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The Most Common Chronic Liver Disease in the World
This transcript has been edited for clarity.
Matthew F. Watto, MD: Welcome back to The Curbsiders. I’m Dr. Matthew Frank Watto, here with my great friend and America’s primary care physician, Dr. Paul Nelson Williams. Paul, what is MASLD?
Paul N. Williams, MD:
Watto: We talked about a really stripped-down way of testing people for MASLD. If we see mildly elevated liver enzymes, what should we be testing, and how does alcohol factor in?
Williams: Before you can make a definitive diagnosis of MASLD, you need to rule out other causes of liver inflammation — things that would cause a patient’s transaminases to increase. Alcohol is synergistic with everything that can harm the liver.
A great place to start is to gauge someone’s alcohol intake to make sure it isn’t causing hepatic inflammation. The phosphatidyl ethanol level is a serologic test to determine chronic, heavy alcohol use. It’s a new kid on the block. I’ve seen it mostly ordered by hepatologists. It is a way of determining whether someone has had fairly consistent alcohol use up to 4 weeks after the fact. The cutoff for a positive test is 20 ng/mL.
Dr Tapper frames the test this way. He isn’t using the test to catch someone in a lie about their alcohol use. He tells patients that he orders this test for all patients with liver inflammation, because alcohol is a common cause. The test helps him better understand the factors that might be affecting the patient’s liver function.
If the test comes back positive, you can have a conversation about that, and if it’s not positive, you move on to the next possible cause. Other fairly common causes of liver inflammation are relatively easy to address.
Watto: Instead of ordering ceruloplasmin or alpha-1 antitrypsin tests, for example, the first thing Dr Tapper recommends is checking for hepatitis B and C. We can cure hepatitis C. We can’t cure hepatitis B, but it’s important to know if the patient has it. Primary care physicians should be comfortable ordering these tests.
Really high ALT levels (eg, in the 200s) don’t usually happen from steatotic liver disease. In those cases, we would send an expanded panel that might include tests for autoimmune hepatitis-ANA, anti–smooth muscle antibody, and IgG levels. Otherwise, most of these patients don’t need much more testing.
What is a FIB4 score and how does that factor in?
Williams: The FIB4 score estimates the degree of fibrosis based on the ALT and AST levels, platelet count, and the patient’s age. These data are plugged into a formula. If the FIB4 score is low (meaning not much fibrosis is present), you can stop there and do your counseling about lifestyle changes and address the reversible factors.
If the FIB4 score is above a certain threshold (1.3 in young adults and 2.0 in older adults), you need to find a more concrete way to determine the degree of fibrosis, typically through imaging.
Elastography can be done either with ultrasound or MRI. Ultrasound is typically ordered, but Dr Tapper recommends doing MRI on patients with a BMI > 40. Those patients are probably better served by doing MRI to determine the degree of liver fibrosis.
Watto: Patients with low FIB4 scores probably don’t need elastography but those with high FIB4 scores do. For the interpretation of ultrasound-based elastography results, Dr Tapper gave us the “rule of 5s”.
Elastography results are reported in kilopascal (kPa) units. A finding of 5 kPa or less is normal. Forty percent of those with a result of 10 kPa might have advanced liver disease. Above 15 kPa, the likelihood of cirrhosis is high, becoming very likely at 25 kPa. Finally, with a result of > 25 kPa, portal hypertension is likely, and you might need to have a conversation about starting the patient on medicine to prevent variceal bleeding.
We are moving toward more noninvasive testing and avoiding biopsies. We have cutoff values for MRI-based elastography as well. Both of these tests can help stage the liver.
What can we tell people about diet?
Williams: Weight loss is helpful. You can reverse fibrosis with weight loss. You can truly help your liver and bring it closer to its healthy baseline with weight loss. A loss of 7.5% body weight can reduce steatohepatitis, and with around 10% of body weight loss, you can actually resolve fibrosis, which is remarkable.
We all know that weight loss can be very therapeutic for many conditions. It’s just very hard to achieve. As primary care doctors, we should use what we have in our armamentarium to achieve that goal. Often, that will include certain medications.
Watto: I like giving patients the 10% number because if they weigh 220 pounds, they need to lose 22 pounds. If they weigh 300 pounds, it’s 30 pounds. Most people who weigh 300 pounds think they need to lose 100 pounds to have any sort of health benefit, but it’s much less than that. So, I do find that helpful.
But now a new drug has been approved. It’s a thyroid memetic called resmetirom. It was from the MAESTRO-NASH trial. Without weight loss, it helped to reverse fibrosis.
This is going to be used more and more in the future. It’s still being worked out exactly where the place is for that drug, so much so that Dr Tapper, as a liver expert, hadn’t even had the chance to prescribe it yet. Of course, it was very recently approved.
Dr. Tapper is one of our most celebrated guests, so check out the full podcast here.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Matthew F. Watto, MD: Welcome back to The Curbsiders. I’m Dr. Matthew Frank Watto, here with my great friend and America’s primary care physician, Dr. Paul Nelson Williams. Paul, what is MASLD?
Paul N. Williams, MD:
Watto: We talked about a really stripped-down way of testing people for MASLD. If we see mildly elevated liver enzymes, what should we be testing, and how does alcohol factor in?
Williams: Before you can make a definitive diagnosis of MASLD, you need to rule out other causes of liver inflammation — things that would cause a patient’s transaminases to increase. Alcohol is synergistic with everything that can harm the liver.
A great place to start is to gauge someone’s alcohol intake to make sure it isn’t causing hepatic inflammation. The phosphatidyl ethanol level is a serologic test to determine chronic, heavy alcohol use. It’s a new kid on the block. I’ve seen it mostly ordered by hepatologists. It is a way of determining whether someone has had fairly consistent alcohol use up to 4 weeks after the fact. The cutoff for a positive test is 20 ng/mL.
Dr Tapper frames the test this way. He isn’t using the test to catch someone in a lie about their alcohol use. He tells patients that he orders this test for all patients with liver inflammation, because alcohol is a common cause. The test helps him better understand the factors that might be affecting the patient’s liver function.
If the test comes back positive, you can have a conversation about that, and if it’s not positive, you move on to the next possible cause. Other fairly common causes of liver inflammation are relatively easy to address.
Watto: Instead of ordering ceruloplasmin or alpha-1 antitrypsin tests, for example, the first thing Dr Tapper recommends is checking for hepatitis B and C. We can cure hepatitis C. We can’t cure hepatitis B, but it’s important to know if the patient has it. Primary care physicians should be comfortable ordering these tests.
Really high ALT levels (eg, in the 200s) don’t usually happen from steatotic liver disease. In those cases, we would send an expanded panel that might include tests for autoimmune hepatitis-ANA, anti–smooth muscle antibody, and IgG levels. Otherwise, most of these patients don’t need much more testing.
What is a FIB4 score and how does that factor in?
Williams: The FIB4 score estimates the degree of fibrosis based on the ALT and AST levels, platelet count, and the patient’s age. These data are plugged into a formula. If the FIB4 score is low (meaning not much fibrosis is present), you can stop there and do your counseling about lifestyle changes and address the reversible factors.
If the FIB4 score is above a certain threshold (1.3 in young adults and 2.0 in older adults), you need to find a more concrete way to determine the degree of fibrosis, typically through imaging.
Elastography can be done either with ultrasound or MRI. Ultrasound is typically ordered, but Dr Tapper recommends doing MRI on patients with a BMI > 40. Those patients are probably better served by doing MRI to determine the degree of liver fibrosis.
Watto: Patients with low FIB4 scores probably don’t need elastography but those with high FIB4 scores do. For the interpretation of ultrasound-based elastography results, Dr Tapper gave us the “rule of 5s”.
Elastography results are reported in kilopascal (kPa) units. A finding of 5 kPa or less is normal. Forty percent of those with a result of 10 kPa might have advanced liver disease. Above 15 kPa, the likelihood of cirrhosis is high, becoming very likely at 25 kPa. Finally, with a result of > 25 kPa, portal hypertension is likely, and you might need to have a conversation about starting the patient on medicine to prevent variceal bleeding.
We are moving toward more noninvasive testing and avoiding biopsies. We have cutoff values for MRI-based elastography as well. Both of these tests can help stage the liver.
What can we tell people about diet?
Williams: Weight loss is helpful. You can reverse fibrosis with weight loss. You can truly help your liver and bring it closer to its healthy baseline with weight loss. A loss of 7.5% body weight can reduce steatohepatitis, and with around 10% of body weight loss, you can actually resolve fibrosis, which is remarkable.
We all know that weight loss can be very therapeutic for many conditions. It’s just very hard to achieve. As primary care doctors, we should use what we have in our armamentarium to achieve that goal. Often, that will include certain medications.
Watto: I like giving patients the 10% number because if they weigh 220 pounds, they need to lose 22 pounds. If they weigh 300 pounds, it’s 30 pounds. Most people who weigh 300 pounds think they need to lose 100 pounds to have any sort of health benefit, but it’s much less than that. So, I do find that helpful.
But now a new drug has been approved. It’s a thyroid memetic called resmetirom. It was from the MAESTRO-NASH trial. Without weight loss, it helped to reverse fibrosis.
This is going to be used more and more in the future. It’s still being worked out exactly where the place is for that drug, so much so that Dr Tapper, as a liver expert, hadn’t even had the chance to prescribe it yet. Of course, it was very recently approved.
Dr. Tapper is one of our most celebrated guests, so check out the full podcast here.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Matthew F. Watto, MD: Welcome back to The Curbsiders. I’m Dr. Matthew Frank Watto, here with my great friend and America’s primary care physician, Dr. Paul Nelson Williams. Paul, what is MASLD?
Paul N. Williams, MD:
Watto: We talked about a really stripped-down way of testing people for MASLD. If we see mildly elevated liver enzymes, what should we be testing, and how does alcohol factor in?
Williams: Before you can make a definitive diagnosis of MASLD, you need to rule out other causes of liver inflammation — things that would cause a patient’s transaminases to increase. Alcohol is synergistic with everything that can harm the liver.
A great place to start is to gauge someone’s alcohol intake to make sure it isn’t causing hepatic inflammation. The phosphatidyl ethanol level is a serologic test to determine chronic, heavy alcohol use. It’s a new kid on the block. I’ve seen it mostly ordered by hepatologists. It is a way of determining whether someone has had fairly consistent alcohol use up to 4 weeks after the fact. The cutoff for a positive test is 20 ng/mL.
Dr Tapper frames the test this way. He isn’t using the test to catch someone in a lie about their alcohol use. He tells patients that he orders this test for all patients with liver inflammation, because alcohol is a common cause. The test helps him better understand the factors that might be affecting the patient’s liver function.
If the test comes back positive, you can have a conversation about that, and if it’s not positive, you move on to the next possible cause. Other fairly common causes of liver inflammation are relatively easy to address.
Watto: Instead of ordering ceruloplasmin or alpha-1 antitrypsin tests, for example, the first thing Dr Tapper recommends is checking for hepatitis B and C. We can cure hepatitis C. We can’t cure hepatitis B, but it’s important to know if the patient has it. Primary care physicians should be comfortable ordering these tests.
Really high ALT levels (eg, in the 200s) don’t usually happen from steatotic liver disease. In those cases, we would send an expanded panel that might include tests for autoimmune hepatitis-ANA, anti–smooth muscle antibody, and IgG levels. Otherwise, most of these patients don’t need much more testing.
What is a FIB4 score and how does that factor in?
Williams: The FIB4 score estimates the degree of fibrosis based on the ALT and AST levels, platelet count, and the patient’s age. These data are plugged into a formula. If the FIB4 score is low (meaning not much fibrosis is present), you can stop there and do your counseling about lifestyle changes and address the reversible factors.
If the FIB4 score is above a certain threshold (1.3 in young adults and 2.0 in older adults), you need to find a more concrete way to determine the degree of fibrosis, typically through imaging.
Elastography can be done either with ultrasound or MRI. Ultrasound is typically ordered, but Dr Tapper recommends doing MRI on patients with a BMI > 40. Those patients are probably better served by doing MRI to determine the degree of liver fibrosis.
Watto: Patients with low FIB4 scores probably don’t need elastography but those with high FIB4 scores do. For the interpretation of ultrasound-based elastography results, Dr Tapper gave us the “rule of 5s”.
Elastography results are reported in kilopascal (kPa) units. A finding of 5 kPa or less is normal. Forty percent of those with a result of 10 kPa might have advanced liver disease. Above 15 kPa, the likelihood of cirrhosis is high, becoming very likely at 25 kPa. Finally, with a result of > 25 kPa, portal hypertension is likely, and you might need to have a conversation about starting the patient on medicine to prevent variceal bleeding.
We are moving toward more noninvasive testing and avoiding biopsies. We have cutoff values for MRI-based elastography as well. Both of these tests can help stage the liver.
What can we tell people about diet?
Williams: Weight loss is helpful. You can reverse fibrosis with weight loss. You can truly help your liver and bring it closer to its healthy baseline with weight loss. A loss of 7.5% body weight can reduce steatohepatitis, and with around 10% of body weight loss, you can actually resolve fibrosis, which is remarkable.
We all know that weight loss can be very therapeutic for many conditions. It’s just very hard to achieve. As primary care doctors, we should use what we have in our armamentarium to achieve that goal. Often, that will include certain medications.
Watto: I like giving patients the 10% number because if they weigh 220 pounds, they need to lose 22 pounds. If they weigh 300 pounds, it’s 30 pounds. Most people who weigh 300 pounds think they need to lose 100 pounds to have any sort of health benefit, but it’s much less than that. So, I do find that helpful.
But now a new drug has been approved. It’s a thyroid memetic called resmetirom. It was from the MAESTRO-NASH trial. Without weight loss, it helped to reverse fibrosis.
This is going to be used more and more in the future. It’s still being worked out exactly where the place is for that drug, so much so that Dr Tapper, as a liver expert, hadn’t even had the chance to prescribe it yet. Of course, it was very recently approved.
Dr. Tapper is one of our most celebrated guests, so check out the full podcast here.
A version of this article appeared on Medscape.com.
Can We Repurpose Obesity Drugs to Reverse Liver Disease?
Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.
Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.
The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.
In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.
The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
More Than One Risk Factor in Play
MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.
It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.
Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.
The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.
Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
Single Agents
The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.
“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.
One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.
Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.
A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.
Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”
Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.
A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.
Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
Dual and Triple Mechanisms of Action
Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.
“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.
An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.
A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.
“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”
The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.
In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.
Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.
The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said.
Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.
Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.
Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.
A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.
This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
Obstacles and Warnings
Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.
GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.
Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.
Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.
“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.
Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.
“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.
“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.
Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
A version of this article first appeared on Medscape.com.
Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.
Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.
The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.
In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.
The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
More Than One Risk Factor in Play
MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.
It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.
Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.
The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.
Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
Single Agents
The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.
“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.
One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.
Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.
A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.
Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”
Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.
A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.
Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
Dual and Triple Mechanisms of Action
Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.
“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.
An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.
A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.
“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”
The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.
In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.
Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.
The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said.
Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.
Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.
Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.
A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.
This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
Obstacles and Warnings
Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.
GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.
Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.
Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.
“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.
Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.
“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.
“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.
Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
A version of this article first appeared on Medscape.com.
Metabolic dysfunction–associated steatotic liver disease (MASLD) has become the most common liver disease worldwide, with a global prevalence of 32.4%. Its growth over the past three decades has occurred in tandem with increasing rates of obesity and type 2 diabetes — two cornerstones of MASLD.
Higher rates of MASLD and metabolic dysfunction–associated steatohepatitis (MASH) with fibrosis are present in adults with obesity and diabetes, noted Arun Sanyal, MD, professor and director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia.
The success surrounding the medications for obesity and type 2 diabetes, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs), has sparked studies investigating whether they could also be an effective treatment for liver disease.
In particular, GLP-1 RAs help patients lose weight and/or control diabetes by mimicking the function of the gut hormone GLP-1, released in response to nutrient intake, and are able to increase insulin secretion and reduce glucagon secretion, delay gastric emptying, and reduce appetite and caloric intake.
The studies for MASLD are testing whether these functions will also work against liver disease, either directly or indirectly, through obesity and diabetes control. The early results are promising.
More Than One Risk Factor in Play
MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic risk factors: Overweight/obesity, hypertension, hyperglycemia, dyslipidemia with either low-plasma high-density lipoprotein cholesterol or high triglycerides, or treatment for these conditions.
It is a grim trajectory if the disease progresses to MASH, as the patient may accumulate hepatic fibrosis and go on to develop cirrhosis and/or hepatocellular carcinoma.
Typically, more than one risk factor is at play in MASLD, noted Adnan Said, MD, chief of the Division of Gastroenterology and Hepatology at the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin.
“It most commonly occurs in the setting of weight gain and obesity, which are epidemics in the United States and worldwide, as well as the associated condition — metabolic syndrome — which goes along with obesity and includes type 2 diabetes, hyperlipidemia, hypertension, and sleep apnea,” Said, a hepatology and gastroenterology professor at the University of Wisconsin–Madison, told this news organization.
The research surrounding MASLD is investigating GLP-1 RAs as single agents and in combination with other drugs.
