) showed the greatest difference (59% vs. 17%, P less than .01), compared with the placebo arm. However, there was no difference in improvement in fibrosis stage between the two groups (43% in the 0.4-mg group vs. 33% in the placebo group, ^P = .48).⁵³ Gastrointestinal adverse events were common in the semaglutide arm.

“Spontaneous” NASH resolution and fibrosis improvement are commonly seen in participants assigned to placebo arms in clinical trials. A recent meta-analysis of 43 RCTs including 2649 placebo-treated patients showed a pooled estimate of NASH resolution without worsening of fibrosis and 1 stage reduction or more in fibrosis of 12% and 19%, respectively. Relevant factors involved in “spontaneous” NASH improvement are unknown but could be related to changes in BMI resulting from lifestyle changes, race and ethnicity, age, and, likely, NAFLD-related genetic variations, although more data is needed to better understand the histologic response in placebo-treated patients.⁵⁴

Semaglutide injections (2.4 mg once weekly) or (2.0 mg once weekly) have been recently approved by the FDA for chronic weight management in adults with obesity or overweight with at least one weight-related condition or glucose control of T2D, respectively. Of note, the semaglutide dose used in the NASH trial is not currently available for the treatment of patients who are overweight/obese or have T2D, but the beneficial effects on body weight reductions and glucose control are similar overall to the effects seen with currently available doses for management of obesity or diabetes. One may consider using semaglutide in patients who are overweight/obese or have T2D with NASH, but in the senior author’s experience, it has been quite challenging to receive the payer’s approval, as its use is not specifically approved to treat liver disease.¹
 

How to follow patients with NAFLD in the clinic

Once a diagnosis of NAFLD is made, the use of noninvasive testing may aid to identify which patients are at high risk of fibrosis. Easy to use clinical tools, such as the NAFLD Fibrosis Score and the Fib-4 index, and liver stiffness measurements using vibration-controlled transient elastography (FibroScan) or magnetic resonance elastography (MRE) are clinically useful noninvasive tools for identifying patients with NAFLD who have a higher likelihood of progressing to advanced fibrosis.^1,55 The use of either NAFLD Fibrosis Score (less than -1.455) or Fib-4 index (less than 1.30) low cutoffs may be particularly useful to rule out advanced fibrosis. People with a NAFLD Fibrosis Score (greater than –1.455) or Fib-4 index (greater than 1.30) should undergo liver stiffness measurement (LSM) via FibroScan. Those with an LSM of 8 kPa or higher should be referred to specialized care, where a decision to perform a liver biopsy and initiate monitoring and therapy will be taken. MRE is the most accurate noninvasive method for the estimation of liver fibrosis. When MRE is available, it can be a diagnostic alternative to accurately rule in and rule out patients with advanced fibrosis. This technique can be preferred in clinical trials, but it is rarely used in clinical practice because it is expensive and not easily available. Reassessment by noninvasive scores at 1-3 years’ follow-up will be considered for those with an LSM less than 8 kPa. Patients with NASH cirrhosis should be screened for both gastroesophageal varix and HCC according to the American Association for the Study of Liver Diseases guidelines.^56-57

Dr. Vilar-Gomez is assistant professor in the division of gastroenterology and hepatology at Indiana University, Indianapolis. Dr. Chalasani is vice president for academic affairs at Indiana University Health, Indianapolis, and the David W. Crabb Professor of Gastroenterology and Hepatology and an adjunct professor of anatomy, cell biology, and physiology in the division of gastroenterology and hepatology at Indiana University. Dr. Vilar-Gomez reports no financial conflicts of interest. Dr. Chalasani serves as a paid consultant to AbbVie, Boehringer-Ingelheim, Altimmune, Madrigal, Lilly, Zydus, and Galectin. He receives research support from Galectin and DSM.

