Relative proportions of acute viral hepatitis in the U.S. Courtesy of Science Press Internet Services and AstraZeneca.

Natural medicine has much to offer individuals with hepatitis C (HCV) infection and other chronic liver disorders. And that’s a good thing, because the burden of HCV, in terms of individual morbidity and socioeconomic cost, is growing at a disturbing rate. Antiviral pharmacotherapy, while clearly better than it was a decade ago, still leaves much room for improvement.

HCV infection is the most common cause of chronic hepatitis, cirrhosis and hepatocellular cancer in the US (Liang TJ, et al. Ann Intern Med 2000; 132:296–305). It is also the number one reason for liver transplants.

An estimated 1.8% of the US population (3.9 million Americans) carries antibodies to HCV, and the prevalence of chronic infection is estimated at 2.7 million (Alter MJ, et al. N Engl J Med 1999; 341:556–562). That’s based on screening of non-institutionalized populations. When incarcerated individuals are added, the total increases to 4 million; 30%–40% of prisoners in the US are thought to be infected with HCV (Ruiz JD, et al. West J Med 1999; 170:156–160).

The cost of managing HCV reached $5.5 billion in 1997, and is expected to triple in the next 5 years. This will be accompanied by a doubling of mortality and a 5-fold increase in liver transplants. According to David Bernstein, MD, of North Shore University Hospital, Manhasset, NY, who recently authored a study on treatment of HCV and its effect on quality of life (Hepatology 2002; 35(3):704–708), “there is no way our medical system can handle this epidemic.”

	Evolution of acute hepatitis. At least 85% of patients with acute infections will develop chronic disease, and 20%–40% of chronic cases will develop cirrhosis. The time course is highly variable. Courtesy of Science Press Internet Services and AstraZeneca.
	Hepatitis C virus (HCV) coated with radiogold-labeled antibodies to HCV. HCV is an enveloped, single-stranded RNA virus with an average diameter of 30 to 70 nm. HCV is difficult to culture in lab settings, and has seldom been photographed Courtesy of X. Li, Miami, FL, and AstraZeneca’s GastroAtlas—www.gastroatlas.com.

Progression of HCV infection to cirrhosis and hepatocellular carcinoma occurs over a 20-year period and is usually asymptomatic until late stages. As a result, many infected individuals are not aware they have it. The most consistent risk factors for progression to fibrosis and cirrhosis are age over 40, male gender and alcohol consumption (Poynard T, et al. J Hepatol 2001; 34:730). Because alcohol has been positively correlated with increased viral load (Sherman KE, et al. Hepatology 1999; 30(1):265–270) infected individuals should completely avoid alcohol regardless of how else they are being treated.

Standard Therapy Often Falls Short

Conventional drug therapy for HCV centers on injected pegylated interferon and oral ribavirin. This combination produces virus-free states in over 70% of those with genotype 2 and 3 HCV and between 40% and 50% with genotype 1 (Fried M, et al. Gastroenterology 2001; 120:A55; Manns M, et al. Lancet 2001; 358:958–965).

Hepatitis C virus (HCV) coated with radiogold-labeled antibodies to HCV. HCV is an enveloped, single-stranded RNA virus with an average diameter of 30 to 70 nm. HCV is difficult to culture in lab settings, and has seldom been photographed Courtesy of X. Li, Miami, FL, and AstraZeneca’s GastroAtlas—www.gastroatlas.com.
But the data from these drug approval trials may not apply to all chronic HCV patients because the trials had significant exclusion criteria. More than 50% of all HCV-infected people would be ineligible for these trials (Strader D. Hepatology 2002; 36:S226–S236). In excluded populations, such as children, the elderly, those with ongoing drug or alcohol abuse, renal disease, severe psychiatric or neurologic disease, autoimmune disorders, decompensated cirrhosis, organ transplant recipients, and those with co-morbidities (diabetes, etc.), the efficacy and side effects of interferon/ribavirin remain unknown. It is already clear that African-Americans do not respond as well to standard treatment as Caucasians.

The major drawback to conventional treatment is the significant side effect profile of both interferon and ribavirin. Adverse effects, including fatigue, muscle pain, nausea, lack of appetite, anemia, neutropenia, thrombocytopenia, irritability, and depression, occur in 80%–90% of patients. Between 4% and 27% of patients discontinue treatment within the first 24 weeks (Bernstein D, et al. Hepatology 2002; 35(3):704–708).