Finding treatment is critical, as there is only one drug — resmetirom — approved for the treatment of MASH with moderate to advanced fibrosis. But because it’s not approved for earlier stages, a treatment gap exists. The drug also doesn’t produce weight loss, which is key to treating MASLD. And while GLP-1 RAs help patients with the weight loss that is critical to MASLD, they are only approved by the US Food and Drug Administration (FDA) for obesity and type 2 diabetes.
Single Agents
The GLP-1 RAs liraglutide and semaglutide, both approved for diabetes and weight loss, are being studied as single agents against liver disease, Said said.
“Their action in the setting of MASLD and MASH is primarily indirect, through systemic pathways, improving these conditions via weight loss, as well as by improving insulin sensitivity and reducing lipotoxicity,” he added.
One of the first trials of these agents for liver disease was in 2016. In that double-blind, randomized, 48-week clinical trial of liraglutide in patients with MASH and overweight, 39% of patients who received liraglutide had a resolution of MASH compared with only 9% of those who received placebo. Moreover, only 9% vs 36% of patients in the treatment vs placebo group had progression of fibrosis.
Since then, a 72-week phase 2 trial in patients with MASH, liver fibrosis (stages F1-F3), and overweight or obesity found that once-daily subcutaneous semaglutide (0.1, 0.2, or 0.4 mg) outperformed placebo on MASH resolution without worsening of fibrosis (36%-59% vs 17%) and on weight loss (5%-13% vs 1%), with the greatest benefits at the largest dose. However, neoplasms were reported in 15% of patients receiving semaglutide vs 8% of those receiving placebo.
A phase 1 trial involving patients with liver stiffness, steatosis, and overweight or obesity found significantly greater reductions in liver fat at 48 weeks with semaglutide vs placebo, as well as decreases in liver enzymes, body weight, and A1c. There was no significant difference in liver stiffness.
Furthermore, a meta-analysis of eight studies found that treatment with 24 weeks of semaglutide significantly improved liver enzymes, reduced liver stiffness, and improved metabolic parameters in patients with MASLD/MASH. The authors cautioned that gastrointestinal adverse effects “could be a major concern.”
Several studies have found other GLP-1 RAs, including exenatide and dulaglutide, have a beneficial impact on liver injury indices and liver steatosis.
A new retrospective observational study offers evidence that GLP-1 RAs may have a direct impact on MASLD, independent of weight loss. Among the 28% of patients with type 2 diabetes and MASLD who received a GLP-1 RA, there was a significant reduction not only in body mass index but also in A1c, liver enzymes, and controlled attenuation parameter scores. A beneficial impact on liver parameters was observed even in patients who didn’t lose weight. While there was no difference in liver stiffness measurement, the median 60-month follow-up time may not have been long enough to capture such changes.
Another study indicated that the apparent benefits of GLP-1 RAs, in this case semaglutide, may not extend to patients whose disease has progressed to cirrhosis.
Dual and Triple Mechanisms of Action
Newer agents with double or triple mechanisms of action appear to have a more direct effect on the liver.
“Dual agents may have an added effect by improving MASLD directly through adipose regulation and thermogenesis, thereby improving fibrosis,” Said said.
An example is tirzepatide, a GLP-1 RA and an agonist of glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin. When used together as co-agonists, GLP-1 and GIP have been shown to increase insulin and glucagonostatic response and may work synergistically.
A new phase 2 trial that randomly assigned patients with biopsy-confirmed MASH and moderate or severe fibrosis to receive either once-weekly subcutaneous tirzepatide at one of three doses (5, 10, or 15 mg) or placebo found that tirzepatide at each dosage outperformed placebo in resolution of MASH without worsening of fibrosis.
“These findings were encouraging,” Said said. “We’ll see if the results continue into phase 3 trials.”
The combination of GLP-1 RAs with glucagon (GCG) receptor agonists also has garnered interest.
In a phase 2 trial, adults with biopsy-confirmed MASH and fibrosis stages F1-F3 were randomly assigned to receive either one of three doses of the GLP-1/GCG RA survodutide (2.4, 4.8, or 6 mg) or placebo. Survodutide at each dose was found to be superior to placebo in improving MASH without the worsening of fibrosis, reducing liver fat content by at least 30%, and decreasing liver fibrosis by at least one stage, with the 4.8-mg dose showing the best performance for each measure. However, adverse events, including nausea, diarrhea, and vomiting, were more frequent with survodutide than with placebo.
Trials of triple-action agents (GLP-1/GIP/GCG RAs) are underway too.
The hope is the triple agonists could deliver greater reduction in hepatic fat in patients with MASLD, Sanyal said.
Sanyal further noted that a reduction in liver fat is important, citing a meta-analysis that showed ≥ 30% relative decline in liver fat is associated with higher odds of histologic response and MASH resolution.
Sanyal pointed to efocipegtrutide (HM15211), a GLP-1/GIP/GCG RA, which demonstrated significant liver fat reduction after 12 weeks in patients with MASLD in a phase 1b/2a randomized, placebo-controlled trial and is now in phase 2 development.
Another example is retatrutide (LY3437943), a once-weekly injectable, that was associated with up to a 24.2% reduction in body weight at 48 weeks, compared with 2.1% with placebo, in a phase 2 trial involving patients with obesity.
A sub-study assessed the mean relative change from baseline in liver fat at 24 weeks. These participants, who also had MASLD and ≥ 10% of liver fat content, were randomly assigned to receive either retatrutide in one of four doses (1, 4, 8, or 12 mg) or placebo for 48 weeks. All doses of retatrutide showed significantly greater reduction in liver fat content compared with placebo in weeks 24-48, with a mean relative liver fat reduction > 80% at the two higher doses. Moreover, ≥ 80% of participants on the higher retatrutide doses experienced ≥ 70% reduction in liver fat at 48 weeks, compared with 0% reduction in those on placebo, and hepatic steatosis resolved in > 85% of these participants.
This space “continues to evolve at a rapid rate,” Sanyal said. For example, oral dual-action agents are under development.
Obstacles and Warnings
Sanyal warned that GLP-1 RAs can cause nausea, so they have to be introduced at a low dose and slowly titrated upward. They should be used with caution in people with a history of multiple endocrine neoplasia. There is also a small but increased risk for gallstone formation and gallstone-induced pancreatitis with rapid weight loss.
GLP-1 RAs may increase the risk for suicidal ideation, with the authors of a recent study calling for “urgent clarification” regarding this possibility.
Following reports of suicidality submitted through its Adverse Events Reporting System, the FDA concluded that it could find no causal relationship between these agents and increased risk for suicidal ideation but also that it could not “definitively rule out that a small risk may exist” and would continue to investigate.
Access to GLP-1 RAs is an obstacle as well. Semaglutide continues to be on the FDA’s shortage list.
“This is improving, but there are still issues around getting approval from insurance companies,” Sanyal said.
Many patients discontinue use because of tolerability or access issues, which is problematic because most regain the weight they had lost while on the medication.
“Right now, we see GLP-1 RAs as a long-term therapeutic commitment, but there is a lot of research interest in figuring out if there’s a more modest benefit — almost an induction-remission maintenance approach to weight loss,” Sanyal said. These are “evolving trends,” and it’s unclear how they will unfold.
“As of now, you have to decide that if you’re putting your patient on these medications, they will have to take them on a long-term basis and include that consideration in your risk-benefit analysis, together with any concerns about adverse effects,” he said.
Sanyal reported consulting for Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Said received research support from Exact Sciences, Boehringer Ingelheim, and Mallinckrodt.
A version of this article first appeared on Medscape.com.
New Guidelines Emphasize Liver Care in T2D, Obesity
MADRID — Individuals with type 2 diabetes and/or obesity plus one or more metabolic risk factors are at a higher risk for metabolic dysfunction–associated steatotic liver disease (MASLD) with fibrosis and progression to more severe liver disease, stated new European guidelines that provide recommendations for diagnosis and management.
“The availability of improved treatment options underlines the need to identify at-risk individuals with MASLD early, as we now possess the tools to positively influence the course of the diseases, which is expected to prevent relevant clinical events,” stated the clinical practice guidelines, updated for the first time since 2016.
“Now we have guidelines that tell clinicians how to monitor the liver,” said Amalia Gastaldelli, PhD, research director at the Institute of Clinical Physiology of the National Research Council in Pisa, Italy, and a member of the panel that developed the guidelines.
Dr. Gastaldelli moderated a session focused on the guidelines at the annual meeting of the European Association for the Study of Diabetes (EASD). In an interview after the session, Dr. Gastaldelli, who leads a cardiometabolic risk research group, stressed the importance of the liver’s role in the body and the need for diabetes specialists to start paying more attention to this vital organ.
“It’s an important organ for monitoring because liver disease is silent, and the patient doesn’t feel unwell until disease is severe,” she said. “Diabetologists already monitor the eye, the heart, the kidney, and so on, but the liver is often neglected,” she said. A 2024 study found that the global pooled prevalence of MASLD among patients with type 2 diabetes was 65.33%.
Dr. Gastaldelli noted the importance of liver status in diabetes care. The liver makes triglycerides and very-low-density lipoprotein cholesterol, which are all major risk factors for atherosclerosis and cardiovascular disease (CVD), she said, as well as producing glucose, which in excess can lead to hyperglycemia.
The guidelines were jointly written by EASD, the European Association for the Study of the Liver, and the European Association for the Study of Obesity, and published in Diabetologia, The Journal of Hepatology, and Obesity Facts.
A Metabolic Condition
In the EASD meeting session, Dr. Gastaldelli discussed the reasons for, and implications of, shifting the name from nonalcoholic fatty liver disease (NAFLD) to MASLD.
“The name change focuses on the fact that this is a metabolic disease, while NAFLD had no mention of this and was considered stigmatizing by patients, especially in relation to the words ‘fatty’ and ‘nonalcoholic,’” she said.
According to the guidelines, MASLD is defined as liver steatosis in the presence of one or more cardiometabolic risk factor(s) and the absence of excess alcohol intake.
MASLD has become the most common chronic liver disease and includes isolated steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), MASH-related fibrosis, and cirrhosis.
In the overarching group of steatotic liver disease, a totally new intermediate category has been added: MASLD with moderate (increased) alcohol intake (MetALD), which represents MASLD in people who consume greater amounts of alcohol per week (140-350 g/week and 210-420 g/week for women and men, respectively).
The change in the nomenclature has been incremental and regional, Dr. Gastaldelli said. “The definition first changed from NAFLD to MAFLD, which recognizes the importance of metabolism in the pathophysiology of this disease but does not take into account alcohol intake. MAFLD is still used in Asia, Australasia, and North Africa, while Europe and the Americas have endorsed MASLD.”
Case-Finding and Diagnosis
Identifying MASLD cases in people at risk remains incidental, largely because it is a silent disease and is symptom-free until it becomes severe, said Dr. Gastaldelli.
The guideline recognizes that individuals with type 2 diabetes or obesity with additional metabolic risk factor(s) are at a higher risk for MASLD with fibrosis and progression to MASH.
Assessment strategies for severe liver fibrosis in MASLD include the use of noninvasive tests in people who have cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity or in the presence of one or more metabolic risk factors.
Dr. Gastaldelli noted that type 2 diabetes, metabolic syndrome, and obesity, including abdominal obesity identified by large waist circumference, are the major risk factors and should be warning signs.
“We need to consider abdominal obesity too — we’ve published data in relatively lean people, body mass index < 25, with MASH but without diabetes. Most of the patients accumulated fat viscerally and in the liver and had hypertriglyceridemia and hypercholesterolemia,” she said.
“The guidelines reflect this because the definition of MASLD includes steatosis plus at least one metabolic factor — waist circumference, for example, which is related to visceral fat, hyperlipidemia, or hyperglycemia. Of note, in both pharmacological and diet-induced weight loss, the decrease in liver fat was associated with the decrease in visceral fat.”
The noninvasive biomarker test, Fibrosis-4 (FIB-4) may be used to assess the risk for liver fibrosis. The FIB-4 index is calculated using a patient’s age and results of three blood tests — aspartate aminotransferase, alanine aminotransferase, and platelet count.
Advanced fibrosis (grade F3-F4) “is a major risk factor for severe outcomes,” said Dr. Gastaldelli. A FIB-4 test result below 1.3 indicates low risk for advanced liver fibrosis, 1.30-2.67 indicates intermediate risk, and above 2.67 indicates high risk.
“When fibrosis increases, then liver enzymes increase and the platelets decrease,” said Dr. Gastaldelli. “It is not a perfect tool, and we need to add in age because at a young age, it is prone to false negatives and when very old — false positives. It’s important to take a global view, especially if the patient has persistent high liver enzymes, but FIB-4 is low.”
“And if they have more than one metabolic risk factor, proceed with more tests, for example, transient elastography,” she advised. Imaging techniques such as transient elastography may rule out or rule in advanced fibrosis, which is predictive of liver-related outcomes.
“However, imaging techniques only diagnose steatosis and fibrosis, and right now, MASH can only be diagnosed with liver biopsy because we do not have any markers of liver inflammation and ballooning. In the future, noninvasive tests based on imaging and blood tests will be used to identify patients with MASH,” she added.
Management of MASLD — Lifestyle and Treatment
“Pharmacological treatments are designed for [patients] with MASH and fibrosis grade F2 or F3, but not MASLD,” Dr. Gastaldelli said. As such, lifestyle interventions are the mainstay of management — including weight loss, dietary changes, physical exercise, and low to no alcohol consumption. “Eating good-quality food and reducing calories are both important because the metabolism responds differently to different nutrients,” Dr. Gastaldelli said.
“In particular, the guidelines advise dietary management because some foods carry liver toxicity, for example, sugary foods with sucrose/fructose especially,” she said, adding that, “complex carbohydrates are less harmful than refined carbohydrates. Processed foods should be avoided if possible because they contain sugars, [as well as] saturated fats and hydrogenated fat, which is particularly bad for the liver. Olive oil is better than butter or margarine, which are rich in saturated fat, and fish and white meat are preferable.”
She added that a diet to help manage type 2 diabetes was not so dissimilar because sugar again needs to be reduced.
If a patient has severe obesity (and MASLD), data show that bariatric surgery is beneficial. “It not only helps weight loss, but it improves liver histology and has been shown to improve or resolve type 2 diabetes and reduce CVD risk. Importantly, regarding fibrosis, nutritional management after the bariatric surgery is the most important thing,” said Dr. Gastaldelli.
Optimal management of comorbidities — including the use of incretin-based therapies such as semaglutide or tirzepatide for type 2 diabetes or obesity, if indicated — is advised, according to the guidelines.
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to have a beneficial effect on MASH, said Dr. Gastaldelli. “They have not shown effectiveness in the resolution of fibrosis, but this might take longer to manifest. However, if the medication is started early enough, it may prevent severe fibrosis. Significant weight loss, both with lifestyle and pharmacological treatment, should lead to an improvement in the liver too.”
There are currently no drugs available in Europe for the treatment of noncirrhotic MASH and severe fibrosis (stage ≥ 2). Resmetirom is the first approved MASH-targeted treatment in noncirrhotic MASH and significant liver fibrosis, with histological effectiveness on steatohepatitis and fibrosis, together with an acceptable safety and tolerability profile, but, for the moment, this agent is only available in United States.
Finally, turning to MASH-related cirrhosis, the guidelines advise adaptations of metabolic drugs, nutritional counseling, and surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
After the session, this news organization spoke to Tushy Kailayanathan, MBBS BSc, medical director of the liver MRI company, Perspectum, who reviewed the limitations of the FIB-4 test. The FIB-4 test identifies those with advanced fibrosis in the liver, for example, patients with hepatitis C, she noted; however, “it performs worse in type 2 diabetic patients and in the elderly. There is little clinical guidance on the adjustment of FIB-4 thresholds needed for these high cardiometabolic risk groups. The priority patients are missed by FIB-4 because those individuals with early and active disease may not yet have progressed to advanced disease detected by FIB-4.”
These individuals are exactly those amenable to primary care prevention strategies, said Dr. Kailayanathan. Because of the nature of early and active liver disease in patients with high cardiometabolic risk, it would make sense to shift some diagnostic protocols into primary care.
“These individuals are exactly those amenable to primary care prevention strategies at annual diabetic review because they are likely to have modifiable cardiometabolic risk factors such as metabolic syndrome and would benefit from lifestyle and therapeutic intervention, including GLP-1 RAs and SGLT2is [sodium-glucose cotransporter-2 inhibitors],” she said. “Case-finding and detection of early-stage MASLD is a priority in diabetics, and there is an unmet need for accurate biomarkers to measure liver fat and inflammation early.”
Dr. Gastaldelli has been on the advisory board or consulting for Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Fractyl, Pfizer, Merck-MSD, MetaDeq and a speaker for Eli Lilly, Novo Nordisk, and Pfizer. Dr. Kailayanathan is medical director at Perspectum, a UK-based company involved in liver imaging technology.
A version of this article first appeared on Medscape.com.
MADRID — Individuals with type 2 diabetes and/or obesity plus one or more metabolic risk factors are at a higher risk for metabolic dysfunction–associated steatotic liver disease (MASLD) with fibrosis and progression to more severe liver disease, stated new European guidelines that provide recommendations for diagnosis and management.
“The availability of improved treatment options underlines the need to identify at-risk individuals with MASLD early, as we now possess the tools to positively influence the course of the diseases, which is expected to prevent relevant clinical events,” stated the clinical practice guidelines, updated for the first time since 2016.
