Maged Rizk, MD

The prevalence of gallstones is approximately 10% to 15% of the adult US population.^1,2 Most cases are asymptomatic, as gallstones are usually discovered incidentally during routine imaging for other abdominal conditions, and only about 20% of patients with asymptomatic gallstones develop clinically significant complications.^2,3

Nevertheless, gallstones carry significant healthcare costs. In 2004, the median inpatient cost for any gallstone-related disease was $11,584, with an overall annual cost of $6.2 billion.^4,5

Laparoscopic cholecystectomy is the standard treatment for symptomatic cholelithiasis. For asymptomatic cholelithasis, the usual approach is expectant management (“watch and wait”), but prophylactic cholecystectomy may be an option in certain patients at high risk.

CHEMICAL COMPOSITION

Gallstones can be classified into 2 main categories based on their predominant chemical composition: cholesterol or pigment.

Cholesterol gallstones

About 75% of gallstones are composed of cholesterol.^3,4 In the past, this type of stone was thought to be caused by gallbladder inflammation, bile stasis, and absorption of bile salts from damaged mucosa. However, it is now known that cholesterol gallstones are the result of biliary supersaturation caused by cholesterol hypersecretion into the gallbladder, gallbladder hypomotility, accelerated cholesterol nucleation and crystallization, and mucin gel accumulation.

Pigment gallstones

Black pigment gallstones account for 10% to 15% of all gallstones.⁶ They are caused by chronic hemolysis in association with supersaturation of bile with calcium hydrogen bilirubinate, along with deposition of calcium carbonate, phosphate, and inorganic salts.⁷

Brown pigment stones, accounting for 5% to 10% of all gallstones,⁶ are caused by infection in the obstructed bile ducts, where bacteria that produce beta-glucuronidase, phospholipase, and slime contribute to formation of the stone.^8,9

RISK FACTORS FOR GALLSTONES

Age. After age 40, the risk increases dramatically, with an incidence 4 times higher for those ages 40 to 69 than in younger people.¹⁰

Female sex. Women of reproductive age are 4 times more likely to develop gallstones than men, but this gap narrows after menopause.¹¹ The higher risk is attributed to female sex hormones, pregnancy, and oral contraceptive use. Estrogen decreases secretion of bile salts and increases secretion of cholesterol into the gallbladder, which leads to cholesterol supersaturation. Progesterone acts synergistically by causing hypomobility of the gallbladder, which in turn leads to bile stasis.^12,13

Ethnicity. The risk is higher in Mexican Americans and Native Americans than in other ethnic groups.¹⁴

Rapid weight loss, such as after bariatric surgery, occurs from decreased caloric intake and promotes bile stasis, while lipolysis increases cholesterol mobilization and secretion into the gallbladder. This creates an environment conducive to bile supersaturation with cholesterol, leading to gallstone formation.

Chronic hemolytic disorders carry an increased risk of developing calcium bilirubinate stones due to increased excretion of bilirubin during hemolysis.

Obesity and diabetes mellitus are both attributed to insulin resistance. Obesity also increases bile stasis and cholesterol saturation.

Most patients with gallstones (cholelithiasis) experience no symptoms. Their gallstones are often discovered incidentally during imaging tests for unrelated or unexplained abdominal symptoms. Most patients with asymptomatic gallstones remain symptom-free, while about 20% develop gallstone-related symptoms.^2,3

Abdominal pain is the most common symptom. The phrase biliary colic—suggesting pain that is fluctuating in nature—appears ubiquitously in the medical literature, but it does not correctly characterize the pain associated with gallstones.

Most patients with gallstone symptoms describe a constant and often severe pain in the right upper abdomen, epigastrium, or both, often persisting for 30 to 120 minutes. Symptoms are frequently reported in the epigastrium when only visceral pain fibers are stimulated due to gallbladder distention. This is usually called midline pain; however, pain occurs in the back and right shoulder in up to 60% of patients, with involvement of somatic fibers.^15,16 Gallstone pain is not relieved by change of position or passage of stool or gas.

Onset of symptoms more than an hour after eating or in the late evening or at night also  very strongly suggests biliary pain. Patients with a history of biliary pain are more likely to experience it again, with a 69% chance of developing recurrent pain within 2 years.¹⁷

GALLSTONE-RELATED COMPLICATIONS

Acute gallbladder inflammation (cholecystitis)

Gallbladder inflammation (cholecystitis) is the most common complication, occurring in up to 10% of symptomatic cases. Many patients with acute cholecystitis present with right upper quadrant pain that may be accompanied by anorexia, nausea, or vomiting. Inspiratory arrest on deep palpation of the right upper quadrant (Murphy sign) has a specificity of 79% to 96% for acute cholecystitis.²⁰ Markers of systemic inflammation such as fever, elevated white blood cell count, and elevated C-reactive protein are highly suggestive of acute cholecystitis.^20,21

Bile duct stones (choledocholithiasis)

Bile duct stones (choledocholithiasis) are detected in 3.4% to 12% of patients with gallstones.^22,23 Most stones in the common bile duct migrate there from the gallbladder via the cystic duct. Less commonly, primary duct stones form in the duct due to biliary stasis. Removing the gallbladder does not completely eliminate the risk of bile duct stones, as stones can remain or recur after surgery.

Bile duct stones can obstruct the common bile duct, which disrupts normal bile flow and leads to jaundice. Other symptoms may include pruritus, right upper quadrant pain, nausea, and vomiting. Serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), and alkaline phosphatase are usually high.²⁴

Acute bacterial infection (cholangitis)

Acute bacterial infection of the biliary system (cholangitis) is usually associated with obstruction of the common bile duct. Common symptoms of acute cholangitis include right upper quadrant pain, fever, and jaundice (Charcot triad), and these are present in about 50% to 75% of cases.²¹ In severe cases, patients can develop altered mental status and septicemic shock in addition to the Charcot triad, a condition called the Reynold pentad. White blood cell counts and serum levels of C-reactive protein, bilirubin, aminotransferases, and alkaline phosphatase are usually elevated.²¹

Pancreatitis

Approximately 4% to 8% of patients with gallstones develop inflammation of the pancreas (pancreatitis).²⁵ The diagnosis of acute pancreatitis requires at least 2 of the following:^26,27

• Abdominal pain (typically epigastric, often radiating to the back)
• Amylase or lipase levels at least 3 times above the normal limit
• Imaging findings that suggest acute pancreatitis.

Gallstone-related pancreatitis should be considered if the ALT level is greater than 150 U/mL, which has a 97% specificity for gallstone-related pancreatitis.²⁸

Transabdominal ultrasonography, with a sensitivity of 84% to 89% and a specificity of up to 99%, is the test of choice for detecting gallstones.²⁹ The characteristic findings of acute cholecystitis on ultrasonography include enlargement of the gallbladder, thickening of the gallbladder wall, presence of pericholecystic fluid, and tenderness elicited by the ultrasound probe over the gallbladder (sonographic Murphy sign).

Scintigraphy as a second test

Acute cholecystitis is primarily a clinical diagnosis and typically does not require additional imaging beyond ultrasonography. When there is discordance between clinical and ultrasonographic findings, the most accurate second imaging test is scintigraphy of the biliary tract, usually performed with technetium-labeled hydroxy iminodiacetic acid. Given intravenously, the radionuclide is rapidly taken up by the liver and then secreted into the bile. In acute cholecystitis, the cystic duct is functionally occluded and the isotope does not enter the gallbladder, creating an imaging void compared with a normal appearance.

Scintigraphy is more sensitive than abdominal ultrasonography, with a sensitivity of up to 97% vs 81% to 88%, respectively.^29,30 The tests have about equal specificity.

Even though scintigraphy is more sensitive, abdominal ultrasonography is often the initial test for patients with suspected acute cholecystitis because it is more widely available, takes less time, does not involve radiation exposure, and can assess for the presence or absence of gallstones and dilation of the intra- and extrahepatic bile ducts.

Looking for stones in the common bile duct

When acute cholangitis due to choledocholithiasis is suspected, abdominal ultrasonography is a prudent initial test to look for gallstones or biliary dilation suggesting obstruction by stones in the common bile duct. Abdominal ultrasonography has only a 22% to 55% sensitivity for visualizing stones in the common bile duct, but it has a 77% to 87% sensitivity for detecting common bile duct dilation, a surrogate marker of stones.³¹

The normal bile duct diameter ranges from 3 to 6 mm, although mild dilation is often seen in older patients or after cholecystectomy or Roux-en-Y gastric bypass surgery.^32,33 Bile duct dilation of up to 10 mm can be considered normal in patients after cholecystectomy.³⁴ A normal-appearing bile duct on ultrasonography has a negative predictive value of 95% for excluding common bile duct stones.³¹

Endoscopic ultrasonography (EUS), magnetic resonance cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP) have similar sensitivity (89%–94%, 85%–92%, and 89%–93%, respectively) and specificity (94%–95%, 93%–97%, and 100%, respectively) for detecting common bile duct stones.^35–37 EUS is superior to MRCP in detecting stones smaller than 6 mm.³⁸

ERCP should be reserved for managing rather than diagnosing common bile duct stones because of the risk of pancreatitis and perforation. Patients undergoing cholecystectomy who are suspected of having choledocholithiasis may undergo intraoperative cholangiography or laparoscopic common bile duct ultrasonography.

WATCH AND WAIT, OR INTERVENE?

Asymptomatic gallstones

Standard treatment for these patients is expectant management. Cholecystectomy is not recommended for patients with asymptomatic gallstones.⁴⁷ Nevertheless, some patients may benefit from prophylactic cholecystectomy. We and others⁴⁸ suggest considering cholecystectomy in the following patients.

Patients with chronic hemolytic anemia (including children with sickle cell anemia and spherocytosis). These patients have a higher risk of developing calcium bilirubinate stones, and cholecystectomy has improved outcomes.⁴⁹ It should be noted that most of these data come from pediatric populations and have been extrapolated to adults.

Native Americans, who have a higher risk of gallbladder cancer if they have gallstones.^2,50

Conversely, calcification of the gallbladder wall (“porcelain gallbladder”) is no longer considered an absolute indication for cholecystectomy. This condition was thought to be associated with a high rate of gallbladder carcinoma, but analyses of larger, more recent data sets found much smaller risks.^51,52 Further, cholecystectomy in these patients was found to be associated with high rates of postoperative complications. Thus, prophylactic cholecystectomy is no longer recommended in asymptomatic cases of porcelain gallbladder.

In addition, concomitant cholecystectomy in patients undergoing bariatric surgery is no longer considered the therapeutic standard. Historically, cholecystectomy was performed in these patients because of the increased risk of gallstones associated with rapid weight loss after surgery. However, research now weighs against concomitant cholecystectomy with bariatric surgery and most other abdominal surgeries for asymptomatic gallstones.⁵³

Based on information in reference 48.

For patients experiencing acute cholecystitis, laparoscopic cholecystectomy within 72 hours is recommended.⁴⁸ There were safety concerns regarding higher rates of morbidity and conversion from laparoscopic to open cholecystectomy in patients who underwent surgery before the acute cholecystitis episode had settled. However, a large meta-analysis found no significant difference between early and delayed laparoscopic cholecystectomy in bile duct injury or conversion rates.⁵⁴ Further, early cholecystectomy—defined as within 1 week of symptom onset—has been found to reduce gallstone-related complications, shorten hospital stays, and lower costs.^55–57 If the patient cannot undergo surgery, percutaneous cholecystotomy or novel endoscopic gallbladder drainage interventions can be used.

Reprinted from ASGE Standards of Practice Committee; Maple JT, Ben-Menachem T, Anderson MA, et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endoscp 2010; 71:1–9 with permission from Elsevier.

Several variables predict the presence of bile duct stones in patients who have symptoms (Table 4). Based on these predictors, the ASGE classifies the probabilities as low (< 10%), intermediate (10% to 50%), and high (> 50%)³¹:

• 
  Low-risk patients require no further evaluation of the common bile duct
• High-risk patients should undergo preoperative ERCP and stone extraction if needed
• Intermediate-risk patients should undergo preoperative imaging with EUS or MRCP or intraoperative bile duct evaluation, depending on the availability, costs, and local expertise.

Patients with associated cholangitis should be given intravenous fluids and broad-spectrum antibiotics. Biliary decompression should be done as early as possible to decrease the risk of morbidity and mortality. For acute cholangitis, ERCP is the treatment of choice.²⁵

Patients with acute gallstone pancreatitis should receive conservative management with intravenous isotonic solutions and pain control, followed by laparoscopic cholecystectomy.⁴⁸

The timing of laparoscopic cholecystectomy in acute gallstone pancreatitis has been debated. Studies conducted during the era of open cholecystectomy reported similar or worse outcomes if cholecystectomy was done sooner rather than later.

However, in 1999, Uhl et al⁵⁸ reported that 48 of 77 patients admitted with acute gallstone pancreatitis were able to undergo laparoscopic cholecystectomy during the same admission. Success rates were 85% (30 of 35 patients) in those with mild disease and 62% (8 of 13 patients) in those with severe disease. They concluded laparoscopic cholecystectomy could be safely performed within 7 days in patients with mild disease, whereas in severe disease at least 3 weeks should elapse because of the risk of infection.

In a randomized trial published in 2010, Aboulian et al⁵⁹ reported that hospital length of stay (the primary end point) was shorter in 25 patients who underwent laparoscopic cholecystectomy early (within 48 hours of admission) than in 25 patients who underwent surgery after abdominal pain had resolved and laboratory enzymes showed a normalizing trend, 3.5 vs 5.8 days (P = .0016). Rates of perioperative complications and need for conversion to open surgery were similar between the 2 groups.

If there is associated cholangitis, patients should also be given broad-spectrum antibiotics and should undergo ERCP within 24 hours of admission.^25–27

SUMMARY

Gallstones are common in US adults. Abdominal ultrasonography is the diagnostic imaging test of choice to detect gallbladder stones and assess for findings suggestive of acute cholecystitis and dilation of the common bile duct. Fortunately, most gallstones are asymptomatic and can usually be managed expectantly. In patients who have symptoms or have gallstone complications, laparoscopic cholecystectomy is the standard of care.

