Chronic Hepatitis C: The Hidden Epidemic

Definition of the Problem
On August 17, 2012, the Centers for Disease Control and Prevention (CDC) released recommendations for testing all persons in the US born between 1945 and 1965 for hepatitis C infection.1 The Baby Boomer generation has been targeted because the CDC has determined that 75% of all chronic hepatitis C cases are between 47 and 67 years of age and the prevalence is five times higher in this age group than in any other.1

According to the Institute of Medicine, only 25% of those who are infected know their status and, given that there are an estimated 3.9 to 4.9 million persons living with hepatitis C virus (HCV) infection in the US, that means approximately 3 to 3.7 million American Baby Boomers currently have chronic hepatitis C and don’t know it.1,2 The majority of this group is believed to have been infected between 1980 and 1990, with an estimated 230,000 infections per year during that decade.4 By 1992, the year that sensitive assays for the identification of HCV were developed, the number of reported new cases had already declined by 78%, probably a result of a saturation of the drug-injecting population.5 The number of new cases has steadily declined each year since, and in 2010 there were only 17,000 new cases of acute infection.6,7

The take-away here is that most of the chronic hepatitis C population has been infected for at least 20 years, and the development of serious complications from the virus – cirrhosis and primary liver cancer – begin to develop at this point.8 Models based on the current statistics predict that 1 million cases of cirrhosis and 400,000 cases of hepatocellular carcinoma (currently the fastest-growing lethal cancer in the US) will occur in the next 23 years as a result of chronic hepatitis C infection unless the course of testing, diagnosis, and treatment changes.9,10

This treatment strategy is estimated to result in an additional diagnosis of 808,000 more cases and result in 416,000 more patients who qualify for treatment due to symptomatology or the presence of bridging fibrosis on liver biopsy.1 Standard treatment consists of: pegylated interferon, ribavirin, and (for genotype 1) direct-acting antivirals (DAA). Total treatment costs for this population are estimated at over $20 billion: that comes to a little under $50,000 per patient.11

The CDC admits that the current testing strategy has failed. Barriers to testing – lack of health insurance and limited access to health care – exist for the most at-risk groups: injection drug users.12 Risk-based testing (testing those with a history of injection or intranasal drug [use even if it was only once], blood transfusion or solid organ transplant prior to July 1992, hemodialysis, recipients of clotting factors before 1987, being born to an HCV-positive mother, HIV positive, elevated ALT [alanine transaminase] or other signs/symptoms of liver disease, current sexual partners of HCV-positive individuals) has not been effective. In one survey, 45% of those currently infected could not identify any known risk.8 The other admitted failure is due to health-care providers themselves; the Institute of Medicine found that knowledge about both hepatitis B and C among primary care providers “is generally poor.”13 This included understanding whom to screen for infection, how to test, and testing interpretation for hepatitis C infection.

Testing for Hepatitis C Infection
It was 2006 and the physician whom I was practicing with, a brilliant former ER doctor for years, referred a patient to me whom he had diagnosed with hepatitis C. The only lab that had been run on this man was a positive recombinant immunoassay (RIBA) HCV antibody. I had to explain to both the patient and the doctor that he only had exposure to the virus and might not, after all, have a chronic infection (which, it turns out, he didn’t). Exposure to the virus and the development of antibodies only ensures immune response to the virus; approximately 15% to 45% of those exposed are able to fight off the infection but will remain antibody positive.14 All positive anti-HCV tests (whether enzyme immunoassay [EIA] or recombinant immunoblot assay [RIBA]) need to be followed with a qualitative or quantitative test to detect presence or absence of virus (HCV RNA polymerase chain reaction [PCR]). HCV infection can be detected by HCV antibody testing 8 to 12 weeks after infection and will be detected in >97% of persons by 6 months after exposure. Testing for the presence of the virus using HCV RNA testing is the most immediate and dependable; it can be detected in serum 2 weeks after exposure.14

Even though an elevated ALT with no explanation is reason enough to test for HCV, ALT alone cannot be used to screen for HCV. Studies show that only about 30% of asymptomatic infected individuals will have an ALT over the normal lab reference range.15

Once a diagnosis of chronic hepatitis C has been made, the following counseling recom­menda­tions are important8:

1.  Assess immunity to hepatitis A and B. In hepatitis C, an acute infection of either can result in fulminant and potentially fatal hepatitis. If patients are not immune to either virus, vaccination is recommended.

