Hepatology

Ultrasonography screening intervals of less than 6-12 months were associated with early detection of hepatocellular carcinoma, as well as increased life expectancy and quality of life, according to data from a nationwide comparative effectiveness study of nearly 60,000 patients in Taiwan.

Many international societies, including the American Association for the Study of Liver Diseases, the Asian Pacific Association for the Study of the Liver, and the European Association for the Study of the Liver, recommend abdominal ultrasonography screening for hepatocellular carcinoma (HCC) with or without alpha-fetoprotein every 6 months for patients at increased risk for HCC, wrote Shih-Chiang Kuo, MD, of National Cheng Kung University, Tainan, Taiwan, and colleagues.

However, some studies do not support this recommendation, and data suggest that “adherence to regular screenings by high-risk patients has been inadequate, leading to reduced overall benefits of ultrasonography screening in real-world practice,” and the impact of screening schedules on quality of life has not been assessed, they said.

In a study published in JAMA Network Open, the researchers identified adults with newly diagnosed HCC from 2002 through 2015 using data from the Taiwan National Cancer Registry. Barcelona Clinic Liver Cancer (BCLC) staging information was available for 42,081 men and 17,113 women; the average age was 62 years for men and 69 years for women. The patients were divided into five cohorts based on the time between their last ultrasonography screening and an index date of 90 days before their HCC diagnosis. These groups were 6 months (0-6 months), 12 months (7-12 months), 24 months (13-24 months), 36 months (25-36 months), and longer than 36 months.

“For both sexes, the proportions of patients with HCC classified as being in earlier stages (stage 0 and A) were higher in subcohorts with shorter screening intervals since the most recent ultrasonography,” the researchers wrote.

The researchers also assessed quality of life measures using the European Quality of Life Five-Dimensions in 807 men (3,370 repeated assessments) and 252 women (1,044 repeated assessments). Among men, the loss of quality of life expectancy in terms of quality of life years (QALYs) was 10.0, 11.1, 12.1, 13.1, and 14.6 for screening intervals of 6 months, 12 months, 24 months, 36 months, and beyond 36 months, respectively. The corresponding QALYs for women at the same screening intervals were 9.0, 9.7, 10.3, 10.7, and 11.4, respectively.

In a subgroup analysis according to underlying liver disease, patients with underlying hepatitis B virus infection or cirrhosis showed the greatest benefits from shorter screening intervals. For those with hepatitis B virus infection, abdominal ultrasonography screening 6 months or less prior to diagnosis of HCC was associated with an additional 4.8 QALYs for men and 2.8 QALYs for women, compared with screening longer than 36 months prior to diagnosis. The corresponding savings in QALY for men and women with underlying cirrhosis was 4.8 QALYs and 2.4 QALYs. Patients with no underlying liver disease also benefited from shorter intervals, with potential savings of 3.2 QALYs for men and 1.6 QALYs for women in the 6-month screening groups, compared with the longer than 36 months groups.

However, less than half of the men overall underwent screening withing 6 months or 12 months before diagnosis (31.4% and 39.3%, respectively); for women, 42.2% received screening within 6 months of diagnosis and 51.9% received screening within 12 months.

The study findings were limited by several factors including the use of only the last screening before diagnosis, which allows the possibility that patients in the 6- or 12-month groups did not have regular screening, the researchers noted. In addition, the lack of data on quality of life for women with BCLC stage D might have caused an underestimation of quality of life loss, they said. However, the results were strengthened by the use of a national database and long follow-up period, they said.

The results support intervals of 6-12 months or less for regular ultrasonography screening as a way to improve early detection of HCC, “and may save lives and improve utility for patients with HCC from a lifetime perspective,” the researchers emphasized. “Because people with underlying risk factors (including hepatitis B virus or hepatitis C virus infection, cirrhosis, and alcoholic liver disease) showed only slightly more frequent ultrasonography screening than those without underlying risk factors, we recommend improving this clinical practice,” they concluded.
 

Impact of identifying risk

“This study is important because HCC remains the third leading cause of cancer deaths, and the 5-year survival rate is low,” said Atsushi Sakuraba, MD, of the University of Chicago, in an interview.

Dr. Sakuraba said that he was not surprised by any of the study findings. “Earlier diagnosis of cancer is often associated with improved outcome in many cancers,” he noted.

However, “Overutilization of resources may lead to increased health care costs, so correct identification of high-risk populations is needed,” Dr. Sakuraba said.

Additional research is warranted in several areas in order to make an impact on clinical practice, Dr. Sakuraba said, notably, “confirmation in other countries and ethnicities where the incidence of viral hepatitis varies.” Comparison to other tests, such as tumor markers, CT, and MRI, is needed as well, he concluded.

The study was supported by the Taiwan Ministry of Science and Technology. The researchers had no financial conflicts to disclose. Dr. Sakuraba had no financial conflicts to disclose.

Ultrasonography screening intervals of less than 6-12 months were associated with early detection of hepatocellular carcinoma, as well as increased life expectancy and quality of life, according to data from a nationwide comparative effectiveness study of nearly 60,000 patients in Taiwan.

Many international societies, including the American Association for the Study of Liver Diseases, the Asian Pacific Association for the Study of the Liver, and the European Association for the Study of the Liver, recommend abdominal ultrasonography screening for hepatocellular carcinoma (HCC) with or without alpha-fetoprotein every 6 months for patients at increased risk for HCC, wrote Shih-Chiang Kuo, MD, of National Cheng Kung University, Tainan, Taiwan, and colleagues.

However, some studies do not support this recommendation, and data suggest that “adherence to regular screenings by high-risk patients has been inadequate, leading to reduced overall benefits of ultrasonography screening in real-world practice,” and the impact of screening schedules on quality of life has not been assessed, they said.

In a study published in JAMA Network Open, the researchers identified adults with newly diagnosed HCC from 2002 through 2015 using data from the Taiwan National Cancer Registry. Barcelona Clinic Liver Cancer (BCLC) staging information was available for 42,081 men and 17,113 women; the average age was 62 years for men and 69 years for women. The patients were divided into five cohorts based on the time between their last ultrasonography screening and an index date of 90 days before their HCC diagnosis. These groups were 6 months (0-6 months), 12 months (7-12 months), 24 months (13-24 months), 36 months (25-36 months), and longer than 36 months.

“For both sexes, the proportions of patients with HCC classified as being in earlier stages (stage 0 and A) were higher in subcohorts with shorter screening intervals since the most recent ultrasonography,” the researchers wrote.

The researchers also assessed quality of life measures using the European Quality of Life Five-Dimensions in 807 men (3,370 repeated assessments) and 252 women (1,044 repeated assessments). Among men, the loss of quality of life expectancy in terms of quality of life years (QALYs) was 10.0, 11.1, 12.1, 13.1, and 14.6 for screening intervals of 6 months, 12 months, 24 months, 36 months, and beyond 36 months, respectively. The corresponding QALYs for women at the same screening intervals were 9.0, 9.7, 10.3, 10.7, and 11.4, respectively.

In a subgroup analysis according to underlying liver disease, patients with underlying hepatitis B virus infection or cirrhosis showed the greatest benefits from shorter screening intervals. For those with hepatitis B virus infection, abdominal ultrasonography screening 6 months or less prior to diagnosis of HCC was associated with an additional 4.8 QALYs for men and 2.8 QALYs for women, compared with screening longer than 36 months prior to diagnosis. The corresponding savings in QALY for men and women with underlying cirrhosis was 4.8 QALYs and 2.4 QALYs. Patients with no underlying liver disease also benefited from shorter intervals, with potential savings of 3.2 QALYs for men and 1.6 QALYs for women in the 6-month screening groups, compared with the longer than 36 months groups.

However, less than half of the men overall underwent screening withing 6 months or 12 months before diagnosis (31.4% and 39.3%, respectively); for women, 42.2% received screening within 6 months of diagnosis and 51.9% received screening within 12 months.

The study findings were limited by several factors including the use of only the last screening before diagnosis, which allows the possibility that patients in the 6- or 12-month groups did not have regular screening, the researchers noted. In addition, the lack of data on quality of life for women with BCLC stage D might have caused an underestimation of quality of life loss, they said. However, the results were strengthened by the use of a national database and long follow-up period, they said.

The results support intervals of 6-12 months or less for regular ultrasonography screening as a way to improve early detection of HCC, “and may save lives and improve utility for patients with HCC from a lifetime perspective,” the researchers emphasized. “Because people with underlying risk factors (including hepatitis B virus or hepatitis C virus infection, cirrhosis, and alcoholic liver disease) showed only slightly more frequent ultrasonography screening than those without underlying risk factors, we recommend improving this clinical practice,” they concluded.
 

Impact of identifying risk

“This study is important because HCC remains the third leading cause of cancer deaths, and the 5-year survival rate is low,” said Atsushi Sakuraba, MD, of the University of Chicago, in an interview.

Dr. Sakuraba said that he was not surprised by any of the study findings. “Earlier diagnosis of cancer is often associated with improved outcome in many cancers,” he noted.

However, “Overutilization of resources may lead to increased health care costs, so correct identification of high-risk populations is needed,” Dr. Sakuraba said.

Additional research is warranted in several areas in order to make an impact on clinical practice, Dr. Sakuraba said, notably, “confirmation in other countries and ethnicities where the incidence of viral hepatitis varies.” Comparison to other tests, such as tumor markers, CT, and MRI, is needed as well, he concluded.

The study was supported by the Taiwan Ministry of Science and Technology. The researchers had no financial conflicts to disclose. Dr. Sakuraba had no financial conflicts to disclose.

Ultrasonography screening intervals of less than 6-12 months were associated with early detection of hepatocellular carcinoma, as well as increased life expectancy and quality of life, according to data from a nationwide comparative effectiveness study of nearly 60,000 patients in Taiwan.

Many international societies, including the American Association for the Study of Liver Diseases, the Asian Pacific Association for the Study of the Liver, and the European Association for the Study of the Liver, recommend abdominal ultrasonography screening for hepatocellular carcinoma (HCC) with or without alpha-fetoprotein every 6 months for patients at increased risk for HCC, wrote Shih-Chiang Kuo, MD, of National Cheng Kung University, Tainan, Taiwan, and colleagues.

However, some studies do not support this recommendation, and data suggest that “adherence to regular screenings by high-risk patients has been inadequate, leading to reduced overall benefits of ultrasonography screening in real-world practice,” and the impact of screening schedules on quality of life has not been assessed, they said.

In a study published in JAMA Network Open, the researchers identified adults with newly diagnosed HCC from 2002 through 2015 using data from the Taiwan National Cancer Registry. Barcelona Clinic Liver Cancer (BCLC) staging information was available for 42,081 men and 17,113 women; the average age was 62 years for men and 69 years for women. The patients were divided into five cohorts based on the time between their last ultrasonography screening and an index date of 90 days before their HCC diagnosis. These groups were 6 months (0-6 months), 12 months (7-12 months), 24 months (13-24 months), 36 months (25-36 months), and longer than 36 months.

“For both sexes, the proportions of patients with HCC classified as being in earlier stages (stage 0 and A) were higher in subcohorts with shorter screening intervals since the most recent ultrasonography,” the researchers wrote.

The researchers also assessed quality of life measures using the European Quality of Life Five-Dimensions in 807 men (3,370 repeated assessments) and 252 women (1,044 repeated assessments). Among men, the loss of quality of life expectancy in terms of quality of life years (QALYs) was 10.0, 11.1, 12.1, 13.1, and 14.6 for screening intervals of 6 months, 12 months, 24 months, 36 months, and beyond 36 months, respectively. The corresponding QALYs for women at the same screening intervals were 9.0, 9.7, 10.3, 10.7, and 11.4, respectively.

In a subgroup analysis according to underlying liver disease, patients with underlying hepatitis B virus infection or cirrhosis showed the greatest benefits from shorter screening intervals. For those with hepatitis B virus infection, abdominal ultrasonography screening 6 months or less prior to diagnosis of HCC was associated with an additional 4.8 QALYs for men and 2.8 QALYs for women, compared with screening longer than 36 months prior to diagnosis. The corresponding savings in QALY for men and women with underlying cirrhosis was 4.8 QALYs and 2.4 QALYs. Patients with no underlying liver disease also benefited from shorter intervals, with potential savings of 3.2 QALYs for men and 1.6 QALYs for women in the 6-month screening groups, compared with the longer than 36 months groups.

However, less than half of the men overall underwent screening withing 6 months or 12 months before diagnosis (31.4% and 39.3%, respectively); for women, 42.2% received screening within 6 months of diagnosis and 51.9% received screening within 12 months.

The study findings were limited by several factors including the use of only the last screening before diagnosis, which allows the possibility that patients in the 6- or 12-month groups did not have regular screening, the researchers noted. In addition, the lack of data on quality of life for women with BCLC stage D might have caused an underestimation of quality of life loss, they said. However, the results were strengthened by the use of a national database and long follow-up period, they said.

The results support intervals of 6-12 months or less for regular ultrasonography screening as a way to improve early detection of HCC, “and may save lives and improve utility for patients with HCC from a lifetime perspective,” the researchers emphasized. “Because people with underlying risk factors (including hepatitis B virus or hepatitis C virus infection, cirrhosis, and alcoholic liver disease) showed only slightly more frequent ultrasonography screening than those without underlying risk factors, we recommend improving this clinical practice,” they concluded.
 

Impact of identifying risk

“This study is important because HCC remains the third leading cause of cancer deaths, and the 5-year survival rate is low,” said Atsushi Sakuraba, MD, of the University of Chicago, in an interview.

Dr. Sakuraba said that he was not surprised by any of the study findings. “Earlier diagnosis of cancer is often associated with improved outcome in many cancers,” he noted.

However, “Overutilization of resources may lead to increased health care costs, so correct identification of high-risk populations is needed,” Dr. Sakuraba said.

Additional research is warranted in several areas in order to make an impact on clinical practice, Dr. Sakuraba said, notably, “confirmation in other countries and ethnicities where the incidence of viral hepatitis varies.” Comparison to other tests, such as tumor markers, CT, and MRI, is needed as well, he concluded.

The study was supported by the Taiwan Ministry of Science and Technology. The researchers had no financial conflicts to disclose. Dr. Sakuraba had no financial conflicts to disclose.

A multidisciplinary panel of U.S. experts released a “Call to Action” for improved screening, diagnosis, and treatment of patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) on July 26, an effort organized by the American Gastroenterological Association in collaboration with seven other U.S. medical organizations including several endocrinology groups.

The published statement, “Preparing for the NASH Epidemic: A Call to Action,” proposes several urgent steps for the U.S. clinical community to provide better-focused and better-coordinated care for patients at risk for developing or having NAFLD or NASH, particularly among “emerging” at-risk cohorts such as patients with diabetes and obesity. It appears in the journals Gastroenterology, Diabetes Care, Metabolism: Clinical and Experimental, and Obesity.

The statement’s central pitch is that improvements in care won’t be possible unless the several medical specialties that deal with affected or at-risk patients stop working “in separate silos,” and instead create “a collective action plan,” and also organize multidisciplinary teams that “integrate primary care, hepatology, obesity medicine, endocrinology, and diabetology via well-defined care pathways.”

“The overarching goal” is a “unified, international public health response to NAFLD and NASH,” said the statement, which stemmed from a conference held in July 2020 that included representatives from not only the lead gastroenterology group but also the American Diabetes Association, the American Association for the Study of Liver Diseases, the American Association of Clinical Endocrinologists, The Endocrine Society, The American Academy of Family Physicians, The Obesity Society, and the American College of Osteopathic Family Physicians.

The statement cites sobering prevalence numbers, with estimates that NAFLD exists in more than half the patients with type 2 diabetes, while NASH affects about a third, rates that translate into many millions of affected Americans, given recent estimates that the U.S. prevalence of type 2 diabetes exceeds 30 million people. And the numbers continue to rise along with increases in the prevalence of obesity and type 2 diabetes.

“It’s an enormously common disease, and there are not enough gastroenterologists, to say nothing of hepatologists, to care for every patient with NAFLD,” said Anna Mae Diehl, MD, a gastroenterologist and professor at Duke University in Durham, N.C., who was not involved with the conference nor in writing the statement.

Clinical care pathways coming soon

Another key part of this initiative is development of clinical care pathways that will have “careful explication of each step in screening, diagnosis, and treatment,” and will be designed to inform the practice of primary care physicians (PCPs) as well as clinicians from the various specialties that deal with these patients.

The clinical care pathways are on track to come out later in 2021, said Fasiha Kanwal, MD, a professor and chief of gastroenterology at Baylor College of Medicine in Houston, and lead author on the Call to Action document.

“The Pathways will include practical recommendations about whom to screen and when to refer, and the criteria primary care physicians can use for diagnosis and risk stratification,” Dr. Kanwal said in an interview. “Patients can benefit from a standardized approach.”

The new document also includes results from a recent survey about NAFLD and NASH management completed by 751 U.S. physicians, including 401 (53%) primary care physicians, 175 gastroenterologists, (23%) and 175 endocrinologists (23%; percentages total 99% because of rounding).

The results showed “significant gaps in knowledge about whom to screen and how to diagnose and treat patients at high risk for NASH,” concluded the statement’s authors. Barely more than a third of the respondents knew that almost all patients with severe obesity likely have NAFLD, and fewer than half the endocrinologists and the primary care physicians appreciated that NAFLD is very common among patients with type 2 diabetes.
 

‘Understanding of NAFLD is not there’

“I applaud this effort that calls attention to an emerging public health problem. This paper and survey are great ideas. The findings are not surprising, but they’re important,” said Dr. Diehl said in an interview. “Much more needs to be done” including changes in social behavior and government policies.

“The public’s understanding of NAFLD is not there,” and many physicians also have an incomplete understanding of NAFLD and more serious stages of metabolic liver disease. “Physicians know that patients with obesity are at risk for heart disease, diabetes, and stroke, but they may not always be aware that these patients can also have cirrhosis,” noted Dr. Diehl, who published in 2019 a call to action for NAFLD of her own with some associates.

“My referrals are fueled by primary care physicians who recognize patients with significant liver disease. It would be great to outline recommended practice; I have no doubt that providers will embrace this,” as well as the broader concept of multidisciplinary teams, another focus of the statement. Dr. Diehl cited the “Cancer Center model,” where an oncologist takes primary responsibility for caring for a cancer patient while coordinating care with other specialists, an approach facilitated by EMRs that allow seamless data and chart sharing and something that many health systems have either already adopted or are moving toward.

She said the NASH Call to Action may help catalyze broader application of this model to many more patients with NAFLD or NASH, and noted that some U.S. centers already use this approach – including Dr. Diehl’s program at Duke – which brings together her gastroenterology colleagues with cardiologists, radiologists, endocrinologists, and bariatric surgeons. But she noted that for most patients with metabolic liver disease, the hub clinician needs to be a PCP, especially for patients with earlier-stage disease, because the number of affected patients is so huge.

“Key steps toward establishing such teams include establishing protocols for risk stratification and referral, definition of roles and responsibilities, and buy-in from institutions and payers. Clearly a lot of work needs to occur to get to these multidisciplinary teams,” said Dr. Kanwal.

Ralph A. DeFronzo, MD, professor and deputy director of the Texas Diabetes Institute at UT Health San Antonio, who was not involved with the conference or statement, had a different take on what the future of NASH and NAFLD care may look like.

“Endocrinologists, hepatologists, and obesity experts will work within their individual specialties to diagnose and manage NASH,” he said in an interview. But he acknowledged that “an integrated effort by specialists would be important” to help “primary care physicians who are less familiar with the disease.”
 

Controversy over pioglitazone?

Dr. DeFronzo endorsed development of clinical care pathways as “important,” but also as a potential source of “controversy, especially with respect to treatment.”

The Call to Action statement cites lifestyle-based therapies, such as an appropriate diet; regular, moderate exercise; and elimination when possible of obesogenic medications as cornerstone interventions for patients with NAFLD or early-stage NASH, interventions that can be prescribed by PCPs. For patients with NASH and stage 2 or worse fibrosis, the statement endorses liver-directed pharmacotherapy. While noting that no agents currently carry a Food and Drug Administration–approved indication for treating NASH, the statement cites evidence that 800 IU/day of vitamin E improves steatosis in patients with NASH but not type 2 diabetes.

For patients with type 2 diabetes, the statement notes that results from five randomized trials indicated that pioglitazone could reverse steatohepatitis, findings that led to its recommendation in guidelines from a modest circle of medical groups, including the American Association for the Study of Liver Diseases and the European Association for the Study of Diabetes. However, the 2021 Standards of Medical Care in Diabetes from the American Diabetes Association gives these agents limited endorsement, saying: “Pioglitazone, vitamin E treatment, and liraglutide treatment of biopsy-proven nonalcoholic steatohepatitis have each been shown to improve liver histology, but effects on longer-term clinical outcomes are not known.”

“The strongest evidence by far is for pioglitazone for treating NAFLD and NASH,” said Dr. DeFronzo, a vocal proponent of the drug for this indication. But he added that “hepatologists don’t feel comfortable with drugs from the thiazolidinedione class,” which includes pioglitazone.

“We don’t yet know how to optimally configure the health system for NAFLD and NASH to make it more efficient and helpful to patients, but models exist, and the approach is evolving,” said Dr. Diehl.