The prevalence of gallstones is approximately 10% to 15% of the adult US population.^1,2 Most cases are asymptomatic, as gallstones are usually discovered incidentally during routine imaging for other abdominal conditions, and only about 20% of patients with asymptomatic gallstones develop clinically significant complications.^2,3

Nevertheless, gallstones carry significant healthcare costs. In 2004, the median inpatient cost for any gallstone-related disease was $11,584, with an overall annual cost of $6.2 billion.^4,5

Laparoscopic cholecystectomy is the standard treatment for symptomatic cholelithiasis. For asymptomatic cholelithasis, the usual approach is expectant management (“watch and wait”), but prophylactic cholecystectomy may be an option in certain patients at high risk.

CHEMICAL COMPOSITION

Gallstones can be classified into 2 main categories based on their predominant chemical composition: cholesterol or pigment.

Cholesterol gallstones

About 75% of gallstones are composed of cholesterol.^3,4 In the past, this type of stone was thought to be caused by gallbladder inflammation, bile stasis, and absorption of bile salts from damaged mucosa. However, it is now known that cholesterol gallstones are the result of biliary supersaturation caused by cholesterol hypersecretion into the gallbladder, gallbladder hypomotility, accelerated cholesterol nucleation and crystallization, and mucin gel accumulation.

Pigment gallstones

Black pigment gallstones account for 10% to 15% of all gallstones.⁶ They are caused by chronic hemolysis in association with supersaturation of bile with calcium hydrogen bilirubinate, along with deposition of calcium carbonate, phosphate, and inorganic salts.⁷

Brown pigment stones, accounting for 5% to 10% of all gallstones,⁶ are caused by infection in the obstructed bile ducts, where bacteria that produce beta-glucuronidase, phospholipase, and slime contribute to formation of the stone.^8,9

RISK FACTORS FOR GALLSTONES

Age. After age 40, the risk increases dramatically, with an incidence 4 times higher for those ages 40 to 69 than in younger people.¹⁰

Female sex. Women of reproductive age are 4 times more likely to develop gallstones than men, but this gap narrows after menopause.¹¹ The higher risk is attributed to female sex hormones, pregnancy, and oral contraceptive use. Estrogen decreases secretion of bile salts and increases secretion of cholesterol into the gallbladder, which leads to cholesterol supersaturation. Progesterone acts synergistically by causing hypomobility of the gallbladder, which in turn leads to bile stasis.^12,13

Ethnicity. The risk is higher in Mexican Americans and Native Americans than in other ethnic groups.¹⁴

Rapid weight loss, such as after bariatric surgery, occurs from decreased caloric intake and promotes bile stasis, while lipolysis increases cholesterol mobilization and secretion into the gallbladder. This creates an environment conducive to bile supersaturation with cholesterol, leading to gallstone formation.

Chronic hemolytic disorders carry an increased risk of developing calcium bilirubinate stones due to increased excretion of bilirubin during hemolysis.

Obesity and diabetes mellitus are both attributed to insulin resistance. Obesity also increases bile stasis and cholesterol saturation.

Most patients with gallstones (cholelithiasis) experience no symptoms. Their gallstones are often discovered incidentally during imaging tests for unrelated or unexplained abdominal symptoms. Most patients with asymptomatic gallstones remain symptom-free, while about 20% develop gallstone-related symptoms.^2,3

Abdominal pain is the most common symptom. The phrase biliary colic—suggesting pain that is fluctuating in nature—appears ubiquitously in the medical literature, but it does not correctly characterize the pain associated with gallstones.

Most patients with gallstone symptoms describe a constant and often severe pain in the right upper abdomen, epigastrium, or both, often persisting for 30 to 120 minutes. Symptoms are frequently reported in the epigastrium when only visceral pain fibers are stimulated due to gallbladder distention. This is usually called midline pain; however, pain occurs in the back and right shoulder in up to 60% of patients, with involvement of somatic fibers.^15,16 Gallstone pain is not relieved by change of position or passage of stool or gas.

Onset of symptoms more than an hour after eating or in the late evening or at night also  very strongly suggests biliary pain. Patients with a history of biliary pain are more likely to experience it again, with a 69% chance of developing recurrent pain within 2 years.¹⁷

GALLSTONE-RELATED COMPLICATIONS

Acute gallbladder inflammation (cholecystitis)

Gallbladder inflammation (cholecystitis) is the most common complication, occurring in up to 10% of symptomatic cases. Many patients with acute cholecystitis present with right upper quadrant pain that may be accompanied by anorexia, nausea, or vomiting. Inspiratory arrest on deep palpation of the right upper quadrant (Murphy sign) has a specificity of 79% to 96% for acute cholecystitis.²⁰ Markers of systemic inflammation such as fever, elevated white blood cell count, and elevated C-reactive protein are highly suggestive of acute cholecystitis.^20,21

Bile duct stones (choledocholithiasis)

Bile duct stones (choledocholithiasis) are detected in 3.4% to 12% of patients with gallstones.^22,23 Most stones in the common bile duct migrate there from the gallbladder via the cystic duct. Less commonly, primary duct stones form in the duct due to biliary stasis. Removing the gallbladder does not completely eliminate the risk of bile duct stones, as stones can remain or recur after surgery.

Bile duct stones can obstruct the common bile duct, which disrupts normal bile flow and leads to jaundice. Other symptoms may include pruritus, right upper quadrant pain, nausea, and vomiting. Serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), and alkaline phosphatase are usually high.²⁴

Acute bacterial infection (cholangitis)

Acute bacterial infection of the biliary system (cholangitis) is usually associated with obstruction of the common bile duct. Common symptoms of acute cholangitis include right upper quadrant pain, fever, and jaundice (Charcot triad), and these are present in about 50% to 75% of cases.²¹ In severe cases, patients can develop altered mental status and septicemic shock in addition to the Charcot triad, a condition called the Reynold pentad. White blood cell counts and serum levels of C-reactive protein, bilirubin, aminotransferases, and alkaline phosphatase are usually elevated.²¹

Pancreatitis

Approximately 4% to 8% of patients with gallstones develop inflammation of the pancreas (pancreatitis).²⁵ The diagnosis of acute pancreatitis requires at least 2 of the following:^26,27

• Abdominal pain (typically epigastric, often radiating to the back)
• Amylase or lipase levels at least 3 times above the normal limit
• Imaging findings that suggest acute pancreatitis.

Gallstone-related pancreatitis should be considered if the ALT level is greater than 150 U/mL, which has a 97% specificity for gallstone-related pancreatitis.²⁸

Transabdominal ultrasonography, with a sensitivity of 84% to 89% and a specificity of up to 99%, is the test of choice for detecting gallstones.²⁹ The characteristic findings of acute cholecystitis on ultrasonography include enlargement of the gallbladder, thickening of the gallbladder wall, presence of pericholecystic fluid, and tenderness elicited by the ultrasound probe over the gallbladder (sonographic Murphy sign).

Scintigraphy as a second test

Acute cholecystitis is primarily a clinical diagnosis and typically does not require additional imaging beyond ultrasonography. When there is discordance between clinical and ultrasonographic findings, the most accurate second imaging test is scintigraphy of the biliary tract, usually performed with technetium-labeled hydroxy iminodiacetic acid. Given intravenously, the radionuclide is rapidly taken up by the liver and then secreted into the bile. In acute cholecystitis, the cystic duct is functionally occluded and the isotope does not enter the gallbladder, creating an imaging void compared with a normal appearance.

Scintigraphy is more sensitive than abdominal ultrasonography, with a sensitivity of up to 97% vs 81% to 88%, respectively.^29,30 The tests have about equal specificity.

Even though scintigraphy is more sensitive, abdominal ultrasonography is often the initial test for patients with suspected acute cholecystitis because it is more widely available, takes less time, does not involve radiation exposure, and can assess for the presence or absence of gallstones and dilation of the intra- and extrahepatic bile ducts.

Looking for stones in the common bile duct

When acute cholangitis due to choledocholithiasis is suspected, abdominal ultrasonography is a prudent initial test to look for gallstones or biliary dilation suggesting obstruction by stones in the common bile duct. Abdominal ultrasonography has only a 22% to 55% sensitivity for visualizing stones in the common bile duct, but it has a 77% to 87% sensitivity for detecting common bile duct dilation, a surrogate marker of stones.³¹

The normal bile duct diameter ranges from 3 to 6 mm, although mild dilation is often seen in older patients or after cholecystectomy or Roux-en-Y gastric bypass surgery.^32,33 Bile duct dilation of up to 10 mm can be considered normal in patients after cholecystectomy.³⁴ A normal-appearing bile duct on ultrasonography has a negative predictive value of 95% for excluding common bile duct stones.³¹

Endoscopic ultrasonography (EUS), magnetic resonance cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP) have similar sensitivity (89%–94%, 85%–92%, and 89%–93%, respectively) and specificity (94%–95%, 93%–97%, and 100%, respectively) for detecting common bile duct stones.^35–37 EUS is superior to MRCP in detecting stones smaller than 6 mm.³⁸

ERCP should be reserved for managing rather than diagnosing common bile duct stones because of the risk of pancreatitis and perforation. Patients undergoing cholecystectomy who are suspected of having choledocholithiasis may undergo intraoperative cholangiography or laparoscopic common bile duct ultrasonography.

WATCH AND WAIT, OR INTERVENE?

Asymptomatic gallstones

Standard treatment for these patients is expectant management. Cholecystectomy is not recommended for patients with asymptomatic gallstones.⁴⁷ Nevertheless, some patients may benefit from prophylactic cholecystectomy. We and others⁴⁸ suggest considering cholecystectomy in the following patients.

Patients with chronic hemolytic anemia (including children with sickle cell anemia and spherocytosis). These patients have a higher risk of developing calcium bilirubinate stones, and cholecystectomy has improved outcomes.⁴⁹ It should be noted that most of these data come from pediatric populations and have been extrapolated to adults.

Native Americans, who have a higher risk of gallbladder cancer if they have gallstones.^2,50

Conversely, calcification of the gallbladder wall (“porcelain gallbladder”) is no longer considered an absolute indication for cholecystectomy. This condition was thought to be associated with a high rate of gallbladder carcinoma, but analyses of larger, more recent data sets found much smaller risks.^51,52 Further, cholecystectomy in these patients was found to be associated with high rates of postoperative complications. Thus, prophylactic cholecystectomy is no longer recommended in asymptomatic cases of porcelain gallbladder.

In addition, concomitant cholecystectomy in patients undergoing bariatric surgery is no longer considered the therapeutic standard. Historically, cholecystectomy was performed in these patients because of the increased risk of gallstones associated with rapid weight loss after surgery. However, research now weighs against concomitant cholecystectomy with bariatric surgery and most other abdominal surgeries for asymptomatic gallstones.⁵³

Based on information in reference 48.

For patients experiencing acute cholecystitis, laparoscopic cholecystectomy within 72 hours is recommended.⁴⁸ There were safety concerns regarding higher rates of morbidity and conversion from laparoscopic to open cholecystectomy in patients who underwent surgery before the acute cholecystitis episode had settled. However, a large meta-analysis found no significant difference between early and delayed laparoscopic cholecystectomy in bile duct injury or conversion rates.⁵⁴ Further, early cholecystectomy—defined as within 1 week of symptom onset—has been found to reduce gallstone-related complications, shorten hospital stays, and lower costs.^55–57 If the patient cannot undergo surgery, percutaneous cholecystotomy or novel endoscopic gallbladder drainage interventions can be used.

Reprinted from ASGE Standards of Practice Committee; Maple JT, Ben-Menachem T, Anderson MA, et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endoscp 2010; 71:1–9 with permission from Elsevier.

Several variables predict the presence of bile duct stones in patients who have symptoms (Table 4). Based on these predictors, the ASGE classifies the probabilities as low (< 10%), intermediate (10% to 50%), and high (> 50%)³¹:

• 
  Low-risk patients require no further evaluation of the common bile duct
• High-risk patients should undergo preoperative ERCP and stone extraction if needed
• Intermediate-risk patients should undergo preoperative imaging with EUS or MRCP or intraoperative bile duct evaluation, depending on the availability, costs, and local expertise.

Patients with associated cholangitis should be given intravenous fluids and broad-spectrum antibiotics. Biliary decompression should be done as early as possible to decrease the risk of morbidity and mortality. For acute cholangitis, ERCP is the treatment of choice.²⁵

Patients with acute gallstone pancreatitis should receive conservative management with intravenous isotonic solutions and pain control, followed by laparoscopic cholecystectomy.⁴⁸

The timing of laparoscopic cholecystectomy in acute gallstone pancreatitis has been debated. Studies conducted during the era of open cholecystectomy reported similar or worse outcomes if cholecystectomy was done sooner rather than later.

However, in 1999, Uhl et al⁵⁸ reported that 48 of 77 patients admitted with acute gallstone pancreatitis were able to undergo laparoscopic cholecystectomy during the same admission. Success rates were 85% (30 of 35 patients) in those with mild disease and 62% (8 of 13 patients) in those with severe disease. They concluded laparoscopic cholecystectomy could be safely performed within 7 days in patients with mild disease, whereas in severe disease at least 3 weeks should elapse because of the risk of infection.

In a randomized trial published in 2010, Aboulian et al⁵⁹ reported that hospital length of stay (the primary end point) was shorter in 25 patients who underwent laparoscopic cholecystectomy early (within 48 hours of admission) than in 25 patients who underwent surgery after abdominal pain had resolved and laboratory enzymes showed a normalizing trend, 3.5 vs 5.8 days (P = .0016). Rates of perioperative complications and need for conversion to open surgery were similar between the 2 groups.

If there is associated cholangitis, patients should also be given broad-spectrum antibiotics and should undergo ERCP within 24 hours of admission.^25–27

SUMMARY

Gallstones are common in US adults. Abdominal ultrasonography is the diagnostic imaging test of choice to detect gallbladder stones and assess for findings suggestive of acute cholecystitis and dilation of the common bile duct. Fortunately, most gallstones are asymptomatic and can usually be managed expectantly. In patients who have symptoms or have gallstone complications, laparoscopic cholecystectomy is the standard of care.