2.  Eliminating alcohol consumption. Evens as little as 10 grams/day has been shown to increase risk for liver fibrosis.16 The AUDIT assessment is recommended to be used in all hepatitis C-infected patients to determine if assistance is needed in altering alcohol intake.17

3.  Obtaining HIV status. HIV positivity is a comorbidity that rapidly accelerates both conditions.

4.  For persons who are overweight (BMI ≥ 25kg/m2) or obese (BMI ≥ 30kg/m2), weight loss will improve steatosis (fatty liver) and increase the potential of responding to treatment.

5.  To minimize transmission, blood donation is not recommended and sharing of personal health objects such as toothbrushes, dental appliances, razors, nail clippers should be avoided.

Indications/contraindications and recommendations for individualized standard treatment can be found on the AASLD website and are beyond the scope of this article.8

Nutrients in HCV
There are no documented, well-designed clinical trials showing that alternative treatments result in sustained viral responses (no detectable viral load 6 months after the cessation of treatment) in those with chronic hepatitis C. The preliminary research using autohemotherapy with ozone is intriguing and will need to be repeated more carefully in larger populations before it can be seen as equivalent in effect to standard therapies. The work currently being done in the Department of Tropical Medicine and Gastroenterology at Assiut University in Egypt has so far been promising, showing normalization of ALT in 57% and elimination of virus in 25% of 40 patients who had received 30 sessions of autohemotherapy with ozone.18

Nutrient supplementation can be extremely helpful for those undergoing standard treatment and those who do not qualify for or do not wish to undergo standard treatment. Nutrient and botanical medicine is helpful as well for those who have failed or do not qualify for standard treatment; evidence shows that they both help slow fibrosis and prevent the development of hepatic encephalopathy. A comprehensive view of the literature is too broad for the scope of this article; the following is a short synopsis of nutrients important in addressing the oxidant damage inherent in this chronic viral infection and of nutrients used in conjunction with standard treatment (peginterferon, ribavirin, and the newly approved direct acting antivirals).

The body utilizes antioxidants (vitamins E, C, and A, selenium, glutathione, zinc, carotenes, coenzyme Q10, methionine, and cysteine) to prevent cellular damage and the possible progression of damaged genetic cell material to the formation of cancer cells. There is evidence that this “oxidant stress” and the free radical damage that follows is one of the main mechanisms in both hepatitis B and C that leads to the development of cirrhosis and primary liver cancer.19 Many hepatology researchers have proposed that the progression of liver cell damage to fibrosis is actually controlled by antioxidants 20

Levels of specific antioxidants – glutathione; selenium; vitamins A, C, and E – have been found to be significantly lower in the blood of those with chronic hepatitis C. Even patients in the early stages of the disease, with minimal evidence of fibrosis on liver biopsy, were found to have significantly lower levels of selenium, vitamin E, vitamin A, and glutathione.21 A direct relationship between low levels of antioxidants, higher levels of oxidant stress and more advanced fibrosis and cirrhosis was found in this group. Those with cirrhosis had significantly higher levels of oxidant stress and significantly lower levels of selenium, vitamin A, and vitamin E.

Selenium
Selenium, in animal and human research, has been shown to reduce incidence in a number of cancers and in the recurrence of cancer, particularly in those with the lowest levels of selenium.22,23

In China hepatitis is epidemic; 180 million Chinese have either chronic hepatitis B or C. Large trials in Qidong province, where chronic hepatitis is the major risk factor for primary liver cancer, have found a significant relationship between low blood selenium levels and increased risk for liver cancer.24 Smoking, low vitamin A, and low carotene levels in those with HCV infection appeared to increase risk the most. These studies also found a significant positive effect of selenium supplementation in reducing risk for primary liver cancer and the incidence of viral hepatitis.22-24

