What is the association between polyfluoroalkyl substance exposure and risk of non-viral hepatocellular carcinoma?

Today, in a highly industrialized society living amid many synthetic goods, exposure to a host of chemicals is unavoidable. This includes per- and polyfluoroalkyl substances (PFAS), a class of chemicals categorized among the persistent organic pollutants (POPs). Many earlier animal studies have shown evidence that these compounds are present in almost all individuals in high-income countries and in a very high proportion of people globally.

Study: Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort. Image Credit: Explode/Shutterstock
Study: Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort. Image Credit: Explode/Shutterstock

PFAS alter the metabolism of fat, glucose, and amino acids in the liver. They are also associated with a higher risk of fatty degeneration of the liver and hepatocellular carcinoma (HCC). A new human study examines the data to determine whether this link holds true in our species.   


Liver cancer ranks sixth on the list of common cancers, causing the third-highest number of deaths from cancer in the world in 2020. The incidence of this cancer has, meanwhile, gone up more than threefold in the USA in the last 40 years and is the fifth and seventh leading cause of death from cancer among American men and women.

HCC is the most frequently encountered form of liver cancer, comprising 85% of all cases, with fewer than one in five surviving five years from diagnosis. Viral hepatitis, especially hepatitis B and C, is associated with a significant risk for HCC, but non-alcoholic fatty liver disease (NAFLD) is causing an increasing number of HCC. In fact, by 2030, this may be the dominant precursor of HCC.

Some progress has been made over the last ten years due to falling rates of hepatitis B and C. Still, as NAFLD, metabolic syndrome, and non-alcoholic steatohepatitis (NASH) increase both globally and in the USA, HCC is likely to go up. Therefore, risk factors for this deadly condition must be identified as targets for early intervention and monitoring of those at high risk.

The current study, published online in the journal JHEP Reports, looks at PFAS, which are endocrine disruptors and potential hepatotoxins. Some of them have half-lives between 3-7 years. As shown in rodent studies, many of them are sequestered in the liver, causing abnormalities in the metabolism of fats, amino acids, and sugars in this organ, associated with liver injury,

The link between these compounds and HCC is thus worthy of urgent investigation in humans. Earlier studies have shown a rise in liver enzymes with higher levels of PFAS in adults, and markers of cell death in the liver have also shown a rise. NAFLD in adults and children may be linked to PFAS exposure as well, mediated by metabolic aberrations.

The present study is the first prospective population-based examination of the hypothesis that PFAS exposure is associated with non-viral HCC via metabolic impairments. The researchers sought to understand whether the levels of PFAS in the subjects could predict the future risk of HCC with a metabolomics study to explore the metabolic changes in the same cohort.

The data came from the Multiethnic Cohort (MEC) cohort and included 50 cases of non-viral HCC and 50 controls without diagnosed liver disease. Using medical claims records and viral testing, the non-viral HCC cases were found to be due to NAFLD in two out of three people, with less than a tenth due to alcoholic liver injury and just over a quarter due to cirrhosis of unknown origin.

What did the study show?

The cases and controls were matched for age, sex, ethnicity, and geographical area and had similar smoking or alcohol use rates. Conversely, HCC cases were more likely to be obese, overweight, or to have type 2 diabetes mellitus.

PFAS were found in all subjects, with levels similar to those reported by an earlier national study in 2000. Educational status did not affect PFAS levels, indicating that socioeconomic status was not a risk factor for exposure. The most common PFAS was perfluorooctane sulfonic acid (PFOS), detected in almost a third of subjects.

The levels of PFAS in blood before the date of HCC diagnosis were associated with the risk of HCC, especially PFOS levels. In fact, when PFOS exceeded ~55 mcg/L, the odds of developing HCC were 4.5 times higher.

Also, the metabolomics study showed that one in ten of the molecules tested were linked to high PFAS and 6 to PFOS exposure. A technique called functional pathway analysis showed that 18 metabolic pathways were found to be operating at higher levels. These involved amino acid, sugar, and glycan metabolism.

Almost 500 metabolites were associated with HCC on liquid chromatography with high-resolution mass spectrometry (LC–HRMS), with 13 metabolic pathways being enriched. Again, these primarily implicated sugar, glycan, and aromatic amino acid metabolic processes.

Some enriched pathways were common to PFOS and HCC, including the metabolism of tryptophan, keratin sulfate and heparin sulfate, chondroitin sulfate, and the breakdown of N-glycans. Four metabolites were linked to both these parameters, including glucose and α-Ketoisovaleric acid.

α-Ketoisovaleric acid is the metabolite most closely associated with PFOS exposure and HCC risk. This branched-chain ketoacid (BCKA) is formed during the breakdown of branched-chain amino acids and may be, along with similar byproducts, be a marker of liver injury in children exposed to PFAS.

Again, a bile acid called 7α-Hydroxy-3-oxo-4-cholestenoate was linked to both parameters. Bile acids are key to energy metabolism and may play an important part in abnormal weight gain and NASH, besides being potentially linked to HCC in humans. PFAS may impair the processing of bile acids and thus cause liver injury.

Butyric acid is a short-chain fatty acid (SCFAs) produced by the fermentation of sugars by gut microbes and is among the SCFAs that regulate energy metabolism in accordance with the body's needs and availability of energy. They may also be linked to NAFLD.

What does this mean?

The study is the first to identify an association between PFAS and HCC prospectively. It shows a positive association between high PFOS exposure and the risk of non-viral HCC. Moreover, metabolomics study techniques revealed that several metabolites were enriched in those with higher PFOS levels, and these people were also at higher risk of this type of cancer.

Our findings suggest that PFAS exposure may increase risk of HCC via alterations in glucose metabolism, bile acid metabolism, and metabolism of branched chain amino acids.”

This corroborates similar associations between PFAS and other cancers in the general population. Moreover, the study showed higher fasting glucose levels in those most exposed to PFOS, and the higher fasting glucose levels were linked to a higher risk of HCC.

Since high fasting glucose is a diagnostic parameter for type 2 diabetes, the risk of non-viral HCC could be partly, at least, due to the dysregulation of glucose metabolism and the resulting loss of insulin sensitivity and hypersecretion of insulin caused by high PFAS exposure.

Our results provide the first human evidence that PFAS associated alterations in [BCKAs, bile acids and SCFAs] may increase risk of HCC.” Further studies are indicated to validate and extend these findings.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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