What is the association between exposure to polyfluoroalkyl substances and the risk of nonviral hepatocellular carcinoma?

In a highly industrialized society where we live today in many synthetic products, exposure to many chemicals is unavoidable. class of perfluoroalkyl substances and polyfluoroalkyl substances (PFAS). Many early animal studies provide evidence that these compounds are present in nearly all individuals in high-income countries and are present in a very high percentage of people worldwide.

PFAS alters fat, glucose, and amino acid metabolism in the liver. It also increases the 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 for our species.

prologue

Liver cancer ranks sixth on the list of common cancers and is the third leading cause of cancer deaths in 2020 worldwide. Meanwhile, the incidence of this cancer has more than tripled in the United States over the past 40 years, and it is the fifth and seventh leading cause of death from cancer in men and women in the United States.

HCC is the most frequent form of liver cancer, accounting for 85% of all cases, and less than 1 in 5 survives 5 years after diagnosis.Viral hepatitis, particularly hepatitis B and C, is associated with a significant risk of HCC, but non-alcoholic fatty liver disease (NAFLD) is causing an increase in HCC. In fact, by 2030, this could be a major precursor to HCC.

Some progress has been made in the last decade as the incidence of hepatitis B and C has declined. Still, HCC is likely to rise as NAFLD, metabolic syndrome, and non-alcoholic steatohepatitis (NASH) are on the rise globally and in the United States. Therefore, risk factors for this fatal condition should be identified for early intervention and surveillance of people at high risk.

Current research published online in journals JHEP reportfocuses on PFAS, an endocrine disruptor and potential hepatotoxin. Some of them have a half-life of 3 to 7 years. It causes abnormalities in sugar metabolism and is associated with liver damage.

Therefore, the association of these compounds with HCC deserves urgent investigation in humans. Previous studies have shown elevated liver enzymes with higher levels of her PFAS in adults, as well as elevated markers of liver cell death. Her NAFLD in adults and children may also be related to her PFAS exposure mediated by metabolic abnormalities.

The present study is the first prospective population-based investigation of the hypothesis that PFAS exposure is associated with non-viral HCC through metabolic disturbances. The researchers sought to understand whether a subject’s level of PFAS could predict her future risk of HCC in a metabolomics study to investigate metabolic changes in the same cohort.

Data were obtained from a multiethnic cohort (MEC) cohort, which included 50 cases of nonviral HCC and 50 controls without diagnosed liver disease. Using medical claims records and viral testing, nonviral HCC cases were found to be due to his NAFLD in 2 of his 3 cases, and less than 1/10 were due to alcoholic liver disease. , and just over a quarter were due to cirrhosis of unknown cause.

What did the study show?

Cases and controls were matched for age, sex, ethnicity, geographic region, and had similar smoking or alcohol use prevalence. Conversely, HCC cases were more likely to be obese, overweight, or type 2 diabetic.

PFAS were detected in all subjects at levels similar to those reported in the previous national survey in 2000. Her most common PFAS was perfluorooctanesulfonic acid (PFOS), which was detected in nearly one-third of subjects.

Blood PFAS levels before the date of HCC diagnosis were associated with the risk of HCC, especially PFOS levels. In fact, PFOS above 55 mcg/L was associated with a 4.5-fold increased chance of developing HCC.

Metabolomics studies also showed that one-tenth of the molecules tested were associated with high PFAS and six with PFOS exposure. A technique called functional pathway analysis revealed that 18 metabolic pathways function at a higher level. These included amino acid, sugar, and glycan metabolism.

Approximately 500 metabolites have been associated with HCC by liquid chromatography with high-resolution mass spectrometry (LC-HRMS), enriched for 13 metabolic pathways. Again, these are primarily concerned with metabolic processes of sugars, glycans, and aromatic amino acids.

Several enhanced pathways were common to PFOS and HCC, including tryptophan, keratin sulfate, heparin sulfate, chondroitin sulfate metabolism, and N-glycan degradation. Four metabolites were associated with both of these parameters, including glucose and α-ketoisovalerate.

α-Ketoisovalerate 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, along with similar byproducts, may be a marker of liver damage in children exposed to PFAS.

Again, a bile acid termed 7α-hydroxy-3-oxo-4-cholestenoic acid was associated with both parameters. Bile acids are key to energy metabolism, may be associated with HCC in humans, and may play an important role in abnormal weight gain and NASH. PFAS can inhibit bile acid processing and cause liver damage.

Butyric acid is a short-chain fatty acid (SCFA) produced by fermentation of sugars by intestinal microorganisms and is one of the SCFAs that regulate energy metabolism according to the body’s needs and energy availability. It may also be associated with NAFLD.

What does this mean?

This study is the first to prospectively identify an association between PFAS and HCC. This indicates a positive association between high PFOS exposure and the risk of non-viral HCC. Additionally, metabolomics research techniques have revealed that several metabolites are enriched in people with higher PFOS levels, and these people are also at increased risk for this type of cancer.

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

This supports similar associations between PFAS and other cancers in the general population. In addition, the study showed that those most exposed to PFOS had higher fasting blood glucose levels, and that the higher the fasting blood glucose level, the higher the risk of HCC for him.

Since fasting hyperglycemia is a diagnostic parameter for type 2 diabetes, the risk of nonviral HCC is caused, at least in part, by dysregulation of glucose metabolism and consequent loss of insulin sensitivity and high PFAS exposure. may be due to excessive secretion of insulin .

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