The prevalence of gallstones is approximately 10% to 15% of the adult US population.^1,2 Most cases are asymptomatic, as gallstones are usually discovered incidentally during routine imaging for other abdominal conditions, and only about 20% of patients with asymptomatic gallstones develop clinically significant complications.^2,3

Nevertheless, gallstones carry significant healthcare costs. In 2004, the median inpatient cost for any gallstone-related disease was $11,584, with an overall annual cost of $6.2 billion.^4,5

Laparoscopic cholecystectomy is the standard treatment for symptomatic cholelithiasis. For asymptomatic cholelithasis, the usual approach is expectant management (“watch and wait”), but prophylactic cholecystectomy may be an option in certain patients at high risk.

CHEMICAL COMPOSITION

Gallstones can be classified into 2 main categories based on their predominant chemical composition: cholesterol or pigment.

Cholesterol gallstones

About 75% of gallstones are composed of cholesterol.^3,4 In the past, this type of stone was thought to be caused by gallbladder inflammation, bile stasis, and absorption of bile salts from damaged mucosa. However, it is now known that cholesterol gallstones are the result of biliary supersaturation caused by cholesterol hypersecretion into the gallbladder, gallbladder hypomotility, accelerated cholesterol nucleation and crystallization, and mucin gel accumulation.

Pigment gallstones

Black pigment gallstones account for 10% to 15% of all gallstones.⁶ They are caused by chronic hemolysis in association with supersaturation of bile with calcium hydrogen bilirubinate, along with deposition of calcium carbonate, phosphate, and inorganic salts.⁷

Brown pigment stones, accounting for 5% to 10% of all gallstones,⁶ are caused by infection in the obstructed bile ducts, where bacteria that produce beta-glucuronidase, phospholipase, and slime contribute to formation of the stone.^8,9

RISK FACTORS FOR GALLSTONES

Age. After age 40, the risk increases dramatically, with an incidence 4 times higher for those ages 40 to 69 than in younger people.¹⁰

Female sex. Women of reproductive age are 4 times more likely to develop gallstones than men, but this gap narrows after menopause.¹¹ The higher risk is attributed to female sex hormones, pregnancy, and oral contraceptive use. Estrogen decreases secretion of bile salts and increases secretion of cholesterol into the gallbladder, which leads to cholesterol supersaturation. Progesterone acts synergistically by causing hypomobility of the gallbladder, which in turn leads to bile stasis.^12,13

Ethnicity. The risk is higher in Mexican Americans and Native Americans than in other ethnic groups.¹⁴

Rapid weight loss, such as after bariatric surgery, occurs from decreased caloric intake and promotes bile stasis, while lipolysis increases cholesterol mobilization and secretion into the gallbladder. This creates an environment conducive to bile supersaturation with cholesterol, leading to gallstone formation.

Chronic hemolytic disorders carry an increased risk of developing calcium bilirubinate stones due to increased excretion of bilirubin during hemolysis.

Obesity and diabetes mellitus are both attributed to insulin resistance. Obesity also increases bile stasis and cholesterol saturation.

Most patients with gallstones (cholelithiasis) experience no symptoms. Their gallstones are often discovered incidentally during imaging tests for unrelated or unexplained abdominal symptoms. Most patients with asymptomatic gallstones remain symptom-free, while about 20% develop gallstone-related symptoms.^2,3

Abdominal pain is the most common symptom. The phrase biliary colic—suggesting pain that is fluctuating in nature—appears ubiquitously in the medical literature, but it does not correctly characterize the pain associated with gallstones.

Most patients with gallstone symptoms describe a constant and often severe pain in the right upper abdomen, epigastrium, or both, often persisting for 30 to 120 minutes. Symptoms are frequently reported in the epigastrium when only visceral pain fibers are stimulated due to gallbladder distention. This is usually called midline pain; however, pain occurs in the back and right shoulder in up to 60% of patients, with involvement of somatic fibers.^15,16 Gallstone pain is not relieved by change of position or passage of stool or gas.

Onset of symptoms more than an hour after eating or in the late evening or at night also  very strongly suggests biliary pain. Patients with a history of biliary pain are more likely to experience it again, with a 69% chance of developing recurrent pain within 2 years.¹⁷

GALLSTONE-RELATED COMPLICATIONS

Acute gallbladder inflammation (cholecystitis)

Gallbladder inflammation (cholecystitis) is the most common complication, occurring in up to 10% of symptomatic cases. Many patients with acute cholecystitis present with right upper quadrant pain that may be accompanied by anorexia, nausea, or vomiting. Inspiratory arrest on deep palpation of the right upper quadrant (Murphy sign) has a specificity of 79% to 96% for acute cholecystitis.²⁰ Markers of systemic inflammation such as fever, elevated white blood cell count, and elevated C-reactive protein are highly suggestive of acute cholecystitis.^20,21

Bile duct stones (choledocholithiasis)

Bile duct stones (choledocholithiasis) are detected in 3.4% to 12% of patients with gallstones.^22,23 Most stones in the common bile duct migrate there from the gallbladder via the cystic duct. Less commonly, primary duct stones form in the duct due to biliary stasis. Removing the gallbladder does not completely eliminate the risk of bile duct stones, as stones can remain or recur after surgery.

Bile duct stones can obstruct the common bile duct, which disrupts normal bile flow and leads to jaundice. Other symptoms may include pruritus, right upper quadrant pain, nausea, and vomiting. Serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase (ALT), and alkaline phosphatase are usually high.²⁴

Acute bacterial infection (cholangitis)

Acute bacterial infection of the biliary system (cholangitis) is usually associated with obstruction of the common bile duct. Common symptoms of acute cholangitis include right upper quadrant pain, fever, and jaundice (Charcot triad), and these are present in about 50% to 75% of cases.²¹ In severe cases, patients can develop altered mental status and septicemic shock in addition to the Charcot triad, a condition called the Reynold pentad. White blood cell counts and serum levels of C-reactive protein, bilirubin, aminotransferases, and alkaline phosphatase are usually elevated.²¹

Pancreatitis

Approximately 4% to 8% of patients with gallstones develop inflammation of the pancreas (pancreatitis).²⁵ The diagnosis of acute pancreatitis requires at least 2 of the following:^26,27

• Abdominal pain (typically epigastric, often radiating to the back)
• Amylase or lipase levels at least 3 times above the normal limit
• Imaging findings that suggest acute pancreatitis.

Gallstone-related pancreatitis should be considered if the ALT level is greater than 150 U/mL, which has a 97% specificity for gallstone-related pancreatitis.²⁸

Transabdominal ultrasonography, with a sensitivity of 84% to 89% and a specificity of up to 99%, is the test of choice for detecting gallstones.²⁹ The characteristic findings of acute cholecystitis on ultrasonography include enlargement of the gallbladder, thickening of the gallbladder wall, presence of pericholecystic fluid, and tenderness elicited by the ultrasound probe over the gallbladder (sonographic Murphy sign).

Scintigraphy as a second test

Acute cholecystitis is primarily a clinical diagnosis and typically does not require additional imaging beyond ultrasonography. When there is discordance between clinical and ultrasonographic findings, the most accurate second imaging test is scintigraphy of the biliary tract, usually performed with technetium-labeled hydroxy iminodiacetic acid. Given intravenously, the radionuclide is rapidly taken up by the liver and then secreted into the bile. In acute cholecystitis, the cystic duct is functionally occluded and the isotope does not enter the gallbladder, creating an imaging void compared with a normal appearance.

Scintigraphy is more sensitive than abdominal ultrasonography, with a sensitivity of up to 97% vs 81% to 88%, respectively.^29,30 The tests have about equal specificity.

Even though scintigraphy is more sensitive, abdominal ultrasonography is often the initial test for patients with suspected acute cholecystitis because it is more widely available, takes less time, does not involve radiation exposure, and can assess for the presence or absence of gallstones and dilation of the intra- and extrahepatic bile ducts.

Looking for stones in the common bile duct

When acute cholangitis due to choledocholithiasis is suspected, abdominal ultrasonography is a prudent initial test to look for gallstones or biliary dilation suggesting obstruction by stones in the common bile duct. Abdominal ultrasonography has only a 22% to 55% sensitivity for visualizing stones in the common bile duct, but it has a 77% to 87% sensitivity for detecting common bile duct dilation, a surrogate marker of stones.³¹

The normal bile duct diameter ranges from 3 to 6 mm, although mild dilation is often seen in older patients or after cholecystectomy or Roux-en-Y gastric bypass surgery.^32,33 Bile duct dilation of up to 10 mm can be considered normal in patients after cholecystectomy.³⁴ A normal-appearing bile duct on ultrasonography has a negative predictive value of 95% for excluding common bile duct stones.³¹

Endoscopic ultrasonography (EUS), magnetic resonance cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP) have similar sensitivity (89%–94%, 85%–92%, and 89%–93%, respectively) and specificity (94%–95%, 93%–97%, and 100%, respectively) for detecting common bile duct stones.^35–37 EUS is superior to MRCP in detecting stones smaller than 6 mm.³⁸

ERCP should be reserved for managing rather than diagnosing common bile duct stones because of the risk of pancreatitis and perforation. Patients undergoing cholecystectomy who are suspected of having choledocholithiasis may undergo intraoperative cholangiography or laparoscopic common bile duct ultrasonography.

WATCH AND WAIT, OR INTERVENE?

Asymptomatic gallstones

Standard treatment for these patients is expectant management. Cholecystectomy is not recommended for patients with asymptomatic gallstones.⁴⁷ Nevertheless, some patients may benefit from prophylactic cholecystectomy. We and others⁴⁸ suggest considering cholecystectomy in the following patients.

Patients with chronic hemolytic anemia (including children with sickle cell anemia and spherocytosis). These patients have a higher risk of developing calcium bilirubinate stones, and cholecystectomy has improved outcomes.⁴⁹ It should be noted that most of these data come from pediatric populations and have been extrapolated to adults.

Native Americans, who have a higher risk of gallbladder cancer if they have gallstones.^2,50

Conversely, calcification of the gallbladder wall (“porcelain gallbladder”) is no longer considered an absolute indication for cholecystectomy. This condition was thought to be associated with a high rate of gallbladder carcinoma, but analyses of larger, more recent data sets found much smaller risks.^51,52 Further, cholecystectomy in these patients was found to be associated with high rates of postoperative complications. Thus, prophylactic cholecystectomy is no longer recommended in asymptomatic cases of porcelain gallbladder.

In addition, concomitant cholecystectomy in patients undergoing bariatric surgery is no longer considered the therapeutic standard. Historically, cholecystectomy was performed in these patients because of the increased risk of gallstones associated with rapid weight loss after surgery. However, research now weighs against concomitant cholecystectomy with bariatric surgery and most other abdominal surgeries for asymptomatic gallstones.⁵³

Based on information in reference 48.

For patients experiencing acute cholecystitis, laparoscopic cholecystectomy within 72 hours is recommended.⁴⁸ There were safety concerns regarding higher rates of morbidity and conversion from laparoscopic to open cholecystectomy in patients who underwent surgery before the acute cholecystitis episode had settled. However, a large meta-analysis found no significant difference between early and delayed laparoscopic cholecystectomy in bile duct injury or conversion rates.⁵⁴ Further, early cholecystectomy—defined as within 1 week of symptom onset—has been found to reduce gallstone-related complications, shorten hospital stays, and lower costs.^55–57 If the patient cannot undergo surgery, percutaneous cholecystotomy or novel endoscopic gallbladder drainage interventions can be used.

Reprinted from ASGE Standards of Practice Committee; Maple JT, Ben-Menachem T, Anderson MA, et al. The role of endoscopy in the evaluation of suspected choledocholithiasis. Gastrointest Endoscp 2010; 71:1–9 with permission from Elsevier.

Several variables predict the presence of bile duct stones in patients who have symptoms (Table 4). Based on these predictors, the ASGE classifies the probabilities as low (< 10%), intermediate (10% to 50%), and high (> 50%)³¹:

• 
  Low-risk patients require no further evaluation of the common bile duct
• High-risk patients should undergo preoperative ERCP and stone extraction if needed
• Intermediate-risk patients should undergo preoperative imaging with EUS or MRCP or intraoperative bile duct evaluation, depending on the availability, costs, and local expertise.

Patients with associated cholangitis should be given intravenous fluids and broad-spectrum antibiotics. Biliary decompression should be done as early as possible to decrease the risk of morbidity and mortality. For acute cholangitis, ERCP is the treatment of choice.²⁵

Patients with acute gallstone pancreatitis should receive conservative management with intravenous isotonic solutions and pain control, followed by laparoscopic cholecystectomy.⁴⁸

The timing of laparoscopic cholecystectomy in acute gallstone pancreatitis has been debated. Studies conducted during the era of open cholecystectomy reported similar or worse outcomes if cholecystectomy was done sooner rather than later.

However, in 1999, Uhl et al⁵⁸ reported that 48 of 77 patients admitted with acute gallstone pancreatitis were able to undergo laparoscopic cholecystectomy during the same admission. Success rates were 85% (30 of 35 patients) in those with mild disease and 62% (8 of 13 patients) in those with severe disease. They concluded laparoscopic cholecystectomy could be safely performed within 7 days in patients with mild disease, whereas in severe disease at least 3 weeks should elapse because of the risk of infection.

In a randomized trial published in 2010, Aboulian et al⁵⁹ reported that hospital length of stay (the primary end point) was shorter in 25 patients who underwent laparoscopic cholecystectomy early (within 48 hours of admission) than in 25 patients who underwent surgery after abdominal pain had resolved and laboratory enzymes showed a normalizing trend, 3.5 vs 5.8 days (P = .0016). Rates of perioperative complications and need for conversion to open surgery were similar between the 2 groups.

If there is associated cholangitis, patients should also be given broad-spectrum antibiotics and should undergo ERCP within 24 hours of admission.^25–27

SUMMARY

Gallstones are common in US adults. Abdominal ultrasonography is the diagnostic imaging test of choice to detect gallbladder stones and assess for findings suggestive of acute cholecystitis and dilation of the common bile duct. Fortunately, most gallstones are asymptomatic and can usually be managed expectantly. In patients who have symptoms or have gallstone complications, laparoscopic cholecystectomy is the standard of care.

A 31-year-old woman presents to the office with a chief complaint of right mid-abdominal pain that began 1 day ago. She says she did not seek medical attention earlier because she had to be at work that morning and she thought the pain would resolve on its own.

