Why Triple Antioxidants Relieve the Symptoms of Chronic Hepatitis C,

by George D. Henderson, 5 - 10 - 2007

Just because you have a positive test for Hep C, a bad outcome is far from inevitable. Many people with Hepatitis C never develop symptoms. Even if you’re already sick with chronic Hepatitis C you can turn your life around, by making healthier diet, exercise and drug choices and by using the appropriate dietary supplements to replace the body’s depleted antioxidants and assist the recovering liver. This article describes how antioxidants are depleted in hepatitis C, the methods of antioxidant repletion, and the results of antioxidant protocols in hepatitis C. It’s important to realize that antioxidants are not an antiviral therapy; viral levels will only decline slowly. The benefit of antioxidants is that they can prevent lipid peroxidation (the mechanism of liver damage in cirrhosis) and reduce or prevent the disabling symptoms of hepatitis: fatigue, nausea, pain, depression, tiredness, irritability. They improve liver function by protecting existing liver cells and protecting the DNA in new cells (formed to replace the liver cells destroyed by immune attack) from the damage that causes the decline in liver function seen in long-term cirrhosis [1. Berkson 1997]

I know these methods work because I use them myself. In four years I have gone from being very sick, depressed and addicted to being healthy, happy and productive, with liver enzymes well inside the normal range.

Tests, studies and trials involving hepatitis C populations all over the world show the same results; compared to healthy populations, people with chronic hepatitis C (CHC) have depleted levels of antioxidants (both dietary, e.g. beta-carotene, vitamin E, lycopene, and endogenous, e.g. glutathione, alpha-lipoic acid), antioxidant enzymes, and most vitamins and minerals used in antioxidant synthesis (e.g. selenium, zinc, magnesium). The only minerals whose levels are regularly found to be normal or elevated in hepatitis C are iron and copper, transition elements which are a source of free radicals.

This systemic antioxidant depletion is characteristic of CHC, and the depletion is more marked in patients with cirrhosis. The wide-ranging consequences of this antioxidant depletion syndrome account for most of the unpleasant, disabling and life-threatening symptoms of CHC, including muscle fatigue, depression, and liver damage. There are no longer enough antioxidants being produced to quench the free radicals that are generated in the course of the liver cells performing their normal duties, let alone deal with the reactive peroxides that are generated by the immune system’s attack on the infected liver cells, and this shortfall is what allows the lipid peroxidation process that causes hepatocellular fibrosis and leads to cirrhosis.

Antioxidant precursors include the amino acid l-methionine, which is in demand for the production of immunoglobulins (antibodies) and the antioxidants l-cysteine, glutathione (GSH), alpha-lipoic acid (ALA), Co-enzyme Q10 (CoQ10), carnitine, taurine, and creatine. Given a limited supply of l-methionine the body will supply its essential systems first; the immune system has priority, and the needs of the muscles come last. In order for the limited intake of l-methionine to supply l-cysteine for antibody production and GSH for immune cell function and liver cell protection (and the production of liver GSH in CHC is often inadequate to provide such protection), the muscles become starved of taurine, creatine, carnitine, GSH, and ALA. Antioxidants are needed by muscle cells both to produce energy and to recover after exertion, and this explains why fatigue and muscle pain (myalgia) so often result from a liver infection (because immune cells exist in the blood, they are able to absorb nutrients before they can nourish muscle cells). Parallel processes play a role in depression and insomnia; l-methionine is also the precursor for the methyl-donor S-adenosylmethionine (SAMe) which plays a vital role in serotonin synthesis (methyl donors including SAMe, B6, B12, folic acid and betaine act in the methylation cycle, which metabolises dietary l-methionine and l-cysteine; these being depleted or the cycle being otherwise blocked can also deplete glutathione [2. Von Konynenburg, 2004]). The increasing demand for l-methionine’s many metabolites in chronic hepatitis C creates a bottleneck in the body’s antioxidant and methyl-donor supply lines.

There has been considerable research and experimentation done to learn which combination and dosage of antioxidants is most effective at reversing the depletion that occurs in hepatitis C and relieving the symptoms of CHC, including protecting against cirrhosis and liver cancer. A consensus has developed favouring a combination of Alpha-lipoic acid (lipoic acid), Selenium, Silymarin (milk thistle), and vitamins E and C, the so-called “triple antioxidant” method. Other antioxidants used include SAMe and glycyrrhizin from liquorice and a number of Japanese trials have successfully used an IV product called Stronger Neo-Minophagen C, which is a compound of glycyrrhizin, l-cysteine, l-glycine and dl-methionine [5: H Kumada 2002], but the advantage of Triple Antioxidants is that they are safe enough, and convenient and effective enough, to be taken by people who are not lucky enough to have a doctor willing to study, diagnose and treat the antioxidant depletion caused by CHC. Although this treatment was developed through the study and treatment of CHC by doctors and scientists working in world-renowned hospitals and universities, and cannot be called an “alternative therapy”, many doctors in this country (N.Z.) seem content to wait for new treatments to arrive via the drug companies and the government drug purchasing agency Pharmac and are embarrassed about standing out from the herd. New Zealand is a very small country (c. 4.5 million); waiting for a sophisticated new treatment to appear in mainstream health care here is analogous to waiting for a sophisticated food product to appear on the shelves of a small town “Four Square” store, when it has long been on the shelves of the big city supermarkets.

