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HCV and Oxidative Stress
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HCV and Oxidative Stress

Just as I had pieced the interaction of HCV and Oxidative Stress together so that it made sense to me, I ran into this. I wont tell you how much time I could have saved if I had found this article from HCVAdvocate sooner. HRs little list of supplements don’t seem so weird now do they.
Notice the Interaction between Oxidative Stress and Insulin Resistance.
If you want to work out why Tx didn’t work for you spend some time looking into that.


Oxidative Stress and the Liver
Liz Highleyman
Oxidative stress – the build-up of highly reactive forms of oxygen and other so-called “free radicals” in the body – has been linked to a wide range of detrimental effects, including liver damage.

A growing body of research indicates that oxidative stress is a major mechanism underlying drug-induced liver toxicity and alcoholic liver disease. Oxidative damage also contributes to steatosis (fat buildup in the liver), fibrosis, and liver cancer. Hepatitis C virus (HCV) itself promotes oxidative stress, and this effect is magnified in people coinfected with HIV. Oxidative stress, in turn, facilitates HCV replication.

What Is Oxidative Stress?
It is well known that oxygen is essential for life, and oxygen molecules are among the thousands that naturally exist within the body. As a result of normal metabolism, however, atoms and molecules can acquire an extra electron, becoming free radicals. Because they have an unpaired electron, radicals easily form bonds with other molecules, “stealing” their electrons and setting off a chemical chain reaction. Highly reactive forms of oxygen are known as reactive oxygen species; reactive nitrogen is also involved.

Free radical production rises when the body is under physiological stress, for example due to chronic infection, consumption of a high-fat diet, or exposure to environmental hazards such as pollution or radiation. Impairment of mitochondria – the tiny “power plants” within cells – can cause increased release of free radicals due to less efficient energy production.

Oxidative stress occurs when production of free radicals exceeds the body’s natural antioxidant defense mechanisms. The interaction between oxygen radicals and other molecules can alter proteins and fats, damage cell structures, and disrupt various cellular processes. Oxidative stress can damage cell membranes and DNA, causing mutations in a cell’s genetic code. It interferes with cytokine production and cell signaling, and appears to play a role in apoptosis (programmed cell death); chronic conditions such as atherosclerosis, neurodegenerative diseases, and cancer; and the overall aging process.

But reactive oxygen forms are not purely detrimental; they also play crucial roles in cell signaling, immune defense against pathogens, and recruitment of blood platelets to sites of injury.

Continued below
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Liver Damage Due to Oxidative Stress
Some of the chemicals that cause liver toxicity promote oxidative stress when they are processed in the liver. Acetaminophen, for example, is toxic at high doses because it is broken down into a chemical that causes oxidative damage in the liver. N-acetyl-cysteine, a precursor of the natural antioxidant glutathione, is used as an antidote. The breakdown of alcohol, especially after heavy or prolonged drinking, can produce harmful oxygen radicals that contribute to cirrhosis and other adverse outcomes.

Several studies have found that people with chronic hepatitis C have a higher degree of oxidative stress and decreased glutathione levels. A recent Italian study of more than 100 hepatitis C patients reported in the March 2008 Journal of Hepatology, for example, found that 61% had evidence of oxidative stress regardless of age, sex, HCV viral load, genotype, body mass index, or severity of liver inflammation.

HCV infection itself can worsen oxidative stress in the liver, but how it does so is not fully understood. Laboratory studies have shown that HCV proteins directly induce production of reactive oxygen species in hepatocytes; the virus also promotes oxidative damage in the liver due to chronic inflammation. Interestingly, hepatitis B virus does not seem to have a similar effect on oxidative stress. Excess iron in the liver also plays a role, probably by depleting glutathione stores.

Oxidative stress, in turn, disrupts interferon signaling pathways, blunting the antiviral effect of natural interferon alpha and potentially reducing response to interferon-based treatment. It encourages lipid peroxidation, a process whereby free radicals break down fats by taking their electrons, producing byproducts that contribute to liver steatosis. Oxygen radicals and lipid peroxidation byproducts also stimulate release of pro-inflammatory cytokines and promote hepatic stellate cell activity leading to fibrosis progression.

The June 2007 Journal of Gastroenterology and Hepatology included a review of studies showing that oxidative stress and the resulting activation of the body’s antioxidant mechanisms promotes development of hepatocellular carcinoma. Systemic oxidative stress contributes to some of the metabolic complications and other extrahepatic manifestations commonly seen in people with chronic hepatitis C. Free radicals, for example, are known to affect insulin sensitivity; the aforementioned Italian study found that among individuals with HCV genotypes other than 3, those with oxidative stress were more likely to have insulin resistance, steatosis, and fibrosis.

