Chapter 171 Hepatitis
General Considerations
Hepatitis B is caused by a virus of the Hepadnaviridae family and is transmitted via the parenteral route through blood or blood products, through sexual contact, or from mother–child transmission during pregnancy and childbirth. Prior to its identification in 1963, it was known as serum hepatitis. Approximately 350 to 400 million people worldwide, including 1.25 million people in the United States, are chronically infected with the hepatitis B virus (HBV), defined through blood work as a positive hepatitis B surface antigen (HBsAg) and a positive hepatitis B core antibody (HBcAb). Chronic HBV infection is the most common cause of cirrhosis and liver cancer worldwide.1
Hepatitis C is caused by a virus of the Flaviviridae family and is transmitted via the percutaneous route through blood-to-blood contact. Intravenous drug users, anyone who received a blood or a blood-product transfusion prior to 1992, individuals born to a mother infected with the hepatitis C virus (HCV), and those who may be at increased risk for exposure to infected blood, such as health care or public safety workers, are at increased risk of infection. Unlike the case with HBV, sexual contact is an inefficient means of HCV transmission. Prior to its identification in 1989, it was known as non-A non-B hepatitis. An estimated 130 million people worldwide, 5 million of whom are in the United States, have been exposed to HCV, and approximately 350,000 to 500,000 people per year die of HCV-related liver disease.2,3
Symptoms and Signs
Acute viral hepatitis may be totally asymptomatic, or may be an extremely debilitating disease manifesting with jaundice, flulike symptoms, decreased appetite, abdominal pain, nausea, diarrhea, vomiting, and fatigue. Typically, the more severely ill and jaundiced a person is during the acute phase of hepatitis, the better his or her chances of not progressing into chronic hepatitis. The probability of developing chronic disease is approximately 1% to 5% in HBV- infected adults and approximately 90% to 95% in HBV-infected infants. Hepatitis A never leads to chronic disease. Hepatitis C progresses to chronicity in 55% to 85% of infected individuals, with females and children being less likely to progress to chronic diseases than male adults.4,5 The symptoms of chronic hepatitis vary from virtually nonexistent to relentless fatigue as well as signs and symptoms of decompensated cirrhosis, such as ascites, variceal bleeding, and hepatic encephalopathy.
Diagnostic Considerations
Prevention
It is considered safe to administer the hepatitis B vaccine to pregnant women if needed. Infants born to HBsAg-positive mothers should receive both the hepatitis B vaccination and the hepatitis B immune globulin (HBIG) within 12 hours of birth. See Box 171-1 for a list of those at increased risk for hepatitis B and who therefore should receive the hepatitis B vaccination.
BOX 171-1 Groups Recommended to Receive the Hepatitis B Vaccination
• All newborns with HBsAg-positive mothers
• At-risk children age 11 or 12 who did not receive the vaccine at birth
• People of any age who have more than one sex partner within a 6-month period
• People with a sexually transmitted disease
• Immigrants from geographic areas in which HBV is endemic—Asia, sub-Saharan Africa, Middle East, Amazon basin
• Children born in the United States to a person from an HBV-endemic area
• Adopted children from HBV-endemic areas
• Intravenous drug users and their sex partners
• People with blood-clotting-factor disorders
• Those who have intimate or household contact with a person who is an HBV carrier (HBsAg-positive).
• People who work in health care
• Public safety workers who may come into contact with blood
• People receiving hemodialysis
• People who live or work in an institution for the developmentally disabled
Therapeutic Considerations
Conventional Therapies
The goals of treatment of chronic hepatitis are to achieve sustained viral suppression or total elimination of the virus from the body; to slow or prevent progression to cirrhosis, hepatic decompensation, and HCC; and to prevent transmission to others. Chronic hepatitis B is not curable. Conventional treatment options for hepatitis B include either nucleoside/nucleotide analogues (NAs) or pegylated interferon. Interferons (IFNs) are a family of proteins made naturally by the body that have antiviral, antiproliferative, and immunomodulatory properties. IFN and pegylated IFN have been shown to be effective in reducing HBV replication and inducing disease remission. However, the efficacy of IFN is limited to a narrow population of HBV patients. In addition, its numerous side effects, difficult subcutaneous route of administration, cost, and associated high relapse rate after medication is discontinued have hampered its use for patients with chronic HBV. There are currently five FDA-approved NAs for the treatment of chronic HBV. NAs are quite effective for suppressing HBV replication, induction of disease remission, and the improvement of long-term outcomes. However, the length of time during which patients are treated is not predefined; and is determined by specific parameters that may differ from one patient to another, and treatment may be indefinite for some. Furthermore, long-term use of NAs can be complicated by the selection of antiviral-resistant mutations.
In contrast to hepatitis B, hepatitis C is a curable disease in many patients. This is referred to as a sustained virologic response rate (SVR) and ranges between approximately 20% to 90% (i.e., it is a measure of virus suppression). Length and success of HCV treatment are dependent upon a variety of factors (see Box 171-2). Pegylated interferon (PI) administered subcutaneously once a week, along with oral ribavirin (RBV) pills daily for 24 to 48 weeks, is the current standard of care (SOC) treatment for patients with chronic hepatitis C genotypes 2 and 3, and was the SOC for patients with genotype 1 (G1), the most common and most difficult to cure genotype worldwide. In May 2011, a major advance in the field of hepatology occurred. With the addition of a protease inhibitor, either telaprevir (Incivek, manufactured by Vertex) or boceprevir, (Victrelis, manufactured by Merck), to SOC treatment, SVRs jumped from approximately 42% to as high as 86% for many G1 patients. And, between 44% and 60% of treatment naïve G1 patients are now capable of being cured in just 24 to 28 weeks as opposed to 48 weeks. However, numerous adverse events (AEs), complex treatment regimens, exorbitant costs, and the potential for the development of drug-resistance, may decrease their therapeutic usefulness. This underscores the need for clinicians to be aware of the effects of natural and integrative therapies on the progression of HCV, and of the potential benefits of these therapies either with or without SOC treatment for chronic hepatitis C.