She reports no fever, headache, anorexia, nausea, vomiting, malaise, loss of weight, melena, or changes in bowel habits. She describes the pain as sharp, localized to the right side, and radiating to the vulva upon sitting up. She denies any association of pain with current dietary habits or bowel function. She has no recollection of precipitating or alleviating factors, including the use of analgesics to reduce the pain.

On further discussion, she mentions that 1 year ago she began experiencing chronic abdominal pain, which she says is sometimes exacerbated by coughing, by standing for extended periods of time, and during menses, and is alleviated upon lying down.

She has regular menstrual periods, and her last one ended 7 days ago.

Her surgical history includes two uncomplicated cesarean deliveries. She does not use tobacco, alcohol, or illicit substances. She is not aware of any allergies to drugs or foods.

She appears to be in no acute distress and has been sitting quietly thus far. She seems to have positioned her hand on her abdomen over the corresponding area of pain.

On physical examination, vital signs are within normal limits, and she is alert and oriented to person, place, and time. Her sclerae are anicteric, and the pupils are equal, round, and reactive to light.

Her complete blood cell count, metabolic panel, and initial imaging tests are normal

Cardiovascular and pulmonary examinations are also within normal limits. Examination of the abdomen elicits tenderness and guarding along the lateral border of the rectus abdominis muscle on the right side at the level of umbilicus, with no rebound tenderness or rigidity. The liver and spleen are not enlarged, and no abdominal mass is detected. No skin rash, joint swelling, or peripheral edema is noted. A neurologic examination is normal.

1. With the information provided, which of the following is least likely to be causing her symptoms?

• Chronic mesenteric ischemia
• Peptic ulcer
• Acute cholecystitis
• Slipping rib syndrome

CHRONIC MESENTERIC ISCHEMIA

Chronic mesenteric ischemia is the least likely diagnosis because the patient lacks risk factors for atherosclerosis and because she does not have postprandial pain, which is pathognomonic for chronic mesenteric ischemia. It is thought to be caused by a decrease in blood flow through the splanchnic vessels.¹ Symptoms tend to arise after eating because of a postprandial increase in metabolic demands.¹ These patients also often have atherosclerotic risk factors such as hypertension, hyperlipidemia, and smoking causing coronary artery disease, or a history of stroke.

The primary symptom is abdominal pain, most often described as achy, crampy, or spastic episodes of pain, usually occurring within 2 hours of eating.² Weight loss is common, as patients can develop a fear of eating. Postprandial pain may also be associated with nausea, vomiting, and bloating.

Findings on clinical examination are usually less severe than the actual symptoms. Visceral duplex or multidetector computed tomography (CT) is an excellent tool to detect blood flow in potential stenotic vessels.²

PEPTIC ULCER DISEASE

Peptic ulcer disease is not a likely diagnosis in this patient because she has no history of taking nonsteroidal anti-inflammatory drugs (NSAIDs).

A study of US patients between 1997 and 2007 reported an annual incidence of peptic ulcer disease of 0.05% to 0.19% depending on the method of diagnosis.³ Peptic ulcer is thought to result from increased gastric acid secretion with a resultant inflammatory response, leading to erosion and ulceration.

The most common possible catalysts include Helicobacter pylori infection, NSAIDs, smoking, alcohol use, and hypersecretory states such as Zollinger-Ellison syndrome.^4–6 Complications include internal bleeding, perforation causing peritonitis, and penetration to adjacent organs.

Pathophysiology

Peptic ulcer is the result of an increase in the normal level of gastric acid and a decrease in the protective ability of the gastric mucosa.⁷ Cytoprotection may be lost through a decrease in the products of arachidonic acid metabolism (eg, prostaglandins, which have a protective effect) or an increase in leukotriene B4 (LTB4), which has a damaging effect. Prostaglandins are thought not only to protect the normal gastric mucosa, but also to provide an antisecretory effect.

On the other hand, leukotrienes—specifically LTB4 and LTC4—are proinflammatory agents and can damage the gastric mucosa. NSAIDs enhance the production of leuko­trienes through the 5-lipoxygenase pathway. The ability of LTB4 to cause degranulation and release of lysosomal enzymes may play a vital role in the inflammatory response to NSAIDs.^8–10 LTC4 may promote gastric mucosal damage through a reduction of tissue perfusion resulting from the promotion of vascular stasis.^8,11,12

Symptoms help differentiate ulcer type

The classic symptom is burning epigastric pain after meals. Pain that occurs immediately after meals is a classic symptom of gastric ulcer. Pain that occurs 2 to 3 hours after meals and that is relieved by food or antacids is a strong indicator of duodenal ulcer.¹³ Other symptoms include dyspepsia, bloating, distention, heartburn, and chest discomfort.¹³

Accurate diagnosis is vital in selecting the proper treatment. Diagnostic tests may include H pylori testing, upper-gastrointestinal endoscopy, and radiography with barium swallow.

CHOLECYSTITIS

In cholecystitis, the primary complaint is pain, usually in the right upper quadrant of the abdomen. Patients describe sudden, sharp, and intense pain that radiates to the back or shoulder. Patients may report pain after heavy meals, and some report nausea and vomiting. Cholecystitis is in the differential diagnosis of this patient because of the anatomic location of her pain.

The diagnosis is confirmed by imaging. Abdominal ultrasonography, technetium-99m hepatic iminodiacetic acid scanning, and CT are the most commonly used studies.¹⁴

Cholecystitis can be acute or chronic. Acute cholecystitis is categorized as calculous or acalculous. Calculous cholecystitis is multifactorial, but the primary cause is blockage of the cystic duct by gallstones.¹⁵ Other factors include irritants such as lysolecithin (released during bile stasis), which can trigger gallbladder inflammation,^15–17 and infection.¹⁸

When the cystic duct is blocked, bile builds up inside the gallbladder, causing irritation and inflammation of the walls of the gallbladder.¹⁴

Acalculous cholecystitis, which resembles calculous cholecystitis but without the gallstones,¹⁹ accounts for 2% to 15% of all cases of acute cholecystitis.^19,20 It has been observed in hospitalized critically ill patients, but it can also present in an outpatient setting, most often in elderly men with vascular disease.²¹ Causes include infection, trauma, and tumor obstruction, resulting in endothelial injury, gallbladder stasis, ischemia, and eventually necrosis.^14,20,22,23

SLIPPING RIB SYNDROME

Slipping rib syndrome, also known as Tietze syndrome, is believed to be caused by hypermobile costal cartilage. The affected rib slips behind the rib above on contraction of the abdominal wall. This displacement increases the probability of costal nerve impingement and tissue inflammation producing unilateral, sharp, subcostal and upper-abdominal pain.

In this patient, slipping rib syndrome is a possible diagnosis because of the location of the pain and because the pain described by the patient is highly suggestive of neuropathic pain.

Slipping rib syndrome is diagnosed clinically by a “hooking” maneuver: the clinician hooks his or her fingers at the patient’s subcostal area, reproducing the pain by movement of the ribs anteriorly.²⁴ When this test is performed in our patient the result is negative, ruling out slipping rib syndrome.

THE WORKUP CONTINUES

A complete blood cell count and comprehensive metabolic panel are within normal limits. Abdominal duplex ultrasonography reveals no celiac or mesenteric occlusions, thus ruling out chronic mesenteric ischemia.

Noncontrast CT shows no renal or ureteric stones and no evidence of bleeding in the urinary tract. CT with contrast shows no bowel distention, no evidence of hernia, and a normal appendix and ovaries.

2. After exclusion of the previous choices, which of the following is the most likely cause of her symptoms?

• Anterior cutaneous nerve entrapment syndrome (ACNES)
• Ovarian cyst
• Renal stones
• Appendicitis
• Ventral hernia
• Median arcuate ligament syndrome

ANTERIOR CUTANEOUS NERVE ENTRAPMENT SYNDROME

ACNES is the most likely diagnosis. A study published in 2013 indicated that many cases of functional abdominal pain may actually be undiagnosed cases of chronic abdominal wall pain such as ACNES.²⁵ The condition, first described in 1972,²⁶ is thought to be caused by thoracic cutaneous intercostal nerve entrapment between the abdominal muscles, causing pain at the point of entrapment.

The patient may present with pain that is either acute or chronic. Acute pain is localized more on the right side close to an old scar, or at the outer edge of the rectus abdominis muscle. The pain may vary from dull to burning to sharp; it can radiate horizontally in the upper half of the abdomen or obliquely in the lower half of the abdomen with movements such as twisting and sitting up.²⁷

Despite the acute pain, patients are able to carry on daily functions. The pain may be alleviated by lying down.

The pain may be misdiagnosed as gynecologic or renal. In younger men, the pain may raise concern about hernia, and in older patients, cancer.²⁷ Patients may complain of chronic intermittent pain, usually unilateral, and to a lesser extent bilateral.²⁷

The anatomic location of the pain usually reflects the intercostal nerve involved. The pain is not related to eating or to bowel movements.²⁵ Some patients report exacerbation upon coughing or standing, during menses, and with use of oral contraceptives.^28,29 When inquiring about surgical history, it is common to find that the patient has had multiple abdominal surgical procedures.

On examination, the patient has nondistressing pain, with a hand often placed over the painful area.²⁷ On firm palpation, a tender spot of less than 2 cm can be detected.

The diagnosis can be confirmed with a positive Carnett test. The patient lies supine on the examination table with the arms crossed over the chest, then elevates the head or the feet to tense the abdominal muscles.^26,27 If doing so reproduces the pain (ie, a positive test), this increases the suspicion of ACNES; if the pain decreases or is not reproducible, an intra-abdominal cause is more likely.

A positive Carnett test helps rule out visceral involvement

If the pain is difficult to localize, the “pinch test” can be done by using the thumb and index finger to pinch and lift the skin of the abdomen, including the subcutaneous layer of fat, first on one side and then on the other. This helps determine the side with greater pain.²⁷

OVARIAN CYSTS

Ovarian cysts are fluid-filled sacs on the surface of or within the ovary. They are often benign and require no intervention. However, 5% to 10% of US women with a suspicious ovarian mass undergo a surgical procedure, and 13% to 21% of these are found to have a malignancy.^30,31

Ovarian cysts are usually painless unless complicated by rupture or bleeding. Patients who present with pain describe it as dull and aching and in the abdomen or pelvis. In rare cases, ovarian cysts can be large enough to cause pain from torsion. Other symptoms may include delayed menses and bleeding outside of the menstrual period.^32–34

Ovarian cysts are thought to be caused by hormonal changes during the menstrual cycle. They can be detected during pelvic examination or during pelvic ultrasonography. Cysts that are primarily fluid-filled are generally benign and require no intervention. On the other hand, cysts composed of solid material require intervention.

Treatment depends on several factors, including size and type of cyst, the patient’s age, and whether torsion is present. Treatment can range from observation to medical or surgical management. Laparoscopic surgery is commonly used when surgical treatment is warranted.

RENAL STONES

From 10% to 15% of US adults develop a kidney stone at some time during their life.³⁵ There is no single cause, but one factor that promotes stone formation is a greater amount of crystal-forming substances in the urine, such as calcium, oxalate, and uric acid.³⁶ Most renal stones are calcium oxalate, uric acid, struvite, or cysteine.

Symptoms arise when the stone moves within the urinary tract. Patients present to the emergency room in severe distress, usually with flank pain that radiates to the lower abdomen or groin. The pain is episodic, fluctuates in intensity, and may present with dysuria, frequency, or urgency. It is also associated with nausea and vomiting.³⁷

Renal stones are diagnosed through a series of laboratory and imaging studies. Imaging studies include plain radiography (which can miss small stones), renal sonography, and computed tomography without contrast.

APPENDICITIS

In the United States, the lifetime risk of developing appendicitis is 8.6% in men and 6.7% in women.³⁸ Appendicitis is one of the most common reasons for emergency surgery.

Appendicitis is thought to result from obstruction by fecal matter blocking the opening of the appendix or from a viral infection (eg, with an adenovirus).^39,40 The resulting bacterial growth can cause the appendix to become inflamed and purulent.

Patients typically present with umbilical or epigastric pain radiating to the right lower quadrant of the abdomen. Over time, the pain becomes sharper. Certain movements can exacerbate the pain, and lying down may alleviate it. Other symptoms are nausea, vomiting, loss of appetite, and low-grade fever.

If the pain is difficult to localize, the ‘pinch test’ can help determine the more painful side

Findings on the abdominal examination that help to confirm the diagnosis include rigidity and tenderness, classically localized to a point two-thirds of the way from the umbilicus to the anterior superior iliac spine. Rebound tenderness is usually present. Up to 25% of cases in some series presented atypically, with variable location and findings on physical examination (eg, bowel irregularities, indigestion, flatulence, generalized malaise). In addition to the physical examination, laboratory testing and imaging (ultrasonography, CT) may aid in confirming the diagnosis of appendicitis or any other cause of the pain.³⁸

VENTRAL HERNIA

Ventral hernia is a bulging of abdominal organs or other tissues through a defect of the musculature of the abdominal wall. Ventral hernia is categorized by its location as epigastric, abdominal, or incisional. An open abdominal procedure is the cause in nearly 10% of cases⁴¹; the herniation occurs with weakening of the surgical scar.

Ventral hernia is usually detected on physical examination, and patients may present after noting a bulge in the abdominal wall. Symptoms vary. Some patients have no symptoms, while others have mild abdominal discomfort or severe abdominal pain as well as nausea and vomiting. Imaging with CT, ultrasonography, or magnetic resonance imaging helps confirm the diagnosis. Complications of ventral hernia include incarceration and bowel strangulation.

MEDIAN ARCUATE LIGAMENT SYNDROME

Median arcuate ligament syndrome is a challenging diagnosis and a very rare cause of abdominal pain. It is thought to be caused by celiac artery compression by fibroligamentous bands. Pain fluctuates with respiration and is greater during expiration.

Patients may present with recurrent episodes of crampy postprandial pain that cause them to avoid eating, resulting in weight loss. The pain may be associated with nausea, vomiting, and bloating.