Some studies have shown that oxidative stress improves with successful interferon-based therapy. But treatment itself can cause some forms of oxidative damage, such as red blood cell destruction associated with ribavirin. Further, HCV itself contributes to mitochondrial dysfunction, which may be worsened by drugs that cause mitochondrial toxicity – including ribavirin, especially in combination with certain antiretroviral medications used to treat HIV.

HCV, steatosis, alcohol use, drug toxicity and other factors associated with oxidative liver damage can interact and have an additive or “multi-hit” effect, which helps explain why people with chronic viral hepatitis are more susceptible to liver damage due to heavy alcohol use or hepatotoxic medications – and why experts recommended that people with chronic hepatitis C drink little or no alcohol and exercise extra caution when using drugs that could potentially harm the liver.

Managing Oxidative Stress
Antioxidants are agents that act as “scavengers,” binding with – and thereby neutralizing  – free radicals. The body produces its own antioxidants including glutathione and superoxide dismutase to “mop up” radicals generated during normal metabolism. Imbalances can occur, however, due to either increased free radical production or decreased antioxidant levels, as often happens when faced with environmental stressors or chronic disease.

Antioxidants are also available in many foods and dietary supplements, for example vitamins C and E. Other supplements, including alpha-lipoic acid, N-acetyl-cysteine, and coenzyme Q10 are used in the production of natural antioxidants in the body. Trace minerals such as selenium and zinc enable the activity of antioxidant enzymes. Good food sources of antioxidants include the polyphenols, flavonoids, and carotenoids found in berries, citrus fruit, pomegranates, tomatoes, carrots, cabbage, broccoli, olive oil, dark chocolate, walnuts, red wine, coffee, and tea.

Because oxidative stress plays a role in many types of cell damage, antioxidants have been widely studied for the prevention and treatment of disease. Several large epidemiological studies have shown an association between a diet high in plant antioxidants and decreased risk of cardiovascular disease and cancer.

But while animal and human research indicates that a shortage of natural antioxidants is detrimental, the benefits of supplemental antioxidants are less clear. A few studies have shown that consuming large doses of antioxidant supplements (for example vitamin E) may actually be harmful, possibly because some antioxidants can exert a pro-oxidant effect at high levels.

Antioxidants have been studied for liver diseases including chronic hepatitis C. The benefits of many complementary and alternative therapies – such as silymarin (derived from milk thistle), glycyrrhizin (derived from licorice root), and ursodeoxycholic acid (found in bear bile) – may be largely due to their antioxidant effects, potentially both retarding HCV replication and reducing liver inflammation and fibrosis related to oxidative damage.

An Israeli study of 50 chronic hepatitis C patients, for example, found that using a preparation of 11 oral and injected antioxidants (including herbs, vitamins C and E, lipoic acid, and L-glutathione) for 20 weeks was associated with ALT normalization, decreased HCV RNA, and histological improvement. But several other studies of N-acetyl-cysteine, L-glutathione, and other antioxidants in people with hepatitis C and other types of chronic liver disease have produced conflicting data.

While research on isolated supplements remains mixed, however, there is little controversy about the benefits of consuming antioxidants as part of a healthy, balanced, low-fat diet rich in fruits, vegetables, and whole grains.

Choi, J. and Ou, J. Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. American Journal Physiol Gastrointes Liver Physiol 290(5): G847-851. May 2006.

Koike, K. Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways. Journal of Gastroenterology & Hepatology 22(Suppl 1):S108-S111. June 2007.

Levent, G. et al., Oxidative stress and antioxidant defense in patients with chronic hepatitis C before and after pegylated interferon alfa-2b plus ribavirin therapy. Journal of Translational Medicine 4:25. June 2006.

Mantena, S. et al. Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radical Biology & Medicine. January 3, 2008 (Epub ahead of print).

Melhem, A. et al. Treatment of chronic hepatitis C virus infection via antioxidants: results of a phase I clinical trial. Journal of Clinical Gastroenterology. 39(8): 737-742. September 2005.

Vidali, M. et al. Interplay between oxidative stress and hepatic steatosis in the progression of chronic hepatitis C. Journal of Hepatology 48(3): 399-406. March 2008.
Very good and interesting article.  I think I'll pass on the bear bile ... and stick with the dark chocolate and coffee. :)
Excellent dude!
I'm really happy you posted this. For me personally it validates the supplements I'm taking. And it also validates that I decided to take them at a lower dosage.

Good to have you back!


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