Lifestyle Recommendations
Sleep
Experimental studies have demonstrated that sleep deprivation results in poorer immune function, such as reduced natural killer cell activity, suppressed interleukin-2 production, and increased levels of circulating proinflammatory cytokines.6,7 A recent study showed that survival was inversely associated with sleep disturbance among 156 patients with cirrhosis. The study’s authors suggested that tailored behavioral interventions might help to improve overall health-related quality of life and could potentially improve patient outcomes.8 Sleep problems have been reported in patients with chronic hepatitis C, with about 60% to 65% of individuals reporting such complaints. Subjects administered IFN-α demonstrated increased waking after sleep onset, decreased sleep efficiency, and reduced stage 3 and/or 4 sleep.9 Evidence also suggests that impairments in sleep quality exist independent of antiviral therapy with IFN-α and prior to the advanced stages of liver disease.10 Sleep deprivation has also been found to attenuate antibody response to hepatitis A immunization.11 In terms of sleep duration, individuals with less than 7 hours of regular sleep are approximately three times more likely to develop a cold when exposed to nasally introduced rhinovirus than those with 8 hours or more of sleep.12 It may therefore be prudent to encourage proper sleep habits and a duration of 8 hours or more in order to optimize immune and antiviral benefits in the hepatitis patient as well.
Exercise
The benefits of exercise for people with liver disease are numerous. Studies of patients with hepatitis C incorporating exercise as part of their therapy with SOC show that they can safely participate in an exercise program, create clear changes in the way they perceive their bodies and its capacities, as well as improve their self-confidence, all of which can lead to far-reaching changes in the way this disease and the constraints of treatment are perceived.13 Because fatigue is probably the most common as well as one of the most bothersome symptoms affecting people with chronic hepatitis, exercise can provide a boost of energy and also improve cardiovascular function. Exercise leads to a reduction in total body fat, which is important to all people with liver disease. When total body fat is reduced, the fat content of the liver is also reduced, often resulting in a significant reduction in elevated liver enzymes.13 Thus, it is recommended that all patients with chronic hepatitis incorporate an exercise program combining weight training and aerobics into their daily routine as tolerated once they have been medically cleared by their physicians.
Diet
Nutritional treatment decisions for those with acute viral hepatitis should be symptom directed. In general, the focus should be on replacing fluids through consumption of vegetable broths, diluted vegetable juices (diluted with 50% water), and herbal teas in order to avoid dehydration, especially if diarrhea is present. Alcohol should be completely avoided because it can trigger a relapse of acute hepatitis.
Fruit and Hepatitis C
Blueberries have been found to inhibit the replication of HCV,14 and rats fed diets high in blueberries were protected from developing acute hepatitis.15 This effect may be due to the antioxidant properties of the flavonoid proanthocyanidin that is a component of blueberry leaves.
Naringenin, a flavanoid contained in grapefruit and other citrus fruits, has been found to have antiinflammatory, antioxidant, and lipid-lowering properties and may act as a promoter of carbohydrate metabolism. Naringenin has been found to lower very low density lipoprotein cholesterol. It is suspected that the hepatitis C virus may “hitch a ride” on cholesterol—a theory that has held up in test tube experiments. Studies have demonstrated that naringenin can inhibit or reduce steatosis, (the deposition of fat in the liver),16 in addition to inhibiting HCV viral replication.17 It is important to remember that grapefruit contains furanocoumarins and flavonoids, which can inhibit components of the cytochrome P450 drug metabolism pathway leading to toxic levels of many medications.18,19
Caffeine and Hepatitis C
The mechanism by which caffeine exerts its hepatoprotective effect is under investigation. Data from two population-based studies found that people consuming more than 2 cups of coffee a day were less likely to have elevated serum liver enzymes and were less likely to have chronic liver disease when compared with those who did not drink coffee.20,21 The protective effect of coffee drinking on the development of cirrhosis and its complications, including HCC, has also been shown.22–25
Higher coffee consumption was associated with less hepatic steatosis, a lower ratio of serum aspartate (AST)/alanine aminotransferase (ALT), and lower α-fetoprotein levels in patients with hepatitis C. Patients who drank more than 2 to 3 cups of coffee a day had a lower incidence of disease progression and less fibrosis on histologic evaluation compared with HCV patients who drank less coffee.22,26 Similar results were not seen in patients who got caffeine from other sources or who consumed decaffeinated coffee. Caffeine may also reduce the fatigue associated with HCV and/or chronic liver disease. Although the exact coffee intake necessary to obtain benefits is unclear, it appears reasonable for patients with hepatitis C to drink 2 to 4 cups of regular coffee daily.
Whey Protein
A product of the milk curding process, whey may boost immune function, protect against free-radical damage, and improve cellular glutathione levels. A preliminary trial found that 24 g of whey protein daily reduced serum ALT levels and increased plasma glutathione levels in people with hepatitis B but not those with hepatitis C.27
Nutrient Therapeutics
Vitamins C and E
Patients with hepatitis C treated with pegylated interferon and ribavirin were found to have higher SVRs and to be less likely to experience ribavirin-associated anemia when they supplemented this antiviral treatment with vitamins C and E.28,29 It should be kept in mind that vitamin C increases iron absorption and many patients with hepatitis C already have elevated iron stores.
