Cave said the liver is a target organ for chemicals because it metabolizes the substances. (Photo courtesy of Michael Garske)

Matthew Cave, M.D., from the University of Louisville, made a strong case for the association between exposures to certain environmental chemicals and liver diseases. He addressed diseases such as fatty liver disease, steatohepatitis, and liver cancer at an Aug. 16 seminar sponsored by the NIEHS Epidemiology Branch and hosted by NIEHS and National Toxicology Program Director Linda Birnbaum, Ph.D.

Revolutionizing Innovative, Visionary Environmental health Research (RIVER) grantee Cave (see sidebar) is a gastroenterologist and liver transplant hepatologist who has become increasingly active in environmental health research and raising awareness about the liver’s vital role in environmental health.

“The liver is a very important target organ for environmental chemicals,” he said. “Through multiple cohorts and exposures, we can see a signal, and in many cases, we’re able to produce an animal model showing that there could be causality,” he said, speaking of the connection between chemical exposures and liver disease.

Birnbaum introduced Cave, who is her long-time collaborator. (Photo courtesy of Michael Garske)

Rubbertown

His interest in the field was sparked by a unique set of circumstances. Trained as a chemical engineer, Cave gravitated toward medicine as he became involved in occupational health. “So how in the world did a hepatologist from Louisville, Kentucky get interested in environmental health?” he asked his NIEHS audience. “And why would he start doing epidemiologic and mechanistic studies in mice?”

The answer lies in events that date back to World War II, when the Japanese cut off shipping lanes, leading to a shortage of rubber in the United States. A synthetic rubber plant, in an industrial area called Rubbertown, was established in Louisville to meet the demand.

Vinyl chloride

Over the years, countless workers were exposed to vinyl chloride, which is a component of synthetic rubber. In the early 1970s, a plant doctor noted a cluster of four cases of hepatic hemangiosarcoma, a rare form of liver cancer.

Vinyl chloride is a colorless gas composed of 1 chloride, 2 carbon, and 3 hydrogen atoms (C2H3Cl). It is used to make polyvinyl chloride for a variety of plastic products, including pipes, wire and cable coatings, and packaging materials. Vinyl chloride is also a combustion product in tobacco smoke. (Wikimedia)

That led to a health surveillance program and a biorepository that now contains over 7000 samples, including liver biopsies from the mid-1970s. Cases of hepatic hemangiosarcoma still occur — a total of 26 to date, despite dramatic reductions in workplace exposures.

Cave analyzed biopsies from 25 workers highly exposed to vinyl chloride. Eighty-four percent of the samples showed fatty liver disease. Inflamed fatty liver showed up in 80 percent. That condition, known as steatohepatitis, is a precursor of liver cancer.

The study was published in 2010, and marked the first use of a term coined by Cave — toxicant-associated steatohepatitis, or TASH.

Cave presented considerable data to support his assertions about liver disease and environmental exposures. (Photo courtesy of Michael Garske)

Following the leads

Cave continued to explore his suspicions of a link between liver diseases and exposures to chemicals such as polychlorinated biphenyls (PCBs), dioxins, and per- and polyfluoroalkyl substances, or PFAS. Using data from the National Health and Nutrition Examination Survey and other databases, he was able to look at exposures in industrial settings and the general environment.

Cave is developing biomarkers and describing mechanisms that may be at work in fatty liver diseases — a condition found in one in four people in the world. “The hope is that we can look at mechanisms and develop new treatments we can bring back to the patients,” said Cave.

Citation:
Cave M, Falkner KC, Ray M, Joshi-Barve S, Brock G, Khan R, Bon Homme M, McClain CJ. 2010. Toxicant-associated steatohepatitis in vinyl chloride workers. Hepatology 51(2):474−478.

(Ernie Hood is a contract writer for the NIEHS Office of Communications and Public Liaison.)