Hepatology

Non-alcoholic fatty liver disease (NAFLD) and metabolic associated fatty liver disease (MAFLD) demonstrate highly similar clinical courses and mortality rates, and a name change may not be clinically beneficial, based on data from more than 17,000 patients.

Instead, etiologic subcategorization of fatty liver disease (FLD) should be considered, reported lead author Zobair M. Younossi, MD, of Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Va., and colleagues.

“There is debate about whether NAFLD is an appropriate name as the term ‘non-alcoholic’ overemphasizes the absence of alcohol use and underemphasizes the importance of the metabolic risk factors which are the main drivers of disease progression,” the investigators wrote in Hepatology. “It has been suggested that MAFLD may better reflect these risk factors. However, such a recommendation is made despite a lack of a general consensus on the definition of ‘metabolic health’ and disagreements in endocrinology circles about the term ‘metabolic syndrome.’ Nevertheless, a few investigators have suggested that MAFLD but not NAFLD is associated with increased fibrosis and mortality.”

To look for clinical differences between the two disease entities, Dr. Younossi and colleagues turned to the National Health and Nutrition Examination Survey (NHANES). Specifically, the NHANES III and NHANES 2017-2018 cohorts were employed, including 12,878 and 4,328 participants, respectively.

MAFLD was defined as FLD with overweight/obesity, evidence of metabolic dysregulation, or type 2 diabetes mellitus. NAFLD was defined as FLD without excessive alcohol consumption or other causes of chronic liver disease. Patients were sorted into four groups: NAFLD, MAFLD, both disease types, or neither disease type. Since the categories were not mutually exclusive, the investigators compared clinical characteristics based on 95% confidence intervals. If no overlap was found, then differences were deemed statistically significant.

Diagnoses of NAFLD and MAFLD were highly concordant (kappa coefficient = 0.83-0.94). After a median of 22.8 years follow-up, no significant differences were found between groups for cause-specific mortality, all-cause mortality, or major clinical characteristics except those inherent to the disease definitions (for example, lack of alcohol use in NAFLD). Greatest risk factors for advanced fibrosis in both groups were obesity, high-risk fibrosis, and type 2 diabetes mellitus.

As anticipated, by definition, alcoholic liver disease and excess alcohol use were documented in approximately 15% of patients with MAFLD, but in no patients with NAFLD. As such, alcoholic liver disease predicted liver-specific mortality for MAFLD (hazard ratio, 4.50; 95% confidence interval, 1.89-10.75) but not NAFLD. Conversely, insulin resistance predicted liver-specific mortality in NAFLD (HR, 3.57; 95% CI, 1.35-9.42) but not MAFLD (HR, 0.84; 95% CI, 0.36-1.95).

“These data do not support the notion that a name change from NAFLD to MAFLD will better capture the risk for long-term outcomes of these patients or better define metabolically at-risk patients who present with FLD,” the investigators concluded. “On the other hand, enlarging the definition to FLD with subcategories of ‘alcoholic,’ ‘non-alcoholic,’ ‘drug-induced,’ etc. has merit and needs to be further considered. In this context, a true international consensus group of experts supported by liver and non-liver scientific societies must undertake an evidence-based and comprehensive approach to this issue and assess both the benefits and risks of changing the name.”

According to Rohit Loomba, MD, director of the NAFLD research center and professor of medicine in the division of gastroenterology and hepatology at University of California, San Diego, the study offers a preview of the consequences if NAFLD were changed to MAFLD, most notably by making alcohol a key driver of outcomes.

“If we change the name of a disease entity ... how does that impact natural history?” Dr. Loomba asked in an interview. “This paper gives you an idea. If you start calling it MAFLD, then people are dying from alcohol use, and they’re not dying from what we are currently seeing patients with NAFLD die of.”

He also noted that the name change could disrupt drug development and outcome measures since most drugs currently in development are directed at nonalcoholic steatohepatitis (NASH).

“Is it worth the headache?” Dr. Loomba asked. “How are we going to define NASH-related fibrosis? That probably will remain the same because the therapies that we will use to address that will remain consistent with what we are currently pursuing. ... It’s probably premature to change the nomenclature before assessing the impact on finding new treatment.”

Dr. Younossi disclosed relationships with BMS, Novartis, Gilead, and others. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals, and Viking Therapeutics.

Non-alcoholic fatty liver disease (NAFLD) and metabolic associated fatty liver disease (MAFLD) demonstrate highly similar clinical courses and mortality rates, and a name change may not be clinically beneficial, based on data from more than 17,000 patients.

Instead, etiologic subcategorization of fatty liver disease (FLD) should be considered, reported lead author Zobair M. Younossi, MD, of Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Va., and colleagues.

“There is debate about whether NAFLD is an appropriate name as the term ‘non-alcoholic’ overemphasizes the absence of alcohol use and underemphasizes the importance of the metabolic risk factors which are the main drivers of disease progression,” the investigators wrote in Hepatology. “It has been suggested that MAFLD may better reflect these risk factors. However, such a recommendation is made despite a lack of a general consensus on the definition of ‘metabolic health’ and disagreements in endocrinology circles about the term ‘metabolic syndrome.’ Nevertheless, a few investigators have suggested that MAFLD but not NAFLD is associated with increased fibrosis and mortality.”

To look for clinical differences between the two disease entities, Dr. Younossi and colleagues turned to the National Health and Nutrition Examination Survey (NHANES). Specifically, the NHANES III and NHANES 2017-2018 cohorts were employed, including 12,878 and 4,328 participants, respectively.

MAFLD was defined as FLD with overweight/obesity, evidence of metabolic dysregulation, or type 2 diabetes mellitus. NAFLD was defined as FLD without excessive alcohol consumption or other causes of chronic liver disease. Patients were sorted into four groups: NAFLD, MAFLD, both disease types, or neither disease type. Since the categories were not mutually exclusive, the investigators compared clinical characteristics based on 95% confidence intervals. If no overlap was found, then differences were deemed statistically significant.

Diagnoses of NAFLD and MAFLD were highly concordant (kappa coefficient = 0.83-0.94). After a median of 22.8 years follow-up, no significant differences were found between groups for cause-specific mortality, all-cause mortality, or major clinical characteristics except those inherent to the disease definitions (for example, lack of alcohol use in NAFLD). Greatest risk factors for advanced fibrosis in both groups were obesity, high-risk fibrosis, and type 2 diabetes mellitus.

As anticipated, by definition, alcoholic liver disease and excess alcohol use were documented in approximately 15% of patients with MAFLD, but in no patients with NAFLD. As such, alcoholic liver disease predicted liver-specific mortality for MAFLD (hazard ratio, 4.50; 95% confidence interval, 1.89-10.75) but not NAFLD. Conversely, insulin resistance predicted liver-specific mortality in NAFLD (HR, 3.57; 95% CI, 1.35-9.42) but not MAFLD (HR, 0.84; 95% CI, 0.36-1.95).

“These data do not support the notion that a name change from NAFLD to MAFLD will better capture the risk for long-term outcomes of these patients or better define metabolically at-risk patients who present with FLD,” the investigators concluded. “On the other hand, enlarging the definition to FLD with subcategories of ‘alcoholic,’ ‘non-alcoholic,’ ‘drug-induced,’ etc. has merit and needs to be further considered. In this context, a true international consensus group of experts supported by liver and non-liver scientific societies must undertake an evidence-based and comprehensive approach to this issue and assess both the benefits and risks of changing the name.”

According to Rohit Loomba, MD, director of the NAFLD research center and professor of medicine in the division of gastroenterology and hepatology at University of California, San Diego, the study offers a preview of the consequences if NAFLD were changed to MAFLD, most notably by making alcohol a key driver of outcomes.

“If we change the name of a disease entity ... how does that impact natural history?” Dr. Loomba asked in an interview. “This paper gives you an idea. If you start calling it MAFLD, then people are dying from alcohol use, and they’re not dying from what we are currently seeing patients with NAFLD die of.”

He also noted that the name change could disrupt drug development and outcome measures since most drugs currently in development are directed at nonalcoholic steatohepatitis (NASH).

“Is it worth the headache?” Dr. Loomba asked. “How are we going to define NASH-related fibrosis? That probably will remain the same because the therapies that we will use to address that will remain consistent with what we are currently pursuing. ... It’s probably premature to change the nomenclature before assessing the impact on finding new treatment.”

Dr. Younossi disclosed relationships with BMS, Novartis, Gilead, and others. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals, and Viking Therapeutics.

Non-alcoholic fatty liver disease (NAFLD) and metabolic associated fatty liver disease (MAFLD) demonstrate highly similar clinical courses and mortality rates, and a name change may not be clinically beneficial, based on data from more than 17,000 patients.

Instead, etiologic subcategorization of fatty liver disease (FLD) should be considered, reported lead author Zobair M. Younossi, MD, of Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Va., and colleagues.

“There is debate about whether NAFLD is an appropriate name as the term ‘non-alcoholic’ overemphasizes the absence of alcohol use and underemphasizes the importance of the metabolic risk factors which are the main drivers of disease progression,” the investigators wrote in Hepatology. “It has been suggested that MAFLD may better reflect these risk factors. However, such a recommendation is made despite a lack of a general consensus on the definition of ‘metabolic health’ and disagreements in endocrinology circles about the term ‘metabolic syndrome.’ Nevertheless, a few investigators have suggested that MAFLD but not NAFLD is associated with increased fibrosis and mortality.”

To look for clinical differences between the two disease entities, Dr. Younossi and colleagues turned to the National Health and Nutrition Examination Survey (NHANES). Specifically, the NHANES III and NHANES 2017-2018 cohorts were employed, including 12,878 and 4,328 participants, respectively.

MAFLD was defined as FLD with overweight/obesity, evidence of metabolic dysregulation, or type 2 diabetes mellitus. NAFLD was defined as FLD without excessive alcohol consumption or other causes of chronic liver disease. Patients were sorted into four groups: NAFLD, MAFLD, both disease types, or neither disease type. Since the categories were not mutually exclusive, the investigators compared clinical characteristics based on 95% confidence intervals. If no overlap was found, then differences were deemed statistically significant.

Diagnoses of NAFLD and MAFLD were highly concordant (kappa coefficient = 0.83-0.94). After a median of 22.8 years follow-up, no significant differences were found between groups for cause-specific mortality, all-cause mortality, or major clinical characteristics except those inherent to the disease definitions (for example, lack of alcohol use in NAFLD). Greatest risk factors for advanced fibrosis in both groups were obesity, high-risk fibrosis, and type 2 diabetes mellitus.

As anticipated, by definition, alcoholic liver disease and excess alcohol use were documented in approximately 15% of patients with MAFLD, but in no patients with NAFLD. As such, alcoholic liver disease predicted liver-specific mortality for MAFLD (hazard ratio, 4.50; 95% confidence interval, 1.89-10.75) but not NAFLD. Conversely, insulin resistance predicted liver-specific mortality in NAFLD (HR, 3.57; 95% CI, 1.35-9.42) but not MAFLD (HR, 0.84; 95% CI, 0.36-1.95).

“These data do not support the notion that a name change from NAFLD to MAFLD will better capture the risk for long-term outcomes of these patients or better define metabolically at-risk patients who present with FLD,” the investigators concluded. “On the other hand, enlarging the definition to FLD with subcategories of ‘alcoholic,’ ‘non-alcoholic,’ ‘drug-induced,’ etc. has merit and needs to be further considered. In this context, a true international consensus group of experts supported by liver and non-liver scientific societies must undertake an evidence-based and comprehensive approach to this issue and assess both the benefits and risks of changing the name.”

According to Rohit Loomba, MD, director of the NAFLD research center and professor of medicine in the division of gastroenterology and hepatology at University of California, San Diego, the study offers a preview of the consequences if NAFLD were changed to MAFLD, most notably by making alcohol a key driver of outcomes.

“If we change the name of a disease entity ... how does that impact natural history?” Dr. Loomba asked in an interview. “This paper gives you an idea. If you start calling it MAFLD, then people are dying from alcohol use, and they’re not dying from what we are currently seeing patients with NAFLD die of.”

He also noted that the name change could disrupt drug development and outcome measures since most drugs currently in development are directed at nonalcoholic steatohepatitis (NASH).

“Is it worth the headache?” Dr. Loomba asked. “How are we going to define NASH-related fibrosis? That probably will remain the same because the therapies that we will use to address that will remain consistent with what we are currently pursuing. ... It’s probably premature to change the nomenclature before assessing the impact on finding new treatment.”

Dr. Younossi disclosed relationships with BMS, Novartis, Gilead, and others. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals, and Viking Therapeutics.

A relationship between consumption of dairy products and risk of various cancers has been intensively investigated in the past but yielded inconclusive or conflicting results. Now a large new study comparing Chinese dairy consumption with that in the United Kingdom, shows that increased dairy consumption was linked to higher risks of liver cancer and female breast cancer.

The study, by researchers from Oxford University’s department of population health, and Peking University and the Chinese Academy of Medical Sciences in Beijing, used data from the China Kadoorie Biobank Study, a long-term prospective study involving more than over 510,000 participants recruited from 10 geographically diverse areas across China, including both rural and urban regions. They compared this to data from the UK biobank.

Subjects were 59% female, 41% male, aged 30-79 years, and had no history of cancer at recruitment between 2004 and 2008. Food questionnaires were completed at the outset and participants followed for an average of 11 years, using national cancer and death registries and health insurance records to identify new cancer diagnoses, including both fatal and nonfatal events.

Participants were categorized into three groups according to how often they consumed dairy products (primarily milk):

• Regular consumers (at least once a week): 20.4% of the cohort.
• Monthly consumers: 11.1%.
• Nonconsumers who never or rarely consumed dairy products: 68.5%.

Average dairy consumption was 37.9 g/day overall and 80.8 g/day among regular consumers. This compares with an average consumption of around 300 g/day in participants in the UK Biobank cohort.

Over the course of the study, 29,277 new cancer cases were recorded, including 6,282 lung, 2,582 female breast, 3,577 stomach, 3,350 colorectal, and 3,191 liver cancer cases.

