HEPATITIS B

OVERVIEW

Hepatitis B virus (HBV) infection is a global health problem. More than 2 billion people are infected with HBV (as of 2004); more than 350 million are chronic carriers.1-3 In the United States alone, more than one million are chronic carriers. Over 150,000 new symptomatic infections are diagnosed each year.4 A significant portion of those who develop chronic hepatitis B (CHB) infections will die from cirrhosis and primary hepatocellular carcinoma.3,5 As a human carcinogen, HBV is second in importance only to tobacco.6,7

EPIDEMIOLOGY AND GENETICS

• Communicability
• Natural History
• Diagnosis
• Viral Characteristics
• Hepatitis B Virus

New infections have declined overall because of increased vaccination among adults and modification of high-risk behavior. However, steady increases in infection occur in three major risk groups: sexually active heterosexuals, homosexual men, and injection drug users.7 Despite a decline in HBV infection in the United States, incidence of hepatocellular carcinoma has almost doubled in the last 15 years. Deaths from hepatocellular carcinoma have increased by 40% because of the large pool of individuals infected before the advent of immunization programs.8

Half of the world population lives in areas where HBV is endemic. Patterns of infection vary geographically and in population subgroups.2,3 In North America, Western Europe, and Australia, prevalence of chronic infection is less than 1%.9,10 Prevalence is between 1% and 8% in Eastern Europe, the Mediterranean, the Middle East, Japan, and parts of South America9,11 and greater than 8% in Asia and Africa.9,12 HBV might be much higher in some population groups than national averages. For example, in Canada where prevalence of chronic infection is less than 1%, the HBV carrier rate in Vietnamese refugees is 12%.13

The HBV transmission route varies with endemicity of the HBV infection, and endemicity is influenced by the age when infection is acquired. In countries of high endemicity, HBV infection is commonly acquired during the preschool years or from a mother during birth.14 In areas of intermediate endemicity, transmission is usually perinatal or acquired from close contacts (horizontal transmission).15,16 Transmission of HBV from friends and family is not fully understood: it might be from blood or saliva contacting open wounds or from sharing personal items.17 In areas of low endemicity, most HBV infections are acquired in early adulthood through parenteral transmission or unprotected sex.10 The most common parenteral route is intravenous drug use.18 Other routes of infection can occur: contaminated surgical instruments, ear piercing, tattooing, and acupuncture.12 HBV infection is considered a sexually transmitted disease. It is dramatically increased in people who have other sexually transmitted diseases or have more than three sexual partners in 6 months.3 Transmission by blood transfusion, once common worldwide, is now rare.

Communicability

HBV is a highly resilient virus that is easily transmitted. The virus is 100 times more infectious than HIV, and the risk of seroconversion to HBV after a single exposure to infected blood is as high as 30%.4 Man is the only natural host for HBV. Infection is spread by contact with blood and body fluids,3,7 including semen, vaginal secretions, and saliva.16 HBV is estimated to live outside the body for 7 to 30 days, making indirect inoculation through inanimate objects possible.3,7 Common germicides kill HBV easily: chlorine bleach, ethanol, and isopropanol.19

Anyone who comes in contact with infected blood is at high-risk for HBV infection, including healthcare workers, laboratory technicians, injection drug users, men who have sex with men, dialysis patients, HIV-infected individuals, and family members and sexual contacts of people already infected with HBV. All people born in highly endemic areas are at risk.3,7 Approximately 25% of HBV patients appear to have no risk factors. This is usually attributed to reluctance to report high-risk behavior or to as yet unrecognized routes of infection.

Natural History

HBV infection causes an inflammatory reaction that destroys liver cells and often impairs liver function. The clinical spectrum of HBV infection is highly variable, ranging from asymptomatic chronic carriers to fulminant hepatitis. Age at the time of infection, viral characteristics, and exogenous factors (e.g., coinfection or alcohol use) all influence the natural history of the disease. Only a minority of those infected acutely with HBV will develop symptoms. When infection is acquired during birth, it is usually asymptomatic and becomes chronic. About 90% of adults with acute HBV recover completely; however, a small number are unable to clear the virus and become carriers.9

Diagnosis

An HBV infection shares important diagnostic features with other hepatitis viruses. They are indistinguishable from each other in the acute stages and consequently difficult to diagnose by symptoms alone.20 Symptoms of acute viral hepatitis vary from a minor flu-like illness to liver failure. Most patients with acute HBV infection develop only a few mild, nonspecific symptoms and sustain minimal damage to liver tissue. Infection usually begins suddenly (prodromal phase). Symptoms vary in the prodromal phase. Many patients think they have the flu. They might experience low-grade fever, fatigue, loss of appetite, a distaste for cigarettes, nonspecific malaise, nausea and vomiting, nondescript upper abdominal discomfort—or no symptoms at all. The liver is enlarged in half of infected individuals; about 20% also have an enlarged spleen. The icteric (jaundice) phase follows in 3 to 10 days. During the icteric phase, the urine darkens, and the skin might 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 acute infection is mild, when diagnosed with chronic hepatitis many years later, many patients do not remember the original infection.20