Selenium levels in HIV/HCV coinfected individuals have been shown to be even lower than in those who are only HIV infected.26 Although no clinical studies with selenium have been done in coinfection of HIV and HBV or HCV, it appears that supplementation with a yeast-based selenium may be able to decrease risk for primary liver cancer in HBV or HCV. Selenium is toxic in high doses, and safe supplementation levels are below 2 mg. per day.27 Standard selenium supplementation levels used in cancer-prevention and HIV treatment trials are 200 to 400 micrograms per day.28,29

N-Acetylcysteine (NAC)
Glutathione is a sulfur-based peptide (a protein precursor) and a crucial activator of cytotoxic T cells, which kill viruses and cancer cells.30 Depletion of glutathione causes liver and kidney failure, and ultimately death. Low glutathione levels are found in people with cataracts, HIV, HCV, and cirrhosis.31 People with cirrhosis of the liver appear to have difficulty manufacturing glutathione – levels have been shown to be 30% below normal.32 Levels of the active form of glutathione, reduced glutathione, are significantly below normal in people who have alcoholic hepatitis or HCV.33,34 Studies have shown that individuals with HCV who have the lowest glutathione levels also have higher viral loads and more evidence of liver damage.35

NAC has been shown to increase blood glutathione levels in HIV, and one study using NAC in HCV treatment with interferon led to a normalization of glutathione and liver enzymes along with a significant decrease in viral load.36,37 However, the results of studies using NAC in HCV are conflicting: three other studies with similar doses of NAC and interferon had no significant effect on viral load, liver enzymes, or glutathione levels.38-40 Daily doses necessary to raise glutathione levels in studies with HIV were between 3200 and 8000 mg.35 Unfortunately, doses that high often cause significant nausea. Studies of HIV-infected individuals who improved on a combined antioxidant protocol of NAC, glutamine, vitamin C, vitamin E, selenium, and beta-carotene indicate that antioxidants may need to be given as a group in chronic viral infections to have any effect.40 NAC should always be taken with meals or avoided in stomach ulcers because it can thin the mucous lining of the stomach and worsen ulcers.

Alpha-Lipoic Acid
Alpha-lipoic acid (ALA) is a fatty acid and antioxidant that is depleted when the liver is under stress. ALA has a history of use in Europe, where it is used to treat liver disorders because of its apparent ability to help the liver repair itself.41 Human, animal, and cell culture studies have shown that alpha-lipoic acid effectively raises cellular levels of glutathione in doses that are possible with the equivalent of an oral supplement of 600 mg. daily.42-49 ALA also helps recycle and regenerate other antioxidants, including vitamins E and C, helping to maintain optimal levels of these nutrients in the body.47 ALA has been given to humans in doses up to 1200 mg intravenously with infrequent reports of nausea and vomiting, and in oral doses up to 1000 mg daily with no reported side effects.48,49 Oral ALA doses of 500 to 1000 mg have been well tolerated in placebo-controlled studies.44

Vitamin E
Vitamin E is an antioxidant that works in the lipid compartments of the body, including the outer layers of cells (cell membranes), and is necessary for the protection of liver cell membranes. Animal studies have shown that d-alpha-tocopherol (the most commonly used form of vitamin E) inhibits the genetic mechanisms that lead to cirrhosis.50 There is also some evidence in human HCV infection that vitamin E appears to work similarly by interrupting the biochemical pathway that leads to fibrosis in the liver. Levels of 1200 IU of vitamin E were able to completely interrupt this pathway in a small study of patients with HCV.51 Vitamin E has also been shown to have a positive effect on liver enzyme levels. When used in combination with selenium, NAC, and interferon, the combination improved viral loads and response to therapy when selenium and NAC alone did not improve the response to interferon.52 The dose of vitamin E used in these studies, 800 to 1200 IU/day, is safe with the exception of patients on coumadin, or those with a vitamin K deficiency.

Improving Response to Standard Therapy
Having low levels of glutathione decreases the chance of responding to standard therapy, and improving both transmethylation and transulfuration may improve interferon signaling in the presence of HCV. S-adenosyl-L-methionine (SAMe) and betaine improve this signaling pathway in the liver in cell culture that expresses HCV proteins.53 In an open label pilot, 29 patients who had failed standard treatment with pegylated interferon and ribavirin were given 400 mg of SAMe t.i.d. and 3 g of anhydrous betaine b.i.d. one week before being retreated with standard therapy.54 The majority of these patients (79%) were genotype 1, had advanced fibrosis (cirrhosis), and had already failed this same therapy. This is the most difficult population to treat and has been shown to have the lowest glutathione levels.55 Although only 10% of these patients showed a sustained viral response (no viral load) at the end of treatment, 17 of them had shown an early viral response, a predictor of a response to therapy. This trial did show that these nutrients are safe in standard treatment, and hopefully more trials will be done in this area with a much longer lead-in time prior to starting treatment or retreatment.