Analyses correlating cases with consumption took into account a range of other factors potentially affecting cancer risk, including age, sex, region, family history of cancer, socioeconomic status (education and income), lifestyle factors (alcohol intake, smoking, physical activity, soy consumption, and fresh fruit intake), body mass index, chronic hepatitis B virus infection, and female reproductive factors.

Higher dairy intakes linked with risk of liver and breast cancers

Results revealed that higher regular dairy intake was associated with significantly higher risks of liver cancer and female breast cancer, both common types of cancer in China. Analyses indicated that for each 50-g/day intake, the risks increased by 12% and 17%, respectively.

There was also an increase in total cancer diagnoses, and an increased risk of lymphoma, though this was not statistically significant after correction for confounders. No association was found between dairy products and colorectal cancer, prostate cancer, or any other site-specific cancer.

The research, published in BMC Medicine, is the first major study to investigate dairy consumption and cancer risk in Chinese adults. The results conflict with previous studies on Western populations, which have suggested that dairy products may be associated with a lower risk of colorectal cancer and a higher risk of prostate cancer but have found no clear link for breast or other types of cancer.

Lead researchers Maria Kakkoura, PhD, MSc, and associate professor Huaidong Du, MD, PhD, told this news organization that, although they don’t know the reason for the difference, “there is clear evidence that colorectal cancer has a different incidence pattern in China, compared with Western countries. Other risk factors, like adiposity, may have a stronger effect on the risk of colorectal cancer in Western countries than in China.” Notably, the mean body mass index in the study population was around 23 kg/m², they said – by contrast in the United Kingdom it is 27.6 kg/m2.

Effects not necessarily causal

Ian Givens, PhD, professor of food chain nutrition at the University of Reading (England), said the study was “potentially very important for Chinese people, if it can be confirmed that dairy products affect the risk of breast and/or liver cancer differently in Chinese subjects to those in Western Societies, especially as dairy consumption in China is much lower than in most Western diets.”

He added: “As always it needs to be kept in mind that this type of study can only establish associations with disease risk, not cause.”

Dr. Kakkoura, nutritional epidemiologist at Oxford (England) University’s department of population health, said: “This was the first major study to investigate the link between dairy products and cancer risk in a Chinese population. Further studies are needed to validate these current findings, establish if these associations are causal, and investigate the potential underlying mechanisms involved.”

The researchers said that, while the results do not prove causation, “there are several plausible biological mechanisms that may explain these associations.” They pointed to higher dairy consumption potentially increasing levels of insulinlike growth factor-I, known to promote cell proliferation and associated with higher risks of several types of cancer.

In addition, estrogen and progesterone present in cows’ milk may play a role in increasing breast cancer risk, whilst saturated and trans-fatty acids from dairy products may increase the risk of liver cancer. As many Chinese people are lactase deficient, dairy products may also be broken down into products that affect cancer risk.

No justification for dietary change

Confounding factors may also have influenced the results, commented Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow at Aston University, Birmingham, England. “Those in the study who consumed dairy were more likely to live in cities and have other health conditions, including cardiovascular disease and diabetes – although some of these factors were considered in the analysis, not all of these covariates were, which could influence the findings.

“In my view this study alone does not provide strong evidence that reducing dairy intake would reduce cancer risk.”

He added: “Although the paper suggests a 12% increased relative risk for female breast cancer, this does not equate to 12 more cases per 100 individuals – in absolute terms this would be more like 1 or 2 cases per 1,000 people.”

Similarly, Kevin McConway, PhD, emeritus professor of applied statistics at the Open University, Milton Keynes, England, said: “An issue is that there were many differences between the people that consumed different amounts of dairy products, apart from their difference in dairy consumption. For instance, of those who never or rarely consumed dairy products, fewer than a third lived in urban areas, but of regular dairy consumers (at least once a week), 83% lived in urban areas. Regular consumers were considerably more likely to be well educated than those who never or rarely consumed dairy products, and there were other differences too. 

“So if, as the researchers found, a greater proportion of the regular consumers than of the never or rare consumers had a cancer diagnosis, that could have been because of their different dairy consumption, or it could have been (in part or entirely) because of the different places they lived, or their different education levels, or any of the other factors on which the groups differed.

“One can never be sure that all the relevant factors have been adjusted for. That’s why the researchers rightly say that these results can’t establish whether the associations between dairy consumption and the risks of some cancers, that they found, are there because the dairy consumption differences change the cancer risks in a cause-and-effect way. They might, or they might not.”

He cautioned: “I don’t think anyone should decide to change their individual diet solely because of the results of this new study.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, London, told this news organization: “This early-stage study found an association between dairy consumption and the risks of certain cancers, but that doesn’t mean that they’re causing them or that people need to avoid dairy. Dairy products can be part of a healthy balanced diet and, in the U.K., the Food Standards Agency regulates them to make sure they’re safe. There’s good evidence that dairy reduces the risk of bowel cancer, but no clear evidence for other cancer types, and this is no different for people who are lactose intolerant.”

A version of this article first appeared on Medscape UK.

A relationship between consumption of dairy products and risk of various cancers has been intensively investigated in the past but yielded inconclusive or conflicting results. Now a large new study comparing Chinese dairy consumption with that in the United Kingdom, shows that increased dairy consumption was linked to higher risks of liver cancer and female breast cancer.

The study, by researchers from Oxford University’s department of population health, and Peking University and the Chinese Academy of Medical Sciences in Beijing, used data from the China Kadoorie Biobank Study, a long-term prospective study involving more than over 510,000 participants recruited from 10 geographically diverse areas across China, including both rural and urban regions. They compared this to data from the UK biobank.

Subjects were 59% female, 41% male, aged 30-79 years, and had no history of cancer at recruitment between 2004 and 2008. Food questionnaires were completed at the outset and participants followed for an average of 11 years, using national cancer and death registries and health insurance records to identify new cancer diagnoses, including both fatal and nonfatal events.

Participants were categorized into three groups according to how often they consumed dairy products (primarily milk):

• Regular consumers (at least once a week): 20.4% of the cohort.
• Monthly consumers: 11.1%.
• Nonconsumers who never or rarely consumed dairy products: 68.5%.

Average dairy consumption was 37.9 g/day overall and 80.8 g/day among regular consumers. This compares with an average consumption of around 300 g/day in participants in the UK Biobank cohort.

Over the course of the study, 29,277 new cancer cases were recorded, including 6,282 lung, 2,582 female breast, 3,577 stomach, 3,350 colorectal, and 3,191 liver cancer cases.

Analyses correlating cases with consumption took into account a range of other factors potentially affecting cancer risk, including age, sex, region, family history of cancer, socioeconomic status (education and income), lifestyle factors (alcohol intake, smoking, physical activity, soy consumption, and fresh fruit intake), body mass index, chronic hepatitis B virus infection, and female reproductive factors.

Higher dairy intakes linked with risk of liver and breast cancers

Results revealed that higher regular dairy intake was associated with significantly higher risks of liver cancer and female breast cancer, both common types of cancer in China. Analyses indicated that for each 50-g/day intake, the risks increased by 12% and 17%, respectively.

There was also an increase in total cancer diagnoses, and an increased risk of lymphoma, though this was not statistically significant after correction for confounders. No association was found between dairy products and colorectal cancer, prostate cancer, or any other site-specific cancer.

The research, published in BMC Medicine, is the first major study to investigate dairy consumption and cancer risk in Chinese adults. The results conflict with previous studies on Western populations, which have suggested that dairy products may be associated with a lower risk of colorectal cancer and a higher risk of prostate cancer but have found no clear link for breast or other types of cancer.

Lead researchers Maria Kakkoura, PhD, MSc, and associate professor Huaidong Du, MD, PhD, told this news organization that, although they don’t know the reason for the difference, “there is clear evidence that colorectal cancer has a different incidence pattern in China, compared with Western countries. Other risk factors, like adiposity, may have a stronger effect on the risk of colorectal cancer in Western countries than in China.” Notably, the mean body mass index in the study population was around 23 kg/m², they said – by contrast in the United Kingdom it is 27.6 kg/m2.

Effects not necessarily causal

Ian Givens, PhD, professor of food chain nutrition at the University of Reading (England), said the study was “potentially very important for Chinese people, if it can be confirmed that dairy products affect the risk of breast and/or liver cancer differently in Chinese subjects to those in Western Societies, especially as dairy consumption in China is much lower than in most Western diets.”

He added: “As always it needs to be kept in mind that this type of study can only establish associations with disease risk, not cause.”

Dr. Kakkoura, nutritional epidemiologist at Oxford (England) University’s department of population health, said: “This was the first major study to investigate the link between dairy products and cancer risk in a Chinese population. Further studies are needed to validate these current findings, establish if these associations are causal, and investigate the potential underlying mechanisms involved.”

The researchers said that, while the results do not prove causation, “there are several plausible biological mechanisms that may explain these associations.” They pointed to higher dairy consumption potentially increasing levels of insulinlike growth factor-I, known to promote cell proliferation and associated with higher risks of several types of cancer.

In addition, estrogen and progesterone present in cows’ milk may play a role in increasing breast cancer risk, whilst saturated and trans-fatty acids from dairy products may increase the risk of liver cancer. As many Chinese people are lactase deficient, dairy products may also be broken down into products that affect cancer risk.

No justification for dietary change

Confounding factors may also have influenced the results, commented Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow at Aston University, Birmingham, England. “Those in the study who consumed dairy were more likely to live in cities and have other health conditions, including cardiovascular disease and diabetes – although some of these factors were considered in the analysis, not all of these covariates were, which could influence the findings.

“In my view this study alone does not provide strong evidence that reducing dairy intake would reduce cancer risk.”

He added: “Although the paper suggests a 12% increased relative risk for female breast cancer, this does not equate to 12 more cases per 100 individuals – in absolute terms this would be more like 1 or 2 cases per 1,000 people.”

Similarly, Kevin McConway, PhD, emeritus professor of applied statistics at the Open University, Milton Keynes, England, said: “An issue is that there were many differences between the people that consumed different amounts of dairy products, apart from their difference in dairy consumption. For instance, of those who never or rarely consumed dairy products, fewer than a third lived in urban areas, but of regular dairy consumers (at least once a week), 83% lived in urban areas. Regular consumers were considerably more likely to be well educated than those who never or rarely consumed dairy products, and there were other differences too. 

“So if, as the researchers found, a greater proportion of the regular consumers than of the never or rare consumers had a cancer diagnosis, that could have been because of their different dairy consumption, or it could have been (in part or entirely) because of the different places they lived, or their different education levels, or any of the other factors on which the groups differed.

“One can never be sure that all the relevant factors have been adjusted for. That’s why the researchers rightly say that these results can’t establish whether the associations between dairy consumption and the risks of some cancers, that they found, are there because the dairy consumption differences change the cancer risks in a cause-and-effect way. They might, or they might not.”

He cautioned: “I don’t think anyone should decide to change their individual diet solely because of the results of this new study.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, London, told this news organization: “This early-stage study found an association between dairy consumption and the risks of certain cancers, but that doesn’t mean that they’re causing them or that people need to avoid dairy. Dairy products can be part of a healthy balanced diet and, in the U.K., the Food Standards Agency regulates them to make sure they’re safe. There’s good evidence that dairy reduces the risk of bowel cancer, but no clear evidence for other cancer types, and this is no different for people who are lactose intolerant.”

A version of this article first appeared on Medscape UK.

A relationship between consumption of dairy products and risk of various cancers has been intensively investigated in the past but yielded inconclusive or conflicting results. Now a large new study comparing Chinese dairy consumption with that in the United Kingdom, shows that increased dairy consumption was linked to higher risks of liver cancer and female breast cancer.

The study, by researchers from Oxford University’s department of population health, and Peking University and the Chinese Academy of Medical Sciences in Beijing, used data from the China Kadoorie Biobank Study, a long-term prospective study involving more than over 510,000 participants recruited from 10 geographically diverse areas across China, including both rural and urban regions. They compared this to data from the UK biobank.

Subjects were 59% female, 41% male, aged 30-79 years, and had no history of cancer at recruitment between 2004 and 2008. Food questionnaires were completed at the outset and participants followed for an average of 11 years, using national cancer and death registries and health insurance records to identify new cancer diagnoses, including both fatal and nonfatal events.

Participants were categorized into three groups according to how often they consumed dairy products (primarily milk):

• Regular consumers (at least once a week): 20.4% of the cohort.
• Monthly consumers: 11.1%.
• Nonconsumers who never or rarely consumed dairy products: 68.5%.

Average dairy consumption was 37.9 g/day overall and 80.8 g/day among regular consumers. This compares with an average consumption of around 300 g/day in participants in the UK Biobank cohort.

Over the course of the study, 29,277 new cancer cases were recorded, including 6,282 lung, 2,582 female breast, 3,577 stomach, 3,350 colorectal, and 3,191 liver cancer cases.

Analyses correlating cases with consumption took into account a range of other factors potentially affecting cancer risk, including age, sex, region, family history of cancer, socioeconomic status (education and income), lifestyle factors (alcohol intake, smoking, physical activity, soy consumption, and fresh fruit intake), body mass index, chronic hepatitis B virus infection, and female reproductive factors.

Higher dairy intakes linked with risk of liver and breast cancers

Results revealed that higher regular dairy intake was associated with significantly higher risks of liver cancer and female breast cancer, both common types of cancer in China. Analyses indicated that for each 50-g/day intake, the risks increased by 12% and 17%, respectively.

There was also an increase in total cancer diagnoses, and an increased risk of lymphoma, though this was not statistically significant after correction for confounders. No association was found between dairy products and colorectal cancer, prostate cancer, or any other site-specific cancer.

The research, published in BMC Medicine, is the first major study to investigate dairy consumption and cancer risk in Chinese adults. The results conflict with previous studies on Western populations, which have suggested that dairy products may be associated with a lower risk of colorectal cancer and a higher risk of prostate cancer but have found no clear link for breast or other types of cancer.