Dr. Diehl and Dr. Kanwal had no relevant disclosures. Dr. DeFronzo has been a speaker on behalf of AstraZeneca and Novo Nordisk, has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, and Janssen, and has received research funding from AstraZeneca, Janssen and Merck.

[email protected]

A multidisciplinary panel of U.S. experts released a “Call to Action” for improved screening, diagnosis, and treatment of patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) on July 26, an effort organized by the American Gastroenterological Association in collaboration with seven other U.S. medical organizations including several endocrinology groups.

The published statement, “Preparing for the NASH Epidemic: A Call to Action,” proposes several urgent steps for the U.S. clinical community to provide better-focused and better-coordinated care for patients at risk for developing or having NAFLD or NASH, particularly among “emerging” at-risk cohorts such as patients with diabetes and obesity. It appears in the journals Gastroenterology, Diabetes Care, Metabolism: Clinical and Experimental, and Obesity.

The statement’s central pitch is that improvements in care won’t be possible unless the several medical specialties that deal with affected or at-risk patients stop working “in separate silos,” and instead create “a collective action plan,” and also organize multidisciplinary teams that “integrate primary care, hepatology, obesity medicine, endocrinology, and diabetology via well-defined care pathways.”

“The overarching goal” is a “unified, international public health response to NAFLD and NASH,” said the statement, which stemmed from a conference held in July 2020 that included representatives from not only the lead gastroenterology group but also the American Diabetes Association, the American Association for the Study of Liver Diseases, the American Association of Clinical Endocrinologists, The Endocrine Society, The American Academy of Family Physicians, The Obesity Society, and the American College of Osteopathic Family Physicians.

The statement cites sobering prevalence numbers, with estimates that NAFLD exists in more than half the patients with type 2 diabetes, while NASH affects about a third, rates that translate into many millions of affected Americans, given recent estimates that the U.S. prevalence of type 2 diabetes exceeds 30 million people. And the numbers continue to rise along with increases in the prevalence of obesity and type 2 diabetes.

“It’s an enormously common disease, and there are not enough gastroenterologists, to say nothing of hepatologists, to care for every patient with NAFLD,” said Anna Mae Diehl, MD, a gastroenterologist and professor at Duke University in Durham, N.C., who was not involved with the conference nor in writing the statement.

Clinical care pathways coming soon

Another key part of this initiative is development of clinical care pathways that will have “careful explication of each step in screening, diagnosis, and treatment,” and will be designed to inform the practice of primary care physicians (PCPs) as well as clinicians from the various specialties that deal with these patients.

The clinical care pathways are on track to come out later in 2021, said Fasiha Kanwal, MD, a professor and chief of gastroenterology at Baylor College of Medicine in Houston, and lead author on the Call to Action document.

“The Pathways will include practical recommendations about whom to screen and when to refer, and the criteria primary care physicians can use for diagnosis and risk stratification,” Dr. Kanwal said in an interview. “Patients can benefit from a standardized approach.”

The new document also includes results from a recent survey about NAFLD and NASH management completed by 751 U.S. physicians, including 401 (53%) primary care physicians, 175 gastroenterologists, (23%) and 175 endocrinologists (23%; percentages total 99% because of rounding).

The results showed “significant gaps in knowledge about whom to screen and how to diagnose and treat patients at high risk for NASH,” concluded the statement’s authors. Barely more than a third of the respondents knew that almost all patients with severe obesity likely have NAFLD, and fewer than half the endocrinologists and the primary care physicians appreciated that NAFLD is very common among patients with type 2 diabetes.
 

‘Understanding of NAFLD is not there’

“I applaud this effort that calls attention to an emerging public health problem. This paper and survey are great ideas. The findings are not surprising, but they’re important,” said Dr. Diehl said in an interview. “Much more needs to be done” including changes in social behavior and government policies.

“The public’s understanding of NAFLD is not there,” and many physicians also have an incomplete understanding of NAFLD and more serious stages of metabolic liver disease. “Physicians know that patients with obesity are at risk for heart disease, diabetes, and stroke, but they may not always be aware that these patients can also have cirrhosis,” noted Dr. Diehl, who published in 2019 a call to action for NAFLD of her own with some associates.

“My referrals are fueled by primary care physicians who recognize patients with significant liver disease. It would be great to outline recommended practice; I have no doubt that providers will embrace this,” as well as the broader concept of multidisciplinary teams, another focus of the statement. Dr. Diehl cited the “Cancer Center model,” where an oncologist takes primary responsibility for caring for a cancer patient while coordinating care with other specialists, an approach facilitated by EMRs that allow seamless data and chart sharing and something that many health systems have either already adopted or are moving toward.

She said the NASH Call to Action may help catalyze broader application of this model to many more patients with NAFLD or NASH, and noted that some U.S. centers already use this approach – including Dr. Diehl’s program at Duke – which brings together her gastroenterology colleagues with cardiologists, radiologists, endocrinologists, and bariatric surgeons. But she noted that for most patients with metabolic liver disease, the hub clinician needs to be a PCP, especially for patients with earlier-stage disease, because the number of affected patients is so huge.

“Key steps toward establishing such teams include establishing protocols for risk stratification and referral, definition of roles and responsibilities, and buy-in from institutions and payers. Clearly a lot of work needs to occur to get to these multidisciplinary teams,” said Dr. Kanwal.

Ralph A. DeFronzo, MD, professor and deputy director of the Texas Diabetes Institute at UT Health San Antonio, who was not involved with the conference or statement, had a different take on what the future of NASH and NAFLD care may look like.

“Endocrinologists, hepatologists, and obesity experts will work within their individual specialties to diagnose and manage NASH,” he said in an interview. But he acknowledged that “an integrated effort by specialists would be important” to help “primary care physicians who are less familiar with the disease.”
 

Controversy over pioglitazone?

Dr. DeFronzo endorsed development of clinical care pathways as “important,” but also as a potential source of “controversy, especially with respect to treatment.”

The Call to Action statement cites lifestyle-based therapies, such as an appropriate diet; regular, moderate exercise; and elimination when possible of obesogenic medications as cornerstone interventions for patients with NAFLD or early-stage NASH, interventions that can be prescribed by PCPs. For patients with NASH and stage 2 or worse fibrosis, the statement endorses liver-directed pharmacotherapy. While noting that no agents currently carry a Food and Drug Administration–approved indication for treating NASH, the statement cites evidence that 800 IU/day of vitamin E improves steatosis in patients with NASH but not type 2 diabetes.

For patients with type 2 diabetes, the statement notes that results from five randomized trials indicated that pioglitazone could reverse steatohepatitis, findings that led to its recommendation in guidelines from a modest circle of medical groups, including the American Association for the Study of Liver Diseases and the European Association for the Study of Diabetes. However, the 2021 Standards of Medical Care in Diabetes from the American Diabetes Association gives these agents limited endorsement, saying: “Pioglitazone, vitamin E treatment, and liraglutide treatment of biopsy-proven nonalcoholic steatohepatitis have each been shown to improve liver histology, but effects on longer-term clinical outcomes are not known.”

“The strongest evidence by far is for pioglitazone for treating NAFLD and NASH,” said Dr. DeFronzo, a vocal proponent of the drug for this indication. But he added that “hepatologists don’t feel comfortable with drugs from the thiazolidinedione class,” which includes pioglitazone.

“We don’t yet know how to optimally configure the health system for NAFLD and NASH to make it more efficient and helpful to patients, but models exist, and the approach is evolving,” said Dr. Diehl.

Dr. Diehl and Dr. Kanwal had no relevant disclosures. Dr. DeFronzo has been a speaker on behalf of AstraZeneca and Novo Nordisk, has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, and Janssen, and has received research funding from AstraZeneca, Janssen and Merck.

[email protected]

A multidisciplinary panel of U.S. experts released a “Call to Action” for improved screening, diagnosis, and treatment of patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) on July 26, an effort organized by the American Gastroenterological Association in collaboration with seven other U.S. medical organizations including several endocrinology groups.

The published statement, “Preparing for the NASH Epidemic: A Call to Action,” proposes several urgent steps for the U.S. clinical community to provide better-focused and better-coordinated care for patients at risk for developing or having NAFLD or NASH, particularly among “emerging” at-risk cohorts such as patients with diabetes and obesity. It appears in the journals Gastroenterology, Diabetes Care, Metabolism: Clinical and Experimental, and Obesity.

The statement’s central pitch is that improvements in care won’t be possible unless the several medical specialties that deal with affected or at-risk patients stop working “in separate silos,” and instead create “a collective action plan,” and also organize multidisciplinary teams that “integrate primary care, hepatology, obesity medicine, endocrinology, and diabetology via well-defined care pathways.”

“The overarching goal” is a “unified, international public health response to NAFLD and NASH,” said the statement, which stemmed from a conference held in July 2020 that included representatives from not only the lead gastroenterology group but also the American Diabetes Association, the American Association for the Study of Liver Diseases, the American Association of Clinical Endocrinologists, The Endocrine Society, The American Academy of Family Physicians, The Obesity Society, and the American College of Osteopathic Family Physicians.

The statement cites sobering prevalence numbers, with estimates that NAFLD exists in more than half the patients with type 2 diabetes, while NASH affects about a third, rates that translate into many millions of affected Americans, given recent estimates that the U.S. prevalence of type 2 diabetes exceeds 30 million people. And the numbers continue to rise along with increases in the prevalence of obesity and type 2 diabetes.

“It’s an enormously common disease, and there are not enough gastroenterologists, to say nothing of hepatologists, to care for every patient with NAFLD,” said Anna Mae Diehl, MD, a gastroenterologist and professor at Duke University in Durham, N.C., who was not involved with the conference nor in writing the statement.

Clinical care pathways coming soon

Another key part of this initiative is development of clinical care pathways that will have “careful explication of each step in screening, diagnosis, and treatment,” and will be designed to inform the practice of primary care physicians (PCPs) as well as clinicians from the various specialties that deal with these patients.

The clinical care pathways are on track to come out later in 2021, said Fasiha Kanwal, MD, a professor and chief of gastroenterology at Baylor College of Medicine in Houston, and lead author on the Call to Action document.

“The Pathways will include practical recommendations about whom to screen and when to refer, and the criteria primary care physicians can use for diagnosis and risk stratification,” Dr. Kanwal said in an interview. “Patients can benefit from a standardized approach.”

The new document also includes results from a recent survey about NAFLD and NASH management completed by 751 U.S. physicians, including 401 (53%) primary care physicians, 175 gastroenterologists, (23%) and 175 endocrinologists (23%; percentages total 99% because of rounding).

The results showed “significant gaps in knowledge about whom to screen and how to diagnose and treat patients at high risk for NASH,” concluded the statement’s authors. Barely more than a third of the respondents knew that almost all patients with severe obesity likely have NAFLD, and fewer than half the endocrinologists and the primary care physicians appreciated that NAFLD is very common among patients with type 2 diabetes.
 

‘Understanding of NAFLD is not there’

“I applaud this effort that calls attention to an emerging public health problem. This paper and survey are great ideas. The findings are not surprising, but they’re important,” said Dr. Diehl said in an interview. “Much more needs to be done” including changes in social behavior and government policies.

“The public’s understanding of NAFLD is not there,” and many physicians also have an incomplete understanding of NAFLD and more serious stages of metabolic liver disease. “Physicians know that patients with obesity are at risk for heart disease, diabetes, and stroke, but they may not always be aware that these patients can also have cirrhosis,” noted Dr. Diehl, who published in 2019 a call to action for NAFLD of her own with some associates.

“My referrals are fueled by primary care physicians who recognize patients with significant liver disease. It would be great to outline recommended practice; I have no doubt that providers will embrace this,” as well as the broader concept of multidisciplinary teams, another focus of the statement. Dr. Diehl cited the “Cancer Center model,” where an oncologist takes primary responsibility for caring for a cancer patient while coordinating care with other specialists, an approach facilitated by EMRs that allow seamless data and chart sharing and something that many health systems have either already adopted or are moving toward.

She said the NASH Call to Action may help catalyze broader application of this model to many more patients with NAFLD or NASH, and noted that some U.S. centers already use this approach – including Dr. Diehl’s program at Duke – which brings together her gastroenterology colleagues with cardiologists, radiologists, endocrinologists, and bariatric surgeons. But she noted that for most patients with metabolic liver disease, the hub clinician needs to be a PCP, especially for patients with earlier-stage disease, because the number of affected patients is so huge.

“Key steps toward establishing such teams include establishing protocols for risk stratification and referral, definition of roles and responsibilities, and buy-in from institutions and payers. Clearly a lot of work needs to occur to get to these multidisciplinary teams,” said Dr. Kanwal.

Ralph A. DeFronzo, MD, professor and deputy director of the Texas Diabetes Institute at UT Health San Antonio, who was not involved with the conference or statement, had a different take on what the future of NASH and NAFLD care may look like.

“Endocrinologists, hepatologists, and obesity experts will work within their individual specialties to diagnose and manage NASH,” he said in an interview. But he acknowledged that “an integrated effort by specialists would be important” to help “primary care physicians who are less familiar with the disease.”
 

Controversy over pioglitazone?

Dr. DeFronzo endorsed development of clinical care pathways as “important,” but also as a potential source of “controversy, especially with respect to treatment.”

The Call to Action statement cites lifestyle-based therapies, such as an appropriate diet; regular, moderate exercise; and elimination when possible of obesogenic medications as cornerstone interventions for patients with NAFLD or early-stage NASH, interventions that can be prescribed by PCPs. For patients with NASH and stage 2 or worse fibrosis, the statement endorses liver-directed pharmacotherapy. While noting that no agents currently carry a Food and Drug Administration–approved indication for treating NASH, the statement cites evidence that 800 IU/day of vitamin E improves steatosis in patients with NASH but not type 2 diabetes.

For patients with type 2 diabetes, the statement notes that results from five randomized trials indicated that pioglitazone could reverse steatohepatitis, findings that led to its recommendation in guidelines from a modest circle of medical groups, including the American Association for the Study of Liver Diseases and the European Association for the Study of Diabetes. However, the 2021 Standards of Medical Care in Diabetes from the American Diabetes Association gives these agents limited endorsement, saying: “Pioglitazone, vitamin E treatment, and liraglutide treatment of biopsy-proven nonalcoholic steatohepatitis have each been shown to improve liver histology, but effects on longer-term clinical outcomes are not known.”

“The strongest evidence by far is for pioglitazone for treating NAFLD and NASH,” said Dr. DeFronzo, a vocal proponent of the drug for this indication. But he added that “hepatologists don’t feel comfortable with drugs from the thiazolidinedione class,” which includes pioglitazone.

“We don’t yet know how to optimally configure the health system for NAFLD and NASH to make it more efficient and helpful to patients, but models exist, and the approach is evolving,” said Dr. Diehl.

Dr. Diehl and Dr. Kanwal had no relevant disclosures. Dr. DeFronzo has been a speaker on behalf of AstraZeneca and Novo Nordisk, has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, and Janssen, and has received research funding from AstraZeneca, Janssen and Merck.

[email protected]

Busting the myth of skipping breakfast

Your mother told you that breakfast was the most important meal of the day. Cereal marketing teams banked on that, selling breakfast to millions of people based on a common turn of phrase like “an apple a day keeps the doctor away.” Well, what if the notion of breakfast’s importance isn’t just marketing BS?

NorthStar203/iStock/Getty Images Plus

A new study suggests that adults who don’t eat breakfast are setting themselves up for a nutritional gap. Common breakfast foods pack a ton of calcium, fiber, and vitamin C from milk, cereals, and fruit. Christopher Taylor, PhD, senior author of the study and professor of dietetics at the Ohio State University, Columbus, said that if you’re not getting those nutrients from foods at breakfast, there’s a tendency to skip them throughout the rest of your day.

Data from a sample of the National Health and Nutrition Examination Survey – 30,889 adults aged 19 and older who participated between 2005 and 2016 – showed that 15.2% of participants reported skipping breakfast.

The research team then estimated nutrient consumption using federal dietary studies and guidelines and compared it to Food and Nutrition Board of National Academies nutrient recommendations. The breakfast skippers, they determined, were missing out on pronounced levels of fiber, magnesium, iron, calcium, and vitamins A, B₁, B₂, B₃, C, and D and were more likely to fall prey to lower-quality snacking. Cue those Oreos at 3 pm.

You may get more total calories within the day by eating breakfast, but your lunch, dinner, and snacks are much larger when you skip it. So the case of breakfast being the most important meal of the day checks out. Who knew that Tony the Tiger – and Mom – were actually on to something?
 

The bitter taste of a healthy liver

Alcohol and liver disease. They go together like, well, alcohol and liver disease. But alcohol isn’t the only reason people get liver disease, and now there’s a potential new treatment for people with hepatic steatosis on the way to becoming nonalcoholic fatty liver disease: beer.

Okay, not literally beer, but a pair of compounds derived from hops, the plant that gives beer its color and bitter flavor. In a study published in eLife, researchers from Oregon State University fed mice either a low-fat diet or a high-fat diet to induce hepatic steatosis, with some on the high-fat diet receiving either xanthohumol, a prenylated flavonoid from the hop plant, or tetrahydroxanthohumol, a hydrogenated derivative of xanthohumol.

Courtesy Oregon State University

Life’s great mysteries, from A to zinc

Thanks to science, we now have answers to what were once unanswerable questions: Is Jello a solid or a liquid? If someone leads but no one follows, are they just out for a walk? Does zinc inhibit or promote the growth of kidney stones? How many licks does it take to get to the center of a Tootsie Pop? (Turns out science really did answer this one.)

If you’re anything like us, then you’ve been following the big debate on the two competing theories involving the role of zinc in kidney stone formation for years. One theory says that zinc stops the growth of calcium oxalate crystals that make up stones. The other says that zinc alters the surfaces of crystals, which encourages growth.

We can’t stand the suspense any longer, so here goes: The answer to “does zinc inhibit or promote the growth of kidney stones?” is … yes.

decade3d/Thinkstock

Babies’ ‘gut instinct’ to cry

At some point or another, you’ve probably been told not to “be such a baby” when you were scared of something. If you’ve been called a crybaby, it may be an indicator that you had a different gut microbiome as an infant.

Investigators from Michigan State University and the University of North Carolina say that babies who react more strongly to scary situations have different gut microbiomes compared with babies who don’t have such a strong reaction. The way babies react to scary situations can say a lot about their future, and there is even some evidence that gut microbiomes may have something to do with mental health.

©a-fitz/iStockphoto.com

Busting the myth of skipping breakfast

Your mother told you that breakfast was the most important meal of the day. Cereal marketing teams banked on that, selling breakfast to millions of people based on a common turn of phrase like “an apple a day keeps the doctor away.” Well, what if the notion of breakfast’s importance isn’t just marketing BS?

NorthStar203/iStock/Getty Images Plus

A new study suggests that adults who don’t eat breakfast are setting themselves up for a nutritional gap. Common breakfast foods pack a ton of calcium, fiber, and vitamin C from milk, cereals, and fruit. Christopher Taylor, PhD, senior author of the study and professor of dietetics at the Ohio State University, Columbus, said that if you’re not getting those nutrients from foods at breakfast, there’s a tendency to skip them throughout the rest of your day.

Data from a sample of the National Health and Nutrition Examination Survey – 30,889 adults aged 19 and older who participated between 2005 and 2016 – showed that 15.2% of participants reported skipping breakfast.

The research team then estimated nutrient consumption using federal dietary studies and guidelines and compared it to Food and Nutrition Board of National Academies nutrient recommendations. The breakfast skippers, they determined, were missing out on pronounced levels of fiber, magnesium, iron, calcium, and vitamins A, B₁, B₂, B₃, C, and D and were more likely to fall prey to lower-quality snacking. Cue those Oreos at 3 pm.

You may get more total calories within the day by eating breakfast, but your lunch, dinner, and snacks are much larger when you skip it. So the case of breakfast being the most important meal of the day checks out. Who knew that Tony the Tiger – and Mom – were actually on to something?
 

The bitter taste of a healthy liver

Alcohol and liver disease. They go together like, well, alcohol and liver disease. But alcohol isn’t the only reason people get liver disease, and now there’s a potential new treatment for people with hepatic steatosis on the way to becoming nonalcoholic fatty liver disease: beer.

Okay, not literally beer, but a pair of compounds derived from hops, the plant that gives beer its color and bitter flavor. In a study published in eLife, researchers from Oregon State University fed mice either a low-fat diet or a high-fat diet to induce hepatic steatosis, with some on the high-fat diet receiving either xanthohumol, a prenylated flavonoid from the hop plant, or tetrahydroxanthohumol, a hydrogenated derivative of xanthohumol.

Courtesy Oregon State University

Life’s great mysteries, from A to zinc

Thanks to science, we now have answers to what were once unanswerable questions: Is Jello a solid or a liquid? If someone leads but no one follows, are they just out for a walk? Does zinc inhibit or promote the growth of kidney stones? How many licks does it take to get to the center of a Tootsie Pop? (Turns out science really did answer this one.)

If you’re anything like us, then you’ve been following the big debate on the two competing theories involving the role of zinc in kidney stone formation for years. One theory says that zinc stops the growth of calcium oxalate crystals that make up stones. The other says that zinc alters the surfaces of crystals, which encourages growth.

