Hepatitis C

EPIDEMIOLOGY AND GENETICS

• Prevalence
• Natural History
• Genetic Profile and HCV
• HCV and Alcohol
• HCV and HIV

Prevalence

HCV infects approximately 170 million people worldwide. Nearly 4 million Americans have antibodies to HCV, indicating ongoing or previous infection with the virus. Chronic hepatitis C (CHC) is the most common chronic blood-borne infection in the U.S. and is the cause of approximately 40% of chronic liver disease. It is a condition that can progress to cirrhosis and hepatocellular carcinoma. Because of improved screening methods for blood products, the annual incidence of new infections decreased by more than 80% from 1989 to 1996. HCV is responsible for 8,000 to 10,000 deaths annually.1

In the past, hepatitis was spread primarily through infected blood and blood products.2 Today the most common mode of HCV transmission is injection drug use,3-5 occupational exposure (e.g., needle-stick accidents),1,6,7 sexual contact,8 and blood transfusion.1,9 Over the last 20 years, there has been an increase in HCV due to intravenous drug use and high-risk sexual behavior, but transfusion-related HCV has declined precipitously.1 Even with multiple sexual partners, the risk of sexual transmission of HCV is minimal.8 The risk is markedly increased by coinfection with HIV and hepatitis B virus10 and other sexually transmitted diseases. The risk of transmission of HCV from mother to baby is about 5%, but there is no evidence that breast-feeding is a risk factor.11 Homosexual contacts are not a risk factor for HCV transmission.12

Approximately one third of HIV-positive individuals in the U.S. are infected with HCV. This is, in part, explained by shared risk factors for both infections. However, for unknown reasons, HIV infection also increases the susceptibility to infection with HCV.1 HIV is much more likely to be transmitted than HCV.10 However, sexual transmission more likely in coinfected than in only HCV-infected individuals.13 Transmission from mother to baby is more likely by HCV-HIV coinfected mothers;12 the converse is also true, i.e., HIV transmission to the fetus is more likely in doubly infected mothers.

Natural History

The course and outcome of HCV infection is highly variable—from spontaneous resolution to end-stage liver disease.1,14,15 The time from the onset of the infection to the end-stages of disease may be decades.16 The course and prognosis for an HCV-infected patient varies with the individual. Genetic makeup and immunologic status alter the course and duration of the disease. Some people have mild symptoms; in others the symptoms are severe. Some people respond to treatment and recover completely—others remain chronically infected. The genetic character of both the virus and the infected individual contribute to these variations in outcome, disease susceptibility and progression, and success of treatment. In fact, the existence of numerous clinical syndromes associated with HCV points to the genetically linked character of the HCV infection. Researchers have already identified genes associated with the variability of the immune response in diseases such as malaria,17 tuberculosis, leprosy,18 AIDS and hepatitis B;19 consequently, the HCV research now underway focuses on the immunogenetics of HCV infection (www.clinicaltrials.gov).

The natural history of HCV infection also varies with geography, age, gender, characteristics of the virus, and type of treatment. Older age, cirrhosis, coinfection with hepatitis B or HIV, alcohol use, and male gender all predict a more severe disease course and a more severe long-term outcome.20

About 15% of those who are acutely infected clear the infection.21,22 The remaining 85% develop CHC, a disease that is benign and asymptomatic in many.21,22 Progression of the disease is exceptionally slow.20,23 Even asymptotic HCV-positive people are carriers of the virus and are at risk of developing chronic liver disease, cirrhosis, and hepatocellular carcinoma 20 or 30 years after the initial infection.24 Liver disease may progress to end-stage organ failure and result in ascites, esophageal varices, or encephalopathy.22

An analysis of a large group of HCV-positive people found no difference in the death rate between them and a control group 18 years after infection. Death due to liver disease was 3.2% for the HCV-positive enrollees and 1.5% for the controls. Of those in the group who died from liver disease, 71% were heavy drinkers. There were marked differences in morbidity, but it was confined largely to those with cirrhosis. Fewer than 8% had developed advanced liver disease over the 18-year period.20

Genetic Profile and HCV

Genetic differences create considerable disparity among racial and ethnic groups in the progression of CHC and in response to treatment.25 HCV infection has a different natural history in minority populations than in Caucasians. Effectiveness of antiviral drugs varies with race and ethnicity, as well.26

In the U.S., HCV infection is more common in minority populations (3.2%, African-Americans; 2.1%, Hispanics; and 1.5%, Caucasian);27 and they are disproportionately affected. African-Americans and Hispanics have more complications of liver disease more frequently and have a lower response to antiviral drugs.24,28 The viral load (amount of virus in the blood) is higher among ethnic minorities. African-Americans do not clear the virus as well as Caucasians29 which results in a higher rate of chronic infection.26,30

The rate of development of fibrosis and severe liver disease is higher for minorities24 and three times higher for Hispanics.26,31 This disparity may be due to the higher rate of metabolic syndrome, a genetically linked disease, in that population. Insulin resistance, a symptom that characterizes the metabolic syndrome,32 is a major risk factor for the development of non-alcoholic fatty liver disease. Approximately 15% of patients with this type of fatty liver disease develop fibrosis that leads to cirrhosis or hepatocellular carcinoma.33,34 African-Americans tend to have lower liver enzyme levels (a positive indicator for CHC) and less cirrhosis and liver damage—this advantageous profile is attributed to genetic differences.35 Although progression to cirrhosis is lower among African-Americans,30 the incidence of hepatocellular carcinoma is higher, however.36,37

HCV and Alcohol

About 25% of people with alcoholic liver disease are HCV-positive.38 Their viral loads of alcoholics are greater,39 and their time to development of cirrhosis and hepatocellular carcinoma is shorter.40,41 The risk for hepatocellular carcinoma in alcoholic cirrhotics is eight times higher with HCV infection.42 HCV causes more severe liver injury in alcoholics, especially those with cirrhosis.43 The reason for this association is unclear. Socioeconomic factors have been implicated, but there is a high prevalence of HCV among alcoholics with liver disease without a history of intravenous drug use.38,44 Factors such as the amount of alcohol consumed, age at the time of infection, and gender have greater influence on progression of the disease than the virus itself. Actively drinking alcoholics are more likely to have HCV in the blood than non-alcoholics with no other risk factors for hepatitis—suggesting that alcoholism is a predisposing factor for HCV infection.44

The question is, do alcohol and HCV act synergistically to cause liver injury? Alcohol may speed up viral replication—there is a correlation between HCV levels in the blood and the amount of alcohol consumed; or it may modify the ability of HCV to “turn on” the genes that cause hepatocellular carcinoma.45 Alcoholics with HCV infection have higher hepatic iron concentrations; this might increase HCV replication.46 Whatever the mechanism, even moderate alcohol drinking enhances the progression of liver disease appreciably.

HCV and HIV

HCV is a significant cause of liver disease in those who are HIV-positive.47 Cirrhosis due to HCV is probably as high as 22% at the time of death in HIV-HCV coinfected patients.48 Hepatocellular carcinoma appears at a younger age and after a shorter time in individuals in people with a combination of HCV and HIV infections.1 The encroachment of HCV infection into the HIV-positive population is so pervasive that is it now considered an opportunistic infection by many physicians.49

ANATOMY AND PHYSIOLOGY (STRUCTURE AND FUNCTION)

The liver is the largest and heaviest visceral organ in the body. The two lobes of the liver are made up of microscopic functional units called lobules that are bounded by portal triads and central veins. Each portal triad is the center of a microvascular unit called an acinus. Lobules contain enlarged capillaries (sinusoids), hepatocytes (liver cells), and a number of specialized cells. Most of the cells in the liver are hepatocytes. They are responsible for the liver's central role in metabolism and regulation of blood. Hepatocytes manufacturer bile, store absorbed vitamins and minerals, convert glucose to glycogen and glycogen to glucose, make plasma proteins from amino acids, detoxify chemicals, and destroy pathogens. Pit cells may be tissue lymphocytes that function similarly to natural killer cell functions. Ito cells store vitamin A, synthesize various proteins, and can transform into fibroblasts in response to injury. Kupffer's cells are macrophages that destroy microbes, foreign particles, and worn out blood cells, as well as remove endotoxins and modulate the immune response. The liver can also eliminate toxic substances, such as alcohol and drugs, by neutralizing them with the cytochrome P450 system. Cytochrome P450 enzymes contain iron and are specialized for oxidizing chemicals which makes them more water soluble and more easily eliminated by the kidneys. Overproduction of P450 enzymes is toxic to the liver. The liver can also detoxify harmful substances by attaching molecules to their side chains which changes their chemical composition and makes them inactive.

PATHOPHYSIOLOGY

The kinetics of acute HCV infection is uncertain. In the first stage of infection, there is no immune response and HCV replicates without injury to liver cells. In the second stage, viral replication slows, probably due to cytokines such as interferon-a. In the final stage, at about 12 weeks, there is a strong cytotoxic response in which T cells destroy infected cells; a rapid clearance of infected cells follows.60,61 Laboratory studies have shown that those who clear an acute infection have a more vigorous T-cell response to HCV and consequently developed fewer viral subtypes. Apparently an increase in the cellular immune response coupled with inhibition of viral replication with interferon-a can eradicate the virus.78

The overwhelming majority of those infected cannot clear the virus in the acute stage and consequently develop a chronic infection. The classic clinical picture of a CHC infection is a persistent low-grade inflammation and fibrotic changes of the hepatocytes that eventually progresses to cirrhosis.79

ETIOLOGY AND MECHANISMS OF ACTION

The factors that determine whether a HCV infection becomes chronic have not been completely elucidated. Research to date has focused on viral factors, such as genotype or viral load; however, the tendency to either clear the infection or develop a progressive disease appears to be influenced by the genetic makeup of the host coupled with the interaction of several of the defensive mechanism of the body.80 The effectiveness of an immune response determines the extent of inflammation and necrosis sustained by the liver—e.g., a marginal immune response will cause fewer symptoms, but is less likely to eradicate the virus.