Lead researchers Maria Kakkoura, PhD, MSc, and associate professor Huaidong Du, MD, PhD, told this news organization that, although they don’t know the reason for the difference, “there is clear evidence that colorectal cancer has a different incidence pattern in China, compared with Western countries. Other risk factors, like adiposity, may have a stronger effect on the risk of colorectal cancer in Western countries than in China.” Notably, the mean body mass index in the study population was around 23 kg/m², they said – by contrast in the United Kingdom it is 27.6 kg/m2.

Effects not necessarily causal

Ian Givens, PhD, professor of food chain nutrition at the University of Reading (England), said the study was “potentially very important for Chinese people, if it can be confirmed that dairy products affect the risk of breast and/or liver cancer differently in Chinese subjects to those in Western Societies, especially as dairy consumption in China is much lower than in most Western diets.”

He added: “As always it needs to be kept in mind that this type of study can only establish associations with disease risk, not cause.”

Dr. Kakkoura, nutritional epidemiologist at Oxford (England) University’s department of population health, said: “This was the first major study to investigate the link between dairy products and cancer risk in a Chinese population. Further studies are needed to validate these current findings, establish if these associations are causal, and investigate the potential underlying mechanisms involved.”

The researchers said that, while the results do not prove causation, “there are several plausible biological mechanisms that may explain these associations.” They pointed to higher dairy consumption potentially increasing levels of insulinlike growth factor-I, known to promote cell proliferation and associated with higher risks of several types of cancer.

In addition, estrogen and progesterone present in cows’ milk may play a role in increasing breast cancer risk, whilst saturated and trans-fatty acids from dairy products may increase the risk of liver cancer. As many Chinese people are lactase deficient, dairy products may also be broken down into products that affect cancer risk.

No justification for dietary change

Confounding factors may also have influenced the results, commented Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow at Aston University, Birmingham, England. “Those in the study who consumed dairy were more likely to live in cities and have other health conditions, including cardiovascular disease and diabetes – although some of these factors were considered in the analysis, not all of these covariates were, which could influence the findings.

“In my view this study alone does not provide strong evidence that reducing dairy intake would reduce cancer risk.”

He added: “Although the paper suggests a 12% increased relative risk for female breast cancer, this does not equate to 12 more cases per 100 individuals – in absolute terms this would be more like 1 or 2 cases per 1,000 people.”

Similarly, Kevin McConway, PhD, emeritus professor of applied statistics at the Open University, Milton Keynes, England, said: “An issue is that there were many differences between the people that consumed different amounts of dairy products, apart from their difference in dairy consumption. For instance, of those who never or rarely consumed dairy products, fewer than a third lived in urban areas, but of regular dairy consumers (at least once a week), 83% lived in urban areas. Regular consumers were considerably more likely to be well educated than those who never or rarely consumed dairy products, and there were other differences too. 

“So if, as the researchers found, a greater proportion of the regular consumers than of the never or rare consumers had a cancer diagnosis, that could have been because of their different dairy consumption, or it could have been (in part or entirely) because of the different places they lived, or their different education levels, or any of the other factors on which the groups differed.

“One can never be sure that all the relevant factors have been adjusted for. That’s why the researchers rightly say that these results can’t establish whether the associations between dairy consumption and the risks of some cancers, that they found, are there because the dairy consumption differences change the cancer risks in a cause-and-effect way. They might, or they might not.”

He cautioned: “I don’t think anyone should decide to change their individual diet solely because of the results of this new study.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, London, told this news organization: “This early-stage study found an association between dairy consumption and the risks of certain cancers, but that doesn’t mean that they’re causing them or that people need to avoid dairy. Dairy products can be part of a healthy balanced diet and, in the U.K., the Food Standards Agency regulates them to make sure they’re safe. There’s good evidence that dairy reduces the risk of bowel cancer, but no clear evidence for other cancer types, and this is no different for people who are lactose intolerant.”

A version of this article first appeared on Medscape UK.

New clinical practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) are the first to be targeted specifically to primary care and endocrinology clinical settings.

They include 34 evidence-based clinical practice recommendations for screening, diagnosis, management, and referral, presented in a table and an algorithm flow chart as well as detailed text.

The new guidelines are by the American Association of Clinical Endocrinology and cosponsored by the American Association for the Study of Liver Diseases. They were presented at the annual scientific & clinical congress of the AACE and simultaneously published in Endocrine Practice.

These are “the first of this type for this field of medicine. The vast majority of patients with NAFLD are being seen in the primary care and endocrinology settings. Only when they get to the more advanced disease are they being referred to the liver specialists. So, we need to be the ones who are diagnosing and managing these patients because there just aren’t enough liver specialists to do that,” Scott Isaacs, MD, cochair of the writing panel for the guidelines, said in an interview.

80 million Americans have NAFLD, but very few are aware

The spectrum of NAFLD ranges from nonprogressive steatosis to the progressive conditions nonalcoholic steatohepatitis, fibrotic NASH, and end-stage NASH cirrhosis. And NASH, in turn, is a major cause of liver cancer. NAFLD is also strongly associated with insulin resistance, type 2 diabetes, atherogenesis, and myocardial dysfunction.

The global prevalence of NAFLD is about 25% and NASH, about 12%-14%. However, a recent study found that, among patients in endocrine and primary care clinics, more than 70% of patients with type 2 diabetes and more than 90% with type 2 diabetes who had a body mass index above 35 kg/m2 also had NAFLD, and more than 20% of those patients had significant liver fibrosis.

Problematically, very few people are aware they have either. “It’s so common. At least 80 million Americans have this but only about 6% know they have it. We talk about it a lot, but it’s not talked about enough,” said Dr. Isaacs, an endocrinologist who practices in Atlanta.

In fact, most cases of NAFLD are diagnosed incidentally when people undergo an ultrasound or a CT scan for another reason. And, in about 70% of cases the liver enzymes are normal, and those patients rarely undergo liver workups, Dr. Isaacs noted.

In an accompanying editorial, Suthat Liangpunsakul, MD, wrote: “In my perspective, as a hepatologist, this AACE guideline is very practical and easy to incorporate into routine practice in primary care and endocrinology settings. ... Early identification and risk stratification of patients with NAFLD, especially the degree of hepatic fibrosis, are required to reduce downstream health care costs and triage unwarranted specialty care referrals.”

And “an effective screening strategy may also identify those in primary care and endocrinology settings who may benefit from an appropriate referral to hepatologists before the development of portal hypertension complications, decompensated liver disease, and hepatocellular carcinoma,” added Dr. Liangpunsakul, professor of medicine in the division of gastroenterology and hepatology at Indiana University, Indianapolis.
 

Screening advised using new FIB-4 test

The guideline calls for screening all patients at high risk for NAFLD, including those with prediabetes, type 2 diabetes, obesity, and/or two or more cardiometabolic risk factors, or those with hepatic steatosis found on imaging, and/or persistently elevated plasma aminotransferase levels (that is, for more than 6 months).

The recommended screening test is the Fibrosis-4 (FIB-4) index, calculated using the patient’s age, AST level, platelet count, and ALT level: FIB-4 score = age (years) x AST (U/L)/PLT (10⁹/L) x ALT ½ (U/L).

Recently approved by the Food and Drug Administration, the FIB-4 has been demonstrated to help identify liver disease in primary care settings.

“We really want to encourage clinicians to do the screening. The first step is the FIB-4 test. It’s a mathematical calculation using blood tests that we do anyway,” Dr. Isaacs said in an interview.

The FIB-4 stratifies patients as being low, intermediate, or high risk for liver fibrosis. Those at low risk can be managed in primary care or endocrinology settings with a focus on obesity management and cardiovascular disease prevention. “Those at low risk on FIB-4 still have a high cardiovascular disease risk. They still need to be managed,” Dr. Isaacs observed.

For those at intermediate risk, a second noninvasive test – either a liver stiffness measurement by elastography or an enhanced liver fibrosis test – is advised. If the patient is found to be at high risk or is still indeterminant after two noninvasive tests, referral to a liver specialist for further testing, including possible biopsy, is advised.

Those found to be at high risk with the FIB-4 should also be referred to hepatology. In both the intermediate- and high-risk groups, management should be multidisciplinary, including a hepatologist, endocrinologist, and other professionals to prevent both cardiovascular disease and progression to cirrhosis, the guidelines say.

“The diagnosis isn’t about diagnosing liver fat. It’s about diagnosing fibrosis, or the risk for clinically significant fibrosis. That’s really where the challenge lies,” Dr. Isaacs commented.
 

NAFLD treatment in endocrinology and primary care: CVD prevention

During the presentation at the AACE meeting, guideline panel cochair Kenneth Cusi, MD, chief of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, summarized current and future treatments for NAFLD.

Lifestyle intervention, cardiovascular risk reduction, and weight loss for those who are overweight or obese are recommended for all patients with NAFLD, including structured weight-loss programs, antiobesity medications, and bariatric surgery if indicated.

There are currently no FDA-approved medications specifically for NASH, but pioglitazone, approved for type 2 diabetes, and glucagonlike peptide–1 agonists, approved for type 2 diabetes and weight loss, have been shown to be effective in treating the condition and preventing progression. Other treatments are in development, Dr. Cusi said.  

The guideline also includes a section on diagnosis and management of NAFLD in children and adolescents. Here, the FIB-4 is not recommended because it isn’t accurate due to the age part of the equation, so liver enzyme tests are used in pediatric patients considered at high risk because of clinical factors. Management is similar to adults, except not all medications used in adults are approved for use in children.

In the editorial, Dr. Liangpunsakul cautioned that “the level of uptake and usage of the guideline may be an obstacle.”

To remedy that, he advised that “the next effort should gear toward distributing this guideline to the targeted providers and developing the ‘feedback platforms’ on its execution in the real-world. ... The successful implementation of this AACE guideline by the primary care providers and endocrinologists, hopefully, will deescalate the future burden of NAFLD-related morbidity and mortality.”

Dr. Isaacs and Dr. Liangpunsakul have reported no relevant financial relationships. Dr. Cusi has reported receiving research support towards the University of Florida as principal investigator from the National Institute of Health, Echosens, Inventiva, Nordic Bioscience, Novo Nordisk, Poxel, Labcorp, and Zydus, and is a consultant for Altimmune, Akero, Arrowhead, AstraZeneca, 89Bio, Bristol-Myers Squibb, Coherus, Intercept, Lilly, Madrigal, Merck, Novo Nordisk, Quest, Sagimet, Sonic Incytes, Terns, and Thera Technologies.

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

New clinical practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) are the first to be targeted specifically to primary care and endocrinology clinical settings.

They include 34 evidence-based clinical practice recommendations for screening, diagnosis, management, and referral, presented in a table and an algorithm flow chart as well as detailed text.

The new guidelines are by the American Association of Clinical Endocrinology and cosponsored by the American Association for the Study of Liver Diseases. They were presented at the annual scientific & clinical congress of the AACE and simultaneously published in Endocrine Practice.

These are “the first of this type for this field of medicine. The vast majority of patients with NAFLD are being seen in the primary care and endocrinology settings. Only when they get to the more advanced disease are they being referred to the liver specialists. So, we need to be the ones who are diagnosing and managing these patients because there just aren’t enough liver specialists to do that,” Scott Isaacs, MD, cochair of the writing panel for the guidelines, said in an interview.

80 million Americans have NAFLD, but very few are aware

The spectrum of NAFLD ranges from nonprogressive steatosis to the progressive conditions nonalcoholic steatohepatitis, fibrotic NASH, and end-stage NASH cirrhosis. And NASH, in turn, is a major cause of liver cancer. NAFLD is also strongly associated with insulin resistance, type 2 diabetes, atherogenesis, and myocardial dysfunction.

The global prevalence of NAFLD is about 25% and NASH, about 12%-14%. However, a recent study found that, among patients in endocrine and primary care clinics, more than 70% of patients with type 2 diabetes and more than 90% with type 2 diabetes who had a body mass index above 35 kg/m2 also had NAFLD, and more than 20% of those patients had significant liver fibrosis.

Problematically, very few people are aware they have either. “It’s so common. At least 80 million Americans have this but only about 6% know they have it. We talk about it a lot, but it’s not talked about enough,” said Dr. Isaacs, an endocrinologist who practices in Atlanta.

In fact, most cases of NAFLD are diagnosed incidentally when people undergo an ultrasound or a CT scan for another reason. And, in about 70% of cases the liver enzymes are normal, and those patients rarely undergo liver workups, Dr. Isaacs noted.

In an accompanying editorial, Suthat Liangpunsakul, MD, wrote: “In my perspective, as a hepatologist, this AACE guideline is very practical and easy to incorporate into routine practice in primary care and endocrinology settings. ... Early identification and risk stratification of patients with NAFLD, especially the degree of hepatic fibrosis, are required to reduce downstream health care costs and triage unwarranted specialty care referrals.”

And “an effective screening strategy may also identify those in primary care and endocrinology settings who may benefit from an appropriate referral to hepatologists before the development of portal hypertension complications, decompensated liver disease, and hepatocellular carcinoma,” added Dr. Liangpunsakul, professor of medicine in the division of gastroenterology and hepatology at Indiana University, Indianapolis.
 

Screening advised using new FIB-4 test

The guideline calls for screening all patients at high risk for NAFLD, including those with prediabetes, type 2 diabetes, obesity, and/or two or more cardiometabolic risk factors, or those with hepatic steatosis found on imaging, and/or persistently elevated plasma aminotransferase levels (that is, for more than 6 months).

The recommended screening test is the Fibrosis-4 (FIB-4) index, calculated using the patient’s age, AST level, platelet count, and ALT level: FIB-4 score = age (years) x AST (U/L)/PLT (10⁹/L) x ALT ½ (U/L).

Recently approved by the Food and Drug Administration, the FIB-4 has been demonstrated to help identify liver disease in primary care settings.

“We really want to encourage clinicians to do the screening. The first step is the FIB-4 test. It’s a mathematical calculation using blood tests that we do anyway,” Dr. Isaacs said in an interview.

The FIB-4 stratifies patients as being low, intermediate, or high risk for liver fibrosis. Those at low risk can be managed in primary care or endocrinology settings with a focus on obesity management and cardiovascular disease prevention. “Those at low risk on FIB-4 still have a high cardiovascular disease risk. They still need to be managed,” Dr. Isaacs observed.

