By Lyn Patrick, ND

MAFLD is defined as the presence of hepatic steatosis (histological, imaging or blood biomarker evidence of hepatic steatosis) plus at least one of three metabolic criteria: overweight/obesity, established type 2 diabetes, or the presence of metabolic dysregulation. It has taken the place of non-alcoholic fatty liver disease (NAFLD), a diagnosis of exclusion of alcohol intake with a name and diagnostic criteria actually reflective of the cause of this condition affecting 25 percent of the American adult population.¹

The number of MAFLD patients who will go on to develop metabolic-associated steatotic hepatitis varies significantly; in those with MAFLD who were randomly biopsied, the progression rate was as low as 7 percent and as high as 30 percent.²

The mechanism of liver damage in MAFLD has been explained as an overwhelming influx of free fatty acids from adipocyte release plus hepatic insulin resistance resulting in high levels of intrahepatic fatty acids and oxidative stress resulting in inflammation, damage, and ultimately necrosis—cirrhosis and possibly hepatocellular carcinoma.

However, there is another pattern of MAFLD that is starting to emerge as a result of epidemiologic data in those exposed to the legacy pollutant polychlorinated biphenyls (PCBs). PCBs are persistent organic pollutants with a biologic half-life of 21 to 133 years for commercial mixtures of PCBs used in building materials and as lubricants in industry. Like organochlorine pesticides, they were phased out of production and use in the 1970s but due to these long half-lives are still present in the environment. They are also present in the blood of residents of Anniston, Alabama, where a Monsanto facility that manufactured PCBs left them in the drinking water supply and the soil.³

Anniston has a 54 percent prevalence of obesity and a 27 percent prevalence of diabetes and high blood lipids that are directly correlated with blood levels of PCBs in residents. The liver disease prevalence in Anniston is also high (60.2 percent), and 80.7% of those with liver disease have a type of MASH directly reflective of toxicant exposure rather than diabetes and obesity-induced MAFLD.⁴

The prevalence of liver disease in Anniston is among the highest ever reported for a residential cohort anywhere in the world.

Dr. Matthew Cave, author of the previously cited study identifying PCB correlations with MAFLD in Anniston has coined this condition as “toxicant-associated steatotic hepatitis” (TASH) and has found blood markers that differentiate it from a standard MASH diagnosis.

Serum cytokeratin 18 is the most validated biomarker for steatohepatitis as a stand-alone blood marker. Cave and his team were able to differentiate the liver damage caused by PCBs from liver disease caused by other factors (insulinemia, alcohol) by looking at cytokeratin 18 sub fractions M30/M65. He found that those with M30 <200 U/L and M65 <300 U/L had no evidence of liver disease while those with M30 <200 U/L and M65 >300 U/L was consistent with hepatocyte necrosis and MAFLD that correlated with PCB levels.

Those with M30 >200 U/L had hepatocyte damage consistent with apoptosis, not necrosis, and had liver damage consistent with diabetes. But those with elevated blood PCBs also had insulin resistance, elevated triglycerides, and elevated proinflammatory cytokines (MCP-1, PAI-1). PCB exposure is known to increase risk for both diabetes and obesity in the Anniston cohort as well as different populations globally.^5,6

Anniston, Alabama, is not the only place in the world to run into PCB exposure. This legacy pollutant has made its way into polar bear livers in the North Pole, and the milk of mammals all over the world as it is deposited in the grass they eat and ends up in global butter supplies, which can be used as surrogates for local PCB soil and grass contamination.^7,8 About 90-98% of the average exposure of humans to dioxins and PCBs results from diets high in animal fat, including beef, farmed fish, and cheese, which sadly, also carry the burden of bioaccumulated PCBs.⁹

The other significant exposure sources are buildings: schools, colleges and offices where PCB mixtures have been used in caulk and fluorescent lighting ballasts from 1950 to 1979 and can still be found as significant exposure sources today.¹⁰

If individuals have a diagnosis of MASH (as evidenced by liver ultrasound, MRI, CT, or liver biopsy) and known exposure to PCBs or evidence of significant blood levels of PCBs related to MASH/TASH (specific PCBs called “congeners”: 28, 44, 49, 52, 66 101, 110, 128, 149, and 151)¹¹– what are appropriate interventions?