Ribavirin causes hemolytic anemia, and dose reductions are often necessary when patients’ hematocrits and lymphocyte counts drop. To minimize this side effect, studies have shown that eicosapentaenoic acid (EPA), vitamin C, and vitamin E are effective when given during treatment to prevent lymphopenia and declines in hemoglobin levels. The amounts used in the trials were 1.2 g EPA, 600 to 750 mg vitamin C, and 300 to 500 IU of vitamin E.56,57 These doses could be considered conservative, and in this author’s clinical experience, 1.2 g of EPA, 1000 IU of mixed tocopherol, and 2000 mg of vitamin C t.i.d. are safe and well tolerated for hepatitis C patients on standard therapy.

Zinc is an important nutrient in the management of chronic liver disease due to its role in urea metabolism. In cirrhosis, incomplete metabolism of urea leads to increased levels of brain ammonia and is one of the causes of hepatic encephalopathy, leading to fatigue, insomnia, memory loss, and psychosis. When used in a weight-based dosing regimen (0.6 mg elemental zinc/kg body weight) it has been shown to slow fibrosis progression and platelet decline as well as significantly lowering the incidence of hepatocellular carcinoma.58 Zinc supplementation has been shown to be effective during treatment in decreasing gastrointestinal side effects. Zinc L-carnosine chelate (a common form of zinc in Japan, where the study was done) was used in a 75 mg twice daily dose (equivalent to a total 34 mg of elemental zinc) and found to prevent gas, bloating, constipation, and diarrhea seen with standard treatment.59

Vitamin D deficiency is common in chronic liver disease and is related to both fibrosis and poor response to treatment in all genotype 1 patients.60 In a group of post–liver transplant chronic hepatitis C patients, of those supplemented with 800 IU of vitamin D, those who reached the normal or near normal reference range were more than twice as likely to achieve a sustained viral response than those who were D deficient and not on supplementation.61 In one survey, higher pretreatment serum vitamin D levels were related to high responsiveness to standard treatment in patients with HCV genotype 2/3, but not in patients with HCV genotype 1.62

Finally, milk thistle (silymarin) is the most commonly used botanical by 72% of those surveyed with chronic hepatitis C in the US. Although there is no evidence that silymarin improves ALT, viral load, or quality of life measurements on doses of either 600 or 1200 mg daily, the use of silymarin has been related to a significant slowing of fibrosis progression in a large survey of users vs. nonusers.63,64 Intravenous silibinin (an active component of milk thistle used intravenously in Europe) has been shown to be useful when used along with standard treatment in those who have failed initial treatment.65

New data using direct-acting antivirals (boceprevir, telaprevir) in conjunction with peginterferon/ribavirin in genotype 1 patients show that viral clearance occurred in 66% to 75%. This is a significant improvement over previous data with genotype 1 infection, where only 30% to 40% sustained viral response is the average.66 However, the side effect profile of this combination is significantly greater that pegylated interferon/ribavirin alone: anemia, nausea, diarrhea, chills, irritability, metallic taste in mouth, vomiting, fatigue, hair loss, neutropenia, thrombopenia, pruritis, and rashes.67

Carefully designed and supported drug-approval trials, however, may not duplicate themselves in the real world. A study looking at real-world treatment showed that only 28% of those who qualified for treatment were actually treated.68 As we continue to see increasing numbers of patients requesting testing for chronic hepatitis C and increasing numbers of new diagnoses, the need for a critical application of all available interventions (botanical, nutrient, and, when appropriate, pharmaceutical) will be necessary in order to stem the tide of rapidly rising liver disease in the US.