Cell-mediated immunity, especially natural killer cells and cytotoxic T-lymphocytes, play a role in chronic liver disease and the mechanisms of liver damage.81 The inflammatory response produces reactive oxygen species and cytokines.82,83 Cytokines combat viral infections, indirectly through the immune response and directly through inhibition of viral replication.84 Pro-inflammatory cytokines, such as interferon-a, tumor necrosis factor-a, and interleukins (ILs)-1 and -6, produce antiviral immune responses; anti-inflammatory or “permissive” cytokines, such as IL-4 and IL-10, downregulate the immune response. An inappropriate ratio of pro-inflammatory and anti-inflammatory cytokines may alter individual outcomes or the effect of antiviral drugs.80 Pro-inflammatory cytokine levels are elevated in CHC, hepatocellular carcinoma, and cirrhosis, but HCV may have some degree of resistance to inhibition by cytokines.84-87

Genetic factors are important determinants of inflammatory cytokine production and are closely linked to susceptibility to liver disease.88 In response to an immune stimulus, cytokines bind to cell membranes and signal the cell to alter its behavior through gene expression. Although the immune system plays a protective role in the body,89 the oxidant molecules produced as part of the inflammatory response may damage healthy tissue. The enhanced cytokine and reactive oxygen species production that follows bacterial infection, for example, is designed to combat bacteria; but during the battle, it can damage the body and accelerate disease. Some of the oxidative damage to the liver seen in CHC is due to excessive production of pro-inflammatory cytokines.90,91

The influence of cytokines IL-10 and -12 on liver disease has been the subject of dozens of studies. There is agreement among investigators that the capacity to produce IL-10 among individuals has a major genetic determinant, but there is little agreement on whether these cytokines are favorable or unfavorable prognostic indicators for the clinical outcome of CHC.80

Apoptosis, or programmed cell death, is an antiviral mechanisms employed by liver cells.92 It is thought that cytotoxic T-lymphocytes trigger apoptosis in infected cells; this interrupts viral replication and eliminates infected cells. However, many viruses escape from the immune system by encoding proteins that repress apoptosis. Inappropriate apoptosis is implicated in the pathogenesis of CHC; in fact, repeated cell damage caused by inappropriate apoptosis can induce HCC. Some researchers think that apoptosis is a mechanism for viral shedding rather than for viral elimination.93 HCV-infected hepatocytes can induce or inhibit apoptosis—inhibition of apoptosis results in a chronic infection. The antiviral effect of interferon-a may be mediated through induction of apoptosis. The degree of apoptosis in the liver of patients with CHC does not correlate with transaminase levels, viral load, or genotype; rather, it is directly proportional to the number T-lymphocytes.92

DIAGNOSIS OF HCV INFECTION

• Symptoms of CHC
• Differential Diagnosis
• Viral Genetics
• Diagnostic Tests
• Liver Function Tests
• Virological Markers
• Confirming a Diagnosis of HCV Infection
• Hepatocellular Carcinoma Screening

Symptoms of CHC

Acute viral hepatitis is difficult to diagnose;50 symptoms can vary from a minor flu-like illness to liver failure. Most patients with acute HCV develop only a few mild, nonspecific symptoms and sustain minimal damage to liver tissue. Infection with HCV usually begins suddenly—this is called the prodromal phase. Symptoms vary in this phase; many people think they have the flu. Patients may experience low-grade fever, fatigue, loss of appetite, a distaste for cigarettes, nonspecific malaise, nausea and vomiting, and nondescript upper abdominal discomfort—or no symptoms at all. The liver is enlarged in half of infected individuals and about 20% of them also have an enlarged spleen. The icteric, or jaundice phase follows in 3 to 10 days. During this phase, the urine darkens and the skin may develop a yellow hue; other symptoms typically regress. During the 2- to 4-week recovery phase that follows, patients either clear the virus completely or develop a chronic infection. Because the course of the acute infection is mild, many people do not remember the original infection when they are diagnosed with CHC many years later.16

Symptoms of chronic viral hepatitis are variable; they might include fatigue, mild abdominal pain, nausea, poor appetite, muscle and joint pains, weight loss, and occasional bouts of jaundice.1 Severity of symptoms is not related to the seriousness of the disease. Approximately 15% of chronically infected adults develop cirrhosis within 20 years of the initial infection.3 Development of cirrhosis of the liver is often asymptomatic, and some patients are unaware of their HCV infection until they are diagnosed with advanced disease—notably, liver failure and hepatocellular carcinoma.51

Differential Diagnosis

Diagnosis of acute HCV infection is based on clinical symptoms and liver enzyme levels and antibodies to HCV in the blood. An antibody test can take 8 to 12 weeks following initial exposure;52 direct measurement of the genetic material of the virus (HCV RNA) in the blood is a more accurate test. Liver damage is reflected in elevations of the liver enzymes.6 One third of CHC patients have persistently normal enzyme levels; therefore a positive diagnosis relies on detection of anti-HCV antibodies or virus. A liver biopsy is used to grade the severity of liver disease, not for a diagnosis.53,54

Viral Genetics

HCV is a small single-stranded, RNA virus: 6 distinct HCV strains with distinct genetic characteristics (genotypes) have been identified, as well as 11 subtypes.1,55 The HCV genotype is an intrinsic viral characteristic—it does not change. The subtype can change its amino acid pattern over time and mutate over the course of the infection. This substantial immunogenic variability allows the virus to reproduce and mutate rapidly, and consequently, evade the immune response of the host.56,57 This creates a persistent infection that is difficult to cure (NIH 2002) and complicates vaccine development.16 Genotype and subtype have a direct influence on disease virulence, severity of fibrosis (formation of scar tissue), and development of cirrhosis or hepatocellular carcinoma.51,58 The genetic diversity of HCV creates a virus that has the ability to escape the immune system of its host. This leads to a high rate of chronic infections and lack of immunity to reinfection in repeatedly exposed individuals. Genotypes and their subtypes vary geographically. Some genotypes of HCV are geographically restricted; others are distributed worldwide. Genotype 1 is the most common in the U.S. and is responsible for greater than 70% of infections.1,19 It is associated with severe chronic liver disease and lower rates of response to treatment with antiviral drugs.55 Patients with HCV genotypes 2 or 3 have about a 25% greater chance of response to treatment than those with HCV genotype 1.59-62

The success of pharmaceutical treatment depends on the specific genotype. Although HCV genotype and viral load are the strongest predictors of response to treatment,63,64 most scientists think that one viral genotype is no more virulent than any other and that other factors are responsible for the variation seen in treatment outcomes.65

Diagnostic Tests

Diagnostic tests for hepatitis C are divided into two broad categories: tests to assess damage to the liver and tests to identify the type and amount of the hepatitis virus.66,67

Hepatitis C

Liver Function Tests

Serum ALT (SGPT) and AST (SGOT).

Serum alanine aminotransferase (ALT) (SGPT) and aspartate aminotransferase (AST) (SGOT) are enzymes produced in the liver. ALT and AST are used as rough indicators (or markers) of the degree of liver cell inflammation.51 In fact there is probably only a weak association between the ALT levels and inflammatory changes. Although elevations of these liver enzymes are frequently seen in both acute and chronic hepatic C,51 they are not related to severity or outcome of the disease68,69 or to inflammatory changes or degree of fibrosis.66,67 ALT can be normal even in those with liver damage, and ALT can be elevated in diseases other than CHC.70 AST can be very high in acute hepatitis and drop to normal or slightly elevated in chronic hepatitis.69 ALT is very useful for monitoring the effectiveness of antiviral drug treatment for CHC. The response to treatment is judged in terms of ALT normalization during and after treatment.69

Virological Markers

There are two types of virological tests—those that identify specific antibodies produced by immune cells in response to invading virus and those that test for the virus itself. Virologic tests have no prognostic value. They do not correlate with the severity of liver injury, and they cannot predict the natural course of the disease.

Anti-HCV Antibody Tests.

Enzyme immunoassays (EIA) and enzyme-linked immunosorbent assays (ELISA). EIA and ELISA are used to detect antibodies to the virus in the blood, which indicated exposure to HCV. Enzyme assays cannot distinguish exposure to the virus from an active infection. It takes about 7 to 8 weeks from the time of infection until antibodies have formed in the blood. Eventually all infected individuals will have detectable anti-HCV antibodies. If an infection spontaneously resolves, the anti-HCV antibodies may persist or disappear after several years. All people with CHC will have antibodies—although they might become undetectable in severe immunodepression.1,71

HCV RIBA.

The HCV RIBA test is used to detect false positive anti-HCV test, especially “weakly” positive results. It also detects antibodies to the virus.1,71

Quantitative HCV Tests.

“Viral load” means the number of viral particles in the blood. Detection of HCV RNA, the genetic material of HCV, indicates an active infection. HCV RNA can usually be detected 1 or 2 weeks after infection. Then it rises to a peak, after which it either disappears when the infection resolves spontaneously or falls and stabilizes into a chronic hepatitis. There is no correlation between HCV RNA level and degree of liver damage, except in end-stage liver disease when HCV RNA levels low or undetectable.72 Qualitative HCV-RNA testing is also used to monitor the effectiveness of treatment.

HCV Viral Genotyping.

Genotyping is used to determine the genetic makeup of the virus causing the infection and the length of treatment. Genotype 1 is less likely to respond to treatment than genotypes 2 or 3; for that reason, it usually requires longer treatment. The HCV genotype can also be determined by serotyping, i.e., testing for type-specific antibodies with an EIA. The assay can identify type but not subtype.73,74

Confirming a Diagnosis of HCV Infection

Acute HCV Infection.

A diagnosis of an acute HCV infection is confirmed with anti-HCV and HCV RNA tests. Detection of HCV RNA without anti-HCV strongly indicates acute hepatitis C. Acute HCV infection is unlikely if HCV RNA is absent, but there are no anti-HCV antibodies.1

Chronic HCV Infection.

The presence of both anti-HCV and HCV RNA is diagnostic of CHC. The exception would be the absence of anti-HCV antibodies and the presence of HCV RNA in a profoundly immunodepressed patient.1

Liver Biopsy.

Liver biopsy is the gold standard for assessing the liver cell injury and determining the prognosis of a patient with CHC. There are several biopsy scoring systems used. All measure the same parameters: fibrosis, necrosis, and inflammation in the liver. A high score indicates a higher risk of rapid disease progression and cirrhosis and as such is used to decide if treatment should be started. Patients with cirrhosis have a high risk of developing hepatocellular carcinoma.75 Although there is some diagnostic information that only it can provide, a liver biopsy has several serous shortcomings. In some instances, it may be appropriate to forgo biopsy before initiating antiviral therapy—because of excessive risk to the patient, for example. There is a small but definite risk with a biopsy; the death rate is -0.12%, and 5% of those who undergo biopsies have complication.76,77

Hepatocellular Carcinoma Screening

Alpha-fetoprotein levels and ultrasound testing are used to screen for hepatocellular carcinoma. CT and MRI scans and hepatic angiography are used to confirm ultrasound findings in patients with cirrhosis.36,37 When a biopsy is used to test for hepatocellular carcinoma there is a small risk that the tumor will spread along the needle track.

PHARMACOLOGY

• Interferon-alpha (a)
• Pharmacological Treatment Options
• Non-Pharmacological Options
• Prevention and Prophylaxis
• Drugs under Development
• Choosing a Treatment

Interferon-alpha (a)

Interferon-a is an antiviral protein produced naturally by cells that have been invaded by pathogens. It plays a vital role in the regulation of the immune system by controlling the body’s reaction to viruses. Interferon-a increases the activity of natural killer cells, a type of white blood cell, and blocks the production of the genetic material produced by a virus. There are three types of interferon (a, ß, and y). Synthetic interferon-alpha (a) is genetically engineered and used as a treatment for HCV infection. Today, interferon is an integral part of most treatment regimes for CHC.