We can’t stand the suspense any longer, so here goes: The answer to “does zinc inhibit or promote the growth of kidney stones?” is … yes.

decade3d/Thinkstock

Babies’ ‘gut instinct’ to cry

At some point or another, you’ve probably been told not to “be such a baby” when you were scared of something. If you’ve been called a crybaby, it may be an indicator that you had a different gut microbiome as an infant.

Investigators from Michigan State University and the University of North Carolina say that babies who react more strongly to scary situations have different gut microbiomes compared with babies who don’t have such a strong reaction. The way babies react to scary situations can say a lot about their future, and there is even some evidence that gut microbiomes may have something to do with mental health.

©a-fitz/iStockphoto.com

Busting the myth of skipping breakfast

Your mother told you that breakfast was the most important meal of the day. Cereal marketing teams banked on that, selling breakfast to millions of people based on a common turn of phrase like “an apple a day keeps the doctor away.” Well, what if the notion of breakfast’s importance isn’t just marketing BS?

NorthStar203/iStock/Getty Images Plus

A new study suggests that adults who don’t eat breakfast are setting themselves up for a nutritional gap. Common breakfast foods pack a ton of calcium, fiber, and vitamin C from milk, cereals, and fruit. Christopher Taylor, PhD, senior author of the study and professor of dietetics at the Ohio State University, Columbus, said that if you’re not getting those nutrients from foods at breakfast, there’s a tendency to skip them throughout the rest of your day.

Data from a sample of the National Health and Nutrition Examination Survey – 30,889 adults aged 19 and older who participated between 2005 and 2016 – showed that 15.2% of participants reported skipping breakfast.

The research team then estimated nutrient consumption using federal dietary studies and guidelines and compared it to Food and Nutrition Board of National Academies nutrient recommendations. The breakfast skippers, they determined, were missing out on pronounced levels of fiber, magnesium, iron, calcium, and vitamins A, B₁, B₂, B₃, C, and D and were more likely to fall prey to lower-quality snacking. Cue those Oreos at 3 pm.

You may get more total calories within the day by eating breakfast, but your lunch, dinner, and snacks are much larger when you skip it. So the case of breakfast being the most important meal of the day checks out. Who knew that Tony the Tiger – and Mom – were actually on to something?
 

The bitter taste of a healthy liver

Alcohol and liver disease. They go together like, well, alcohol and liver disease. But alcohol isn’t the only reason people get liver disease, and now there’s a potential new treatment for people with hepatic steatosis on the way to becoming nonalcoholic fatty liver disease: beer.

Okay, not literally beer, but a pair of compounds derived from hops, the plant that gives beer its color and bitter flavor. In a study published in eLife, researchers from Oregon State University fed mice either a low-fat diet or a high-fat diet to induce hepatic steatosis, with some on the high-fat diet receiving either xanthohumol, a prenylated flavonoid from the hop plant, or tetrahydroxanthohumol, a hydrogenated derivative of xanthohumol.

Courtesy Oregon State University

Life’s great mysteries, from A to zinc

Thanks to science, we now have answers to what were once unanswerable questions: Is Jello a solid or a liquid? If someone leads but no one follows, are they just out for a walk? Does zinc inhibit or promote the growth of kidney stones? How many licks does it take to get to the center of a Tootsie Pop? (Turns out science really did answer this one.)

If you’re anything like us, then you’ve been following the big debate on the two competing theories involving the role of zinc in kidney stone formation for years. One theory says that zinc stops the growth of calcium oxalate crystals that make up stones. The other says that zinc alters the surfaces of crystals, which encourages growth.

We can’t stand the suspense any longer, so here goes: The answer to “does zinc inhibit or promote the growth of kidney stones?” is … yes.

decade3d/Thinkstock

Babies’ ‘gut instinct’ to cry

At some point or another, you’ve probably been told not to “be such a baby” when you were scared of something. If you’ve been called a crybaby, it may be an indicator that you had a different gut microbiome as an infant.

Investigators from Michigan State University and the University of North Carolina say that babies who react more strongly to scary situations have different gut microbiomes compared with babies who don’t have such a strong reaction. The way babies react to scary situations can say a lot about their future, and there is even some evidence that gut microbiomes may have something to do with mental health.

©a-fitz/iStockphoto.com

A third dose of a COVID-19 vaccine can boost antibody levels in people who previously received a solid organ transplant and had an unsatisfactory response to their first two mRNA shots, according to data from a newly published 30-patient case series.

All of those with low titers before the third dose had high titers after receiving the additional shot, but only about 33% of those with negative initial responses had detectable antibodies after the third dose, according to the paper, published in Annals of Internal Medicine.

Researchers at Johns Hopkins, Baltimore, who keep a COVID-19 vaccine registry, perform antibody tests on all registry subjects and inform them of their results. Registry participants were asked to inform the research team if they received a third dose, and, the research team tracked the immune responses of those who did.

The participants in this case series had low antibody levels and received a third dose of the vaccine on their own between March 20 and May 10 of 2021.
 

Third dose results

In this cases series – thought to be the first to look at third vaccine shots in this type of patient group – all six of those who had low antibody titers before the third dose had high-positive titers after the third dose.

Of the 24 individuals who had negative antibody titers before the third dose, just 6 had high titers after the third dose.

Two of the participants had low-positive titers, and 16 were negative.

“Several of those boosted very nicely into ranges seen, using these assays, in healthy persons,” said William Werbel, MD, a fellow in infectious disease at Johns Hopkins Medicine, Baltimore, who helped lead the study. Those with negative levels, even if they responded, tended to have lower titers, he said.

“The benefits at least from an antibody perspective were not the same for everybody and so this is obviously something that needs to be considered when thinking about selecting patients” for a COVID-19 prevention strategy, he said.

Reactions to the vaccine were low to moderate, such as some arm pain and fatigue.

“Showing that something is safe in that special, vulnerable population is important,” Dr. Werbel said. “We’re all wanting to make sure that we’re doing no harm.”

Dr. Werbel noted that there was no pattern in the small series based on the organ transplanted or in the vaccines used. As their third shot, 15 of the patients received the Johnson & Johnson vaccine; 9 received Moderna; and 6 received Pfizer-BioNTech.
 

Welcome news, but larger studies needed

“To think that a third dose could confer protection for a significant number of people is of course extremely welcome news,” said Christian Larsen, MD, DPhil, professor of surgery in the transplantation division at Emory University, Atlanta, who was not involved in the study. “It’s the easiest conceivable next intervention.”

He added, “We just want studies to confirm that – larger studies.”

Dr. Werbel stressed the importance of looking at third doses in these patients in a more controlled fashion in a randomized trial, to more carefully monitor safety and how patients fare when starting with one type of vaccine and switching to another, for example.

Richard Wender, MD, chair of family medicine and community health at the University of Pennsylvania, Philadelphia, said the findings are a reminder that there is still a lot that is unknown about COVID-19 and vaccination.

“We still don’t know who will or will not benefit from a third dose,” he said. “And our knowledge is evolving.  For example, a recent study suggested that people with previous infection and who are vaccinated may have better and longer protection than people with vaccination alone. We’re still learning.”

He added that specialists, not primary care clinicians, should be relied upon to respond to this emerging vaccination data. Primary care doctors are very busy in other ways – such as in getting children caught up on vaccinations and helping adults return to managing their chronic diseases, Dr. Wender noted.

“Their focus needs to be on helping to overcome hesitancy, mistrust, lack of information, or antivaccination sentiment to help more people feel comfortable being vaccinated – this is a lot of work and needs constant focus. In short, primary care clinicians need to focus chiefly on the unvaccinated,” he said.

“Monitoring immunization recommendations for unique at-risk populations should be the chief responsibility of teams providing subspecialty care, [such as for] transplant patients, people with chronic kidney disease, cancer patients, and people with other chronic illnesses.  This will allow primary care clinicians to tackle their many complex jobs.”
 

Possible solutions for those with low antibody responses

Dr. Larsen said that those with ongoing low antibody responses might still have other immune responses, such as a T-cell response. Such patients also could consider changing their vaccine type, he said.

“At the more significant intervention level, there may be circumstances where one could change the immunosuppressive drugs in a controlled way that might allow a better response,” suggested Dr. Larsen. “That’s obviously going to be something that requires a lot more thought and careful study.”

Dr. Werbel said that other options might need to be considered for those having no response following a third dose. One possibility is trying a vaccine with an adjuvant, such as the Novavax version, which might be more widely available soon.

“If you’re given a third dose of a very immunogenic vaccine – something that should work – and you just have no antibody development, it seems relatively unlikely that doing the same thing again is going to help you from that perspective, and for all we know might expose you to more risk,” Dr. Werbel noted.
 

Participant details

None of the 30 patients were thought to have ever had COVID-19. On average, patients had received their transplant 4.5 years before their original vaccination. In 25 patients, maintenance immunosuppression included tacrolimus or cyclosporine along with mycophenolate. Corticosteroids were also used for 24 patients, sirolimus was used for one patient, and belatacept was used for another patient.

Fifty-seven percent of patients had received the Pfizer/BioNTech vaccine originally, and 43% the Moderna vaccine. Most of the patients were kidney recipients, with two heart, three liver, one lung, one pancreas and one kidney-pancreas.

Dr. Werbel, Dr. Wender, and Dr. Larsen reported no relevant disclosures.

A third dose of a COVID-19 vaccine can boost antibody levels in people who previously received a solid organ transplant and had an unsatisfactory response to their first two mRNA shots, according to data from a newly published 30-patient case series.

All of those with low titers before the third dose had high titers after receiving the additional shot, but only about 33% of those with negative initial responses had detectable antibodies after the third dose, according to the paper, published in Annals of Internal Medicine.

Researchers at Johns Hopkins, Baltimore, who keep a COVID-19 vaccine registry, perform antibody tests on all registry subjects and inform them of their results. Registry participants were asked to inform the research team if they received a third dose, and, the research team tracked the immune responses of those who did.

The participants in this case series had low antibody levels and received a third dose of the vaccine on their own between March 20 and May 10 of 2021.
 

Third dose results

In this cases series – thought to be the first to look at third vaccine shots in this type of patient group – all six of those who had low antibody titers before the third dose had high-positive titers after the third dose.

Of the 24 individuals who had negative antibody titers before the third dose, just 6 had high titers after the third dose.

Two of the participants had low-positive titers, and 16 were negative.

“Several of those boosted very nicely into ranges seen, using these assays, in healthy persons,” said William Werbel, MD, a fellow in infectious disease at Johns Hopkins Medicine, Baltimore, who helped lead the study. Those with negative levels, even if they responded, tended to have lower titers, he said.

“The benefits at least from an antibody perspective were not the same for everybody and so this is obviously something that needs to be considered when thinking about selecting patients” for a COVID-19 prevention strategy, he said.

Reactions to the vaccine were low to moderate, such as some arm pain and fatigue.

“Showing that something is safe in that special, vulnerable population is important,” Dr. Werbel said. “We’re all wanting to make sure that we’re doing no harm.”

Dr. Werbel noted that there was no pattern in the small series based on the organ transplanted or in the vaccines used. As their third shot, 15 of the patients received the Johnson & Johnson vaccine; 9 received Moderna; and 6 received Pfizer-BioNTech.
 

Welcome news, but larger studies needed

“To think that a third dose could confer protection for a significant number of people is of course extremely welcome news,” said Christian Larsen, MD, DPhil, professor of surgery in the transplantation division at Emory University, Atlanta, who was not involved in the study. “It’s the easiest conceivable next intervention.”

He added, “We just want studies to confirm that – larger studies.”

Dr. Werbel stressed the importance of looking at third doses in these patients in a more controlled fashion in a randomized trial, to more carefully monitor safety and how patients fare when starting with one type of vaccine and switching to another, for example.

Richard Wender, MD, chair of family medicine and community health at the University of Pennsylvania, Philadelphia, said the findings are a reminder that there is still a lot that is unknown about COVID-19 and vaccination.

“We still don’t know who will or will not benefit from a third dose,” he said. “And our knowledge is evolving.  For example, a recent study suggested that people with previous infection and who are vaccinated may have better and longer protection than people with vaccination alone. We’re still learning.”

He added that specialists, not primary care clinicians, should be relied upon to respond to this emerging vaccination data. Primary care doctors are very busy in other ways – such as in getting children caught up on vaccinations and helping adults return to managing their chronic diseases, Dr. Wender noted.

“Their focus needs to be on helping to overcome hesitancy, mistrust, lack of information, or antivaccination sentiment to help more people feel comfortable being vaccinated – this is a lot of work and needs constant focus. In short, primary care clinicians need to focus chiefly on the unvaccinated,” he said.

“Monitoring immunization recommendations for unique at-risk populations should be the chief responsibility of teams providing subspecialty care, [such as for] transplant patients, people with chronic kidney disease, cancer patients, and people with other chronic illnesses.  This will allow primary care clinicians to tackle their many complex jobs.”
 

Possible solutions for those with low antibody responses

Dr. Larsen said that those with ongoing low antibody responses might still have other immune responses, such as a T-cell response. Such patients also could consider changing their vaccine type, he said.

“At the more significant intervention level, there may be circumstances where one could change the immunosuppressive drugs in a controlled way that might allow a better response,” suggested Dr. Larsen. “That’s obviously going to be something that requires a lot more thought and careful study.”

Dr. Werbel said that other options might need to be considered for those having no response following a third dose. One possibility is trying a vaccine with an adjuvant, such as the Novavax version, which might be more widely available soon.

“If you’re given a third dose of a very immunogenic vaccine – something that should work – and you just have no antibody development, it seems relatively unlikely that doing the same thing again is going to help you from that perspective, and for all we know might expose you to more risk,” Dr. Werbel noted.
 

Participant details

None of the 30 patients were thought to have ever had COVID-19. On average, patients had received their transplant 4.5 years before their original vaccination. In 25 patients, maintenance immunosuppression included tacrolimus or cyclosporine along with mycophenolate. Corticosteroids were also used for 24 patients, sirolimus was used for one patient, and belatacept was used for another patient.

Fifty-seven percent of patients had received the Pfizer/BioNTech vaccine originally, and 43% the Moderna vaccine. Most of the patients were kidney recipients, with two heart, three liver, one lung, one pancreas and one kidney-pancreas.

Dr. Werbel, Dr. Wender, and Dr. Larsen reported no relevant disclosures.

A third dose of a COVID-19 vaccine can boost antibody levels in people who previously received a solid organ transplant and had an unsatisfactory response to their first two mRNA shots, according to data from a newly published 30-patient case series.

All of those with low titers before the third dose had high titers after receiving the additional shot, but only about 33% of those with negative initial responses had detectable antibodies after the third dose, according to the paper, published in Annals of Internal Medicine.

Researchers at Johns Hopkins, Baltimore, who keep a COVID-19 vaccine registry, perform antibody tests on all registry subjects and inform them of their results. Registry participants were asked to inform the research team if they received a third dose, and, the research team tracked the immune responses of those who did.

The participants in this case series had low antibody levels and received a third dose of the vaccine on their own between March 20 and May 10 of 2021.
 

Third dose results

In this cases series – thought to be the first to look at third vaccine shots in this type of patient group – all six of those who had low antibody titers before the third dose had high-positive titers after the third dose.

Of the 24 individuals who had negative antibody titers before the third dose, just 6 had high titers after the third dose.

Two of the participants had low-positive titers, and 16 were negative.

“Several of those boosted very nicely into ranges seen, using these assays, in healthy persons,” said William Werbel, MD, a fellow in infectious disease at Johns Hopkins Medicine, Baltimore, who helped lead the study. Those with negative levels, even if they responded, tended to have lower titers, he said.

“The benefits at least from an antibody perspective were not the same for everybody and so this is obviously something that needs to be considered when thinking about selecting patients” for a COVID-19 prevention strategy, he said.

Reactions to the vaccine were low to moderate, such as some arm pain and fatigue.

“Showing that something is safe in that special, vulnerable population is important,” Dr. Werbel said. “We’re all wanting to make sure that we’re doing no harm.”

Dr. Werbel noted that there was no pattern in the small series based on the organ transplanted or in the vaccines used. As their third shot, 15 of the patients received the Johnson & Johnson vaccine; 9 received Moderna; and 6 received Pfizer-BioNTech.
 

Welcome news, but larger studies needed

“To think that a third dose could confer protection for a significant number of people is of course extremely welcome news,” said Christian Larsen, MD, DPhil, professor of surgery in the transplantation division at Emory University, Atlanta, who was not involved in the study. “It’s the easiest conceivable next intervention.”

He added, “We just want studies to confirm that – larger studies.”

Dr. Werbel stressed the importance of looking at third doses in these patients in a more controlled fashion in a randomized trial, to more carefully monitor safety and how patients fare when starting with one type of vaccine and switching to another, for example.

Richard Wender, MD, chair of family medicine and community health at the University of Pennsylvania, Philadelphia, said the findings are a reminder that there is still a lot that is unknown about COVID-19 and vaccination.

“We still don’t know who will or will not benefit from a third dose,” he said. “And our knowledge is evolving.  For example, a recent study suggested that people with previous infection and who are vaccinated may have better and longer protection than people with vaccination alone. We’re still learning.”

He added that specialists, not primary care clinicians, should be relied upon to respond to this emerging vaccination data. Primary care doctors are very busy in other ways – such as in getting children caught up on vaccinations and helping adults return to managing their chronic diseases, Dr. Wender noted.

“Their focus needs to be on helping to overcome hesitancy, mistrust, lack of information, or antivaccination sentiment to help more people feel comfortable being vaccinated – this is a lot of work and needs constant focus. In short, primary care clinicians need to focus chiefly on the unvaccinated,” he said.

“Monitoring immunization recommendations for unique at-risk populations should be the chief responsibility of teams providing subspecialty care, [such as for] transplant patients, people with chronic kidney disease, cancer patients, and people with other chronic illnesses.  This will allow primary care clinicians to tackle their many complex jobs.”
 

Possible solutions for those with low antibody responses

Dr. Larsen said that those with ongoing low antibody responses might still have other immune responses, such as a T-cell response. Such patients also could consider changing their vaccine type, he said.

“At the more significant intervention level, there may be circumstances where one could change the immunosuppressive drugs in a controlled way that might allow a better response,” suggested Dr. Larsen. “That’s obviously going to be something that requires a lot more thought and careful study.”

Dr. Werbel said that other options might need to be considered for those having no response following a third dose. One possibility is trying a vaccine with an adjuvant, such as the Novavax version, which might be more widely available soon.

“If you’re given a third dose of a very immunogenic vaccine – something that should work – and you just have no antibody development, it seems relatively unlikely that doing the same thing again is going to help you from that perspective, and for all we know might expose you to more risk,” Dr. Werbel noted.
 

Participant details

None of the 30 patients were thought to have ever had COVID-19. On average, patients had received their transplant 4.5 years before their original vaccination. In 25 patients, maintenance immunosuppression included tacrolimus or cyclosporine along with mycophenolate. Corticosteroids were also used for 24 patients, sirolimus was used for one patient, and belatacept was used for another patient.

Fifty-seven percent of patients had received the Pfizer/BioNTech vaccine originally, and 43% the Moderna vaccine. Most of the patients were kidney recipients, with two heart, three liver, one lung, one pancreas and one kidney-pancreas.

Dr. Werbel, Dr. Wender, and Dr. Larsen reported no relevant disclosures.

It follows that, as the prevalence of obesity among people with type 1 diabetes mellitus (T1DM) increases, so would the incidence of nonalcoholic fatty liver (NAFL), as it does in type 2 diabetes.

However, researchers in Finland report that the incidence of NAFL in T1DM is much lower, and that the use of the waist-to-height ratio to calculate midsection girth could be a low-cost alternative to MRI and computed tomography to more precisely diagnose NAFL in T1DM.

In a cross-sectional analysis of 121 adults with T1DM in the Finnish Diabetic Nephropathy study, known as FinnDiane, researchers from the University of Helsinki report in Diabetes Care that a waist-to-height ratio of 0.5 showed a relatively high rate of accuracy for identifying NAFL that was statistically significant (P = .04).

Lead author Erika B. Parente, MD, PhD, a researcher at the Folkhälsän Research Center in Helsinki, noted that the findings do not identify any causality between what the researchers called visceral adiposity and NAFL. “As long as they have accumulation of fat in the center of body and they can develop this low-grade inflammation that also goes to insulin-load sensitivity, people with T1DM can accumulate fat in the liver as do people with T2DM and the general population,” she said in an interview.

These findings build on her group’s previous work published in Scientific Reports showing a strong relationship between waist-to-height ratio and visceral fat percentage in adults with T1DM. The most recent FinnDiane analysis found no similar relationship between NAFL and fat tissue in the hips, arms and legs, and total adipose tissue.
 

Better than BMI as a measure

“We also found that waist-to-height ratio is better than body mass index to identify those individuals at higher risk of having NAFL,” Dr. Parente said. However, it’s not possible to predict which patients referred to imaging evaluation after being screened by waist-to-height ratio of 0.5 will surely have NAFL, she added.

That answer, she said, would require a longitudinal and cost-effectiveness study with larger population.

The waist-to-height ratio cutoff of 0.5 showed an 86% sensitivity and 55% specificity for NAFL, whereas BMI of 26.6 kg/m² showed an 79% sensitivity and 57% specificity.