References

1. Chalasani N et al. Hepatology 2018;67:328-57.

2. Söderberg C et al. Hepatology 2010;51:595-602.

3. Sanyal AJ et al. N Engl J Med 2021;385:1559-69.

4. Vilar-Gomez E et al. Gastroenterology 2018;155:443-57.e17.

5. Younossi ZM et al. Hepatology 2016;64:73-84.

6. EASL-EASD-EASO. J Hepatol 2016;64:1388-402.

7. Wong VW et al. J Hepatol 2018; 69:1349-56.

8. Vilar-Gomez E et al. Gastroenterology 2015;149:367-78.e5; quiz e14-5.

9. Promrat K et al. Hepatology 2010;51:121-9.

10. Wong VW et al. J Hepatol 2013;59:536-42.

11. Berzigotti A et al. Hepatology 2017;65:1293-1305.

12. Sacks FM et al. N Engl J Med 2009;360:859-73.

13. Vilar-Gomez E et al. Hepatology 2022 Jun;75(6):1491-1506.

14. Zelber-Sagi S et al. Liver Int 2017;37:936-49.

15. Hassani Zadeh S et al. J Gastroenterol Hepatol 2021;36:1470-8.

16. Yaskolka Meir A et al. Gut 2021;70:2085-95.

17. Sung KC et al. J Hepatol 2016;65:791-7.

18. Orci LA et al. Clin Gastroenterol Hepatol 2016;14:1398-411.

19. Ryu S et al. J Hepatol 2015;63:1229-37.

20. Kim D et al. Hepatology 2020;72:1556-68.

21. Kim D et al. Clin Gastroenterol Hepatol 2021;19:1240-7.e5.

22. Ascha MS et al. Hepatology 2010;51:1972-8.

23. Bambha K et al. Liver Int 2014;34:1250-8.

24. Lee Y et al. Clin Gastroenterol Hepatol 2019;17:1040-60.e11.

25. Grönroos S et al. JAMA Surg 2021;156:137-46.

26. Fakhry TK et al. Surg Obes Relat Dis 2019;15:502-11.

27. Seeberg KA et al. Ann Intern Med 2022;175:74-83.

28. Bower G et al. Obes Surg 2015;25:2280-9.

29. Jan A et al. Obes Surg 2015;25:1518-26.

30. Hanipah ZN et al. Obes Surg 2018;28:3431-8.

31. Are VS et al. Am J Gastroenterol 2020;115:1849-56.

32. Aminian A et al. JAMA 2021;326:2031-42.

33. Vuppalanchi R et al. Ann Surg 2022;275:e174-80.

34. Simon TG et al. Gut 2021. doi: 10.1136/gutjnl-2021-325724.

35. Lonardo A et al. J Hepatol 2018;68:335-52.

36. Chalasani N et al. Gastroenterology 2004;126:1287-92.

37. Pastori D et al. Dig Liver Dis 2015;47:4-11.

38. Kim RG et al. Clin Gastroenterol Hepatol 2017;15:1521-30.e8.

39. Ahmad J et al. Dig Dis Sci 2017;62:3596-604.

40. Chalasani NP et al. Am J Gastroenterol 2021;116(5):878-98.

41. Rinella ME et al. Hepatology 2019;70:1424-36.

42. Younossi ZM et al. Lancet 2019;394:2184-96.

43. Ratziu V. Clin Liver Dis (Hoboken) 2021;17:398-400.

44. Sanyal AJ et al. N Engl J Med 2010;341:1675-85.

45. Schürks M et al. BMJ 2010;341:c5702.

46. Cusi K et al. Ann Intern Med 2016;165:305-15.

47. Lewis JD et al. JAMA 2015;314:265-77.

48. Billington EO et al. Diabetologia 2015;58:2238-46.

49. Lewis JD et al. Diabetes Care 2011;34:916-22.

50. Erdmann E et al. Diabetes Care 2007;30:2773-8.

51. Viscoli CM et al. J Clin Endocrinol Metab 2017;102:914-22.

52. Armstong MJ et al. Lancet 2016;387:679-90.

53. Newsome PN et al. N Engl J Med 2021;384:1113-24.

54. Ng CH et al. Hepatology 2022;75:1647-61.

55. Kanwal F et al. Gastroenterology 2021;161:1030-1042.e8.

56. Garcia-Tsao G et al. Hepatology 2017;65:310-35.

57. Heimbach JK et al. Hepatology 2018;67:358-80.

Nonalcoholic fatty liver disease (NAFLD) is defined by the presence of hepatic steatosis detected on either imaging or histology in the absence of secondary causes of fatty liver (e.g., excessive alcohol consumption) or other chronic liver diseases.¹ For practical NAFLD diagnosis purposes, excessive alcohol intake can be defined as an active or recent history of more than 21 standard drinks per week in men and more than¹⁴ standard drinks per week in women. For the sake of terminology, NAFLD is characterized by fatty liver infiltration, affecting at least 5% of hepatocytes, with no evidence of hepatocyte injury, whereas nonalcoholic steatohepatitis (NASH) is defined as the presence of necroinflammation with or without fibrosis in a background of fatty liver.¹

Natural history

NASH and the degree of fibrosis are the two most important determinants of the natural history of NAFLD. NASH can evolve into fibrosis and cirrhosis, whereas advanced fibrosis and cirrhosis (stages 3 or 4 of fibrosis) significantly increase the risk of liver-related decompensation and mortality. NAFLD, per se, has been associated with an increased risk of overall mortality, compared with that of the general population.² The three most common causes of mortality for patients with NAFLD are cardiovascular diseases (CVD), extrahepatic malignancies, and liver-related deaths. Mortality and liver-related events, including hepatic decompensation and hepatocellular carcinoma (HCC), may significantly increase in a dose-dependent manner with increasing fibrosis stages, and stages 3 or 4 of fibrosis may display the highest rates of all-cause mortality and liver-related events.^3,4 It is important to note, however, that almost 15% of HCCs occur in patients with NAFLD who do not have cirrhosis.⁵ The presence of commonly associated comorbidities such as obesity, insulin resistance or diabetes, dyslipidemia, hypothyroidism, polycystic ovary syndrome, and sleep apnea may contribute to an increased risk of NASH and advanced fibrosis and, therefore, an accelerated clinical course of NAFLD.

Nonpharmacological interventions

Lifestyle modification

Lifestyle modification to achieve weight loss remains a first-line intervention in patients with NAFLD. Weight loss achieved either by hypocaloric diet alone or in conjunction with increased physical activity can be beneficial for all patients with NAFLD. The benefits extend not only to those who are overweight and obese but also to those within normal body weight (lean NAFLD).^1,6,7 Weight loss of approximately 3%-5% is necessary to improve hepatic steatosis, but a greater weight loss (7%-10%) is required to improve other histopathological features like necroinflammatory lesions and fibrosis.^8-10 Individuals with higher BMI and/or type 2 diabetes (T2D) will require a larger weight reduction to achieve a similar benefit on NAFLD-related features.^7,8 Weight loss via lifestyle changes can also decrease hepatic venous pressure gradient (HVPG), with greater declines reported among those with more than 10% weight loss.¹¹