CHC can largely be prevented if an infection is treated with interferon when the virus is first contracted. Unfortunately, most acute cases of hepatitis C have no symptoms, so only a small percent of acute HCV infections are recognized and no treatment is given. Although the results to date are relatively disappointing, traditional antiviral treatment for CHC is evolving. Current treatment is three-pronged: antiviral medication, management of complications, and liver transplant.16 The primary treatment goal is long-term eradication of HCV RNA from the blood; secondary goals are reversal of damage to liver tissue and preservation of overall health and quality of life.

Treatment success is measured in terms of virological, biochemical, and histological responses.1,62 Virological response measures the decrease in viral load. The criterion for a cure is “sustained virological response” which indicates that a patient is free of virus 6 months after stopping treatment.62 Biochemical response is evaluated by changes in the levels of enzymes produced in the liver. It is a less reliable indicator of improvement than virological response because levels may fluctuate during treatment.22 The histological response is measured by the improvement in the condition of liver tissue. Improvement in liver histology is directly related to slowing of the disease and the avoidance of cirrhosis and liver cancer.1

Pharmacological Treatment Options

Interferon-a

All current treatment options are based on some type of synthetic interferon-a. Treatment with interferon-a alone can sometimes completely eradicate HCV infection.94 In general, however, 24 weeks of treatment with interferon-a usually results in sustained virological response in fewer than 20% of patients.77 Its anti-viral activity lasts only a short time and it has side effects that can affect the quality of life dramatically. Interferon-a alone is no longer a first-line treatment for HCV infection because better treatments have been developed. Today treatment with interferon-a alone is reserved for patients who cannot tolerate the newer drugs, such as Ribavirin.95-97

Pegylated Interferon-a and Ribavirin

Pegylated interferon-a remains in the blood longer than standard interferon-a; this gives it the advantage of a longer duration of action.98 On average, treatment with pegylated interferon-a yields a substantial increase in sustained virological response and a modest improvement in liver tissue compared with standard interferon-a. A combination of interferon-a plus the antiviral drug ribavirin has significant benefits over standard interferon-a alone: 48 weeks of interferon-a plus ribavirin treatment usually results in sustained virological responses ranging from 38 to 43%.77 Pegylated interferon-a plus ribavirin is significantly more effective than standard interferon-a plus ribavirin or pegylated interferon-a alone. It is the most effective pharmaceutical treatment for patients at risk for cirrhosis and other liver diseases.1 This combination has yielded the highest sustained virological response to date and produced significantly superior responses in some patients who are considered difficult to treat. Lengths of treatment with pegylated interferon-a and doses of ribavirin are based on HCV genotype. For example, patients with genotypes 2 and 3 are treated for 24 weeks with a standard dose of ribavirin; while patients with genotype 1 are treated for 48 weeks and with a higher dose of ribavirin. With either regime, the decision to continue therapy is based on a positive virological response at 24 weeks.99

Side Effects and Contraindications to Interferon and Ribavirin

The drugs currently used to treat CHC are contraindicated for patients who could be susceptible to the psychiatric side effects caused by interferon-a or who have a medical condition that could complicate interferon-a therapy. Coexisting psychiatric disorders and substance and alcohol abuse are the most common contraindications to antiviral therapy. Poorly controlled autoimmune disease, bone marrow compromise, certain blood disorders, hyperthyroidism, and pregnancy are contraindications to treatment; as well as active substance and alcohol abuse. Contraindications to ribavirin include marked anemia and/or kidney, coronary artery, and cerebrovascular disease.100,101 Corticosteroids are contraindicated in ordinary cases because they enhance viral replication and suppress the immune system.16

Nearly all patients experienced side effects—more so with pegylated interferon-a than with interferon-a. The most common side effects of interferon-a and ribavirin combinations are fatigue, flu-like symptoms, gastrointestinal disturbance, depression, and blood abnormalities.102 Other frequently seen adverse events are headache, fever, bone and muscle pain, nausea, anorexia, weight loss, hair loss, and itching.103 Rates as high as 50% for myalgia, fatigue, and headache are not unusual;102 and blood count abnormalities are a common reason for reduction of the dose of pegylated interferon-a. Ribavirin can cause hemolytic anemia that requires a dose reduction in as many as 10% of patients. The potential for fetal injury with ribavirin requires diligent contraception during treatment.104 Treatment with interferon-a and ribavirin often result in discontinuation or dose reduction, particularly in longer courses of treatment.77 This is problematic because the dose and duration of interferon-a and ribavirin significantly influence the likelihood of achieving a sustained virological response.

Non-Pharmacological Options

Liver Transplant

CHC is the most common reason for adult liver transplantation.16 Although HCV infection recurs after transplant, the course of the disease is generally indolent, and long-term survival rates are relatively high.16 In a study that followed patients after transplantation, the 5-year survival rate was approximately 80% in spite of the fact that more than 95% of the recipients had virus in their blood.105 Unfortunately, many CHC patients are not eligible for a liver transplant either because of medical history or cost.

Iron Reduction

All microorganisms need iron to reproduce, including HCV. HCV-positive patients with higher serum iron levels are more likely to develop chronic infections, and those with lower levels are more likely to resolve infections spontaneously. Larger stores of hepatic iron in the body appear to accelerate cirrhosis and hepatocellular carcinoma and impede interferon (IFN). Decreases in serum iron concentrations (hypoferremia) that occur with infections and inflammatory conditions are a defense mechanism to fight infection.106 This reaction is due mainly to interleukin-1, a mediator of the inflammatory response.82 Iron reduction by phlebotomy (bloodletting) can reduce ALT levels107 and, in some cases, result in a decrease in viral load. Using interferon after iron reduction can result in larger decreases in viral load and significant improvement in biochemical and virological responses.23 The reasons for the interaction of iron and HCV are unclear. There is experimental evidence that iron increases oxidative stress and enhances peroxidation of lipids. On the other hand, iron also damages T-cells and impairs humoral immunity.106

Ursodeoxycholic Acid (Ursodiol)

Ursodeoxycholic acid is a bile acid that can be beneficial in chronic inflammatory conditions of the liver.106 It is currently approved for the treatment of cholesterol-based gallstones and primary biliary cirrhosis. Ursodiol’s “off label” benefits include lowering elevated liver enzymes and alleviating some of the clinical symptoms of liver disease such as itching. The mechanism by which ursodiol limits hepatocyte injury in chronic liver diseases and retards the progression of liver disease in primary biliary cirrhosis is unclear. Ursodiol’s immunomodulatory effect has been demonstrated in studies; it may inhibit cytotoxic cytokine production which in turn may reduce lipid peroxidation in hepatocytes. In the laboratory, ursodeoxycholic acid protected hepatocytes against apoptosis induced by alcohol. Many viral genomes encode proteins that repress apoptosis to escape immune defenses. If apoptosis of liver cells contributes to the pathogenesis of hepatitis, the ability of the anti-apoptotic ursodeoxycholic acid to limit hepatocyte injury makes sense.93

Ursodeoxycholic acid has been the subject of many clinical trials in which it reduced ALT levels, in the both the absence and the presence of interferon. It demonstrated the ability to potentate the effect of interferon in interferon-resistant patients. A combination of interferon and ursodeoxycholic acid prolonged the effects of interferon by delaying or reducing the severity of a biochemical relapse.108 Although ursodeoxycholic acid produces no anti-viral effect, it does reduce disease activity108,109 and appears to a suitable substitute for patients who can not tolerate interferon.110 When ursodeoxycholic acid was used in combination with interferon-a, it was no more effective than interferon alone in inducing a biochemical response in previously untreated patients.111 The most common side effects of ursodeoxycholic acid are constipation, gas, indigestion, nausea, and vomiting.112

Prevention and Prophylaxis

Vaccine

There is no vaccine against HCV. A vaccine has been difficult to develop because the HCV viral protein is highly variable and the titers of the antibodies produced by patients in response to HCV are of low and of specific subtypes.113

Immune Globulin

It is not clear if immune globulin is effective and it usefulness as prophylaxis is debatable.16 When immune globulin was used before transfusion in a clinical trial, it conferred significant protection against HCV.114

Drugs under Development

There are a number of promising new drugs in early stages of development to treat CHC.

HCV Protease Inhibitors

The success of protease inhibitors in HIV treatment has generated interest in them for hepatitis. Unlike interferon-a and ribavirin, which act through general mechanisms, protease inhibitors have the potential to target HCV specifically. HCV enzyme NS3 serine protease is essential for viral replication; protease inhibitors block the NS3 serine protease. HCV protease also appears to inhibit cellular defenses against viral infection. HCV protease inhibits interferon-a regulatory factor-3 and consequently blocks infected cells from triggering interferon-a defense pathways. Theoretically, HCV protease inhibitors could work synergistically with interferon-a, making it more effective with lower doses.115 VX-950 is a protease inhibitor in early phase I studies.

Interferon and Interleukin

Interferon Beta (Interferon-ß). In a small trial, interferon-ß had some very modest success when it was used for retreatment of patients with genotype Ib who had responded to interferon-a in the past but relapsed.116

Interferon gamma-1b (Interferon-y 1b) (Actimmune™). This drug is a naturally occurring protein that stimulates the immune system. Preclinical studies demonstrated strong synergistic effects between interferon alfacon-1 and interferon gamma-1b. In a trial enrolling patients with CHC and advanced cirrhosis who had failed standard treatment, Actimmune did not meet its primary endpoint, the reversal of liver fibrosis. In a study that retreated patients with interferon alfacon-1 and interferon gamma-1b for 48 weeks, 38% of patients achieved undetectable viral loads at the end of 12 weeks and 65% had a decline in viral load or were HCV RNA negative. All patients had a reduction in serum ALT that was below the upper limit of normal.115

Alphaferon (Albuferon™). Alphaferon is a protein genetically engineered by fusing interferon to human albumin in order to extend the half-life to increase the effectiveness of interferon.117

IL-10. A small study of IL-10 achieved significant reduction in serum ALT and hepatic inflammation, but increased HCV viral burden via alterations in immunologic viral surveillance.118

Antivirals

Amantadine. Results were mixed in several studies conducted to test a combination of interferon-a plus ribavirin with and without amantadine. In a clinical trial, amantadine caused a significant decline in ALT: 9% of patients cleared the virus and 7% had a sustained virologic response 6 months after treatment.119

Viramidine. This prodrug of ribavirin has demonstrated antiviral activity comparable to ribavirin and may be a safer substitute for ribavirin. A recent trial of a viramidine and pegylated interferon-a combination showed significantly lower incidence of hemolytic anemia compared with amantadine.120

Immunomodulating Agents

Thymalfasin (Zadaxin). When this immunomodulating agent was used in combination with pegylated interferon-a, it increased the early virologic response rates from 20 to 36% in patients who had previously failed therapy.121

Isatoribine. Isatoribine activates the innate immune response by stimulating natural killer cells and macrophages and induction of cytokines including interferon-a. It achieved some reduction in viral load in a small preliminary study.