The diagnosis is confirmed by duplex ultrasonography, angiography, or magnetic resonance angiography. Treatment is surgical division of the fibroligamentous band and crus, and this is often done laparascopically. In patients with severe persistent celiac artery stenosis, angioplasty and stenting may be considered.²

CASE CONTINUED

Before the physical examination, our patient identifies the location of her pain. A Carnett test is performed, as for ACNES: the patient is placed in the supine position and is instructed to cross both arms over her chest. In an effort to promote muscle tension, she is asked to elevate her head off the examination table, as if performing a mini sit-up, and as she does this, pressure is applied to the identified tender area. The pain is easily reproduced, further confirming involvement of the abdominal wall rather than the viscera. After this, electromyography shows abnormal findings. The patient is then  referred to the pain management clinic for a diagnostic nerve block.

3. Which of the following is the first-line treatment of ACNES?

• Local injection of anesthetic
• Surgical neurectomy

LOCAL INJECTION OF ANESTHETIC

Local injection of anesthetic is the first-line treatment of ACNES.

Since ACNES is underdiagnosed, the patient may be less likely to be familiar with it. He or she should receive a detailed explanation of the condition and its management; this will help achieve a successful outcome.

Local anesthetic injection is used for both diagnosis and treatment; 2% lidocaine (or an equivalent) or dehydrated (absolute) alcohol or both can eliminate the pain caused by ACNES. The injection is commonly done under ultrasonographic guidance (Figure 1).⁴²

Complete pain relief may be achieved with a single injection, but some patients require up to five injections.

The adjuvant use of corticosteroids in ACNES to reduce inflammation is controversial.

If anesthetic injections bring only minimal pain relief or if the patient has nerve entrapment in a scar, then surgical neurectomy is an option.⁴³ The procedure is performed under local anesthesia, as the patient’s response aids in identifying the specific nerve or nerves involved.

RETURNING TO THE PATIENT

After a long discussion with our patient about ACNES and the treatment options, she  agrees to undergo nerve block in the hope of relieving her pain. She receives a 0.5-mL injection of 2% lidocaine subcutaneously, and within minutes she reports relief of pain. She cannot believe that with a simple injection her pain was relieved. We advise her to return if her pain recurs or if new symptoms arise.

KEEP ACNES IN MIND

ACNES is one of the most commonly misdiagnosed conditions of patients presenting to the outpatient clinic with acute or chronic abdominal pain. This is because the focus is directed to intra-abdominal causes. But if ACNES is kept in consideration from the beginning of the patient encounter, extensive testing, time, and patient anxiety may be reduced significantly. A simple physical examination and the Carnett test aid in raising suspicion of ACNES. If ACNES is confirmed, ultrasonographically guided local anesthetic injection is both diagnostic and therapeutic.

A 31-year-old woman presents to the office with a chief complaint of right mid-abdominal pain that began 1 day ago. She says she did not seek medical attention earlier because she had to be at work that morning and she thought the pain would resolve on its own.

She reports no fever, headache, anorexia, nausea, vomiting, malaise, loss of weight, melena, or changes in bowel habits. She describes the pain as sharp, localized to the right side, and radiating to the vulva upon sitting up. She denies any association of pain with current dietary habits or bowel function. She has no recollection of precipitating or alleviating factors, including the use of analgesics to reduce the pain.

On further discussion, she mentions that 1 year ago she began experiencing chronic abdominal pain, which she says is sometimes exacerbated by coughing, by standing for extended periods of time, and during menses, and is alleviated upon lying down.

She has regular menstrual periods, and her last one ended 7 days ago.

Her surgical history includes two uncomplicated cesarean deliveries. She does not use tobacco, alcohol, or illicit substances. She is not aware of any allergies to drugs or foods.

She appears to be in no acute distress and has been sitting quietly thus far. She seems to have positioned her hand on her abdomen over the corresponding area of pain.

On physical examination, vital signs are within normal limits, and she is alert and oriented to person, place, and time. Her sclerae are anicteric, and the pupils are equal, round, and reactive to light.

Her complete blood cell count, metabolic panel, and initial imaging tests are normal

Cardiovascular and pulmonary examinations are also within normal limits. Examination of the abdomen elicits tenderness and guarding along the lateral border of the rectus abdominis muscle on the right side at the level of umbilicus, with no rebound tenderness or rigidity. The liver and spleen are not enlarged, and no abdominal mass is detected. No skin rash, joint swelling, or peripheral edema is noted. A neurologic examination is normal.

1. With the information provided, which of the following is least likely to be causing her symptoms?

• Chronic mesenteric ischemia
• Peptic ulcer
• Acute cholecystitis
• Slipping rib syndrome

CHRONIC MESENTERIC ISCHEMIA

Chronic mesenteric ischemia is the least likely diagnosis because the patient lacks risk factors for atherosclerosis and because she does not have postprandial pain, which is pathognomonic for chronic mesenteric ischemia. It is thought to be caused by a decrease in blood flow through the splanchnic vessels.¹ Symptoms tend to arise after eating because of a postprandial increase in metabolic demands.¹ These patients also often have atherosclerotic risk factors such as hypertension, hyperlipidemia, and smoking causing coronary artery disease, or a history of stroke.

The primary symptom is abdominal pain, most often described as achy, crampy, or spastic episodes of pain, usually occurring within 2 hours of eating.² Weight loss is common, as patients can develop a fear of eating. Postprandial pain may also be associated with nausea, vomiting, and bloating.

Findings on clinical examination are usually less severe than the actual symptoms. Visceral duplex or multidetector computed tomography (CT) is an excellent tool to detect blood flow in potential stenotic vessels.²

PEPTIC ULCER DISEASE

Peptic ulcer disease is not a likely diagnosis in this patient because she has no history of taking nonsteroidal anti-inflammatory drugs (NSAIDs).

A study of US patients between 1997 and 2007 reported an annual incidence of peptic ulcer disease of 0.05% to 0.19% depending on the method of diagnosis.³ Peptic ulcer is thought to result from increased gastric acid secretion with a resultant inflammatory response, leading to erosion and ulceration.

The most common possible catalysts include Helicobacter pylori infection, NSAIDs, smoking, alcohol use, and hypersecretory states such as Zollinger-Ellison syndrome.^4–6 Complications include internal bleeding, perforation causing peritonitis, and penetration to adjacent organs.

Pathophysiology

Peptic ulcer is the result of an increase in the normal level of gastric acid and a decrease in the protective ability of the gastric mucosa.⁷ Cytoprotection may be lost through a decrease in the products of arachidonic acid metabolism (eg, prostaglandins, which have a protective effect) or an increase in leukotriene B4 (LTB4), which has a damaging effect. Prostaglandins are thought not only to protect the normal gastric mucosa, but also to provide an antisecretory effect.

On the other hand, leukotrienes—specifically LTB4 and LTC4—are proinflammatory agents and can damage the gastric mucosa. NSAIDs enhance the production of leuko­trienes through the 5-lipoxygenase pathway. The ability of LTB4 to cause degranulation and release of lysosomal enzymes may play a vital role in the inflammatory response to NSAIDs.^8–10 LTC4 may promote gastric mucosal damage through a reduction of tissue perfusion resulting from the promotion of vascular stasis.^8,11,12

Symptoms help differentiate ulcer type

The classic symptom is burning epigastric pain after meals. Pain that occurs immediately after meals is a classic symptom of gastric ulcer. Pain that occurs 2 to 3 hours after meals and that is relieved by food or antacids is a strong indicator of duodenal ulcer.¹³ Other symptoms include dyspepsia, bloating, distention, heartburn, and chest discomfort.¹³

Accurate diagnosis is vital in selecting the proper treatment. Diagnostic tests may include H pylori testing, upper-gastrointestinal endoscopy, and radiography with barium swallow.

CHOLECYSTITIS

In cholecystitis, the primary complaint is pain, usually in the right upper quadrant of the abdomen. Patients describe sudden, sharp, and intense pain that radiates to the back or shoulder. Patients may report pain after heavy meals, and some report nausea and vomiting. Cholecystitis is in the differential diagnosis of this patient because of the anatomic location of her pain.

The diagnosis is confirmed by imaging. Abdominal ultrasonography, technetium-99m hepatic iminodiacetic acid scanning, and CT are the most commonly used studies.¹⁴

Cholecystitis can be acute or chronic. Acute cholecystitis is categorized as calculous or acalculous. Calculous cholecystitis is multifactorial, but the primary cause is blockage of the cystic duct by gallstones.¹⁵ Other factors include irritants such as lysolecithin (released during bile stasis), which can trigger gallbladder inflammation,^15–17 and infection.¹⁸

When the cystic duct is blocked, bile builds up inside the gallbladder, causing irritation and inflammation of the walls of the gallbladder.¹⁴

Acalculous cholecystitis, which resembles calculous cholecystitis but without the gallstones,¹⁹ accounts for 2% to 15% of all cases of acute cholecystitis.^19,20 It has been observed in hospitalized critically ill patients, but it can also present in an outpatient setting, most often in elderly men with vascular disease.²¹ Causes include infection, trauma, and tumor obstruction, resulting in endothelial injury, gallbladder stasis, ischemia, and eventually necrosis.^14,20,22,23

SLIPPING RIB SYNDROME

Slipping rib syndrome, also known as Tietze syndrome, is believed to be caused by hypermobile costal cartilage. The affected rib slips behind the rib above on contraction of the abdominal wall. This displacement increases the probability of costal nerve impingement and tissue inflammation producing unilateral, sharp, subcostal and upper-abdominal pain.

In this patient, slipping rib syndrome is a possible diagnosis because of the location of the pain and because the pain described by the patient is highly suggestive of neuropathic pain.

Slipping rib syndrome is diagnosed clinically by a “hooking” maneuver: the clinician hooks his or her fingers at the patient’s subcostal area, reproducing the pain by movement of the ribs anteriorly.²⁴ When this test is performed in our patient the result is negative, ruling out slipping rib syndrome.

THE WORKUP CONTINUES

A complete blood cell count and comprehensive metabolic panel are within normal limits. Abdominal duplex ultrasonography reveals no celiac or mesenteric occlusions, thus ruling out chronic mesenteric ischemia.

Noncontrast CT shows no renal or ureteric stones and no evidence of bleeding in the urinary tract. CT with contrast shows no bowel distention, no evidence of hernia, and a normal appendix and ovaries.

2. After exclusion of the previous choices, which of the following is the most likely cause of her symptoms?

• Anterior cutaneous nerve entrapment syndrome (ACNES)
• Ovarian cyst
• Renal stones
• Appendicitis
• Ventral hernia
• Median arcuate ligament syndrome

ANTERIOR CUTANEOUS NERVE ENTRAPMENT SYNDROME

ACNES is the most likely diagnosis. A study published in 2013 indicated that many cases of functional abdominal pain may actually be undiagnosed cases of chronic abdominal wall pain such as ACNES.²⁵ The condition, first described in 1972,²⁶ is thought to be caused by thoracic cutaneous intercostal nerve entrapment between the abdominal muscles, causing pain at the point of entrapment.

The patient may present with pain that is either acute or chronic. Acute pain is localized more on the right side close to an old scar, or at the outer edge of the rectus abdominis muscle. The pain may vary from dull to burning to sharp; it can radiate horizontally in the upper half of the abdomen or obliquely in the lower half of the abdomen with movements such as twisting and sitting up.²⁷

Despite the acute pain, patients are able to carry on daily functions. The pain may be alleviated by lying down.

The pain may be misdiagnosed as gynecologic or renal. In younger men, the pain may raise concern about hernia, and in older patients, cancer.²⁷ Patients may complain of chronic intermittent pain, usually unilateral, and to a lesser extent bilateral.²⁷

The anatomic location of the pain usually reflects the intercostal nerve involved. The pain is not related to eating or to bowel movements.²⁵ Some patients report exacerbation upon coughing or standing, during menses, and with use of oral contraceptives.^28,29 When inquiring about surgical history, it is common to find that the patient has had multiple abdominal surgical procedures.

On examination, the patient has nondistressing pain, with a hand often placed over the painful area.²⁷ On firm palpation, a tender spot of less than 2 cm can be detected.

The diagnosis can be confirmed with a positive Carnett test. The patient lies supine on the examination table with the arms crossed over the chest, then elevates the head or the feet to tense the abdominal muscles.^26,27 If doing so reproduces the pain (ie, a positive test), this increases the suspicion of ACNES; if the pain decreases or is not reproducible, an intra-abdominal cause is more likely.

A positive Carnett test helps rule out visceral involvement

If the pain is difficult to localize, the “pinch test” can be done by using the thumb and index finger to pinch and lift the skin of the abdomen, including the subcutaneous layer of fat, first on one side and then on the other. This helps determine the side with greater pain.²⁷

OVARIAN CYSTS

Ovarian cysts are fluid-filled sacs on the surface of or within the ovary. They are often benign and require no intervention. However, 5% to 10% of US women with a suspicious ovarian mass undergo a surgical procedure, and 13% to 21% of these are found to have a malignancy.^30,31

Ovarian cysts are usually painless unless complicated by rupture or bleeding. Patients who present with pain describe it as dull and aching and in the abdomen or pelvis. In rare cases, ovarian cysts can be large enough to cause pain from torsion. Other symptoms may include delayed menses and bleeding outside of the menstrual period.^32–34

Ovarian cysts are thought to be caused by hormonal changes during the menstrual cycle. They can be detected during pelvic examination or during pelvic ultrasonography. Cysts that are primarily fluid-filled are generally benign and require no intervention. On the other hand, cysts composed of solid material require intervention.

Treatment depends on several factors, including size and type of cyst, the patient’s age, and whether torsion is present. Treatment can range from observation to medical or surgical management. Laparoscopic surgery is commonly used when surgical treatment is warranted.

RENAL STONES

From 10% to 15% of US adults develop a kidney stone at some time during their life.³⁵ There is no single cause, but one factor that promotes stone formation is a greater amount of crystal-forming substances in the urine, such as calcium, oxalate, and uric acid.³⁶ Most renal stones are calcium oxalate, uric acid, struvite, or cysteine.

Symptoms arise when the stone moves within the urinary tract. Patients present to the emergency room in severe distress, usually with flank pain that radiates to the lower abdomen or groin. The pain is episodic, fluctuates in intensity, and may present with dysuria, frequency, or urgency. It is also associated with nausea and vomiting.³⁷

Renal stones are diagnosed through a series of laboratory and imaging studies. Imaging studies include plain radiography (which can miss small stones), renal sonography, and computed tomography without contrast.