“Now we have guidelines that tell clinicians how to monitor the liver,” said Amalia Gastaldelli, PhD, research director at the Institute of Clinical Physiology of the National Research Council in Pisa, Italy, and a member of the panel that developed the guidelines.
Dr. Gastaldelli moderated a session focused on the guidelines at the annual meeting of the European Association for the Study of Diabetes (EASD). In an interview after the session, Dr. Gastaldelli, who leads a cardiometabolic risk research group, stressed the importance of the liver’s role in the body and the need for diabetes specialists to start paying more attention to this vital organ.
“It’s an important organ for monitoring because liver disease is silent, and the patient doesn’t feel unwell until disease is severe,” she said. “Diabetologists already monitor the eye, the heart, the kidney, and so on, but the liver is often neglected,” she said. A 2024 study found that the global pooled prevalence of MASLD among patients with type 2 diabetes was 65.33%.
Dr. Gastaldelli noted the importance of liver status in diabetes care. The liver makes triglycerides and very-low-density lipoprotein cholesterol, which are all major risk factors for atherosclerosis and cardiovascular disease (CVD), she said, as well as producing glucose, which in excess can lead to hyperglycemia.
The guidelines were jointly written by EASD, the European Association for the Study of the Liver, and the European Association for the Study of Obesity, and published in Diabetologia, The Journal of Hepatology, and Obesity Facts.
A Metabolic Condition
In the EASD meeting session, Dr. Gastaldelli discussed the reasons for, and implications of, shifting the name from nonalcoholic fatty liver disease (NAFLD) to MASLD.
“The name change focuses on the fact that this is a metabolic disease, while NAFLD had no mention of this and was considered stigmatizing by patients, especially in relation to the words ‘fatty’ and ‘nonalcoholic,’” she said.
According to the guidelines, MASLD is defined as liver steatosis in the presence of one or more cardiometabolic risk factor(s) and the absence of excess alcohol intake.
MASLD has become the most common chronic liver disease and includes isolated steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), MASH-related fibrosis, and cirrhosis.
In the overarching group of steatotic liver disease, a totally new intermediate category has been added: MASLD with moderate (increased) alcohol intake (MetALD), which represents MASLD in people who consume greater amounts of alcohol per week (140-350 g/week and 210-420 g/week for women and men, respectively).
The change in the nomenclature has been incremental and regional, Dr. Gastaldelli said. “The definition first changed from NAFLD to MAFLD, which recognizes the importance of metabolism in the pathophysiology of this disease but does not take into account alcohol intake. MAFLD is still used in Asia, Australasia, and North Africa, while Europe and the Americas have endorsed MASLD.”
Case-Finding and Diagnosis
Identifying MASLD cases in people at risk remains incidental, largely because it is a silent disease and is symptom-free until it becomes severe, said Dr. Gastaldelli.
The guideline recognizes that individuals with type 2 diabetes or obesity with additional metabolic risk factor(s) are at a higher risk for MASLD with fibrosis and progression to MASH.
Assessment strategies for severe liver fibrosis in MASLD include the use of noninvasive tests in people who have cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity or in the presence of one or more metabolic risk factors.
Dr. Gastaldelli noted that type 2 diabetes, metabolic syndrome, and obesity, including abdominal obesity identified by large waist circumference, are the major risk factors and should be warning signs.
“We need to consider abdominal obesity too — we’ve published data in relatively lean people, body mass index < 25, with MASH but without diabetes. Most of the patients accumulated fat viscerally and in the liver and had hypertriglyceridemia and hypercholesterolemia,” she said.
“The guidelines reflect this because the definition of MASLD includes steatosis plus at least one metabolic factor — waist circumference, for example, which is related to visceral fat, hyperlipidemia, or hyperglycemia. Of note, in both pharmacological and diet-induced weight loss, the decrease in liver fat was associated with the decrease in visceral fat.”
The noninvasive biomarker test, Fibrosis-4 (FIB-4) may be used to assess the risk for liver fibrosis. The FIB-4 index is calculated using a patient’s age and results of three blood tests — aspartate aminotransferase, alanine aminotransferase, and platelet count.
Advanced fibrosis (grade F3-F4) “is a major risk factor for severe outcomes,” said Dr. Gastaldelli. A FIB-4 test result below 1.3 indicates low risk for advanced liver fibrosis, 1.30-2.67 indicates intermediate risk, and above 2.67 indicates high risk.
“When fibrosis increases, then liver enzymes increase and the platelets decrease,” said Dr. Gastaldelli. “It is not a perfect tool, and we need to add in age because at a young age, it is prone to false negatives and when very old — false positives. It’s important to take a global view, especially if the patient has persistent high liver enzymes, but FIB-4 is low.”
“And if they have more than one metabolic risk factor, proceed with more tests, for example, transient elastography,” she advised. Imaging techniques such as transient elastography may rule out or rule in advanced fibrosis, which is predictive of liver-related outcomes.
“However, imaging techniques only diagnose steatosis and fibrosis, and right now, MASH can only be diagnosed with liver biopsy because we do not have any markers of liver inflammation and ballooning. In the future, noninvasive tests based on imaging and blood tests will be used to identify patients with MASH,” she added.
Management of MASLD — Lifestyle and Treatment
“Pharmacological treatments are designed for [patients] with MASH and fibrosis grade F2 or F3, but not MASLD,” Dr. Gastaldelli said. As such, lifestyle interventions are the mainstay of management — including weight loss, dietary changes, physical exercise, and low to no alcohol consumption. “Eating good-quality food and reducing calories are both important because the metabolism responds differently to different nutrients,” Dr. Gastaldelli said.
“In particular, the guidelines advise dietary management because some foods carry liver toxicity, for example, sugary foods with sucrose/fructose especially,” she said, adding that, “complex carbohydrates are less harmful than refined carbohydrates. Processed foods should be avoided if possible because they contain sugars, [as well as] saturated fats and hydrogenated fat, which is particularly bad for the liver. Olive oil is better than butter or margarine, which are rich in saturated fat, and fish and white meat are preferable.”
She added that a diet to help manage type 2 diabetes was not so dissimilar because sugar again needs to be reduced.
If a patient has severe obesity (and MASLD), data show that bariatric surgery is beneficial. “It not only helps weight loss, but it improves liver histology and has been shown to improve or resolve type 2 diabetes and reduce CVD risk. Importantly, regarding fibrosis, nutritional management after the bariatric surgery is the most important thing,” said Dr. Gastaldelli.
Optimal management of comorbidities — including the use of incretin-based therapies such as semaglutide or tirzepatide for type 2 diabetes or obesity, if indicated — is advised, according to the guidelines.
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to have a beneficial effect on MASH, said Dr. Gastaldelli. “They have not shown effectiveness in the resolution of fibrosis, but this might take longer to manifest. However, if the medication is started early enough, it may prevent severe fibrosis. Significant weight loss, both with lifestyle and pharmacological treatment, should lead to an improvement in the liver too.”
There are currently no drugs available in Europe for the treatment of noncirrhotic MASH and severe fibrosis (stage ≥ 2). Resmetirom is the first approved MASH-targeted treatment in noncirrhotic MASH and significant liver fibrosis, with histological effectiveness on steatohepatitis and fibrosis, together with an acceptable safety and tolerability profile, but, for the moment, this agent is only available in United States.
Finally, turning to MASH-related cirrhosis, the guidelines advise adaptations of metabolic drugs, nutritional counseling, and surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
After the session, this news organization spoke to Tushy Kailayanathan, MBBS BSc, medical director of the liver MRI company, Perspectum, who reviewed the limitations of the FIB-4 test. The FIB-4 test identifies those with advanced fibrosis in the liver, for example, patients with hepatitis C, she noted; however, “it performs worse in type 2 diabetic patients and in the elderly. There is little clinical guidance on the adjustment of FIB-4 thresholds needed for these high cardiometabolic risk groups. The priority patients are missed by FIB-4 because those individuals with early and active disease may not yet have progressed to advanced disease detected by FIB-4.”
These individuals are exactly those amenable to primary care prevention strategies, said Dr. Kailayanathan. Because of the nature of early and active liver disease in patients with high cardiometabolic risk, it would make sense to shift some diagnostic protocols into primary care.
“These individuals are exactly those amenable to primary care prevention strategies at annual diabetic review because they are likely to have modifiable cardiometabolic risk factors such as metabolic syndrome and would benefit from lifestyle and therapeutic intervention, including GLP-1 RAs and SGLT2is [sodium-glucose cotransporter-2 inhibitors],” she said. “Case-finding and detection of early-stage MASLD is a priority in diabetics, and there is an unmet need for accurate biomarkers to measure liver fat and inflammation early.”
Dr. Gastaldelli has been on the advisory board or consulting for Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Fractyl, Pfizer, Merck-MSD, MetaDeq and a speaker for Eli Lilly, Novo Nordisk, and Pfizer. Dr. Kailayanathan is medical director at Perspectum, a UK-based company involved in liver imaging technology.
A version of this article first appeared on Medscape.com.
MADRID — Individuals with type 2 diabetes and/or obesity plus one or more metabolic risk factors are at a higher risk for metabolic dysfunction–associated steatotic liver disease (MASLD) with fibrosis and progression to more severe liver disease, stated new European guidelines that provide recommendations for diagnosis and management.
“The availability of improved treatment options underlines the need to identify at-risk individuals with MASLD early, as we now possess the tools to positively influence the course of the diseases, which is expected to prevent relevant clinical events,” stated the clinical practice guidelines, updated for the first time since 2016.
“Now we have guidelines that tell clinicians how to monitor the liver,” said Amalia Gastaldelli, PhD, research director at the Institute of Clinical Physiology of the National Research Council in Pisa, Italy, and a member of the panel that developed the guidelines.
Dr. Gastaldelli moderated a session focused on the guidelines at the annual meeting of the European Association for the Study of Diabetes (EASD). In an interview after the session, Dr. Gastaldelli, who leads a cardiometabolic risk research group, stressed the importance of the liver’s role in the body and the need for diabetes specialists to start paying more attention to this vital organ.
“It’s an important organ for monitoring because liver disease is silent, and the patient doesn’t feel unwell until disease is severe,” she said. “Diabetologists already monitor the eye, the heart, the kidney, and so on, but the liver is often neglected,” she said. A 2024 study found that the global pooled prevalence of MASLD among patients with type 2 diabetes was 65.33%.
Dr. Gastaldelli noted the importance of liver status in diabetes care. The liver makes triglycerides and very-low-density lipoprotein cholesterol, which are all major risk factors for atherosclerosis and cardiovascular disease (CVD), she said, as well as producing glucose, which in excess can lead to hyperglycemia.
The guidelines were jointly written by EASD, the European Association for the Study of the Liver, and the European Association for the Study of Obesity, and published in Diabetologia, The Journal of Hepatology, and Obesity Facts.
A Metabolic Condition
In the EASD meeting session, Dr. Gastaldelli discussed the reasons for, and implications of, shifting the name from nonalcoholic fatty liver disease (NAFLD) to MASLD.
“The name change focuses on the fact that this is a metabolic disease, while NAFLD had no mention of this and was considered stigmatizing by patients, especially in relation to the words ‘fatty’ and ‘nonalcoholic,’” she said.
According to the guidelines, MASLD is defined as liver steatosis in the presence of one or more cardiometabolic risk factor(s) and the absence of excess alcohol intake.
MASLD has become the most common chronic liver disease and includes isolated steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), MASH-related fibrosis, and cirrhosis.
In the overarching group of steatotic liver disease, a totally new intermediate category has been added: MASLD with moderate (increased) alcohol intake (MetALD), which represents MASLD in people who consume greater amounts of alcohol per week (140-350 g/week and 210-420 g/week for women and men, respectively).
The change in the nomenclature has been incremental and regional, Dr. Gastaldelli said. “The definition first changed from NAFLD to MAFLD, which recognizes the importance of metabolism in the pathophysiology of this disease but does not take into account alcohol intake. MAFLD is still used in Asia, Australasia, and North Africa, while Europe and the Americas have endorsed MASLD.”
Case-Finding and Diagnosis
Identifying MASLD cases in people at risk remains incidental, largely because it is a silent disease and is symptom-free until it becomes severe, said Dr. Gastaldelli.
The guideline recognizes that individuals with type 2 diabetes or obesity with additional metabolic risk factor(s) are at a higher risk for MASLD with fibrosis and progression to MASH.
Assessment strategies for severe liver fibrosis in MASLD include the use of noninvasive tests in people who have cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity or in the presence of one or more metabolic risk factors.
Dr. Gastaldelli noted that type 2 diabetes, metabolic syndrome, and obesity, including abdominal obesity identified by large waist circumference, are the major risk factors and should be warning signs.
“We need to consider abdominal obesity too — we’ve published data in relatively lean people, body mass index < 25, with MASH but without diabetes. Most of the patients accumulated fat viscerally and in the liver and had hypertriglyceridemia and hypercholesterolemia,” she said.
“The guidelines reflect this because the definition of MASLD includes steatosis plus at least one metabolic factor — waist circumference, for example, which is related to visceral fat, hyperlipidemia, or hyperglycemia. Of note, in both pharmacological and diet-induced weight loss, the decrease in liver fat was associated with the decrease in visceral fat.”
The noninvasive biomarker test, Fibrosis-4 (FIB-4) may be used to assess the risk for liver fibrosis. The FIB-4 index is calculated using a patient’s age and results of three blood tests — aspartate aminotransferase, alanine aminotransferase, and platelet count.
Advanced fibrosis (grade F3-F4) “is a major risk factor for severe outcomes,” said Dr. Gastaldelli. A FIB-4 test result below 1.3 indicates low risk for advanced liver fibrosis, 1.30-2.67 indicates intermediate risk, and above 2.67 indicates high risk.
“When fibrosis increases, then liver enzymes increase and the platelets decrease,” said Dr. Gastaldelli. “It is not a perfect tool, and we need to add in age because at a young age, it is prone to false negatives and when very old — false positives. It’s important to take a global view, especially if the patient has persistent high liver enzymes, but FIB-4 is low.”
“And if they have more than one metabolic risk factor, proceed with more tests, for example, transient elastography,” she advised. Imaging techniques such as transient elastography may rule out or rule in advanced fibrosis, which is predictive of liver-related outcomes.
“However, imaging techniques only diagnose steatosis and fibrosis, and right now, MASH can only be diagnosed with liver biopsy because we do not have any markers of liver inflammation and ballooning. In the future, noninvasive tests based on imaging and blood tests will be used to identify patients with MASH,” she added.
Management of MASLD — Lifestyle and Treatment
“Pharmacological treatments are designed for [patients] with MASH and fibrosis grade F2 or F3, but not MASLD,” Dr. Gastaldelli said. As such, lifestyle interventions are the mainstay of management — including weight loss, dietary changes, physical exercise, and low to no alcohol consumption. “Eating good-quality food and reducing calories are both important because the metabolism responds differently to different nutrients,” Dr. Gastaldelli said.
“In particular, the guidelines advise dietary management because some foods carry liver toxicity, for example, sugary foods with sucrose/fructose especially,” she said, adding that, “complex carbohydrates are less harmful than refined carbohydrates. Processed foods should be avoided if possible because they contain sugars, [as well as] saturated fats and hydrogenated fat, which is particularly bad for the liver. Olive oil is better than butter or margarine, which are rich in saturated fat, and fish and white meat are preferable.”
She added that a diet to help manage type 2 diabetes was not so dissimilar because sugar again needs to be reduced.
If a patient has severe obesity (and MASLD), data show that bariatric surgery is beneficial. “It not only helps weight loss, but it improves liver histology and has been shown to improve or resolve type 2 diabetes and reduce CVD risk. Importantly, regarding fibrosis, nutritional management after the bariatric surgery is the most important thing,” said Dr. Gastaldelli.
Optimal management of comorbidities — including the use of incretin-based therapies such as semaglutide or tirzepatide for type 2 diabetes or obesity, if indicated — is advised, according to the guidelines.
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to have a beneficial effect on MASH, said Dr. Gastaldelli. “They have not shown effectiveness in the resolution of fibrosis, but this might take longer to manifest. However, if the medication is started early enough, it may prevent severe fibrosis. Significant weight loss, both with lifestyle and pharmacological treatment, should lead to an improvement in the liver too.”
There are currently no drugs available in Europe for the treatment of noncirrhotic MASH and severe fibrosis (stage ≥ 2). Resmetirom is the first approved MASH-targeted treatment in noncirrhotic MASH and significant liver fibrosis, with histological effectiveness on steatohepatitis and fibrosis, together with an acceptable safety and tolerability profile, but, for the moment, this agent is only available in United States.
Finally, turning to MASH-related cirrhosis, the guidelines advise adaptations of metabolic drugs, nutritional counseling, and surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
After the session, this news organization spoke to Tushy Kailayanathan, MBBS BSc, medical director of the liver MRI company, Perspectum, who reviewed the limitations of the FIB-4 test. The FIB-4 test identifies those with advanced fibrosis in the liver, for example, patients with hepatitis C, she noted; however, “it performs worse in type 2 diabetic patients and in the elderly. There is little clinical guidance on the adjustment of FIB-4 thresholds needed for these high cardiometabolic risk groups. The priority patients are missed by FIB-4 because those individuals with early and active disease may not yet have progressed to advanced disease detected by FIB-4.”