Drugs That Disrupt the Viral Lifecycle

SCH 6. In laboratory studies, SCH 6 effectively inhibited HCV replication and did not appear to induce cytotoxic morphological changes or apoptosis.122

ISIS 14803 (Antisense Inhibitor). ISIS 14803 inhibits HCV replication and protein expression in cell culture and mouse models. In two very small preliminary studies, ISIS caused transient reductions in HCV RNA levels, as well as flares in serum ALT levels that were up to five times the upper limit of normal. Investigators attribute the transient reductions in plasma HCV RNA levels to an antiviral effect.123

Merimepodib (VX-497). Merimepodib indirectly reduces cellular GTP—the molecule required for DNA and RNA synthesis. In a small study, merimepodib demonstrated a statistically significant antiviral response in combination with pegylated interferon-a and ribavirin.124

Ribozymes (HepBzyme™). Ribozymes appear to disrupt the viral lifecycle of HBV and HCV by cleaving RNA. HepBzyme significantly reduced HBV in animal studies and appears to be as effective as lamivudine. Combinations of HepBzyme and interferon or HepBzyme and lamivudine resulted in additive downregulation of the production of the HBV antigen.125

Drugs to Reduce Side Effects of Interferon and Ribavirin

Epoetin Alfa. Interferon-a and ribavirin combinations sometimes induce anemia severe enough to force dose reduction or discontinuation of ribavirin. When epoetin alfa was added to the combination treatment in a 16-week trial, patients were able to maintain their ribavirin dose and hemoglobin levels.126 In anemic patients, epoetin corrected anemia and enabled 84% of patients to maintain their ribavirin dose.127

Dronabinol. Anorexia, nausea and vomiting are common side effects of ribavirin and interferon-a as well as major causes of discontinuation of treatment. Dronabinol is a synthetic cannabinoid approved for treatment of side effects AIDS patients on cancer chemotherapy. In a clinical trial, 40% of the patients agreed that dronabinol was an effective treatment of major side effects caused by ribavirin and interferon-a.128

Combination Treatments

With Pegalated Interferon-a. There were favorable results in all arms of a trial of pegylated interferon-a in combination with mycophenolate mofetil, amantadine, and ribavirin for the treatment of relapsers and non-responders to interferon-a. All pegylated interferon-a combinations had appreciable virologic response rates. Pegylated interferon-a plus amantadine and ribavirin had the most favorable benefits.126

NM283. NM283 is being developed for use by patients, including liver transplant patients who cannot use interferon. Clinical trials are planned for mid-2004.129

Hepatitis C

Choosing a Treatment

In principle, all patients with an HCV infection are candidates for antiviral drugs, but the impact of interferon-a on long-term outcome in CHC is unclear. There is reluctance to use interferon because of the poor overall response to treatment, numerous side effects, and the risk of anemia.100 Further, interferon is expensive64 and must be given by injection. Often patients cannot tolerate the side effects or they have contraindications. Most people who discontinue treatment relapse; successful long-term viral suppression is only about 35% overall. Usually long-term low-dose maintenance is required.16

Successful treatment with interferon varies widely with genetic makeup, race, ethnic group, gender, and dose and length of treatment.1 Viral genetics also play an important role in the response to pegylated interferon-a.130 Factors that predict a positive response to interferon-a include low serum levels of HCV RNA, HCV genotype 2 or 3, younger age, female sex, and lack of advanced cirrhosis before treatment starts.64 About half of HCV-positive individuals in the U.S. are infected with genotype 1 and have high viral loads.131 People with HCV genotype 1 infection, regardless of viral load, have a poorer response to interferon-a than other HVC genotypes.132,133

There are compelling reasons to opt for interferon treatment: frequently symptoms lessen, liver enzyme levels return to normal, and—although fibrosis may progress—inflammation of the liver subsides.16 Most importantly, the risk of cirrhosis and liver cancer can be lessened.1 Interferon might provide some long-term improvement in liver histology.134 Studies found a modest but significant reduction in hepatocellular carcinoma in patients who respond completely to interferon.135 There is some evidence that people whose liver enzymes normalize may have a decreased risk of hepatocellular carcinoma and decreased progression of liver disease.1

One large trial demonstrated that interferon-a treatment, regardless of response, conferred some long-term benefits.1 The current thinking is that interferon-a is most beneficial for those at greatest risk for cirrhosis. Ironically, the people at greatest risk for cirrhosis, such as alcoholics and individuals with HCV-HIV co-infections,43 are the least likely to tolerate the side effects of treatment with antiviral drugs and the least able to commit to a year-long course of treatment.136 Those who can be treated with interferon-a are also excellent candidates for alternative treatment either as a replacement or as an adjunct to their traditional pharmaceutical regime.

It is difficult to draw conclusions or generalize about the effectiveness of a traditional treatment because most clinical trials that test interferon-a, alone or in combination, exclude so called “difficult-to-treat” patients. People who are HIV-positive, mentally ill, or use recreational intravenous drugs cannot enroll in a trial. Previous treatment with interferon-a or complicating conditions, such as kidney disease and hemophilia, warrant exclusion. There are methodological limitations among the studies that make comparisons of interferon-a to alternative treatments problematic, as well. In clinical trials, for example, the success of treatment with interferon-a is measured in terms of sustained virological response at 6 months. Treatment lasts 24 weeks or 48 weeks for patients with genotype 1; frequently trial participants are followed-up for 6 years.51 This is not the case with alternative treatment in which there are no uniform parameters, and trials cannot be extrapolated to standard treatment comparisons. Response to interferon-a is modified by a number of factors, such asgenotype and viral load; it is not known if alternative treatment is effected in the same way.69 Individuals who have failed to respond to treatment with interferon-a are excluded from additional interferon trials, but included in alternative trials.

Factors that Predict a Response to Interferon

Only a minority of patients respond to treatment with interferon. Because of the cost, side effects, and inconvenience of 24 to 48 weeks of treatment, it is useful to know the factors associated with a greater or lesser likelihood of response to interferon when deciding on treatment. Early response to treatment (i.e., reduction in viral load during the first month) is the best identifier of a person who will respond positively.137 Greater likelihood of response is also associated with a younger age, women, low body weight, low pretreatment viral load, viral genotypes other than type 1, absence of fibrosis or cirrhosis, higher or longer doses of interferon, and low hepatic iron levels.138 Unfortunately, none of these factors is sufficiently predictive to accurately identification of all patients.139

Factors that Affect the Decision to Use Interferon

About 15% of HCV-positive individuals have normal serum ALT levels.140 They usually have very mild liver disease,21,141 and many are asymptomatic 142. Response to interferon is poor in these patients and there is usually not an appreciable improvement of liver tissue.143,144 In some cases, interferon induces a reactivation of liver disease.145

In general, responsiveness to interferon is diminished when cirrhosis is present, although there is more than a 50% probability of sustained response in those who are able to maintain a virological response during treatment.146,147 In two large well-controlled studies, treatment with interferon decreased the incidence of hepatocellular carcinoma. However, analysis failed to show a significant independent effect of interferon on survival. The beneficial effects of interferon are not convincingly documented for most cirrhotic patients, but interferon does provide an important reduction in complications of cirrhosis for those with a sustained response to therapy.148

Although it might take decades to appear, CHC is a major risk factor for hepatocellular carcinoma. After 20 years of infection, about 8% of patients can be expected to have hepatocellular carcinoma.149,150 Risk factors for developing hepatocellular carcinoma are older age, male gender, and severe liver disease. Most cases of HCV-related hepatocellular carcinoma occur in the people who already have cirrhosis, suggesting that liver disease is the risk factor for hepatocellular carcinoma not HCV infection.149 In fact, Japanese studies demonstrated that the risk of hepatocellular carcinoma is lower in patients with HCV-related cirrhosis who have been treated with interferon whether they had a good response or not.151

NUTRITIONAL THERAPY

• Innovative Options
• Supplements and Nutritional Therapies
• Antioxidant Vitamins
• Glutathione
• Phosphatidylcholine
• Selenium
• DHEA
• Botanical Medicines

Innovative Options

The current pharmaceutical choices for CHC are imperfect. Eradication of the HCV virus—the ultimate goal—is impossible for most patients. More treatment options are urgently needed, and more reasonable goals must be set. New endpoints under consideration are reduction of virus levels in the blood, decrease in hepatic inflammation and the rate of progression of hepatic fibrosis, and delay of development of cirrhosis and hepatocellular carcinoma. Viewing interferon and ribavirin treatment in terms of these endpoints might result in new protocols for treatment of CHC.106

There is a recognized group of medicinal herbs and supplements with proven antiviral and biochemical actions that are effective for treatment of CHC. They have been used safely worldwide to treat liver disease—some for thousands of years. Today they have the added advantage of being available in a standardized extracted form and of being tested in clinical trials that enroll thousands of participants. All of the medicines detailed here have been the subject of numerous placebo-controlled clinical trials, animal studies, and in in vitro studies.

Supplements and Nutritional Therapies

The antioxidant defenses of the body may not provide adequate protection against the oxidative molecules produced by the immune system during the inflammatory process. Slowing cytokine production and maintaining antioxidant defenses depends on nutrient intake. Nutrients absorbed from the food we eat influence the inflammatory aspects of the immune system by altering cytokine production and limiting the responsiveness of target tissues to cytokines. Alterations in the intake of fats, antioxidant nutrients, protein, and certain amino acids can reduce inflammation by interacting with the body’s cytokine and reactive oxygen species biology.152

The intake of metallic micronutrients such as copper, zinc, and selenium influences the activity of antioxidant enzymes. A number of constituents of defense are acquired directly by the intake of nutrients that have antioxidant properties. These include ascorbic acid, tocopherols, beta-carotene, and a number of phytochemicals, such as catechins and tannins from tea. When the immune system is stimulated, pro-inflammatory cytokines increase the activities of the enzymes that detoxify oxidants, such as superoxide dismutase and catalase.153

Antioxidant Vitamins

The components of antioxidant defense interact directly and indirectly to maintain the antioxidant capacity of tissues. Vitamins E and C and glutathione are intimately linked in antioxidant defense.154 Vitamin E influences inflammatory and immune function. Vitamin E deficiency impairs cellular and humoral immunity and supplementation lowers the incidence of infectious disease.155,156 Vitamin C is a key component of antioxidant defense.157 Some small studies have demonstrated that vitamin C might play a role in the effect of exercise on the immune function.158,159 Inflammation is inversely related to the intakes of vitamins C and E in smokers.160 The absorption of iron is significantly enhanced by the presence of vitamin C.161 Vitamin B has widespread effects on immune function and is an indirect contributor to antioxidant defenses. Vitamins B12 and B6 are a co-factor in the metabolic pathway for the biosynthesis of cysteine which is necessary for glutathione synthesis.161 Deficiencies in B vitamins and vitamin E create abnormalities in the cell-mediated immune response and supplementation with vitamins C, A, E, and B vitamins and improves lymphocyte function.154

Glutathione

Glutathione, a molecule composed of glycine, glutamate, and cysteine, is key to the regulation of cellular activity. Depletion of glutathione below a certain level causes cell death. Glutathione is synthesized and highly concentrated in the liver where it plays a key role in the cytochrome P450 detoxification system. It protects cells by quenching free radicals; in its reduced form, glutathione has potent antioxidant action. Glutathione is a major antioxidant made by the body and is important in the manufacture of lymphocytes.161 Cytokine production in response to inflammatory stimuli depends on the ability of the body to produce glutathione.162 Attack by free radicals depletes glutathione, and low levels of glutathione are linked to many diseases. Aging alters glutathione status so that reduced glutathione tends to be lower and oxidized glutathione rises.163 Malnutrition164 and alcoholism165 cause deficiencies of glutathione precursors and consequently limits glutathione synthesis.166 There is a relationship between liver damage and production of free radicals during inflammatory processes. In CHC, liver damage is attributed to an imbalance in the oxidation and reduction processes and to glutathione depletion. Chronic inflammation provoked by the replication of HCV and might also have a role.167 Monocyte glutathione is low in hepatitis C and altered glutathione status is a feature of cirrhosis and nonalcoholic liver disease.165,168,169

Nutrients that Raise Glutathione Levels

Glutathione stimulation is a primary immune-modulating mechanism. The amino acid precursors to glutathione increase glutathione concentration in relevant tissues and stimulate immunity.170 Taking supplementary glutathione and its precursors, such as alpha-lipoic acid, N-acetyl-cysteine, S-adenosyl-L-methionine, increases glutathione in the body.