Vitamin E levels have been shown to be low in both serum30 and liver tissue31 in people with hepatitis as well as in those who later develop liver cancer from chronic hepatitis. In one preliminary trial of adults with hepatitis C, administering 1200 IU/day of vitamin E for 8 weeks appeared to reduce liver damage.32 In another study, 544 IU of vitamin E/day for 24 weeks improved the response to interferon/antioxidant therapy, although the results did not reach statistical significance.33
Zinc and Hepatitis C
Zinc is essential to the normal functioning of the immune system and may protect the liver from chemical damage. Some researchers believe that zinc may protect the body from viruses, including the common cold. Blood zinc levels have been shown to inversely correlate with progression of chronic hepatitis C, and zinc deficiency is often present in patients with hepatitis C who also have HCC and/or cirrhosis. Oral zinc supplementation (150 mg/day) may slow HCV progression and reduce the incidence of HCC in these patients.35,36 In addition, zinc supplementation may improve the response to interferon treatment in patients with chronic hepatitis C.37,38 One study using 17 mg of zinc twice daily (in the form of a zinc complex of L-carnosine) enhanced the response to interferon therapy in patients with chronic hepatitis C.39 However, it is not clear whether this benefit was due primarily to the zinc or the carnosine. Although daily doses up to 100 mg of zinc may boost the immune system and improve the response to interferon, an excess of this amount may be immunosuppressive. It should also be kept in mind that excessive zinc consumption may lead to nausea, vomiting, and diarrhea, all possible side effects of HCV antiviral SOC therapy.
Vitamin D and Hepatitis C
Patients with chronic hepatitis C often have lower serum levels of 25 hydroxy (OH) vitamin D than individuals without hepatitis C and approximately one third of these patients are severely vitamin D–deficient.40 Decreased 25 (OH) vitamin D serum levels have been independently correlated with both the severity of inflammation and fibrosis on histologic evaluation, as well as with a reduced incidence of sustained virologic responses (SVRs) to therapy with SOC pegylated interferon (PI) plus ribavirin (RBV).41 Additional preliminary findings have suggested that supplementation with vitamin D (1000-4000 IU/day) with the goal of achieving a serum level greater than 32 ng/mL may improve SVRs in some HCV patients treated with SOC antiviral therapy. These results suggest that the immunomodulatory properties of vitamin D may act in synergy with this antiviral therapy. Further evaluation revealed that tissue expression of cytochrome P450 25-hydroxylating liver enzymes CYP27A1 paralleled with vitamin D levels and inversely correlated with hepatic necroinflammatory activity. Although further study is expected, because population-based studies have concluded that up to 75% of Americans are deficient in vitamin D,42 it seems reasonable for all patients with hepatitis C to add vitamin D to their antiviral regimens.
Selenium
Selenium is a trace element required for the activity of the enzyme glutathione peroxidase, an oxidant mediator essential to human health. Its deficiency is associated with various pathologies, including immune dysfunction, cancer, and liver necrosis. Whole blood and plasma selenium levels in 59 patients with chronic liver pathologies including alcoholic and viral liver cirrhosis were found to be significantly lower than in healthy controls.43 Another study of hepatocellular carcinoma cell lines reveals that liver cancer cells are able to acquire a selective survival advantage that is prominent under conditions of selenium deficiency and oxidative stress.44 Oxidative stress is a well-known feature in late-stage cirrhotic liver disease, and subsequent study has found it to occur much earlier than had previously been thought.45 Yu and colleagues found that selenium deficiency correlated with the development of HCC in patients with chronic hepatitis B46 and that patients supplemented with 200 mcg of selenium daily were less likely to develop HCC as compared with nonsupplemented individuals.47 Given this information and the safety of selenium when used in doses below 1000 mcg, it is reasonable to employ selenium in a hepatitis protocol.
S-Adenosyl Methionine (SAMe) and Hepatitis C
SAMe functions as a methyl group donor. In a mouse model SAMe has been shown to enhance interferon’s antiviral properties.99 In a small pilot study performed on G1 HCV nonresponders to pegylated interferon plus ribavirin, it was demonstrated that those patients who were retreated with the same regimen but supplemented with 400 mg SAMe tablets per day, displayed both improved early viral kinetics and interferon signaling. This led to enhanced interferon responsiveness and resulted in a higher percentage of patients achieving SVR.100
Liver Extracts
The oral administration of liver extracts has been used in the treatment of many chronic liver diseases since 1896. Numerous investigations into the therapeutic efficacy of liver extracts have demonstrated that these extracts promote hepatic regeneration and are quite effective in the treatment of chronic liver disease, including chronic active hepatitis.48–50 For example, in one double-blind study, 556 patients with chronic hepatitis were given either 70 mg of a liver extract or a placebo three times daily.50 At the end of 3 months, the group receiving the liver extract had far lower liver enzyme (aminotransaminase) levels, suggesting that liver extract may have an antiinflammatory effect on the liver. This study must be interpreted with caution, because the cause of chronic hepatitis was not clearly stated.
Thymus Extracts
The effectiveness of orally administered bovine thymus in viral hepatitis is reflective of broad-spectrum immune system enhancement presumably mediated by improved thymus gland activity. Several double-blind studies in both acute and chronic hepatitis B have shown that thymus extracts may be effective. In these studies, a therapeutic effect was noted by accelerated decreases of liver enzymes (transaminases), elimination of the virus, and a higher rate of seroconversion to anti-HBe.51,52 (see Chapter 56 for additional information on the thymus gland).
Botanical Medicines
Although long-term clinical trials have yet to confirm the efficacy of plant medicines,53 several have been investigated for their effects in viral hepatitis. The two with the most positive results are licorice (Glycyrrhiza glabra) and silymarin (the flavonoid complex from milk thistle, Silybum marianum).