These individuals are exactly those amenable to primary care prevention strategies, said Dr. Kailayanathan. Because of the nature of early and active liver disease in patients with high cardiometabolic risk, it would make sense to shift some diagnostic protocols into primary care.
“These individuals are exactly those amenable to primary care prevention strategies at annual diabetic review because they are likely to have modifiable cardiometabolic risk factors such as metabolic syndrome and would benefit from lifestyle and therapeutic intervention, including GLP-1 RAs and SGLT2is [sodium-glucose cotransporter-2 inhibitors],” she said. “Case-finding and detection of early-stage MASLD is a priority in diabetics, and there is an unmet need for accurate biomarkers to measure liver fat and inflammation early.”
Dr. Gastaldelli has been on the advisory board or consulting for Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Fractyl, Pfizer, Merck-MSD, MetaDeq and a speaker for Eli Lilly, Novo Nordisk, and Pfizer. Dr. Kailayanathan is medical director at Perspectum, a UK-based company involved in liver imaging technology.
A version of this article first appeared on Medscape.com.
FROM EASD 2024
AI-Assisted Pathology Poised to Transform Liver Disease Care
Although the technology is not yet approved for routine clinical use, it’s constantly improving and aims to address the limitations inherent in today’s pathology processes.
“You do a biopsy, but instead of having a pathologist read it with their very rough scores of stage 1, 2, or 3, you read it by an AI-driven machine that can quantify it with a score of 1.5 or 1.75 instead of 1 or 2,” Vlad Ratziu, MD, PhD, professor of hepatology at the Sorbonne Université and Hôpital Pitié-Salpêtrière Medical School in Paris, France, and coeditor of The Journal of Hepatology, said in an interview.
“The technology is automated, more sensitive to change, and more highly quantitative. It has implications for liver disease diagnoses, clinical trials, and treatments,” added Dr. Ratziu, who has written about the promise and challenges inherent in developing treatments for metabolic dysfunction–associated steatotic liver disease (MASLD).
To explore the potential impact of AI-powered technologies for the clinic, this news organization spoke with representatives from three companies identified by Dr. Ratziu as leaders in the field: HistoIndex, PathAI, and PharmaNest. Each company uses proprietary technology augmented by AI, and their tools have been used in published trials.
Moving Toward Better Diagnoses and Disease Management
The traditional approach for staging liver fibrosis relies on trained pathologists manually evaluating stained tissue samples obtained from biopsies of the liver.
But this method, though still considered the gold standard, doesn’t always provide the granularity needed for an accurate diagnosis or a reliable assessment in clinical trials, said Dean Tai, PhD, HistoIndex’s cofounder and chief scientific officer.
Although noninvasive tests (NITs), alone or with traditional histologic examination, are increasingly used during clinical management because they are less invasive and more repeatable for disease monitoring, they are limited in their precision and ability to provide comprehensive information, Dr. Tai said. That’s because “no single NIT or single-dimensional measurement of a biomarker offers a full assessment of disease activity, fibrogenic drive, and fibrosis load.”
In contrast, AI provides “a highly reproducible and objective assessment of liver fibrosis severity,” he said. “It eliminates the variability associated with staining methods, while revealing changes in the nano-architecture and morphology of collagen fibers not discernible by the human eye or current NITs, especially in the early stages of fibrosis or in cases of simultaneous progression and regression.”
Mathieu Petitjean, PhD, founder and CEO of PharmaNest, has a similar view.
Although degree of liver fibrosis is associated with long-term outcomes of patients with MASLD, “poor detection thresholds due to their categorical nature mean that small and relevant changes are not reflected by changes in staging,” he said. “The reliable detection [with AI] of subtle changes in the phenotypes of fibrosis will significantly enrich the understanding of progression and regression of fibrosis severity.”
The ability of AI-based tools to see patterns the human eye cannot also means they could “help in predicting which patient may respond to a drug, in order to get the right treatments to the right patients as soon as possible,” said Katy Wack, PhD, vice president of clinical development at PathAI.
“Additionally, AI-based algorithms have been developed to provide more quantitative continuous scores to better capture change and discover new tissue-based biomarkers, which may be prognostic or predictive of clinical benefit,” she said.
Such tools are currently undergoing testing and validation for use in trials and diagnostically.
The standardization and reproducibility offered by AI-driven technology could facilitate more consistent diagnoses across different healthcare settings, Dr. Tai suggested. “As the integration of the technology with other blood-, imaging-, and omics-based techniques evolves, it may enable earlier detection of liver diseases, more accurate monitoring of disease progression, and better evaluation of treatment responses, ultimately improving patient care and outcomes.”
More Effective Clinical Trials
The limitations of conventional pathology may be responsible, at least in part, for the repeated failure of novel compounds to move from phase 2 to phase 3 clinical trials, and from clinical trials to approval, the sources agreed.
“In clinical trials, patients are subject to enrollment criteria using liver biopsies, which are scored with a composite scoring system involving four different histologic components to grade and stage the disease,” Dr. Wack noted.
However, there is wide variability between pathologists on biopsy scoring, and an individual pathologist presented with the same sample may give it a different score after some time has passed, she said.
That means “we are using a nonstandardized and inconsistent scoring system to determine whether a patient can be enrolled or not into a trial,” Dr. Wack said.
The change in the composite score over a follow-up period, usually 1-2 years, determines whether a patient has responded to the candidate drug and, ultimately, whether that drug could be considered for approval, Dr. Wack said.
Because scores at the baseline and follow-up timepoints are not precise and inconsistent across pathologist readers, and even the same reader over time, there are often many “false-positive” and “false-negative” responses that can result in potential therapeutics either failing or succeeding in clinical trials, she said.
To address this variability in biopsy scoring as it relates to clinical trials, regulatory bodies have recommended a consensus approach, in which multiple pathologists read the same biopsy independently and a median score is used, or pathologists convene to come to an agreement, Dr. Wack said.
“This is a very costly and burdensome approach and is still subject to interconsensus panel variation,” she said.
The introduction of digital pathology using validated digital viewers, where pathologists can view a glass slide digitally and pan and zoom over the image as they can with a microscope, means that many pathologists can read the same slide in parallel, she explained.
“If they need to discuss, they can do so efficiently over a phone call, each using their own computer screen and shared annotation tools to facilitate their discussion.”
Although this consensus approach can improve consistency, it still leads to variability in scoring across different groups of pathologists, Dr. Wack said.
This is where AI-assisted pathology comes into play.
“With this approach, a pathologist still views the image digitally, but an algorithm has predicted and highlighted key features and recommended quantitative scores,” she said.
This approach has been shown to increase precision for pathologists, thereby increasing reproducibility and standardizing scoring across timepoints and clinical trials.
What’s Ahead
These AI tools could address pathology’s lack of scalability, the result of a limited number of trained pathologists capable of doing liver biopsy assessments, Dr. Tai said.
“Digital pathology workflows enable the transformation of conventional histologic glass slides into large digital images using scanners, allowing significant productivity gains in terms of workflow and collaboration,” he said.
Although AI-assisted pathology tools are still being validated, their promise for improving diagnoses and uncovering new treatments is clear, the interviewees agreed.
Extending its use to stage fibrosis in other liver diseases, such as primary biliary cholangitis, primary sclerosing cholangitis, and alcoholic liver disease, is also in progress on an experimental basis but will take time to validate.
“The landscape will evolve quickly in the coming 3-4 years,” Dr. Petitjean predicted. “To start, their intended use will likely be limited to a decision-support tool to enhance the performance of pathologists and perhaps stratify or triage cases sent for routine vs expert review.”
Dr. Petitjean even suggested that the increasing role of NITs and the amount of data being generated prospectively and retrospectively around liver biomarkers could mean that liver biopsies might not be needed one day.
A version of this article appeared on Medscape.com.
Although the technology is not yet approved for routine clinical use, it’s constantly improving and aims to address the limitations inherent in today’s pathology processes.
“You do a biopsy, but instead of having a pathologist read it with their very rough scores of stage 1, 2, or 3, you read it by an AI-driven machine that can quantify it with a score of 1.5 or 1.75 instead of 1 or 2,” Vlad Ratziu, MD, PhD, professor of hepatology at the Sorbonne Université and Hôpital Pitié-Salpêtrière Medical School in Paris, France, and coeditor of The Journal of Hepatology, said in an interview.
“The technology is automated, more sensitive to change, and more highly quantitative. It has implications for liver disease diagnoses, clinical trials, and treatments,” added Dr. Ratziu, who has written about the promise and challenges inherent in developing treatments for metabolic dysfunction–associated steatotic liver disease (MASLD).
To explore the potential impact of AI-powered technologies for the clinic, this news organization spoke with representatives from three companies identified by Dr. Ratziu as leaders in the field: HistoIndex, PathAI, and PharmaNest. Each company uses proprietary technology augmented by AI, and their tools have been used in published trials.
Moving Toward Better Diagnoses and Disease Management
The traditional approach for staging liver fibrosis relies on trained pathologists manually evaluating stained tissue samples obtained from biopsies of the liver.
But this method, though still considered the gold standard, doesn’t always provide the granularity needed for an accurate diagnosis or a reliable assessment in clinical trials, said Dean Tai, PhD, HistoIndex’s cofounder and chief scientific officer.
Although noninvasive tests (NITs), alone or with traditional histologic examination, are increasingly used during clinical management because they are less invasive and more repeatable for disease monitoring, they are limited in their precision and ability to provide comprehensive information, Dr. Tai said. That’s because “no single NIT or single-dimensional measurement of a biomarker offers a full assessment of disease activity, fibrogenic drive, and fibrosis load.”
In contrast, AI provides “a highly reproducible and objective assessment of liver fibrosis severity,” he said. “It eliminates the variability associated with staining methods, while revealing changes in the nano-architecture and morphology of collagen fibers not discernible by the human eye or current NITs, especially in the early stages of fibrosis or in cases of simultaneous progression and regression.”
Mathieu Petitjean, PhD, founder and CEO of PharmaNest, has a similar view.
Although degree of liver fibrosis is associated with long-term outcomes of patients with MASLD, “poor detection thresholds due to their categorical nature mean that small and relevant changes are not reflected by changes in staging,” he said. “The reliable detection [with AI] of subtle changes in the phenotypes of fibrosis will significantly enrich the understanding of progression and regression of fibrosis severity.”
The ability of AI-based tools to see patterns the human eye cannot also means they could “help in predicting which patient may respond to a drug, in order to get the right treatments to the right patients as soon as possible,” said Katy Wack, PhD, vice president of clinical development at PathAI.
“Additionally, AI-based algorithms have been developed to provide more quantitative continuous scores to better capture change and discover new tissue-based biomarkers, which may be prognostic or predictive of clinical benefit,” she said.
Such tools are currently undergoing testing and validation for use in trials and diagnostically.
The standardization and reproducibility offered by AI-driven technology could facilitate more consistent diagnoses across different healthcare settings, Dr. Tai suggested. “As the integration of the technology with other blood-, imaging-, and omics-based techniques evolves, it may enable earlier detection of liver diseases, more accurate monitoring of disease progression, and better evaluation of treatment responses, ultimately improving patient care and outcomes.”
More Effective Clinical Trials
The limitations of conventional pathology may be responsible, at least in part, for the repeated failure of novel compounds to move from phase 2 to phase 3 clinical trials, and from clinical trials to approval, the sources agreed.
“In clinical trials, patients are subject to enrollment criteria using liver biopsies, which are scored with a composite scoring system involving four different histologic components to grade and stage the disease,” Dr. Wack noted.
However, there is wide variability between pathologists on biopsy scoring, and an individual pathologist presented with the same sample may give it a different score after some time has passed, she said.
That means “we are using a nonstandardized and inconsistent scoring system to determine whether a patient can be enrolled or not into a trial,” Dr. Wack said.
The change in the composite score over a follow-up period, usually 1-2 years, determines whether a patient has responded to the candidate drug and, ultimately, whether that drug could be considered for approval, Dr. Wack said.
Because scores at the baseline and follow-up timepoints are not precise and inconsistent across pathologist readers, and even the same reader over time, there are often many “false-positive” and “false-negative” responses that can result in potential therapeutics either failing or succeeding in clinical trials, she said.
To address this variability in biopsy scoring as it relates to clinical trials, regulatory bodies have recommended a consensus approach, in which multiple pathologists read the same biopsy independently and a median score is used, or pathologists convene to come to an agreement, Dr. Wack said.
“This is a very costly and burdensome approach and is still subject to interconsensus panel variation,” she said.
The introduction of digital pathology using validated digital viewers, where pathologists can view a glass slide digitally and pan and zoom over the image as they can with a microscope, means that many pathologists can read the same slide in parallel, she explained.
“If they need to discuss, they can do so efficiently over a phone call, each using their own computer screen and shared annotation tools to facilitate their discussion.”
Although this consensus approach can improve consistency, it still leads to variability in scoring across different groups of pathologists, Dr. Wack said.
This is where AI-assisted pathology comes into play.
“With this approach, a pathologist still views the image digitally, but an algorithm has predicted and highlighted key features and recommended quantitative scores,” she said.
This approach has been shown to increase precision for pathologists, thereby increasing reproducibility and standardizing scoring across timepoints and clinical trials.
What’s Ahead
These AI tools could address pathology’s lack of scalability, the result of a limited number of trained pathologists capable of doing liver biopsy assessments, Dr. Tai said.
“Digital pathology workflows enable the transformation of conventional histologic glass slides into large digital images using scanners, allowing significant productivity gains in terms of workflow and collaboration,” he said.
Although AI-assisted pathology tools are still being validated, their promise for improving diagnoses and uncovering new treatments is clear, the interviewees agreed.
Extending its use to stage fibrosis in other liver diseases, such as primary biliary cholangitis, primary sclerosing cholangitis, and alcoholic liver disease, is also in progress on an experimental basis but will take time to validate.
“The landscape will evolve quickly in the coming 3-4 years,” Dr. Petitjean predicted. “To start, their intended use will likely be limited to a decision-support tool to enhance the performance of pathologists and perhaps stratify or triage cases sent for routine vs expert review.”
Dr. Petitjean even suggested that the increasing role of NITs and the amount of data being generated prospectively and retrospectively around liver biomarkers could mean that liver biopsies might not be needed one day.
A version of this article appeared on Medscape.com.
Although the technology is not yet approved for routine clinical use, it’s constantly improving and aims to address the limitations inherent in today’s pathology processes.
“You do a biopsy, but instead of having a pathologist read it with their very rough scores of stage 1, 2, or 3, you read it by an AI-driven machine that can quantify it with a score of 1.5 or 1.75 instead of 1 or 2,” Vlad Ratziu, MD, PhD, professor of hepatology at the Sorbonne Université and Hôpital Pitié-Salpêtrière Medical School in Paris, France, and coeditor of The Journal of Hepatology, said in an interview.
“The technology is automated, more sensitive to change, and more highly quantitative. It has implications for liver disease diagnoses, clinical trials, and treatments,” added Dr. Ratziu, who has written about the promise and challenges inherent in developing treatments for metabolic dysfunction–associated steatotic liver disease (MASLD).
To explore the potential impact of AI-powered technologies for the clinic, this news organization spoke with representatives from three companies identified by Dr. Ratziu as leaders in the field: HistoIndex, PathAI, and PharmaNest. Each company uses proprietary technology augmented by AI, and their tools have been used in published trials.
Moving Toward Better Diagnoses and Disease Management
The traditional approach for staging liver fibrosis relies on trained pathologists manually evaluating stained tissue samples obtained from biopsies of the liver.
But this method, though still considered the gold standard, doesn’t always provide the granularity needed for an accurate diagnosis or a reliable assessment in clinical trials, said Dean Tai, PhD, HistoIndex’s cofounder and chief scientific officer.
Although noninvasive tests (NITs), alone or with traditional histologic examination, are increasingly used during clinical management because they are less invasive and more repeatable for disease monitoring, they are limited in their precision and ability to provide comprehensive information, Dr. Tai said. That’s because “no single NIT or single-dimensional measurement of a biomarker offers a full assessment of disease activity, fibrogenic drive, and fibrosis load.”
In contrast, AI provides “a highly reproducible and objective assessment of liver fibrosis severity,” he said. “It eliminates the variability associated with staining methods, while revealing changes in the nano-architecture and morphology of collagen fibers not discernible by the human eye or current NITs, especially in the early stages of fibrosis or in cases of simultaneous progression and regression.”
Mathieu Petitjean, PhD, founder and CEO of PharmaNest, has a similar view.
Although degree of liver fibrosis is associated with long-term outcomes of patients with MASLD, “poor detection thresholds due to their categorical nature mean that small and relevant changes are not reflected by changes in staging,” he said. “The reliable detection [with AI] of subtle changes in the phenotypes of fibrosis will significantly enrich the understanding of progression and regression of fibrosis severity.”
The ability of AI-based tools to see patterns the human eye cannot also means they could “help in predicting which patient may respond to a drug, in order to get the right treatments to the right patients as soon as possible,” said Katy Wack, PhD, vice president of clinical development at PathAI.