Triple antioxidants interact to enhance one another’s antioxidant activity. For example, both Sylimarin and ALA promote GSH synthesis and reduce oxidised glutathione; ALA also reduces oxidised vitamin C and vitamin E. Selenium, in the glutathione peroxidase enzyme, catalyses both the synthesis of GSH and its antioxidant activity, and enhances the lipo-protective activity of vitamin E (in other words, vitamin E prevents lipid peroxidation at lower doses in the presence of adequate selenium). In thioredoxin reductase, selenium reduces oxidised vitamin C, and possibly restores the activity of other antioxidants. HCV itself encodes for selenium and HCV infection can worsen selenium depletion, which has the effect of making any mercury present more toxic as mercury can form a safe intrametallic compound with selenium or conjugate safely with glutathione; as GSH depletion and selenium deficiencies are linked, relatively low levels of mercury can become problematic when either Se or GSH is depleted. Some viruses, e.g. Cocksackie viruses, mutate more virulently when selenium is deficient, and mutation of HCV helps the virus avoid immune attack.

Triple Antioxidants as developed by Burt Berkson MD, and the similar mixed antioxidants (not including selenium) recently trialed in Israel provide benefits in the following parameters; [1: Berkson 1997, 3: Melhen et al. 2005]

Liver Enzymes: are rapidly reduced, tending to become normal. In most cases where ALT is normalized it stays normal once treatment is stopped; however it is recommended that antioxidant therapy be maintained as long as the disease persists, or renewed if liver enzymes rise or symptoms recur. ALT levels are an indication of ongoing liver damage, not of viral load, but the destruction of infected liver cells accelerates the spread of HCV. The normalization of liver enzymes is indicative of a low rate of hepatocellular necrosis.

Fatigue: Alpha-lipoic acid is able to replete GSH, and consquently elevates taurine, carnitine and creatine in muscles. ALA increases glutathione synthesis and glutathione transports cysteine into cells, where it acts as a precursor for intracellular GSH and other antioxidants. ALA also reactivates GSH and other antioxidants from the oxidized to the (active) reduced phase. Glutathione, N-acetyl l-cysteine (NAC), l-methionine, whey protein and other precursors have also been used. Ascorbic acid plays an essential role in l-carnitine synthesis. In the Israeli trial 58% of patients had improved scores in the SF-36 quality of life questionnaire after treatment. The ability of triple antioxidants to restore normal, pre-disease energy levels is usually the first benefit to be appreciated by the patient.

Viral Load: A decrease in viral load (one log) was seen in 25% of the Israeli subjects (few of whom received all of the triple antioxidants) after 20-40 weeks and a significant decrease was seen in all three of Berkson’s patients over a longer period. A steady decrease in viral load can be expected throughout long-term treatment, but the decrease does not account for the beneficial effects of triple antioxidants, which can still occur when the viral load stays more or less constant. In no case so far has viral load increased during antioxidant treatment.
In subjects with seriously depleted antioxidant levels, antioxidant repletion (like combination therapy) may cause HCV and other infective organisms to die off so rapidly that the consequent toxic load causes distress – this is known as the Herxheimer reaction, and may last for a few days. For this reason Berkson advised drinking 8 glasses of water daily, to protect the kidneys as the toxins are flushed out. Because viral load tends to decrease slowly in antioxidant therapy, and because people with high HCV loads are used to feeling bad, the Herxheimer reaction is seldom recognized, but its possiblility needs to be borne in mind.

Histology: histological improvement was noted in 36.1% of the Israeli subjects. In a separate study, high dose Vitamin E (d-alpha tocopherol) alone stopped the progress of fibrosis, preventing cirrhosis, for as long as treatment lasted [4: Houglum et al. 1977]. Alpha-lipoic acid increases the antioxidant activity of vitamin E. Antioxidants have the potential to prevent lipid peroxidation, the disease process that causes fibrosis. That neither selenium nor any other mineral was included in the Israeli trial may account for the failure of some participants to respond to mixed antioxidants as selenium is needed for the synthesis of antioxidant enzymes and for the formation of glutathione itself.
In a Chinese population study selenium supplementation (200mcg) reduced the rate of hepatocellular cancer (HCC) in subjects with cirrhosis due to chronic HBV to zero, and in a population study involving subjects with both HBV and/or HCV a similar protective effect of high selenium levels was seen in both groups. Selenium is needed for the glutathione peroxidase family of antioxidant enzymes. At high doses excess selenium becomes methylated and this methylation product is believed to have a pharmacological action that protects against many cancers.