Glycyrrhiza Glabra (Licorice Root)
Glycyrrhizin is the component of licorice root most responsible for its benefits. Glycyrrhizin has been shown to reduce serum alanine transaminase and aspartate transaminase values. Glycyrrhizin inhibits immune-mediated cytotoxicity against hepatocytes and also antagonizes nuclear factor (NF)-κ B, a transcription factor that activates genes encoding inflammatory cytokines.39
Licorice has been shown to stimulate the production of the body’s natural supply of interferon. This may account for its popularity in Japan, where it is sometimes used in the treatment of chronic viral hepatitis.54–59 When used intravenously, licorice has been demonstrated to lower liver enzymes,60 and studies have suggested a possible beneficial effect in treating hepatitis C and in decreasing the risk of HCV-associated HCC.61,62 A product called Stronger Neominophagen C (SNMC) consists of 200 mg of glycyrrhizin, 100 mg of cysteine, and 2000 mg of glycine in 100 mL of physiologic saline. When it is administered intravenously, liver enzymes were decreased in approximately 40% of patients54–58; however, the HCV load was not reduced. Furthermore, the beneficial effect of SNMC on the reduction of liver enzymes was short-lived: after discontinuation of this supplement, ALT elevations returned. A similar outcome was found by others.60
In a study of 453 Japanese patients diagnosed with chronic hepatitis C, 84 were treated with SNMC at a dosage of 100 mL/day for 8 weeks, followed by treatments two to seven times weekly for periods up to 16 years. The rates of cumulative HCC and cirrhosis in year 10 were 7% and 12%, respectively; in year 15, they were 12% and 21%, respectively. And in a cohort of HCV patients who were unresponsive to interferon therapy, intravenous glycyrrhizin decreased the risk of progression to HCC.63 Unfortunately the beneficial results of glycyrrhizin in hepatitis are not consistent. When lower doses of oral glycyrrhizin were used, significant reductions in ALT levels were not observed. Many have concluded that although licorice may reduce ALT elevations, long-term beneficial effects on HCV-associated fibrosis have not been shown.64
Silybum Marianum (Milk Thistle)
The origins of the effects of milk thistle on the liver can be traced back to ancient Roman times when Pliny the Elder (AD 23-79) referred to the milky juice of this plant as being excellent for “carrying off bile.” John Gerard, a sixteenth-century British herbalist, recommended milk thistle for “expelling melancholy,” a symptom attributed to liver disease during that era. In Germany, during the nineteenth century, doctors commonly treated jaundice and other liver diseases with an extract from milk thistle seeds. In 1949, German researchers found that milk thistle appeared to protect the livers of animals exposed to high doses of carbon tetrachloride, a potent hepatotoxin.
Silymarin inhibits hepatic damage by doing the following:
• Acting as a direct antioxidant and free radical scavenger
• Increasing the intracellular content of glutathione and superoxide dismutase
Silymarin has been used to treat both acute and chronic hepatitis of varying etiologies. In a study conducted in patients with acute viral hepatitis, 29 patients treated with silymarin showed greater improvements in serum levels of bilirubin and liver enzymes compared with the placebo group.65
Other investigators specifically evaluating the antiviral effect of silymarin on patients with hepatitis C concluded that improvements in some symptoms occurred when silymarin was administered orally but that it failed to exert an antiviral effect or result in significant reductions in ALT or improvements in ultrasound abnormalities related to hepatitis C.66,67
A newer form of silymarin that binds it to phosphatidylcholine (referred to as silymarin phytosome) may provide greater benefit. A growing body of research indicates that phosphatidylcholine-bound silymarin is better absorbed and produces better clinical results than the unbound variety.68–73 These benefits were demonstrated in a study involving 232 patients with chronic hepatitis (viral, alcoholic, or chemically induced) treated with silymarin phytosome at either 120 mg twice a day or 120 mg three times a day for up to 120 days.73 Liver function returned to normal faster in patients given silymarin phytosome compared with both the commercially available silymarin and placebo.
Intravenous silibinin is capable of the greatest suppression of hepatitis C viral replication. The first study that provided clear evidence of the antiviral effects of silymarin in humans with hepatitis C was published in 2008 by Ferenci and colleagues.74 These investigators found that such patients who were nonresponders to SOC treatment were able to achieve undetectable HCV RNA levels after intravenous administration of silibinin for 15 days. Although these results proved to be temporary, the antiviral effect of intravenous silibinin was permanent for one patient with hepatitis C who received this treatment for 2 weeks after liver transplantation. This suggests that silibinin may be capable of preventing graft reinfection with HCV.75 Further studies are needed to confirm these promising results.
Phyllanthus Amarus
P. amarus is an Asian herb with a long history of use in liver disorders. A preliminary report in 1988 demonstrated that 59% of patients with hepatitis B had lost the hepatitis B surface antigen when tested 15 to 20 days after treatment with a preparation of P. amarus (200 mg of the dried, powdered, sterilized plant in capsules three times a day).76 In this double-blind study, only 4% (1 of 23) placebo-treated controls tested negative. Although this report was met with a great deal of excitement,77 these results have not been confirmed by other researchers,77–80 indicating that either the type of extract used was not effective or that Phyllanthus itself is not effective.
Combination Approach with Antioxidant and Botanical Therapy
A report by Berkson describes three patients with advanced cirrhosis, portal hypertension, and esophageal varices secondary to chronic hepatitis C infection who were effectively treated with a low-cost combination program.81 Although these patients were originally given extremely poor prognoses, all “recovered quickly,” showed improved liver enzymes, and were able to resume their normal daily activities. One patient revealed a substantial improvement in her condition within only 2 weeks. The other patients progressed to health within 4 to 7 months.