“Additionally, AI-based algorithms have been developed to provide more quantitative continuous scores to better capture change and discover new tissue-based biomarkers, which may be prognostic or predictive of clinical benefit,” she said.
Such tools are currently undergoing testing and validation for use in trials and diagnostically.
The standardization and reproducibility offered by AI-driven technology could facilitate more consistent diagnoses across different healthcare settings, Dr. Tai suggested. “As the integration of the technology with other blood-, imaging-, and omics-based techniques evolves, it may enable earlier detection of liver diseases, more accurate monitoring of disease progression, and better evaluation of treatment responses, ultimately improving patient care and outcomes.”
More Effective Clinical Trials
The limitations of conventional pathology may be responsible, at least in part, for the repeated failure of novel compounds to move from phase 2 to phase 3 clinical trials, and from clinical trials to approval, the sources agreed.
“In clinical trials, patients are subject to enrollment criteria using liver biopsies, which are scored with a composite scoring system involving four different histologic components to grade and stage the disease,” Dr. Wack noted.
However, there is wide variability between pathologists on biopsy scoring, and an individual pathologist presented with the same sample may give it a different score after some time has passed, she said.
That means “we are using a nonstandardized and inconsistent scoring system to determine whether a patient can be enrolled or not into a trial,” Dr. Wack said.
The change in the composite score over a follow-up period, usually 1-2 years, determines whether a patient has responded to the candidate drug and, ultimately, whether that drug could be considered for approval, Dr. Wack said.
Because scores at the baseline and follow-up timepoints are not precise and inconsistent across pathologist readers, and even the same reader over time, there are often many “false-positive” and “false-negative” responses that can result in potential therapeutics either failing or succeeding in clinical trials, she said.
To address this variability in biopsy scoring as it relates to clinical trials, regulatory bodies have recommended a consensus approach, in which multiple pathologists read the same biopsy independently and a median score is used, or pathologists convene to come to an agreement, Dr. Wack said.
“This is a very costly and burdensome approach and is still subject to interconsensus panel variation,” she said.
The introduction of digital pathology using validated digital viewers, where pathologists can view a glass slide digitally and pan and zoom over the image as they can with a microscope, means that many pathologists can read the same slide in parallel, she explained.
“If they need to discuss, they can do so efficiently over a phone call, each using their own computer screen and shared annotation tools to facilitate their discussion.”
Although this consensus approach can improve consistency, it still leads to variability in scoring across different groups of pathologists, Dr. Wack said.
This is where AI-assisted pathology comes into play.
“With this approach, a pathologist still views the image digitally, but an algorithm has predicted and highlighted key features and recommended quantitative scores,” she said.
This approach has been shown to increase precision for pathologists, thereby increasing reproducibility and standardizing scoring across timepoints and clinical trials.
What’s Ahead
These AI tools could address pathology’s lack of scalability, the result of a limited number of trained pathologists capable of doing liver biopsy assessments, Dr. Tai said.
“Digital pathology workflows enable the transformation of conventional histologic glass slides into large digital images using scanners, allowing significant productivity gains in terms of workflow and collaboration,” he said.
Although AI-assisted pathology tools are still being validated, their promise for improving diagnoses and uncovering new treatments is clear, the interviewees agreed.
Extending its use to stage fibrosis in other liver diseases, such as primary biliary cholangitis, primary sclerosing cholangitis, and alcoholic liver disease, is also in progress on an experimental basis but will take time to validate.
“The landscape will evolve quickly in the coming 3-4 years,” Dr. Petitjean predicted. “To start, their intended use will likely be limited to a decision-support tool to enhance the performance of pathologists and perhaps stratify or triage cases sent for routine vs expert review.”
Dr. Petitjean even suggested that the increasing role of NITs and the amount of data being generated prospectively and retrospectively around liver biomarkers could mean that liver biopsies might not be needed one day.
A version of this article appeared on Medscape.com.
FDA OKs Subcutaneous Atezolizumab Formulation for Multiple Cancer Indications
Approved indications include non–small cell lung cancer (NSCLC), SCLC, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. Specific indications are available with the full prescribing information at Drugs@FDA.
This is the first programmed death–ligand 1 inhibitor to gain approval for subcutaneous administration.
“This approval represents a significant option to improve the patient experience,” Ann Fish-Steagall, RN, Senior Vice President of Patient Services at the LUNGevity Foundation stated in a Genentech press release.
Subcutaneous atezolizumab and hyaluronidase-tqjs was evaluated in the open-label, randomized IMscin001 trial of 371 adult patients with locally advanced or metastatic NSCLC who were not previously exposed to cancer immunotherapy and who had disease progression following treatment with platinum-based chemotherapy. Patients were randomized 2:1 to receive subcutaneous or IV administration until disease progression or unacceptable toxicity.
Atezolizumab exposure, the primary outcome measure of the study, met the lower limit of geometric mean ratio above the prespecified threshold of 0.8 (cycle 1C trough, 1.05; area under the curve for days 0-21, 0.87).
No notable differences were observed in overall response rate, progression-free survival, or overall survival between the two formulations, according to the FDA approval notice.
The confirmed overall response rate was 9% in the subcutaneous arm and 8% intravenous arm.
Adverse events of any grade occurring in at least 10% of patients were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
The recommended dose for subcutaneous injection is one 15 mL injection, which contains 1875 mg of atezolizumab and 30,000 units of hyaluronidase.
Injections should be administered in the thigh over approximately 7 minutes every 3 weeks. By contrast, IV administration generally takes 30-60 minutes.
A version of this article first appeared on Medscape.com.
Approved indications include non–small cell lung cancer (NSCLC), SCLC, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. Specific indications are available with the full prescribing information at Drugs@FDA.
This is the first programmed death–ligand 1 inhibitor to gain approval for subcutaneous administration.
“This approval represents a significant option to improve the patient experience,” Ann Fish-Steagall, RN, Senior Vice President of Patient Services at the LUNGevity Foundation stated in a Genentech press release.
Subcutaneous atezolizumab and hyaluronidase-tqjs was evaluated in the open-label, randomized IMscin001 trial of 371 adult patients with locally advanced or metastatic NSCLC who were not previously exposed to cancer immunotherapy and who had disease progression following treatment with platinum-based chemotherapy. Patients were randomized 2:1 to receive subcutaneous or IV administration until disease progression or unacceptable toxicity.
Atezolizumab exposure, the primary outcome measure of the study, met the lower limit of geometric mean ratio above the prespecified threshold of 0.8 (cycle 1C trough, 1.05; area under the curve for days 0-21, 0.87).
No notable differences were observed in overall response rate, progression-free survival, or overall survival between the two formulations, according to the FDA approval notice.
The confirmed overall response rate was 9% in the subcutaneous arm and 8% intravenous arm.
Adverse events of any grade occurring in at least 10% of patients were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
The recommended dose for subcutaneous injection is one 15 mL injection, which contains 1875 mg of atezolizumab and 30,000 units of hyaluronidase.
Injections should be administered in the thigh over approximately 7 minutes every 3 weeks. By contrast, IV administration generally takes 30-60 minutes.
A version of this article first appeared on Medscape.com.
Approved indications include non–small cell lung cancer (NSCLC), SCLC, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. Specific indications are available with the full prescribing information at Drugs@FDA.
This is the first programmed death–ligand 1 inhibitor to gain approval for subcutaneous administration.
“This approval represents a significant option to improve the patient experience,” Ann Fish-Steagall, RN, Senior Vice President of Patient Services at the LUNGevity Foundation stated in a Genentech press release.
Subcutaneous atezolizumab and hyaluronidase-tqjs was evaluated in the open-label, randomized IMscin001 trial of 371 adult patients with locally advanced or metastatic NSCLC who were not previously exposed to cancer immunotherapy and who had disease progression following treatment with platinum-based chemotherapy. Patients were randomized 2:1 to receive subcutaneous or IV administration until disease progression or unacceptable toxicity.
Atezolizumab exposure, the primary outcome measure of the study, met the lower limit of geometric mean ratio above the prespecified threshold of 0.8 (cycle 1C trough, 1.05; area under the curve for days 0-21, 0.87).
No notable differences were observed in overall response rate, progression-free survival, or overall survival between the two formulations, according to the FDA approval notice.
The confirmed overall response rate was 9% in the subcutaneous arm and 8% intravenous arm.
Adverse events of any grade occurring in at least 10% of patients were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.
The recommended dose for subcutaneous injection is one 15 mL injection, which contains 1875 mg of atezolizumab and 30,000 units of hyaluronidase.
Injections should be administered in the thigh over approximately 7 minutes every 3 weeks. By contrast, IV administration generally takes 30-60 minutes.
A version of this article first appeared on Medscape.com.
Baveno VI Criteria Appear Cost-Effective for Detecting Varices in Cirrhosis
Compared with endoscopy, , according to new research.
Although upper gastrointestinal endoscopy continues to be the gold standard for detecting varices, the Baveno VI criteria combine liver stiffness and platelet count values to rule out high-risk varices, which can save on endoscopy costs.
“The Baveno VI criteria can reduce the need for endoscopies in patients with cirrhosis, but it is important to ascertain if they are also cost-effective,” said senior author Emmanuel Tsochatzis, MD, professor of hepatology at the University College London Institute for Liver and Digestive Health and Royal Free Hospital in London.
“Our findings confirm that the application of these criteria is highly cost-effective, and given the fact that they are also safe, should be considered for widespread implementation,” he said.
The study was published online in Clinical Gastroenterology and Hepatology.
Baveno VI Criteria Analysis
On the basis of the Baveno VI Consensus, endoscopy screening can be avoided in patients with compensated advanced chronic liver disease and Child-Pugh A cirrhosis who have a platelet count > 150,000/mm3 and a liver stiffness measurement < 20 kPa.
In addition, expanded Baveno VI criteria have suggested optimized cut-off values to avoid even more endoscopies — at a platelet value of > 110,000/mm3 and a liver stiffness < 25 kPa.
Previous research indicates that the expanded criteria could avoid double the number of endoscopies, the authors wrote, with a risk of missing high-risk varices in 1.6% of patients with the criteria and 0.6% of overall study participants. Both criteria have been validated in large groups of patients with compensated cirrhosis of different etiologies, but the cost-effectiveness hasn’t been analyzed.
Dr. Tsochatzis and colleagues created an analytical decision model to estimate the costs and benefits of using the Baveno VI criteria as compared with endoscopy as the standard of care among a hypothetical cohort of 1000 patients with Child-Pugh A cirrhosis. The research team looked at costs and clinical outcomes based on the United Kingdom National Health Service perspective at 1 year from diagnosis and then estimated the expected costs and outcomes at 5 years and 20 years, including factors such as liver disease progression and variceal bleeding.
As part of the model, the Baveno VI criteria were implemented at annual screenings with targeted endoscopy for patients who met the criteria, as compared with endoscopy as a biannual screening using esophagogastroduodenoscopy for everyone.
In general, the Baveno VI criteria were cost-effective compared with endoscopy in all analyses, including all time points, as well as deterministic and probabilistic sensitivity analyses. The cost of using the criteria was £67 per patient, as compared with £411 per patient for esophagogastroduodenoscopy.
For the 1000 patients, the criteria produced 0.16 additional quality-adjusted life years (QALYs) per patient at an incremental cost of £326, or about $443, over 5 years. This resulted in an incremental cost-effectiveness ratio (ICER) of £2081, or $2830, per additional QALY gained.
In addition, the incremental net monetary benefit of the Baveno VI criteria was £2808, or $3819, over 5 years per patient.
The results were also consistent and cost-effective in Canada and Spain using relevant cost inputs from those countries. In Canada, the ICER per QALY estimates were €3535, or $3712, over 5 years and €4610, or $4841, over 20 years. In Spain, the ICER per QALY estimates were €1966, or $2064, over 5 years and €2225, or $2336, over 20 years.
Baveno VI Considerations
Despite the small risk of false negatives, the Baveno VI criteria could avoid unnecessary endoscopies and provide significant cost savings, the study authors wrote.
“It should be mentioned, however, that sparing endoscopies could result in missing the incidental detection of esophageal and gastric cancers, particularly in patients with higher risk, such as those who misuse alcohol,” Dr. Tsochatzis said.
Future studies could investigate ways to broaden the applicability of the Baveno VI criteria to other patient subgroups, identify optimal cut-off points, and incorporate patients with systemic therapies.
“Baveno VI criteria can be safely used to avoid endoscopy in a substantial proportion of patients with compensated cirrhosis,” said Wayne Bai, MBChB, a gastroenterologist at Waikato Hospital and the University of Auckland in New Zealand.
Dr. Bai, who wasn’t involved with this study, has researched the Baveno VI criteria and participated in Baveno VII criteria meetings. In an analysis of more than two dozen studies, he and colleagues found that the Baveno VI criteria had a pooled 99% negative predictive value for ruling out high-risk varices and weren’t affected by the cause of cirrhosis. However, expanding the criteria had suboptimal performance in some cases.
“The progressive change in approach to the management of compensated cirrhosis, progressively focusing on treating portal hypertension with beta-blockers independently of the presence of varices, might render these criteria less relevant,” he said.
The authors were supported by funds from the National Institute for Health and Care Research Applied Research Collaboration North Thames, the Instituto de Salud Carlos III, and the European Union’s European Regional Development Fund and European Social Fund. Dr Bai reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
Compared with endoscopy, , according to new research.
Although upper gastrointestinal endoscopy continues to be the gold standard for detecting varices, the Baveno VI criteria combine liver stiffness and platelet count values to rule out high-risk varices, which can save on endoscopy costs.
“The Baveno VI criteria can reduce the need for endoscopies in patients with cirrhosis, but it is important to ascertain if they are also cost-effective,” said senior author Emmanuel Tsochatzis, MD, professor of hepatology at the University College London Institute for Liver and Digestive Health and Royal Free Hospital in London.
“Our findings confirm that the application of these criteria is highly cost-effective, and given the fact that they are also safe, should be considered for widespread implementation,” he said.
The study was published online in Clinical Gastroenterology and Hepatology.
Baveno VI Criteria Analysis
On the basis of the Baveno VI Consensus, endoscopy screening can be avoided in patients with compensated advanced chronic liver disease and Child-Pugh A cirrhosis who have a platelet count > 150,000/mm3 and a liver stiffness measurement < 20 kPa.
In addition, expanded Baveno VI criteria have suggested optimized cut-off values to avoid even more endoscopies — at a platelet value of > 110,000/mm3 and a liver stiffness < 25 kPa.
Previous research indicates that the expanded criteria could avoid double the number of endoscopies, the authors wrote, with a risk of missing high-risk varices in 1.6% of patients with the criteria and 0.6% of overall study participants. Both criteria have been validated in large groups of patients with compensated cirrhosis of different etiologies, but the cost-effectiveness hasn’t been analyzed.
Dr. Tsochatzis and colleagues created an analytical decision model to estimate the costs and benefits of using the Baveno VI criteria as compared with endoscopy as the standard of care among a hypothetical cohort of 1000 patients with Child-Pugh A cirrhosis. The research team looked at costs and clinical outcomes based on the United Kingdom National Health Service perspective at 1 year from diagnosis and then estimated the expected costs and outcomes at 5 years and 20 years, including factors such as liver disease progression and variceal bleeding.
As part of the model, the Baveno VI criteria were implemented at annual screenings with targeted endoscopy for patients who met the criteria, as compared with endoscopy as a biannual screening using esophagogastroduodenoscopy for everyone.
In general, the Baveno VI criteria were cost-effective compared with endoscopy in all analyses, including all time points, as well as deterministic and probabilistic sensitivity analyses. The cost of using the criteria was £67 per patient, as compared with £411 per patient for esophagogastroduodenoscopy.
For the 1000 patients, the criteria produced 0.16 additional quality-adjusted life years (QALYs) per patient at an incremental cost of £326, or about $443, over 5 years. This resulted in an incremental cost-effectiveness ratio (ICER) of £2081, or $2830, per additional QALY gained.
In addition, the incremental net monetary benefit of the Baveno VI criteria was £2808, or $3819, over 5 years per patient.
The results were also consistent and cost-effective in Canada and Spain using relevant cost inputs from those countries. In Canada, the ICER per QALY estimates were €3535, or $3712, over 5 years and €4610, or $4841, over 20 years. In Spain, the ICER per QALY estimates were €1966, or $2064, over 5 years and €2225, or $2336, over 20 years.
Baveno VI Considerations
Despite the small risk of false negatives, the Baveno VI criteria could avoid unnecessary endoscopies and provide significant cost savings, the study authors wrote.
“It should be mentioned, however, that sparing endoscopies could result in missing the incidental detection of esophageal and gastric cancers, particularly in patients with higher risk, such as those who misuse alcohol,” Dr. Tsochatzis said.
Future studies could investigate ways to broaden the applicability of the Baveno VI criteria to other patient subgroups, identify optimal cut-off points, and incorporate patients with systemic therapies.
“Baveno VI criteria can be safely used to avoid endoscopy in a substantial proportion of patients with compensated cirrhosis,” said Wayne Bai, MBChB, a gastroenterologist at Waikato Hospital and the University of Auckland in New Zealand.
Dr. Bai, who wasn’t involved with this study, has researched the Baveno VI criteria and participated in Baveno VII criteria meetings. In an analysis of more than two dozen studies, he and colleagues found that the Baveno VI criteria had a pooled 99% negative predictive value for ruling out high-risk varices and weren’t affected by the cause of cirrhosis. However, expanding the criteria had suboptimal performance in some cases.