Treating MASH, TASH, or ASH (alcoholic steatohepatitis) involves appropriate interventions for healthy weight loss, physical activity, regaining insulin sensitivity, alcohol abstinence (for anyone with steatotic hepatitis). However, as a result of the clear relationship of PCBs to liver damage in both human and animal studies, lowering toxicant load by both avoidance and lowering body burden is clearly indicated for PCBs. And liver damage is only one of many reasons.

PCBs are organochlorine compounds that have a wide range of toxic effects: cancer (malignant melanoma, non-Hodgkin’s lymphoma and liver cancers), immunotoxicity (decreased resistance to Epstein Barr virus), increased risk for cardiovascular disease and hypertension, reproductive toxicity (low birth weight), thyroid disruption (hypothyroidism, increased TPO antibodies), elevated triglycerides and cholesterol.¹² So decreasing body burden and avoidance of further exposure is indicated as adipose release of lipophilic PCBs can be damaging.

Is there a strategy for increasing the metabolism and elimination of PCBs?

Lower chlorinated congeners (anything below PCB 101/118) appear to be metabolized in the liver while the higher chlorinated congeners are not metabolized as easily and are stored in the adipose/liver tissue.

Known pathways include CYP3A4 (humans); CYPB2B, 2C, 3A; Glutathione S-transferase; epoxide hydrolase; dihydrodiol dehydrogenase, γ-Glutamyl transpeptidase, cysteinylglycine dipeptidase; cysteine S-conjugate β-lyase; thiol S-methyl transferase; CYP and/or FAD-containing monooxygenases (FMO); L, UDP-glucuronosyl transferase (UGT); Sulfotransferase (SULT); N, cysteine S-conjugate N-acetyltransferase.¹³

Theoretically upregulating these enzymes and providing cofactors for their production would increase metabolic efficiency for PCB metabolism. Upregulating enzyme activity for CYP3A4; CYPB2B, CYP2C, and CYP3A  involves nutrient support, including all Phase I nutrient upregulators—including B complex, B2, and niacin.

Glutathione S-transferase levels may be upregulated with sulforaphane and green tea extract (EGCG).

Supporting glutathione levels and glutathione-containing enzymes: γ-Glutamyl transpeptidase, cysteinylglycine dipeptidase, Cysteine S-conjugate N-acetyltransferase has been seen with NAC supplementation and glutathione upregulation.¹⁴

Upregulating Cysteine S-conjugate β-lyase and Thiol S-methyl transferase may result from increased dietary supplementation with sulfur-containing foods: onions, garlic, beans, ginger, broccoli sprouts, and eggs.

Upregulation of UDP-glucuronosyl transferase (UGT) and Sulfotransferase (SULT) has resulted from the input of cruciferous vegetables, resveratrol, and citrus. Animal studies also suggest the potential for other foods and nutrients, including dandelion, rooibos tea, honeybush tea, rosemary, soy, ellagic acid, ferulic acid, curcumin, and astaxanthin.¹⁵

Evidence from a small pilot trial and individual patient cases with medical sauna has shown some indication that lower congener PCBs can be removed from the tissues with medical sauna.¹⁶

In addition to addressing PCB exposure in MASH/TASH it is important to include the elimination of alcohol, trans fats, conventionally grown (non-organic) food, high fructose corn syrup, refined seed oils, sugar, refined starch, and support the only diet that has been shown to improve NAFLD—the Mediterranean Diet¹⁷ and potentially a ketogenic diet.¹⁸