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.20 Severity of symptoms is not related to seriousness of the disease. Approximately 15% of chronically infected adults develop cirrhosis within 20 years of initial infection. Development of cirrhosis of the liver is often asymptomatic. Some patients are unaware of their infection until they are diagnosed with advanced disease—notably, liver failure and hepatocellular carcinoma.21

Viral Characteristics

All viruses, including HBV, produce proteins in the blood called antigens (Ag). Antibodies (Ab) are proteins produced by immune system cells that recognize and interact with viral antigens to make them ineffective. Each antibody is specific for one antigen. The presence of antibodies to a certain antigen indicates a previous exposure to that antigen. Seroconversion is the development of antibodies in the blood, i.e., a change in blood status from antigen positive (+) and antibody negative (-) to antigen (-) and antibody (+) (Ag+, Ab- to Ag-, Ab+). The body produces antibodies to surface antigens as part of a normal immune response to infection. Development of cellular and humoral immunity to viral antigens is protective—recombinant viral antigens provide the basis for the several vaccines currently available.

Hepatitis B Virus

Hepatitis B virus (HBV) is highly complex. It is a member of the hepadnaviruses family of DNA viruses. The whole virion (smallest unit of a mature virus) is a sphere that is composed of an inner core (nucleocapsid) surrounded by an outer protein coat (envelope). The core contains double-stranded circular HBV-DNA, DNA polymerase, and two proteins: HBcAg (c, core or Dane particle) and HBeAg. Eighty percent of the viral envelope is composed of a protein known as HBsAg (s, surface). During HBV infection, large quantities of HBsAg are produced in the liver. Following infection, the virus invades the liver cells where it replicates. HBV particles are then secreted from the liver cells and released into the circulation where they can infect neighboring hepatocytes or be transmitted to a new host via blood or other body fluids. One peculiar feature of HBV is the great excess of envelope material (HBsAg) found in the circulation.22

Several viral components, antigens, and antibodies are considered markers of disease and are used to diagnosis and monitor the treatment of patients with chronic hepatitis B (CHB) .

Hepatitis B Virus-DNA

The presence of HBV-DNA in blood correlates with infectivity and is used as a marker of viral replication and a predictor of response to therapy.

Hepatitis B Surface Antigen

If hepatitis B surface antigen (HBsAg) is detected in blood, then HBV is present. HBsAg is usually the first indicator of an acute HBV infection and implies infectivity. HBsAg appears 1 to 6 weeks before clinical or biochemical illness develops and disappears during convalescence. It can be detected in high levels in serum during acute or chronic hepatitis.20

Hepatitis B Surface Antibody

Hepatitis B surface antibody [HBsAb (anti-HBs)] is formed in response to HBsAg. HBsAb appears weeks or months after recovery from an infection and usually lasts for life. Detection of HBsAb in blood indicates recovery from a HBV infection and development of long-term immunity. HBsAb (anti-HBs) can be produced in response to vaccination or recovery from an actual HBV infection. It might be undetectable in patients who have recovered fully from infection.

Seroconversion from HBsAg (+)/HBsAb (-) to HBsAg (-)/HBsAb (+) indicates a cure of an HBV infection. In some individuals, HBsAg persists after acute infection and HBsAb does not develop; these patients usually develop CHB or become asymptomatic carriers of the virus.

Hepatitis B Core Antigen

Hepatitis B core antigen (HBcAg) is the inner core that encloses viral HBV-DNA. HBcAg is a peptide derived from HBcAg on the surface of hepatocytes that induces the immune response that kills infected cells. HBcAg can be found in infected liver cells, but is undetectable in blood.20

Hepatitis B Core Antibody

Presence of hepatitis B core antibody [HBcAb (anti-HBc)] indicates previous or ongoing infection with HBV. It is detected in virtually all individuals who have ever been exposed to HBV. HBcAb appears at the onset of symptoms and usually persists for life. Unlike HBsAb, HBcAb does not provide any protection or immunity against HBV. It is also found in chronic carriers of HBsAg, who are unable to mount a response to HBcAg. The presence of HBcAb alone cannot be used to distinguish acute from chronic infection. Individuals with persistent infection and those who have recovered from HBV infection are positive for HBcAb. HBcAb is mainly from the IgG class of immune globulins (type G) in a chronic infection and the IgM class in acute infection. In some cases, IgM HBcAb is the only marker of a recent HBV infection, although its presence is not an absolutely reliable marker of acute illness.23

Hepatitis B e Antigen

Hepatitis B e antigen (HBeAg) is derived from the viral core and parallels the production of viral DNA polymerase. HBeAg serves as a marker of active viral replication and indicates that an individual is potentially infectious. HBeAg is associated with a diminished immune response. In almost all cases, HBeAg is found only in those who are HBV-DNA (+).24,25

Hepatitis B e Antibody

Hepatitis B e antibody [HBeAb (anti-HBe)] indicates lower infectivity and usually a benign outcome. Seroconversion from HBeAg (+) to HBeAb (+) indicates a significant decrease in viral load.20 HBeAb appears after HBeAg has stopped replicating.