“The most important message from our research is that health care professionals should be aware that individuals with T1DM can have NAFL, and waist-to-height ratio may help to identify those at higher risk,” she said.

The prevalence of NAFL among the adults with T1DM in the study was 11.6%, which is lower than the prevalence other studies reported in T2DM – 76% in a U.S. study – and in the general population – ranging from 19% to 46%. This underscores, Dr. Parente noted, the importance of using waist-to-height ratio in T1DM patients to determine the status of NAFL.

She said that few studies have investigated the consequences of NAFL in T1DM, pointing to two that linked NAFL with chronic kidney disease and cardiovascular disease in T1DM (Diabetes Care. 2014;37:1729-36; J Hepatol. 2010;53:713-8). “Most of the studies about the consequences of NAFL included people with T2DM,” she said. “From our research, we cannot conclude about the impact of NAFL in cardiovascular or kidney complications in our population because this is a cross-sectional study.”

That question may be answered by a future follow-up study of the ongoing FinnDiane study, she said.

The study is a “good reminder” that people with central adiposity and metabolic syndrome can develop NAFL disease, said Jeanne Marie Clark, MD, MPH, of Johns Hopkins University, Baltimore. “Even patients we may not think of having insulin resistance, such as those with T1DM.”

However, Dr. Clark added, “I do not think we can really determine which measure of central adiposity is best.” She noted that the study was “pretty small” with only 14 patients who had NAFL disease. “Waist-to-height ratio is certainly a reasonable option,” she added. “Waist circumference alone is known to be a strong predictor. I would say some measure is better than none, and it should be more routine in clinical practice.”

Dr. Parente disclosed financial relationships with Eli Lilly, Abbott, AstraZeneca, Sanofi, and Boehringer Ingelheim. Two of eight coauthors disclosed financial relationships with AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Elo Water, Fresenius, GE Healthcare, Medscape, Merck Sharpe and Dohme, Mundipharma, Novo Nordisk, Peer-Voice, Sanofi, and Sciarc. The remaining coauthors had no disclosures.

Dr. Clark had no disclosures.

It follows that, as the prevalence of obesity among people with type 1 diabetes mellitus (T1DM) increases, so would the incidence of nonalcoholic fatty liver (NAFL), as it does in type 2 diabetes.

However, researchers in Finland report that the incidence of NAFL in T1DM is much lower, and that the use of the waist-to-height ratio to calculate midsection girth could be a low-cost alternative to MRI and computed tomography to more precisely diagnose NAFL in T1DM.

In a cross-sectional analysis of 121 adults with T1DM in the Finnish Diabetic Nephropathy study, known as FinnDiane, researchers from the University of Helsinki report in Diabetes Care that a waist-to-height ratio of 0.5 showed a relatively high rate of accuracy for identifying NAFL that was statistically significant (P = .04).

Lead author Erika B. Parente, MD, PhD, a researcher at the Folkhälsän Research Center in Helsinki, noted that the findings do not identify any causality between what the researchers called visceral adiposity and NAFL. “As long as they have accumulation of fat in the center of body and they can develop this low-grade inflammation that also goes to insulin-load sensitivity, people with T1DM can accumulate fat in the liver as do people with T2DM and the general population,” she said in an interview.

These findings build on her group’s previous work published in Scientific Reports showing a strong relationship between waist-to-height ratio and visceral fat percentage in adults with T1DM. The most recent FinnDiane analysis found no similar relationship between NAFL and fat tissue in the hips, arms and legs, and total adipose tissue.
 

Better than BMI as a measure

“We also found that waist-to-height ratio is better than body mass index to identify those individuals at higher risk of having NAFL,” Dr. Parente said. However, it’s not possible to predict which patients referred to imaging evaluation after being screened by waist-to-height ratio of 0.5 will surely have NAFL, she added.

That answer, she said, would require a longitudinal and cost-effectiveness study with larger population.

The waist-to-height ratio cutoff of 0.5 showed an 86% sensitivity and 55% specificity for NAFL, whereas BMI of 26.6 kg/m² showed an 79% sensitivity and 57% specificity.

“The most important message from our research is that health care professionals should be aware that individuals with T1DM can have NAFL, and waist-to-height ratio may help to identify those at higher risk,” she said.

The prevalence of NAFL among the adults with T1DM in the study was 11.6%, which is lower than the prevalence other studies reported in T2DM – 76% in a U.S. study – and in the general population – ranging from 19% to 46%. This underscores, Dr. Parente noted, the importance of using waist-to-height ratio in T1DM patients to determine the status of NAFL.

She said that few studies have investigated the consequences of NAFL in T1DM, pointing to two that linked NAFL with chronic kidney disease and cardiovascular disease in T1DM (Diabetes Care. 2014;37:1729-36; J Hepatol. 2010;53:713-8). “Most of the studies about the consequences of NAFL included people with T2DM,” she said. “From our research, we cannot conclude about the impact of NAFL in cardiovascular or kidney complications in our population because this is a cross-sectional study.”

That question may be answered by a future follow-up study of the ongoing FinnDiane study, she said.

The study is a “good reminder” that people with central adiposity and metabolic syndrome can develop NAFL disease, said Jeanne Marie Clark, MD, MPH, of Johns Hopkins University, Baltimore. “Even patients we may not think of having insulin resistance, such as those with T1DM.”

However, Dr. Clark added, “I do not think we can really determine which measure of central adiposity is best.” She noted that the study was “pretty small” with only 14 patients who had NAFL disease. “Waist-to-height ratio is certainly a reasonable option,” she added. “Waist circumference alone is known to be a strong predictor. I would say some measure is better than none, and it should be more routine in clinical practice.”

Dr. Parente disclosed financial relationships with Eli Lilly, Abbott, AstraZeneca, Sanofi, and Boehringer Ingelheim. Two of eight coauthors disclosed financial relationships with AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Elo Water, Fresenius, GE Healthcare, Medscape, Merck Sharpe and Dohme, Mundipharma, Novo Nordisk, Peer-Voice, Sanofi, and Sciarc. The remaining coauthors had no disclosures.

Dr. Clark had no disclosures.

It follows that, as the prevalence of obesity among people with type 1 diabetes mellitus (T1DM) increases, so would the incidence of nonalcoholic fatty liver (NAFL), as it does in type 2 diabetes.

However, researchers in Finland report that the incidence of NAFL in T1DM is much lower, and that the use of the waist-to-height ratio to calculate midsection girth could be a low-cost alternative to MRI and computed tomography to more precisely diagnose NAFL in T1DM.

In a cross-sectional analysis of 121 adults with T1DM in the Finnish Diabetic Nephropathy study, known as FinnDiane, researchers from the University of Helsinki report in Diabetes Care that a waist-to-height ratio of 0.5 showed a relatively high rate of accuracy for identifying NAFL that was statistically significant (P = .04).

Lead author Erika B. Parente, MD, PhD, a researcher at the Folkhälsän Research Center in Helsinki, noted that the findings do not identify any causality between what the researchers called visceral adiposity and NAFL. “As long as they have accumulation of fat in the center of body and they can develop this low-grade inflammation that also goes to insulin-load sensitivity, people with T1DM can accumulate fat in the liver as do people with T2DM and the general population,” she said in an interview.

These findings build on her group’s previous work published in Scientific Reports showing a strong relationship between waist-to-height ratio and visceral fat percentage in adults with T1DM. The most recent FinnDiane analysis found no similar relationship between NAFL and fat tissue in the hips, arms and legs, and total adipose tissue.
 

Better than BMI as a measure

“We also found that waist-to-height ratio is better than body mass index to identify those individuals at higher risk of having NAFL,” Dr. Parente said. However, it’s not possible to predict which patients referred to imaging evaluation after being screened by waist-to-height ratio of 0.5 will surely have NAFL, she added.

That answer, she said, would require a longitudinal and cost-effectiveness study with larger population.

The waist-to-height ratio cutoff of 0.5 showed an 86% sensitivity and 55% specificity for NAFL, whereas BMI of 26.6 kg/m² showed an 79% sensitivity and 57% specificity.

“The most important message from our research is that health care professionals should be aware that individuals with T1DM can have NAFL, and waist-to-height ratio may help to identify those at higher risk,” she said.

The prevalence of NAFL among the adults with T1DM in the study was 11.6%, which is lower than the prevalence other studies reported in T2DM – 76% in a U.S. study – and in the general population – ranging from 19% to 46%. This underscores, Dr. Parente noted, the importance of using waist-to-height ratio in T1DM patients to determine the status of NAFL.

She said that few studies have investigated the consequences of NAFL in T1DM, pointing to two that linked NAFL with chronic kidney disease and cardiovascular disease in T1DM (Diabetes Care. 2014;37:1729-36; J Hepatol. 2010;53:713-8). “Most of the studies about the consequences of NAFL included people with T2DM,” she said. “From our research, we cannot conclude about the impact of NAFL in cardiovascular or kidney complications in our population because this is a cross-sectional study.”

That question may be answered by a future follow-up study of the ongoing FinnDiane study, she said.

The study is a “good reminder” that people with central adiposity and metabolic syndrome can develop NAFL disease, said Jeanne Marie Clark, MD, MPH, of Johns Hopkins University, Baltimore. “Even patients we may not think of having insulin resistance, such as those with T1DM.”

However, Dr. Clark added, “I do not think we can really determine which measure of central adiposity is best.” She noted that the study was “pretty small” with only 14 patients who had NAFL disease. “Waist-to-height ratio is certainly a reasonable option,” she added. “Waist circumference alone is known to be a strong predictor. I would say some measure is better than none, and it should be more routine in clinical practice.”

Dr. Parente disclosed financial relationships with Eli Lilly, Abbott, AstraZeneca, Sanofi, and Boehringer Ingelheim. Two of eight coauthors disclosed financial relationships with AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Elo Water, Fresenius, GE Healthcare, Medscape, Merck Sharpe and Dohme, Mundipharma, Novo Nordisk, Peer-Voice, Sanofi, and Sciarc. The remaining coauthors had no disclosures.

Dr. Clark had no disclosures.

New guidelines from the American College of Gastroenterology on idiosyncratic drug-induced liver injury (DILI) emphasize that idiosyncratic DILI is increasingly driven by the burgeoning popularity of herbal and dietary supplements, as well as tyrosine kinase inhibitors and immune checkpoint inhibitors used to treat cancer.

Sebastian Kaulitzki/Science Photo Library

The guidelines, which represent an update from 2014, are published in The American Journal of Gastroenterology.

DILI is commonly seen by gastroenterologists and hepatologists, but it is challenging to diagnose because there are many potential causes, and no objective diagnostic tests. Its incidence in the general population is low, but it must be considered when facing unexplained liver injury. Its potential presence should also be considered when prescribing gastrointestinal medications like azathioprine, anti–tumor necrosis factor agents, and sulfonamides.

DILI can be characterized as intrinsic or idiosyncratic. Intrinsic DILI is somewhat predictable, based on human or animal studies that have revealed the potential for liver toxicity at higher doses. The best-known example is acetaminophen. Idiosyncratic DILI is rarer and shows up in individuals with a preexisting susceptibility. Clinical signs of idiosyncratic DILI are more diverse than intrinsic DILI. The ACG guideline focuses on idiosyncratic DILI, since guidelines are already available for intrinsic DILI.

Idiosyncratic DILI diagnosis can have a wide range of presentations, including asymptomatic liver biochemistry, jaundice, liver failure, and chronic hepatitis. Diagnosis is made by eliminating other potential causes.

In the presence of hepatocellular jaundice, mortality can reach 10%. DILI patients who develop progressive jaundice, regardless of concomitant coagulopathy, should be sent to a tertiary center and may be a candidate for liver transplantation.

Corticosteroids may be considered when there is uncertainty if a liver injury is from DILI or autoimmune hepatitis, but this remains controversial because some studies have shown benefit, while others have not, according to Bubu Banini, MD, PhD, assistant professor of medicine and research director of the metabolic health and weight management program at Yale University, New Haven, Conn. “Large-scale randomized controlled trials are needed for further elucidation of the role of steroids in DILI. For now, the guideline recommends consideration of steroid therapy, particularly in patients with features of autoimmune hepatitis,” she added.

An important factor driving DILI is the increasing popularity of herbal supplements, as well as increased use of some cancer therapies. “With the advent of immune checkpoint inhibitors as effective therapies for a variety of malignancies, physicians need to be aware of the potential side effects of these agents and the possibility of immune checkpoint inhibitor–related drug induced liver injury,” Dr. Banini said. The updated ACG guideline summarizes current FDA-approved immune checkpoint inhibitors and their potential to cause DILI. The drugs can also lead to reactivation of hepatitis B infection. Studies have shown liver enzyme elevation occurs in about 30% of patients treated with immune checkpoint inhibitors.

The guidelines recommend assessing DILI patients for hepatitis B and C, and treating patients prior to, or in combination with, immune checkpoint inhibitors or other chemotherapy drugs. The recommendations are in line with preliminary data from the ICI field, according to Dr. Banini.

Dr. Banini also noted there has been an increase in the use of herbal and dietary supplements in the United States over the past decade, and these now account for about one-fifth of DILI cases. The guidelines recommend that severe cholestatic disease from these agents should be managed similarly to cases caused by prescription drugs, and patients should be considered for liver transplant if necessary.

A web-based 6-month mortality calculator for suspected DILI is available. It uses Model for End-Stage Liver Disease, Charlson comorbidity Index, and serum albumin data. Those variables predict mortality in liver disease, and an independent analysis showed they predict 6-month mortality in DILI.

DILI is difficult to diagnose, but physicians should keep it in mind when faced with a case of liver enzyme abnormality, where other possibilities have been excluded. “With over a thousand medications potentially causing DILI, physicians should be familiar with LiverTox as a very useful and practical resource. The DILI mortality calculator can serve as a clinical tool to predict 6-month mortality in patients with suspected DILI,” Dr. Banini said.

Some authors disclosed relationships with several pharmaceutical companies. Dr. Banini reports having nothing to disclose.

New guidelines from the American College of Gastroenterology on idiosyncratic drug-induced liver injury (DILI) emphasize that idiosyncratic DILI is increasingly driven by the burgeoning popularity of herbal and dietary supplements, as well as tyrosine kinase inhibitors and immune checkpoint inhibitors used to treat cancer.

Sebastian Kaulitzki/Science Photo Library

The guidelines, which represent an update from 2014, are published in The American Journal of Gastroenterology.

DILI is commonly seen by gastroenterologists and hepatologists, but it is challenging to diagnose because there are many potential causes, and no objective diagnostic tests. Its incidence in the general population is low, but it must be considered when facing unexplained liver injury. Its potential presence should also be considered when prescribing gastrointestinal medications like azathioprine, anti–tumor necrosis factor agents, and sulfonamides.

DILI can be characterized as intrinsic or idiosyncratic. Intrinsic DILI is somewhat predictable, based on human or animal studies that have revealed the potential for liver toxicity at higher doses. The best-known example is acetaminophen. Idiosyncratic DILI is rarer and shows up in individuals with a preexisting susceptibility. Clinical signs of idiosyncratic DILI are more diverse than intrinsic DILI. The ACG guideline focuses on idiosyncratic DILI, since guidelines are already available for intrinsic DILI.

Idiosyncratic DILI diagnosis can have a wide range of presentations, including asymptomatic liver biochemistry, jaundice, liver failure, and chronic hepatitis. Diagnosis is made by eliminating other potential causes.

In the presence of hepatocellular jaundice, mortality can reach 10%. DILI patients who develop progressive jaundice, regardless of concomitant coagulopathy, should be sent to a tertiary center and may be a candidate for liver transplantation.

Corticosteroids may be considered when there is uncertainty if a liver injury is from DILI or autoimmune hepatitis, but this remains controversial because some studies have shown benefit, while others have not, according to Bubu Banini, MD, PhD, assistant professor of medicine and research director of the metabolic health and weight management program at Yale University, New Haven, Conn. “Large-scale randomized controlled trials are needed for further elucidation of the role of steroids in DILI. For now, the guideline recommends consideration of steroid therapy, particularly in patients with features of autoimmune hepatitis,” she added.

An important factor driving DILI is the increasing popularity of herbal supplements, as well as increased use of some cancer therapies. “With the advent of immune checkpoint inhibitors as effective therapies for a variety of malignancies, physicians need to be aware of the potential side effects of these agents and the possibility of immune checkpoint inhibitor–related drug induced liver injury,” Dr. Banini said. The updated ACG guideline summarizes current FDA-approved immune checkpoint inhibitors and their potential to cause DILI. The drugs can also lead to reactivation of hepatitis B infection. Studies have shown liver enzyme elevation occurs in about 30% of patients treated with immune checkpoint inhibitors.

The guidelines recommend assessing DILI patients for hepatitis B and C, and treating patients prior to, or in combination with, immune checkpoint inhibitors or other chemotherapy drugs. The recommendations are in line with preliminary data from the ICI field, according to Dr. Banini.

Dr. Banini also noted there has been an increase in the use of herbal and dietary supplements in the United States over the past decade, and these now account for about one-fifth of DILI cases. The guidelines recommend that severe cholestatic disease from these agents should be managed similarly to cases caused by prescription drugs, and patients should be considered for liver transplant if necessary.

A web-based 6-month mortality calculator for suspected DILI is available. It uses Model for End-Stage Liver Disease, Charlson comorbidity Index, and serum albumin data. Those variables predict mortality in liver disease, and an independent analysis showed they predict 6-month mortality in DILI.

DILI is difficult to diagnose, but physicians should keep it in mind when faced with a case of liver enzyme abnormality, where other possibilities have been excluded. “With over a thousand medications potentially causing DILI, physicians should be familiar with LiverTox as a very useful and practical resource. The DILI mortality calculator can serve as a clinical tool to predict 6-month mortality in patients with suspected DILI,” Dr. Banini said.

Some authors disclosed relationships with several pharmaceutical companies. Dr. Banini reports having nothing to disclose.

New guidelines from the American College of Gastroenterology on idiosyncratic drug-induced liver injury (DILI) emphasize that idiosyncratic DILI is increasingly driven by the burgeoning popularity of herbal and dietary supplements, as well as tyrosine kinase inhibitors and immune checkpoint inhibitors used to treat cancer.

Sebastian Kaulitzki/Science Photo Library

The guidelines, which represent an update from 2014, are published in The American Journal of Gastroenterology.

DILI is commonly seen by gastroenterologists and hepatologists, but it is challenging to diagnose because there are many potential causes, and no objective diagnostic tests. Its incidence in the general population is low, but it must be considered when facing unexplained liver injury. Its potential presence should also be considered when prescribing gastrointestinal medications like azathioprine, anti–tumor necrosis factor agents, and sulfonamides.

DILI can be characterized as intrinsic or idiosyncratic. Intrinsic DILI is somewhat predictable, based on human or animal studies that have revealed the potential for liver toxicity at higher doses. The best-known example is acetaminophen. Idiosyncratic DILI is rarer and shows up in individuals with a preexisting susceptibility. Clinical signs of idiosyncratic DILI are more diverse than intrinsic DILI. The ACG guideline focuses on idiosyncratic DILI, since guidelines are already available for intrinsic DILI.

Idiosyncratic DILI diagnosis can have a wide range of presentations, including asymptomatic liver biochemistry, jaundice, liver failure, and chronic hepatitis. Diagnosis is made by eliminating other potential causes.

In the presence of hepatocellular jaundice, mortality can reach 10%. DILI patients who develop progressive jaundice, regardless of concomitant coagulopathy, should be sent to a tertiary center and may be a candidate for liver transplantation.

Corticosteroids may be considered when there is uncertainty if a liver injury is from DILI or autoimmune hepatitis, but this remains controversial because some studies have shown benefit, while others have not, according to Bubu Banini, MD, PhD, assistant professor of medicine and research director of the metabolic health and weight management program at Yale University, New Haven, Conn. “Large-scale randomized controlled trials are needed for further elucidation of the role of steroids in DILI. For now, the guideline recommends consideration of steroid therapy, particularly in patients with features of autoimmune hepatitis,” she added.

An important factor driving DILI is the increasing popularity of herbal supplements, as well as increased use of some cancer therapies. “With the advent of immune checkpoint inhibitors as effective therapies for a variety of malignancies, physicians need to be aware of the potential side effects of these agents and the possibility of immune checkpoint inhibitor–related drug induced liver injury,” Dr. Banini said. The updated ACG guideline summarizes current FDA-approved immune checkpoint inhibitors and their potential to cause DILI. The drugs can also lead to reactivation of hepatitis B infection. Studies have shown liver enzyme elevation occurs in about 30% of patients treated with immune checkpoint inhibitors.

The guidelines recommend assessing DILI patients for hepatitis B and C, and treating patients prior to, or in combination with, immune checkpoint inhibitors or other chemotherapy drugs. The recommendations are in line with preliminary data from the ICI field, according to Dr. Banini.

Dr. Banini also noted there has been an increase in the use of herbal and dietary supplements in the United States over the past decade, and these now account for about one-fifth of DILI cases. The guidelines recommend that severe cholestatic disease from these agents should be managed similarly to cases caused by prescription drugs, and patients should be considered for liver transplant if necessary.

A web-based 6-month mortality calculator for suspected DILI is available. It uses Model for End-Stage Liver Disease, Charlson comorbidity Index, and serum albumin data. Those variables predict mortality in liver disease, and an independent analysis showed they predict 6-month mortality in DILI.