Alpha-Lipoic Acid (ALA) (Thioctic Acid). Alpha-lipoic acid is a potent antioxidant with a critical role in the energy-producing structures in cells.171 As an antioxidant, alpha-lipoic acid is unique. Although it acts like a vitamin, it is not classified as such because it is synthesized in the body.161,172 It is soluble in both lipids and water and can act as an antioxidant in both mediums.173 It is active in both its oxidized form and its reduced form, dihydrolipoic acid (DHLA).171,174 Alpha-lipoic acid is able to regenerate vitamin C175 and E176 and to raise intracellular glutathione levels significantly.177

Alpha-lipoic acid has therapeutic applications in many conditions that involve oxidative stress.171 It has been studied as a treatment for diabetes,171,178 as well as a variety of disorders related to the eye. It is used extensively to treat liver disease and is an accepted antidote to poisons and drugs that are metabolized in the liver. Alpha-lipoic acid is a highly effective treatment for Amanita mushroom poisoning.171 It has the ability to chelate copper, manganese, mercury, and zinc,179 reduce cadmium-induced hepatotoxins,172 and protect from arsenic poisoning. There have been preliminary studies of alpha-lipoic acid as a treatment of alcoholic liver disease. However, as with all trials involving alcohol use, it is difficult to separate the effects of abstinence from alcohol from those of the treatment.

Alpha-lipoic acid has very few side effects; the most common are nausea and vomiting. Although it is safe in standard doses,178 low doses in thiamin-deficient rats were fatally toxic180— thiamin-deficiency is a condition that is common in alcoholics. Individuals who are deficient in thiamine in should take vitamin B1 along with alpha lipoic acid. Alpha-lipoic acid lowers blood sugar levels181 and theoretically could cause hypoglycemia in diabetics. Alpha-lipoic acid interacts with the chemotherapy drugs doxorubicin.182

N-Acetyl-Cysteine (NAC). N-acetyl-cysteine has anti-mutagenic and anti-carcinogenic properties and is a powerful scavenger of free radicals. It is a precursor of glutathione—conversion of N-acetyl-cysteine to two of its major metabolites cysteine and inorganic sulfite accounts for its protective effects.123,183,184 N-acetyl-cysteine is converted to circulating cysteine after it is absorbed by the intestines. It increases the synthesis of glutathione only when there is a demand for it; in fact, it might only concentrate in the tissues where it is required.134,185-187 N-acetyl-cysteine can modulate the concentrations of certain cytokines. In laboratory studies, it has increased IL-1 and IL-2 levels when they were at low concentrations and decreased these cytokines at higher concentrations.188

N-acetyl-cysteine is also used to treat hepatotoxic conditions, especially those that increase oxidative stress or decrease glutathione185. It is an established antidote for acetaminophen overdose189—a condition known to deplete liver glutathione.190 N-acetyl-cysteine might have a role in the treatment of liver cancer. It has demonstrated the ability to inhibit cell growth and proliferation in cancer cell lines191-193 and prevent the transformation of carcinogens into more toxic compounds.194 In laboratory experiments, it reduced experimentally induced intestinal tumors195 and inhibited the induction of tumors by some carcinogens.196

It is conjectured that the relative ineffectiveness of interferon for treatment of CHC can be attributed to glutathione imbalance. Supplementing interferon with a glutathione precursor would increase its effectiveness and that antioxidants might act in synergy with interferon. To test this theory, there have been several trials of a combination treatment of interferon with N-acetyl-cysteine. Results of one study showed that supplementation of interferon with N-acetyl-cysteine enhanced the response to interferon, but had no effect when it was taken alone.197

N-acetyl-cysteine is generally safe and side effects are infrequent.198 The most common side effects at high doses are nausea, vomiting, and gastrointestinal disturbances. People with chronic liver disease tend to have an increase in blood N-acetyl-cysteine coupled with a decreased ability to clear N-acetyl-cysteine with intravenous doses.199 In healthy individuals, N-acetyl-cysteine might act as an oxidant and lower the levels of reduced glutathione.200

S-Adenosylmethionine (SAMe). SAMe is a sulfur-containing amino acid derivative found in the cells of all mammals.201 It is formed by an enzyme-catalyzed reaction between methionine and ATP, an important energy source in the body202 SAMe provides methyl groups for biosynthesis and is a major glutathione precursor that participates in detoxification reactions and in the manufacture of antioxidants.161 Folic acid and vitamin B12 are necessary for the resynthesis of SAMe,202,203 and there is evidence that folate deprivation contributes to methyl insufficiency.204

SAMe has been used all over the world to treat depression,205,206 arthritis, osteoporosis,207,208 fibromyalgia,209 and Parkinson's disease;210 as well as certain liver211 and gallbladder diseases.212

SAMe is a physiological donor of methyl groups in enzymatic reactions. Cirrhotic damage to the liver prevents the conversion of SAMe from methionine.169 The mechanism is probably due to multiple abnormalities in sulfur metabolism in cirrhosis. Hypomethylation213 is strongly associated with carcinogenesis. In fact, methyl-deficient diets have caused liver cancer in animals; and diets containing lipotropes—a group of nutrients that includes methionine, folic acid, and vitamin B6 and B12—have prevented their development. Lipotrope-deficient diets can cause extensive liver damage including fatty livers.204 SAMe also reduced hepatic necrosis in rats with methyl deficient diets.169

SAMe is highly concentrated in a normal liver,214 and low levels of SAMe are a feature of cirrhosis.202 SAMe supplementation significantly restores the glutathione depletion in patients with chronic liver disease.215 Animal and human studies have shown that SAMe lessens the symptoms of liver disease caused by alcohol,216 toxic chemicals,204 and prescription and over-the-counter drugs.204 In a clinical trial, SAMe, taken over a period of 2 years, lowered the death rate of patients with alcoholic cirrhosis.217

In clinical trials of limited duration, there have been no serious side effects with SAMe. The most common side effect is mild gastrointestinal distress. Because SAMe has antidepressant activity, there is the possibility that it might trigger a manic episode in those with manic-depressive illness.204 SAMe should not be taken with any antidepressants, including MAO inhibitors, SSRIs, and tricyclics without consulting a physician.218 SAMe might inhibit of blood platelet aggregation.204 Although SAMe might relieve some side effects of the Parkinson's drug levodopa, it might also reduce its effectiveness over time.219

Whey. Whey (milk serum) protein is isolated from milk. Its potent antioxidant activity is due to its high concentration of the amino acid cysteine, a component of glutathione.220 Whey contains several important biological components that have properties that enhance the immune system. For example, ß-lactoglobulin modulates lymphatic responses.221 a-Lactalbumin has a direct effect on B and T lymphocyte function and has the ability to reduce oxidative stress because of its iron chelating properties. Lactoperoxidase catalyzes the reduction of hydrogen peroxide.222,223 Approximately 15% of whey proteins are immunoglobulins, the antibodies that confer immunity.224

Lactoferrin. Lactoferrin, a major component of whey protein, is an iron-binding glycoprotein that acts as an antioxidant—apolactoferrin is the iron-depleted form of lactoferrin.225 Lactoferrin has far-reaching antiviral and immunomodulatory properties.226 It can activate natural killer cells and neutrophils, induce colony-stimulating factor activity and enhance macrophage cytotoxicity,227-230 as well as decrease inflammation through the regulation of certain cytokines (TNF, IL-6).231 In the laboratory, lactoferrin inhibited metastasis of primary tumors in mice.232 When a high lactoferrin whey concentrate and the anticancer drug were combined, cytotoxicity was enhanced by inducing a higher rate of apoptosis.233 In small studies, bovine lactoferrin prevented HCV infection in human liver cells234 and decreased HCV RNA and liver enzymes in patients with low pretreatment viral loads of HCV.235 In a subsequent small, clinical trial, only a small percent of patients achieved significant decreases in ALT and HCV RNA levels and all of those who responded relapsed during the follow-up period.236 In a small open study that enrolled patients with HBV and HCV infections, ALT activity and lipid peroxide levels decreased, while glutathione, IL-2, and natural killer activity increased in the HBV group. However, there were no significant changes in the CHC group.237 There are not enough data to fully explain the considerable difference between the HBV and HCV groups. Apart from the obvious difference in virus, the small sample size should be considered. There have been a number of clinical trials in immune-compromised populations, such as AIDS and cancer patients, in which low glutathione levels are common. Significantly elevated glutathione levels were achieved with whey; however, results varied with different commercial products.238-241 As a rule, individuals who are lactose-intolerant can use whey proteins because lactose is removed during processing. Those who have true milk allergies should not use whey.