Herbal Therapies, Antioxidants Prevent Fibrosis

Histologic view of bridging necrosis and fibrosis, indicative of an advanced state of chronic hepatitis C.
A liver biopsy specimen showing well-established cirrhosis secondary to hepatitis C. Photos courtesy of Science Press Internet Services and AstraZeneca.

Progression of HCV is not simply a result of viral activity. In fact, viral load, viral strain or genotype do not significantly correlate with progression to liver damage. A patient’s immune response is instrumental in determining both resolution of the acute infection and the degree of inflammation and fibrosis. Activation of the immune response, specifically Th2 cytokines, generates free radicals that can then cause hepatic damage, fibrosis and eventually cirrhosis (Ning Q, et al. Hepatology 1996; 24:355A).

While standard drug treatment can eradicate the virus, it may not adequately prevent fibrosis. This is important because inhibition of fibrosis and prevention of cirrhosis could markedly reduce the complications of HCV and the mortality related to liver failure and hepatocellular carcinoma. Certain plant medicines and antioxidants have potential to prevent hepatic fibrosis, cirrhosis and hepatocellular carcinoma (Gebhardt R. Planta Med 2002; 68:289–296).

HCV patients are certainly seeking out botanical therapies. A survey of patients in 6 US liver clinics showed that 33%–75% used “complementary and alternative medicine” (CAM) therapies, and 12%–50% of CAM users included herbal therapies. Nearly all herb users specifically used milk thistle (Silybum marianum) (Seef LB, et al. Hepatology 2002; 34(4):595–603).

Antioxidants like resveratrol and quercetin have been found to exert antifibrotic effects. Silymarin and silibinin (an isomer of silymarin), among the active components of S. marianum, are also potent antifibrotics (Gebhardt R. Planta Med 2002; 68:289–296).

Because hepatitis B and C have been major public health problems in Asia, and herbal medicine is widely practiced, plant-based therapies for HCV have been well studied in Asia. Roughly 3.8% of China’s population (48 million people) is infected with HCV. The incidence in Japan is between 1.3% and 3.2%, and Japan has the highest rate of hepatocellular carcinoma in the industrialized world. Traditional Chinese Medicine (TCM) and herbal traditions in Korea and Japan include many botanicals with significant antifibrotic activity.

Milk Thistle and Silymarin

Silymarin, an aggregate of bioactive flavonolignans in S. marianum (milk thistle), is the most commonly used botanical by liver disease patients in the US (Seef L, op. cit.). It appears to be hepatoprotective through multiple mechanisms: antioxidant activity, antifibrotic effects, toxin blockade at the membrane level, immunomodulation, anti-inflammatory effects and enhanced hepatic protein synthesis (Agency for Healthcare Research and Quality 2000. U.S. DHHS Rockville, Md. Publication 01-E024).

There are 3 well-designed studies of silymarin in chronic viral hepatitis. In the first, a 12-month treatment with 420 mg per day of silymarin produced a trend towards liver biopsy improvement, but not enough to reach significance (Kiesewetter E, et al. Leber Magen Darm 1977; 7:318–323). The other two studies involved HCV patients. In the first, patients were given a patented complex of silybinin and phosphatidlycholine called Silipide. Compared with placebo, Silipide significantly lowered AST, ALT, and GGTP within 7 days (Buzzelli G, et al. Int J Clin Pharm Ther Toxicol 1993; 31:456–460). In a longer study, Silipide produced significant decreases in both AST and ALT after 2 months (Moscarella S, et al. Curr Ther Res 1993; 53:98–102). The dosage in both studies was 240 mg, twice daily, taken on an empty stomach.

Although silymarin or Silipide do not appear to adversely affect conventional drug therapy for HCV (ribavirin and interferon), silymarin can slow the metabolism of certain drugs via the CYP3A4 hepatic enzyme system and may increase blood levels of SSRIs, certain antifungals, and statins (Venkataramanan R, et al. Drug Metabol Disp 2000; 28(11):1270–1273).

