~Hepatitis C, Part 4 - Nutritional Therapy
- Innovative Options
- Supplements and Nutritional Therapies
- Antioxidant Vitamins
- Botanical Medicines
The current pharmaceutical choices for CHC are imperfect. Eradication of the HCV virus — the ultimate goal — is impossible for most patients. More treatment options are urgently needed, and more reasonable goals must be set. New endpoints under consideration are reduction of virus levels in the blood, decrease in hepatic inflammation and the rate of progression of hepatic fibrosis, and delay of development of cirrhosis and hepatocellular carcinoma. Viewing interferon and ribavirin treatment in terms of these endpoints might result in new protocols for treatment of CHC.106
There is a recognized group of medicinal herbs and supplements with proven antiviral and biochemical actions that are effective for treatment of CHC. They have been used safely worldwide to treat liver disease — some for thousands of years. Today they have the added advantage of being available in a standardized extracted form and of being tested in clinical trials that enroll thousands of participants. All of the medicines detailed here have been the subject of numerous placebo-controlled clinical trials, animal studies, and in in vitro studies.
Supplements and Nutritional Therapies
The antioxidant defenses of the body may not provide adequate protection against the oxidative molecules produced by the immune system during the inflammatory process. Slowing cytokine production and maintaining antioxidant defenses depends on nutrient intake. Nutrients absorbed from the food we eat influence the inflammatory aspects of the immune system by altering cytokine production and limiting the responsiveness of target tissues to cytokines. Alterations in the intake of fats, antioxidant nutrients, protein, and certain amino acids can reduce inflammation by interacting with the body's cytokine and reactive oxygen species biology.152
The intake of metallic micronutrients such as copper, zinc, and selenium influences the activity of antioxidant enzymes. A number of constituents of defense are acquired directly by the intake of nutrients that have antioxidant properties. These include ascorbic acid, tocopherols, beta-carotene, and a number of phytochemicals, such as catechins and tannins from tea. When the immune system is stimulated, pro-inflammatory cytokines increase the activities of the enzymes that detoxify oxidants, such as superoxide dismutase and catalase.153
The components of antioxidant defense interact directly and indirectly to maintain the antioxidant capacity of tissues. Vitamins E and C and glutathione are intimately linked in antioxidant defense.154 Vitamin E influences inflammatory and immune function. Vitamin E deficiency impairs cellular and humoral immunity and supplementation lowers the incidence of infectious disease.155,156 Vitamin C is a key component of antioxidant defense.157 Some small studies have demonstrated that vitamin C might play a role in the effect of exercise on the immune function.158,159 Inflammation is inversely related to the intakes of vitamins C and E in smokers.160 The absorption of iron is significantly enhanced by the presence of vitamin C.161 Vitamin B has widespread effects on immune function and is an indirect contributor to antioxidant defenses. Vitamins B12 and B6 are a co-factor in the metabolic pathway for the biosynthesis of cysteine which is necessary for glutathione synthesis.161 Deficiencies in B vitamins and vitamin E create abnormalities in the cell-mediated immune response and supplementation with vitamins C, A, E, and B vitamins and improves lymphocyte function.154
Glutathione, a molecule composed of glycine, glutamate, and cysteine, is key to the regulation of cellular activity. Depletion of glutathione below a certain level causes cell death. Glutathione is synthesized and highly concentrated in the liver where it plays a key role in the cytochrome P450 detoxification system. It protects cells by quenching free radicals; in its reduced form, glutathione has potent antioxidant action. Glutathione is a major antioxidant made by the body and is important in the manufacture of lymphocytes.161 Cytokine production in response to inflammatory stimuli depends on the ability of the body to produce glutathione.162 Attack by free radicals depletes glutathione, and low levels of glutathione are linked to many diseases. Aging alters glutathione status so that reduced glutathione tends to be lower and oxidized glutathione rises.163 Malnutrition164 and alcoholism165 cause deficiencies of glutathione precursors and consequently limits glutathione synthesis.166 There is a relationship between liver damage and production of free radicals during inflammatory processes. In CHC, liver damage is attributed to an imbalance in the oxidation and reduction processes and to glutathione depletion. Chronic inflammation provoked by the replication of HCV and might also have a role.167 Monocyte glutathione is low in hepatitis C and altered glutathione status is a feature of cirrhosis and nonalcoholic liver disease.165,168,169
Nutrients that Raise Glutathione Levels
Glutathione stimulation is a primary immune-modulating mechanism. The amino acid precursors to glutathione increase glutathione concentration in relevant tissues and stimulate immunity.170 Taking supplementary glutathione and its precursors, such as alpha-lipoic acid, N-acetyl-cysteine, S-adenosyl-L-methionine, increases glutathione in the body.