Acupuncture and Chinese Medicine Herbs
In a study of 60 patients with hepatitis B, 30 were given acupuncture once a day for 30 minutes for 4 to 6 weeks while the other 30, the control group, continued their conventional medication. Those in the treatment group had significantly shorter recovery times, greater symptom improvement, and lower interleukin-8 levels.82 Studies have also investigated the use of acupuncture to improve secondary and comorbid symptoms such as depression and myalgias. One 6-week trial categorized 28 patients: group one comprised 13 patients with high depression and myalgia scores; group two was made up of 11 patients with low depression but high myalgia scores; and group three consisted of 4 patients with high depression but low myalgia scores. When compared with baseline levels, significant improvement was shown in end-treatment depression and myalgia scores.75 Although no positive outcomes regarding improved viral load using acupuncture have been shown, acupuncture may help other symptoms, improve immune balance, and lower comorbidities in patients with hepatitis. More study is needed, but given the possible benefit and low risk, acupuncture may be a reasonable therapy.
Because the standard operating procedure for acupuncture mandates the use of clean-needle technique, the risk of hepatitis from acupuncture is considered extremely low.83 Acupuncture may help to improve symptoms and hepatic function. A patient should look for a practitioner who uses only disposable needles as opposed to resterilized needles.
Sho-saiko-to or “Xiao Chai Hu Tang”
Sho-saiko-to (named Xiao Chai Hu Tang in Chinese) is a botanical formulation containing seven herbs traditionally used to treat liver and gastrointestinal disorders.84 This formula has been shown in animal models to prevent liver injury and promote liver regeneration by inhibiting oxidative stress on lipid peroxidation in hepatocytes and hepatic stellate cells85,86 and, in human trials, to prevent the progression of cirrhosis to HCC.87 One prospective study of 260 patients also found that it increased the survival of those with chronic viral hepatitis by reducing progression to HCC.88
Clinical studies are ongoing at Sloan Kettering to determine whether Sho-saiko-to can increase survival in patients with liver cancer. Of note, this treatment is contraindicated with interferon drug therapy because there is an increased risk of pneumonitis,89 and Sho-saiko-to has been reported to cause acute hepatitis.90 Thus, until further studies prove otherwise, its use in patients with liver disease is not recommended.
Hepatotoxic Supplements
Used mostly for hyperlipidemia, niacin may be contraindicated in patients with compromised liver function. Known to cause flushing, headache, and stomachache in some people, doses above 20 mg91 and/or sustained-release forms at doses of 2 g/day or higher92,93 may contribute to liver toxicity and should be avoided in patients with hepatitis. Used for mood and glycemic regulation, a specific form of niacin called niacinamide seems not to induce abnormalities and is considered a safer option,94 but it should be avoided in hepatitis when other options are available.
Excessive consumption of vitamin A (acute doses of over 100, 000 IU or chronic doses of 25,000 to 100,000 IU daily for over a year) may cause hypervitaminosis A, which can lead to cirrhosis and its complications.95 Vitamin A’s potential to cause liver toxicity is enhanced by alcohol consumption, by an excessive intake of other fat-soluble vitamins, and by a vitamin C deficiency.
Hepatotoxic Botanicals
Given the pharmacologic nature of plant medicines, it is important to remember that some commonly used botanicals may be hepatotoxic and should be avoided in patients with hepatitis. Perhaps the most researched is Symphytum officinale (comfrey). These effects are most likely due to various hepatotoxic pyrrolizidine alkaloids (PAs) such as lasiocarpine and symphytine and their related N-oxides.96 Although used most often as a topical vulnerary remedy, Symphytum PAs may still be absorbed through the skin and should be avoided in patients with liver disease. Piper methysticum (kava kava) has also been implicated in hepatic liver damage.97 A number of these reported cases of kava toxicity seemed to involve poor documentation, preexisting conditions, kava overdose, or concomitant polypharmacy. Although considered safe at normal doses for people without liver disease,98 those with hepatic conditions should avoid kava kava as a precaution.
Therapeutic Approach
Nutritional Supplements
Vitamin D: 1000 to 4000 IU a day
Whey protein: for hepatitis B at 24 g a day
Botanical Medicines
Glycyrrhiza glabra (licorice): Powdered root: 1 to 2 g three times daily, fluid extract (1:1): 2 to 4 mL (1 to 2 g) three times daily, solid (dry powdered) extract (5% glycyrrhetinic acid content): 250 to 500 mg three times daily. Intravenous administration may be the most effective form. Note: chronic licorice administration may call for an increased intake of potassium-rich foods. Silybum marianum (milk thistle). The standard dose of milk thistle (70 to 210 mg three times daily) is based on its silymarin content. For this reason, standardized extracts are preferred.The best results are achieved at higher dosages (i.e., 150 to 300 mg three times daily). The dosage for silybin bound to phosphatidylcholine is 120 mg two to three times daily between meals. Intravenous silibinin may be the most effective form.
1. CDC. Hepatitis B Vaccination Coverage Among Adults — United States. 2004 Morbidity and Mortality Weekly Report (MMWR). 2006 (May 12);55(18):505–529.
2. Perz J.F., Armstrong G.L., Farrington L.A., et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45(4):529–538.
3. Alter M.J. Epidemiology of hepatitis C virus infection. World J Gastroenterol. 2007 May 7;13(17):2436–2441. Review
4. Strader D.B., Seeff L.B. The natural history of chronic hepatitis C infection. Eur J Gastroenterol Hepatol. 1996;8:324–328.
5. Seeff L.B., Hoofnagle J.H. National Institutes of Health Consensus Development Conference: management of hepatitis C: 2002. Hepatology. 2002;36(suppl):S1–S2.