Licorice Extract

In Japan, a licorice root (Glycyrrhiza glabra) extract called glycyrrhizin or “Stronger Neo Minophagen C” (SNMC) has been used to treat chronic hepatitis for over 20 years. Currently in Japan, 100 million ampules of SNMC are sold each year, and they are indicated specifically for people who do not respond to interferon. SNMC is given intravenously by health care providers or in home health care settings. Glycyrrhizin appears to work not as an antiviral, but as a hepatoprotective substance with documented antioxidant activity and the ability to impede liver fibrosis (Seef, op. cit.).

A long-term study of chronic HCV patients showed that glycyrrhizin significantly lowered serum ALT levels in 36% of cases and decreased the risk of progression to cirrhosis or liver cancer (Arase Y, et al. Cancer 1997; 79:1494–1500). Those treated with 200 mg glycyrrhizin, 2–7 times weekly for an average of 10 years, had half the risk of cirrhosis or liver cancer as those who received only vitamin K.

Glycyrrhizin extract (or licorice root in the whole form) given orally or intravenously can cause hypertension, hypokalemia, or edema because glycyrrhizin can alter aldosterone production, especially at doses over 400 mg per day (Kumagi A, et al. Pharmacol Ther 1979; 7:2933). As a result, glycyrrhizin is contraindicated in hypertension and renal failure. SNMC contains 2 g of glycine for every 200 mg of glycyrrhiza to minimize these side effects. Twelve of 84 patients in the Arase study developed low serum potassium or hypertension, but all were normalized with spironolactone. None had to discontinue glycyrrhizin.

A German trial looked at the effect of SNMC in patients with chronic HCV, the majority of whom had not responded to conventional treatment (Tekla GJ. Is J Gastroenterology 2001; 96:2432–2437). After 4 weeks, a significantly greater number of patients on SNMC had normal serum ALT. The frequency, not the total dose of glycyrrhizin, determined the effect. The authors suggest daily administration for the first two weeks, followed by thrice weekly dosing. Although intravenous SNMC is not yet FDA approved in the US, compounding pharmacies such as Dallas-based ApotheCure (800-969-6601; www.apothecure.com) can provide an intravenous form of glycyrrhizic acid, the key ingredient in SNMC.

There are no studies of oral glycyrrhizin in chronic HCV, but it has been used in hepatitis B (Xianshi S, et al. J Tradit Chin Med 1984; 4:127–132). A small controlled study of patients given 750 mg glycyrrhizin orally twice daily for 1 month showed a 25% full recovery rate. No recovery was seen in the placebo group. It remains to be seen whether herbs effective in HBV will prove effective in HCV; the viruses differ greatly in how they influence immune response.

Chinese Medicine as Interferon Adjunct

Misha R. Cohen, OMD, L.Ac., has been treating chronic hepatitis since 1976. In 1989, when HCV was recognized as a distinct virus, she started a program for people with HCV at the Quan Yin Healing Arts Center in San Francisco. In the last few years, she’s seen a vast increase in HCV infected individuals.

“Currently, the majority of new patients here are people with HCV. Until the last year, almost all came for alternatives to interferon. Recently, since the advent of more efficacious interferon therapy, I have been seeing many new clients who want Chinese medicine as an adjunct or complement to interferon.”

Ideally, Ms. Cohen has patients begin adjunctive treatment at least 12 weeks prior to starting interferon. “We are able to prepare people physically, emotionally and spiritually through diet, acupuncture, herbal medicine and Qi Gong. The goal is to help the liver achieve the healthiest state possible prior to beginning interferon, as well as help people to lose weight (if appropriate) and stop drinking (if necessary). After interferon and ribavirin is begun, we treat the side effects.”

Anecdotally, it appears that people using TCM and Western treatment together have better outcomes, possibly due to better toleration of medication and enhancement of drug efficacy. Ms. Cohen is currently developing a research project with two experienced hepatologists who specialize in HCV. “I have had an ongoing mutual referral relationship for ten years with one of them.”

“For the approximately 70 percent of people for whom interferon therapy is not recommended or who are unwilling to try it, we have had good success in reducing fatigue, improving appetite, eliminating costal pain, and helping digestive problems. On an anecdotal level, I can report that many of my clients also have improvement in both liver enzymes and liver function.”