Notes
1.   Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus among persons born during 1945-1965. MMWR. August 17, 2012/61(RR04):1–18.
2.   Colvin HM, Mitchell AE, eds. Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C. Institute of Medicine. Washington, DC: National Academies Press; 2009:237.
3.   Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705–714.
4.   Armstrong GL, Alter MJ, McQuillan GM, Margolis HS. The past incidence of hepatitis C virus infection: implications for the future burden of chronic liver disease in the United States. Hepatology. 2000;31:777–782.
5.   CDC. Viral hepatitis surveillance, United States, 2009–2011 [Web page]. http://www.cdc.gov/hepatitis/Statistics/2010Surveillance/index.htm. Accessed August 31, 2012.
6.   CDC. Hepatitis C virus transmission at an outpatient hemodialysis unit-New York, 2001–2008. MMWR. 2009;58:189–194.
7.   CDC. Viral hepatitis surveillance, United States, 2009–2011. Op cit.
8.   Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver D. Diagnosis, management, and treatment of hepatitis C: an update. [Practice Guideline.] Hepatology. 2009;49:1335–1374.
9.   Rein DB, Wittenborn JS, Weinbaum CM, Sabin M, Smith BD, Lesesne SB. Forecasting the morbidity and mortality associated with prevalent cases of pre-cirrhotic chronic hepatitis C in the United States. Dig Liver Dis. 2011;43:66–72.
10. El-Serag HB. Epidemiology of hepatocellular carcinoma in USA. Hepatol Res. 2007;37(Suppl 2):S88–S94.
11. Rein D, Smith BD, Wittenborn JS, Lesesne SB. The cost-effectiveness of birth cohort hepatitis C antibody screening in U.S. primary care settings. Ann Intern Med. 2012;156:263–270. Modified and reprinted with permission from Annals of Internal Medicine.
12. Volk ML, Tocco R, Saini S, Lok AS. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50:1750–1755.
13. Colvin et al. Op cit.
14. CDC. Hepatitis C FAQs for health professionals [Web page]. http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm Accessed August 31, 2012
15. Conry-Cantilena C, VanRaden M, Gibble J, et. al. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med. 1996; 334:1691–1696.
16. Monto A, Alonzo J, Watson JJ, et al. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol. Hepatology. 2002;36:729–736.
17. Allen JP, Wilson VB, eds. Assessing Alcohol Problems. A Guide for Clinicians and Researchers. 2nd ed. National Institutes of Health National Institute on Alcohol Abuse and Alcoholism MSC 9304. AUDIT [online document]. http://pubs.niaaa.nih.gov/publications/Audit.pdf.
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19. Waris G, Siddiqui A. Regulatory mechanisms of viral hepatitis B and C. J Biosci 2003;28:311–321.
20. Parola M, Robino G. Oxidative stress-related molecules and liver fibrosis. J Hepatol 2001;35:297–306.
21. Sanjiv KJ, Pemberton PW, Smith A, et al. Oxidative stress in chronic hepatitis C: not just a feature of late stage disease. J Hepatol 2002;36(6):805–811.
22. Clark LC, Dalkin B, Krongrad A, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol 1998;81(5):730–734.
23. Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996;276:1957–1963.
24. Yu SY, Zhu YJ, Li WG. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res 1997;56(1):117–124.
25. Yu SY, Zhu YJ, Li WG. Chemoprevention trial of primary liver cancer in high risk populations with nutritional supplementation of selenium in China. Biol Trace Elem Res 1989;20:15–22.
26. Look MP, Rockstroh GS, Rao KA. Serum selenium, plasma glutathione, and erythrocyte glutathione peroxidase levels in asymptomatic versus symptomatic human immunodeficiency virus-1 (HIV-1) infection. Eur J Clin Nutr 1997;15(5):266–272.
27. Combs GF. Impact of selenium and cancer-prevention findings on the nutrition-health paradigm. Nutr Cancer 2001;40(1):6–11.
28. Clark LC, Dalkin B, Krongrad A, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol 1998;81(5):730–734.
29. Clark LC, Combs GF Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 1996;276:1957–1963.