DILI is difficult to diagnose, but physicians should keep it in mind when faced with a case of liver enzyme abnormality, where other possibilities have been excluded. “With over a thousand medications potentially causing DILI, physicians should be familiar with LiverTox as a very useful and practical resource. The DILI mortality calculator can serve as a clinical tool to predict 6-month mortality in patients with suspected DILI,” Dr. Banini said.

Some authors disclosed relationships with several pharmaceutical companies. Dr. Banini reports having nothing to disclose.

Anti–apolipoprotein A-I (apo A-I) antibodies are common in nonalcoholic fatty liver disease and may not only drive its development but also underlie the link between NAFLD and cardiovascular disease, suggests a novel analysis.

Conducting a clinical analysis and a series of experiments, Sabrina Pagano, PhD, diagnostic department, Geneva University Hospital, and colleagues looked for anti–apo A-I antibodies in patients with NAFLD and then examined their impact on hepatic cells and inflammatory markers.

They found that nearly half of 137 patients with NAFLD were seropositive, and that the antibodies were associated with increased lipid accumulation in the liver, altered triglyceride metabolism, and proinflammatory effects on liver cells.

“We hypothesize that anti–apo A-I IgG may be a potential driver in the development of NAFLD, and further studies are needed to support anti–apo A-I IgG as a possible link between NAFLD and cardiovascular disease,” Dr. Pagano said.

The research was presented at the European Atherosclerosis Society 2021 Virtual Congress.

Asked whether anti–apo A-I antibodies could represent a potential treatment target for NAFLD, Dr. Pagano said in an interview that they have “already developed a peptide that is recognized by the antibodies in order to try to reverse the anti–apo A-I deleterious effect.”

While this was successful in vitro, “unfortunately we didn’t observe ... the peptide reverse of these anti–apo A-I effects in mice, so ... for the moment it’s a little early,” to say whether it represents a promising target.

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, said that the results are “very interesting and encouraging.”

He said that his own global burden of disease analysis, which is set to be published soon, showed that the worldwide prevalence of NAFLD is 11%, “representing almost 900 million cases,” and a more than 33% increase in prevalence in the past 30 years.

Consequently, any “attempt to have effective, especially early, diagnosis and treatment,” is highly anticipated.

Dr. Banach said the findings from the experimental analyses are “very interesting and promising,” especially regarding the proinflammatory effects of anti–apo A-I antibodies.

However, he underlined that the clinical part, looking at antibody seropositivity in patients with NAFLD, was limited by the lack of a control group, and there was no indication as to what treatment the patients received, despite it being clear that many were obese.

Dr. Banach also believes that, taking into account the patient characteristics, it is likely that most of the patients had the more severe nonalcoholic steatohepatitis, and “it would be additionally useful to see the autoantibodies levels both in NASH and NAFLD.”

Nevertheless, the clinical utility of measuring anti–apo A-I antibodies is limited at this stage.

He said that the lack of “good, easy, and cheap diagnostic methods based on both laboratory and imaging data” for NAFLD means it would be difficult to determine whether assessing antibody seropositivity “might be indeed an added value.”
 

Independent predictors

Dr. Pagano explained that anti–apo A-I antibodies, which target the major protein fraction of HDL cholesterol, are independent predictors of cardiovascular events in high-risk populations.

They are also independently associated with cardiovascular disease in the general population, as well as atherosclerotic plaque vulnerability in both mice and humans.

She said that apo A-I antibodies have a metabolic role in vivo, and have been shown in vitro to disrupt cholesterol metabolism, promoting foam cell formation.

Studies have also indicated they play a role in hepatic fibrosis, predicting the development of cirrhosis in individuals with chronic hepatitis C infection.

The team therefore set out to determine the presence of anti–apo A-I antibodies in individuals with NAFLD, defined here as fatty acid levels greater than 5% of liver weight, as well as their effect on hepatic cells.

Working with colleagues at Magna Græcia University of Catanzaro (Italy), they obtained serum samples from 137 patients with NAFLD confirmed on ultrasound.

The patients had an average age of 49 years, and 48.9% were male. The median body mass index was 31.8 kg/m². Cholesterol levels were typically in the intermediate range.

They found that 46% of the participants had anti–apo A-I IgG antibodies, “which is quite high when compared with the 15%-20% positivity that we retrieved from the general population,” Dr. Pagano said.

To explore the link between high anti–apo A-I antibodies and NAFLD, the team studied hepatic cells, treating them with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, for 24 hours.

This revealed that anti–apo A-I IgG antibodies were associated with a significant increase in liquid droplet content in hepatic cells, compared with both cells treated with control IgG (P = .0008), and untreated cells (P = .0002).

Next, the team immunized apo E knockout mice with anti–apo A-I or control IgG antibodies. After 16 weeks, they found there was a significant increase in liver lipid content in mice given anti–apo A-I antibodies versus those treated with controls (P = .03).

They then asked whether anti–apo A-I antibodies could affect triglyceride metabolism. They examined the expression of the transcription factor sterol regulatory element binding protein (SREBP) and regulation of the triglyceride and cholesterol pathways.

Treating hepatic cells again for 24 hours with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, showed that anti–apo A-I antibodies were associated with “dramatic” increases in the active form of SREBP.

They also found that expression of two key enzymes in the triglyceride pathway, fatty acid synthetase and glycerol phosphate acyltransferase, was substantially decreased in the presence anti–apo A-I antibodies.

In both experiments, the untreated hepatic cells and those exposed to control IgG antibodies showed no significant changes.

“These results suggest that negative feedback ... turns off these enzymes, probably due to the lipid overload that is found in the cells after 24 hours of anti–apo A-I treatment,” Dr. Pagano said.

Finally, the researchers observed that anti–apo A-I, but not control antibodies, were associated with increases in inflammatory markers in liver cells.

Specifically, exposure to the antibodies was linked to an approximately 10-fold increase in interleukin-6 levels, as well as an approximate 25-fold increase in IL-8, and around a 7-fold increase in tumor necrosis factor–alpha.

Dr. Pagano suggested that the inflammatory effects are “probably mediated by binding anti–apo A-I antibodies to toll-like receptor 2, which has been previously described in macrophages.”

No funding was declared. The study authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Anti–apolipoprotein A-I (apo A-I) antibodies are common in nonalcoholic fatty liver disease and may not only drive its development but also underlie the link between NAFLD and cardiovascular disease, suggests a novel analysis.

Conducting a clinical analysis and a series of experiments, Sabrina Pagano, PhD, diagnostic department, Geneva University Hospital, and colleagues looked for anti–apo A-I antibodies in patients with NAFLD and then examined their impact on hepatic cells and inflammatory markers.

They found that nearly half of 137 patients with NAFLD were seropositive, and that the antibodies were associated with increased lipid accumulation in the liver, altered triglyceride metabolism, and proinflammatory effects on liver cells.

“We hypothesize that anti–apo A-I IgG may be a potential driver in the development of NAFLD, and further studies are needed to support anti–apo A-I IgG as a possible link between NAFLD and cardiovascular disease,” Dr. Pagano said.

The research was presented at the European Atherosclerosis Society 2021 Virtual Congress.

Asked whether anti–apo A-I antibodies could represent a potential treatment target for NAFLD, Dr. Pagano said in an interview that they have “already developed a peptide that is recognized by the antibodies in order to try to reverse the anti–apo A-I deleterious effect.”

While this was successful in vitro, “unfortunately we didn’t observe ... the peptide reverse of these anti–apo A-I effects in mice, so ... for the moment it’s a little early,” to say whether it represents a promising target.

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, said that the results are “very interesting and encouraging.”

He said that his own global burden of disease analysis, which is set to be published soon, showed that the worldwide prevalence of NAFLD is 11%, “representing almost 900 million cases,” and a more than 33% increase in prevalence in the past 30 years.

Consequently, any “attempt to have effective, especially early, diagnosis and treatment,” is highly anticipated.

Dr. Banach said the findings from the experimental analyses are “very interesting and promising,” especially regarding the proinflammatory effects of anti–apo A-I antibodies.

However, he underlined that the clinical part, looking at antibody seropositivity in patients with NAFLD, was limited by the lack of a control group, and there was no indication as to what treatment the patients received, despite it being clear that many were obese.

Dr. Banach also believes that, taking into account the patient characteristics, it is likely that most of the patients had the more severe nonalcoholic steatohepatitis, and “it would be additionally useful to see the autoantibodies levels both in NASH and NAFLD.”

Nevertheless, the clinical utility of measuring anti–apo A-I antibodies is limited at this stage.

He said that the lack of “good, easy, and cheap diagnostic methods based on both laboratory and imaging data” for NAFLD means it would be difficult to determine whether assessing antibody seropositivity “might be indeed an added value.”
 

Independent predictors

Dr. Pagano explained that anti–apo A-I antibodies, which target the major protein fraction of HDL cholesterol, are independent predictors of cardiovascular events in high-risk populations.

They are also independently associated with cardiovascular disease in the general population, as well as atherosclerotic plaque vulnerability in both mice and humans.

She said that apo A-I antibodies have a metabolic role in vivo, and have been shown in vitro to disrupt cholesterol metabolism, promoting foam cell formation.

Studies have also indicated they play a role in hepatic fibrosis, predicting the development of cirrhosis in individuals with chronic hepatitis C infection.

The team therefore set out to determine the presence of anti–apo A-I antibodies in individuals with NAFLD, defined here as fatty acid levels greater than 5% of liver weight, as well as their effect on hepatic cells.

Working with colleagues at Magna Græcia University of Catanzaro (Italy), they obtained serum samples from 137 patients with NAFLD confirmed on ultrasound.

The patients had an average age of 49 years, and 48.9% were male. The median body mass index was 31.8 kg/m². Cholesterol levels were typically in the intermediate range.

They found that 46% of the participants had anti–apo A-I IgG antibodies, “which is quite high when compared with the 15%-20% positivity that we retrieved from the general population,” Dr. Pagano said.

To explore the link between high anti–apo A-I antibodies and NAFLD, the team studied hepatic cells, treating them with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, for 24 hours.

This revealed that anti–apo A-I IgG antibodies were associated with a significant increase in liquid droplet content in hepatic cells, compared with both cells treated with control IgG (P = .0008), and untreated cells (P = .0002).

Next, the team immunized apo E knockout mice with anti–apo A-I or control IgG antibodies. After 16 weeks, they found there was a significant increase in liver lipid content in mice given anti–apo A-I antibodies versus those treated with controls (P = .03).

They then asked whether anti–apo A-I antibodies could affect triglyceride metabolism. They examined the expression of the transcription factor sterol regulatory element binding protein (SREBP) and regulation of the triglyceride and cholesterol pathways.

Treating hepatic cells again for 24 hours with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, showed that anti–apo A-I antibodies were associated with “dramatic” increases in the active form of SREBP.

They also found that expression of two key enzymes in the triglyceride pathway, fatty acid synthetase and glycerol phosphate acyltransferase, was substantially decreased in the presence anti–apo A-I antibodies.

In both experiments, the untreated hepatic cells and those exposed to control IgG antibodies showed no significant changes.

“These results suggest that negative feedback ... turns off these enzymes, probably due to the lipid overload that is found in the cells after 24 hours of anti–apo A-I treatment,” Dr. Pagano said.

Finally, the researchers observed that anti–apo A-I, but not control antibodies, were associated with increases in inflammatory markers in liver cells.

Specifically, exposure to the antibodies was linked to an approximately 10-fold increase in interleukin-6 levels, as well as an approximate 25-fold increase in IL-8, and around a 7-fold increase in tumor necrosis factor–alpha.

Dr. Pagano suggested that the inflammatory effects are “probably mediated by binding anti–apo A-I antibodies to toll-like receptor 2, which has been previously described in macrophages.”

No funding was declared. The study authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Anti–apolipoprotein A-I (apo A-I) antibodies are common in nonalcoholic fatty liver disease and may not only drive its development but also underlie the link between NAFLD and cardiovascular disease, suggests a novel analysis.

Conducting a clinical analysis and a series of experiments, Sabrina Pagano, PhD, diagnostic department, Geneva University Hospital, and colleagues looked for anti–apo A-I antibodies in patients with NAFLD and then examined their impact on hepatic cells and inflammatory markers.

They found that nearly half of 137 patients with NAFLD were seropositive, and that the antibodies were associated with increased lipid accumulation in the liver, altered triglyceride metabolism, and proinflammatory effects on liver cells.

“We hypothesize that anti–apo A-I IgG may be a potential driver in the development of NAFLD, and further studies are needed to support anti–apo A-I IgG as a possible link between NAFLD and cardiovascular disease,” Dr. Pagano said.

The research was presented at the European Atherosclerosis Society 2021 Virtual Congress.

Asked whether anti–apo A-I antibodies could represent a potential treatment target for NAFLD, Dr. Pagano said in an interview that they have “already developed a peptide that is recognized by the antibodies in order to try to reverse the anti–apo A-I deleterious effect.”

While this was successful in vitro, “unfortunately we didn’t observe ... the peptide reverse of these anti–apo A-I effects in mice, so ... for the moment it’s a little early,” to say whether it represents a promising target.

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, said that the results are “very interesting and encouraging.”

He said that his own global burden of disease analysis, which is set to be published soon, showed that the worldwide prevalence of NAFLD is 11%, “representing almost 900 million cases,” and a more than 33% increase in prevalence in the past 30 years.

Consequently, any “attempt to have effective, especially early, diagnosis and treatment,” is highly anticipated.

Dr. Banach said the findings from the experimental analyses are “very interesting and promising,” especially regarding the proinflammatory effects of anti–apo A-I antibodies.

However, he underlined that the clinical part, looking at antibody seropositivity in patients with NAFLD, was limited by the lack of a control group, and there was no indication as to what treatment the patients received, despite it being clear that many were obese.

Dr. Banach also believes that, taking into account the patient characteristics, it is likely that most of the patients had the more severe nonalcoholic steatohepatitis, and “it would be additionally useful to see the autoantibodies levels both in NASH and NAFLD.”

Nevertheless, the clinical utility of measuring anti–apo A-I antibodies is limited at this stage.

He said that the lack of “good, easy, and cheap diagnostic methods based on both laboratory and imaging data” for NAFLD means it would be difficult to determine whether assessing antibody seropositivity “might be indeed an added value.”
 

Independent predictors

Dr. Pagano explained that anti–apo A-I antibodies, which target the major protein fraction of HDL cholesterol, are independent predictors of cardiovascular events in high-risk populations.

They are also independently associated with cardiovascular disease in the general population, as well as atherosclerotic plaque vulnerability in both mice and humans.

She said that apo A-I antibodies have a metabolic role in vivo, and have been shown in vitro to disrupt cholesterol metabolism, promoting foam cell formation.

Studies have also indicated they play a role in hepatic fibrosis, predicting the development of cirrhosis in individuals with chronic hepatitis C infection.

The team therefore set out to determine the presence of anti–apo A-I antibodies in individuals with NAFLD, defined here as fatty acid levels greater than 5% of liver weight, as well as their effect on hepatic cells.

Working with colleagues at Magna Græcia University of Catanzaro (Italy), they obtained serum samples from 137 patients with NAFLD confirmed on ultrasound.

The patients had an average age of 49 years, and 48.9% were male. The median body mass index was 31.8 kg/m². Cholesterol levels were typically in the intermediate range.

They found that 46% of the participants had anti–apo A-I IgG antibodies, “which is quite high when compared with the 15%-20% positivity that we retrieved from the general population,” Dr. Pagano said.

To explore the link between high anti–apo A-I antibodies and NAFLD, the team studied hepatic cells, treating them with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, for 24 hours.

This revealed that anti–apo A-I IgG antibodies were associated with a significant increase in liquid droplet content in hepatic cells, compared with both cells treated with control IgG (P = .0008), and untreated cells (P = .0002).

Next, the team immunized apo E knockout mice with anti–apo A-I or control IgG antibodies. After 16 weeks, they found there was a significant increase in liver lipid content in mice given anti–apo A-I antibodies versus those treated with controls (P = .03).

They then asked whether anti–apo A-I antibodies could affect triglyceride metabolism. They examined the expression of the transcription factor sterol regulatory element binding protein (SREBP) and regulation of the triglyceride and cholesterol pathways.

Treating hepatic cells again for 24 hours with anti–apo A-I IgG antibodies or control IgG antibodies, or leaving them untreated, showed that anti–apo A-I antibodies were associated with “dramatic” increases in the active form of SREBP.

They also found that expression of two key enzymes in the triglyceride pathway, fatty acid synthetase and glycerol phosphate acyltransferase, was substantially decreased in the presence anti–apo A-I antibodies.

In both experiments, the untreated hepatic cells and those exposed to control IgG antibodies showed no significant changes.

“These results suggest that negative feedback ... turns off these enzymes, probably due to the lipid overload that is found in the cells after 24 hours of anti–apo A-I treatment,” Dr. Pagano said.

Finally, the researchers observed that anti–apo A-I, but not control antibodies, were associated with increases in inflammatory markers in liver cells.

Specifically, exposure to the antibodies was linked to an approximately 10-fold increase in interleukin-6 levels, as well as an approximate 25-fold increase in IL-8, and around a 7-fold increase in tumor necrosis factor–alpha.

Dr. Pagano suggested that the inflammatory effects are “probably mediated by binding anti–apo A-I antibodies to toll-like receptor 2, which has been previously described in macrophages.”

No funding was declared. The study authors disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The risk for serious liver injury with obeticholic acid (Ocaliva, Intercept Pharmaceuticals) has prompted the U.S. Food and Drug Administration to restrict its use in patients with primary biliary cholangitis (PBC) and advanced cirrhosis.  

The agency has added a new contraindication to the obeticholic acid prescribing information and patient medication guide stating that the drug should not be used in patients with PBC and advanced cirrhosis. 

The boxed warning on the label has also been revised to include this information.

For patients with PBC who do not have advanced cirrhosis, the FDA believes the benefits of Ocaliva outweigh the risks, based on the original clinical trials.

Five years ago, the FDA granted accelerated approval to obeticholic acid in combination with ursodeoxycholic acid (UDCA) in adults who fail to respond adequately to UDCA, or as a monotherapy in adults who cannot tolerate UDCA.  

Since then, the FDA has identified 25 cases of serious liver injury leading to liver decompensation or liver failure in patients with PBC and cirrhosis who were taking obeticholic acid at recommended doses.

According to the FDA, 18 of the cases happened in patients with PBC and compensated cirrhosis who experienced liver injury that led to decompensation. Ten of these patients had evidence or suspicion of portal hypertension at baseline; in the other eight patients, it was unclear whether portal hypertension was present.

PBC was not expected to progress rapidly in these patients, yet they experienced accelerated clinical deterioration within months of starting obeticholic acid, the FDA said.

The median time to liver decompensation after initiating treatment was 4 months (range, 2 weeks to 10 months). Four patients with PBC and compensated cirrhosis needed a liver transplant within 1.3 years after starting obeticholic acid, and one patient died from liver failure.

The other seven cases of serious liver injury occurred in patients with PBC and decompensated cirrhosis, two of whom died. 

Although there was a temporal relationship between starting obeticholic acid and liver injury, it is difficult to distinguish a drug-induced effect from disease progression in the patients with advanced baseline liver disease, the FDA cautioned.

The median time to a new decompensation event after starting the drug was 2.5 months (range, 10 days to 8 months).

Before starting obeticholic acid, clinicians should determine whether a patient with PBC has advanced cirrhosis as the drug is now contraindicated in these patients, the FDA said.

During obeticholic acid treatment, patients should be routinely monitored for progression of PBC with laboratory and clinical assessments to determine whether the drug needs to be discontinued.

The medication should be permanently discontinued in patients with cirrhosis who progress to advanced cirrhosis.

Patients should also be monitored for clinically significant liver-related adverse reactions that may manifest as development of acute-on-chronic liver disease with nausea, vomiting, diarrhea, jaundice, scleral icterus, and/or dark urine.

Obeticholic acid should be stopped permanently in any patient who develops these symptoms, the FDA advised.

Health care professionals are encouraged to report adverse events or side effects related to the use of obeticholic acid to MedWatch, FDA’s adverse event reporting site.

A version of this article first appeared on Medscape.com.

The risk for serious liver injury with obeticholic acid (Ocaliva, Intercept Pharmaceuticals) has prompted the U.S. Food and Drug Administration to restrict its use in patients with primary biliary cholangitis (PBC) and advanced cirrhosis.  

The agency has added a new contraindication to the obeticholic acid prescribing information and patient medication guide stating that the drug should not be used in patients with PBC and advanced cirrhosis. 

The boxed warning on the label has also been revised to include this information.

For patients with PBC who do not have advanced cirrhosis, the FDA believes the benefits of Ocaliva outweigh the risks, based on the original clinical trials.

Five years ago, the FDA granted accelerated approval to obeticholic acid in combination with ursodeoxycholic acid (UDCA) in adults who fail to respond adequately to UDCA, or as a monotherapy in adults who cannot tolerate UDCA.  

Since then, the FDA has identified 25 cases of serious liver injury leading to liver decompensation or liver failure in patients with PBC and cirrhosis who were taking obeticholic acid at recommended doses.