“The progressive change in approach to the management of compensated cirrhosis, progressively focusing on treating portal hypertension with beta-blockers independently of the presence of varices, might render these criteria less relevant,” he said.
The authors were supported by funds from the National Institute for Health and Care Research Applied Research Collaboration North Thames, the Instituto de Salud Carlos III, and the European Union’s European Regional Development Fund and European Social Fund. Dr Bai reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
Compared with endoscopy, , according to new research.
Although upper gastrointestinal endoscopy continues to be the gold standard for detecting varices, the Baveno VI criteria combine liver stiffness and platelet count values to rule out high-risk varices, which can save on endoscopy costs.
“The Baveno VI criteria can reduce the need for endoscopies in patients with cirrhosis, but it is important to ascertain if they are also cost-effective,” said senior author Emmanuel Tsochatzis, MD, professor of hepatology at the University College London Institute for Liver and Digestive Health and Royal Free Hospital in London.
“Our findings confirm that the application of these criteria is highly cost-effective, and given the fact that they are also safe, should be considered for widespread implementation,” he said.
The study was published online in Clinical Gastroenterology and Hepatology.
Baveno VI Criteria Analysis
On the basis of the Baveno VI Consensus, endoscopy screening can be avoided in patients with compensated advanced chronic liver disease and Child-Pugh A cirrhosis who have a platelet count > 150,000/mm3 and a liver stiffness measurement < 20 kPa.
In addition, expanded Baveno VI criteria have suggested optimized cut-off values to avoid even more endoscopies — at a platelet value of > 110,000/mm3 and a liver stiffness < 25 kPa.
Previous research indicates that the expanded criteria could avoid double the number of endoscopies, the authors wrote, with a risk of missing high-risk varices in 1.6% of patients with the criteria and 0.6% of overall study participants. Both criteria have been validated in large groups of patients with compensated cirrhosis of different etiologies, but the cost-effectiveness hasn’t been analyzed.
Dr. Tsochatzis and colleagues created an analytical decision model to estimate the costs and benefits of using the Baveno VI criteria as compared with endoscopy as the standard of care among a hypothetical cohort of 1000 patients with Child-Pugh A cirrhosis. The research team looked at costs and clinical outcomes based on the United Kingdom National Health Service perspective at 1 year from diagnosis and then estimated the expected costs and outcomes at 5 years and 20 years, including factors such as liver disease progression and variceal bleeding.
As part of the model, the Baveno VI criteria were implemented at annual screenings with targeted endoscopy for patients who met the criteria, as compared with endoscopy as a biannual screening using esophagogastroduodenoscopy for everyone.
In general, the Baveno VI criteria were cost-effective compared with endoscopy in all analyses, including all time points, as well as deterministic and probabilistic sensitivity analyses. The cost of using the criteria was £67 per patient, as compared with £411 per patient for esophagogastroduodenoscopy.
For the 1000 patients, the criteria produced 0.16 additional quality-adjusted life years (QALYs) per patient at an incremental cost of £326, or about $443, over 5 years. This resulted in an incremental cost-effectiveness ratio (ICER) of £2081, or $2830, per additional QALY gained.
In addition, the incremental net monetary benefit of the Baveno VI criteria was £2808, or $3819, over 5 years per patient.
The results were also consistent and cost-effective in Canada and Spain using relevant cost inputs from those countries. In Canada, the ICER per QALY estimates were €3535, or $3712, over 5 years and €4610, or $4841, over 20 years. In Spain, the ICER per QALY estimates were €1966, or $2064, over 5 years and €2225, or $2336, over 20 years.
Baveno VI Considerations
Despite the small risk of false negatives, the Baveno VI criteria could avoid unnecessary endoscopies and provide significant cost savings, the study authors wrote.
“It should be mentioned, however, that sparing endoscopies could result in missing the incidental detection of esophageal and gastric cancers, particularly in patients with higher risk, such as those who misuse alcohol,” Dr. Tsochatzis said.
Future studies could investigate ways to broaden the applicability of the Baveno VI criteria to other patient subgroups, identify optimal cut-off points, and incorporate patients with systemic therapies.
“Baveno VI criteria can be safely used to avoid endoscopy in a substantial proportion of patients with compensated cirrhosis,” said Wayne Bai, MBChB, a gastroenterologist at Waikato Hospital and the University of Auckland in New Zealand.
Dr. Bai, who wasn’t involved with this study, has researched the Baveno VI criteria and participated in Baveno VII criteria meetings. In an analysis of more than two dozen studies, he and colleagues found that the Baveno VI criteria had a pooled 99% negative predictive value for ruling out high-risk varices and weren’t affected by the cause of cirrhosis. However, expanding the criteria had suboptimal performance in some cases.
“The progressive change in approach to the management of compensated cirrhosis, progressively focusing on treating portal hypertension with beta-blockers independently of the presence of varices, might render these criteria less relevant,” he said.
The authors were supported by funds from the National Institute for Health and Care Research Applied Research Collaboration North Thames, the Instituto de Salud Carlos III, and the European Union’s European Regional Development Fund and European Social Fund. Dr Bai reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Not Kidding: Yellow Dye 5 May Lead to Invisibility
Applying the dye to lab mice made their skin temporarily transparent, allowing Stanford University researchers to observe the rodents’ digestive system, muscle fibers, and blood vessels, according to a study published in Science.
“It’s a stunning result,” said senior author Guosong Hong, PhD, who is assistant professor of materials science and engineering at Stanford University in California. “If the same technique could be applied to humans, it could offer a variety of benefits in biology, diagnostics, and even cosmetics.”
The work drew upon optical concepts first described in the early 20th century to form a surprising theory: Applying a light-absorbing substance could render skin transparent by reducing the chaotic scattering of light as it strikes proteins, fats, and water in tissue.
A search for a suitable light absorber led to FD&C Yellow 5, also called tartrazine, a synthetic color additive certified by the Food and Drug Administration (FDA) for use in foods, cosmetics, and medications.
Rubbed on live mice (after areas of fur were removed using a drugstore depilatory cream), tartrazine rendered skin on their bellies, hind legs, and heads transparent within 5 minutes. With the naked eye, the researchers watched a mouse’s intestines, bladder, and liver at work. Using a microscope, they observed muscle fibers and saw blood vessels in a living mouse’s brain — all without making incisions. Transparency faded quickly when the dye was washed off.
Someday, the concept could be used in doctors’ offices and hospitals, Dr. Hong said.
“Instead of relying on invasive biopsies, doctors might be able to diagnose deep-seated tumors by simply examining a person’s tissue without the need for invasive surgical removal,” he said. “This technique could potentially make blood draws less painful by helping phlebotomists easily locate veins under the skin. It could also enhance procedures like laser tattoo removal by allowing more precise targeting of the pigment beneath the skin.”
From Cake Frosting to Groundbreaking Research
Yellow 5 food dye can be found in everything from cereal, soda, spices, and cake frosting to lipstick, mouthwash, shampoo, dietary supplements, and house paint. Although it’s in some topical medications, more research is needed before it could be used in human diagnostics, said Christopher J. Rowlands, PhD, a senior lecturer in the Department of Bioengineering at Imperial College London, England, where he studies biophotonic instrumentation — ways to image structures inside the body more quickly and clearly.
But the finding could prove useful in research. In a commentary published in Science, Dr. Rowlands and his colleague Jon Gorecki, PhD, an experimental optical physicist also at Imperial College London, noted that the dye could be an alternative to other optical clearing agents currently used in lab studies, such as glycerol, fructose, or acetic acid. Advantages are the effect is reversible and works at lower concentrations with fewer side effects. This could broaden the types of studies possible in lab animals, so researchers don’t have to rely on naturally transparent creatures like nematodes and zebrafish.
The dye could also be paired with imaging techniques such as MRI or electron microscopy.
“Imaging techniques all have pros and cons,” Dr. Rowlands said. “MRI can see all the way through the body albeit with limited resolution and contrast. Electron microscopy has excellent resolution but limited compatibility with live tissue and penetration depth. Optical microscopy has subcellular resolution, the ability to label things, excellent biocompatibility but less than 1 millimeter of penetration depth. This clearing method will give a substantial boost to optical imaging for medicine and biology.”
The discovery could improve the depth imaging equipment can achieve by tenfold, according to the commentary.
Brain research especially stands to benefit. “Neurobiology in particular will have great use for combinations of multiphoton, optogenetics, and tissue clearing to record and control neural activity over (potentially) the whole mouse brain,” he said.
Refraction, Absorption, and The Invisible Man
The dye discovery has distant echoes in H.G. Wells’ 1897 novel The Invisible Man, Dr. Rowlands noted. In the book, a serum makes the main character invisible by changing the light scattering — or refractive index (RI) — of his cells to match the air around him.
The Stanford engineers looked to the past for inspiration, but not to fiction. They turned to a concept first described in the 1920s called the Kramers-Kronig relations, a mathematical principle that can be applied to relationships between the way light is refracted and absorbed in different materials. They also read up on Lorentz oscillation, which describes how electrons and atoms inside molecules react to light.
They reasoned that light-absorbing compounds could equalize the differences between the light-scattering properties of proteins, lipids, and water that make skin opaque.
With that, the search was on. The study’s first author, postdoctoral researcher Zihao Ou, PhD, began testing strong dyes to find a candidate. Tartrazine was a front-runner.
“We found that dye molecules are more efficient in raising the refractive index of water than conventional RI-matching agents, thus resulting in transparency at a much lower concentration,” Dr. Hong said. “The underlying physics, explained by the Lorentz oscillator model and Kramers-Kronig relations, reveals that conventional RI matching agents like fructose are not as efficient because they are not ‘colored’ enough.”
What’s Next
Though the dye is already in products that people consume and apply to their skin, medical use is years away. In some people, tartrazine can cause skin or respiratory reactions.
The National Science Foundation (NSF), which helped fund the research, posted a home or classroom activity related to the work on its website. It involves painting a tartrazine solution on a thin slice of raw chicken breast, making it transparent. The experiment should only be done while wearing a mask, eye protection, lab coat, and lab-quality nitrile gloves for protection, according to the NSF.
Meanwhile, Dr. Hong said his lab is looking for new compounds that will improve visibility through transparent skin, removing a red tone seen in the current experiments. And they’re looking for ways to induce cells to make their own “see-through” compounds.
“We are exploring methods for cells to express intensely absorbing molecules endogenously, enabling genetically encoded tissue transparency in live animals,” he said.
A version of this article first appeared on Medscape.com.
Applying the dye to lab mice made their skin temporarily transparent, allowing Stanford University researchers to observe the rodents’ digestive system, muscle fibers, and blood vessels, according to a study published in Science.
“It’s a stunning result,” said senior author Guosong Hong, PhD, who is assistant professor of materials science and engineering at Stanford University in California. “If the same technique could be applied to humans, it could offer a variety of benefits in biology, diagnostics, and even cosmetics.”
The work drew upon optical concepts first described in the early 20th century to form a surprising theory: Applying a light-absorbing substance could render skin transparent by reducing the chaotic scattering of light as it strikes proteins, fats, and water in tissue.
A search for a suitable light absorber led to FD&C Yellow 5, also called tartrazine, a synthetic color additive certified by the Food and Drug Administration (FDA) for use in foods, cosmetics, and medications.
Rubbed on live mice (after areas of fur were removed using a drugstore depilatory cream), tartrazine rendered skin on their bellies, hind legs, and heads transparent within 5 minutes. With the naked eye, the researchers watched a mouse’s intestines, bladder, and liver at work. Using a microscope, they observed muscle fibers and saw blood vessels in a living mouse’s brain — all without making incisions. Transparency faded quickly when the dye was washed off.
Someday, the concept could be used in doctors’ offices and hospitals, Dr. Hong said.
“Instead of relying on invasive biopsies, doctors might be able to diagnose deep-seated tumors by simply examining a person’s tissue without the need for invasive surgical removal,” he said. “This technique could potentially make blood draws less painful by helping phlebotomists easily locate veins under the skin. It could also enhance procedures like laser tattoo removal by allowing more precise targeting of the pigment beneath the skin.”
From Cake Frosting to Groundbreaking Research
Yellow 5 food dye can be found in everything from cereal, soda, spices, and cake frosting to lipstick, mouthwash, shampoo, dietary supplements, and house paint. Although it’s in some topical medications, more research is needed before it could be used in human diagnostics, said Christopher J. Rowlands, PhD, a senior lecturer in the Department of Bioengineering at Imperial College London, England, where he studies biophotonic instrumentation — ways to image structures inside the body more quickly and clearly.
But the finding could prove useful in research. In a commentary published in Science, Dr. Rowlands and his colleague Jon Gorecki, PhD, an experimental optical physicist also at Imperial College London, noted that the dye could be an alternative to other optical clearing agents currently used in lab studies, such as glycerol, fructose, or acetic acid. Advantages are the effect is reversible and works at lower concentrations with fewer side effects. This could broaden the types of studies possible in lab animals, so researchers don’t have to rely on naturally transparent creatures like nematodes and zebrafish.
The dye could also be paired with imaging techniques such as MRI or electron microscopy.
“Imaging techniques all have pros and cons,” Dr. Rowlands said. “MRI can see all the way through the body albeit with limited resolution and contrast. Electron microscopy has excellent resolution but limited compatibility with live tissue and penetration depth. Optical microscopy has subcellular resolution, the ability to label things, excellent biocompatibility but less than 1 millimeter of penetration depth. This clearing method will give a substantial boost to optical imaging for medicine and biology.”
The discovery could improve the depth imaging equipment can achieve by tenfold, according to the commentary.
Brain research especially stands to benefit. “Neurobiology in particular will have great use for combinations of multiphoton, optogenetics, and tissue clearing to record and control neural activity over (potentially) the whole mouse brain,” he said.
Refraction, Absorption, and The Invisible Man
The dye discovery has distant echoes in H.G. Wells’ 1897 novel The Invisible Man, Dr. Rowlands noted. In the book, a serum makes the main character invisible by changing the light scattering — or refractive index (RI) — of his cells to match the air around him.
The Stanford engineers looked to the past for inspiration, but not to fiction. They turned to a concept first described in the 1920s called the Kramers-Kronig relations, a mathematical principle that can be applied to relationships between the way light is refracted and absorbed in different materials. They also read up on Lorentz oscillation, which describes how electrons and atoms inside molecules react to light.
They reasoned that light-absorbing compounds could equalize the differences between the light-scattering properties of proteins, lipids, and water that make skin opaque.
With that, the search was on. The study’s first author, postdoctoral researcher Zihao Ou, PhD, began testing strong dyes to find a candidate. Tartrazine was a front-runner.
“We found that dye molecules are more efficient in raising the refractive index of water than conventional RI-matching agents, thus resulting in transparency at a much lower concentration,” Dr. Hong said. “The underlying physics, explained by the Lorentz oscillator model and Kramers-Kronig relations, reveals that conventional RI matching agents like fructose are not as efficient because they are not ‘colored’ enough.”
What’s Next
Though the dye is already in products that people consume and apply to their skin, medical use is years away. In some people, tartrazine can cause skin or respiratory reactions.
The National Science Foundation (NSF), which helped fund the research, posted a home or classroom activity related to the work on its website. It involves painting a tartrazine solution on a thin slice of raw chicken breast, making it transparent. The experiment should only be done while wearing a mask, eye protection, lab coat, and lab-quality nitrile gloves for protection, according to the NSF.
Meanwhile, Dr. Hong said his lab is looking for new compounds that will improve visibility through transparent skin, removing a red tone seen in the current experiments. And they’re looking for ways to induce cells to make their own “see-through” compounds.
“We are exploring methods for cells to express intensely absorbing molecules endogenously, enabling genetically encoded tissue transparency in live animals,” he said.
A version of this article first appeared on Medscape.com.
Applying the dye to lab mice made their skin temporarily transparent, allowing Stanford University researchers to observe the rodents’ digestive system, muscle fibers, and blood vessels, according to a study published in Science.
“It’s a stunning result,” said senior author Guosong Hong, PhD, who is assistant professor of materials science and engineering at Stanford University in California. “If the same technique could be applied to humans, it could offer a variety of benefits in biology, diagnostics, and even cosmetics.”
The work drew upon optical concepts first described in the early 20th century to form a surprising theory: Applying a light-absorbing substance could render skin transparent by reducing the chaotic scattering of light as it strikes proteins, fats, and water in tissue.
A search for a suitable light absorber led to FD&C Yellow 5, also called tartrazine, a synthetic color additive certified by the Food and Drug Administration (FDA) for use in foods, cosmetics, and medications.
Rubbed on live mice (after areas of fur were removed using a drugstore depilatory cream), tartrazine rendered skin on their bellies, hind legs, and heads transparent within 5 minutes. With the naked eye, the researchers watched a mouse’s intestines, bladder, and liver at work. Using a microscope, they observed muscle fibers and saw blood vessels in a living mouse’s brain — all without making incisions. Transparency faded quickly when the dye was washed off.
Someday, the concept could be used in doctors’ offices and hospitals, Dr. Hong said.