Asian Botanical Combination Formulas

A recent Cochrane Collaboration metanalysis evaluated effects of different Chinese herbal combination formulas on either HCV titers or biochemical parameters (ALT, AST) (Cochrane Database of Systematic Reviews. Medicinal herbs for hepatitis C. November 2002). Of the 10 randomized trials selected, 4 herbal combinations had a significant effect on ALT, clearance of anti-HCV antibody or HCV RNA. Bing Gan plus interferon, Bing Gan Tang plus interferon-alpha, Yi Zhu, and Yi Er Gan Tang all had significant effects on either viral replication or liver inflammation. Each of these formulas is unique, but they share several botanical ingredients including Glycyrrhiza (licorice) root, Salvia root, Curcuma (turmeric), Schisandra, Ligustrum, and Atractylodis.

Gomisin A (Schisantherin A), an active compound in Schisandra chinensis berries, may be a key antiviral compound. In a study of 37 patients with HCV, an herbal formula containing Schisandra, significantly reduced viral load in 21% of those treated (Cyong JC, et al. Am J Chin Med 2000; 28:351–360). Gomisin A was found to have significant antiviral properties. Schisandra has also been used in China to treat hepatitis B. According to Qingcai Zhang, MD, L.Ac., a physician who also practices TCM in New York City, studies involving 4,558 patients showed Schisandra can normalize ALT levels in 75% of cases within 2–3 months.

Oleanolic acid, a bioactive component in Ligustrum fructus, another TCM botanical, can normalize ALT in 70% of chronic liver disease patients treated within a 50 day trial period, added Dr. Zhang.

Sho-saiko-to or TJ-9, a popular herbal formula in Japan, can lower the incidence of hepatocellular carcinoma in chronic hepatitis B. The formula had significant antifibrotic effects in animal studies (Shimizu I, et al. Hepatology 1999; 29:149–160). Scutellaria baicalensis georgi (skullcap) root, a major component of the formula, has strong antioxidant and antifibrotic effects. Two active ingredients in Scutellaria, baicalin and baicalein, are flavonoids with structure and activity similar to silybinin and quercetin (Geerts A, et al. Hepatology 1999; 29:282–283).

Though effective against HBV, Sho-saiko-to is contraindicated in HCV. Minor Bupleurum, a constituent of Sho-saiko-to, is thought to be responsible for 16 fatal cases of interstitial pneumonitis in chronic HCV patients in Japan. This herb, along with Pinella and a component of licorice root (liquirtin) cause interstitial pneumonitis when given with interferon. The Japanese government now issues warning labels on Sho-saiko-to indicating it should never be taken with interferon.

Nutritional Therapies for Hepatitis

Chronic HCV patients have lower blood levels of glutathione, selenium, and vitamins A, C, and E compared to healthy HCV-negative controls (Sanjiv KJ, et al. J Hepatol 2002; 36:805–811). They also have elevated oxidative stress markers that positively correlate with low blood levels of antioxidants. These indicators of oxidative damage correlate with increased measures of liver fibrosis. Most importantly, the correlation was evident even in asymptomatic patients with minimal fibrosis.

The Sanjiv study suggests that nutritional deficiencies exist even in early stages of disease, and that oxidative stress may be related to the progression of fibrosis. Though it does not prove that antioxidant supplementation will prevent cirrhosis, other evidence clearly shows that oxidant stress is one of the main precursors of fibrosis and cirrhosis (Patrick L. Altern Med Rev 1999; 4: 220–238).

Low selenium levels have been found in all stages of chronic HCV infection; patients with cirrhosis had levels 60% of normal. In studies of chronic hepatitis B and C, those with HCV have significantly lower selenium levels. Those co-infected with HIV and HCV have even lower levels (Look MP, et al. Eur J Cl Nutr 1997; 51:266–272). This proves to be a sensitive predictor of HIV mortality.