6. Vgontzas A.N., Zoumakis E., Bixler E.O., et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab. 2004;89(5):2119–2126.
7. Opp M.R., Born J., Irwin M.R. Sleep and the immune system. Ader R., ed. Psychoneuroimmunology, 4th ed., New York, NY: Academic Press, 2007. 579-561
8. Kanwal F., Gralnick I.M., Rays R.D., et al. Health related quality of life predicts mortality in patients with advanced chronic liver disease. Clin Gastrolenterol Hepatol. 2009;7:793–799.
9. Raison C.L., Rye D.B., Woolwine B.J., et al. Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol Psychiatry. 2010;15(68(10)):942–949.
10. Carlson M.D., Hilsabeck R.C., Barakat F., et al. Role of sleep disturbance in chronic hepatitis C infection. Curr Hepat Rep. 2010;9(1):25–29.
11. Lange T., Perras B., Fehm H.L., et al. Sleep enhances the human antibody response to hepatitis A vaccination. Psychosom Med. 2003;65(5):831–835.
12. Cohen S., Doyle W.J., Alper C.M., et al. Sleep habits and susceptibility to the common cold. Arch Intern Med. 2009 Jan 12;169(1):62–67.
13. Payan J.L., Pillard F., Mascarell V., et al. Is physical activity possible and beneficial for patients with hepatitis C receiving pegylated interferon and ribavirin therapy? Gastroenterol Clin Biol. 2009 Jan;33(1 Pt 1):8–14.
14. Takeshita M., Ishida Y., Akamatsu E., et al. Proanthocyanidin from blueberry leaves suppresses expression of subgenomic hepatitis C virus RNA. J Biol Chem. 2009 Aug 7;284(32):21165–21176.
15. Wang Y.P., Cheng M.L., Zhang B.F., et al. Effects of blueberry on hepatic fibrosis and transcription factor Nrf2 in rats. World J Gastroenterol. 2010 Jun 7;16(21):2657–2663.
16. Mulvihill E.E., Allister E.M., Sutherland B.G., et al. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes. 2009 Oct;58(10):2198–2210.
17. Nahmias Y., Goldwasser J., Casali M., et al. Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology. 2008 May;47(5):1437–1445.
18. Bailey D.G., Malcolm J., Arnold O., et al. Grapefruit juice-drug interactions. Br J Clin Pharmacol. 1998;46:101–110.
19. Dahan A., Altman H. Food-drug interaction: grapefruit juice augments drug bioavailability: mechanism, extent and relevance. Eur J Clin Nutr. 2004;58:1–9.
20. Ruhl C.E., Everhart J.E. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology. 2005 Dec;129(6):1928–1936.
21. Ruhl C.E., Everhart J.E. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2005 Jan;128(1):24–32.
22. Modi A.A., Feld J.J., Park Y. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology. 2010 Jan;51(1):201–209.
23. Tverdal A., Skurtveit S. Coffee intake and mortality from liver cirrhosis. Ann Epidemiol. 2003 Jul;13(6):419–423.
24. Larsson S.C., Wolk A. Coffee consumption and risk of liver cancer: a meta-analysis. Gastroenterology. 2007 May;132(5):1740–1745. Epub 2007 Mar 24
25. Bravi F., Bosetti C., Tavani A., et al. Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology. 2007 Aug;46(2):430–435.
26. Freedman N.D., Everhart J.E., Lindsay K.L., et al. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology. 2009 Nov;50(5):1360–1369.
27. Watanabe A., Okada K., Shimizu Y., et al. Nutritional therapy of chronic hepatitis by whey protein (non-heated). J Med. 2000;31:283–302.
28. Brass C.A., Piken E. Do Antioxidants ameliorate ribavirin related anemia in HCV patients. Gastroenterology. 1999;116(4):A1192–A1193.
29. Kawaguchi Y., Mizuta T., Takahashi K., et al. High-dose vitamins E and C supplementation prevents ribavirin-induced hemolytic anemia in patients with chronic hepatitis C. Hepatol Res. 2007 May;37(5):317–324.
30. Jain S.K., Pemberton P.W., Smith A., et al. Oxidative stress in chronic hepatitis C: not just a feature of late stage disease. J Hepatol. 2002;36:805–811.
31. Evans J.L., Goldfine I.D. Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol Ther. 2000;2:401–413.
32. Pande M., Flora S.J. Lead induced oxidative damage and its response to combined administration of alpha-lipoic acid and succimers in rats. Toxicology. 2002;177:187–196.
33. Suh J.H., Shigeno E.T., Morrow J.D., et al. Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. FASEB J. 2001;15:700–706.
34. Ebara M., Fukuda H., Hatano R., et al. Metal contents in the liver of patients with chronic liver disease caused by hepatitis C virus. Reference to hepatocellular carcinoma. Oncology. 2003;65(4):323–330.
35. 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 Nov;45(3):292–303.
36. Palmer M., Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology. 1990 Nov;99(5):1408–1413.
37. Takagi H., Nagamine T., Abe T., et al. 2001 Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C. J Viral Hepat. 2001 Sep;8(5):367–371.
38. Suzuki A., Lindor K., St Saver J., et al. Effect of changes on body weight and lifestyle in nonalcoholic fatty liver disease. J Hepatol. 2005 Dec;43(6):1060–1066.
39. Bean P. The use of alternative medicine in the treatment of hepatitis C. Am Clin Lab. 2002;21:19–21.
40. Abu Mouch S., Fireman Z., Jarchovsky J., et al. Vitamin D supplement improve SVR in chronic hepatitis C (genotype 1) naive patients treated with peg interferon and ribavirin. Vienna, Austria: 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010); April 14-18, 2010.