For those at intermediate risk, a second noninvasive test – either a liver stiffness measurement by elastography or an enhanced liver fibrosis test – is advised. If the patient is found to be at high risk or is still indeterminant after two noninvasive tests, referral to a liver specialist for further testing, including possible biopsy, is advised.

Those found to be at high risk with the FIB-4 should also be referred to hepatology. In both the intermediate- and high-risk groups, management should be multidisciplinary, including a hepatologist, endocrinologist, and other professionals to prevent both cardiovascular disease and progression to cirrhosis, the guidelines say.

“The diagnosis isn’t about diagnosing liver fat. It’s about diagnosing fibrosis, or the risk for clinically significant fibrosis. That’s really where the challenge lies,” Dr. Isaacs commented.
 

NAFLD treatment in endocrinology and primary care: CVD prevention

During the presentation at the AACE meeting, guideline panel cochair Kenneth Cusi, MD, chief of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, summarized current and future treatments for NAFLD.

Lifestyle intervention, cardiovascular risk reduction, and weight loss for those who are overweight or obese are recommended for all patients with NAFLD, including structured weight-loss programs, antiobesity medications, and bariatric surgery if indicated.

There are currently no FDA-approved medications specifically for NASH, but pioglitazone, approved for type 2 diabetes, and glucagonlike peptide–1 agonists, approved for type 2 diabetes and weight loss, have been shown to be effective in treating the condition and preventing progression. Other treatments are in development, Dr. Cusi said.  

The guideline also includes a section on diagnosis and management of NAFLD in children and adolescents. Here, the FIB-4 is not recommended because it isn’t accurate due to the age part of the equation, so liver enzyme tests are used in pediatric patients considered at high risk because of clinical factors. Management is similar to adults, except not all medications used in adults are approved for use in children.

In the editorial, Dr. Liangpunsakul cautioned that “the level of uptake and usage of the guideline may be an obstacle.”

To remedy that, he advised that “the next effort should gear toward distributing this guideline to the targeted providers and developing the ‘feedback platforms’ on its execution in the real-world. ... The successful implementation of this AACE guideline by the primary care providers and endocrinologists, hopefully, will deescalate the future burden of NAFLD-related morbidity and mortality.”

Dr. Isaacs and Dr. Liangpunsakul have reported no relevant financial relationships. Dr. Cusi has reported receiving research support towards the University of Florida as principal investigator from the National Institute of Health, Echosens, Inventiva, Nordic Bioscience, Novo Nordisk, Poxel, Labcorp, and Zydus, and is a consultant for Altimmune, Akero, Arrowhead, AstraZeneca, 89Bio, Bristol-Myers Squibb, Coherus, Intercept, Lilly, Madrigal, Merck, Novo Nordisk, Quest, Sagimet, Sonic Incytes, Terns, and Thera Technologies.

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

New clinical practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) are the first to be targeted specifically to primary care and endocrinology clinical settings.

They include 34 evidence-based clinical practice recommendations for screening, diagnosis, management, and referral, presented in a table and an algorithm flow chart as well as detailed text.

The new guidelines are by the American Association of Clinical Endocrinology and cosponsored by the American Association for the Study of Liver Diseases. They were presented at the annual scientific & clinical congress of the AACE and simultaneously published in Endocrine Practice.

These are “the first of this type for this field of medicine. The vast majority of patients with NAFLD are being seen in the primary care and endocrinology settings. Only when they get to the more advanced disease are they being referred to the liver specialists. So, we need to be the ones who are diagnosing and managing these patients because there just aren’t enough liver specialists to do that,” Scott Isaacs, MD, cochair of the writing panel for the guidelines, said in an interview.

80 million Americans have NAFLD, but very few are aware

The spectrum of NAFLD ranges from nonprogressive steatosis to the progressive conditions nonalcoholic steatohepatitis, fibrotic NASH, and end-stage NASH cirrhosis. And NASH, in turn, is a major cause of liver cancer. NAFLD is also strongly associated with insulin resistance, type 2 diabetes, atherogenesis, and myocardial dysfunction.

The global prevalence of NAFLD is about 25% and NASH, about 12%-14%. However, a recent study found that, among patients in endocrine and primary care clinics, more than 70% of patients with type 2 diabetes and more than 90% with type 2 diabetes who had a body mass index above 35 kg/m2 also had NAFLD, and more than 20% of those patients had significant liver fibrosis.

Problematically, very few people are aware they have either. “It’s so common. At least 80 million Americans have this but only about 6% know they have it. We talk about it a lot, but it’s not talked about enough,” said Dr. Isaacs, an endocrinologist who practices in Atlanta.

In fact, most cases of NAFLD are diagnosed incidentally when people undergo an ultrasound or a CT scan for another reason. And, in about 70% of cases the liver enzymes are normal, and those patients rarely undergo liver workups, Dr. Isaacs noted.

In an accompanying editorial, Suthat Liangpunsakul, MD, wrote: “In my perspective, as a hepatologist, this AACE guideline is very practical and easy to incorporate into routine practice in primary care and endocrinology settings. ... Early identification and risk stratification of patients with NAFLD, especially the degree of hepatic fibrosis, are required to reduce downstream health care costs and triage unwarranted specialty care referrals.”

And “an effective screening strategy may also identify those in primary care and endocrinology settings who may benefit from an appropriate referral to hepatologists before the development of portal hypertension complications, decompensated liver disease, and hepatocellular carcinoma,” added Dr. Liangpunsakul, professor of medicine in the division of gastroenterology and hepatology at Indiana University, Indianapolis.
 

Screening advised using new FIB-4 test

The guideline calls for screening all patients at high risk for NAFLD, including those with prediabetes, type 2 diabetes, obesity, and/or two or more cardiometabolic risk factors, or those with hepatic steatosis found on imaging, and/or persistently elevated plasma aminotransferase levels (that is, for more than 6 months).

The recommended screening test is the Fibrosis-4 (FIB-4) index, calculated using the patient’s age, AST level, platelet count, and ALT level: FIB-4 score = age (years) x AST (U/L)/PLT (10⁹/L) x ALT ½ (U/L).

Recently approved by the Food and Drug Administration, the FIB-4 has been demonstrated to help identify liver disease in primary care settings.

“We really want to encourage clinicians to do the screening. The first step is the FIB-4 test. It’s a mathematical calculation using blood tests that we do anyway,” Dr. Isaacs said in an interview.

The FIB-4 stratifies patients as being low, intermediate, or high risk for liver fibrosis. Those at low risk can be managed in primary care or endocrinology settings with a focus on obesity management and cardiovascular disease prevention. “Those at low risk on FIB-4 still have a high cardiovascular disease risk. They still need to be managed,” Dr. Isaacs observed.

For those at intermediate risk, a second noninvasive test – either a liver stiffness measurement by elastography or an enhanced liver fibrosis test – is advised. If the patient is found to be at high risk or is still indeterminant after two noninvasive tests, referral to a liver specialist for further testing, including possible biopsy, is advised.

Those found to be at high risk with the FIB-4 should also be referred to hepatology. In both the intermediate- and high-risk groups, management should be multidisciplinary, including a hepatologist, endocrinologist, and other professionals to prevent both cardiovascular disease and progression to cirrhosis, the guidelines say.

“The diagnosis isn’t about diagnosing liver fat. It’s about diagnosing fibrosis, or the risk for clinically significant fibrosis. That’s really where the challenge lies,” Dr. Isaacs commented.
 

NAFLD treatment in endocrinology and primary care: CVD prevention

During the presentation at the AACE meeting, guideline panel cochair Kenneth Cusi, MD, chief of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville, summarized current and future treatments for NAFLD.

Lifestyle intervention, cardiovascular risk reduction, and weight loss for those who are overweight or obese are recommended for all patients with NAFLD, including structured weight-loss programs, antiobesity medications, and bariatric surgery if indicated.

There are currently no FDA-approved medications specifically for NASH, but pioglitazone, approved for type 2 diabetes, and glucagonlike peptide–1 agonists, approved for type 2 diabetes and weight loss, have been shown to be effective in treating the condition and preventing progression. Other treatments are in development, Dr. Cusi said.  

The guideline also includes a section on diagnosis and management of NAFLD in children and adolescents. Here, the FIB-4 is not recommended because it isn’t accurate due to the age part of the equation, so liver enzyme tests are used in pediatric patients considered at high risk because of clinical factors. Management is similar to adults, except not all medications used in adults are approved for use in children.

In the editorial, Dr. Liangpunsakul cautioned that “the level of uptake and usage of the guideline may be an obstacle.”

To remedy that, he advised that “the next effort should gear toward distributing this guideline to the targeted providers and developing the ‘feedback platforms’ on its execution in the real-world. ... The successful implementation of this AACE guideline by the primary care providers and endocrinologists, hopefully, will deescalate the future burden of NAFLD-related morbidity and mortality.”

Dr. Isaacs and Dr. Liangpunsakul have reported no relevant financial relationships. Dr. Cusi has reported receiving research support towards the University of Florida as principal investigator from the National Institute of Health, Echosens, Inventiva, Nordic Bioscience, Novo Nordisk, Poxel, Labcorp, and Zydus, and is a consultant for Altimmune, Akero, Arrowhead, AstraZeneca, 89Bio, Bristol-Myers Squibb, Coherus, Intercept, Lilly, Madrigal, Merck, Novo Nordisk, Quest, Sagimet, Sonic Incytes, Terns, and Thera Technologies.

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

A complaint filed with the U.S. Department of Justice (DOJ) alleges that Alabama’s Medicaid program is illegally denying curative drug treatment for hepatitis C virus (HCV) infection to people with substance use disorder.

The complaint was filed May 9 by the Center for Health Law and Policy Innovation (CHLPI) of Harvard Law School, in partnership with AIDS Alabama.

It alleges that Alabama Medicaid has a policy of denying HCV treatment to people who have used illegal drugs or alcohol in the past 6 months.

CHLPI and AIDS Alabama argue that these restrictions violate the Americans With Disabilities Act, which protects people who are disabled because of substance use disorder.

“Forced sobriety policies don’t just unfairly prevent people with substance use disorder from accessing life-saving treatment; they also severely hamper public health efforts to stop the spread of the disease,” Kevin Costello, CHLPI’s litigation director, said in a statement.

“These policies are rooted in stigma, not science, and they violate antidiscrimination provisions of the Americans With Disabilities Act,” Mr. Costello said.

Filing an administrative complaint against Alabama is “an important milestone in fighting sobriety restrictions,” he added.
 

Morally wrong

Kathie Hiers, CEO of AIDS Alabama, noted that Alabama’s health outcomes are among the worst in the nation.

“Policies that prevent adequate medical care from being provided must end. HCV now has a cure, and withholding that cure from Alabamians based on a moral judgment is wrong and certainly doesn’t follow the science,” Ms. Hiers added.

Direct-acting antiviral (DAA) therapy can cure up to 99% of people living with HCV.

The complaint against Alabama Medicaid builds on CHLPI’s successful policy advocacy and litigation campaigns to expand access to DAA therapy in state Medicaid programs across the country.

Since 2017, 19 states have removed treatment restrictions that were based on drug or alcohol use. In other states, however, “severe, illegal sobriety restrictions remain,” according to CHLPI.

Alabama, Mississippi, Arkansas, South Carolina, and South Dakota still require Medicaid enrollees with HCV to prove they have not used drugs or alcohol for 6 months before they can receive treatment. Iowa, North Dakota, and West Virginia have a 3-month abstinence requirement.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommend DAA therapy for all patients with chronic HCV infection, regardless of drug or alcohol use.

CHLPI intends to expand this “enforcement campaign” to all states where sobriety restrictions persist.

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

A complaint filed with the U.S. Department of Justice (DOJ) alleges that Alabama’s Medicaid program is illegally denying curative drug treatment for hepatitis C virus (HCV) infection to people with substance use disorder.

The complaint was filed May 9 by the Center for Health Law and Policy Innovation (CHLPI) of Harvard Law School, in partnership with AIDS Alabama.

It alleges that Alabama Medicaid has a policy of denying HCV treatment to people who have used illegal drugs or alcohol in the past 6 months.

CHLPI and AIDS Alabama argue that these restrictions violate the Americans With Disabilities Act, which protects people who are disabled because of substance use disorder.

“Forced sobriety policies don’t just unfairly prevent people with substance use disorder from accessing life-saving treatment; they also severely hamper public health efforts to stop the spread of the disease,” Kevin Costello, CHLPI’s litigation director, said in a statement.

“These policies are rooted in stigma, not science, and they violate antidiscrimination provisions of the Americans With Disabilities Act,” Mr. Costello said.

Filing an administrative complaint against Alabama is “an important milestone in fighting sobriety restrictions,” he added.
 

Morally wrong

Kathie Hiers, CEO of AIDS Alabama, noted that Alabama’s health outcomes are among the worst in the nation.

“Policies that prevent adequate medical care from being provided must end. HCV now has a cure, and withholding that cure from Alabamians based on a moral judgment is wrong and certainly doesn’t follow the science,” Ms. Hiers added.

Direct-acting antiviral (DAA) therapy can cure up to 99% of people living with HCV.

The complaint against Alabama Medicaid builds on CHLPI’s successful policy advocacy and litigation campaigns to expand access to DAA therapy in state Medicaid programs across the country.

Since 2017, 19 states have removed treatment restrictions that were based on drug or alcohol use. In other states, however, “severe, illegal sobriety restrictions remain,” according to CHLPI.

Alabama, Mississippi, Arkansas, South Carolina, and South Dakota still require Medicaid enrollees with HCV to prove they have not used drugs or alcohol for 6 months before they can receive treatment. Iowa, North Dakota, and West Virginia have a 3-month abstinence requirement.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommend DAA therapy for all patients with chronic HCV infection, regardless of drug or alcohol use.

CHLPI intends to expand this “enforcement campaign” to all states where sobriety restrictions persist.

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

A complaint filed with the U.S. Department of Justice (DOJ) alleges that Alabama’s Medicaid program is illegally denying curative drug treatment for hepatitis C virus (HCV) infection to people with substance use disorder.