APPENDICITIS

In the United States, the lifetime risk of developing appendicitis is 8.6% in men and 6.7% in women.³⁸ Appendicitis is one of the most common reasons for emergency surgery.

Appendicitis is thought to result from obstruction by fecal matter blocking the opening of the appendix or from a viral infection (eg, with an adenovirus).^39,40 The resulting bacterial growth can cause the appendix to become inflamed and purulent.

Patients typically present with umbilical or epigastric pain radiating to the right lower quadrant of the abdomen. Over time, the pain becomes sharper. Certain movements can exacerbate the pain, and lying down may alleviate it. Other symptoms are nausea, vomiting, loss of appetite, and low-grade fever.

If the pain is difficult to localize, the ‘pinch test’ can help determine the more painful side

Findings on the abdominal examination that help to confirm the diagnosis include rigidity and tenderness, classically localized to a point two-thirds of the way from the umbilicus to the anterior superior iliac spine. Rebound tenderness is usually present. Up to 25% of cases in some series presented atypically, with variable location and findings on physical examination (eg, bowel irregularities, indigestion, flatulence, generalized malaise). In addition to the physical examination, laboratory testing and imaging (ultrasonography, CT) may aid in confirming the diagnosis of appendicitis or any other cause of the pain.³⁸

VENTRAL HERNIA

Ventral hernia is a bulging of abdominal organs or other tissues through a defect of the musculature of the abdominal wall. Ventral hernia is categorized by its location as epigastric, abdominal, or incisional. An open abdominal procedure is the cause in nearly 10% of cases⁴¹; the herniation occurs with weakening of the surgical scar.

Ventral hernia is usually detected on physical examination, and patients may present after noting a bulge in the abdominal wall. Symptoms vary. Some patients have no symptoms, while others have mild abdominal discomfort or severe abdominal pain as well as nausea and vomiting. Imaging with CT, ultrasonography, or magnetic resonance imaging helps confirm the diagnosis. Complications of ventral hernia include incarceration and bowel strangulation.

MEDIAN ARCUATE LIGAMENT SYNDROME

Median arcuate ligament syndrome is a challenging diagnosis and a very rare cause of abdominal pain. It is thought to be caused by celiac artery compression by fibroligamentous bands. Pain fluctuates with respiration and is greater during expiration.

Patients may present with recurrent episodes of crampy postprandial pain that cause them to avoid eating, resulting in weight loss. The pain may be associated with nausea, vomiting, and bloating.

The diagnosis is confirmed by duplex ultrasonography, angiography, or magnetic resonance angiography. Treatment is surgical division of the fibroligamentous band and crus, and this is often done laparascopically. In patients with severe persistent celiac artery stenosis, angioplasty and stenting may be considered.²

CASE CONTINUED

Before the physical examination, our patient identifies the location of her pain. A Carnett test is performed, as for ACNES: the patient is placed in the supine position and is instructed to cross both arms over her chest. In an effort to promote muscle tension, she is asked to elevate her head off the examination table, as if performing a mini sit-up, and as she does this, pressure is applied to the identified tender area. The pain is easily reproduced, further confirming involvement of the abdominal wall rather than the viscera. After this, electromyography shows abnormal findings. The patient is then  referred to the pain management clinic for a diagnostic nerve block.

3. Which of the following is the first-line treatment of ACNES?

• Local injection of anesthetic
• Surgical neurectomy

LOCAL INJECTION OF ANESTHETIC

Local injection of anesthetic is the first-line treatment of ACNES.

Since ACNES is underdiagnosed, the patient may be less likely to be familiar with it. He or she should receive a detailed explanation of the condition and its management; this will help achieve a successful outcome.

Local anesthetic injection is used for both diagnosis and treatment; 2% lidocaine (or an equivalent) or dehydrated (absolute) alcohol or both can eliminate the pain caused by ACNES. The injection is commonly done under ultrasonographic guidance (Figure 1).⁴²

Complete pain relief may be achieved with a single injection, but some patients require up to five injections.

The adjuvant use of corticosteroids in ACNES to reduce inflammation is controversial.

If anesthetic injections bring only minimal pain relief or if the patient has nerve entrapment in a scar, then surgical neurectomy is an option.⁴³ The procedure is performed under local anesthesia, as the patient’s response aids in identifying the specific nerve or nerves involved.

RETURNING TO THE PATIENT

After a long discussion with our patient about ACNES and the treatment options, she  agrees to undergo nerve block in the hope of relieving her pain. She receives a 0.5-mL injection of 2% lidocaine subcutaneously, and within minutes she reports relief of pain. She cannot believe that with a simple injection her pain was relieved. We advise her to return if her pain recurs or if new symptoms arise.

KEEP ACNES IN MIND

ACNES is one of the most commonly misdiagnosed conditions of patients presenting to the outpatient clinic with acute or chronic abdominal pain. This is because the focus is directed to intra-abdominal causes. But if ACNES is kept in consideration from the beginning of the patient encounter, extensive testing, time, and patient anxiety may be reduced significantly. A simple physical examination and the Carnett test aid in raising suspicion of ACNES. If ACNES is confirmed, ultrasonographically guided local anesthetic injection is both diagnostic and therapeutic.

A 31-year-old woman presents to the office with a chief complaint of right mid-abdominal pain that began 1 day ago. She says she did not seek medical attention earlier because she had to be at work that morning and she thought the pain would resolve on its own.

She reports no fever, headache, anorexia, nausea, vomiting, malaise, loss of weight, melena, or changes in bowel habits. She describes the pain as sharp, localized to the right side, and radiating to the vulva upon sitting up. She denies any association of pain with current dietary habits or bowel function. She has no recollection of precipitating or alleviating factors, including the use of analgesics to reduce the pain.

On further discussion, she mentions that 1 year ago she began experiencing chronic abdominal pain, which she says is sometimes exacerbated by coughing, by standing for extended periods of time, and during menses, and is alleviated upon lying down.

She has regular menstrual periods, and her last one ended 7 days ago.

Her surgical history includes two uncomplicated cesarean deliveries. She does not use tobacco, alcohol, or illicit substances. She is not aware of any allergies to drugs or foods.

She appears to be in no acute distress and has been sitting quietly thus far. She seems to have positioned her hand on her abdomen over the corresponding area of pain.

On physical examination, vital signs are within normal limits, and she is alert and oriented to person, place, and time. Her sclerae are anicteric, and the pupils are equal, round, and reactive to light.

Her complete blood cell count, metabolic panel, and initial imaging tests are normal

Cardiovascular and pulmonary examinations are also within normal limits. Examination of the abdomen elicits tenderness and guarding along the lateral border of the rectus abdominis muscle on the right side at the level of umbilicus, with no rebound tenderness or rigidity. The liver and spleen are not enlarged, and no abdominal mass is detected. No skin rash, joint swelling, or peripheral edema is noted. A neurologic examination is normal.

1. With the information provided, which of the following is least likely to be causing her symptoms?

• Chronic mesenteric ischemia
• Peptic ulcer
• Acute cholecystitis
• Slipping rib syndrome

CHRONIC MESENTERIC ISCHEMIA

Chronic mesenteric ischemia is the least likely diagnosis because the patient lacks risk factors for atherosclerosis and because she does not have postprandial pain, which is pathognomonic for chronic mesenteric ischemia. It is thought to be caused by a decrease in blood flow through the splanchnic vessels.¹ Symptoms tend to arise after eating because of a postprandial increase in metabolic demands.¹ These patients also often have atherosclerotic risk factors such as hypertension, hyperlipidemia, and smoking causing coronary artery disease, or a history of stroke.

The primary symptom is abdominal pain, most often described as achy, crampy, or spastic episodes of pain, usually occurring within 2 hours of eating.² Weight loss is common, as patients can develop a fear of eating. Postprandial pain may also be associated with nausea, vomiting, and bloating.

Findings on clinical examination are usually less severe than the actual symptoms. Visceral duplex or multidetector computed tomography (CT) is an excellent tool to detect blood flow in potential stenotic vessels.²

PEPTIC ULCER DISEASE

Peptic ulcer disease is not a likely diagnosis in this patient because she has no history of taking nonsteroidal anti-inflammatory drugs (NSAIDs).

A study of US patients between 1997 and 2007 reported an annual incidence of peptic ulcer disease of 0.05% to 0.19% depending on the method of diagnosis.³ Peptic ulcer is thought to result from increased gastric acid secretion with a resultant inflammatory response, leading to erosion and ulceration.

The most common possible catalysts include Helicobacter pylori infection, NSAIDs, smoking, alcohol use, and hypersecretory states such as Zollinger-Ellison syndrome.^4–6 Complications include internal bleeding, perforation causing peritonitis, and penetration to adjacent organs.

Pathophysiology

Peptic ulcer is the result of an increase in the normal level of gastric acid and a decrease in the protective ability of the gastric mucosa.⁷ Cytoprotection may be lost through a decrease in the products of arachidonic acid metabolism (eg, prostaglandins, which have a protective effect) or an increase in leukotriene B4 (LTB4), which has a damaging effect. Prostaglandins are thought not only to protect the normal gastric mucosa, but also to provide an antisecretory effect.

On the other hand, leukotrienes—specifically LTB4 and LTC4—are proinflammatory agents and can damage the gastric mucosa. NSAIDs enhance the production of leuko­trienes through the 5-lipoxygenase pathway. The ability of LTB4 to cause degranulation and release of lysosomal enzymes may play a vital role in the inflammatory response to NSAIDs.^8–10 LTC4 may promote gastric mucosal damage through a reduction of tissue perfusion resulting from the promotion of vascular stasis.^8,11,12

Symptoms help differentiate ulcer type

The classic symptom is burning epigastric pain after meals. Pain that occurs immediately after meals is a classic symptom of gastric ulcer. Pain that occurs 2 to 3 hours after meals and that is relieved by food or antacids is a strong indicator of duodenal ulcer.¹³ Other symptoms include dyspepsia, bloating, distention, heartburn, and chest discomfort.¹³

Accurate diagnosis is vital in selecting the proper treatment. Diagnostic tests may include H pylori testing, upper-gastrointestinal endoscopy, and radiography with barium swallow.

CHOLECYSTITIS

In cholecystitis, the primary complaint is pain, usually in the right upper quadrant of the abdomen. Patients describe sudden, sharp, and intense pain that radiates to the back or shoulder. Patients may report pain after heavy meals, and some report nausea and vomiting. Cholecystitis is in the differential diagnosis of this patient because of the anatomic location of her pain.

The diagnosis is confirmed by imaging. Abdominal ultrasonography, technetium-99m hepatic iminodiacetic acid scanning, and CT are the most commonly used studies.¹⁴

Cholecystitis can be acute or chronic. Acute cholecystitis is categorized as calculous or acalculous. Calculous cholecystitis is multifactorial, but the primary cause is blockage of the cystic duct by gallstones.¹⁵ Other factors include irritants such as lysolecithin (released during bile stasis), which can trigger gallbladder inflammation,^15–17 and infection.¹⁸

When the cystic duct is blocked, bile builds up inside the gallbladder, causing irritation and inflammation of the walls of the gallbladder.¹⁴

Acalculous cholecystitis, which resembles calculous cholecystitis but without the gallstones,¹⁹ accounts for 2% to 15% of all cases of acute cholecystitis.^19,20 It has been observed in hospitalized critically ill patients, but it can also present in an outpatient setting, most often in elderly men with vascular disease.²¹ Causes include infection, trauma, and tumor obstruction, resulting in endothelial injury, gallbladder stasis, ischemia, and eventually necrosis.^14,20,22,23

SLIPPING RIB SYNDROME

Slipping rib syndrome, also known as Tietze syndrome, is believed to be caused by hypermobile costal cartilage. The affected rib slips behind the rib above on contraction of the abdominal wall. This displacement increases the probability of costal nerve impingement and tissue inflammation producing unilateral, sharp, subcostal and upper-abdominal pain.

In this patient, slipping rib syndrome is a possible diagnosis because of the location of the pain and because the pain described by the patient is highly suggestive of neuropathic pain.

Slipping rib syndrome is diagnosed clinically by a “hooking” maneuver: the clinician hooks his or her fingers at the patient’s subcostal area, reproducing the pain by movement of the ribs anteriorly.²⁴ When this test is performed in our patient the result is negative, ruling out slipping rib syndrome.

THE WORKUP CONTINUES

A complete blood cell count and comprehensive metabolic panel are within normal limits. Abdominal duplex ultrasonography reveals no celiac or mesenteric occlusions, thus ruling out chronic mesenteric ischemia.

Noncontrast CT shows no renal or ureteric stones and no evidence of bleeding in the urinary tract. CT with contrast shows no bowel distention, no evidence of hernia, and a normal appendix and ovaries.

2. After exclusion of the previous choices, which of the following is the most likely cause of her symptoms?

• Anterior cutaneous nerve entrapment syndrome (ACNES)
• Ovarian cyst
• Renal stones
• Appendicitis
• Ventral hernia
• Median arcuate ligament syndrome

ANTERIOR CUTANEOUS NERVE ENTRAPMENT SYNDROME

ACNES is the most likely diagnosis. A study published in 2013 indicated that many cases of functional abdominal pain may actually be undiagnosed cases of chronic abdominal wall pain such as ACNES.²⁵ The condition, first described in 1972,²⁶ is thought to be caused by thoracic cutaneous intercostal nerve entrapment between the abdominal muscles, causing pain at the point of entrapment.

The patient may present with pain that is either acute or chronic. Acute pain is localized more on the right side close to an old scar, or at the outer edge of the rectus abdominis muscle. The pain may vary from dull to burning to sharp; it can radiate horizontally in the upper half of the abdomen or obliquely in the lower half of the abdomen with movements such as twisting and sitting up.²⁷

Despite the acute pain, patients are able to carry on daily functions. The pain may be alleviated by lying down.

The pain may be misdiagnosed as gynecologic or renal. In younger men, the pain may raise concern about hernia, and in older patients, cancer.²⁷ Patients may complain of chronic intermittent pain, usually unilateral, and to a lesser extent bilateral.²⁷

The anatomic location of the pain usually reflects the intercostal nerve involved. The pain is not related to eating or to bowel movements.²⁵ Some patients report exacerbation upon coughing or standing, during menses, and with use of oral contraceptives.^28,29 When inquiring about surgical history, it is common to find that the patient has had multiple abdominal surgical procedures.

