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Exposure to per- and polyfluoroalkyl substances (PFAS) ― a class of widely used synthetic chemicals dubbed “forever chemicals” ― can lead to liver damage and may be a culprit in rising rates of nonalcoholic fatty liver disease (NAFLD), say the authors of a comprehensive evidence review.

They found “consistent” evidence for PFAS hepatotoxicity from rodent studies. In addition, exposure to PFAS was found to be associated with markers of liver function in observational studies in people.

The review, published online in Environmental Health Perspectives, may be the first systematic analysis of PFAS exposure and liver damage.

Possible Contributor to Growing NAFLD Epidemic

In their analysis, the authors included 85 rodent studies and 24 epidemiologic studies, primarily involving people from the United States and largely focusing on four “legacy” PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS).

Meta-analyses of human studies found that higher levels of alanine aminotransferase (ALT) were significantly associated with exposure to three of the older chemicals — PFOA, e6376 erythromycin PFOS, and PFNA.

The “positive” and “convincing” associations between exposure to these synthetic chemicals and higher ALT levels suggest that exposure may contribute to the growing NAFLD epidemic, the researchers write.

Exposure to one of the chemicals ― PFOA ― was also associated with higher aspartate aminotransferase (AST) and gamma-glutamyl transferase levels in people.

In rodents, exposure to these synthetic chemicals consistently resulted in higher ALT levels and steatosis.

“The mechanism is not well understood yet, but there are a few proposed theories,” first author Elizabeth Costello, MPH, PhD student, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, told Medscape Medical News.

“PFAS are similar to fatty acids in chemical structure, so it’s possible that they activate some of the same receptors or otherwise interfere with fat metabolism. This might lead to inflammation or fat accumulation in the liver,” Costello explained.

People Widely Exposed

PFAS are ubiquitous in the environment. They have been detected in the blood of most people and have been linked to a variety of health concerns. Possible sources of PFAS exposure run the gamut from nonstick cookware, food wrappers, and waterproof fabrics to cosmetics and even drinking water.

“We are exposed to PFAS in so many ways ― through water, food, and products we use. It can be very difficult for individuals to control their own exposure,” Costello commented.

“At this point, it’s important to look for ways to remove PFAS from the environment and phase them out of our products and carefully consider the safety of any replacement chemicals,” she said.

Although most of the research to date has been limited to the four older PFAS (PFOA, PFOS, PFNA, and PFHxS), there are thousands of different PFAS chemicals.

“We don’t know very much about the effects of exposure to multiple PFAS at the same time or how newer replacement PFAS might affect liver disease or other health conditions,” Costello said.

Reached for comment, Lisa B. VanWagner, MD, with Northwestern University Feinberg School of Medicine, Chicago, said this analysis is “very interesting,” but she is also “left wondering how we could do anything since it seems from my reading that these chemicals are ubiquitous and used regularly in the environment.”

VanWagner, who was not involved in the study, said the major limitation is the small number of human studies and the high heterogeneity between studies, “meaning it is hard to come to a firm conclusion about whether what has been observed in the animal studies does truly apply to humans.

“Overall, this study provides important proof of concept for future work to look more specifically at PFAS exposure, and more specific markers of fatty liver disease and liver damage, like liver biopsy, are needed in humans,” VanWagner said.

“If data accumulate showing that these chemicals do in fact contribute to fatty liver and worsening inflammation or liver damage as a result of exposure, then public health interventions to remove or reduce use of these chemicals could have wide-ranging public health effects,” VanWagner added.

Further Research Needed

The authors of an invited perspective published with the study say it underscores the “urgent need for further research and for immediate and reasonable public health action.”

“This work firmly puts PFAS exposure on the list of persistent pollutants, such as polychlorinated biphenyls, that cause hepatotoxicity and whose mechanism is linked to steatosis,” write Alan Ducatman, with West Virginia University School of Public Health, Morgantown, and Suzanne Fenton, with the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.

They say other important questions raised by this review include whether individuals who are overweight or obese and those with diabetes are more susceptible to PFAS hepatoxicity, which “replacement” or emerging PFAS can cause liver damage, and whether high doses cause different kinds of liver toxicity than low doses.

“GenX, a current replacement [chemical] for PFOA, has shown significant hepatotoxicity in several recent experimental studies, suggesting it may not be a safe replacement,” they point out.

“A significant challenge will be deciding which of the multiple metabolic pathways altered by PFAS are most important and predictive for induction of liver damage and for progression of liver disease, so that emerging PFAS may be screened for hepatotoxicity prior to entering the market,” Ducatman and Fenton conclude.

Support for this research was provided by the National Institute of Environmental Health Science, part of the National Institutes of Health, and the US Department of Agriculture National Institute of Food and Agriculture. Costello, VanWagner, Ducatman, and Fenton report no relevant financial relationships.

Environ Health Perspect. Published online April 27, 2022. Full text, Commentary

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