The complaint was filed May 9 by the Center for Health Law and Policy Innovation (CHLPI) of Harvard Law School, in partnership with AIDS Alabama.

It alleges that Alabama Medicaid has a policy of denying HCV treatment to people who have used illegal drugs or alcohol in the past 6 months.

CHLPI and AIDS Alabama argue that these restrictions violate the Americans With Disabilities Act, which protects people who are disabled because of substance use disorder.

“Forced sobriety policies don’t just unfairly prevent people with substance use disorder from accessing life-saving treatment; they also severely hamper public health efforts to stop the spread of the disease,” Kevin Costello, CHLPI’s litigation director, said in a statement.

“These policies are rooted in stigma, not science, and they violate antidiscrimination provisions of the Americans With Disabilities Act,” Mr. Costello said.

Filing an administrative complaint against Alabama is “an important milestone in fighting sobriety restrictions,” he added.
 

Morally wrong

Kathie Hiers, CEO of AIDS Alabama, noted that Alabama’s health outcomes are among the worst in the nation.

“Policies that prevent adequate medical care from being provided must end. HCV now has a cure, and withholding that cure from Alabamians based on a moral judgment is wrong and certainly doesn’t follow the science,” Ms. Hiers added.

Direct-acting antiviral (DAA) therapy can cure up to 99% of people living with HCV.

The complaint against Alabama Medicaid builds on CHLPI’s successful policy advocacy and litigation campaigns to expand access to DAA therapy in state Medicaid programs across the country.

Since 2017, 19 states have removed treatment restrictions that were based on drug or alcohol use. In other states, however, “severe, illegal sobriety restrictions remain,” according to CHLPI.

Alabama, Mississippi, Arkansas, South Carolina, and South Dakota still require Medicaid enrollees with HCV to prove they have not used drugs or alcohol for 6 months before they can receive treatment. Iowa, North Dakota, and West Virginia have a 3-month abstinence requirement.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommend DAA therapy for all patients with chronic HCV infection, regardless of drug or alcohol use.

CHLPI intends to expand this “enforcement campaign” to all states where sobriety restrictions persist.

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

In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.

Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.

Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.

“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”

Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”

In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”

“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”

The research was published online in Gastroenterology.
 

Looking at the big picture of PPIs in people with cirrhosis

The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.

However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.

To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.

They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.

In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).

Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.

Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.

Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.

However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).

Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).

The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
 

Large study suggests limited protective PPI indication

Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.

“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.

“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”

“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.

Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”

In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”

Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.

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

In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.

Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.

Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.

“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”

Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”

In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”

“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”

The research was published online in Gastroenterology.
 

Looking at the big picture of PPIs in people with cirrhosis

The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.

However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.

To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.

They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.

In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).

Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.

Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.

Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.

However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).

Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).

The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
 

Large study suggests limited protective PPI indication

Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.

“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.

“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”

“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.

Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”

In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”

Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.

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

In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.

Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.

Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.

“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”

Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”

In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”

“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”

The research was published online in Gastroenterology.
 

Looking at the big picture of PPIs in people with cirrhosis

The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.

However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.

To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.

They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.

In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).

Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.

Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.

Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.

However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).

Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).

The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
 

Large study suggests limited protective PPI indication

Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.

“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.

“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”

“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.

Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”

In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”

Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This is a transcript of a video that first appeared on Medscape.com. It has been edited for clarity.

On April 21, 2022, the Centers for Disease Control and Prevention released a Health Alert Network advisory regarding a cluster of nine cases of acute hepatitis in children in Alabama over a 5-month period from October 2021 to February 2022 – a rate substantially higher than what would be expected, given the relative rarity of hepatitis in children.

Standard workup was negative for the common causative agents – hepatitis A, B, and C – and no toxic exposures were identified. But there was one common thread among all these kids: They all tested positive for adenovirus.

And that is really strange.

There are about 100 circulating adenoviruses in the world that we know of, and around 50 of them infect humans. If you are an adult, it’s a virtual certainty that you have been infected with an adenovirus in the past. Most strains cause symptoms we would describe as the common cold: runny nose, sore throat. Some strains cause conjunctivitis (pink eye). Some cause gastrointestinal illness – the stomach bugs that kids get.

It’s the banality of adenovirus that makes this hepatitis finding so surprising.

The United States is not alone in reporting this new hepatitis syndrome. As of April 21, 169 cases have been reported across the world, including 114 in the United Kingdom.

Of the 169 cases reported worldwide, 74 had evidence of adenovirus infection. On molecular testing, 18 of those were adenovirus 41.

What I wanted to do today was go through the various hypotheses for what could be going on with these hepatitis cases, one by one, and highlight the evidence supporting them. We won’t reach a conclusion, but hopefully by the end, the path forward will be more clear. OK, let’s get started.

Hypothesis 1: Nothing is happening.

It’s worth noting that “clusters” of disease occur all the time, even when no relevant epidemiologic process has occurred. If there is some baseline rate of hepatitis, every once in a while, through bad luck alone, you’d see a group of cases all at once. This is known as the clustering illusion. And I’m quite confident in saying that this is not the case here.

For one, this phenomenon is worldwide, as we know from the World Health Organization report. In fact, the CDC didn’t provide the most detailed data about the nine (now 12) cases in the United States. This study from Scotland is the first to give a detailed accounting of cases, reporting on 13 cases of acute hepatitis of unknown cause in kids at a single hospital from January to April. Typically, the hospital sees fewer than four cases of hepatitis per year. Five of these 13 kids tested positive for adenovirus. So let’s take the clustering illusion off the list.

Hypothesis 2: It’s adenovirus.

The major evidence supporting adenovirus as the causative agent here is that a lot of these kids had adenovirus, and adenovirus 41 – a gut-tropic strain – in particular. This is important, because stool testing might be necessary for diagnosis and lots of kids with this condition didn’t get that. In other words, we have hard evidence of adenovirus infection in about 40% of the cases so far, but the true number might be substantially higher.

That said, adenovirus is seasonal, and we are in adenovirus season. Granted, 40% seems quite a bit higher than the background infection rate, but we have to be careful not to assume that correlation means causation.

The evidence against adenovirus, even adenovirus 41, is that this acute hepatitis syndrome is new, and adenovirus 41 is not. To be fair, we know adenoviruses can cause acute hepatitis, but the vast majority of reports are in immunocompromised individuals – organ transplant recipients and those with HIV. I was able to find just a handful of cases of immunocompetent kids developing hepatitis from adenovirus prior to this current outbreak.

The current outbreak would exceed the published literature by nearly two orders of magnitude. It feels like something else has to be going on.

Hypothesis 3: It’s coronavirus.

SARS-CoV-2 is a strange virus, both in its acute presentation and its long-term outcomes. It was clear early in the pandemic that some children infected by the coronavirus would develop MIS-C – multisystem inflammatory syndrome in children. MIS-C is associated with hepatitis in about 10% of children, according to this New England Journal of Medicine

But the presentation of these kids is quite different from MIS-C; fever is rare, for example. The WHO reports that of the 169 identified cases so far, 20 had active COVID infection. The Scotland cohort suggests that a similar proportion had past COVID infections. In other times, we might consider this a smoking gun, but at this point a history of COVID is not remarkable – after the Omicron wave, it’s about as common to have a history of COVID as it is not to have a history of COVID.

A brief aside here. This is not because of coronavirus vaccination. Of the more than 100 cases reported in the United Kingdom, none of these kids were vaccinated. So let’s put aside the possibility that this is a vaccine effect – there’s no real evidence to support that.

Which brings us to …

Hypothesis 4: It’s coronavirus and adenovirus.

This is sort of intriguing and can work a few different ways, via a direct and indirect path.

In the direct path, we posit that COVID infection does something to kids’ immune systems – something we don’t yet understand that limits their ability to fight off adenovirus. There is some support for this idea. This study in Immunity found that COVID infection can functionally impair dendritic cells and T-cells, including natural killer cells. These cells are important components of our innate antiviral immunity.

There’s an indirect path as well. COVID has led to lockdowns, distancing, masking – stuff that prevents kids from being exposed to germs from other kids. Could a lack of exposure to adenovirus or other viruses because of distancing increase the risk for severe disease when restrictions are lifted? Also possible – the severity of respiratory syncytial virus (RSV) infections this year is substantially higher than what we’ve seen in the past, for example.

And finally, hypothesis 5: This is something new.

We can’t ignore the possibility that this is simply a new disease-causing agent. Toxicology studies so far have been negative, and we wouldn’t expect hepatitis from a chemical toxin to appear in multiple countries around the world; this is almost certainly a biological phenomenon. It is possible that this is a new strain of adenovirus 41, or that adenovirus is a red herring altogether. Remember, we knew about “non-A/non-B viral hepatitis” for more than 2 decades before hepatitis C was discovered.

The pace of science is faster now, fortunately, and information is coming out quickly. As we learn more, we’ll share it with you.

Dr. Wilson, MD, MSCE, is an associate professor of medicine at Yale University, New Haven, Conn., and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. Dr. Wilson has disclosed no relevant financial relationships.

 

This is a transcript of a video that first appeared on Medscape.com. It has been edited for clarity.

On April 21, 2022, the Centers for Disease Control and Prevention released a Health Alert Network advisory regarding a cluster of nine cases of acute hepatitis in children in Alabama over a 5-month period from October 2021 to February 2022 – a rate substantially higher than what would be expected, given the relative rarity of hepatitis in children.

Standard workup was negative for the common causative agents – hepatitis A, B, and C – and no toxic exposures were identified. But there was one common thread among all these kids: They all tested positive for adenovirus.

And that is really strange.

There are about 100 circulating adenoviruses in the world that we know of, and around 50 of them infect humans. If you are an adult, it’s a virtual certainty that you have been infected with an adenovirus in the past. Most strains cause symptoms we would describe as the common cold: runny nose, sore throat. Some strains cause conjunctivitis (pink eye). Some cause gastrointestinal illness – the stomach bugs that kids get.

It’s the banality of adenovirus that makes this hepatitis finding so surprising.

The United States is not alone in reporting this new hepatitis syndrome. As of April 21, 169 cases have been reported across the world, including 114 in the United Kingdom.

Of the 169 cases reported worldwide, 74 had evidence of adenovirus infection. On molecular testing, 18 of those were adenovirus 41.

What I wanted to do today was go through the various hypotheses for what could be going on with these hepatitis cases, one by one, and highlight the evidence supporting them. We won’t reach a conclusion, but hopefully by the end, the path forward will be more clear. OK, let’s get started.

Hypothesis 1: Nothing is happening.

It’s worth noting that “clusters” of disease occur all the time, even when no relevant epidemiologic process has occurred. If there is some baseline rate of hepatitis, every once in a while, through bad luck alone, you’d see a group of cases all at once. This is known as the clustering illusion. And I’m quite confident in saying that this is not the case here.

For one, this phenomenon is worldwide, as we know from the World Health Organization report. In fact, the CDC didn’t provide the most detailed data about the nine (now 12) cases in the United States. This study from Scotland is the first to give a detailed accounting of cases, reporting on 13 cases of acute hepatitis of unknown cause in kids at a single hospital from January to April. Typically, the hospital sees fewer than four cases of hepatitis per year. Five of these 13 kids tested positive for adenovirus. So let’s take the clustering illusion off the list.

Hypothesis 2: It’s adenovirus.

The major evidence supporting adenovirus as the causative agent here is that a lot of these kids had adenovirus, and adenovirus 41 – a gut-tropic strain – in particular. This is important, because stool testing might be necessary for diagnosis and lots of kids with this condition didn’t get that. In other words, we have hard evidence of adenovirus infection in about 40% of the cases so far, but the true number might be substantially higher.

That said, adenovirus is seasonal, and we are in adenovirus season. Granted, 40% seems quite a bit higher than the background infection rate, but we have to be careful not to assume that correlation means causation.

The evidence against adenovirus, even adenovirus 41, is that this acute hepatitis syndrome is new, and adenovirus 41 is not. To be fair, we know adenoviruses can cause acute hepatitis, but the vast majority of reports are in immunocompromised individuals – organ transplant recipients and those with HIV. I was able to find just a handful of cases of immunocompetent kids developing hepatitis from adenovirus prior to this current outbreak.

The current outbreak would exceed the published literature by nearly two orders of magnitude. It feels like something else has to be going on.

Hypothesis 3: It’s coronavirus.

SARS-CoV-2 is a strange virus, both in its acute presentation and its long-term outcomes. It was clear early in the pandemic that some children infected by the coronavirus would develop MIS-C – multisystem inflammatory syndrome in children. MIS-C is associated with hepatitis in about 10% of children, according to this New England Journal of Medicine

But the presentation of these kids is quite different from MIS-C; fever is rare, for example. The WHO reports that of the 169 identified cases so far, 20 had active COVID infection. The Scotland cohort suggests that a similar proportion had past COVID infections. In other times, we might consider this a smoking gun, but at this point a history of COVID is not remarkable – after the Omicron wave, it’s about as common to have a history of COVID as it is not to have a history of COVID.

A brief aside here. This is not because of coronavirus vaccination. Of the more than 100 cases reported in the United Kingdom, none of these kids were vaccinated. So let’s put aside the possibility that this is a vaccine effect – there’s no real evidence to support that.

Which brings us to …

Hypothesis 4: It’s coronavirus and adenovirus.

This is sort of intriguing and can work a few different ways, via a direct and indirect path.

In the direct path, we posit that COVID infection does something to kids’ immune systems – something we don’t yet understand that limits their ability to fight off adenovirus. There is some support for this idea. This study in Immunity found that COVID infection can functionally impair dendritic cells and T-cells, including natural killer cells. These cells are important components of our innate antiviral immunity.

There’s an indirect path as well. COVID has led to lockdowns, distancing, masking – stuff that prevents kids from being exposed to germs from other kids. Could a lack of exposure to adenovirus or other viruses because of distancing increase the risk for severe disease when restrictions are lifted? Also possible – the severity of respiratory syncytial virus (RSV) infections this year is substantially higher than what we’ve seen in the past, for example.

And finally, hypothesis 5: This is something new.