Alpha-Lipoic Acid (ALA) (Thioctic Acid). Alpha-lipoic acid is a potent antioxidant with a critical role in the energy-producing structures in cells.171 As an antioxidant, alpha-lipoic acid is unique. Although it acts like a vitamin, it is not classified as such because it is synthesized in the body.161,172 It is soluble in both lipids and water and can act as an antioxidant in both mediums.173 It is active in both its oxidized form and its reduced form, dihydrolipoic acid (DHLA).171,174 Alpha-lipoic acid is able to regenerate vitamin C175 and E176 and to raise intracellular glutathione levels significantly.177
Alpha-lipoic acid has therapeutic applications in many conditions that involve oxidative stress.171 It has been studied as a treatment for diabetes,171,178 as well as a variety of disorders related to the eye. It is used extensively to treat liver disease and is an accepted antidote to poisons and drugs that are metabolized in the liver. Alpha-lipoic acid is a highly effective treatment for Amanita mushroom poisoning.171 It has the ability to chelate copper, manganese, mercury, and zinc,179 reduce cadmium-induced hepatotoxins,172 and protect from arsenic poisoning. There have been preliminary studies of alpha-lipoic acid as a treatment of alcoholic liver disease. However, as with all trials involving alcohol use, it is difficult to separate the effects of abstinence from alcohol from those of the treatment.
Alpha-lipoic acid has very few side effects; the most common are nausea and vomiting. Although it is safe in standard doses,178 low doses in thiamin-deficient rats were fatally toxic180— thiamin-deficiency is a condition that is common in alcoholics. Individuals who are deficient in thiamine in should take vitamin B1 along with alpha lipoic acid. Alpha-lipoic acid lowers blood sugar levels181 and theoretically could cause hypoglycemia in diabetics. Alpha-lipoic acid interacts with the chemotherapy drugs doxorubicin.182
N-Acetyl-Cysteine (NAC). N-acetyl-cysteine has anti-mutagenic and anti-carcinogenic properties and is a powerful scavenger of free radicals. It is a precursor of glutathione—conversion of N-acetyl-cysteine to two of its major metabolites cysteine and inorganic sulfite accounts for its protective effects.123,183,184 N-acetyl-cysteine is converted to circulating cysteine after it is absorbed by the intestines. It increases the synthesis of glutathione only when there is a demand for it; in fact, it might only concentrate in the tissues where it is required.134,185-187 N-acetyl-cysteine can modulate the concentrations of certain cytokines. In laboratory studies, it has increased IL-1 and IL-2 levels when they were at low concentrations and decreased these cytokines at higher concentrations.188
N-acetyl-cysteine is also used to treat hepatotoxic conditions, especially those that increase oxidative stress or decrease glutathione185. It is an established antidote for acetaminophen overdose189—a condition known to deplete liver glutathione.190 N-acetyl-cysteine might have a role in the treatment of liver cancer. It has demonstrated the ability to inhibit cell growth and proliferation in cancer cell lines191-193 and prevent the transformation of carcinogens into more toxic compounds.194 In laboratory experiments, it reduced experimentally induced intestinal tumors195 and inhibited the induction of tumors by some carcinogens.196
It is conjectured that the relative ineffectiveness of interferon for treatment of CHC can be attributed to glutathione imbalance. Supplementing interferon with a glutathione precursor would increase its effectiveness and that antioxidants might act in synergy with interferon. To test this theory, there have been several trials of a combination treatment of interferon with N-acetyl-cysteine. Results of one study showed that supplementation of interferon with N-acetyl-cysteine enhanced the response to interferon, but had no effect when it was taken alone.197
N-acetyl-cysteine is generally safe and side effects are infrequent.198 The most common side effects at high doses are nausea, vomiting, and gastrointestinal disturbances. People with chronic liver disease tend to have an increase in blood N-acetyl-cysteine coupled with a decreased ability to clear N-acetyl-cysteine with intravenous doses.199 In healthy individuals, N-acetyl-cysteine might act as an oxidant and lower the levels of reduced glutathione.200
S-Adenosylmethionine (SAMe). SAMe is a sulfur-containing amino acid derivative found in the cells of all mammals.201 It is formed by an enzyme-catalyzed reaction between methionine and ATP, an important energy source in the body202 SAMe provides methyl groups for biosynthesis and is a major glutathione precursor that participates in detoxification reactions and in the manufacture of antioxidants.161 Folic acid and vitamin B12 are necessary for the resynthesis of SAMe,202,203 and there is evidence that folate deprivation contributes to methyl insufficiency.204