On examination, the patient has nondistressing pain, with a hand often placed over the painful area.²⁷ On firm palpation, a tender spot of less than 2 cm can be detected.

The diagnosis can be confirmed with a positive Carnett test. The patient lies supine on the examination table with the arms crossed over the chest, then elevates the head or the feet to tense the abdominal muscles.^26,27 If doing so reproduces the pain (ie, a positive test), this increases the suspicion of ACNES; if the pain decreases or is not reproducible, an intra-abdominal cause is more likely.

A positive Carnett test helps rule out visceral involvement

If the pain is difficult to localize, the “pinch test” can be done by using the thumb and index finger to pinch and lift the skin of the abdomen, including the subcutaneous layer of fat, first on one side and then on the other. This helps determine the side with greater pain.²⁷

OVARIAN CYSTS

Ovarian cysts are fluid-filled sacs on the surface of or within the ovary. They are often benign and require no intervention. However, 5% to 10% of US women with a suspicious ovarian mass undergo a surgical procedure, and 13% to 21% of these are found to have a malignancy.^30,31

Ovarian cysts are usually painless unless complicated by rupture or bleeding. Patients who present with pain describe it as dull and aching and in the abdomen or pelvis. In rare cases, ovarian cysts can be large enough to cause pain from torsion. Other symptoms may include delayed menses and bleeding outside of the menstrual period.^32–34

Ovarian cysts are thought to be caused by hormonal changes during the menstrual cycle. They can be detected during pelvic examination or during pelvic ultrasonography. Cysts that are primarily fluid-filled are generally benign and require no intervention. On the other hand, cysts composed of solid material require intervention.

Treatment depends on several factors, including size and type of cyst, the patient’s age, and whether torsion is present. Treatment can range from observation to medical or surgical management. Laparoscopic surgery is commonly used when surgical treatment is warranted.

RENAL STONES

From 10% to 15% of US adults develop a kidney stone at some time during their life.³⁵ There is no single cause, but one factor that promotes stone formation is a greater amount of crystal-forming substances in the urine, such as calcium, oxalate, and uric acid.³⁶ Most renal stones are calcium oxalate, uric acid, struvite, or cysteine.

Symptoms arise when the stone moves within the urinary tract. Patients present to the emergency room in severe distress, usually with flank pain that radiates to the lower abdomen or groin. The pain is episodic, fluctuates in intensity, and may present with dysuria, frequency, or urgency. It is also associated with nausea and vomiting.³⁷

Renal stones are diagnosed through a series of laboratory and imaging studies. Imaging studies include plain radiography (which can miss small stones), renal sonography, and computed tomography without contrast.

APPENDICITIS

In the United States, the lifetime risk of developing appendicitis is 8.6% in men and 6.7% in women.³⁸ Appendicitis is one of the most common reasons for emergency surgery.

Appendicitis is thought to result from obstruction by fecal matter blocking the opening of the appendix or from a viral infection (eg, with an adenovirus).^39,40 The resulting bacterial growth can cause the appendix to become inflamed and purulent.

Patients typically present with umbilical or epigastric pain radiating to the right lower quadrant of the abdomen. Over time, the pain becomes sharper. Certain movements can exacerbate the pain, and lying down may alleviate it. Other symptoms are nausea, vomiting, loss of appetite, and low-grade fever.

If the pain is difficult to localize, the ‘pinch test’ can help determine the more painful side

Findings on the abdominal examination that help to confirm the diagnosis include rigidity and tenderness, classically localized to a point two-thirds of the way from the umbilicus to the anterior superior iliac spine. Rebound tenderness is usually present. Up to 25% of cases in some series presented atypically, with variable location and findings on physical examination (eg, bowel irregularities, indigestion, flatulence, generalized malaise). In addition to the physical examination, laboratory testing and imaging (ultrasonography, CT) may aid in confirming the diagnosis of appendicitis or any other cause of the pain.³⁸

VENTRAL HERNIA

Ventral hernia is a bulging of abdominal organs or other tissues through a defect of the musculature of the abdominal wall. Ventral hernia is categorized by its location as epigastric, abdominal, or incisional. An open abdominal procedure is the cause in nearly 10% of cases⁴¹; the herniation occurs with weakening of the surgical scar.

Ventral hernia is usually detected on physical examination, and patients may present after noting a bulge in the abdominal wall. Symptoms vary. Some patients have no symptoms, while others have mild abdominal discomfort or severe abdominal pain as well as nausea and vomiting. Imaging with CT, ultrasonography, or magnetic resonance imaging helps confirm the diagnosis. Complications of ventral hernia include incarceration and bowel strangulation.

MEDIAN ARCUATE LIGAMENT SYNDROME

Median arcuate ligament syndrome is a challenging diagnosis and a very rare cause of abdominal pain. It is thought to be caused by celiac artery compression by fibroligamentous bands. Pain fluctuates with respiration and is greater during expiration.

Patients may present with recurrent episodes of crampy postprandial pain that cause them to avoid eating, resulting in weight loss. The pain may be associated with nausea, vomiting, and bloating.

The diagnosis is confirmed by duplex ultrasonography, angiography, or magnetic resonance angiography. Treatment is surgical division of the fibroligamentous band and crus, and this is often done laparascopically. In patients with severe persistent celiac artery stenosis, angioplasty and stenting may be considered.²

CASE CONTINUED

Before the physical examination, our patient identifies the location of her pain. A Carnett test is performed, as for ACNES: the patient is placed in the supine position and is instructed to cross both arms over her chest. In an effort to promote muscle tension, she is asked to elevate her head off the examination table, as if performing a mini sit-up, and as she does this, pressure is applied to the identified tender area. The pain is easily reproduced, further confirming involvement of the abdominal wall rather than the viscera. After this, electromyography shows abnormal findings. The patient is then  referred to the pain management clinic for a diagnostic nerve block.

3. Which of the following is the first-line treatment of ACNES?

• Local injection of anesthetic
• Surgical neurectomy

LOCAL INJECTION OF ANESTHETIC

Local injection of anesthetic is the first-line treatment of ACNES.

Since ACNES is underdiagnosed, the patient may be less likely to be familiar with it. He or she should receive a detailed explanation of the condition and its management; this will help achieve a successful outcome.

Local anesthetic injection is used for both diagnosis and treatment; 2% lidocaine (or an equivalent) or dehydrated (absolute) alcohol or both can eliminate the pain caused by ACNES. The injection is commonly done under ultrasonographic guidance (Figure 1).⁴²

Complete pain relief may be achieved with a single injection, but some patients require up to five injections.

The adjuvant use of corticosteroids in ACNES to reduce inflammation is controversial.

If anesthetic injections bring only minimal pain relief or if the patient has nerve entrapment in a scar, then surgical neurectomy is an option.⁴³ The procedure is performed under local anesthesia, as the patient’s response aids in identifying the specific nerve or nerves involved.

RETURNING TO THE PATIENT

After a long discussion with our patient about ACNES and the treatment options, she  agrees to undergo nerve block in the hope of relieving her pain. She receives a 0.5-mL injection of 2% lidocaine subcutaneously, and within minutes she reports relief of pain. She cannot believe that with a simple injection her pain was relieved. We advise her to return if her pain recurs or if new symptoms arise.

KEEP ACNES IN MIND

ACNES is one of the most commonly misdiagnosed conditions of patients presenting to the outpatient clinic with acute or chronic abdominal pain. This is because the focus is directed to intra-abdominal causes. But if ACNES is kept in consideration from the beginning of the patient encounter, extensive testing, time, and patient anxiety may be reduced significantly. A simple physical examination and the Carnett test aid in raising suspicion of ACNES. If ACNES is confirmed, ultrasonographically guided local anesthetic injection is both diagnostic and therapeutic.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.

A 32-year-old man presents to the emergency department with excruciating abdominal pain associated with multiple episodes of vomiting for the past 2 days. He reports no fevers, headaches, diarrhea, constipation, hematochezia, melena, musculoskeletal symptoms, or weight loss. His abdominal pain is generalized and crampy. It does not radiate and has no precipitating factors. The pain is relieved only with intravenous narcotics.

See related editorial

He does not smoke, drink alcohol, or use illicit drugs. He has no known drug or food allergies. He says that his current condition causes him emotional stress that affects his performance at work.

About a year ago, after a complicated surgical procedure, he needed chronic high-dose narcotics. A few months later, he developed multiple bouts of abdominal pain and vomiting that required hospital visits. He now takes oral oxycodone 10–15 mg every 4–6 hours.

On admission, his vital signs are stable, but he is in excruciating pain. He is alert and oriented to person, place, and time. His sclera are anicteric, and the pupils are equal, round, and reactive to light. Lung and heart examinations are normal. The abdomen is soft and nondistended but tender in all four quadrants without guarding; the liver and spleen are not palpable, and no abdominal masses are detected. He has no skin rash, joint swelling or tenderness, or peripheral edema. The neurologic examination is normal. Computed tomography (CT) of the abdomen with contrast shows no signs of bowel obstruction, pancreatic calcifications or edema, cholecystitis, or hepatobiliary disease. Results of initial laboratory testing are shown in Table 1.

1. Based on the information available, which is the least likely cause of his symptoms?

• Acute pancreatitis
• Cyclic vomiting syndrome
• Acute intermittent porphyria
• Gastroparesis

Acute pancreatitis

Acute pancreatitis is the least likely cause of his symptoms. It is commonly caused by gallstones, alcohol, hypertriglyceridemia, and certain drugs.¹ The associated abdominal pain is usually epigastric, radiates to the back, and is accompanied by nausea or vomiting, or both. The onset of pain is sudden and rapidly increases in severity within 30 minutes. CT shows enlargement of the pancreas with diffuse edema, heterogeneity of pancreatic parenchyma, peripancreatic stranding, and peripancreatic fluid collections.¹ The diagnosis is based on two of the following three criteria: abdominal pain characteristic of acute pancreatitis; a serum amylase or lipase concentration three or more times the upper limit of normal; and characteristic findings of acute pancreatitis on CT.¹

Cyclic vomiting syndrome

Cyclic vomiting syndrome is thought to be caused by episodic dysautonomia, mitochondrial DNA mutations, and hypothalamic emetic response oversensitivity,^2–4 but the exact pathogenesis is unknown. The syndrome has been strongly linked to migraine and to the chronic excessive use of cannabinoids.^5–9 The Rome III diagnostic criteria¹⁰ are the following: the vomiting episodes are stereotypical, ie, they are acute and last for less than 1 week; the patient has had three or more episodes in the previous year; and the patient has no nausea or vomiting between episodes. The patient must meet all three criteria. A history of migraine or a family history of migraine further supports the diagnosis.

Acute intermittent porphyria

Acute intermittent porphyria is characterized by neurovisceral symptoms such as convulsions, paresis, autonomic dysfunction, constipation, and diarrhea that result from the overproduction of porphyrin precursors and deficiency of porphobilinogen deaminase.¹¹

Most patients have poorly localized, severe, steady abdominal pain that develops over hours to days and that may persist for days to weeks.¹¹ Since the pain is neuropathic, abdominal tenderness is usually minimal during an acute attack. Other clues include signs of ileus, such as constipation, nausea, abdominal distention, or decreased bowel sounds; bladder dysfunction, eg, urinary retention, incontinence, or dysuria; reddish-brown urine; and sensory neuropathy of the chest, back, and extremities.¹¹ Blistering skin lesions are usually not seen. The presence of porphobilinogen in the urine confirms the diagnosis.¹¹

Gastroparesis

Gastroparesis is a result of discoordination between the sympathetic and parasympathetic nervous systems, neurons, and smooth muscles within the stomach, causing a decrease in gastric motility. Common causes are diabetes,¹² scleroderma,¹³ and neurologic disorders.¹⁴ It can also be iatrogenic,¹⁵ resulting from visceral nerve injury and drug treatment with narcotics, calcium channel blockers, muscarinic cholinergic antagonists, or certain antidepressants. Symptoms are related to gastric stasis, ie, abdominal pain from gastric distention, bloating, vomiting, and early satiety.¹⁵ Abdominal pain may worsen after eating, and vomitus usually consists of recently ingested food. These patients may have abdominal distension or tenderness and succussion splash. After excluding possible mechanical obstruction, a gastric-emptying study may be necessary to make the diagnosis.¹⁵

CASE CONTINUED

A serum and urine drug screen in our patient is positive only for opioids. Urine measures of delta-aminolevulinic acid and porphobilinogen are normal. CT angiography of the abdomen shows no signs of mesenteric vascular occlusion. Esophagogastroduodenoscopy shows antral gastritis, but the esophagus and duodenum appear normal, and colonoscopy is normal as well. Histologic study of biopsy specimens obtained during endoscopy is unrevealing. A gastric-emptying study shows delayed emptying. The patient’s abdominal pain and vomiting persist with the initial dose of intravenous narcotic but resolve with escalating doses. When asked, the patient denies an excessive need for hot baths.

2. Which is the most likely diagnosis at this point?

• Narcotic bowel syndrome
• Opioid withdrawal
• Crohn disease
• Chronic pancreatitis
• Chronic mesenteric ischemia
• Cannabinoid hyperemesis

Narcotic bowel syndrome

Narcotic bowel syndrome is the most likely diagnosis. Grunkemeier et al¹⁶ described it as chronic or frequently recurring abdominal pain that is treated with narcotics, either chronically or acutely with high doses, and that includes all the following features¹⁶:

• The pain worsens or resolves incompletely with continued or increasing doses of narcotics
• The pain markedly worsens when the narcotic dose is decreased, and decreases when the drug is reinstituted (the “soarand-crash” effect)
• The frequency, duration, and intensity of the pain episodes gradually increase
• The nature of the pain and its intensity are not explained by a current or previous gastrointestinal diagnosis.¹⁶

This syndrome is common in patients who receive high doses of narcotics for postoperative pain or for other, nonmalignant causes of pain. Patients eventually become dependent on the drugs but are not aware that chronic use activates and facilitates areas in the brain that enhance the perception of pain.¹⁶ A study of a rat model of narcotic bowel syndrome¹⁷ showed that morphine-induced hyperalgesia depends on central sensitization involving the activation of spinal microglia. This eventually results in concomitant peripheral sensitization involving the colonic mucosal neuroimmune system, and also in central or peripheral activation of opioid kappa-receptors by dynorphin release.¹⁷

Patients tend to present with chronic or intermittent colicky abdominal pain that requires escalating doses of narcotics. Eventually, they develop tachyphylaxis and shortened pain-free periods and will require even higher doses of narcotics. This ultimately enhances the perception of pain and worsens opioid bowel symptoms, causing a vicious circle of pain and more narcotic use.¹⁶

Laboratory tests are usually normal, and imaging may show only ileus. Gastric emptying may be delayed in patients who have either narcotic bowel syndrome or gastroparesis, but since abdominal pain from narcotic bowel syndrome is a result of central and visceral hypersensitivity, these patients perceive more severe abdominal pain than patients with gastroparesis alone.