Summary: Antioxidants do not act as potent antivirals, but do tend to restrain HCV replication. Triple antioxidants are effective at preventing cirrhosis and cancer in CHC, and are also effective against fatigue, depression, pain, and GI disturbance (most bile-producing reactions in the liver depend on GSH and taurine is an important constituent of bile salts). Patients are most likely to respond when doses of ALA, ascorbic acid, and glutathione or its precursors can be increased on a PRN basis and when B vitamins including methylation factors [2: R. A. Van Konynenburg 2004] and essential minerals, especially selenium but also magnesium, zinc and manganese, are supplemented.

Many people who have CHC do not develop serious symptoms and stay healthy without treatment. We can hypothesize that a combination of influences may be at play in these individuals: a healthy lifestyle low in oxidative stressors such as alcohol, cigarettes and drugs, a diet low in iron, calories, saturated fats and toxic chemical additives and high in antioxidants and easily assimilable protein, and a genetic predisposition to avoid accumulation of iron and copper, and to produce higher than normal levels of endogenous antioxidants (e.g. GSH, GR, ALA, CoQ10), as well as a genetic tendency against high levels of autoimmune and inflammatory activity. To such an individual life-long infection with hepatitis C might be largely benign, and such habits and genetic tendencies might account for the variable but significant percentage of persons with CHC who never become ill.

It seems it is not always essential to clear the virus to control or eliminate the symptoms of CHC, and in any case viral clearance by chemotherapeutic intervention is not always possible. In developed countries most people with CHC are IVDU, and in Australia, for example, 95% of IVDU will not access combination therapy (interferon plus Ribavirin). In most of these cases antivirals will be medically contraindicated for these individuals due to alcohol or intravenous drug use, mood disorders, autoimmune syndromes etc. It may be thought possible to manage these symptoms in some cases, but this means accepting an increased risk of unwanted outcomes. In any case, antivirals are only effective in approximately half of cases, they are often blamed for causing lasting health problems, and have unpleasant side effects that can seem counterproductive, leading to patients dropping out of treatment. Viral clearance, both spontaneous and chemotherapeutic, is associated with a decreased rate of cirrhosis and hepatocellular cancer, but on long term follow up the other, extrahepatic symptoms of hepatitis C can persist: fatigue, depression, upper right quadrant pain, arthralgia (joint pain) and autoimmune disease have been seen at the same rates, for example nine years after spontaneous clearance, and the picture after chemotherapeutic clearance is often worse, due to the longer period of infection pre-clearance and the effects of the antivirals. Thus antioxidants may be of value to anyone who has ever had Hepatitis C and is in less than perfect health as a result.

There are many cases where antioxidants and antivirals have been combined and in none of these has the antiviral clearance rate suffered. The ability of antioxidants to improve viral clearance rates from combination therapy varies and seems to depend, naturally enough, on the combination and doses of antioxidants; iron levels and the availability of dietary methionine and selenium are other factors that could be critical. Magnesium deficiency is widespread in CHC and magnesium is involved in 350 enzyme reactions, including antioxidant enzymes and the conversion of serotonin into the sleep-promoting and neuroprotective antioxidant melatonin.

A reductionist approach to medicine is singularly unrewarding when dealing with nutrients. The action of any single nutrient depends on its context in the matrix of all nutrients; whether its co-factors are present in sufficient quantity, whether competitive nutrients are present, amongst other things, may be critical. Diet, exercise, water, sunlight are just some of the possible influences. Berkson’s approach [1: Berkson 1997], which can scarcely be bettered, was to supplement the action of the triple antioxidants (alpha lipoic acid 600 mg, selenium 400 mcg, silymarin 900 mg daily in two doses) with moderately high doses of Vitamin E (400 iu d-alpha tocopherol) and vitamin C (4 g ascorbic acid in divided doses), as well as a high dose B complex pill (B100, 2x daily) and a multimineral supplement (including adequate magnesium, zinc, molybdenum, chromium and manganese). He also recommended his patients eat a diet with only moderate calories, eat 5+ fruit and veges, drink 8 glasses of water daily, and get exercise and sunlight.