41. Petta S., Cammà 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 Apr;51(4):1158–1167.
42. Ginde A.A., Liu M.C., Camargo C.A., Jr. Demographic differences and trends of vitamin D insufficiency in the U.S. population, 1988-2004. Arch Intern Med. 2009 Mar 23;169(6):626–632.
43. Czuczejko J., Zachara B.A., Staubach-Topczewska E., et al. Selenium, glutathione and glutathione peroxidases in blood of patients with chronic liver diseases. Acta Biochim Pol. 2003;50:1147–1154.
44. Irmak M.B., Ince G., Ozturk M., et al. Acquired tolerance of hepatocellular carcinoma cells to selenium deficiency: a selective survival mechanism? Cancer Res. 2003;63:6707–6715.
45. Jain S.K., Pemberton P.W., Smith A., et al. Oxidative stress in chronic hepatitis C: not just a feature of late stage disease. J Hepatol. 2002;36:805–811.
46. Yu M.W., Horng I.S., Hsu K.H., et al. Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection. Am J Epidemiol. 1999;150:367–374.
47. Yu S.Y., Zhu Y.J., Li W.G. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res. 1997 Jan;56(1):117–124.
48. Ohbayashi A., Akioka T., Tasaki H. A study of effects of liver hydrolysate on hepatic circulation. J Therapy. 1972;54:1582–1585.
49. Sanbe K., Murata T., Fujisawa K., et al. Treatment of liver disease—with particular reference to liver hydrolysates. Jap J Clin Exp Med. 1973;50:2665–2676.
50. Fujisawa K., Suzuki H., Yamamoto S., et al. Therapeutic effects of liver hydrolysate preparation on chronic hepatitis: a double blind, controlled study. Asian Med J. 1984;26:497–526.
51. Galli M., Crocchiolo P., Negri C., et al. Attempt to treat acute type B hepatitis with an orally administered thymic extract (Thymomodulin): preliminary results. Drugs Exptl Clin Res. 1985;11:665–669.
52. Bortolotti F., Cadrobbi P., Criverllaro C., et al. Effect of an orally administered thymic derivative, Thymodulin, in chronic type B hepatitis in children. Curr Ther Res. 1988;43:67–72.
53. Malnick S., Zimhony O. Herbal medicines have no proven efficacy for Hepatitis C. Evidence-based Healthcare. 2002;6:132–133.
54. Suzuki H., Ohta Y., Takino T., et al. Effects of glycyrrhizin on biochemical tests in patients with chronic hepatitis: double blind trial. Asian Med J. 1984;26:423–438.
55. Mori K., Sakai H., Suzuki S., et al. Effects of glycyrrhizin (SNMC. Stronger Neo-Minophagen C) in hemophilia patients with HIV-1 infection. Tohoku J Exp Med. 1990;162:183–193.
56. Eisenburg J. Treatment of chronic hepatitis B. Part 2: Effect of glycyrrhizinic acid on the course of illness. Fortschr Med. 1992;110:395–398.
57. Acharya S.K., Dasarathy S., Tandon A., et al. A preliminary open trial on interferon stimulator (SNMC) derived from Glycyrrhiza glabra in the treatment of subacute hepatic failure. Indian J Med Res. 1993;98:69–74.
58. Arase Y., Ikeda K., Murashima N., et al. The long term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer. 1997;79:1494–1500.
59. Fiore C., Eisenhut M., Krausse R., et al. Antiviral effects of Glycyrrhiza species. Phytother Res. 2008 Feb;22(2):141–148.
60. van Rossum T.G., Vulto A.G., Hop W.C., et al. Glycyrrhizin-induced reduction of ALT in European patients with chronic hepatitis C. Am J Gastroenterol. 2001 Aug;96(8):2432–2437.
61. Arase Y., Ikeda K., Murashima N., et al. The superiority of laparoscopic examination in predicting hepatocellular carcinoma after interferon therapy for chronic type C hepatitis. Dig Endosc J Pharmacol. 1997;10:613–620.
62. Veldt B.J., Hansen B.E., Ikeda K., et al. Long-term clinical outcome and effect of glycyrrhizin in 1093 chronic hepatitis C patients with non-response or relapse to interferon. Scand J Gastroenterol. 2006 Sep;41(9):1087–1094.
63. Ikeda K., Arase Y., Kobayashi M., et al. A long-term glycyrrhizin injection therapy reduces hepatocellular carcinogenesis rate in patients with interferon-resistant active chronic hepatitis C: a cohort study of 1249 patients. Dig Dis Sci. 2006 Mar;51(3):603–609.
64. Orlent H., Hansen B.E., Willems M., et al. Biochemical and histological effects of 26 weeks of glycyrrhizin treatment in chronic hepatitis C: a randomized phase II trial. J Hepatol. 2006 Oct;45(4):539–546. Epub 2006 Jun 30
65. Deak G., Muzes G., Lang I., et al. Immunomodulator effect of silymarin therapy in chronic alcoholic liver diseases. Orv Hetil. 1990;131:1291–1292. 1295-1296
66. Tanamly M.D., Tadros F., Labeeb S., et al. Randomised double-blinded trial evaluating silymarin for chronic hepatitis C in an Egyptian village: study description and 12-month results. Dig Liver Dis. 2004;36:752–759.
67. Gabbay E., Zigmond E., Pappo O., et al. Antioxidant therapy for chronic hepatitis C after failure of interferon: results of phase II randomized, double-blind placebo controlled clinical trial. World J Gastroenterol. 2007;13:5317–5323.
68. Schandalik R., Gatti G., Perucca E. Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients. Arzneimittelforschung. 1992;42:964–968.