SAMe has been used all over the world to treat depression,205,206 arthritis, osteoporosis,207,208 fibromyalgia,209 and Parkinson's disease;210 as well as certain liver211 and gallbladder diseases.212
SAMe is a physiological donor of methyl groups in enzymatic reactions. Cirrhotic damage to the liver prevents the conversion of SAMe from methionine.169 The mechanism is probably due to multiple abnormalities in sulfur metabolism in cirrhosis. Hypomethylation213 is strongly associated with carcinogenesis. In fact, methyl-deficient diets have caused liver cancer in animals; and diets containing lipotropes—a group of nutrients that includes methionine, folic acid, and vitamin B6 and B12—have prevented their development. Lipotrope-deficient diets can cause extensive liver damage including fatty livers.204 SAMe also reduced hepatic necrosis in rats with methyl deficient diets.169
SAMe is highly concentrated in a normal liver,214 and low levels of SAMe are a feature of cirrhosis.202 SAMe supplementation significantly restores the glutathione depletion in patients with chronic liver disease.215 Animal and human studies have shown that SAMe lessens the symptoms of liver disease caused by alcohol,216 toxic chemicals,204 and prescription and over-the-counter drugs.204 In a clinical trial, SAMe, taken over a period of 2 years, lowered the death rate of patients with alcoholic cirrhosis.217
In clinical trials of limited duration, there have been no serious side effects with SAMe. The most common side effect is mild gastrointestinal distress. Because SAMe has antidepressant activity, there is the possibility that it might trigger a manic episode in those with manic-depressive illness.204 SAMe should not be taken with any antidepressants, including MAO inhibitors, SSRIs, and tricyclics without consulting a physician.218 SAMe might inhibit of blood platelet aggregation.204 Although SAMe might relieve some side effects of the Parkinson's drug levodopa, it might also reduce its effectiveness over time.219
Whey. Whey (milk serum) protein is isolated from milk. Its potent antioxidant activity is due to its high concentration of the amino acid cysteine, a component of glutathione.220 Whey contains several important biological components that have properties that enhance the immune system. For example, ß-lactoglobulin modulates lymphatic responses.221 a-Lactalbumin has a direct effect on B and T lymphocyte function and has the ability to reduce oxidative stress because of its iron chelating properties. Lactoperoxidase catalyzes the reduction of hydrogen peroxide.222,223 Approximately 15% of whey proteins are immunoglobulins, the antibodies that confer immunity.224
Lactoferrin. Lactoferrin, a major component of whey protein, is an iron-binding glycoprotein that acts as an antioxidant—apolactoferrin is the iron-depleted form of lactoferrin.225 Lactoferrin has far-reaching antiviral and immunomodulatory properties.226 It can activate natural killer cells and neutrophils, induce colony-stimulating factor activity and enhance macrophage cytotoxicity,227-230 as well as decrease inflammation through the regulation of certain cytokines (TNF, IL-6).231 In the laboratory, lactoferrin inhibited metastasis of primary tumors in mice.232 When a high lactoferrin whey concentrate and the anticancer drug were combined, cytotoxicity was enhanced by inducing a higher rate of apoptosis.233 In small studies, bovine lactoferrin prevented HCV infection in human liver cells234 and decreased HCV RNA and liver enzymes in patients with low pretreatment viral loads of HCV.235 In a subsequent small, clinical trial, only a small percent of patients achieved significant decreases in ALT and HCV RNA levels and all of those who responded relapsed during the follow-up period.236 In a small open study that enrolled patients with HBV and HCV infections, ALT activity and lipid peroxide levels decreased, while glutathione, IL-2, and natural killer activity increased in the HBV group. However, there were no significant changes in the CHC group.237 There are not enough data to fully explain the considerable difference between the HBV and HCV groups. Apart from the obvious difference in virus, the small sample size should be considered. There have been a number of clinical trials in immune-compromised populations, such as AIDS and cancer patients, in which low glutathione levels are common. Significantly elevated glutathione levels were achieved with whey; however, results varied with different commercial products.238-241 As a rule, individuals who are lactose-intolerant can use whey proteins because lactose is removed during processing. Those who have true milk allergies should not use whey.