According to the FDA, 18 of the cases happened in patients with PBC and compensated cirrhosis who experienced liver injury that led to decompensation. Ten of these patients had evidence or suspicion of portal hypertension at baseline; in the other eight patients, it was unclear whether portal hypertension was present.

PBC was not expected to progress rapidly in these patients, yet they experienced accelerated clinical deterioration within months of starting obeticholic acid, the FDA said.

The median time to liver decompensation after initiating treatment was 4 months (range, 2 weeks to 10 months). Four patients with PBC and compensated cirrhosis needed a liver transplant within 1.3 years after starting obeticholic acid, and one patient died from liver failure.

The other seven cases of serious liver injury occurred in patients with PBC and decompensated cirrhosis, two of whom died. 

Although there was a temporal relationship between starting obeticholic acid and liver injury, it is difficult to distinguish a drug-induced effect from disease progression in the patients with advanced baseline liver disease, the FDA cautioned.

The median time to a new decompensation event after starting the drug was 2.5 months (range, 10 days to 8 months).

Before starting obeticholic acid, clinicians should determine whether a patient with PBC has advanced cirrhosis as the drug is now contraindicated in these patients, the FDA said.

During obeticholic acid treatment, patients should be routinely monitored for progression of PBC with laboratory and clinical assessments to determine whether the drug needs to be discontinued.

The medication should be permanently discontinued in patients with cirrhosis who progress to advanced cirrhosis.

Patients should also be monitored for clinically significant liver-related adverse reactions that may manifest as development of acute-on-chronic liver disease with nausea, vomiting, diarrhea, jaundice, scleral icterus, and/or dark urine.

Obeticholic acid should be stopped permanently in any patient who develops these symptoms, the FDA advised.

Health care professionals are encouraged to report adverse events or side effects related to the use of obeticholic acid to MedWatch, FDA’s adverse event reporting site.

A version of this article first appeared on Medscape.com.

The risk for serious liver injury with obeticholic acid (Ocaliva, Intercept Pharmaceuticals) has prompted the U.S. Food and Drug Administration to restrict its use in patients with primary biliary cholangitis (PBC) and advanced cirrhosis.  

The agency has added a new contraindication to the obeticholic acid prescribing information and patient medication guide stating that the drug should not be used in patients with PBC and advanced cirrhosis. 

The boxed warning on the label has also been revised to include this information.

For patients with PBC who do not have advanced cirrhosis, the FDA believes the benefits of Ocaliva outweigh the risks, based on the original clinical trials.

Five years ago, the FDA granted accelerated approval to obeticholic acid in combination with ursodeoxycholic acid (UDCA) in adults who fail to respond adequately to UDCA, or as a monotherapy in adults who cannot tolerate UDCA.  

Since then, the FDA has identified 25 cases of serious liver injury leading to liver decompensation or liver failure in patients with PBC and cirrhosis who were taking obeticholic acid at recommended doses.

According to the FDA, 18 of the cases happened in patients with PBC and compensated cirrhosis who experienced liver injury that led to decompensation. Ten of these patients had evidence or suspicion of portal hypertension at baseline; in the other eight patients, it was unclear whether portal hypertension was present.

PBC was not expected to progress rapidly in these patients, yet they experienced accelerated clinical deterioration within months of starting obeticholic acid, the FDA said.

The median time to liver decompensation after initiating treatment was 4 months (range, 2 weeks to 10 months). Four patients with PBC and compensated cirrhosis needed a liver transplant within 1.3 years after starting obeticholic acid, and one patient died from liver failure.

The other seven cases of serious liver injury occurred in patients with PBC and decompensated cirrhosis, two of whom died. 

Although there was a temporal relationship between starting obeticholic acid and liver injury, it is difficult to distinguish a drug-induced effect from disease progression in the patients with advanced baseline liver disease, the FDA cautioned.

The median time to a new decompensation event after starting the drug was 2.5 months (range, 10 days to 8 months).

Before starting obeticholic acid, clinicians should determine whether a patient with PBC has advanced cirrhosis as the drug is now contraindicated in these patients, the FDA said.

During obeticholic acid treatment, patients should be routinely monitored for progression of PBC with laboratory and clinical assessments to determine whether the drug needs to be discontinued.

The medication should be permanently discontinued in patients with cirrhosis who progress to advanced cirrhosis.

Patients should also be monitored for clinically significant liver-related adverse reactions that may manifest as development of acute-on-chronic liver disease with nausea, vomiting, diarrhea, jaundice, scleral icterus, and/or dark urine.

Obeticholic acid should be stopped permanently in any patient who develops these symptoms, the FDA advised.

Health care professionals are encouraged to report adverse events or side effects related to the use of obeticholic acid to MedWatch, FDA’s adverse event reporting site.

A version of this article first appeared on Medscape.com.

Liver cirrhosis is implicated in 75% to 85% of ascites cases in the Western world, with heart failure or malignancy accounting for fewer cases.¹ Among patients who have decompensated cirrhosis with ascites, annual mortality is 20%.² Another study showed a 3-year survival rate after onset of ascites of only 56%.³ It is vital for primary care physicians (PCPs) to be alert for ascites not only in patients who have risk factors for chronic liver disease and cirrhosis—eg, a history of alcohol use disorder, chronic viral infections (hepatitis B and C), or metabolic syndrome—but also in patients with abnormal liver function tests and thrombocytopenia. In this review, we discuss the initial assessment of ascites and its long-term management, concentrating on the role of the PCP.

Pathophysiology: Vasodilation leads to a cascade

Splanchnic vasodilation is the main underlying event triggering a pathologic cascade that leads to the development of ascites.⁴ Initially portal hypertension in the setting of liver inflammation and fibrosis causes the release of inflammatory cytokines such as nitric oxide and carbon monoxide. This, in turn, causes the pathologic dilation of splanchnic circulation that decreases effective circulating volume. Activation of the sympathetic nervous system, vasopressin, and renin-­angiotensin-aldosterone system (RAAS) then causes the proximal and distal tubules to increase renal absorption of sodium and water.⁵ The resulting volume overload further decreases the heart’s ability to maintain circulating volume, leading to increased activation of compensating symptoms. This vicious cycle eventually manifests as ascites.⁶

A complex interplay of cirrhosis-associated immune dysfunction (CAID), gut dysbiosis, and increased translocation of microorganisms into ascitic fluid is also an important aspect of the pathogenesis.⁷ CAID (FIGURE 1)^7,8 is an immunodeficient state due to cirrhosis with reduced phagocytic activity by neutrophils and macrophages, T- and B-cell hypoproliferation, and reduced cytotoxicity of natural killer cells. In parallel, there is increased production of inflammatory cytokines due to the effects of damage-associated molecular patterns (DAMPs) from hepatocytes and ­pathogen-associated molecular patterns (PAMPs) from the gut microbiota on the immune system, which leads to many of the manifestations of decompensated cirrhosis including ascites.⁸

Key in on these elementsof the history and exam

Each step of the basic work-up for ascites provides opportunities to refine or redirect the diagnostic inquiry (TABLE).

History

Generally, patients with ascites present with weight gain and symptoms of abdominal distension, such as early satiety, nausea, and vomiting. Besides cirrhosis, rule out other causes of ascites, as treatment differs based on the cause.⁹ Also ask about histories of cancer and cardiac, renal, or thyroid disease.¹⁰

Patients with ascites in the setting of liver disease usually are asymptomatic in its early stages. Common complaints are vague abdominal pain, generalized weakness, malaise, and fatigue.¹¹ Ask patients about risk factors for liver disease such as obesity, diabetes, hypertension, alcohol use, unsafe sexual practices, recent travel, and needle sharing or drug use. Due to a strong association between obstructive sleep apnea and fatty liver disease, consider screening at-risk patients for sleep apnea.¹²

Physical exam

When there are risk factors for liver disease, examine the patient for stigmata of cirrhosis and ascites. Signs of liver disease, aside from ascites, may include spider angiomas on the upper trunk (33% of cirrhosis patients),¹³ gynecomastia (44% of cirrhosis patients),¹⁴ palmar erythema, jaundice, asterixis, and abdominal wall collaterals including caput medusa.¹⁵

Continue to: We suggest a systematic...

We suggest a systematic and targeted approach to using various physical exam maneuvers described in the literature. If the patient has a full/distended abdomen, percuss the flanks. If increased dullness at the flanks is detected, check for shifting dullness, which indicates at least 1500 mL of fluid in the abdomen.¹⁶ Keep in mind that a 10% chance of ascites exists even if shifting dullness is absent.¹⁷ Maneuvers such as the puddle sign and fluid thrill are less accurate than shifting dullness, which has 83% sensitivity and 56% specificity in detecting ascites.¹⁷ Patients with cirrhosis also have a high likelihood of complications from ascites such as inguinal, umbilical, and other hernias.

Diagnostic work-up includes blood tests and ultrasound

Blood tests. The initial work-up for ascites should include complete blood count, complete metabolic panel, and prothrombin time/international normalized ratio.¹⁸

Abdominal ultrasound is recommended as the first-line imaging test.¹⁹ Aside from detecting ascites, it can give an estimate of the volume of ascites and indicate whether it is amenable to paracentesis. A vascular exam added to the standard ultrasound can detect radiologic evidence of portal hypertension such as splenomegaly, portosystemic collaterals, splenorenal shunt, patency of the paraumbilical vein, and portal vein diameter. Patients with established cirrhosis also require abdominal ultrasound every 6 months to screen for hepatocellular cancer.²⁰

Abdominal paracentesis is the cornerstone of ascites evaluation.²¹ It is indicated for every patient with new-onset ascites or for any patient with known ascites and clinical deterioration. Ascitic fluid analysis can be used to easily differentiate portal hypertension from other causes of ascites. It can also be used to rule out bacterial peritonitis. The recommended sites for evaluation are in the left lower quadrant, 3 cm cranially and 3 cm medially from the anterior superior iliac spine.²² A large cohort study showed that abdominal ultrasound-guided paracentesis reduced bleeding complications by 68% following the procedure and is strongly recommended (if available).²³ Generally, paracentesis is a relatively safe procedure with a low risk of complications such as abdominal wall hematoma (1%), hemoperitoneum (< 0.1%), bowel perforation (< 0.1%), and infection (< 0.1%).²⁴

Calculating the serum ascites albumin gradient better characterizes ascitic fluid than total protein-based tests.

Assess all ascitic fluid samples for color, consistency, cell count and differential, albumin, and total protein. These tests are usually sufficient to provide evidence regarding the cause of ascites. If there is suspicion of infection, order a gram stain and culture (80% sensitivity for detecting an infection if obtained prior to initiation of antibiotics)²⁵ and glucose, lactate dehydrogenase (useful to differentiate primary from secondary bacterial peritonitis),²⁶ and amylase tests. Other tests such as cytology, acid-fast bacilli smear and culture, and triglyceride level should only be obtained if specific conditions are suspected based on high pretest probabilities.

Continue to: Calculating serum ascites albumin gradient...

Calculating serum ascites albumin gradient (SAAG) is recommended as it has been shown to better characterize ascitic fluid than total protein-based tests.²⁷ SAAG is calculated by subtracting the level of ascitic fluid albumin from serum albumin level (SAAG = serum albumin – ascitic fluid albumin). A SAAG ≥ 1.1 g/dL is consistent with portal hypertension,²⁸ with approximately 97% accuracy.

After calculating SAAG, look at total protein levels in ascitic fluid. Total protein concentration ≥ 2.5 g/dL with SAAG ≥ 1.1 g/dL has a 78.3% diagnostic accuracy in determining heart failure as the cause of ascites, with a sensitivity of 53.3% and specificity of 86.7%.²⁸ On the other hand, a value of total protein < 2.5 g/dL indicates cirrhosis, liver failure, or acute hepatitis as the cause of fluid build-up.²⁹ Stepwise evaluation of SAAG and total protein and how they can point toward the most likely cause of ascites is presented in FIGURE 2.^27-29

Management

Noninvasive measures

Sodium restriction. The aim of treatment for uncomplicated clinically apparent ascites is sodium restriction and removal of fluid from the body. Dietary salt restriction is complicated, and care should be taken to properly educate patients. Salt restriction advised in the literature has shifted from a strict measure of < 2 g/d³⁰ to more moderate strategies (described below).¹⁸

The 2 main reasons for this easing of restriction are issues with patient compliance and concerns about adverse effects with aggressive salt-restricted diets. One study assessing patient compliance with a salt-restricted diet found that more than two-thirds of the patients were noncompliant,³¹ and 65% of the patients incorrectly assumed they were following the plan, which suggests poor dietary education.³¹ Of the group that was compliant, 20% actually decreased their caloric intake, which can be detrimental in liver disease.³¹ Concerns have been raised that aggressive salt restriction along with diuretic use can lead to diuretic-induced hyponatremia and renal failure.³² Current European Association for the Study of the Liver (EASL) guidelines recommend salt restriction to a more moderate degree (80-120 mmol/d of sodium). This is equivalent to 4.9-6.9 g of salt (1 tablespoon is roughly equivalent to 6 g or 104 mmol of sodium).¹⁸

Diuretics. Initiation and dosage of diuretic therapy is a matter of some controversy. Historically, simultaneous ­administration of a loop diuretic and mineralocorticoid receptor blocker were recommended: 40 mg furosemide and 100 mg spironolactone, keeping the ratio constant with any dosage increases. This was based on a randomized controlled trial (RCT) showing that the combined diuretic therapy effectively mobilized ascites in a shorter period of time and with less frequent adverse effects (eg, hyperkalemia) compared with initial monotherapy.³³

Continue to: On the other hand...

On the other hand, another study with more stable patients and relatively normal renal function showed that starting with a mineralocorticoid receptor blocker alone with sequential dose increments had equivalent benefit with no increase in adverse effects.³⁴ Since the patient population in this study was more in line with what a PCP might encounter, we recommend following this guideline initially and keeping a close watch on serum electrolytes.

Usual maximum doses are spironolactone 400 mg/d and furosemide 160 mg/d.^21,35 Adequate weight loss for patients with diffuse edema is at least 1 kg/d, per EASL guidelines.^36,37 However, this might not be practical in outpatient settings, and a more conservative target of 0.5 kg/d may be used for patients without significant edema.³⁷

It is vital to get accurate daily weights and avoid excessive diuretic use, as it has been associated with intravascular volume depletion and acute kidney injury (25%), hyponatremia (28%),^38,39 and hepatic encephalopathy (30%).⁴⁰ Therefore, patients with acute kidney injury, hyponatremia, acute variceal hemorrhage, or infection should also have their diuretics held until their creatinine returns to baseline.

Invasive measures

Large-volume paracentesis. Patients with extensive and tense ascites should be treated initially with large-volume paracentesis, as this has been shown to predictably remove fluid more effectively than diuretics.³⁸ This should be accompanied by albumin administration, 8 g for every liter of ascitic fluid removed if the total amount exceeds 5 L.⁴¹ Following large-volume paracentesis, manage patients with the standard salt restriction and diuretic regimen.³⁸ Serial large-volume paracentesis is a temporary measure reserved for a select group of patients who are intolerant to diuretics and are not candidates for a shunt.

Transjugular intrahepatic portosystemic shunt (TIPS) is another option to control refractory ascites, but its benefit should be weighed against complications such as hepatic encephalopathy. An RCT found that TIPS with covered stents improved survival in patients with cirrhosis compared with regular large-volume paracentesis.⁴² Patients should be referred to hepatologists to make a determination about TIPS placement. Widely accepted contraindications for the placement of TIPS are decompensated cirrhosis (Child-Pugh > 11, model for end-stage liver disease [MELD] > 18), renal failure (serum creatinine > 3 mg/dL), heart failure, porto-pulmonary hypertension, and uncontrolled sepsis.⁴³ Recurrent or persistent hepatic encephalopathy (West Haven grade ≥ 2) is also a contraindication. The West Haven scale is widely used to measure severity of hepatic encephalopathy, grading it from 1 to 4, with 1 being mild encephalopathy characterized by lack of awareness and shorter attention span, and 4 indicating unresponsiveness or coma.⁴⁴

Continue to: How to manage refractory ascites

Fragile patients are those with refractory ascites that is either unresponsive to standard salt restriction and maximum-dose diuretic therapy or that results in a re-accumulation of ascitic fluid soon after paracentesis.⁴⁵ Specialist care is required to improve survival and quality of life for these patients. They should be referred to a hepatologist for consideration of TIPS placement or liver transplantation.¹⁸

Long-term use of albumin was tested in 2 trials for management of decompensated cirrhosis with ascites, yielding conflicting results. The ANSWER trial from Italy showed benefit with this treatment for prolonged survival.⁴⁶ The other trial, from Spain, showed no benefit from albumin and midodrine administration for survival or for improving complications of cirrhosis.⁴⁷ The contradictory results are likely due to heterogeneous populations in the 2 trials and differences in dose and duration of albumin administration. Hence, no clear recommendations can be made based on the available data; further research is needed.

Getting a handle on bacterial peritonitis

Bacterial peritonitis can be divided into spontaneous bacterial peritonitis (SBP) and secondary bacterial peritonitis. SBP is a common complication in patients with cirrhosis and occurs in around 16% of hospitalized patients, based on 1 study.⁴⁸ SBP is defined as a polymorphonuclear leukocyte count ≥ 250 cells/μL in the absence of a surgically treatable source of infection.⁴⁹ It is believed to be caused by bacterial translocation and is treated empirically with a third-­generation cephalosporin. This treatment has been shown to be effective in 85% of patients.⁵⁰

Diuresis with mineralocorticoid inhibitors alone may be considered for new onset mild-to-moderate ascites in patients with normal renal function.

Patients with SBP are at a higher risk for renal impairment, likely resulting from increased cytokine production and decreased circulatory volume.⁵¹ Concomitant albumin administration has been shown to significantly improve outcomes and to reduce rates of hepatorenal syndrome in patients with serum creatinine > 1 mg/dL, blood urea nitrogen > 30 mg/dL, or total bilirubin > 4 mg/dL.⁵² The recommended amount of albumin is 1.5 g/kg given within 6 hours of SBP detection and repeat administration of 1 g/kg on Day 3.⁵²

Guidelines from the American Association for the Study of Liver Diseases and from EASL recommend the long-term use of daily norfloxacin or trimethoprim-­sulfamethoxazole as secondary prophylaxis in patients who have survived an episode of SBP.^18,30 Long-term antibiotic use is also justified for primary prophylaxis in cirrhosis patients who fulfill certain criteria: ascitic fluid protein < 1.5 g/dL along with impaired renal function (serum creatinine ≥ 1.2 mg/dL, blood urea nitrogen ≥ 25 mg/dL, or serum sodium ≥ 130 mEq/L) or with decompensated cirrhosis (Child-Pugh score ≥ 9 and bilirubin ≥ 3 mg/dL).⁵³ It has been shown to reduce the risk of SBP and hepatorenal syndrome, and improve overall survival.⁵³

Continue to: Avoid these medications

Avoid these medications

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These agents block the action of angiotensin, which is a vital vasoconstrictor, and thereby cause a drop in blood pressure. This has independently been associated with poor outcomes in patients with cirrhosis.³⁷

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are also relatively contraindicated in cirrhosis, as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion. NSAIDs induce vasoconstriction of afferent arterioles in the kidneys, leading to a decreased glomerular filtration rate, further activating RAAS and sympathetic drive. This leads to increased sodium and water retention and worsening ascites.⁵⁴

Improve outcomes by circling in a hepatologist

PCPs can play a vital role in the prevention, treatment, surveillance, and home care of patients with cirrhosis who are at risk for ascites.⁵⁵ Referral of patients with hepatic impairment manifesting as unexplained abnormal liver function tests, new-onset ascites, and/or image findings consistent with cirrhosis to a hepatologist at least once is recommended. Such referrals have been shown to be associated with a better overall outcome.⁵⁶ Patients with known cirrhosis leading to ascites can generally be managed at home with the assistance of specialists and specialized nurses.³⁵

NSAIDs are relatively contraindicated in cirrhosis as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion.

In a study from the University of Michigan, 69% of patients with cirrhosis had at least 1 nonelective readmission; 14% of patients were readmitted within 1 week, and 37% within 1 month.⁵⁷ These are staggering statistics that highlight the gaps in care coordination and management of patients with cirrhosis in the outpatient setting. PCPs can play a vital role in bridging this gap.

A promising framework is suggested by a study from Italy by Morando et al in 2013.⁵⁸ The researchers assessed a specialized health care model for cirrhotic patients and showed significant improvement in health care cost, readmission rate, and overall mortality when compared with the existing model of outpatient care.⁵⁸

Continue to: This was not a blinded study...

This was not a blinded study and there were concerns raised by the scientific community about its design. Because it was conducted in Italy, the results might not be fully applicable to the United States health care setting. However, it did show that better coordination of care leads to significantly better patient outcomes and reduces health care expenditure. Therefore, a more complete understanding of the disease process and latest literature by PCPs, communication with specialists, and comprehensive coordination of care by all parties involved is vital for the management of this patient population.