Because the extra-hepatic HCV syndromes tend to persist even after the desired SVR result of combination therapy, there is a need for antioxidants to be used by these patients, as well as in the conservative management of hepatitis C. For the patient the disease does not end when the virus dies, but when their health is restored to normal. There is no reason to accept continued disability or discomfort due to a past or current infection with HCV when this safe, cheap and convenient treatment yields such a high rate of improvement. “If it’s so good why doesn’t everyone use it?” is the standard question at this juncture, to which the response is two-fold; one, they do: many thousands of HCV sufferers are already using antioxidants. And two: although antioxidant treatment of CHC is safe, convenient, effective, and relatively cheap it is not simple. It is not a one-pill, magic bullet fix. To apply it properly in a given case can take some understanding of antioxidant metabolism, which can be gained by reading, and some awareness of one’s own antioxidant status, which depends on the ability to analyze one’s diet, or on diagnostic tests that, apart from iron levels, are not part of everyday medical practice in N.Z. Many people imagine that antioxidant treatment of Hep C requires the co-operation of a doctor, and if their doctor fobs them off they do nothing, or make a half-hearted attempt, for example taking silymarin or selenium but nothing else, and stopping once there is no further improvement.

My experience with Triple Antioxidants was typical; for years I told my doctors I wanted to try N-acetylcysteine, showing them papers etc. without generating any interest. At that time the only NAC I knew of in New Zealand was being used by hospitals. I went to study NAC in the medical library and discovered the importance of l-methionine and selenium to GSH synthesis. I now knew I could find all I needed in heath shops and pharmacies. I began with selenium, silymarin, vitamin E, vitamin C, and a gram a day of l-cysteine, later switching to NAC or l-methionine. The depression associated with CHC lifted immediately, the abdominal pain ceased, my digestion improved, and my energy levels increased rapidly. After two years I learned the importance of the iron connection and stopped using the foods (Milo, Marmite, most breakfast cereals) and multivitamins that are fortified with non-heme iron; after a few weeks my heath improved further. Four years after beginning daily antioxidants my liver enzymes, which had reduced sharply at the start, became normal. However, switching to Berkson’s triple antioxidants (in the form of a product called Hep C Complete) a few months ago was a great improvement even over my previous regime, and all residual fatigue disappeared. I now seem to have normal levels of physical and mental energy and I no longer tire easily.

I recommend in some cases using 600mg of NAC or l-methionine with the triple antioxidants (or using whey protein or spirulina as a source of readily assimilable protein), using omega-3 fish oil and vitamin D to lessen auto-immune activity, and I emphasize the importance of ensuring adequate magnesium, folate, B6, choline, and Vitamin D, from diet or supplements (it is especially important to sustain vitamin D intake in winter or times of low sun exposure, and an intake of 800-1,200iu is recommended). There is a complementary liver-protecting approach that involves supplying specialised nutrients to rebuild and strengthen the phospholipid cell membranes, and I intend to address this and the needs of the regenerating liver in my next article. Berkson treated each patient individually according to their symptoms, but his basic “Triple Antioxidants” regime is still the gold standard of treatment for preventing and alleviating the symptoms of hepatitis C and protecting the liver, just as combination therapy, for all its faults, is still the gold standard of treatment for killing the hepatitis C virus.

References and Links:

1: Burt Berkson MD’s Triple Antioxidant paper: http://allinone-nutrition.com/6.html The company that maintains this site also sells a triple antioxidant formula, Hep C Complete. This product is good value compared to similar NZ products.

It supplies 600mg Alpha-lipoic acid, 400mcg selenium and 900mg Silymarin per day and should be used with an iron-free multivitamin-and-mineral product high in B complex vitamins and high doses of vitamin C and vitamin E, as Berkson describes.

2: R. A. Van Konynenburg Ph D. Glutathione Depletion – Methylation Cycle Block: A Hypothesis for the Pathogenesis of Chronic Fatigue Syndrome. Based on “Is glutathione depletion an important part of the pathogenesis of chronic fatigue syndrome?”, the poster paper at the Seventh International AACFS Conference 2004. Available online at Phoenix Rising: a guide to ME/CFS treatment. http://phoenix-cfs.org/GSH%20Methylation%20Van%20Konynenburg.htm

3: Mehlen et al. Journal of Clinical Hepatology, September 2005, Treatment of Chronic Hepatitis C Infection via Antioxidants: Results of a Phase 1 Clinical Trial, Melhen et al. “Fifty chronic HCV patients were treated orally on a daily basis for 20 weeks with seven antioxidative oral preparations (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, L-glutathione, and alpha-tocopherol), along with four different intravenous preparations (glycyrrhizin, ascorbic acid, L-glutathione, B-complex) twice weekly for the first 10 weeks, and followed up for an additional 20 weeks. Patients were monitored for HCV-RNA levels, liver enzymes, and liver histology. Assessment of quality of life was performed using the SF-36 questionnaire.”

4: Houglum K et al. A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology. 1977;113(4):1069-1073, cited with related papers in http://hepcchallenge.org/choices/supplements.htm

5: Kumada H. Long-term treatment for chronic hepatitis C with glycyrrhizin (stronger neo-minophagen C) for preventing liver cirrhosis and hepatocellular carcinoma. Oncology 2002; 62:94-100

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