Phosphatidylcholine. Phosphatidylcholine provides the main structural support for the cell membranes of the body and has a role in the regulation of membrane fluidity. It is an essential nutrient and serves as a reservoir of choline.242 Phosphatidylcholine has demonstrated considerable antioxidant protection in numerous animal studies and clinical trials.243,244 It provides protection against chemical toxins and pharmaceutical drugs. Phosphatidylcholine is an excellent source of methyl groups which are crucial for hepatic detoxification.245
Liver disease enhances lipid peroxidation and depletes phosphatidylcholine and glutathione.246 Phosphatidylcholine has consistently shown benefits as a treatment for liver damage. Results from several clinical trials show significantly lower liver enzyme levels, improvement in liver tissue, and a decrease in mortality rate with the use of phosphatidylcholine. Although most phosphatidylcholine studies have been aimed at heavy drinkers, it appears to have applications for the sequelae of CHC. Phosphatidylcholine successfully reduces ALT in CHC patients.247 Because phosphatidylcholine breaks down collagen, it might have a positive effect on liver fibrosis.248 In an animal study, baboons that were force--fed alcohol without phosphatidylcholine progressed to advanced liver fibrosis, while baboons with a phosphatidylcholine-supplemented diet developed fatty liver and mild fibrosis, but did not progress to extensive fibrosis.246 In a clinical trial that enrolled patients with chronic viral hepatitis B or C, treatment with interferon and phosphatidylcholine for 24 weeks reduced ALT levels in 71% of patients with CHC. Additionally, treatment with phosphatidylcholine after termination of interferon treatment reduced the high interferon relapse rate.247 Phosphatidylcholine is safe and non-toxic. Side effects are usually mild and restricted to gastrointestinal complaints, such as diarrhea and nausea.249,250
Selenium. Selenium is a trace mineral251 that is essential for the proper functioning of the immune system.252,253 It has antioxidant properties and is a cofactor in several metabolic pathways.254 Glutathione peroxidase, the enzyme that recycles glutathione, is selenium dependent. Certain breakdown products of selenium in the body are believed to enhance immune cell activity.255
Plant foods are the major dietary source of selenium. Garlic, for example, is rich in selenium. The amount of selenium in a plant depends on the content in the soil where the plants are grown.256 Selenium deficiency is seen in areas where the soil content is low.252,257 Epidemiological investigations have found an association between low nutritional selenium status and increased risk of a variety of diseases.258,259 Selenium deficiency alone does not cause serious disease; it can make the body more susceptible to illness, however.260
Low serum selenium levels are associated with some cancers;116,261,262 and there may be an association of low environmental selenium to conditions as varied as goiter, sudden infant death syndrome, multiple sclerosis,263 and schizophrenia.264 Deaths from cancer are lower among people with higher selenium blood levels;265-268 and the incidence of cancer is higher in areas with low soil selenium levels.257,269 In a large cancer prevention trial, supplemental selenium lowered the risk of prostate, lung, and colorectal cancer;270 it did not affect recurrence of skin cancer, however.270 Data gathered from the 60,000 participants in the Nurses Health Study failed to find a relationship between higher selenium levels and reduced risk of cancer.271 Selenium levels appear to be severely depleted in liver disease. In a small study, serum selenium levels were significantly lower in participants with cirrhosis and hepatitis compared with a control group and lower in individuals with cirrhosis than in those with hepatitis.272