We can’t ignore the possibility that this is simply a new disease-causing agent. Toxicology studies so far have been negative, and we wouldn’t expect hepatitis from a chemical toxin to appear in multiple countries around the world; this is almost certainly a biological phenomenon. It is possible that this is a new strain of adenovirus 41, or that adenovirus is a red herring altogether. Remember, we knew about “non-A/non-B viral hepatitis” for more than 2 decades before hepatitis C was discovered.

The pace of science is faster now, fortunately, and information is coming out quickly. As we learn more, we’ll share it with you.

Dr. Wilson, MD, MSCE, is an associate professor of medicine at Yale University, New Haven, Conn., and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. Dr. Wilson has disclosed no relevant financial relationships.

 

This is a transcript of a video that first appeared on Medscape.com. It has been edited for clarity.

On April 21, 2022, the Centers for Disease Control and Prevention released a Health Alert Network advisory regarding a cluster of nine cases of acute hepatitis in children in Alabama over a 5-month period from October 2021 to February 2022 – a rate substantially higher than what would be expected, given the relative rarity of hepatitis in children.

Standard workup was negative for the common causative agents – hepatitis A, B, and C – and no toxic exposures were identified. But there was one common thread among all these kids: They all tested positive for adenovirus.

And that is really strange.

There are about 100 circulating adenoviruses in the world that we know of, and around 50 of them infect humans. If you are an adult, it’s a virtual certainty that you have been infected with an adenovirus in the past. Most strains cause symptoms we would describe as the common cold: runny nose, sore throat. Some strains cause conjunctivitis (pink eye). Some cause gastrointestinal illness – the stomach bugs that kids get.

It’s the banality of adenovirus that makes this hepatitis finding so surprising.

The United States is not alone in reporting this new hepatitis syndrome. As of April 21, 169 cases have been reported across the world, including 114 in the United Kingdom.

Of the 169 cases reported worldwide, 74 had evidence of adenovirus infection. On molecular testing, 18 of those were adenovirus 41.

What I wanted to do today was go through the various hypotheses for what could be going on with these hepatitis cases, one by one, and highlight the evidence supporting them. We won’t reach a conclusion, but hopefully by the end, the path forward will be more clear. OK, let’s get started.

Hypothesis 1: Nothing is happening.

It’s worth noting that “clusters” of disease occur all the time, even when no relevant epidemiologic process has occurred. If there is some baseline rate of hepatitis, every once in a while, through bad luck alone, you’d see a group of cases all at once. This is known as the clustering illusion. And I’m quite confident in saying that this is not the case here.

For one, this phenomenon is worldwide, as we know from the World Health Organization report. In fact, the CDC didn’t provide the most detailed data about the nine (now 12) cases in the United States. This study from Scotland is the first to give a detailed accounting of cases, reporting on 13 cases of acute hepatitis of unknown cause in kids at a single hospital from January to April. Typically, the hospital sees fewer than four cases of hepatitis per year. Five of these 13 kids tested positive for adenovirus. So let’s take the clustering illusion off the list.

Hypothesis 2: It’s adenovirus.

The major evidence supporting adenovirus as the causative agent here is that a lot of these kids had adenovirus, and adenovirus 41 – a gut-tropic strain – in particular. This is important, because stool testing might be necessary for diagnosis and lots of kids with this condition didn’t get that. In other words, we have hard evidence of adenovirus infection in about 40% of the cases so far, but the true number might be substantially higher.

That said, adenovirus is seasonal, and we are in adenovirus season. Granted, 40% seems quite a bit higher than the background infection rate, but we have to be careful not to assume that correlation means causation.

The evidence against adenovirus, even adenovirus 41, is that this acute hepatitis syndrome is new, and adenovirus 41 is not. To be fair, we know adenoviruses can cause acute hepatitis, but the vast majority of reports are in immunocompromised individuals – organ transplant recipients and those with HIV. I was able to find just a handful of cases of immunocompetent kids developing hepatitis from adenovirus prior to this current outbreak.

The current outbreak would exceed the published literature by nearly two orders of magnitude. It feels like something else has to be going on.

Hypothesis 3: It’s coronavirus.

SARS-CoV-2 is a strange virus, both in its acute presentation and its long-term outcomes. It was clear early in the pandemic that some children infected by the coronavirus would develop MIS-C – multisystem inflammatory syndrome in children. MIS-C is associated with hepatitis in about 10% of children, according to this New England Journal of Medicine

But the presentation of these kids is quite different from MIS-C; fever is rare, for example. The WHO reports that of the 169 identified cases so far, 20 had active COVID infection. The Scotland cohort suggests that a similar proportion had past COVID infections. In other times, we might consider this a smoking gun, but at this point a history of COVID is not remarkable – after the Omicron wave, it’s about as common to have a history of COVID as it is not to have a history of COVID.

A brief aside here. This is not because of coronavirus vaccination. Of the more than 100 cases reported in the United Kingdom, none of these kids were vaccinated. So let’s put aside the possibility that this is a vaccine effect – there’s no real evidence to support that.

Which brings us to …

Hypothesis 4: It’s coronavirus and adenovirus.

This is sort of intriguing and can work a few different ways, via a direct and indirect path.

In the direct path, we posit that COVID infection does something to kids’ immune systems – something we don’t yet understand that limits their ability to fight off adenovirus. There is some support for this idea. This study in Immunity found that COVID infection can functionally impair dendritic cells and T-cells, including natural killer cells. These cells are important components of our innate antiviral immunity.

There’s an indirect path as well. COVID has led to lockdowns, distancing, masking – stuff that prevents kids from being exposed to germs from other kids. Could a lack of exposure to adenovirus or other viruses because of distancing increase the risk for severe disease when restrictions are lifted? Also possible – the severity of respiratory syncytial virus (RSV) infections this year is substantially higher than what we’ve seen in the past, for example.

And finally, hypothesis 5: This is something new.

We can’t ignore the possibility that this is simply a new disease-causing agent. Toxicology studies so far have been negative, and we wouldn’t expect hepatitis from a chemical toxin to appear in multiple countries around the world; this is almost certainly a biological phenomenon. It is possible that this is a new strain of adenovirus 41, or that adenovirus is a red herring altogether. Remember, we knew about “non-A/non-B viral hepatitis” for more than 2 decades before hepatitis C was discovered.

The pace of science is faster now, fortunately, and information is coming out quickly. As we learn more, we’ll share it with you.

Dr. Wilson, MD, MSCE, is an associate professor of medicine at Yale University, New Haven, Conn., and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and hosts a repository of his communication work at www.methodsman.com. Dr. Wilson has disclosed no relevant financial relationships.

 

People with metabolic dysfunction–associated fatty liver disease (MAFLD) – a newly defined condition – may be more likely to die from COVID-19, researchers say.

A cohort of people hospitalized for COVID-19 in Central Military Hospital, Mexico City, who met the criteria for MAFLD died at a higher rate than a control group without fatty liver disease, said Martín Uriel Vázquez-Medina, MSc, a researcher in the National Polytechnic Institute in Mexico City.

Patients who met only the criteria for the traditional classification, nonalcoholic fatty liver disease (NAFLD), also died of COVID-19 at a higher rate than the control group, but the difference was not statistically significant.

“It is important to screen for MAFLD,” Mr. Vázquez-Medina told this news organization. “It’s a new definition, but it has really helped us to identify which patients are going to get worse by COVID-19.”

The study was published in Hepatology Communications.
 

More evidence for clinical relevance of MAFLD

The finding lends support to an initiative to use MAFLD instead of NAFLD to identify patients whose liver steatosis poses a threat to their health, Mr. Vázquez-Medina said.

NAFLD affects as much as a quarter of the world’s population. No drugs have been approved to treat it. Some researchers have reasoned that the imprecision of the definition of NAFLD could be one reason for the lack of progress in treatment.

“NAFLD is something that doesn’t have positive criteria to be diagnosed,” said Mr. Vázquez-Medina. “You only say NAFLD when you don’t find hepatitis or another disease.”

In an article published in Gastroenterology, an international consensus panel proposed MAFLD as an alternative, arguing that a focus on metabolic dysfunction could more accurately reflect the pathogenesis of the disease and help stratify patients.

Previous research has suggested that patients with MAFLD have a higher risk of atherosclerotic cardiovascular disease and that the prevalence of colorectal adenomas is a higher in these patients, compared with patients with NAFLD.

The high prevalence of MAFLD in Mexico – about 30% – could help explain the country’s high rate of mortality from COVID-19, Mr. Vázquez-Medina said. Almost 6% of people diagnosed with COVID in Mexico have died from it, according to the Johns Hopkins University and Medical Center Coronavirus Resource Center.
 

Sorting COVID outcomes by liver steatosis

To understand the interaction of MAFLD, NAFLD, liver fibrosis, and COVID-19, Mr. Vázquez-Medina and his colleagues analyzed the records of all patients admitted to the Central Military Hospital with COVID-19 from April 4, 2020, to June 24, 2020.

They excluded patients for whom complete data were lacking or for whom a liver function test was not conducted in the first 24 hours of hospitalization. Also excluded were patients with significant consumption of alcohol (> 30 g/day for men and > 20 g/day for women) and those with a history of autoimmune liver disease, liver cancer, decompensated cirrhosis, platelet disorders, or myopathies.

The remaining patients were divided into three groups – 220 who met the criteria for MAFLD, 79 who met the criteria for NAFLD but not MAFLD, and 60 other patients as a control group.

The researchers defined MAFLD as the presence of liver steatosis detected with a noninvasive method and one of the following: overweight (body mass index, 25-29.9 kg/m2), type 2 diabetes, or the presence of two metabolic abnormalities (blood pressure > 140/90 mm Hg, plasma triglycerides > 150 mg/dL, plasma high-density lipoprotein cholesterol < 40 mg/dL in men and < 50 mg/dL in women, and prediabetes).

They defined NAFLD as the presence of liver steatosis without the other criteria for MAFLD.

The patients with MAFLD were the most likely to be intubated and were the most likely to die (intubation, 44.09%; mortality, 55%), followed by those with NAFLD (intubation, 40.51%; mortality, 51.9%) and those in the control group (intubation, 20%; mortality, 38.33%).

The difference in mortality between the MAFLD group and the control group was statistically significant (P = .02). The mortality difference between the NAFLD and the control group fell just short of statistical significance (P = .07).

For intubation, the difference between the MAFLD and the control group was highly statistically significant (P = .001), and the difference between the NAFLD and the control group was also statistically significant (P = .01)

Patients with advanced fibrosis and either MAFLD or NAFLD were also more likely to die than patients in the control group with advanced fibrosis.

That’s why screening for MAFLD is important, Mr. Vázquez-Medina said.
 

Next steps and new questions

Future research should examine whether patients with MAFLD have elevated levels of biomarkers for inflammation, such as interleukin 6, Mr. Vázquez-Medina said. A “chronic low proinflammatory state” may be the key to understanding the vulnerability of patients to MAFLD to COVID-19, he speculated.

The metabolic traits associated with MAFLD could explain the higher mortality and intubation rates with COVID, said Rohit Loomba, MD, MHSc, a professor of medicine in the division of gastroenterology at the University of California, San Diego, who was not involved in the study.

“Hypertension, diabetes, and obesity increase the risk of complications from COVID in all patients, whether they have been diagnosed with NAFLD or not,” he told this news organization in an email.

Mr. Vasquez-Medina pointed out that the patients with MAFLD had a higher risk of mortality even after adjusting for age, sex, type 2 diabetes, hypertension, overweight, and obesity (BMI ≥ 30 kg/m2). MAFLD also was more strongly associated with a poor outcome than either hypertension alone or obesity alone. Only age emerged as a significant independent covariate in the study.

Dr. Loomba also questioned whether the regression model used in this study for liver steatosis was “fully reflective of NAFLD.”

The researchers identified liver steatosis with a diagnostic formula that used noninvasive clinical BMI and laboratory tests (alanine aminotransferase), citing a study that found the regression formula was better at diagnosing NAFLD than FibroScan.

Mr. Vázquez-Medina reported no relevant financial relationships. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics. He is co-founder of LipoNexus.

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

People with metabolic dysfunction–associated fatty liver disease (MAFLD) – a newly defined condition – may be more likely to die from COVID-19, researchers say.

A cohort of people hospitalized for COVID-19 in Central Military Hospital, Mexico City, who met the criteria for MAFLD died at a higher rate than a control group without fatty liver disease, said Martín Uriel Vázquez-Medina, MSc, a researcher in the National Polytechnic Institute in Mexico City.

Patients who met only the criteria for the traditional classification, nonalcoholic fatty liver disease (NAFLD), also died of COVID-19 at a higher rate than the control group, but the difference was not statistically significant.

“It is important to screen for MAFLD,” Mr. Vázquez-Medina told this news organization. “It’s a new definition, but it has really helped us to identify which patients are going to get worse by COVID-19.”

The study was published in Hepatology Communications.
 

More evidence for clinical relevance of MAFLD

The finding lends support to an initiative to use MAFLD instead of NAFLD to identify patients whose liver steatosis poses a threat to their health, Mr. Vázquez-Medina said.

NAFLD affects as much as a quarter of the world’s population. No drugs have been approved to treat it. Some researchers have reasoned that the imprecision of the definition of NAFLD could be one reason for the lack of progress in treatment.

“NAFLD is something that doesn’t have positive criteria to be diagnosed,” said Mr. Vázquez-Medina. “You only say NAFLD when you don’t find hepatitis or another disease.”

In an article published in Gastroenterology, an international consensus panel proposed MAFLD as an alternative, arguing that a focus on metabolic dysfunction could more accurately reflect the pathogenesis of the disease and help stratify patients.

Previous research has suggested that patients with MAFLD have a higher risk of atherosclerotic cardiovascular disease and that the prevalence of colorectal adenomas is a higher in these patients, compared with patients with NAFLD.

The high prevalence of MAFLD in Mexico – about 30% – could help explain the country’s high rate of mortality from COVID-19, Mr. Vázquez-Medina said. Almost 6% of people diagnosed with COVID in Mexico have died from it, according to the Johns Hopkins University and Medical Center Coronavirus Resource Center.
 