69. Barzaghi N., Crema F., Gatti G., et al. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet. 1990;15:333–338.
70. Vailati A., Aristia L., Sozze E., et al. Randomized open study of the dose-effect relationship of a short course of IdB 1016 in patients with viral or alcoholic hepatitis. Fitoterapia. 1993;44:219–228.
71. Moscarella S., Giusti A., Marra F., et al. Therapeutic and antilipoperoxidant effects of silybin-phosphatidylcholine complex in chronic liver disease: preliminary results. Curr Ther Res. 1993;53:98–102.
72. Buzzelli G., Moscarella S., Giusti A., et al. A pilot study on the liver protective effect of silybin-phosphatidylcholine complex (IdB 1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxicol. 1993;31:456–460.
73. Marena C., Lampertico M. Preliminary clinical development of silipide: a new complex of silybin in toxic liver disorders. Planta Med. 1991;57(suppl 2):A124–A125.
74. Ferenci P., Scherzer T.M., Kerschner H., et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology. 2008 Nov;135(5):1561–1567. Epub 2008 Aug 3
75. Neumann U.P., Biermer M., Eurich D., et al. Successful prevention of hepatitis C virus (HCV) liver graft reinfection by silibinin mono-therapy. J Hepatol. 2010 Jun;52(6):951–952. Epub 2010 Mar 15
76. Thyagarajan S.P., Subramanian S., Thirunalasundari T., et al. Effect of Phyllanthus amarus on chronic carriers of hepatitis B virus. Lancet. 1988;2:764–766.
77. Leelarasamee A., Trakulsomboon S., Maunwongyathi P., et al. Failure of Phyllanthus amarus to eradicate hepatitis B surface antigen from symptomless carriers. Lancet. 1990;335:1600–1601.
78. Blumberg B.S., Millman I., Venkateswaran P.S., et al. Hepatitis B virus and primary hepatocellular carcinoma: treatment of HBV carriers with Phyllanthus amarus. Vaccine. 1990;8:S86–S92.
79. Berk L., de Man R.A., Schalm S.W., et al. Beneficial effects of Phyllanthus amarus for chronic hepatitis B, not confirmed. J Hepatol. 1991;12:405–406.
80. Milne A., Hopkirk N., Lucas C.R., et al. Failure of New Zealand hepatitis B carriers to respond to Phyllanthus amarus. N Z Med J. 1994;107:243.
81. Berkson B.M. A conservative triple antioxidant approach to the treatment of hepatitis C: combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories. Med Klin (Munich). 1999;94(suppl 3):84–89.
82. Neumann U.P., Biermer M., Eurich D., et al. Successful prevention of hepatitis C virus (HCV) liver graft reinfection by silibinin mono-therapy. J Hepatol. 2010 Jun;52(6):951–952. Epub 2010 Mar 15
84. Bensky D., Gamble A. Chinese Herbal Medicine: Materia Medica. Revised Ed. Seattle: Eastland Press; 1993.
85. Shimizu I. Sho-saiko-to: Japanese herbal medicine for protection against hepatic fibrosis and carcinoma. J Gastroenterol Hepatol. 2000 Mar;15(suppl):D84–D90.
86. Sakaida I., et al. Herbal medicine Sho-saiko-to (TJ-9) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. J Hepatol. 1998;28:298–306.
87. Yamashiki M., et al. Herbal medicine ‘Sho-saiko-to’ induces tumour necrosis factor-alpha and granulocyte colony-stimulating factor in vitro in peripheral blood mononuclear cells of patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 1996;11:137–142.
88. Oka H., Yamamoto S., Kuroki T., et al. Prospective study of chemoprevention of hepatocellular carcinoma with Sho-saiko-to (TJ-9). Cancer. 1995 Sep 1;76(5):743–749.
89. Mizushima Y., Oosaki R., Kobayashi M. Clinical features of pneumonitis induced by herbal drugs. Phytother Res. 1997;11:295–298.
90. Hsu L.M., Huang Y.S., Tsay S.H., et al. Acute hepatitis induced by Chinese hepatoprotective herb, xiao-chai-hu-tang. J Chin Med Assoc. 2006 Feb;69(2):86–88.
91. Coppola A., Brady P.G., Nord H.J. Niacin-induced hepatotoxicity: unusual presentations. South Med J. 1994 Jan;87(1):30–32.
92. Figge H.L., Figge J., Souney P.F., et al. Comparison of excretion of nicotinuric acid after ingestion of two controlled release nicotinic acid preparations in man. J Clin Pharmacol. 1988;28:1136–1140.
93. Dalton T.A., et al. Hepatotoxicity associated with sustained-release niacin. Am J Med. 01-JUL-1992;93(1):102–104.
94. Cervantes-Laurean D., McElvaney N.G., Moss J. Niacin. In: Shils M.E., Olson J.A., Shike M., Ross A.C. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Williams and Wilkins; 1999:401–411.
95. Inkeles S.B., Connor W.E., Illingworth D.R. Hepatic and dermatologic manifestations of chronic hypervitaminosis A in adults. report of two cases. Am J Med. 1986;80(3):491–496.
96. Stickel F., Seitz H.K. The efficacy and safety of comfrey. Public Health Nutr. 2000 Dec;3(4A):501–508.
97. Moulds R.F., Malani J. Kava: herbal panacea or liver poison? Med J Aust. 2003;178:451–453.
98. Teschke R. Kava, kavapyrones and toxic liver injury. Z Gastroenterol. 2003;41:395–404.
99. Duong F.H., Christen V., Filipowicz M., et al. S-Adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro. Hepatology. 2006 Apr;43(4):796–806.
100. Feld J.J., Modi A.A., El-Diwany R., et al. S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders. Gastroenterology. 2011 Mar;140(3):830–839.