CORRESPONDENCE
Muhammad Salman Faisal, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; [email protected]

Liver cirrhosis is implicated in 75% to 85% of ascites cases in the Western world, with heart failure or malignancy accounting for fewer cases.¹ Among patients who have decompensated cirrhosis with ascites, annual mortality is 20%.² Another study showed a 3-year survival rate after onset of ascites of only 56%.³ It is vital for primary care physicians (PCPs) to be alert for ascites not only in patients who have risk factors for chronic liver disease and cirrhosis—eg, a history of alcohol use disorder, chronic viral infections (hepatitis B and C), or metabolic syndrome—but also in patients with abnormal liver function tests and thrombocytopenia. In this review, we discuss the initial assessment of ascites and its long-term management, concentrating on the role of the PCP.

Pathophysiology: Vasodilation leads to a cascade

Splanchnic vasodilation is the main underlying event triggering a pathologic cascade that leads to the development of ascites.⁴ Initially portal hypertension in the setting of liver inflammation and fibrosis causes the release of inflammatory cytokines such as nitric oxide and carbon monoxide. This, in turn, causes the pathologic dilation of splanchnic circulation that decreases effective circulating volume. Activation of the sympathetic nervous system, vasopressin, and renin-­angiotensin-aldosterone system (RAAS) then causes the proximal and distal tubules to increase renal absorption of sodium and water.⁵ The resulting volume overload further decreases the heart’s ability to maintain circulating volume, leading to increased activation of compensating symptoms. This vicious cycle eventually manifests as ascites.⁶

A complex interplay of cirrhosis-associated immune dysfunction (CAID), gut dysbiosis, and increased translocation of microorganisms into ascitic fluid is also an important aspect of the pathogenesis.⁷ CAID (FIGURE 1)^7,8 is an immunodeficient state due to cirrhosis with reduced phagocytic activity by neutrophils and macrophages, T- and B-cell hypoproliferation, and reduced cytotoxicity of natural killer cells. In parallel, there is increased production of inflammatory cytokines due to the effects of damage-associated molecular patterns (DAMPs) from hepatocytes and ­pathogen-associated molecular patterns (PAMPs) from the gut microbiota on the immune system, which leads to many of the manifestations of decompensated cirrhosis including ascites.⁸

Key in on these elementsof the history and exam

Each step of the basic work-up for ascites provides opportunities to refine or redirect the diagnostic inquiry (TABLE).

History

Generally, patients with ascites present with weight gain and symptoms of abdominal distension, such as early satiety, nausea, and vomiting. Besides cirrhosis, rule out other causes of ascites, as treatment differs based on the cause.⁹ Also ask about histories of cancer and cardiac, renal, or thyroid disease.¹⁰

Patients with ascites in the setting of liver disease usually are asymptomatic in its early stages. Common complaints are vague abdominal pain, generalized weakness, malaise, and fatigue.¹¹ Ask patients about risk factors for liver disease such as obesity, diabetes, hypertension, alcohol use, unsafe sexual practices, recent travel, and needle sharing or drug use. Due to a strong association between obstructive sleep apnea and fatty liver disease, consider screening at-risk patients for sleep apnea.¹²

Physical exam

When there are risk factors for liver disease, examine the patient for stigmata of cirrhosis and ascites. Signs of liver disease, aside from ascites, may include spider angiomas on the upper trunk (33% of cirrhosis patients),¹³ gynecomastia (44% of cirrhosis patients),¹⁴ palmar erythema, jaundice, asterixis, and abdominal wall collaterals including caput medusa.¹⁵

Continue to: We suggest a systematic...

We suggest a systematic and targeted approach to using various physical exam maneuvers described in the literature. If the patient has a full/distended abdomen, percuss the flanks. If increased dullness at the flanks is detected, check for shifting dullness, which indicates at least 1500 mL of fluid in the abdomen.¹⁶ Keep in mind that a 10% chance of ascites exists even if shifting dullness is absent.¹⁷ Maneuvers such as the puddle sign and fluid thrill are less accurate than shifting dullness, which has 83% sensitivity and 56% specificity in detecting ascites.¹⁷ Patients with cirrhosis also have a high likelihood of complications from ascites such as inguinal, umbilical, and other hernias.

Diagnostic work-up includes blood tests and ultrasound

Blood tests. The initial work-up for ascites should include complete blood count, complete metabolic panel, and prothrombin time/international normalized ratio.¹⁸

Abdominal ultrasound is recommended as the first-line imaging test.¹⁹ Aside from detecting ascites, it can give an estimate of the volume of ascites and indicate whether it is amenable to paracentesis. A vascular exam added to the standard ultrasound can detect radiologic evidence of portal hypertension such as splenomegaly, portosystemic collaterals, splenorenal shunt, patency of the paraumbilical vein, and portal vein diameter. Patients with established cirrhosis also require abdominal ultrasound every 6 months to screen for hepatocellular cancer.²⁰

Abdominal paracentesis is the cornerstone of ascites evaluation.²¹ It is indicated for every patient with new-onset ascites or for any patient with known ascites and clinical deterioration. Ascitic fluid analysis can be used to easily differentiate portal hypertension from other causes of ascites. It can also be used to rule out bacterial peritonitis. The recommended sites for evaluation are in the left lower quadrant, 3 cm cranially and 3 cm medially from the anterior superior iliac spine.²² A large cohort study showed that abdominal ultrasound-guided paracentesis reduced bleeding complications by 68% following the procedure and is strongly recommended (if available).²³ Generally, paracentesis is a relatively safe procedure with a low risk of complications such as abdominal wall hematoma (1%), hemoperitoneum (< 0.1%), bowel perforation (< 0.1%), and infection (< 0.1%).²⁴

Calculating the serum ascites albumin gradient better characterizes ascitic fluid than total protein-based tests.

Assess all ascitic fluid samples for color, consistency, cell count and differential, albumin, and total protein. These tests are usually sufficient to provide evidence regarding the cause of ascites. If there is suspicion of infection, order a gram stain and culture (80% sensitivity for detecting an infection if obtained prior to initiation of antibiotics)²⁵ and glucose, lactate dehydrogenase (useful to differentiate primary from secondary bacterial peritonitis),²⁶ and amylase tests. Other tests such as cytology, acid-fast bacilli smear and culture, and triglyceride level should only be obtained if specific conditions are suspected based on high pretest probabilities.

Continue to: Calculating serum ascites albumin gradient...

Calculating serum ascites albumin gradient (SAAG) is recommended as it has been shown to better characterize ascitic fluid than total protein-based tests.²⁷ SAAG is calculated by subtracting the level of ascitic fluid albumin from serum albumin level (SAAG = serum albumin – ascitic fluid albumin). A SAAG ≥ 1.1 g/dL is consistent with portal hypertension,²⁸ with approximately 97% accuracy.

After calculating SAAG, look at total protein levels in ascitic fluid. Total protein concentration ≥ 2.5 g/dL with SAAG ≥ 1.1 g/dL has a 78.3% diagnostic accuracy in determining heart failure as the cause of ascites, with a sensitivity of 53.3% and specificity of 86.7%.²⁸ On the other hand, a value of total protein < 2.5 g/dL indicates cirrhosis, liver failure, or acute hepatitis as the cause of fluid build-up.²⁹ Stepwise evaluation of SAAG and total protein and how they can point toward the most likely cause of ascites is presented in FIGURE 2.^27-29

Management

Noninvasive measures

Sodium restriction. The aim of treatment for uncomplicated clinically apparent ascites is sodium restriction and removal of fluid from the body. Dietary salt restriction is complicated, and care should be taken to properly educate patients. Salt restriction advised in the literature has shifted from a strict measure of < 2 g/d³⁰ to more moderate strategies (described below).¹⁸

The 2 main reasons for this easing of restriction are issues with patient compliance and concerns about adverse effects with aggressive salt-restricted diets. One study assessing patient compliance with a salt-restricted diet found that more than two-thirds of the patients were noncompliant,³¹ and 65% of the patients incorrectly assumed they were following the plan, which suggests poor dietary education.³¹ Of the group that was compliant, 20% actually decreased their caloric intake, which can be detrimental in liver disease.³¹ Concerns have been raised that aggressive salt restriction along with diuretic use can lead to diuretic-induced hyponatremia and renal failure.³² Current European Association for the Study of the Liver (EASL) guidelines recommend salt restriction to a more moderate degree (80-120 mmol/d of sodium). This is equivalent to 4.9-6.9 g of salt (1 tablespoon is roughly equivalent to 6 g or 104 mmol of sodium).¹⁸

Diuretics. Initiation and dosage of diuretic therapy is a matter of some controversy. Historically, simultaneous ­administration of a loop diuretic and mineralocorticoid receptor blocker were recommended: 40 mg furosemide and 100 mg spironolactone, keeping the ratio constant with any dosage increases. This was based on a randomized controlled trial (RCT) showing that the combined diuretic therapy effectively mobilized ascites in a shorter period of time and with less frequent adverse effects (eg, hyperkalemia) compared with initial monotherapy.³³

Continue to: On the other hand...

On the other hand, another study with more stable patients and relatively normal renal function showed that starting with a mineralocorticoid receptor blocker alone with sequential dose increments had equivalent benefit with no increase in adverse effects.³⁴ Since the patient population in this study was more in line with what a PCP might encounter, we recommend following this guideline initially and keeping a close watch on serum electrolytes.

Usual maximum doses are spironolactone 400 mg/d and furosemide 160 mg/d.^21,35 Adequate weight loss for patients with diffuse edema is at least 1 kg/d, per EASL guidelines.^36,37 However, this might not be practical in outpatient settings, and a more conservative target of 0.5 kg/d may be used for patients without significant edema.³⁷

It is vital to get accurate daily weights and avoid excessive diuretic use, as it has been associated with intravascular volume depletion and acute kidney injury (25%), hyponatremia (28%),^38,39 and hepatic encephalopathy (30%).⁴⁰ Therefore, patients with acute kidney injury, hyponatremia, acute variceal hemorrhage, or infection should also have their diuretics held until their creatinine returns to baseline.

Invasive measures

Large-volume paracentesis. Patients with extensive and tense ascites should be treated initially with large-volume paracentesis, as this has been shown to predictably remove fluid more effectively than diuretics.³⁸ This should be accompanied by albumin administration, 8 g for every liter of ascitic fluid removed if the total amount exceeds 5 L.⁴¹ Following large-volume paracentesis, manage patients with the standard salt restriction and diuretic regimen.³⁸ Serial large-volume paracentesis is a temporary measure reserved for a select group of patients who are intolerant to diuretics and are not candidates for a shunt.

Transjugular intrahepatic portosystemic shunt (TIPS) is another option to control refractory ascites, but its benefit should be weighed against complications such as hepatic encephalopathy. An RCT found that TIPS with covered stents improved survival in patients with cirrhosis compared with regular large-volume paracentesis.⁴² Patients should be referred to hepatologists to make a determination about TIPS placement. Widely accepted contraindications for the placement of TIPS are decompensated cirrhosis (Child-Pugh > 11, model for end-stage liver disease [MELD] > 18), renal failure (serum creatinine > 3 mg/dL), heart failure, porto-pulmonary hypertension, and uncontrolled sepsis.⁴³ Recurrent or persistent hepatic encephalopathy (West Haven grade ≥ 2) is also a contraindication. The West Haven scale is widely used to measure severity of hepatic encephalopathy, grading it from 1 to 4, with 1 being mild encephalopathy characterized by lack of awareness and shorter attention span, and 4 indicating unresponsiveness or coma.⁴⁴

Continue to: How to manage refractory ascites

Fragile patients are those with refractory ascites that is either unresponsive to standard salt restriction and maximum-dose diuretic therapy or that results in a re-accumulation of ascitic fluid soon after paracentesis.⁴⁵ Specialist care is required to improve survival and quality of life for these patients. They should be referred to a hepatologist for consideration of TIPS placement or liver transplantation.¹⁸

Long-term use of albumin was tested in 2 trials for management of decompensated cirrhosis with ascites, yielding conflicting results. The ANSWER trial from Italy showed benefit with this treatment for prolonged survival.⁴⁶ The other trial, from Spain, showed no benefit from albumin and midodrine administration for survival or for improving complications of cirrhosis.⁴⁷ The contradictory results are likely due to heterogeneous populations in the 2 trials and differences in dose and duration of albumin administration. Hence, no clear recommendations can be made based on the available data; further research is needed.

Getting a handle on bacterial peritonitis

Bacterial peritonitis can be divided into spontaneous bacterial peritonitis (SBP) and secondary bacterial peritonitis. SBP is a common complication in patients with cirrhosis and occurs in around 16% of hospitalized patients, based on 1 study.⁴⁸ SBP is defined as a polymorphonuclear leukocyte count ≥ 250 cells/μL in the absence of a surgically treatable source of infection.⁴⁹ It is believed to be caused by bacterial translocation and is treated empirically with a third-­generation cephalosporin. This treatment has been shown to be effective in 85% of patients.⁵⁰

Diuresis with mineralocorticoid inhibitors alone may be considered for new onset mild-to-moderate ascites in patients with normal renal function.

Patients with SBP are at a higher risk for renal impairment, likely resulting from increased cytokine production and decreased circulatory volume.⁵¹ Concomitant albumin administration has been shown to significantly improve outcomes and to reduce rates of hepatorenal syndrome in patients with serum creatinine > 1 mg/dL, blood urea nitrogen > 30 mg/dL, or total bilirubin > 4 mg/dL.⁵² The recommended amount of albumin is 1.5 g/kg given within 6 hours of SBP detection and repeat administration of 1 g/kg on Day 3.⁵²

Guidelines from the American Association for the Study of Liver Diseases and from EASL recommend the long-term use of daily norfloxacin or trimethoprim-­sulfamethoxazole as secondary prophylaxis in patients who have survived an episode of SBP.^18,30 Long-term antibiotic use is also justified for primary prophylaxis in cirrhosis patients who fulfill certain criteria: ascitic fluid protein < 1.5 g/dL along with impaired renal function (serum creatinine ≥ 1.2 mg/dL, blood urea nitrogen ≥ 25 mg/dL, or serum sodium ≥ 130 mEq/L) or with decompensated cirrhosis (Child-Pugh score ≥ 9 and bilirubin ≥ 3 mg/dL).⁵³ It has been shown to reduce the risk of SBP and hepatorenal syndrome, and improve overall survival.⁵³

Continue to: Avoid these medications

Avoid these medications

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These agents block the action of angiotensin, which is a vital vasoconstrictor, and thereby cause a drop in blood pressure. This has independently been associated with poor outcomes in patients with cirrhosis.³⁷

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are also relatively contraindicated in cirrhosis, as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion. NSAIDs induce vasoconstriction of afferent arterioles in the kidneys, leading to a decreased glomerular filtration rate, further activating RAAS and sympathetic drive. This leads to increased sodium and water retention and worsening ascites.⁵⁴

Improve outcomes by circling in a hepatologist

PCPs can play a vital role in the prevention, treatment, surveillance, and home care of patients with cirrhosis who are at risk for ascites.⁵⁵ Referral of patients with hepatic impairment manifesting as unexplained abnormal liver function tests, new-onset ascites, and/or image findings consistent with cirrhosis to a hepatologist at least once is recommended. Such referrals have been shown to be associated with a better overall outcome.⁵⁶ Patients with known cirrhosis leading to ascites can generally be managed at home with the assistance of specialists and specialized nurses.³⁵

NSAIDs are relatively contraindicated in cirrhosis as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion.

In a study from the University of Michigan, 69% of patients with cirrhosis had at least 1 nonelective readmission; 14% of patients were readmitted within 1 week, and 37% within 1 month.⁵⁷ These are staggering statistics that highlight the gaps in care coordination and management of patients with cirrhosis in the outpatient setting. PCPs can play a vital role in bridging this gap.

A promising framework is suggested by a study from Italy by Morando et al in 2013.⁵⁸ The researchers assessed a specialized health care model for cirrhotic patients and showed significant improvement in health care cost, readmission rate, and overall mortality when compared with the existing model of outpatient care.⁵⁸

Continue to: This was not a blinded study...

This was not a blinded study and there were concerns raised by the scientific community about its design. Because it was conducted in Italy, the results might not be fully applicable to the United States health care setting. However, it did show that better coordination of care leads to significantly better patient outcomes and reduces health care expenditure. Therefore, a more complete understanding of the disease process and latest literature by PCPs, communication with specialists, and comprehensive coordination of care by all parties involved is vital for the management of this patient population.

CORRESPONDENCE
Muhammad Salman Faisal, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; [email protected]

Liver cirrhosis is implicated in 75% to 85% of ascites cases in the Western world, with heart failure or malignancy accounting for fewer cases.¹ Among patients who have decompensated cirrhosis with ascites, annual mortality is 20%.² Another study showed a 3-year survival rate after onset of ascites of only 56%.³ It is vital for primary care physicians (PCPs) to be alert for ascites not only in patients who have risk factors for chronic liver disease and cirrhosis—eg, a history of alcohol use disorder, chronic viral infections (hepatitis B and C), or metabolic syndrome—but also in patients with abnormal liver function tests and thrombocytopenia. In this review, we discuss the initial assessment of ascites and its long-term management, concentrating on the role of the PCP.

Pathophysiology: Vasodilation leads to a cascade

Splanchnic vasodilation is the main underlying event triggering a pathologic cascade that leads to the development of ascites.⁴ Initially portal hypertension in the setting of liver inflammation and fibrosis causes the release of inflammatory cytokines such as nitric oxide and carbon monoxide. This, in turn, causes the pathologic dilation of splanchnic circulation that decreases effective circulating volume. Activation of the sympathetic nervous system, vasopressin, and renin-­angiotensin-aldosterone system (RAAS) then causes the proximal and distal tubules to increase renal absorption of sodium and water.⁵ The resulting volume overload further decreases the heart’s ability to maintain circulating volume, leading to increased activation of compensating symptoms. This vicious cycle eventually manifests as ascites.⁶

A complex interplay of cirrhosis-associated immune dysfunction (CAID), gut dysbiosis, and increased translocation of microorganisms into ascitic fluid is also an important aspect of the pathogenesis.⁷ CAID (FIGURE 1)^7,8 is an immunodeficient state due to cirrhosis with reduced phagocytic activity by neutrophils and macrophages, T- and B-cell hypoproliferation, and reduced cytotoxicity of natural killer cells. In parallel, there is increased production of inflammatory cytokines due to the effects of damage-associated molecular patterns (DAMPs) from hepatocytes and ­pathogen-associated molecular patterns (PAMPs) from the gut microbiota on the immune system, which leads to many of the manifestations of decompensated cirrhosis including ascites.⁸

Key in on these elementsof the history and exam

Each step of the basic work-up for ascites provides opportunities to refine or redirect the diagnostic inquiry (TABLE).

History

Generally, patients with ascites present with weight gain and symptoms of abdominal distension, such as early satiety, nausea, and vomiting. Besides cirrhosis, rule out other causes of ascites, as treatment differs based on the cause.⁹ Also ask about histories of cancer and cardiac, renal, or thyroid disease.¹⁰

Patients with ascites in the setting of liver disease usually are asymptomatic in its early stages. Common complaints are vague abdominal pain, generalized weakness, malaise, and fatigue.¹¹ Ask patients about risk factors for liver disease such as obesity, diabetes, hypertension, alcohol use, unsafe sexual practices, recent travel, and needle sharing or drug use. Due to a strong association between obstructive sleep apnea and fatty liver disease, consider screening at-risk patients for sleep apnea.¹²

Physical exam

When there are risk factors for liver disease, examine the patient for stigmata of cirrhosis and ascites. Signs of liver disease, aside from ascites, may include spider angiomas on the upper trunk (33% of cirrhosis patients),¹³ gynecomastia (44% of cirrhosis patients),¹⁴ palmar erythema, jaundice, asterixis, and abdominal wall collaterals including caput medusa.¹⁵

Continue to: We suggest a systematic...

We suggest a systematic and targeted approach to using various physical exam maneuvers described in the literature. If the patient has a full/distended abdomen, percuss the flanks. If increased dullness at the flanks is detected, check for shifting dullness, which indicates at least 1500 mL of fluid in the abdomen.¹⁶ Keep in mind that a 10% chance of ascites exists even if shifting dullness is absent.¹⁷ Maneuvers such as the puddle sign and fluid thrill are less accurate than shifting dullness, which has 83% sensitivity and 56% specificity in detecting ascites.¹⁷ Patients with cirrhosis also have a high likelihood of complications from ascites such as inguinal, umbilical, and other hernias.

Diagnostic work-up includes blood tests and ultrasound

Blood tests. The initial work-up for ascites should include complete blood count, complete metabolic panel, and prothrombin time/international normalized ratio.¹⁸

Abdominal ultrasound is recommended as the first-line imaging test.¹⁹ Aside from detecting ascites, it can give an estimate of the volume of ascites and indicate whether it is amenable to paracentesis. A vascular exam added to the standard ultrasound can detect radiologic evidence of portal hypertension such as splenomegaly, portosystemic collaterals, splenorenal shunt, patency of the paraumbilical vein, and portal vein diameter. Patients with established cirrhosis also require abdominal ultrasound every 6 months to screen for hepatocellular cancer.²⁰

Abdominal paracentesis is the cornerstone of ascites evaluation.²¹ It is indicated for every patient with new-onset ascites or for any patient with known ascites and clinical deterioration. Ascitic fluid analysis can be used to easily differentiate portal hypertension from other causes of ascites. It can also be used to rule out bacterial peritonitis. The recommended sites for evaluation are in the left lower quadrant, 3 cm cranially and 3 cm medially from the anterior superior iliac spine.²² A large cohort study showed that abdominal ultrasound-guided paracentesis reduced bleeding complications by 68% following the procedure and is strongly recommended (if available).²³ Generally, paracentesis is a relatively safe procedure with a low risk of complications such as abdominal wall hematoma (1%), hemoperitoneum (< 0.1%), bowel perforation (< 0.1%), and infection (< 0.1%).²⁴

Calculating the serum ascites albumin gradient better characterizes ascitic fluid than total protein-based tests.