Sorting COVID outcomes by liver steatosis

To understand the interaction of MAFLD, NAFLD, liver fibrosis, and COVID-19, Mr. Vázquez-Medina and his colleagues analyzed the records of all patients admitted to the Central Military Hospital with COVID-19 from April 4, 2020, to June 24, 2020.

They excluded patients for whom complete data were lacking or for whom a liver function test was not conducted in the first 24 hours of hospitalization. Also excluded were patients with significant consumption of alcohol (> 30 g/day for men and > 20 g/day for women) and those with a history of autoimmune liver disease, liver cancer, decompensated cirrhosis, platelet disorders, or myopathies.

The remaining patients were divided into three groups – 220 who met the criteria for MAFLD, 79 who met the criteria for NAFLD but not MAFLD, and 60 other patients as a control group.

The researchers defined MAFLD as the presence of liver steatosis detected with a noninvasive method and one of the following: overweight (body mass index, 25-29.9 kg/m2), type 2 diabetes, or the presence of two metabolic abnormalities (blood pressure > 140/90 mm Hg, plasma triglycerides > 150 mg/dL, plasma high-density lipoprotein cholesterol < 40 mg/dL in men and < 50 mg/dL in women, and prediabetes).

They defined NAFLD as the presence of liver steatosis without the other criteria for MAFLD.

The patients with MAFLD were the most likely to be intubated and were the most likely to die (intubation, 44.09%; mortality, 55%), followed by those with NAFLD (intubation, 40.51%; mortality, 51.9%) and those in the control group (intubation, 20%; mortality, 38.33%).

The difference in mortality between the MAFLD group and the control group was statistically significant (P = .02). The mortality difference between the NAFLD and the control group fell just short of statistical significance (P = .07).

For intubation, the difference between the MAFLD and the control group was highly statistically significant (P = .001), and the difference between the NAFLD and the control group was also statistically significant (P = .01)

Patients with advanced fibrosis and either MAFLD or NAFLD were also more likely to die than patients in the control group with advanced fibrosis.

That’s why screening for MAFLD is important, Mr. Vázquez-Medina said.
 

Next steps and new questions

Future research should examine whether patients with MAFLD have elevated levels of biomarkers for inflammation, such as interleukin 6, Mr. Vázquez-Medina said. A “chronic low proinflammatory state” may be the key to understanding the vulnerability of patients to MAFLD to COVID-19, he speculated.

The metabolic traits associated with MAFLD could explain the higher mortality and intubation rates with COVID, said Rohit Loomba, MD, MHSc, a professor of medicine in the division of gastroenterology at the University of California, San Diego, who was not involved in the study.

“Hypertension, diabetes, and obesity increase the risk of complications from COVID in all patients, whether they have been diagnosed with NAFLD or not,” he told this news organization in an email.

Mr. Vasquez-Medina pointed out that the patients with MAFLD had a higher risk of mortality even after adjusting for age, sex, type 2 diabetes, hypertension, overweight, and obesity (BMI ≥ 30 kg/m2). MAFLD also was more strongly associated with a poor outcome than either hypertension alone or obesity alone. Only age emerged as a significant independent covariate in the study.

Dr. Loomba also questioned whether the regression model used in this study for liver steatosis was “fully reflective of NAFLD.”

The researchers identified liver steatosis with a diagnostic formula that used noninvasive clinical BMI and laboratory tests (alanine aminotransferase), citing a study that found the regression formula was better at diagnosing NAFLD than FibroScan.

Mr. Vázquez-Medina reported no relevant financial relationships. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics. He is co-founder of LipoNexus.

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

People with metabolic dysfunction–associated fatty liver disease (MAFLD) – a newly defined condition – may be more likely to die from COVID-19, researchers say.

A cohort of people hospitalized for COVID-19 in Central Military Hospital, Mexico City, who met the criteria for MAFLD died at a higher rate than a control group without fatty liver disease, said Martín Uriel Vázquez-Medina, MSc, a researcher in the National Polytechnic Institute in Mexico City.

Patients who met only the criteria for the traditional classification, nonalcoholic fatty liver disease (NAFLD), also died of COVID-19 at a higher rate than the control group, but the difference was not statistically significant.

“It is important to screen for MAFLD,” Mr. Vázquez-Medina told this news organization. “It’s a new definition, but it has really helped us to identify which patients are going to get worse by COVID-19.”

The study was published in Hepatology Communications.
 

More evidence for clinical relevance of MAFLD

The finding lends support to an initiative to use MAFLD instead of NAFLD to identify patients whose liver steatosis poses a threat to their health, Mr. Vázquez-Medina said.

NAFLD affects as much as a quarter of the world’s population. No drugs have been approved to treat it. Some researchers have reasoned that the imprecision of the definition of NAFLD could be one reason for the lack of progress in treatment.

“NAFLD is something that doesn’t have positive criteria to be diagnosed,” said Mr. Vázquez-Medina. “You only say NAFLD when you don’t find hepatitis or another disease.”

In an article published in Gastroenterology, an international consensus panel proposed MAFLD as an alternative, arguing that a focus on metabolic dysfunction could more accurately reflect the pathogenesis of the disease and help stratify patients.

Previous research has suggested that patients with MAFLD have a higher risk of atherosclerotic cardiovascular disease and that the prevalence of colorectal adenomas is a higher in these patients, compared with patients with NAFLD.

The high prevalence of MAFLD in Mexico – about 30% – could help explain the country’s high rate of mortality from COVID-19, Mr. Vázquez-Medina said. Almost 6% of people diagnosed with COVID in Mexico have died from it, according to the Johns Hopkins University and Medical Center Coronavirus Resource Center.
 

Sorting COVID outcomes by liver steatosis

To understand the interaction of MAFLD, NAFLD, liver fibrosis, and COVID-19, Mr. Vázquez-Medina and his colleagues analyzed the records of all patients admitted to the Central Military Hospital with COVID-19 from April 4, 2020, to June 24, 2020.

They excluded patients for whom complete data were lacking or for whom a liver function test was not conducted in the first 24 hours of hospitalization. Also excluded were patients with significant consumption of alcohol (> 30 g/day for men and > 20 g/day for women) and those with a history of autoimmune liver disease, liver cancer, decompensated cirrhosis, platelet disorders, or myopathies.

The remaining patients were divided into three groups – 220 who met the criteria for MAFLD, 79 who met the criteria for NAFLD but not MAFLD, and 60 other patients as a control group.

The researchers defined MAFLD as the presence of liver steatosis detected with a noninvasive method and one of the following: overweight (body mass index, 25-29.9 kg/m2), type 2 diabetes, or the presence of two metabolic abnormalities (blood pressure > 140/90 mm Hg, plasma triglycerides > 150 mg/dL, plasma high-density lipoprotein cholesterol < 40 mg/dL in men and < 50 mg/dL in women, and prediabetes).

They defined NAFLD as the presence of liver steatosis without the other criteria for MAFLD.

The patients with MAFLD were the most likely to be intubated and were the most likely to die (intubation, 44.09%; mortality, 55%), followed by those with NAFLD (intubation, 40.51%; mortality, 51.9%) and those in the control group (intubation, 20%; mortality, 38.33%).

The difference in mortality between the MAFLD group and the control group was statistically significant (P = .02). The mortality difference between the NAFLD and the control group fell just short of statistical significance (P = .07).

For intubation, the difference between the MAFLD and the control group was highly statistically significant (P = .001), and the difference between the NAFLD and the control group was also statistically significant (P = .01)

Patients with advanced fibrosis and either MAFLD or NAFLD were also more likely to die than patients in the control group with advanced fibrosis.

That’s why screening for MAFLD is important, Mr. Vázquez-Medina said.
 

Next steps and new questions

Future research should examine whether patients with MAFLD have elevated levels of biomarkers for inflammation, such as interleukin 6, Mr. Vázquez-Medina said. A “chronic low proinflammatory state” may be the key to understanding the vulnerability of patients to MAFLD to COVID-19, he speculated.

The metabolic traits associated with MAFLD could explain the higher mortality and intubation rates with COVID, said Rohit Loomba, MD, MHSc, a professor of medicine in the division of gastroenterology at the University of California, San Diego, who was not involved in the study.

“Hypertension, diabetes, and obesity increase the risk of complications from COVID in all patients, whether they have been diagnosed with NAFLD or not,” he told this news organization in an email.

Mr. Vasquez-Medina pointed out that the patients with MAFLD had a higher risk of mortality even after adjusting for age, sex, type 2 diabetes, hypertension, overweight, and obesity (BMI ≥ 30 kg/m2). MAFLD also was more strongly associated with a poor outcome than either hypertension alone or obesity alone. Only age emerged as a significant independent covariate in the study.

Dr. Loomba also questioned whether the regression model used in this study for liver steatosis was “fully reflective of NAFLD.”

The researchers identified liver steatosis with a diagnostic formula that used noninvasive clinical BMI and laboratory tests (alanine aminotransferase), citing a study that found the regression formula was better at diagnosing NAFLD than FibroScan.

Mr. Vázquez-Medina reported no relevant financial relationships. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics. He is co-founder of LipoNexus.

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

A new deep learning system can classify hepatocellular nodular lesions (HNLs) via whole-slide images, improving risk stratification of patients and diagnostic rate of hepatocellular carcinoma (HCC), according to investigators.

While the model requires further validation, it could eventually be used to optimize accuracy and efficiency of histologic diagnoses, potentially decreasing reliance on pathologists, particularly in areas with limited access to subspecialists.

In an article published in Gastroenterology, Na Cheng, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues wrote that the “diagnostic process [for HNLs] is laborious, time-consuming, and subject to the experience of the pathologists, often with significant interobserver and intraobserver variability. ... Therefore, [an] automated analysis system is highly demanded in the pathology field, which could considerably ease the workload, speed up the diagnosis, and facilitate the in-time treatment.”

To this end, Dr. Cheng and colleagues developed the hepatocellular-nodular artificial intelligence model (HnAIM) that can scan whole-image slides to identify seven types of tissue: well-differentiated HCC, high-grade dysplastic nodules, low-grade dysplastic nodules, hepatocellular adenoma, focal nodular hyperplasia, and background tissue.

Developing and testing HnAIM was a multistep process that began with three subspecialist pathologists, who independently reviewed and classified liver slides from surgical resection. Unanimous agreement was achieved in 649 slides from 462 patients. These slides were then scanned to create whole-slide images, which were divided into sets for training (70%), validation (15%), and internal testing (15%). Accuracy, measured by area under the curve (AUC), was over 99.9% for the internal testing set. The accuracy of HnAIM was independently, externally validated.

First, HnAIM evaluated liver biopsy slides from 30 patients at one center. Results were compared with diagnoses made by nine pathologists classified as either senior, intermediate, or junior. While HnAIM correctly diagnosed 100% of the cases, senior pathologists correctly diagnosed 94.4% of the cases, followed in accuracy by intermediate (86.7%) and junior (73.3%) pathologists.

The researchers noted that the “rate of agreement with subspecialists was higher for HnAIM than for all 9 pathologists at distinguishing 7 liver tissues, with important diagnostic implications for fragmentary or scarce biopsy specimens.”

Next, HnAIM evaluated 234 samples from three hospitals. Accuracy was slightly lower, with an AUC of 93.5%. The researchers highlighted how HnAIM consistently differentiated precancerous lesions and well-defined HCC from benign lesions and background tissues.

A final experiment showed how HnAIM reacted to the most challenging cases. The investigators selected 12 cases without definitive diagnoses and found that, similar to the findings of three subspecialist pathologists, HnAIM did not reach a single diagnostic conclusion.

The researchers reported that “This may be due to a number of potential reasons, such as inherent uncertainty in the 2-dimensional interpretation of a 3-dimensional specimen, the limited number of tissue samples, and cognitive factors such as anchoring.”

However, HnAIM contributed to the diagnostic process by generating multiple diagnostic possibilities with weighted likelihood. After reviewing these results, the expert pathologists reached consensus in 5 out of 12 cases. Moreover, two out of three expert pathologists agreed on all 12 cases, improving agreement rate from 25% to 100%.

The researchers concluded that the model holds the promise to facilitate human HNL diagnoses and improve efficiency and quality. It can also reduce the workload of pathologists, especially where subspecialists are unavailable.

The study was supported by the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, the Natural Science Foundation of Guangdong Province, and others. The investigators reported no conflicts of interest.

A new deep learning system can classify hepatocellular nodular lesions (HNLs) via whole-slide images, improving risk stratification of patients and diagnostic rate of hepatocellular carcinoma (HCC), according to investigators.

While the model requires further validation, it could eventually be used to optimize accuracy and efficiency of histologic diagnoses, potentially decreasing reliance on pathologists, particularly in areas with limited access to subspecialists.

In an article published in Gastroenterology, Na Cheng, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues wrote that the “diagnostic process [for HNLs] is laborious, time-consuming, and subject to the experience of the pathologists, often with significant interobserver and intraobserver variability. ... Therefore, [an] automated analysis system is highly demanded in the pathology field, which could considerably ease the workload, speed up the diagnosis, and facilitate the in-time treatment.”

To this end, Dr. Cheng and colleagues developed the hepatocellular-nodular artificial intelligence model (HnAIM) that can scan whole-image slides to identify seven types of tissue: well-differentiated HCC, high-grade dysplastic nodules, low-grade dysplastic nodules, hepatocellular adenoma, focal nodular hyperplasia, and background tissue.

Developing and testing HnAIM was a multistep process that began with three subspecialist pathologists, who independently reviewed and classified liver slides from surgical resection. Unanimous agreement was achieved in 649 slides from 462 patients. These slides were then scanned to create whole-slide images, which were divided into sets for training (70%), validation (15%), and internal testing (15%). Accuracy, measured by area under the curve (AUC), was over 99.9% for the internal testing set. The accuracy of HnAIM was independently, externally validated.

First, HnAIM evaluated liver biopsy slides from 30 patients at one center. Results were compared with diagnoses made by nine pathologists classified as either senior, intermediate, or junior. While HnAIM correctly diagnosed 100% of the cases, senior pathologists correctly diagnosed 94.4% of the cases, followed in accuracy by intermediate (86.7%) and junior (73.3%) pathologists.