Interactions between selenium and other dietary constituents may affect the biological properties of selenium. In some studies, selenium supplemented with vitamin A provided an additive effect against breast cancer, but the protective effect was nullified by vitamin C.273 Selenium toxicity is rare in the U.S.— even in areas with high environmental level.274,275 The tolerable upper intake level (UL) for selenium is 400 micrograms per day (mcg/day) for adults.276 High levels of dietary selenium have been associated with decreased levels of thyroid hormones277 as well as impairment of natural killer cells. At extremely high levels hepatotoxicity, gastrointestinal distress, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage have been reported.278,279
DHEA. DHEA is a prohormone. Although small amounts are manufactured in the brain, DHEA is synthesized primarily by the adrenal glands. In women, DHEA is synthesized almost exclusively in the adrenal cortex; in men, the testes secrete from 10 to 25%.280 DHEA production peaks around the age of 25, then declines about 2% each year until the end of life.281-284 DHEA-S (sulfate) is an inactive metabolite of DHEA. DHEA and DHEAS are converted into several active metabolites.281,285-287 They are precursors of about half the androgens in men, 75% of active estrogens in premenopausal women, and all of the active estrogens after menopause.281,288 DHEA-ST (DHEA sulfotransferase) is involved in the hepatic clearance and metabolism of sex steroids. It catalyzes the reaction that forms the biologically inactive compound DHEAS. It is also the enzyme responsible for the inactivation of some potentially hepatotoxic bile acids. DHEA-ST activity and concentration are significantly reduced in several liver diseases, including chronic active hepatitis.289 In a study of the dynamics of DHEAS and other androgens in men with CHC infection, androgens were lower than in healthy men, but there was no correlation between DHEA and CHC infection.290 In non-alcoholic cirrhosis, there is a reduction of androgens (testosterone, DHEA, DHEAS, androstenedione) and a rise of estrogens.291 In a study of cirrhotic men, DHEAS values were significantly lower than normal, suggesting a defect in sulfurylation in men with hepatic cirrhosis.292
The response to DHEA supplementation in humans is sex and age specific. In small studies, DHEA had predominantly androgenic effects and increased testosterone levels about 300% in postmenopausal women;293 but in men over 52 years of age, DHEA increased estradiol and estrone levels but did not affect testosterone levels.294 Unlike cortisol and testosterone, DHEA secretion declines with ageing. However, it is not clear if physiological decline in DHEA secretion represents a harmful deficiency.295 DHEA is currently approved by FDA as an orphan drug for the treatment of adrenal insufficiency; its approval to treat systemic lupus erythematosus (SLE) is expected soon. There is also evidence to justify exploration of DHEA as a treatment of a variety of conditions, especially those associated with low DHEA and DHEAS levels. There is an inverse relationship between the DHEA levels in the body and a number of diseases, including some cancers, diabetes, cardiovascular disease, and Alzheimer's disease.296 Numerous animal studies have demonstrated that DHEA improves immune function and memory and prevents atherosclerosis, cancer, diabetes, and obesity.280,281,296 Unfortunately, distinct species-specific routes of DHEA metabolism and metabolite conversion make it impossible to extrapolate the results of animal studies to humans.297 Additionally, only primates have adrenal glands that secrete large amounts of DHEAS.298,299 DHEA declines substantially with age.300 Consequently, there is interest in DHEA replacement, especially in menopausal woman. Preliminary studies of DHEA replacement of have shown some encouraging results, especially in the area of immune system enhancement.301,301-303
DHEA is probably relatively safe at normal physiological doses. Side effects at physiological doses are breast tenderness, acne, and growth of body hair in women. Doses above 1500 mg daily can cause insulin resistance.301,304-306 In animal studies, DHEA has caused liver damage and pre-neoplastic pancreatic lesions.301,307 The long-term effects of DHEA are unknown. It should not be used by individuals with hormone-dependent cancers.
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