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Oxidative Stress in Chronic Liver Disease: The Role of Glutathione Theodore Hersh, MD, MACG 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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