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Oxidative Stress in Chronic Liver Disease: The Role of Glutathione

Theodore Hersh, MD, MACG
Professor of Medicine, Emeritus, Emory University
Presented at the Georgia G-I Society, Sept. 1999

Glutathione, a tripeptide composed of glutamate, cysteine and glycine, is present in most plants and animal tissues and is the most important and ubiquitous low molecular weight thiol compound. Working intra and extra-cellularly in its reduced form, L-glutathione, abbreviated as “GSH”, is the body’s key antioxidant and protectant. GSH has multiple functions in disease prevention and in detoxification of chemicals and drugs while its depletion is associated with increased risks of toxicity and disease. GSH works synergistically with the other cellular antioxidants to neutralize and scavenge oxygen and other free radical species and thereby prevent or diminish “oxidative stress”.

A deficiency of hepatic GSH and its antioxidant partners and/or an increase in toxic free radical species may contribute to the progression of liver disease. Thus, is there a role for glutathione in the management of patients with alcoholic liver disease and viral hepatitis, particularly those with hepatitis C?

There are only a few studies in the medical literature which relate to the role of antioxidants, particularly L-glutathione, in chronic liver diseases. In 1996, Barbaro and colleagues from Italy reported on the levels of glutathione in liver, blood and lymphocytes of patients with chronic hepatitis C. Some of these patients were also HIV positive. The liver is the most important source of GSH levels in blood, but dietary GSH also raises tissue levels. GSH content in these three sites was significantly reduced in patients with hepatitis C and correlated with the severity of their liver disease as well as with the ability of the hepatitis C virus to replicate. The GSH levels in those cases who also were HIV positive were even more significantly lower than those with hepatitis C who were HIV negative. The lowest GSH levels were more evident in those patients addicted to drugs. Because of these low GSH levels, both diseases are more resistant to anti-viral therapy, interferon for those with chronic hepatitis and antiretroviral drugs for those with HIV. Beloqui’s studies in Pamplona, Spain suggest too that repletion of glutathione levels improves the response to interferon treatment in these cases with hepatitis. DeMaria and co-investigators at the Oklahoma Medical Research Foundation also confirmed that oxidative stress occurs in patients with chronic hepatitis and showed that the levels of free radicals correlated with the activity of the hepatitis. In another study, Dentico and colleagues, also in Italy, repleted glutathione levels with high intravenous doses in patients with fatty livers (steatosis) secondary to alcoholic hepatitis or viral hepatitis (B or C). They recorded marked improvement in patients’ liver tests, lasting even several months after GSH treatment. Charles Lieber at Mt. Sinai in New York also showed the presence of free radicals due to oxidation of lipids in patients with alcoholic liver disease while Fitzgerald and co-workers in Philadelphia concluded that oxidant stress contributes to the deterioration of the liver disease.

What are the conclusions in Mid-1998? The evidence is clear that oxygen and other toxic free radical species resulting from oxidative stress occur in chronic liver disease and contribute to liver damage in various common types of chronic hepatitis. Blood and liver antioxidant levels, particularly those of L-glutathione, are found to be reduced in these patients compared to age matched controls. Thirdly, repletion of L-glutathione appears to improve liver cell damage as reflected by standard liver tests. In chronic hepatitis C, repletion of glutathione not only impairs Virus C replication but also renders interferon anti-viral therapy more efficacious.

Dr. Bonkovsky at the University of Massachusetts has elegantly reviewed the therapeutic options in chronic hepatitis C. He concludes that these preliminary studies are most exciting and worthy of further rigorous clinical evaluations, stating “the future of therapy of chronic hepatitis C will likely include measures to decrease oxidative stress and injury, and the use of multidrug combinations, including inhibitors of hepatitis C virus.” However, every patient with chronic liver disease should consult with their physician for all therapeutic options in the management of their condition.

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