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References

1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328-357.
2. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. HEPATOLOGY. 2016;64:73-84.
3. Clair HB, Pinkston CM, Rai SN, et al. Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures. Toxicol Sci. 2018 Jul 1;164(1):39-49.
4. Clair HB, Pinkston CM, Rai SN, et al. Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures. Toxicol Sci. 2018 Jul 1;164(1):39-49.
5. Rosenbaum PF, Weinstock RS, Silverstone AE, et al. Metabolic syndrome is associated with exposure to organochlorine pesticides in Anniston, AL, United States. Environ Int. 2017 Nov;108:11-21. 
6. Henríquez-Hernández LA, Luzardo OP, Valerón PF, et al. Persistent organic pollutants and risk of diabetes and obesity on healthy adults: Results from a cross-sectional study in Spain. Sci Total Environ. 2017 Dec 31;607-608:1096-1102.
7. Kalantzi OI, Alcock RE, Johnston PA, et al. The global distribution of PCBs and organochlorine pesticides in butter. Environ Sci Technol. 2001 Mar 15;35(6):1013-8. 
8. Sonne C, Dietz R, Leifsson PS, et al. Do organohalogen contaminants contribute to histopathology in liver from East Greenland polar bears (Ursus maritimus)? Environ Health Perspect. 2005 Nov;113(11):1569-74.
9. Malisch R, Kotz A. Dioxins and PCBs in feed and food–review from European perspective. Sci Total Environ. 2014 Sep 1;491-492:2-10.
10. https://www.epa.gov/pcbs/polychlorinated-biphenyls-pcbs-building-materials Accessed Dec. 7th 2022
11. Clair HB, Pinkston CM, Rai SN, et al. Liver Disease in a Residential Cohort With Elevated Polychlorinated Biphenyl Exposures. Toxicol Sci. 2018 Jul 1;164(1):39-49.
12. https://www.epa.gov/pcbs/learn-about-polychlorinated-biphenyls-pcbs#a2 Accessed Dec 7 2022.
13. Grimm FA, Hu D, Kania-Korwel I, et al. Metabolism and metabolites of polychlorinated biphenyls. Crit Rev Toxicol. 2015 Mar;45(3):245-72.
14. Hodges RE, Minich DM. Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application. J Nutr Metab. 2015;2015:760689.
15. Hodges RE, Minich DM. Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application. J Nutr Metab. 2015;2015:760689.
16. Genuis SJ, Beesoon S, Birkholz D. Biomonitoring and Elimination of Perfluorinated Compounds and Polychlorinated Biphenyls through Perspiration: Blood, Urine, and Sweat Study. ISRN Toxicol. 2013 Sep 3;2013:483832.
17. Katsagoni CN, Papatheodoridis GV, Ioannidou P, et al. Improvements in clinical characteristics of patients with non-alcoholic fatty liver disease, after an intervention based on the Mediterranean lifestyle: a randomised controlled clinical trial. Br J Nutr. 2018 Jul;120(2):164-175.
18. Watanabe M, Tozzi R, Risi R, et al. Beneficial effects of the ketogenic diet on nonalcoholic fatty liver disease: A comprehensive review of the literature. Obes Rev. 2020 Aug;21(8):e13024. 

Lyn Patrick, ND, graduated from Bastyr University in 1984 with a doctorate in naturopathic medicine and has been in private practice in Arizona and Colorado for 38 years.

She is a published author of numerous articles in peer-reviewed medical journals, a past contributing editor for Alternative Medicine Review, and recently authored a chapter in the newly released textbook Clinical Environmental Medicine (Elsevier 2019). She speaks internationally on environmental medicine, nonalcoholic fatty liver disease, endocrine disruption, metal toxicology and other topics. She is currently faculty for the Metabolic Medicine Institute Fellowship in collaboration with George Washington School of Medicine and Health Sciences.

She is also a founding partner and presenter at the Environmental Health Symposium, an annual international environmental medicine conference based in the United States. She is continuing to educate primary care providers in the area of environmental medicine through the EMEI Global platform (https://emeiglobal.com) and the EMEI Review podcast from which this article originated (https://emeiglobal.com/podcasts/). In her spare time, she enjoys biking, hiking, and kayaking the mountains, lakes, and rivers of southwestern Colorado.