Phosphatidylcholine

Phosphatidylcholine provides the main structural support for the cell membranes of the body and has a role in the regulation of membrane fluidity. It is an essential nutrient and serves as a reservoir of choline.242 Phosphatidylcholine has demonstrated considerable antioxidant protection in numerous animal studies and clinical trials.243,244 It provides protection against chemical toxins and pharmaceutical drugs. Phosphatidylcholine is an excellent source of methyl groups which are crucial for hepatic detoxification.245

Liver disease enhances lipid peroxidation and depletes phosphatidylcholine and glutathione.246 Phosphatidylcholine has consistently shown benefits as a treatment for liver damage. Results from several clinical trials show significantly lower liver enzyme levels, improvement in liver tissue, and a decrease in mortality rate with the use of phosphatidylcholine. Although most phosphatidylcholine studies have been aimed at heavy drinkers, it appears to have applications for the sequelae of CHC. Phosphatidylcholine successfully reduces ALT in CHC patients.247 Because phosphatidylcholine breaks down collagen, it might have a positive effect on liver fibrosis.248 In an animal study, baboons that were force--fed alcohol without phosphatidylcholine progressed to advanced liver fibrosis, while baboons with a phosphatidylcholine-supplemented diet developed fatty liver and mild fibrosis, but did not progress to extensive fibrosis.246 In a clinical trial that enrolled patients with chronic viral hepatitis B or C, treatment with interferon and phosphatidylcholine for 24 weeks reduced ALT levels in 71% of patients with CHC. Additionally, treatment with phosphatidylcholine after termination of interferon treatment reduced the high interferon relapse rate.247 Phosphatidylcholine is safe and non-toxic. Side effects are usually mild and restricted to gastrointestinal complaints, such as diarrhea and nausea.249,250

Hepatitis C

Selenium

Selenium is a trace mineral251 that is essential for the proper functioning of the immune system.252,253 It has antioxidant properties and is a cofactor in several metabolic pathways.254 Glutathione peroxidase, the enzyme that recycles glutathione, is selenium dependent. Certain breakdown products of selenium in the body are believed to enhance immune cell activity.255

Plant foods are the major dietary source of selenium. Garlic, for example, is rich in selenium. The amount of selenium in a plant depends on the content in the soil where the plants are grown.256 Selenium deficiency is seen in areas where the soil content is low.252,257 Epidemiological investigations have found an association between low nutritional selenium status and increased risk of a variety of diseases.258,259 Selenium deficiency alone does not cause serious disease; it can make the body more susceptible to illness, however.260

Low serum selenium levels are associated with some cancers;116,261,262 and there may be an association of low environmental selenium to conditions as varied as goiter, sudden infant death syndrome, multiple sclerosis,263 and schizophrenia.264 Deaths from cancer are lower among people with higher selenium blood levels;265-268 and the incidence of cancer is higher in areas with low soil selenium levels.257,269 In a large cancer prevention trial, supplemental selenium lowered the risk of prostate, lung, and colorectal cancer;270 it did not affect recurrence of skin cancer, however.270 Data gathered from the 60,000 participants in the Nurses Health Study failed to find a relationship between higher selenium levels and reduced risk of cancer.271 Selenium levels appear to be severely depleted in liver disease. In a small study, serum selenium levels were significantly lower in participants with cirrhosis and hepatitis compared with a control group and lower in individuals with cirrhosis than in those with hepatitis.272

Interactions between selenium and other dietary constituents may affect the biological properties of selenium. In some studies, selenium supplemented with vitamin A provided an additive effect against breast cancer, but the protective effect was nullified by vitamin C.273 Selenium toxicity is rare in the U.S.— even in areas with high environmental level.274,275 The tolerable upper intake level (UL) for selenium is 400 micrograms per day (mcg/day) for adults.276 High levels of dietary selenium have been associated with decreased levels of thyroid hormones277 as well as impairment of natural killer cells. At extremely high levels hepatotoxicity, gastrointestinal distress, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage have been reported.278,279

DHEA

DHEA is a prohormone. Although small amounts are manufactured in the brain, DHEA is synthesized primarily by the adrenal glands. In women, DHEA is synthesized almost exclusively in the adrenal cortex; in men, the testes secrete from 10 to 25%.280 DHEA production peaks around the age of 25, then declines about 2% each year until the end of life.281-284 DHEA-S (sulfate) is an inactive metabolite of DHEA. DHEA and DHEAS are converted into several active metabolites.281,285-287 They are precursors of about half the androgens in men, 75% of active estrogens in premenopausal women, and all of the active estrogens after menopause.281,288 DHEA-ST (DHEA sulfotransferase) is involved in the hepatic clearance and metabolism of sex steroids. It catalyzes the reaction that forms the biologically inactive compound DHEAS. It is also the enzyme responsible for the inactivation of some potentially hepatotoxic bile acids. DHEA-ST activity and concentration are significantly reduced in several liver diseases, including chronic active hepatitis.289 In a study of the dynamics of DHEAS and other androgens in men with CHC infection, androgens were lower than in healthy men, but there was no correlation between DHEA and CHC infection.290 In non-alcoholic cirrhosis, there is a reduction of androgens (testosterone, DHEA, DHEAS, androstenedione) and a rise of estrogens.291 In a study of cirrhotic men, DHEAS values were significantly lower than normal, suggesting a defect in sulfurylation in men with hepatic cirrhosis.292

The response to DHEA supplementation in humans is sex and age specific. In small studies, DHEA had predominantly androgenic effects and increased testosterone levels about 300% in postmenopausal women;293 but in men over 52 years of age, DHEA increased estradiol and estrone levels but did not affect testosterone levels.294 Unlike cortisol and testosterone, DHEA secretion declines with ageing. However, it is not clear if physiological decline in DHEA secretion represents a harmful deficiency.295 DHEA is currently approved by FDA as an orphan drug for the treatment of adrenal insufficiency; its approval to treat systemic lupus erythematosus (SLE) is expected soon. There is also evidence to justify exploration of DHEA as a treatment of a variety of conditions, especially those associated with low DHEA and DHEAS levels. There is an inverse relationship between the DHEA levels in the body and a number of diseases, including some cancers, diabetes, cardiovascular disease, and Alzheimer's disease.296 Numerous animal studies have demonstrated that DHEA improves immune function and memory and prevents atherosclerosis, cancer, diabetes, and obesity.280,281,296 Unfortunately, distinct species-specific routes of DHEA metabolism and metabolite conversion make it impossible to extrapolate the results of animal studies to humans.297 Additionally, only primates have adrenal glands that secrete large amounts of DHEAS.298,299 DHEA declines substantially with age.300 Consequently, there is interest in DHEA replacement, especially in menopausal woman. Preliminary studies of DHEA replacement of have shown some encouraging results, especially in the area of immune system enhancement.301,301-303

DHEA is probably relatively safe at normal physiological doses. Side effects at physiological doses are breast tenderness, acne, and growth of body hair in women. Doses above 1500 mg daily can cause insulin resistance.301,304-306 In animal studies, DHEA has caused liver damage and pre-neoplastic pancreatic lesions.301,307 The long-term effects of DHEA are unknown. It should not be used by individuals with hormone-dependent cancers.

Botanical Medicines

Comparing conventional pharmaceutical drugs to herbal products can be problematic. As a rule, pharmaceuticals have one or two well-understood synthetic ingredients. Herbal ingredients are complex mixtures of dozens of plant chemicals, each with a different action. The constituents responsible for therapeutic effects are frequently unknown or only partly understood. At times, the true usefulness of a botanical is obscured by folklore. Many herbal products are touted as remedies and widely marketed for a wide range of disorders with no trial data to backup claims—or their applications are inferred from other plants with similar chemical components. There are many synthetic and natural antioxidants available, but their activity, bioavailability, and efficacy differ widely. The antioxidants discussed in this section have a broad spectrum of biological, pharmacological and therapeutic activities and are proven to be suited to defend against free radicals and oxidative stress caused by HCV infection.

Grape Seed Skin Extract

Grape seeds contain many chemical compounds, including polyphenols and flavonoids. Proanthocyanidins are mixtures of polyphenols that are closely related to flavonoids.308 Their potent antioxidant and free-radical scavenging309 and vasoprotective effects have been proven in many studies and trials. Proanthocyanidins exert their protective effect partially by increasing the activity of endogenous antioxidants such as glutathione and superoxide dismutase.310 Proanthocyanidins are twice as potent as vitamin E and four times as potent as vitamin C.40,309,311 Proanthocyanidins possess an impressive list of actions, including the ability to inhibit lipid oxidation and platelet aggregation, to promote nitric oxide production, to arrest tumor growth, and to inhibit carcinogenesis. Proanthocyanidins also exert an immunomodulatory effect. In laboratory studies, proanthocyanidins increased the cytotoxicity of natural killer cells, enhanced the production of IL-2, and decreased production of IL-6.312 A diet supplemented with proanthocyanidins increased T- and B-cell activity in mice with age-associated immune deficits.313 Dosing animals with grape seed extract before giving them hepatotoxic doses of acetaminophen significantly attenuated DNA damage and apoptotic and necrotic cell death of liver cells.314 Today grape seed extract is commonly used for prevention and treatment of edema and chronic venous insufficiency.314,315

Proanthocyanidins are generally considered nontoxic and adverse events are rare. There were no adverse effects seen in dogs who were given 130 mg daily of proanthocyanidins from grape seeds per pound of body weight for 1 year. Individuals with bleeding disorders or those who are taking anticoagulant medication or anticipating surgery should not use grape seed extract because of its effect on platelet coagulation.204

Milk Thistle

Silybum marianum, commonly know as milk thistle, has been a treatment for liver diseases for more than 2000 years.316 Its hepatoprotective component is silymarin;317 most research is directed at silybin, silymarin's most biologically active component. As an antioxidant, silymarin reduces free radical production and lipid peroxidation in the liver and slows glutathione depletion.318 In the laboratory, silymarin displayed marked hepatoprotective effects. It significantly reduced hepatic necrosis in rats caused by toxic doses of acetaminophen319 and protected liver cell membranes exposed to an array of hepatotoxins.320,321 It also demonstrated the ability to regenerate hepatic tissue322 and enhanced liver detoxification.323

Silymarin is used commercially as a hepatoprotectant and a treatment for chronic inflammatory liver disorders such as cirrhosis, hepatitis, and alcohol-related fatty liver disease.324 It is well known as a treatment for liver damage caused by toxic chemicals and for occupational liver diseases325 and as an antidote to mushroom poisoning.

Milk thistle extract has been the subject of more than 200 placebo-controlled clinical trials. It is very difficult to sort out the results because doses and treatment protocols were not consistent among studies. Trials lasted from 7 days to 2 years and methods to judge improvement and follow-up varied widely. Unfortunately, many of the studies were poorly designed. In all the trials, the most frequent benefit was lowering of liver enzyme levels. Trials to study alcoholic liver disease showed widely divergent results. Some studies reported normalization of liver function tests, improvements in liver tissue, and significantly lower death rates with silymarin,326-328 while others found no effect on survival or clinical course of liver disease.329,330 Several studies that evaluated the effects of milk thistle on viral hepatitis showed improvement in liver enzymes, but none in liver function.331,332 Two other studies found that the reverse was true.333,334 There are some positive trends in studies of patients with alcoholic and nonalcoholic cirrhosis.329,330 Although silymarin has significant anti-cancer activity in laboratory studies, there have been no studies evaluating milk thistle as a treatment for hepatocellular carcinoma.335,336 Unfortunately, it is not known how silymarin interacts with interferon or ribavirin. A large study of milk thistle therapy in hepatitis funded by the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases is underway.