30. Droge W, Pottmeyer-Gerber C, Schmidt H, et al. Glutathione augments the activation of cytotoxic T lymphocytes in vivo. Immunobiology 1986;172(1–2):151–156.
31. Droge W, Breitkreutz R. Glutathione and immune function. Proc Nutr Soc 2000;59(4):595–600.
32. Burgunder JM, Lauterburg BH. Decreased production of glutathione in patients with cirrhosis. Eur J Clin Invest 1987;17:408–414.
33. Loquecio C, Blanco FD, De Girolamo V. Ethanol consumption, amino acid and glutathione blood levels in patients with and without chronic liver disease. Alcohol Clin Exp Res 1999;23(11):1780–1784.
34. Barbaro G, DiLorenzo G, Soldini M. Hepatic glutathione deficiency in chronic hepatitis C: quantitative evaluation in patients who are HIV positive and HIV negative and correlations with plasmatic and lymphocytic concentrations and with the activity of the liver disease. Am J Gastroenterol 1996;91(12):2569–2573.
35. Herzenberg L, DeRosa SC, Dubs JG, et al. Glutathione deficiency is associated with impaired survival in HIV disease. Proc Nat Acad Sci USA 1997;94(5):1967–1972.
36. Beloqui O, Prieto J, Suarez M, et al. N-acetyl cysteine enhances the response to interferon-alpha in chronic hepatitis C: a pilot study. J Interferon Res 1993;13(4):279–282.
37. Ideo G, Bellobuono A, Tempini S, et al. Antioxidant drugs combined with alpha-interferon in chronic hepatitis C not responsive to alpha-interferon alone: a randomized, multicentre study. Eur J Gastroenterol Hepatol 1999;11(11);1203–1207.
38. Bernhard MC, Junker E, Hettinger A, et al. Time course of total, cysteine, glutathione and homocysteine in plasma of patients with chronic hepatitis C treated with interferon-alpha with and without supplementation with N-acetyl cysteine. J Hepatol 1998;28(5):751–755.
39. Look MP, Gerard A, Rao GS, et al. Interferon/antioxidant combination therapy for chronic hepatitis C-a controlled pilot trial. Antiviral Res 1999;43(2):113–122.
40. Shabert J, et al. Glutamine-antioxidant supplementation increases body cell mass in AIDS patients with weight loss: a randomized, double-blind controlled trial. Nutrition 1999;15:860–864.
41. Bustamante J, Lodge JK, Marcocci L, et al. Alpha-lipoic acid in liver metabolism and disease. Free Rad Biol Med 1998;24(6):1023–1039.
42. Han D, Handelman G. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors 1997;6(3):321–338.
43. Khanna S, Atalay M, Laaksonen DE, Gul M,et al. a-Lipoic acid supplementation: tissue glutathione homeostasis at rest and after exercise. J Appl Physiol 1999;86(4):1191–1196.
44. Han D, Tritschler HJ, Packer L. Alpha-lipoic acid increases intracellular glutathione in a human T-lymphocyte Jurkat cell line. Biochem Biophys Re Commun 1995;207:258–264.
45. Busse E, Zimmer G, Schopohl B, et al. Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. Arsneimittelforschung 1992;42:829–831.
46. Moini H, Packer L, Saris NE. Antioxidant and prooxidant activities of a-lipoic acid and dihydrolipoic acid. Toxicol Appl Pharmacol. 2002;182(1):84–90.)
47. Packer L, Suzuki YJ. Vitamin E and alpha-lipoate: role in antioxidant recycling and activation of the NF-kappa B transcription factor. Mol Aspects Med 1993;14:229–239.
48. Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol. 1997;29(3):315–331.
49. Zeigler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant a-lipoic acid. A 3-week multicentre randomized controlled trial.(ALADIN Study). Diabetologia. 1995;38(12):1425–1433.
50. Chojkier M, Houglum K, Lee KS,et al. Long and short-term d-a-tocopherol supplementation inhibits liver collagen a1(I) gene expression. Am J Physiol 1998;275(6 Pt 1):G1480–1485.
51. Houglum K, Venkataramani A, Lyche 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.
52. von Herbay A, Stahl W, Niederau C, et al. Vitamin E improves the aminotransferase status of patients suffering from viral hepatitis C: a randomized, double-blind, placebo-controlled study. Free Radic Res 1997;27(6):599–605.
53. Duong FH, Christen V, Filipowicz M, Heim MH. S-adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro. Hepatology. 2006:43;796–806.