The researchers noted that the “rate of agreement with subspecialists was higher for HnAIM than for all 9 pathologists at distinguishing 7 liver tissues, with important diagnostic implications for fragmentary or scarce biopsy specimens.”

Next, HnAIM evaluated 234 samples from three hospitals. Accuracy was slightly lower, with an AUC of 93.5%. The researchers highlighted how HnAIM consistently differentiated precancerous lesions and well-defined HCC from benign lesions and background tissues.

A final experiment showed how HnAIM reacted to the most challenging cases. The investigators selected 12 cases without definitive diagnoses and found that, similar to the findings of three subspecialist pathologists, HnAIM did not reach a single diagnostic conclusion.

The researchers reported that “This may be due to a number of potential reasons, such as inherent uncertainty in the 2-dimensional interpretation of a 3-dimensional specimen, the limited number of tissue samples, and cognitive factors such as anchoring.”

However, HnAIM contributed to the diagnostic process by generating multiple diagnostic possibilities with weighted likelihood. After reviewing these results, the expert pathologists reached consensus in 5 out of 12 cases. Moreover, two out of three expert pathologists agreed on all 12 cases, improving agreement rate from 25% to 100%.

The researchers concluded that the model holds the promise to facilitate human HNL diagnoses and improve efficiency and quality. It can also reduce the workload of pathologists, especially where subspecialists are unavailable.

The study was supported by the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, the Natural Science Foundation of Guangdong Province, and others. The investigators reported no conflicts of interest.

A new deep learning system can classify hepatocellular nodular lesions (HNLs) via whole-slide images, improving risk stratification of patients and diagnostic rate of hepatocellular carcinoma (HCC), according to investigators.

While the model requires further validation, it could eventually be used to optimize accuracy and efficiency of histologic diagnoses, potentially decreasing reliance on pathologists, particularly in areas with limited access to subspecialists.

In an article published in Gastroenterology, Na Cheng, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues wrote that the “diagnostic process [for HNLs] is laborious, time-consuming, and subject to the experience of the pathologists, often with significant interobserver and intraobserver variability. ... Therefore, [an] automated analysis system is highly demanded in the pathology field, which could considerably ease the workload, speed up the diagnosis, and facilitate the in-time treatment.”

To this end, Dr. Cheng and colleagues developed the hepatocellular-nodular artificial intelligence model (HnAIM) that can scan whole-image slides to identify seven types of tissue: well-differentiated HCC, high-grade dysplastic nodules, low-grade dysplastic nodules, hepatocellular adenoma, focal nodular hyperplasia, and background tissue.

Developing and testing HnAIM was a multistep process that began with three subspecialist pathologists, who independently reviewed and classified liver slides from surgical resection. Unanimous agreement was achieved in 649 slides from 462 patients. These slides were then scanned to create whole-slide images, which were divided into sets for training (70%), validation (15%), and internal testing (15%). Accuracy, measured by area under the curve (AUC), was over 99.9% for the internal testing set. The accuracy of HnAIM was independently, externally validated.

First, HnAIM evaluated liver biopsy slides from 30 patients at one center. Results were compared with diagnoses made by nine pathologists classified as either senior, intermediate, or junior. While HnAIM correctly diagnosed 100% of the cases, senior pathologists correctly diagnosed 94.4% of the cases, followed in accuracy by intermediate (86.7%) and junior (73.3%) pathologists.

The researchers noted that the “rate of agreement with subspecialists was higher for HnAIM than for all 9 pathologists at distinguishing 7 liver tissues, with important diagnostic implications for fragmentary or scarce biopsy specimens.”

Next, HnAIM evaluated 234 samples from three hospitals. Accuracy was slightly lower, with an AUC of 93.5%. The researchers highlighted how HnAIM consistently differentiated precancerous lesions and well-defined HCC from benign lesions and background tissues.

A final experiment showed how HnAIM reacted to the most challenging cases. The investigators selected 12 cases without definitive diagnoses and found that, similar to the findings of three subspecialist pathologists, HnAIM did not reach a single diagnostic conclusion.

The researchers reported that “This may be due to a number of potential reasons, such as inherent uncertainty in the 2-dimensional interpretation of a 3-dimensional specimen, the limited number of tissue samples, and cognitive factors such as anchoring.”

However, HnAIM contributed to the diagnostic process by generating multiple diagnostic possibilities with weighted likelihood. After reviewing these results, the expert pathologists reached consensus in 5 out of 12 cases. Moreover, two out of three expert pathologists agreed on all 12 cases, improving agreement rate from 25% to 100%.

The researchers concluded that the model holds the promise to facilitate human HNL diagnoses and improve efficiency and quality. It can also reduce the workload of pathologists, especially where subspecialists are unavailable.

The study was supported by the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, the Natural Science Foundation of Guangdong Province, and others. The investigators reported no conflicts of interest.

Liquid biopsy using circulating tumor (ctDNA) detection and profiling is a valuable tool for clinicians in monitoring hepatocellular carcinoma (HCC), particularly in monitoring progression, researchers wrote in a recent review.

Details of the review, led by co–first authors Xueying Lyu and Yu-Man Tsui, both of the department of pathology and State Key Laboratory of Liver Research at the University of Hong Kong, were published in Cellular and Molecular Gastroenterology and Hepatology.

Because there are few treatment options for advanced-stage liver cancer, scientists are searching for noninvasive ways to detect liver cancer before is progresses. Liver resection is the primary treatment for HCC, but the recurrence rate is high. Early detection increases the ability to identify relevant molecular-targeted drugs and helps predict patient response.

There is growing interest in noninvasive circulating cell-free DNA (cfDNA) as well as in ctDNA – both are part of promising strategies to test circulating DNA in the bloodstream. Together with other circulating biomarkers, they are called liquid biopsy.

HCC can be detected noninvasively by detecting plasma ctDNA released from dying cancer cells. Detection depends on determining whether the circulating tumor DNA has the same molecular alterations as its tumor source. cfDNA contains genomic DNA from different tumor clones or tumors from different sites within a patient to help real-time monitoring of tumor progression.

Barriers to widespread clinical use of liquid biopsy include lack of standardization of the collection process. Procedures differ across health systems on how much blood should be collected, which tubes should be used for collection and how samples should be stored and shipped. The study authors suggested that “specialized tubes can be used for blood sample collection to reduce the chance of white blood cell rupture and genomic DNA contamination from the damaged white blood cells.”
 

Further research is needed

The study findings indicated that some aspects of liquid biopsy with cfDNA/ctDNA still need further exploration. For example, the effects of tumor vascularization, tumor aggressiveness, metabolic activity, and cell death mechanism on the dynamics of ctDNA in the bloodstream need to be identified.

It’s not yet clear how cfDNA is released into the bloodstream. Actively released cfDNA from the tumor may convey a different message from cfDNA released passively from dying cells upon treatment. The first represents treatment-resistant cells/subclones while the second represents treatment-responsive cells/subclones. Moreover, it is difficult to detect ctDNA mutation in early stage cancers that have lower tumor burden.

The investigators wrote: “The contributions of cfDNA from apoptosis, necrosis, autophagic cell death, and active release at different time points during disease progression, treatment response, and resistance appearance are poorly understood and will affect interpretation of the clinical observation in cfDNA assays.” A lower limit of detection needs to be determined and a standard curve set so that researchers can quantify the allelic frequencies of the mutants in cfDNA and avoid false-negative detection.

They urged establishing external quality assurance to verify laboratory performance, the proficiency in the cfDNA diagnostic test, and interpretation of results to identify errors in sampling, procedures, and decision making. Legal liability and cost effectiveness of using plasma cfDNA in treatment decisions also need to be considered.

The researchers wrote that, to better understand how ctDNA/cfDNA can be used to complement precision medicine in liver cancer, large multicenter cohorts and long-term follow-up are needed to compare ctDNA-guided decision-making against standard treatment without guidance from ctDNA profiling.

The authors disclosed having no conflicts of interest.

Liquid biopsy using circulating tumor (ctDNA) detection and profiling is a valuable tool for clinicians in monitoring hepatocellular carcinoma (HCC), particularly in monitoring progression, researchers wrote in a recent review.

Details of the review, led by co–first authors Xueying Lyu and Yu-Man Tsui, both of the department of pathology and State Key Laboratory of Liver Research at the University of Hong Kong, were published in Cellular and Molecular Gastroenterology and Hepatology.

Because there are few treatment options for advanced-stage liver cancer, scientists are searching for noninvasive ways to detect liver cancer before is progresses. Liver resection is the primary treatment for HCC, but the recurrence rate is high. Early detection increases the ability to identify relevant molecular-targeted drugs and helps predict patient response.

There is growing interest in noninvasive circulating cell-free DNA (cfDNA) as well as in ctDNA – both are part of promising strategies to test circulating DNA in the bloodstream. Together with other circulating biomarkers, they are called liquid biopsy.

HCC can be detected noninvasively by detecting plasma ctDNA released from dying cancer cells. Detection depends on determining whether the circulating tumor DNA has the same molecular alterations as its tumor source. cfDNA contains genomic DNA from different tumor clones or tumors from different sites within a patient to help real-time monitoring of tumor progression.

Barriers to widespread clinical use of liquid biopsy include lack of standardization of the collection process. Procedures differ across health systems on how much blood should be collected, which tubes should be used for collection and how samples should be stored and shipped. The study authors suggested that “specialized tubes can be used for blood sample collection to reduce the chance of white blood cell rupture and genomic DNA contamination from the damaged white blood cells.”
 

Further research is needed

The study findings indicated that some aspects of liquid biopsy with cfDNA/ctDNA still need further exploration. For example, the effects of tumor vascularization, tumor aggressiveness, metabolic activity, and cell death mechanism on the dynamics of ctDNA in the bloodstream need to be identified.

It’s not yet clear how cfDNA is released into the bloodstream. Actively released cfDNA from the tumor may convey a different message from cfDNA released passively from dying cells upon treatment. The first represents treatment-resistant cells/subclones while the second represents treatment-responsive cells/subclones. Moreover, it is difficult to detect ctDNA mutation in early stage cancers that have lower tumor burden.

The investigators wrote: “The contributions of cfDNA from apoptosis, necrosis, autophagic cell death, and active release at different time points during disease progression, treatment response, and resistance appearance are poorly understood and will affect interpretation of the clinical observation in cfDNA assays.” A lower limit of detection needs to be determined and a standard curve set so that researchers can quantify the allelic frequencies of the mutants in cfDNA and avoid false-negative detection.

They urged establishing external quality assurance to verify laboratory performance, the proficiency in the cfDNA diagnostic test, and interpretation of results to identify errors in sampling, procedures, and decision making. Legal liability and cost effectiveness of using plasma cfDNA in treatment decisions also need to be considered.

The researchers wrote that, to better understand how ctDNA/cfDNA can be used to complement precision medicine in liver cancer, large multicenter cohorts and long-term follow-up are needed to compare ctDNA-guided decision-making against standard treatment without guidance from ctDNA profiling.

The authors disclosed having no conflicts of interest.

Liquid biopsy using circulating tumor (ctDNA) detection and profiling is a valuable tool for clinicians in monitoring hepatocellular carcinoma (HCC), particularly in monitoring progression, researchers wrote in a recent review.

Details of the review, led by co–first authors Xueying Lyu and Yu-Man Tsui, both of the department of pathology and State Key Laboratory of Liver Research at the University of Hong Kong, were published in Cellular and Molecular Gastroenterology and Hepatology.

Because there are few treatment options for advanced-stage liver cancer, scientists are searching for noninvasive ways to detect liver cancer before is progresses. Liver resection is the primary treatment for HCC, but the recurrence rate is high. Early detection increases the ability to identify relevant molecular-targeted drugs and helps predict patient response.

There is growing interest in noninvasive circulating cell-free DNA (cfDNA) as well as in ctDNA – both are part of promising strategies to test circulating DNA in the bloodstream. Together with other circulating biomarkers, they are called liquid biopsy.

HCC can be detected noninvasively by detecting plasma ctDNA released from dying cancer cells. Detection depends on determining whether the circulating tumor DNA has the same molecular alterations as its tumor source. cfDNA contains genomic DNA from different tumor clones or tumors from different sites within a patient to help real-time monitoring of tumor progression.

Barriers to widespread clinical use of liquid biopsy include lack of standardization of the collection process. Procedures differ across health systems on how much blood should be collected, which tubes should be used for collection and how samples should be stored and shipped. The study authors suggested that “specialized tubes can be used for blood sample collection to reduce the chance of white blood cell rupture and genomic DNA contamination from the damaged white blood cells.”
 

Further research is needed

The study findings indicated that some aspects of liquid biopsy with cfDNA/ctDNA still need further exploration. For example, the effects of tumor vascularization, tumor aggressiveness, metabolic activity, and cell death mechanism on the dynamics of ctDNA in the bloodstream need to be identified.

It’s not yet clear how cfDNA is released into the bloodstream. Actively released cfDNA from the tumor may convey a different message from cfDNA released passively from dying cells upon treatment. The first represents treatment-resistant cells/subclones while the second represents treatment-responsive cells/subclones. Moreover, it is difficult to detect ctDNA mutation in early stage cancers that have lower tumor burden.

The investigators wrote: “The contributions of cfDNA from apoptosis, necrosis, autophagic cell death, and active release at different time points during disease progression, treatment response, and resistance appearance are poorly understood and will affect interpretation of the clinical observation in cfDNA assays.” A lower limit of detection needs to be determined and a standard curve set so that researchers can quantify the allelic frequencies of the mutants in cfDNA and avoid false-negative detection.

They urged establishing external quality assurance to verify laboratory performance, the proficiency in the cfDNA diagnostic test, and interpretation of results to identify errors in sampling, procedures, and decision making. Legal liability and cost effectiveness of using plasma cfDNA in treatment decisions also need to be considered.

The researchers wrote that, to better understand how ctDNA/cfDNA can be used to complement precision medicine in liver cancer, large multicenter cohorts and long-term follow-up are needed to compare ctDNA-guided decision-making against standard treatment without guidance from ctDNA profiling.

The authors disclosed having no conflicts of interest.