Milk thistle is safe; there were no signs of toxicity in studies when dogs were given very high doses for 1 year.337 Side effects are mild, and their incidence is low.329 GI disturbances, mild allergic reactions, and laxative effects have occasionally been reported.338

Licorice Root

Licorice root has been an important part of herbal medicine for thousands of years, but today it is most well known as a treatment for peptic ulcers. Licorice root contains a variety of compounds; glycyrrhizin is responsible for most of its pharmacological activity. Glycyrrhizin is converted into glychyrrhetic acid in the body by an enzymatic reaction. Glycyrrhizin has various immune-modulating actions339 as well as potent anti-inflammatory,340 antioxidant, antiviral, and anti-tumor constituents.341 The mechanisms of actions are not fully understood. It is known that glycyrrhizin stabilizes lysosomal membranes.342 It also inhibits the enzyme that breaks down cortisol, resulting in a prolongation of its anti-inflammatory effects.343 Glychyrrhetic acid inhibits the complement cascade344 and might potentate the anti-inflammatory effects of cortisol.343

Glycyrrhizin is active against both DNA and RNA viruses and is effective against viral hepatitis A,345 hepatitis B,346 and hepatitis C in clinical and laboratory studies.347 In Japan, glycyrrhizin is widely used to treat chronic hepatitis B346 and lower ALT levels in patients with CHC.348 Its antiviral mechanism appears to be twofold: a direct inhibitory action on viral replication and function and stimulation of the host immune system T-cells to produce interferon-y.343 This has been demonstrated in several animal studies. When splenic T-cells were transferred from glycyrrhizin-treated mice to mice exposed to the influenza virus, all of the recipients and none of the controls survived. Another study with the same design resulted in improved resistance to herpes simplex virus.349 Glycyrrhizin increased production of IL-10 in the cells of mice with hepatitis.122

Glycyrrhizin lowers ALT levels122,350 and possesses a hepatoprotective effect against cirrhosis and a variety of carcinogens.338,351 A study that evaluated the effect of glycyrrhizin showed that long-term treatment of CHC patients prevented hepatocellular carcinoma. After 15 years, the incidence of hepatocellular carcinoma was 12% in patients treated with glycyrrhizin for a median time of 10 years and 25% for those who had used other supplements or herbal medicines. The relative risk of HCC in patients not treated with glycyrrhizin was higher than those who were.348

Combination treatment with interferon and glycyrrhizin for CHC is also being investigated. In a trial that enrolled patients who had not responded to interferon, 33% of those treated with interferon alone and 64% of those who received interferon plus glycyrrhizin achieved normal serum ALT levels. Histological improvement was not significant, but reversal of histological grade was more frequently in the interferon and glycyrrhizin group.352 In a study of patients who did not respond or were unlikely to respond to interferon, glycyrrhizin lowered serum ALT during treatment, but had no effect on HCV-RNA levels.353 Intravenous treatment with glycyrrhizin induced a significant ALT decrease in non-responders and difficult-to-treat patients, but the effect disappeared when the treatment was stopped.350 When ursodeoxycholic acid was added to glycyrrhizin in a 24-week trial, results showed a significant decrease in ALT levels, but no change in viral load in either group.354

Glycyrrhizin and glychyrrhetic acid inhibit the breakdown of cortisol which can result in the common side effects associated with licorice root: edema, sodium retention and low serum potassium levels, and high blood pressure.355 Patients with cardiovascular or renal disease should discuss the use of licorice root with their physicians.

Green Tea Extract

The Chinese have used the leaves of Camellia sinensis as a treatment for many diseases, for over 4000 years. Green tea contains flavonoids and B and C vitamins356,357 and is rich in the polyphenols, gallic acid and catechin, and their derivatives.358 Epigallocatechin-3-gallate (EGCG) is the major and the most active polyphenol in green tea extracts,359 other components of green tea, such as caffeine and tannin, have therapeutic applications as well.

The potent antioxidant activity of green tea catechins has been well researched. Green tea has a positive influence on lipid metabolism and exerts anti-mutagenic and anticancer effects. The polyphenols in green tea can influence the proliferative processes of the cells.360 Epidemiological studies have showed that green tea reduces the risk of cancer361 and is a successful adjunct to chemotherapy. However, a positive association between green tea consumption and development of stomach and colon cancer also has been reported.362

The hepatoprotective effect of green tea modulates the inflammatory processes and protects against DNA damage.363 Studies in mice showed that green tea inhibited chemical-induced hepatotoxicity.364 Green tea also is an effective treatment for hepatitis.365 Oxidative stress plays a part in activation of hepatic stellate cells during hepatic fibrogenesis. The polyphenols from green tea scavenge oxygen radicals and prevent activation of stellate cells, thereby minimizing liver fibrosis.359 Polyphenols from green tea are potent free radical scavengers.366 In the laboratory, epigallocatechin-3-gallate protected against oxidative stress and hepatotoxins toxicity created by cytochrome P450 enzymes.367

Tea drinking is safe. In fact, a Japanese longevity study that followed 3000 practitioners of the Japanese tea ceremony for 8 years showed a positive correlation between the regular drinking of green tea and a long life.365 There is some evidence that highly condensed tannins and catechins could induce esophageal cancer. Green tea might antagonize the effects of warfarin, an oral anticoagulant.368

Other Botanicals for Hepatitis C

Coffee. A population study of 6000 adults found a positive correlation between coffee and caffeine and a lower risk of liver injury in people with a high risk for liver disease. Individuals with CHC and iron overload were included in the high-risk population studied.369

Mistletoe. In a very small study, a combination treatment of Viscum album (mistletoe) and an extract of Solanum lycopersicum, Fragaria vesca, and Vitis vinifera (Hepatodoron) reduced fibrosis in five of eight patients with HCV infection370

Lycopene. Lycopene is a carotenoid found abundantly in tomatoes and in some red and orange vegetables. In an experiment to distinguish the effects of lycopene from tomato extract on acute liver injury, first rats were force-fed the oxidant carbon tetrachloride and then fed either lycopene or tomato extract. Results showed that that tomato extract, not lycopene, partially protected against acute liver injury due to chemically induced oxidant stress.371 In a clinical trial that enrolled 92 patients with chronic hepatitis C, a tomato-based functional food reduced the severity of ribavirin-related anemia and improved the tolerance to the full dose of ribavirin in patients with chronic hepatitis C.372

FUNCTIONAL AND PRACTICAL MEDICINE

The extent of the impact of poor nutrition on HCV activity and progression of liver damage is unknown. However, the liver is the primary metabolic organ and the intermediary in the metabolism of nutrients and bile salts. As such, it significantly influences absorption, storage, and metabolism in the body. Damage to the liver can lead to vitamin and mineral deficiencies and malnutrition.373

Nutrition can play a critical role in the management of HCV infection at all stages of the disease. Preventive measures, such as dietary changes and avoidance of alcohol, can reduce the progression of liver disease significantly. The consequences of the interaction of HCV with alcohol, HBV, and malnutrition are well recognized. Superinfection with hepatitis A or B virus can lead to liver failure. HCV and alcohol act synergistically to accelerate the development of cirrhosis;374 moreover, alcohol is at least as important as HCV in the process.375 A study that explored the role of diet on disease risk in cirrhotic men showed that a high-fat, low-protein and low-carbohydrate diet significantly increased the risk of cirrhosis and that the alcohol and CHC further increased the risk.270

Being overweight is strongly associated with elevated ALT levels and increases the risk of liver disease. A large, national study found that central adiposity (i.e., higher waist-to-hip circumference ratio) and elevated levels of leptin and insulin were major determinants of the association of overweight with elevated serum ALT.376 A diet that restricts total calories, fat, iron, and protein reduced serum ALT levels in patients with long-term HCV infection.377 Weight reduction and exercise can improve liver function in patients with fatty liver disease374 and may be able to reduce steatosis and fibrosis.373

In addition to increasing the response to treatment and decreasing its side effects, healthy eating can improve the quality of life for HCV patients. Good nutrition has the potential to hinder disease progression, as well. Subtle nutritional deficits are not always obvious at early stages of infection with HCV. Usually liver failure is only evident after most hepatocytes have been destroyed; then it is difficult for the body to use nutrients appropriately, synthesize plasma proteins, and remove toxic substances. HCV patients usually do not need special diets unless they have advanced liver disease or some condition that requires dietary modification, such as diabetes.373

A healthy diet for HCV-positive patients should be composed of foods from all food groups. It should include enough calories and protein to fight infection and regenerate the liver and an ample supply of vegetables and fruit to maximize free radical-fighting antioxidants. High-fat and high-sugar foods should be limited. Ideally, eat small meals that are spread out over the day. In general, low-protein diets promote malnutrition and are only recommended for patients with acute hepatic encephalopathy.373

Dietary modifications can have a beneficial effect on complications of HCV infection, such as cirrhosis, hepatic encephalopathy, and transplantation surgery.373 Dietary needs for individuals with compensated cirrhosis are similar to those with acute HCV infection. However, frequent, small meals improve nitrogen and substrate use, diminish fat and protein oxidation, and prevent depletion of glycogen stores. Because cirrhotic patients experience swings in blood sugar, the diet should be high in complex carbohydrates and low in sugars. Protein needs vary, but these individuals tend to tolerate the protein from dairy and plant sources better than those from meat. Cirrhosis often makes it difficult to digest and absorb dietary fat which results in steatorrhea, i.e., undigested fat in the stool. Reduction of fat to 25% of total calories is recommended. If steatorrhea is severe, supplementation of fat-soluble vitamins might be recommended. Nutritional drinks containing medium-chain triglycerides do not need bile to be absorbed into the bloodstream, and can be helpful when the liver can no longer produce enough bile. Fatty liver can also benefit from reduction of fat in the diet. Sodium is typically restricted for patients with cirrhosis.

Hepatitis C

Encephalopathy is a condition in which ammonia—normally neutralized by the liver—builds up in the body. Untreated, encephalopathy can lead to confusion, personality changes, coma, and death. Encephalopathy is characterized by abnormally high aromatic amino acids and low branched chain amino acids.373 The treatment for encephalopathy373 is usually protein restriction and medication that helps rid the body of ammonia. Even in encephalopathy, protein is never eliminated completely from the diet.373 Supplementing the diet with branched chain amino acids is can improve encephalopathy, particularly in malnourished individuals prone to infection. Because vegetable proteins contain less aromatic amino acids than other foods, a carefully balanced vegetarian-type diet is usually beneficial. Some investigators think that mineral imbalance is implicated in the development of encephalopathy.373

Treatment with Interferon-a and ribavirin induces malnutrition in the early stage of therapy. Anorexia, nausea, and vomiting—frequent side effects of treatment—can cause dehydration, electrolyte imbalances, abnormal metabolism, and weight loss.378 There is a positive connection between elimination of HCV RNA and nutritional status. It has only recently been learned that some amino acids can modulate immunological response. A study that analyzed the effects of nutrition on the clearance of HCV showed that total amino acids and branched chain amino acids decreased during therapy. Early in the course of therapy, the balance of amino acids changed to levels similar to patients with cirrhosis. There was a decrease in total and branched chain amino acids and differences in the concentration of citrulline and ornithine between HCV RNA-negative and HCV RNA-positive groups. These results suggested that modifying the balance of amino acids at the beginning of treatment might upregulate the immunological response by improving the nutritional status. Adequate nutrition support would contribute to patient quality of life as well as decrease the number of patients who withdraw because of side effects.379

Almost all drugs are metabolized in the liver before they are eliminated from the body. Consequently, all medications, even over-the-counter preparations and herbal remedies, are potentially hepatotoxic and should be used with caution in patients with chronic liver disease. Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen should be avoided, in particular. ([See the Acetaminophen Poisoning (Analgesic Toxicity) protocol.).] Some vitamins taken in mega-doses could be harmful. Vitamin A taken in very high doses has caused permanent liver damage.