Selenium may influence progression to liver cancer. In a population study of 7,432 males with HBV or HCV, those with the highest blood selenium levels were 38% less likely to develop primary liver cancer (Yu MW, et al. Am J Epidemiol 1999; 150:367–374). In China, 130,471 people in an area with very high rates of HBV and hepatocellular carcinoma were given salt supplemented with selenium. Eight years later, there was a 33% drop in incidence of hepatocellular carcinoma. Rates in other areas with similar baseline incidence showed no change (Yu SY, et al. Biol Trace Elem Res 1997; 56:117–124). A subset of this population with chronic HBV showed an inverse correlation between liver cancer and selenium. The cancer rates dropped significantly when half of the population was supplemented with 200 mg of selenium for 4 years. Hepatic cancer incidence rose again 4 years after the subjects were taken off the supplement (Yu SY, et al. op. cit.).

Glutathione, manufactured in the liver, is the principal biological antioxidant in mammals. Low glutathione levels seen in HCV are thought to result from the oxidant stress of the chronic viral infection; glutathione is used up faster than the body can replace it. Glutathione however, can’t be replaced by oral supplementation; it is unable to pass by lymphocytes intact and must be manufactured intracellularly.

The amino acid cysteine is usually the rate-limiting component of glutathione production. A pilot study of n-acetyl cysteine (NAC), at a dose of 600 mg thrice daily during interferon treatment, resulted in normalized glutathione and ALT levels in 41% of HCV-infected patients. It also significantly lowered viral load (Beloqui O, et al. J Interferon Res 1993; 13:279–282). However, these findings were not corroborated by subsequent studies (Ideo G, et al. Eur J Gastroenterol Hepatol 1999; 11: 1203–1207; Look MP, et al. Antiviral Res 1999; 43:113–122).

Vitamin E levels appear to be lower in chronic HCV patients, particularly in those with ALT elevations over 100. Vitamin E has been added to antioxidant protocols (NAC and selenium) in conjunction with interferon therapy. Although the addition of vitamin E (544 IU daily) did not prevent relapses in those who eventually failed interferon, there was an improvement in initial response and greater drops in viral load not achieved by NAC and selenium alone (Look MP, et al. op. cit.).

Vitamin E at doses of 800 IU daily lowered ALT and AST levels in half of a small group of HCV patients (Von Herbay A, et al. Free Radic Res 1997; 27:599–605). It appears to act directly as an antifibrotic; doses of 1,200 IU daily in HCV-infected individuals completely interrupted the fibrotic pathway (Houglum K, et al. Gastroenterology 1977; 113:1069–1073). Vitamin E is safe in doses up to 2,000 IU but this is contraindicated in those on coumadin, and in vitamin K deficiency, a potential complication of cirrhosis.

Alpha-lipoic acid (ALA), an antioxidant that is both hydrophilic and lipophilic, has been suggested as part of a comprehensive program for chronic HCV (Burkson B. Clin Prac Alt Med 2000; 1:27–33). Along with vitamin E, vitamin C, coenzyme Q10, and selenium, ALA is responsible for the recycling and availability of reduced glutathione. ALA is more effective than NAC at raising glutathione levels, and it does so at a lower molecular concentration and a lower dose. Studies in HIV+ individuals have shown that 450 mg of ALA daily was able to raise glutathione levels significantly in 14 days (Fuchs J, et al. Arzneimittelforschung 1993; 43:1359).

Cholestasis is a common functional problem in HCV, particularly in those with cirrhosis. S-adenosyl-L-methionine (SAMe), a protein synthesized in hepatic tissue, helps maintain cell membrane integrity and improves bile flow (Frezza M, et al. Gastroenterol 1990; 99:211–215). SAMe has been used in Europe to treat symptoms of HBV and HCV-associated cholestasis: pruritus, jaundice, and fatigue. Doses of 800 mg IV or 800–1,600 mg orally, eliminated symptoms and normalized bilirubin in 16 days (Podymova SD, et al. Klin Med 1998; 76:45–48).

NCCAM Studies Underway

US research on CAM approaches to chronic HCV has been limited so far. But there are currently three studies underway, funded by the National Center for Complementary and Alternative Medicine (NCCAM), to assess the effects of Silipide (Siliphos), silymarin, or Traditional Chinese Medicine in HCV patients unable or unwilling to undergo conventional drug treatment.

Although large randomized trials are yet to be conducted, the role of CAM in conventional allopathic treatment of chronic HCV, now believed to be the leading cause of cirrhosis and liver cancer, will be determined as much by necessity as by popularity.