Opioid withdrawal

Symptoms of opioid withdrawal may appear as soon as 6 to 24 hours after cessation of the opioid in patients known to be dependent on opioids. These patients present with crampy abdominal pain with nausea.¹⁸ Other symptoms include agitation, rhinorrhea, lacrimation, excessive yawning, arthralgias, papillary dilation, and piloerection.¹⁸

Our patient did not have the typical signs of opioid withdrawal.

Crohn disease

Crohn disease is a multisystem disorder with specific clinical and pathologic features. It is characterized by focal, asymmetric, transmural, and occasionally granulomatous inflammation primarily affecting the gastrointestinal tract.¹⁹ Characteristic symptoms include abdominal pain, chronic diarrhea with or without rectal bleeding, and weight loss. Extraintestinal signs may include anemia and inflammatory changes in the eyes, skin, and joints. The diagnosis is based on endoscopic, radiographic, and pathologic findings.¹⁹

Our patient did not have diarrhea or signs of Crohn disease on CT, endoscopy, or histology.

Chronic pancreatitis

Chronic pancreatitis involves progressive inflammatory changes resulting in permanent structural damage to the pancreas and subsequent exocrine and endocrine dysfunction.²⁰ Patients have epigastric abdominal pain that often radiates to the back²⁰; it is associated with eating and is partly relieved with leaning forward. Symptoms of pancreatic insufficiency such as fat malabsorption (resulting in steatorrhea and fat-soluble vitamin deficiency) and diabetes are common. Calcifications within the pancreas on CT suggest chronic pancreatitis.²⁰ Serum lipase and amylase levels may be normal or slightly elevated.²⁰

Our patient’s abdominal pain was not typical of pancreatitis. He had no signs or symptoms of pancreatic insufficiency and no calcifications within the pancreas.

Chronic mesenteric ischemia

Chronic mesenteric ischemia (“intestinal angina”) is caused by a reduction in intestinal blood flow as a result of occlusion, vasospasm, or hypoperfusion of the mesenteric vasculature.²¹ It is commonly seen in patients who smoke or who have atherosclerotic vascular disease. These patients have chronic dull or crampy abdominal pain that usually occurs within 1 hour after eating.²¹ To avoid pain, patients avoid eating, resulting in weight loss.²¹ CT angiography with multi-detector CT is as effective as angiography (the gold standard) in depicting splanchnic arterial anatomy.²²

Our patient is young and has no known risk factors for atherosclerosis such as smoking. His abdominal pain is more intermittent than chronic and is not associated with eating.

Cannabinoid hyperemesis

Cannabinoid hyperemesis should be considered in patients with long-term cannabis use presenting with cyclic vomiting, abdominal pain, compulsive use of hot showers, and improvement of symptoms with cannabis cessation.²³ Although cannabinoids have been recognized for their antiemetic effects, long-term use may eventually cause autonomic instability and disturbances in the hypothalamic-pituitary-adrenal axis, resulting in cyclic vomiting and thermoregulatory impairment.²³

Although our patient presented with multiple episodes of vomiting and abdominal pain, he denied using marijuana, he tested negative for tetrahydrocannabinol, and he did not associate any relief of his symptoms with hot baths.

CASE CONTINUED

Our patient receives intravenous hydration, antiemetics, and a narcotic in tapering intravenous doses, and his symptoms gradually improve. He is discharged from the hospital. However, a few weeks later he is readmitted with the same symptoms of abdominal pain and nausea.

3. What is the cornerstone of treatment for narcotic bowel syndrome?

• Establishing a therapeutic relationship
• Detoxification
• Supportive management with intravenous fluids, antiemetics, and stool-softeners
• Medical management with a short-acting narcotic, clonidine, lorazepam, and desipramine

MANAGEMENT OF NARCOTIC BOWEL SYNDROME

An effective therapeutic relationship with the patient is the cornerstone of treatment and should be established before starting detoxification.¹⁷ The physician must first learn to accept that the patient’s condition is real and must show genuine empathy as well as provide information about the pathophysiologic basis of the condition, the rationale for withholding narcotics, and the detrimental role narcotics play in the vicious circle of pain.

Detoxification involves gradually withdrawing the narcotic and substituting a nonnarcotic such as an antidepressant for pain control, as well as prescribing a drug such as a benzodiazepine or clonidine to prevent withdrawal symptoms and a laxative to prevent constipation.^17,24 The physician must reassure the patient that he or she will not be abandoned in pain and that all medications will be continuously adjusted as needed to keep him or her comfortable throughout the detoxification process.^17,24 The physician must continuously gauge the patient’s willingness to continue with treatment and must also be readily available to address the patient’s concerns in a timely manner.^17,24 Involving family members and friends may provide additional support to the patient. Referral to a functional gastrointestinal motility program, a pain specialist, and a psychologist may also be considered.^17,24 Follow-up care is essential, even after the withdrawal program has ended.^17,24

BACK TO THE PATIENT

After successfully establishing a therapeutic relationship and discussing the treatment plan with our patient, we started him on the same dosage of narcotic that he had been receiving, calculated in intravenous morphine equivalents to achieve maximal comfort, and then decreased the dosage by 10% to 33% daily until he was completely off narcotics. An antidepressant and a benzodiazepine were given simultaneously with narcotic tapering. Oral clonidine (0.1–0.4 mg/day) was given after the narcotic dosage was reduced to about half, and polyethylene glycol was given as needed for constipation. The total duration of detoxification was 7 days.

The patient was referred to a psychologist for cognitive-behavioral and relaxation therapy, as well as for encouragement and support. At 6 months, he had had no recurrence of symptoms.

TAKE-HOME MESSAGE

In the United States, the number of patients taking a narcotic for nonmalignant pain is increasing, ²⁵ and physicians should be more aware of complications such as narcotic bowel syndrome.

Narcotic bowel syndrome should be suspected in any patient with prolonged narcotic use presenting with multiple recurrent episodes of abdominal pain after other causes are ruled out.

Establishing a good therapeutic relationship with the patient is the cornerstone of successful treatment. Patients who understand their condition and are willing to be treated tend to have better outcomes.

Supportive treatment, symptom relief, and emotional support during detoxification increase compliance.

A 47-year-old man who had been diagnosed with rheumatoid arthritis 5 years previously was referred to us for management of bilateral pleural effusions.

At the time of his diagnosis, his symptoms included pain and swelling of both wrists and the metacarpal joints of both hands. His serum C-reactive protein level had been elevated at that time, but he had no detectable rheumatoid factor. Findings on magnetic resonance imaging of the hand were very suggestive of rheumatoid arthritis (Figure 1).

He had been started on the anti-tumor necrosis factor agent etanercept but his symptoms improved only slightly, and therefore a glucocorticoid had been added.

Two years later, he developed abdominal pain, for which he underwent cholecystectomy. However, he continued to have chronic, generalized abdominal pain, and over the next 4 years he lost 25 lb. Upper endoscopy showed no mucosal changes, and multiple random biopsy samples were obtained for histologic evaluation (FIGURE 2) as part of his workup for chronic abdominal pain.

Q: What is the diagnosis?

A: As shown in Figure 2, staining of duodenal specimens showed intact villous architecture, with focal expansion of the lamina propria by “foamy” macrophages, rare plasma cells, and eosinophils, a key feature of Whipple disease. Periodic acid-Schiff staining showed numerous bacilli within the macrophages, thus confirming the diagnosis of Whipple disease. The diagnosis was also confirmed by polymerase chain reaction testing. Staining for acid-fast bacilli was negative.

WHEN TO CONSIDER WHIPPLE DISEASE

Whipple disease is a rare systemic disease with a very low incidence rate worldwide. Thus, its prevalence is difficult to estimate accurately. It is caused by a gram-positive bacterium, Tropheryma whippelii.^1,2 The typical clinical manifestations are diarrhea, abdominal pain, weight loss, and fever. In most patients, these are often preceded by articular symptoms,³ as in our patient, who had articular symptoms for 5 years before he was diagnosed with Whipple disease.

Interestingly, our patient also had pleural effusion, which is uncommon in Whipple disease.⁴

The pathogenesis of Whipple disease is thought to be related to bacterial replication within macrophages, which leads to a systemic immune response and tissue infiltration by the organism.⁵ Histologic evaluation is the most common way to confirm the diagnosis.

As our patient’s disease course illustrates, Whipple disease should be part of the differential diagnosis of arthritis, as antibiotic therapy alone leads to a dramatic clinical response.

Our patient was started on a 2-week course of intravenous ceftriaxone followed by oral sulfamethoxazole and trimethoprim, and his abdominal and articular symptoms completely resolved within 4 weeks.

A 47-year-old man who had been diagnosed with rheumatoid arthritis 5 years previously was referred to us for management of bilateral pleural effusions.

At the time of his diagnosis, his symptoms included pain and swelling of both wrists and the metacarpal joints of both hands. His serum C-reactive protein level had been elevated at that time, but he had no detectable rheumatoid factor. Findings on magnetic resonance imaging of the hand were very suggestive of rheumatoid arthritis (Figure 1).

He had been started on the anti-tumor necrosis factor agent etanercept but his symptoms improved only slightly, and therefore a glucocorticoid had been added.

Two years later, he developed abdominal pain, for which he underwent cholecystectomy. However, he continued to have chronic, generalized abdominal pain, and over the next 4 years he lost 25 lb. Upper endoscopy showed no mucosal changes, and multiple random biopsy samples were obtained for histologic evaluation (FIGURE 2) as part of his workup for chronic abdominal pain.

Q: What is the diagnosis?

A: As shown in Figure 2, staining of duodenal specimens showed intact villous architecture, with focal expansion of the lamina propria by “foamy” macrophages, rare plasma cells, and eosinophils, a key feature of Whipple disease. Periodic acid-Schiff staining showed numerous bacilli within the macrophages, thus confirming the diagnosis of Whipple disease. The diagnosis was also confirmed by polymerase chain reaction testing. Staining for acid-fast bacilli was negative.

WHEN TO CONSIDER WHIPPLE DISEASE

Whipple disease is a rare systemic disease with a very low incidence rate worldwide. Thus, its prevalence is difficult to estimate accurately. It is caused by a gram-positive bacterium, Tropheryma whippelii.^1,2 The typical clinical manifestations are diarrhea, abdominal pain, weight loss, and fever. In most patients, these are often preceded by articular symptoms,³ as in our patient, who had articular symptoms for 5 years before he was diagnosed with Whipple disease.

Interestingly, our patient also had pleural effusion, which is uncommon in Whipple disease.⁴

The pathogenesis of Whipple disease is thought to be related to bacterial replication within macrophages, which leads to a systemic immune response and tissue infiltration by the organism.⁵ Histologic evaluation is the most common way to confirm the diagnosis.

As our patient’s disease course illustrates, Whipple disease should be part of the differential diagnosis of arthritis, as antibiotic therapy alone leads to a dramatic clinical response.

Our patient was started on a 2-week course of intravenous ceftriaxone followed by oral sulfamethoxazole and trimethoprim, and his abdominal and articular symptoms completely resolved within 4 weeks.

A 47-year-old man who had been diagnosed with rheumatoid arthritis 5 years previously was referred to us for management of bilateral pleural effusions.

At the time of his diagnosis, his symptoms included pain and swelling of both wrists and the metacarpal joints of both hands. His serum C-reactive protein level had been elevated at that time, but he had no detectable rheumatoid factor. Findings on magnetic resonance imaging of the hand were very suggestive of rheumatoid arthritis (Figure 1).

He had been started on the anti-tumor necrosis factor agent etanercept but his symptoms improved only slightly, and therefore a glucocorticoid had been added.

Two years later, he developed abdominal pain, for which he underwent cholecystectomy. However, he continued to have chronic, generalized abdominal pain, and over the next 4 years he lost 25 lb. Upper endoscopy showed no mucosal changes, and multiple random biopsy samples were obtained for histologic evaluation (FIGURE 2) as part of his workup for chronic abdominal pain.

Q: What is the diagnosis?

A: As shown in Figure 2, staining of duodenal specimens showed intact villous architecture, with focal expansion of the lamina propria by “foamy” macrophages, rare plasma cells, and eosinophils, a key feature of Whipple disease. Periodic acid-Schiff staining showed numerous bacilli within the macrophages, thus confirming the diagnosis of Whipple disease. The diagnosis was also confirmed by polymerase chain reaction testing. Staining for acid-fast bacilli was negative.

WHEN TO CONSIDER WHIPPLE DISEASE

Whipple disease is a rare systemic disease with a very low incidence rate worldwide. Thus, its prevalence is difficult to estimate accurately. It is caused by a gram-positive bacterium, Tropheryma whippelii.^1,2 The typical clinical manifestations are diarrhea, abdominal pain, weight loss, and fever. In most patients, these are often preceded by articular symptoms,³ as in our patient, who had articular symptoms for 5 years before he was diagnosed with Whipple disease.

Interestingly, our patient also had pleural effusion, which is uncommon in Whipple disease.⁴

The pathogenesis of Whipple disease is thought to be related to bacterial replication within macrophages, which leads to a systemic immune response and tissue infiltration by the organism.⁵ Histologic evaluation is the most common way to confirm the diagnosis.

As our patient’s disease course illustrates, Whipple disease should be part of the differential diagnosis of arthritis, as antibiotic therapy alone leads to a dramatic clinical response.

Our patient was started on a 2-week course of intravenous ceftriaxone followed by oral sulfamethoxazole and trimethoprim, and his abdominal and articular symptoms completely resolved within 4 weeks.