“Instead of relying on invasive biopsies, doctors might be able to diagnose deep-seated tumors by simply examining a person’s tissue without the need for invasive surgical removal,” he said. “This technique could potentially make blood draws less painful by helping phlebotomists easily locate veins under the skin. It could also enhance procedures like laser tattoo removal by allowing more precise targeting of the pigment beneath the skin.”
From Cake Frosting to Groundbreaking Research
Yellow 5 food dye can be found in everything from cereal, soda, spices, and cake frosting to lipstick, mouthwash, shampoo, dietary supplements, and house paint. Although it’s in some topical medications, more research is needed before it could be used in human diagnostics, said Christopher J. Rowlands, PhD, a senior lecturer in the Department of Bioengineering at Imperial College London, England, where he studies biophotonic instrumentation — ways to image structures inside the body more quickly and clearly.
But the finding could prove useful in research. In a commentary published in Science, Dr. Rowlands and his colleague Jon Gorecki, PhD, an experimental optical physicist also at Imperial College London, noted that the dye could be an alternative to other optical clearing agents currently used in lab studies, such as glycerol, fructose, or acetic acid. Advantages are the effect is reversible and works at lower concentrations with fewer side effects. This could broaden the types of studies possible in lab animals, so researchers don’t have to rely on naturally transparent creatures like nematodes and zebrafish.
The dye could also be paired with imaging techniques such as MRI or electron microscopy.
“Imaging techniques all have pros and cons,” Dr. Rowlands said. “MRI can see all the way through the body albeit with limited resolution and contrast. Electron microscopy has excellent resolution but limited compatibility with live tissue and penetration depth. Optical microscopy has subcellular resolution, the ability to label things, excellent biocompatibility but less than 1 millimeter of penetration depth. This clearing method will give a substantial boost to optical imaging for medicine and biology.”
The discovery could improve the depth imaging equipment can achieve by tenfold, according to the commentary.
Brain research especially stands to benefit. “Neurobiology in particular will have great use for combinations of multiphoton, optogenetics, and tissue clearing to record and control neural activity over (potentially) the whole mouse brain,” he said.
Refraction, Absorption, and The Invisible Man
The dye discovery has distant echoes in H.G. Wells’ 1897 novel The Invisible Man, Dr. Rowlands noted. In the book, a serum makes the main character invisible by changing the light scattering — or refractive index (RI) — of his cells to match the air around him.
The Stanford engineers looked to the past for inspiration, but not to fiction. They turned to a concept first described in the 1920s called the Kramers-Kronig relations, a mathematical principle that can be applied to relationships between the way light is refracted and absorbed in different materials. They also read up on Lorentz oscillation, which describes how electrons and atoms inside molecules react to light.
They reasoned that light-absorbing compounds could equalize the differences between the light-scattering properties of proteins, lipids, and water that make skin opaque.
With that, the search was on. The study’s first author, postdoctoral researcher Zihao Ou, PhD, began testing strong dyes to find a candidate. Tartrazine was a front-runner.
“We found that dye molecules are more efficient in raising the refractive index of water than conventional RI-matching agents, thus resulting in transparency at a much lower concentration,” Dr. Hong said. “The underlying physics, explained by the Lorentz oscillator model and Kramers-Kronig relations, reveals that conventional RI matching agents like fructose are not as efficient because they are not ‘colored’ enough.”
What’s Next
Though the dye is already in products that people consume and apply to their skin, medical use is years away. In some people, tartrazine can cause skin or respiratory reactions.
The National Science Foundation (NSF), which helped fund the research, posted a home or classroom activity related to the work on its website. It involves painting a tartrazine solution on a thin slice of raw chicken breast, making it transparent. The experiment should only be done while wearing a mask, eye protection, lab coat, and lab-quality nitrile gloves for protection, according to the NSF.
Meanwhile, Dr. Hong said his lab is looking for new compounds that will improve visibility through transparent skin, removing a red tone seen in the current experiments. And they’re looking for ways to induce cells to make their own “see-through” compounds.
“We are exploring methods for cells to express intensely absorbing molecules endogenously, enabling genetically encoded tissue transparency in live animals,” he said.
A version of this article first appeared on Medscape.com.
FROM SCIENCE
Statins Linked to Improved Liver Health in MASLD
TOPLINE:
METHODOLOGY:
- Although many patients with MASLD have indications for statins, including cardiovascular disease, they are not widely used owing to concerns about possible liver damage and muscle weakness.
- Researchers conducted an observational cohort study to evaluate the long-term effects of statin use in 7988 patients (mean age, 53 years; 58.2% women) with MASLD who underwent at least two vibration-controlled transient elastography exams. The study involved 16 centers in the United States, Europe, and Asia.
- Patients were classified into those with compensated advanced chronic liver disease (cACLD; liver stiffness measurement ≥ 10 kPa) and those without cACLD (liver stiffness measurement < 10 kPa). At baseline, 17% of patients had cACLD.
- Statin prescriptions included simvastatin, pravastatin, atorvastatin, rosuvastatin, lovastatin, fluvastatin, and pitavastatin. At baseline, 40.5% of patients used statins.
- The primary outcome was the composite of all-cause mortality and liver-related events, including cirrhosis, hepatocellular carcinoma, or liver-related mortality. Secondary outcomes included changes in liver stiffness assessed over a median follow-up duration of 4.6 years.
TAKEAWAY:
- Statin usage was associated with a 76.7% lower risk for all-cause mortality and a 62% lower risk of liver-related events than non-use (both P < .001).
- Statin use also was associated with a 46% and 55% lower risk for liver stiffness progression in the cACLD and non-cACLD groups, respectively, than non-use (both P < .001).
- No significant association was found between statin use and liver stiffness regression.
IN PRACTICE:
“The results of this cohort study suggest that statin usage may help reduce CVD [cardiovascular disease] morbidity and mortality rates and slow down liver stiffness progression in both cACLD and non-cALCD patients,” the authors wrote.
SOURCE:
The study, led by Xiao-Dong Zhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China, was published online in Gut.
LIMITATIONS:
The assessment of patients at different intervals may have affected the interpretation of the data. The median follow-up period may be considered short for assessing the progression of CLD. Additionally, residual confounding in statin users could have led to an overestimation of the benefits of statins.
DISCLOSURES:
This study was supported by grants from the National Natural Science Foundation of China and National Key R&D Program of China. Some authors reported receiving personal fees, consulting fees, speaker bureau fees, grants, nonfinancial support, and honoraria for lectures and travel expenses and owning stock options with pharmaceutical and medical device companies outside of the submitted work. Two researchers were employed by Echosens during the conduct of the study.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Although many patients with MASLD have indications for statins, including cardiovascular disease, they are not widely used owing to concerns about possible liver damage and muscle weakness.
- Researchers conducted an observational cohort study to evaluate the long-term effects of statin use in 7988 patients (mean age, 53 years; 58.2% women) with MASLD who underwent at least two vibration-controlled transient elastography exams. The study involved 16 centers in the United States, Europe, and Asia.
- Patients were classified into those with compensated advanced chronic liver disease (cACLD; liver stiffness measurement ≥ 10 kPa) and those without cACLD (liver stiffness measurement < 10 kPa). At baseline, 17% of patients had cACLD.
- Statin prescriptions included simvastatin, pravastatin, atorvastatin, rosuvastatin, lovastatin, fluvastatin, and pitavastatin. At baseline, 40.5% of patients used statins.
- The primary outcome was the composite of all-cause mortality and liver-related events, including cirrhosis, hepatocellular carcinoma, or liver-related mortality. Secondary outcomes included changes in liver stiffness assessed over a median follow-up duration of 4.6 years.
TAKEAWAY:
- Statin usage was associated with a 76.7% lower risk for all-cause mortality and a 62% lower risk of liver-related events than non-use (both P < .001).
- Statin use also was associated with a 46% and 55% lower risk for liver stiffness progression in the cACLD and non-cACLD groups, respectively, than non-use (both P < .001).
- No significant association was found between statin use and liver stiffness regression.
IN PRACTICE:
“The results of this cohort study suggest that statin usage may help reduce CVD [cardiovascular disease] morbidity and mortality rates and slow down liver stiffness progression in both cACLD and non-cALCD patients,” the authors wrote.
SOURCE:
The study, led by Xiao-Dong Zhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China, was published online in Gut.
LIMITATIONS:
The assessment of patients at different intervals may have affected the interpretation of the data. The median follow-up period may be considered short for assessing the progression of CLD. Additionally, residual confounding in statin users could have led to an overestimation of the benefits of statins.
DISCLOSURES:
This study was supported by grants from the National Natural Science Foundation of China and National Key R&D Program of China. Some authors reported receiving personal fees, consulting fees, speaker bureau fees, grants, nonfinancial support, and honoraria for lectures and travel expenses and owning stock options with pharmaceutical and medical device companies outside of the submitted work. Two researchers were employed by Echosens during the conduct of the study.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Although many patients with MASLD have indications for statins, including cardiovascular disease, they are not widely used owing to concerns about possible liver damage and muscle weakness.
- Researchers conducted an observational cohort study to evaluate the long-term effects of statin use in 7988 patients (mean age, 53 years; 58.2% women) with MASLD who underwent at least two vibration-controlled transient elastography exams. The study involved 16 centers in the United States, Europe, and Asia.
- Patients were classified into those with compensated advanced chronic liver disease (cACLD; liver stiffness measurement ≥ 10 kPa) and those without cACLD (liver stiffness measurement < 10 kPa). At baseline, 17% of patients had cACLD.
- Statin prescriptions included simvastatin, pravastatin, atorvastatin, rosuvastatin, lovastatin, fluvastatin, and pitavastatin. At baseline, 40.5% of patients used statins.
- The primary outcome was the composite of all-cause mortality and liver-related events, including cirrhosis, hepatocellular carcinoma, or liver-related mortality. Secondary outcomes included changes in liver stiffness assessed over a median follow-up duration of 4.6 years.
TAKEAWAY:
- Statin usage was associated with a 76.7% lower risk for all-cause mortality and a 62% lower risk of liver-related events than non-use (both P < .001).
- Statin use also was associated with a 46% and 55% lower risk for liver stiffness progression in the cACLD and non-cACLD groups, respectively, than non-use (both P < .001).
- No significant association was found between statin use and liver stiffness regression.
IN PRACTICE:
“The results of this cohort study suggest that statin usage may help reduce CVD [cardiovascular disease] morbidity and mortality rates and slow down liver stiffness progression in both cACLD and non-cALCD patients,” the authors wrote.
SOURCE:
The study, led by Xiao-Dong Zhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China, was published online in Gut.
LIMITATIONS:
The assessment of patients at different intervals may have affected the interpretation of the data. The median follow-up period may be considered short for assessing the progression of CLD. Additionally, residual confounding in statin users could have led to an overestimation of the benefits of statins.
DISCLOSURES:
This study was supported by grants from the National Natural Science Foundation of China and National Key R&D Program of China. Some authors reported receiving personal fees, consulting fees, speaker bureau fees, grants, nonfinancial support, and honoraria for lectures and travel expenses and owning stock options with pharmaceutical and medical device companies outside of the submitted work. Two researchers were employed by Echosens during the conduct of the study.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
A version of this article first appeared on Medscape.com.
Alcohol-Associated Liver Disease’s Changing Demographics
, accounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.
ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.
“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.
Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
As Women Consume More Alcohol, ALD Follows
Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.
Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.
Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.
Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.
Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”
Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.
Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
Certain Ethnic, Racial Minorities Have Higher Rates of ALD
In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.
A 2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.
Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.
ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.
The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.
As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.
Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.
Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.
“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
ALD Rates High in Young Adults, but the Tide May Be Changing
Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.
In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.
ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.
From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”
Younger adults may be more susceptible to ALD due to the way they drink.
In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.
Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).
“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”
Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.
“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
A version of this article first appeared on Medscape.com.
, accounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.
ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.
“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.
Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
As Women Consume More Alcohol, ALD Follows
Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.
Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.
Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.
Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.
Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”
Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.
Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
Certain Ethnic, Racial Minorities Have Higher Rates of ALD
In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.
A 2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.
Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.
ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.
The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.
As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.
Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.
Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.
“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
ALD Rates High in Young Adults, but the Tide May Be Changing
Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.
In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.
ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.
From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”
Younger adults may be more susceptible to ALD due to the way they drink.
In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.
Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).
“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”
Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.
“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
A version of this article first appeared on Medscape.com.
, accounting for approximately 5% of all disease and injury. In the United States, the prevalence of ALD has increased since 2014, and the trajectory accelerated during the COVID-19 pandemic.
ALD encompasses a spectrum of diseases that includes steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma, as well as related complications. Although earlier stages of ALD may be asymptomatic, hepatologists and gastroenterologists rarely see patients at this point.
“Unfortunately, patients with ALD more often present in late stages of disease (decompensated cirrhosis) as compared with other chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease or hepatitis C,” Doug A. Simonetto, MD, associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the Mayo Clinic, Rochester, Minnesota, told this news organization.
Recent data have identified three demographic groups experiencing higher rates of ALD relative to previous periods and who may therefore require special attention. Understanding what makes these groups increasingly susceptible to ALD may allow for improved screening, earlier diagnosis, and potentially the prevention of its most dire consequences.
As Women Consume More Alcohol, ALD Follows
Historically, men have had higher rates of alcohol use, heavy drinking, and alcohol disorders than women. But this gender gap has begun to narrow.
Men born in the early 1900s were 2.2 times more likely to drink alcohol and 3.6 times more likely to experience alcohol-related harms than women, according to a 2016 meta-analysis. By the end of the 1990s, however, women’s drinking had begun to catch up. Men still led in these categories, but only by 1.1 and 1.3 times, respectively.
Rates of binge drinking (defined as at least five drinks in men or at least four drinks in women in an approximately 2-hour period) are also converging between the sexes. The authors of a longitudinal analysis hypothesized that an uptick in young women reporting drinking for social reasons — from 53% in 1987 to 87% in 2020 — was a possible cause.
Greater alcohol consumption among women has translated into higher rates of ALD. Analyzing data from the Global Burden of Disease Study 2019, which looked at hundreds of diseases across 204 countries and territories, researchers reported that the worldwide prevalence of ALD among young women (15-49 years) rose within the past decade. Those in the 20- to 24-year-old age group had the most significant increases in ALD prevalence rates.
Recent US statistics highlight the relative imbalance in ALD’s impact on women, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
“The age-adjusted death rate from alcohol-associated liver cirrhosis increased by 47% between 2000 and 2019, with larger increases for females than for males (83.5% compared to 33%),” Dr. Koob told this news organization. “Larger increases for women are consistent with a general increase in alcohol use among adult women and larger increases in alcohol-related emergency department visits, hospitalizations, and deaths.”
Physiologically, women have a higher risk than men of developing ALD and more severe disease, even at lower levels of alcohol exposure. According to a 2021 review, several proposed mechanisms might play a role, including differences in alcohol metabolism and first-pass metabolism, hormones, and endotoxin and Kupffer cell activation.
Crucially, women are less likely than men to receive in-person therapy or approved medications for alcohol use disorder, according to a 2019 analysis of over 66,000 privately insured adult patients.
Certain Ethnic, Racial Minorities Have Higher Rates of ALD
In the United States, rates of ALD and associated complications are higher among certain minority groups, most prominently Hispanic and Native American individuals.
A 2021 analysis of three large US databases found that Hispanic ethnicity was associated with a 17% increased risk for acute-on-chronic liver failure in patients with ALD-related admissions.
Data also show that Hispanic and White patients have a higher proportion of alcoholic hepatitis than African American patients. And for Hispanic patients admitted for alcoholic hepatitis, they incur significantly more total hospital costs despite having similar mortality rates as White patients.
ALD-related mortality appears higher within certain subgroups of Hispanic patient populations. NIAAA surveillance reports track deaths resulting from cirrhosis in the White, Black, and Hispanic populations. From 2000 to 2019, these statistics show that although death rates from cirrhosis decreased for Hispanic White men, they increased for Hispanic White women, Dr. Koob said.
The latest data show that Native American populations are experiencing ALD at relatively higher rates than other racial/ethnic groups as well. An analysis of nearly 200,000 cirrhosis-related hospitalizations found that ALD, including alcoholic hepatitis, was the most common etiology in American Indian/Alaska Native patients. A separate analysis of the National Inpatient Sample database revealed that discharges resulting from ALD were disproportionately higher among Native American women.
As with Hispanic populations, ALD-associated mortality rates are also higher in Native American populations. The death rate from ALD increased for all racial and ethnic groups by 23.4% from 2019 to 2020, but the biggest increase occurred in the American Indian or Alaska Native populations (34.3% increase, from 20.1 to 27 per 100,000 people). Additionally, over the first two decades of the 21st century, mortality rates resulting from cirrhosis were highest among the American Indian and Alaska Native populations, according to a recently published systematic analysis of US health disparities across five racial/ethnic groups.
Discrepancies in these and other minority groups may be due partly to genetic mechanisms, such as the relatively higher frequency of the PNPLA3 G/G polymorphism, a known risk factor for the development of advanced ALD, among those with Native American ancestry. A host of complex socioeconomic factors, such as income discrepancies and access to care, likely contribute too.
Evidence suggests that alcohol screening interventions are not applied equally across various racial and ethnic groups, Dr. Koob noted.