54. Filipowicz M, Bernsmeier C, et al. S-adenosyl-methionine and betaine improve early virological response in chronic hepatitis C patients with previous nonresponse. PLoS ONE. 5(11):e15492. doi:10.1371/journal.pone.0015492.
55. Genotype 1 with cirrhosis has lowest glutathione levels.
56. Murakami Y, Nagai A, Kawakami et al. Vitamin E and C supplementation prevents decrease of eicosapentaenoic acid in mononuclear cells in chronic hepatitis C patients during combination therapy of interferon and ribavirin. Nutrition. 2006;22:114–122.
57. Kawashima A, Tsukamoto I, Koyabu T, et al. Eicosapentaenoic acid supplementation for chronic hepatitis C patients during combination therapy of pegylated interferon a-2b and ribavirin. Lipids. 2008;43(4):325–328.
58. Matsuoka S, Matsumura H, Nakamura H, et al. Zinc supplementation improves the outcome of chronic hepatitis C and liver cirrhosis. J Clin Biochem Nutr. 2009;45:292–303.
59. Suzuki H, Takagi H, Sohara N, et al. Triple therapy of interferon and ribavirin with zinc supplementation for patients with chronic hepatitis C: a randomized controlled clinical trial. World J Gastroenterol. 2006;28(8):1265–1269.
60. Petta S, Camma C, Scazzone C, et al. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology. 2010;51(4):1158–1167.
61. Bitetto D, Fabris C, Fornasiere E, Pipan C, Fumolo E, Cussigh A, et al. Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C. Transpl Int. 2011;24:43–50.
62. Lange CM, Bojunga J, Ramos-Lopez E, et al. Role of Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol. 2011;54:887–893.
63. Gordon A, Hobbs DA, Bowden DS, et al. Effects of Silybum marianum on serum hepatitis C virus RNA, alanine aminotransferase levels and well-being in patients with chronic hepatitis C. J Gastroenterol Hepatol. 2006 Jan;21(1 Pt 2):275–280.
64. Freedman ND, Curto TM, Morishima C, et al. Silymarin use and liver disease progression in the Hepatitis C Antiviral Longterm Treatment against Cirrhosis trial. Aliment Pharmacol Ther. 2011;33(1):127–137.
65. Rutter C, Scherzer TM, Beinhardt S, et al. Intravenous silibinin as “rescue treatment” for on-treatment non-responders to pegylated interferon/ribavirin combination therapy. Antivir Ther. 2011;16:1327–1333.
66. Hofmann WP, Zeuzem S. A new standard of care for the treatment of chronic HCV infection Nat Rev Gastroenterol Hepatol. 2011;8:257–264.
67. Hezode C et al. Safety of telaprevir and boceprevir in combination with preginterferon alfa/ribavirin, in cirrhotic non responders. First results of the French early access program (ANRS CO20-CUPIC). International Liver Congress 2012.http://mobile.ilcapp.eu/EASL_161/poster_23756/program.aspx.
68. Falck-Ytter Y, Kale H, Mullen K, et al. Surprisingly small effect of antiviral treatment in aptients with hepatitis C Ann Intern Med. 2002;136(4):288–292.

Lyn Patrick, ND, graduated from Bastyr University in 1985 and has practiced in Arizona and Colorado for the last 27 years as a primary-care provider specializing in environmental medicine and chronic hepatitis C. Her expertise in chronic hepatitis C originated with her work in an HIV practice and matured in her collaboration with the Hepatitis C Ambassadors as part of the Hepatitis C Brainstorming Team (http://www.hepcchallenge.org/brainstorming.htm). This international team of doctors, epidemiologists, acupuncturists, NDs, and advocates has worked together to provide an integrative health model for the treatment of chronic hepatitis C and has written a free online book for patients that spans the spectrum of diagnosis and care (http://www.hepcchallenge.org/choices/index.htm). Dr. Patrick also lectures internationally on fatty liver disease and chronic hepatitis C to health-care providers and is currently coteaching a hepatitis C professional training program with Misha Cohen, OMD, through Sylvan lnstitute of Botanical Medicine (http://sylvanbotanical.com/classes/introduction-to-hepatitis-c-integrated-chinese-medicine-w-misha-cohen).

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