Moderate physical activity is recommended for all HCV patients, unless they have decompensated cirrhosis or serious metabolic complications. Exercise will not affect the course of infection, but it can help relieve fatigue, stress, and depression; improve appetite; build up the immune system; and in general improve the quality of life.373

SUMMARY

HCV infection is one of the leading causes of liver disease and one of the major risk factors for developing cirrhosis and hepatocellular carcinoma. The majority of infections become chronic, but the spectrum and progression of disease associated with HCV is highly variable. The particular genotype of the virus influences the choice of treatment and ultimate outcome of the disease. There is no vaccine and conventional treatment options are limited. All current conventional treatments are based on synthetic interferon-a—a combination of pegylated interferon and ribavirin is the most effective treatment available to date. Many people who become HCV-infected are immediately excluded from this treatment because of contraindications to interferon. Of the group than can take interferon, many will not respond to treatment; or they will respond and then relapse. The success rate of retreatment with interferon-a is so low that is not an option except in clinical trials.

The theory behind the pegylated interferon and ribavirin combination is scientifically sound: mimic the body’s own endogenous interferon to boost the immune system and, at the same time, use ribavirin drug to kill the virus. But there is a general agreement that less-toxic and more virus-specific treatments must be developed. There is also a need for better treatment of the principal complications of CHC and the side effects of interferon. Alternative therapies and multifaceted treatment strategies based on scientific evidence that are directed at bolstering the immune system are a welcome addition to the armamentarium of treatments for CHC.

After infection with HCV, the body’s endogenous cytokines mount a defense to combat the virus, indirectly through the immune response and directly through inhibition of viral replication. Pro-inflammatory cytokines, such as interferon and interleukin, produce antiviral immune responses; and that HVC-induced oxidative damage to the liver is due to pro-inflammatory cytokines. A healthy immune system and an appropriate ratio of pro-inflammatory and anti-inflammatory cytokines can improve overall health by combating the virus directly and by increasing the effectiveness of pegylated interferon and ribavirin. Several alternative treatments have demonstrated an ability to increase the response rate of conventional treatment, and many can lower or normalize ALT levels. Epidemiologic studies show that many patients with persistently normal ALT levels do well and do not develop severe cirrhosis or liver cancer.

The nutritional and botanical treatment regimes discussed in this protocol, coupled with a healthy lifestyle, can improve the functioning of the immune system by increasing antioxidant levels in the body and thus minimize damaging effects of free radicals to liver cells.

LIFE EXTENSION’S INTEGRATED PROTOCOL

• Nutritional Recommendations
• Lifestyle Modifications

Nutritional Recommendations

Conventional therapy consists of weekly injections of peginterferon alfa-2b (pegylated interferon) along with a prescribed dose (usually 800-1200 mg a day) of ribavirin (Rebetol). The treatment interval used with these two drugs is determined by the physician.

Iron promotes hepatitis virus-induced liver injury and precludes successful treatment with interferon. Verify that liver iron levels have been reduced before starting interferon therapy. To sufficiently reduce iron levels, some patients require withdrawal of blood before beginning interferon-ribavirin therapy. (HCV patients cannot donate blood; therefore, this blood must be discarded.) Be certain that serum iron levels are at the lowest possible tolerable levels (ideally below 60 mcg/dL of blood) while serum ferritin levels should be maintained in the low normal range of 30-80 nanograms/dL. As long as symptoms of anemia do not appear, lower iron as much as possible (under a physician's supervision).

To block iron absorption and lower iron levels, take:

• Calcium citrate, one to two 1000-mg capsules with iron-containing foods
• Lactoferrin, (apolactoferrin form) one 300-mg capsule 3 times daily (Lactoferrin is also a potent immune-boosting agent.)

To reduce oxidative stress by boosting liver cell glutathione levels, take:

• R+Dihydro-lipoic acid, 150 mg capsule 3 times daily
• N-Acetylcysteine (NAC) – 600 mg capsule once daily
• Whey protein isolate, 20-40 grams daily
• Glutathione, 500 mg capsule once a day on empty stomach
• Methylcobalamin (Vitamin B12) – 5 mg tablet once daily sublingually
• Silibinin extract, 250 mg capsule 3 times daily

To protect and restore liver function by facilitating healthy methylation patterns in the liver critical for life-sustaining enzymatic actions take:

• SAMe, 400 mg tablet 3 times daily.

Additional methylation-enhancing agents that work synergistically with SAMe are:

• Trimethylglycine (TMG), 1000 mg twice daily
• Folic acid, one 800 capsule mcg 3 times daily (combined with methylcobalamin (B12) in the dosage ratio of 800 mcg folic acid and 300 mcg of vitamin B12).

The following choline-containing nutrients enhance the effects of interferon, maintains the stability of liver cell membranes, and are methyl-sparing because they provide preformed methylated compounds.

• HepatoPro (Polyenylphosphatidylcholine) in a dose of 900 mg daily
• CDP-Choline in a dose of 250 mg daily.
• Alpha glycerylphosphorylcholine (GPC) in a dose of 600 mg daily.
• Lecithin Granules in a dose of 10 grams daily.
• Phosphatidylserine in a dose of 100 mg daily.
• Creatine in a dose of 2,000 to 3,000 mg daily.

To provide antioxidants and natural antiviral agents directly to liver cells, take:

• Green tea extract, 2 capsules at breakfast and 2 capsules at lunch (Green tea also helps block iron absorption.) Each capsule should be standardized to provide at least 100 mg of epigallocatechin gallate (EGCG). The EGCG fraction of green tea provides the greatest antioxidant and anticancer effects.
• Garlic, 2700 mg once daily (a high-allicin, 10,000-ppm garlic supplement with food). If stomach irritation or pungent odor causes a problem, take 1000 mg of aged Kyolic garlic extract.
• Grape seed-skin extract (85-95% proanthocyanidin), 100 mg 2-3 times daily.
• Selenium, 200-600 mcg once daily.

To maintain youthful immune function, take:

• DHEA – 15-50 mg once daily sublingually. See DHEA Replacement Protocol for specific information.
• Life Extension Herbal Mix – Standard dose
• Life Extension Mix – Standard dose

The standard doses of Life Extension Mix and Life Extension Herbal Mix. Please note that some hepatitis C patients encounter liver enzyme elevations in response to moderate doses of vitamin A, niacin, and beta carotene in Life Extension Mix. If your liver enzyme levels elevate after using Life Extension Mix, discontinue it and take the other nutrients contained in Life Extension Mix. Beta carotene possesses unique immune-enhancing benefits that could help suppress the hepatitis C virus, but some hepatitis C patients cannot tolerate it.

Lifestyle Modifications

• Do not drink alcoholic beverages. Hepatitis C patients are especially vulnerable to its damaging effects. The liver of hepatitis C patients is especially vulnerable to the damaging effects of alcohol.
• Eat more fresh fruits, vegetables. Foods high in fiber have less saturated and trans fats. These foods naturally provide the many minerals, vitamins, and essential fatty acids we recommend below, and many other beneficial natural substances we have yet to define.
• Reduce stress on and off the job.
• Exercise regularly and keep your weight within normal limits.

If your doctor prescribes medicine to treat your HCV infection, be sure to follow his directions precisely. Make sure he knows all the prescribed and over-the-counter medicines you are taking. The following drugs are some that might be prescribed:

• Branded Interferon
  • Peginterferon (40KD) (Pegasys®; Roche Laboratories; Nutley, New Jersey)—40-KD branched peg chain.
  • Pegylated interferon-2b (12KD) (PEG-Intron™; Schering-Plough; Kenilworth, New Jersey)—12-KD linear peg chain
  • Unmodified interferon (Roferon-A®, Intron A®).
• Branded Ribavirin
  • Rebetron™
• Standard Doses for Chronic hepatitis C
  • Interferon 3 million IU sc three times weekly + oral ribavirin 1200 mg daily in two divided doses
  • Pegylated interferon -2b monotherapy 1.0 µg/kg, once weekly over 24 weeks
  • IFN alfa-2b 3 MIU 3 times a day

For More Information Contact

• American Liver Foundation, 800-GO-LIVER (465-4837); E-mail: webmail@liverfoundation.org, http://gi.ucsf.edu/ALF/alf/alfservs&acts.html
• Hepatitis Foundation International, (301) 622-6400
• HepC Connection 800-522-HEPC, www.hepc-connection.org
• American Association for the Study of Liver Diseases, (703) 299-9766; E-mail: aasld@aasld.org http://www.aasld.org/

Products Available

Silibinin Plus, HepatoPro (PPC) capsules, Pure Gar (high-allicin garlic) or Kyolic aged garlic capsules, Super Selenium, R+Dihydrolipoic acid, alpha-glycerylphosphorylcholine (GPC), lecithin granules, CDP-Choline, phosphatidylserine, DHEA, N-acetyl-cysteine, lactoferrin, SAMe, Life Extension Mix, Life Extension Herbal Mix, grape seed-skin extract, folic acid, creatine, methylcobalamin (B12), TMG, whey protein isolate, L-glutathione, calcium citrate, and standardized green tea capsules (regular and decaffeinated) are available by calling 1-800-544-4440 or by ordering online. Prescription drugs cited should be prescribed by a doctor who treats hepatitis.

Disclaimer

This information (and any accompanying printed material) is not intended to replace the attention or advice of a physician or other healthcare professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a qualified health care professional.

The information published in protocols is only as current as the day the book was sent to the printer. This protocol raises many issues that are subject to change as new data emerge. None of our suggested treatment regimens can guarantee a cure for these diseases.

Janice Roma Kane, DO is a science writer and consultant to the nutraceutical industry. She specializes in phytomedicinals and is the author of numerous monographs and professional articles on the subject. janicekane@medscape.com.

Randall Lee Kohl, MA, PhD, RPh, FCP is a writer, executive editor, and medical director for the Life Extension Foundation. He is a Fellow with the American College of Clinical Pharmacology (since 1990) and served as Research & Technology Operations Manager for NASA from 1980-1992. He is author of over 77 publications, acted as Principal Investigator on 14 clinical research studies, and is a licensed pharmacist in 3 states. Direct comments to rkohl@lef.org.

Hepatitis C

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