“For instance, Subbaraman and colleagues reported that, compared to non-Hispanic White patients, those who identify as Hispanic, Black, or other race or ethnicity were less likely to be screened for alcohol use during visits to healthcare providers. This was particularly true for those with a high school education or less,” he told this news organization. “However, other studies have not found such disparities.”
ALD Rates High in Young Adults, but the Tide May Be Changing
Globally, the prevalence of ALD has increased among both adolescents and young adults since the beginning of the 21st century. The global incidence of alcohol-associated hepatitis in recent years has been greatest among those aged 15-44 years.
In the United States, the increasing rate of ALD-related hospitalizations is primarily driven by the rise in cases of alcoholic hepatitis and acute-on-chronic liver failure among those aged 35 years and younger.
ALD is now the most common indication for liver transplant in those younger than 40 years of age, having increased fourfold between 2003 and 2018.
From 2009 to 2016, people aged 25-34 years experienced the highest average annual increase in cirrhosis-related mortality (10.5%), a trend the authors noted was “driven entirely by alcohol-related liver disease.”
Younger adults may be more susceptible to ALD due to the way they drink.
In a 2021 analysis of the National Health and Nutrition Examination Survey database, the weighted prevalence of harmful alcohol use was 29.3% in those younger than 35 years, compared with 16.9% in those aged 35-64 years. Higher blood alcohol levels resulting from binge drinking may make patients more susceptible to bacterial translocation and liver fibrosis and can increase the likelihood of cirrhosis in those with an underlying metabolic syndrome.
Yet, Dr. Koob said, thinking of “young adults” as one cohort may be misguided because he’s found very different attitudes toward alcohol within that population. Cross-sectional survey data obtained from more than 180,000 young adults indicated that alcohol abstinence increased between 2002 and 2018. Young adults report various reasons for not drinking, ranging from lack of interest to financial and situational barriers (eg, not wanting to interfere with school or work).
“The tide is coming in and out at the same time,” he said. “Younger people under the age of 25 are drinking less each year, are increasingly interested in things like Dry January, and more than half view moderate levels of consumption as unhealthy. People who are 26 years and older are drinking more, are not as interested in cutting back or taking breaks, and are less likely to consider 1 or 2 drinks per day as potentially unhealthy.”
Dr. Koob would like to believe the positive trends around alcohol in the under-25 set prove not only resilient, but someday, dominant.
“We have seen historic increases in alcohol consumption in the last few years — the largest increases in more than 50 years. But we are hopeful that, as the younger cohorts age, we will see lower levels of drinking by adults in mid-life and beyond.”
A version of this article first appeared on Medscape.com.
Could Adipose Tissue Be a Better Measure for Obesity Than BMI?
Take a look at any of the evidence-based US obesity treatment guidelines. The key criteria for diagnosing overweight and obesity is based on the body mass index (BMI).
The guidelines also use BMI to stratify care options to decrease cardiovascular risk. For example, persons with BMI ≥30 are classified as having obesity, and antiobesity medications are recommended. Those with BMI ≥ 40 are classified as having severe obesity, and metabolic bariatric surgery may be appropriate.
But where did these cutoff points for more and less aggressive treatments come from? These BMI cutoffs are based primarily on mortality data collected from large non-Hispanic White populations, without data on potential differences by gender and ethnicity.
For example, it is certainly true that those with BMI ≥ 30 have more cardiovascular risk factors than those with BMI < 30. But Asian American individuals have more risk factors at lower BMIs than do White or African American individuals likely because of more visceral fat accumulation at lower BMIs.
Besides the variation in gender and ethnicity, BMI does not take the type and location of body fat into consideration. Adipose tissue in visceral or ectopic areas have much higher risks for disease than subcutaneous adipose tissue because of the associated inflammation. Measures such as waist circumference, waist-to-hip ratio, and skinfold measurements aim to capture this aspect but often fall short because of variation in techniques.
BMI does not account for muscle mass either, so fit athletes and bodybuilders can be classified as having obesity by BMI alone. More accurate body fat percent measures, such as dual-energy X-ray absorptiometry or MRI specifically for ectopic fat, are labor intensive, expensive, and not feasible to perform in a busy primary care or endocrinology clinic.
Assessing Risks From Obesity Beyond BMI
Clearly, better risk measures than BMI are needed, but until they are available, supplemental clinical tools can aid diagnosis and treatment decisions at obesity medicine specialty centers, endocrinology and diabetes centers, and those centers that focus on the treatment of obesity.
For example, a seca scale can measure percent body fat by bioelectric impedance analysis. This technique also has its limitations, but for persons who are well hydrated, it can be used as a baseline to determine efficacy of behavioral interventions, such as resistance-exercise training and a high-protein diet to protect muscle mass as the patient loses weight.
A lot also can be gleaned from diet and exercise history, social history, family history, and physical exam as well as laboratory analyses. For example, an Asian American patient with a BMI of 26 who has been gaining weight mostly in the abdominal region after age 35 years is likely to have cardiometabolic risk, and a family history can solidify that. An exam can show signs of acanthosis nigricans or an enlarged liver and generous abdominal adipose tissue. This would be the patient in whom you would want to obtain a hemoglobin A1c measurement in the chance that it is elevated at > 5.7 mg/dL, suggesting high risk for type 2 diabetes.
A Fibrosis-4 score can assess the risk for liver disease from aspartate transaminase and alanine aminotransferase and platelet count and age, providing clues to cardiometabolic disease risk.
In the next 10, years there may be a better measure for cardiometabolic risk that is more accurate than BMI is. It could be the sagittal abdominal diameter, which has been purported to more accurately measure visceral abdominal fat. But this has not made it to be one of the vital signs in a busy primary care clinic, however.
Will New Body Fat Tools Change Practice?
In the next 10 years, there may be an affordable gadget to scan the body to determine visceral vs subcutaneous deposition of fat — like radiography for tissue. Now, three-dimensional (3D) total-body scanners can obtain body composition, but they are extremely expensive. The more important clinical question is: How will the use of these imaging modalities change your practice protocol for a particular patient?
Think about the FibroScan, a type of ultrasound used to determine fatty liver disease and fibrosis. We order the test for those patients in whom we already have a strong suspicion for liver disease and, in obesity practices, for fatty liver and metabolic-associated fatty liver disease or metabolic associated steatohepatitis.
The test results do much to educate the patient and help the patient understand the need for aggressive treatment for their obesity. But it doesn’t necessarily change the clinician’s practice protocols and decisions. We would still recommend weight management and medications or surgery to patients regardless of the findings.
A FibroScan is an expense, and not all primary care or endocrine practitioners may feel it necessary to purchase one for the added benefit of patient education. And I would argue that a 3D body scanner is a great tool but more for educational purposes than to really determine practice decision-making or outcomes.
In the meantime, an old-fashioned physical examination, along with a thorough medical, social, and family history should give even the busiest primary care provider enough information to decide whether their patient is a candidate for preventive measures to reduce body fat with diet, exercise, and medication as well as whether the patient is a candidate for metabolic bariatric surgery. Higher suspicion of cardiovascular risk at lower BMI ranges for various ethnicities can help primary care providers pick up on the patients with low BMI but who are at higher risk for type 2 diabetes or prediabetes and cardiovascular disease.
So the answer to whether we need a better measure than the BMI: Yes, we do. We need a physical examination on all patients.
Dr. Apovian, professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, both in Boston, Massachusetts, disclosed ties with Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, L-Nutra, NeuroBo Pharm, Novo, OptumRx, Pain Script, Palatin, Pursuit by You, Roman Health, Xeno, and Riverview School.
A version of this article appeared on Medscape.com.
Take a look at any of the evidence-based US obesity treatment guidelines. The key criteria for diagnosing overweight and obesity is based on the body mass index (BMI).
The guidelines also use BMI to stratify care options to decrease cardiovascular risk. For example, persons with BMI ≥30 are classified as having obesity, and antiobesity medications are recommended. Those with BMI ≥ 40 are classified as having severe obesity, and metabolic bariatric surgery may be appropriate.
But where did these cutoff points for more and less aggressive treatments come from? These BMI cutoffs are based primarily on mortality data collected from large non-Hispanic White populations, without data on potential differences by gender and ethnicity.
For example, it is certainly true that those with BMI ≥ 30 have more cardiovascular risk factors than those with BMI < 30. But Asian American individuals have more risk factors at lower BMIs than do White or African American individuals likely because of more visceral fat accumulation at lower BMIs.
Besides the variation in gender and ethnicity, BMI does not take the type and location of body fat into consideration. Adipose tissue in visceral or ectopic areas have much higher risks for disease than subcutaneous adipose tissue because of the associated inflammation. Measures such as waist circumference, waist-to-hip ratio, and skinfold measurements aim to capture this aspect but often fall short because of variation in techniques.
BMI does not account for muscle mass either, so fit athletes and bodybuilders can be classified as having obesity by BMI alone. More accurate body fat percent measures, such as dual-energy X-ray absorptiometry or MRI specifically for ectopic fat, are labor intensive, expensive, and not feasible to perform in a busy primary care or endocrinology clinic.
Assessing Risks From Obesity Beyond BMI
Clearly, better risk measures than BMI are needed, but until they are available, supplemental clinical tools can aid diagnosis and treatment decisions at obesity medicine specialty centers, endocrinology and diabetes centers, and those centers that focus on the treatment of obesity.
For example, a seca scale can measure percent body fat by bioelectric impedance analysis. This technique also has its limitations, but for persons who are well hydrated, it can be used as a baseline to determine efficacy of behavioral interventions, such as resistance-exercise training and a high-protein diet to protect muscle mass as the patient loses weight.
A lot also can be gleaned from diet and exercise history, social history, family history, and physical exam as well as laboratory analyses. For example, an Asian American patient with a BMI of 26 who has been gaining weight mostly in the abdominal region after age 35 years is likely to have cardiometabolic risk, and a family history can solidify that. An exam can show signs of acanthosis nigricans or an enlarged liver and generous abdominal adipose tissue. This would be the patient in whom you would want to obtain a hemoglobin A1c measurement in the chance that it is elevated at > 5.7 mg/dL, suggesting high risk for type 2 diabetes.
A Fibrosis-4 score can assess the risk for liver disease from aspartate transaminase and alanine aminotransferase and platelet count and age, providing clues to cardiometabolic disease risk.
In the next 10, years there may be a better measure for cardiometabolic risk that is more accurate than BMI is. It could be the sagittal abdominal diameter, which has been purported to more accurately measure visceral abdominal fat. But this has not made it to be one of the vital signs in a busy primary care clinic, however.
Will New Body Fat Tools Change Practice?
In the next 10 years, there may be an affordable gadget to scan the body to determine visceral vs subcutaneous deposition of fat — like radiography for tissue. Now, three-dimensional (3D) total-body scanners can obtain body composition, but they are extremely expensive. The more important clinical question is: How will the use of these imaging modalities change your practice protocol for a particular patient?
Think about the FibroScan, a type of ultrasound used to determine fatty liver disease and fibrosis. We order the test for those patients in whom we already have a strong suspicion for liver disease and, in obesity practices, for fatty liver and metabolic-associated fatty liver disease or metabolic associated steatohepatitis.
The test results do much to educate the patient and help the patient understand the need for aggressive treatment for their obesity. But it doesn’t necessarily change the clinician’s practice protocols and decisions. We would still recommend weight management and medications or surgery to patients regardless of the findings.
A FibroScan is an expense, and not all primary care or endocrine practitioners may feel it necessary to purchase one for the added benefit of patient education. And I would argue that a 3D body scanner is a great tool but more for educational purposes than to really determine practice decision-making or outcomes.
In the meantime, an old-fashioned physical examination, along with a thorough medical, social, and family history should give even the busiest primary care provider enough information to decide whether their patient is a candidate for preventive measures to reduce body fat with diet, exercise, and medication as well as whether the patient is a candidate for metabolic bariatric surgery. Higher suspicion of cardiovascular risk at lower BMI ranges for various ethnicities can help primary care providers pick up on the patients with low BMI but who are at higher risk for type 2 diabetes or prediabetes and cardiovascular disease.
So the answer to whether we need a better measure than the BMI: Yes, we do. We need a physical examination on all patients.
Dr. Apovian, professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, both in Boston, Massachusetts, disclosed ties with Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, L-Nutra, NeuroBo Pharm, Novo, OptumRx, Pain Script, Palatin, Pursuit by You, Roman Health, Xeno, and Riverview School.
A version of this article appeared on Medscape.com.
Take a look at any of the evidence-based US obesity treatment guidelines. The key criteria for diagnosing overweight and obesity is based on the body mass index (BMI).
The guidelines also use BMI to stratify care options to decrease cardiovascular risk. For example, persons with BMI ≥30 are classified as having obesity, and antiobesity medications are recommended. Those with BMI ≥ 40 are classified as having severe obesity, and metabolic bariatric surgery may be appropriate.
But where did these cutoff points for more and less aggressive treatments come from? These BMI cutoffs are based primarily on mortality data collected from large non-Hispanic White populations, without data on potential differences by gender and ethnicity.
For example, it is certainly true that those with BMI ≥ 30 have more cardiovascular risk factors than those with BMI < 30. But Asian American individuals have more risk factors at lower BMIs than do White or African American individuals likely because of more visceral fat accumulation at lower BMIs.
Besides the variation in gender and ethnicity, BMI does not take the type and location of body fat into consideration. Adipose tissue in visceral or ectopic areas have much higher risks for disease than subcutaneous adipose tissue because of the associated inflammation. Measures such as waist circumference, waist-to-hip ratio, and skinfold measurements aim to capture this aspect but often fall short because of variation in techniques.
BMI does not account for muscle mass either, so fit athletes and bodybuilders can be classified as having obesity by BMI alone. More accurate body fat percent measures, such as dual-energy X-ray absorptiometry or MRI specifically for ectopic fat, are labor intensive, expensive, and not feasible to perform in a busy primary care or endocrinology clinic.
Assessing Risks From Obesity Beyond BMI
Clearly, better risk measures than BMI are needed, but until they are available, supplemental clinical tools can aid diagnosis and treatment decisions at obesity medicine specialty centers, endocrinology and diabetes centers, and those centers that focus on the treatment of obesity.
For example, a seca scale can measure percent body fat by bioelectric impedance analysis. This technique also has its limitations, but for persons who are well hydrated, it can be used as a baseline to determine efficacy of behavioral interventions, such as resistance-exercise training and a high-protein diet to protect muscle mass as the patient loses weight.
A lot also can be gleaned from diet and exercise history, social history, family history, and physical exam as well as laboratory analyses. For example, an Asian American patient with a BMI of 26 who has been gaining weight mostly in the abdominal region after age 35 years is likely to have cardiometabolic risk, and a family history can solidify that. An exam can show signs of acanthosis nigricans or an enlarged liver and generous abdominal adipose tissue. This would be the patient in whom you would want to obtain a hemoglobin A1c measurement in the chance that it is elevated at > 5.7 mg/dL, suggesting high risk for type 2 diabetes.
A Fibrosis-4 score can assess the risk for liver disease from aspartate transaminase and alanine aminotransferase and platelet count and age, providing clues to cardiometabolic disease risk.
In the next 10, years there may be a better measure for cardiometabolic risk that is more accurate than BMI is. It could be the sagittal abdominal diameter, which has been purported to more accurately measure visceral abdominal fat. But this has not made it to be one of the vital signs in a busy primary care clinic, however.
Will New Body Fat Tools Change Practice?
In the next 10 years, there may be an affordable gadget to scan the body to determine visceral vs subcutaneous deposition of fat — like radiography for tissue. Now, three-dimensional (3D) total-body scanners can obtain body composition, but they are extremely expensive. The more important clinical question is: How will the use of these imaging modalities change your practice protocol for a particular patient?
Think about the FibroScan, a type of ultrasound used to determine fatty liver disease and fibrosis. We order the test for those patients in whom we already have a strong suspicion for liver disease and, in obesity practices, for fatty liver and metabolic-associated fatty liver disease or metabolic associated steatohepatitis.
The test results do much to educate the patient and help the patient understand the need for aggressive treatment for their obesity. But it doesn’t necessarily change the clinician’s practice protocols and decisions. We would still recommend weight management and medications or surgery to patients regardless of the findings.
A FibroScan is an expense, and not all primary care or endocrine practitioners may feel it necessary to purchase one for the added benefit of patient education. And I would argue that a 3D body scanner is a great tool but more for educational purposes than to really determine practice decision-making or outcomes.
In the meantime, an old-fashioned physical examination, along with a thorough medical, social, and family history should give even the busiest primary care provider enough information to decide whether their patient is a candidate for preventive measures to reduce body fat with diet, exercise, and medication as well as whether the patient is a candidate for metabolic bariatric surgery. Higher suspicion of cardiovascular risk at lower BMI ranges for various ethnicities can help primary care providers pick up on the patients with low BMI but who are at higher risk for type 2 diabetes or prediabetes and cardiovascular disease.
So the answer to whether we need a better measure than the BMI: Yes, we do. We need a physical examination on all patients.
Dr. Apovian, professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, both in Boston, Massachusetts, disclosed ties with Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, L-Nutra, NeuroBo Pharm, Novo, OptumRx, Pain Script, Palatin, Pursuit by You, Roman Health, Xeno, and Riverview School.
A version of this article appeared on Medscape.com.