Assess all ascitic fluid samples for color, consistency, cell count and differential, albumin, and total protein. These tests are usually sufficient to provide evidence regarding the cause of ascites. If there is suspicion of infection, order a gram stain and culture (80% sensitivity for detecting an infection if obtained prior to initiation of antibiotics)²⁵ and glucose, lactate dehydrogenase (useful to differentiate primary from secondary bacterial peritonitis),²⁶ and amylase tests. Other tests such as cytology, acid-fast bacilli smear and culture, and triglyceride level should only be obtained if specific conditions are suspected based on high pretest probabilities.

Continue to: Calculating serum ascites albumin gradient...

Calculating serum ascites albumin gradient (SAAG) is recommended as it has been shown to better characterize ascitic fluid than total protein-based tests.²⁷ SAAG is calculated by subtracting the level of ascitic fluid albumin from serum albumin level (SAAG = serum albumin – ascitic fluid albumin). A SAAG ≥ 1.1 g/dL is consistent with portal hypertension,²⁸ with approximately 97% accuracy.

After calculating SAAG, look at total protein levels in ascitic fluid. Total protein concentration ≥ 2.5 g/dL with SAAG ≥ 1.1 g/dL has a 78.3% diagnostic accuracy in determining heart failure as the cause of ascites, with a sensitivity of 53.3% and specificity of 86.7%.²⁸ On the other hand, a value of total protein < 2.5 g/dL indicates cirrhosis, liver failure, or acute hepatitis as the cause of fluid build-up.²⁹ Stepwise evaluation of SAAG and total protein and how they can point toward the most likely cause of ascites is presented in FIGURE 2.^27-29

Management

Noninvasive measures

Sodium restriction. The aim of treatment for uncomplicated clinically apparent ascites is sodium restriction and removal of fluid from the body. Dietary salt restriction is complicated, and care should be taken to properly educate patients. Salt restriction advised in the literature has shifted from a strict measure of < 2 g/d³⁰ to more moderate strategies (described below).¹⁸

The 2 main reasons for this easing of restriction are issues with patient compliance and concerns about adverse effects with aggressive salt-restricted diets. One study assessing patient compliance with a salt-restricted diet found that more than two-thirds of the patients were noncompliant,³¹ and 65% of the patients incorrectly assumed they were following the plan, which suggests poor dietary education.³¹ Of the group that was compliant, 20% actually decreased their caloric intake, which can be detrimental in liver disease.³¹ Concerns have been raised that aggressive salt restriction along with diuretic use can lead to diuretic-induced hyponatremia and renal failure.³² Current European Association for the Study of the Liver (EASL) guidelines recommend salt restriction to a more moderate degree (80-120 mmol/d of sodium). This is equivalent to 4.9-6.9 g of salt (1 tablespoon is roughly equivalent to 6 g or 104 mmol of sodium).¹⁸

Diuretics. Initiation and dosage of diuretic therapy is a matter of some controversy. Historically, simultaneous ­administration of a loop diuretic and mineralocorticoid receptor blocker were recommended: 40 mg furosemide and 100 mg spironolactone, keeping the ratio constant with any dosage increases. This was based on a randomized controlled trial (RCT) showing that the combined diuretic therapy effectively mobilized ascites in a shorter period of time and with less frequent adverse effects (eg, hyperkalemia) compared with initial monotherapy.³³

Continue to: On the other hand...

On the other hand, another study with more stable patients and relatively normal renal function showed that starting with a mineralocorticoid receptor blocker alone with sequential dose increments had equivalent benefit with no increase in adverse effects.³⁴ Since the patient population in this study was more in line with what a PCP might encounter, we recommend following this guideline initially and keeping a close watch on serum electrolytes.

Usual maximum doses are spironolactone 400 mg/d and furosemide 160 mg/d.^21,35 Adequate weight loss for patients with diffuse edema is at least 1 kg/d, per EASL guidelines.^36,37 However, this might not be practical in outpatient settings, and a more conservative target of 0.5 kg/d may be used for patients without significant edema.³⁷

It is vital to get accurate daily weights and avoid excessive diuretic use, as it has been associated with intravascular volume depletion and acute kidney injury (25%), hyponatremia (28%),^38,39 and hepatic encephalopathy (30%).⁴⁰ Therefore, patients with acute kidney injury, hyponatremia, acute variceal hemorrhage, or infection should also have their diuretics held until their creatinine returns to baseline.

Invasive measures

Large-volume paracentesis. Patients with extensive and tense ascites should be treated initially with large-volume paracentesis, as this has been shown to predictably remove fluid more effectively than diuretics.³⁸ This should be accompanied by albumin administration, 8 g for every liter of ascitic fluid removed if the total amount exceeds 5 L.⁴¹ Following large-volume paracentesis, manage patients with the standard salt restriction and diuretic regimen.³⁸ Serial large-volume paracentesis is a temporary measure reserved for a select group of patients who are intolerant to diuretics and are not candidates for a shunt.

Transjugular intrahepatic portosystemic shunt (TIPS) is another option to control refractory ascites, but its benefit should be weighed against complications such as hepatic encephalopathy. An RCT found that TIPS with covered stents improved survival in patients with cirrhosis compared with regular large-volume paracentesis.⁴² Patients should be referred to hepatologists to make a determination about TIPS placement. Widely accepted contraindications for the placement of TIPS are decompensated cirrhosis (Child-Pugh > 11, model for end-stage liver disease [MELD] > 18), renal failure (serum creatinine > 3 mg/dL), heart failure, porto-pulmonary hypertension, and uncontrolled sepsis.⁴³ Recurrent or persistent hepatic encephalopathy (West Haven grade ≥ 2) is also a contraindication. The West Haven scale is widely used to measure severity of hepatic encephalopathy, grading it from 1 to 4, with 1 being mild encephalopathy characterized by lack of awareness and shorter attention span, and 4 indicating unresponsiveness or coma.⁴⁴

Continue to: How to manage refractory ascites

Fragile patients are those with refractory ascites that is either unresponsive to standard salt restriction and maximum-dose diuretic therapy or that results in a re-accumulation of ascitic fluid soon after paracentesis.⁴⁵ Specialist care is required to improve survival and quality of life for these patients. They should be referred to a hepatologist for consideration of TIPS placement or liver transplantation.¹⁸

Long-term use of albumin was tested in 2 trials for management of decompensated cirrhosis with ascites, yielding conflicting results. The ANSWER trial from Italy showed benefit with this treatment for prolonged survival.⁴⁶ The other trial, from Spain, showed no benefit from albumin and midodrine administration for survival or for improving complications of cirrhosis.⁴⁷ The contradictory results are likely due to heterogeneous populations in the 2 trials and differences in dose and duration of albumin administration. Hence, no clear recommendations can be made based on the available data; further research is needed.

Getting a handle on bacterial peritonitis

Bacterial peritonitis can be divided into spontaneous bacterial peritonitis (SBP) and secondary bacterial peritonitis. SBP is a common complication in patients with cirrhosis and occurs in around 16% of hospitalized patients, based on 1 study.⁴⁸ SBP is defined as a polymorphonuclear leukocyte count ≥ 250 cells/μL in the absence of a surgically treatable source of infection.⁴⁹ It is believed to be caused by bacterial translocation and is treated empirically with a third-­generation cephalosporin. This treatment has been shown to be effective in 85% of patients.⁵⁰

Diuresis with mineralocorticoid inhibitors alone may be considered for new onset mild-to-moderate ascites in patients with normal renal function.

Patients with SBP are at a higher risk for renal impairment, likely resulting from increased cytokine production and decreased circulatory volume.⁵¹ Concomitant albumin administration has been shown to significantly improve outcomes and to reduce rates of hepatorenal syndrome in patients with serum creatinine > 1 mg/dL, blood urea nitrogen > 30 mg/dL, or total bilirubin > 4 mg/dL.⁵² The recommended amount of albumin is 1.5 g/kg given within 6 hours of SBP detection and repeat administration of 1 g/kg on Day 3.⁵²

Guidelines from the American Association for the Study of Liver Diseases and from EASL recommend the long-term use of daily norfloxacin or trimethoprim-­sulfamethoxazole as secondary prophylaxis in patients who have survived an episode of SBP.^18,30 Long-term antibiotic use is also justified for primary prophylaxis in cirrhosis patients who fulfill certain criteria: ascitic fluid protein < 1.5 g/dL along with impaired renal function (serum creatinine ≥ 1.2 mg/dL, blood urea nitrogen ≥ 25 mg/dL, or serum sodium ≥ 130 mEq/L) or with decompensated cirrhosis (Child-Pugh score ≥ 9 and bilirubin ≥ 3 mg/dL).⁵³ It has been shown to reduce the risk of SBP and hepatorenal syndrome, and improve overall survival.⁵³

Continue to: Avoid these medications

Avoid these medications

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These agents block the action of angiotensin, which is a vital vasoconstrictor, and thereby cause a drop in blood pressure. This has independently been associated with poor outcomes in patients with cirrhosis.³⁷

Commonly used medications that should be avoided in patients with cirrhosis and ascites are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are also relatively contraindicated in cirrhosis, as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion. NSAIDs induce vasoconstriction of afferent arterioles in the kidneys, leading to a decreased glomerular filtration rate, further activating RAAS and sympathetic drive. This leads to increased sodium and water retention and worsening ascites.⁵⁴

Improve outcomes by circling in a hepatologist

PCPs can play a vital role in the prevention, treatment, surveillance, and home care of patients with cirrhosis who are at risk for ascites.⁵⁵ Referral of patients with hepatic impairment manifesting as unexplained abnormal liver function tests, new-onset ascites, and/or image findings consistent with cirrhosis to a hepatologist at least once is recommended. Such referrals have been shown to be associated with a better overall outcome.⁵⁶ Patients with known cirrhosis leading to ascites can generally be managed at home with the assistance of specialists and specialized nurses.³⁵

NSAIDs are relatively contraindicated in cirrhosis as they can affect kidney function, induce azotemia, and reduce kidney sodium excretion.

In a study from the University of Michigan, 69% of patients with cirrhosis had at least 1 nonelective readmission; 14% of patients were readmitted within 1 week, and 37% within 1 month.⁵⁷ These are staggering statistics that highlight the gaps in care coordination and management of patients with cirrhosis in the outpatient setting. PCPs can play a vital role in bridging this gap.

A promising framework is suggested by a study from Italy by Morando et al in 2013.⁵⁸ The researchers assessed a specialized health care model for cirrhotic patients and showed significant improvement in health care cost, readmission rate, and overall mortality when compared with the existing model of outpatient care.⁵⁸

Continue to: This was not a blinded study...

This was not a blinded study and there were concerns raised by the scientific community about its design. Because it was conducted in Italy, the results might not be fully applicable to the United States health care setting. However, it did show that better coordination of care leads to significantly better patient outcomes and reduces health care expenditure. Therefore, a more complete understanding of the disease process and latest literature by PCPs, communication with specialists, and comprehensive coordination of care by all parties involved is vital for the management of this patient population.

CORRESPONDENCE
Muhammad Salman Faisal, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195; [email protected]

Nonalcoholic fatty liver disease (NAFLD) in children is almost always caused by excess body weight, not other etiologies, based on a retrospective analysis of 900 patients.

Just 2% of children with overweight or obesity and suspected NAFLD had other causes of liver disease, and none tested positive for autoimmune hepatitis (AIH), reported lead author Toshifumi Yodoshi, MD, PhD, of Cincinnati Children’s Hospital Medical Center, and colleagues.

“Currently, recommended testing of patients with suspected NAFLD includes ruling out the following conditions: AIH, Wilson disease, hemochromatosis, alpha-1 antitrypsin [A1AT] deficiency, viral hepatitis, celiac disease, and thyroid dysfunction,” the investigators wrote in Pediatrics.

Yet evidence supporting this particular battery of tests is scant; just one previous pediatric study has estimated the prevalence of other liver diseases among children with suspected NAFLD. The study showed that the second-most common etiology, after NAFLD, was AIH, at a rate of 4%.

But “the generalizability of these findings is uncertain,” noted Dr. Yodoshi and colleagues, as the study was conducted at one tertiary center in the western United States, among a population that was predominantly Hispanic.

This uncertainty spurred the present study, which was conducted at two pediatric centers: Cincinnati Children’s Hospital Medical Center (2009-2017) and Yale New Haven (Conn.) Children’s Hospital (2012-2017).

The final analysis involved 900 patients aged 18 years or younger with suspected NAFLD based on hepatic steatosis detected via imaging and/or elevated serum aminotransferases. Demographically, a slight majority of the patients were boys (63%), and approximately one-quarter (26%) were Hispanic. Median BMI z score was 2.45, with three out of four patients (76%) exhibiting severe obesity. Out of 900 patients, 358 (40%) underwent liver biopsy, among whom 46% had confirmed nonalcoholic steatohepatitis.

All patients underwent testing to exclude the aforementioned conditions using various diagnostics, revealing that just 2% of the population had etiologies other than NAFLD. Specifically, 11 children had thyroid dysfunction (1.2%), 3 had celiac disease (0.4%), 3 had A1AT deficiency (0.4%), 1 had hemophagocytic lymphohistiocytosis, and 1 had Hodgkin’s lymphoma. None of the children had Wilson disease, hepatitis B or C, or AIH.

Dr. Yodoshi and colleagues highlighted the latter finding, noting that 13% of the patients had autoantibodies for AIH, but “none met composite criteria.” This contrasts with the previous study from 2013, which found an AIH rate of 4%.

“Nonetheless,” the investigators went on, “NAFLD remains a diagnosis of exclusion, and key conditions that require specific treatments must be ruled out in the workup of patients with suspected NAFLD. In the future, the cost-effectiveness of this approach will need to be investigated.”

Interpreting the findings, Francis E. Rushton, MD, of Beaufort (S.C.) Memorial Hospital emphasized the implications for preventive and interventional health care.

“This study showing an absence of etiologies other than obesity in overweight children with NAFLD provides further impetus for pediatricians to work on both preventive and treatment regimens for weight issues,” Dr. Rushton said. “Linking community-based initiatives focused on adequate nutritional support with pediatric clinical support services is critical in solving issues related to overweight in children. Tracking BMI over time and developing healthy habit goals for patients are key parts of clinical interventions.” 

The study was funded by the National Institutes of Health. The investigators reported no conflicts of interest.

Nonalcoholic fatty liver disease (NAFLD) in children is almost always caused by excess body weight, not other etiologies, based on a retrospective analysis of 900 patients.

Just 2% of children with overweight or obesity and suspected NAFLD had other causes of liver disease, and none tested positive for autoimmune hepatitis (AIH), reported lead author Toshifumi Yodoshi, MD, PhD, of Cincinnati Children’s Hospital Medical Center, and colleagues.

“Currently, recommended testing of patients with suspected NAFLD includes ruling out the following conditions: AIH, Wilson disease, hemochromatosis, alpha-1 antitrypsin [A1AT] deficiency, viral hepatitis, celiac disease, and thyroid dysfunction,” the investigators wrote in Pediatrics.

Yet evidence supporting this particular battery of tests is scant; just one previous pediatric study has estimated the prevalence of other liver diseases among children with suspected NAFLD. The study showed that the second-most common etiology, after NAFLD, was AIH, at a rate of 4%.

But “the generalizability of these findings is uncertain,” noted Dr. Yodoshi and colleagues, as the study was conducted at one tertiary center in the western United States, among a population that was predominantly Hispanic.

This uncertainty spurred the present study, which was conducted at two pediatric centers: Cincinnati Children’s Hospital Medical Center (2009-2017) and Yale New Haven (Conn.) Children’s Hospital (2012-2017).

The final analysis involved 900 patients aged 18 years or younger with suspected NAFLD based on hepatic steatosis detected via imaging and/or elevated serum aminotransferases. Demographically, a slight majority of the patients were boys (63%), and approximately one-quarter (26%) were Hispanic. Median BMI z score was 2.45, with three out of four patients (76%) exhibiting severe obesity. Out of 900 patients, 358 (40%) underwent liver biopsy, among whom 46% had confirmed nonalcoholic steatohepatitis.

All patients underwent testing to exclude the aforementioned conditions using various diagnostics, revealing that just 2% of the population had etiologies other than NAFLD. Specifically, 11 children had thyroid dysfunction (1.2%), 3 had celiac disease (0.4%), 3 had A1AT deficiency (0.4%), 1 had hemophagocytic lymphohistiocytosis, and 1 had Hodgkin’s lymphoma. None of the children had Wilson disease, hepatitis B or C, or AIH.

Dr. Yodoshi and colleagues highlighted the latter finding, noting that 13% of the patients had autoantibodies for AIH, but “none met composite criteria.” This contrasts with the previous study from 2013, which found an AIH rate of 4%.

“Nonetheless,” the investigators went on, “NAFLD remains a diagnosis of exclusion, and key conditions that require specific treatments must be ruled out in the workup of patients with suspected NAFLD. In the future, the cost-effectiveness of this approach will need to be investigated.”

Interpreting the findings, Francis E. Rushton, MD, of Beaufort (S.C.) Memorial Hospital emphasized the implications for preventive and interventional health care.

“This study showing an absence of etiologies other than obesity in overweight children with NAFLD provides further impetus for pediatricians to work on both preventive and treatment regimens for weight issues,” Dr. Rushton said. “Linking community-based initiatives focused on adequate nutritional support with pediatric clinical support services is critical in solving issues related to overweight in children. Tracking BMI over time and developing healthy habit goals for patients are key parts of clinical interventions.” 

The study was funded by the National Institutes of Health. The investigators reported no conflicts of interest.

Nonalcoholic fatty liver disease (NAFLD) in children is almost always caused by excess body weight, not other etiologies, based on a retrospective analysis of 900 patients.

Just 2% of children with overweight or obesity and suspected NAFLD had other causes of liver disease, and none tested positive for autoimmune hepatitis (AIH), reported lead author Toshifumi Yodoshi, MD, PhD, of Cincinnati Children’s Hospital Medical Center, and colleagues.

“Currently, recommended testing of patients with suspected NAFLD includes ruling out the following conditions: AIH, Wilson disease, hemochromatosis, alpha-1 antitrypsin [A1AT] deficiency, viral hepatitis, celiac disease, and thyroid dysfunction,” the investigators wrote in Pediatrics.

Yet evidence supporting this particular battery of tests is scant; just one previous pediatric study has estimated the prevalence of other liver diseases among children with suspected NAFLD. The study showed that the second-most common etiology, after NAFLD, was AIH, at a rate of 4%.

But “the generalizability of these findings is uncertain,” noted Dr. Yodoshi and colleagues, as the study was conducted at one tertiary center in the western United States, among a population that was predominantly Hispanic.

This uncertainty spurred the present study, which was conducted at two pediatric centers: Cincinnati Children’s Hospital Medical Center (2009-2017) and Yale New Haven (Conn.) Children’s Hospital (2012-2017).

The final analysis involved 900 patients aged 18 years or younger with suspected NAFLD based on hepatic steatosis detected via imaging and/or elevated serum aminotransferases. Demographically, a slight majority of the patients were boys (63%), and approximately one-quarter (26%) were Hispanic. Median BMI z score was 2.45, with three out of four patients (76%) exhibiting severe obesity. Out of 900 patients, 358 (40%) underwent liver biopsy, among whom 46% had confirmed nonalcoholic steatohepatitis.

All patients underwent testing to exclude the aforementioned conditions using various diagnostics, revealing that just 2% of the population had etiologies other than NAFLD. Specifically, 11 children had thyroid dysfunction (1.2%), 3 had celiac disease (0.4%), 3 had A1AT deficiency (0.4%), 1 had hemophagocytic lymphohistiocytosis, and 1 had Hodgkin’s lymphoma. None of the children had Wilson disease, hepatitis B or C, or AIH.

Dr. Yodoshi and colleagues highlighted the latter finding, noting that 13% of the patients had autoantibodies for AIH, but “none met composite criteria.” This contrasts with the previous study from 2013, which found an AIH rate of 4%.

“Nonetheless,” the investigators went on, “NAFLD remains a diagnosis of exclusion, and key conditions that require specific treatments must be ruled out in the workup of patients with suspected NAFLD. In the future, the cost-effectiveness of this approach will need to be investigated.”

Interpreting the findings, Francis E. Rushton, MD, of Beaufort (S.C.) Memorial Hospital emphasized the implications for preventive and interventional health care.

“This study showing an absence of etiologies other than obesity in overweight children with NAFLD provides further impetus for pediatricians to work on both preventive and treatment regimens for weight issues,” Dr. Rushton said. “Linking community-based initiatives focused on adequate nutritional support with pediatric clinical support services is critical in solving issues related to overweight in children. Tracking BMI over time and developing healthy habit goals for patients are key parts of clinical interventions.” 

The study was funded by the National Institutes of Health. The investigators reported no conflicts of interest.