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 (lobules) that are bounded by portal triads and central veins. Each portal triad is the center of a microvascular unit (an acinus). Lobules contain enlarged capillaries (sinusoids), hepatocytes (liver cells), and specialized cells. Most cells in the liver are hepatocytes which are responsible for the liver's central role in metabolism and regulation of blood constituents. 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.

Specialized cells include PiT-cells that are thought to be tissue lymphocytes that act with natural killer cell functions; Ito cells that store vitamin A, synthesize various proteins, and can transform into fibroblasts in response to injury; and Kupffer's cells which are macrophages that destroy microbes, foreign particles, and worn out blood cells, remove endotoxins, and modulate immune response.

The liver can eliminate toxic substances (e.g., alcohol and drugs) by neutralizing them with the cytochrome P450 system. Cytochrome P450 enzymes contain iron and are specialized for oxidizing chemicals, making them more water soluble and more easily eliminated by the kidneys. Overproduction of P450 enzymes is toxic to the liver. The liver can detoxify harmful substances by attaching molecules to their side chains, changing their chemical composition and making them inactive.

PATHOPHYSIOLOGY

• Chronic Hepatitis B: Life Cycle
• Hepatitis B Virus: Clinical Syndromes
• HBeAg Status
• Mutant Hepatitis B Viruses
• Outcome
• Genotyping
• Liver Function Tests
• Treatment Goals

HBV itself usually does not kill liver hepatocytes—liver injury is usually caused by an immune attack by the body against HBV. A vigorous immune response is responsible for complete viral clearance as well as the most severe liver injury. Individuals with immature or depressed immune systems are more likely to become asymptomatic chronic carriers of HBV.26 The effectiveness of an immune response determines the extent of inflammation and necrosis sustained by the liver. For example, 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, have a role in chronic liver disease and the mechanisms of liver damage.27 The inflammatory response produces reactive oxygen species and cytokines.28,29 Cytokines combat viral infections, indirectly through the immune response and directly through inhibition of viral replication.30 Pro-inflammatory cytokines (e.g., interferon-a, tumor necrosis factor-a, and interleukins IL-1 and IL-6) produce antiviral immune responses. Anti-inflammatory or “permissive” cytokines (IL-4 and IL-10) down-regulate the immune response. An inappropriate ratio of pro-inflammatory and anti-inflammatory cytokines might alter individual outcomes or the effect of antiviral drugs.31

Genetic factors are important determinants of inflammatory cytokine production and are closely linked to susceptibility to liver disease.32 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,33 the oxidant molecules produced as part of the inflammatory response might damage healthy tissue. For example, the enhanced cytokine and reactive oxygen species production that follows bacterial infection is designed to combat bacteria. Yet during the battle, it can damage the body and accelerate disease. Some of the oxidative damage to the liver seen in viral hepatitis is due to excessive production of pro-inflammatory cytokines.34

Chronic Hepatitis B: Life Cycle

Chronic hepatitis B (CHB) is defined as persistence of HBsAg and HBcAb and detectable HBV-DNA in the blood for more than 6 months. Factors that effect progression through the stages in a host include gender, genetics, coinfection with other viruses, immunosuppressive drugs, and development of HBV mutants.9 The life cycle of CHB can be divided into four successive stages of infection that are present in some form in all individuals infected with HBV (see Table 1):

Stage 1. Immunotolerant

The first stage is an incubation period that lasts from a few weeks in a healthy adult to years in a neonate. The immunotolerant stage is frequently asymptomatic. There is active replication of HBV-DNA in the blood, HBsAg and HBeAg are detectable, and alanine aminotransferase (ALT) is normal or minimally elevated.9

Stage 2. Immunoactive

Symptoms might appear during the second stage. An immunologic response develops or improves. HBV-DNA levels decrease as infected cells die. Flares of ALT might be seen. In some patients, these flares are followed by HBeAg to HBeAb seroconversion. In an acute HBV infection, the immunoactive stage is symptomatic and lasts 3 or 4 weeks. In CHB, Stage 2 might last more than 10 years and lead to cirrhosis.9

Stage 3. Inactive Carrier or Non-Replicative

If a host is able to mount an immune response that eliminates or greatly reduces infected cells, the third stage begins. In Stage 3, viral DNA markedly decreases and ALT levels are normal. In some patients, HBsAg becomes undetectable and the infection is resolved; others might develop HBeAg (-) CHB.9

Stage 4. Immune

Not all individuals infected with HBV reach the immune stage. Individuals who do are unlikely to become reinfected. During Stage 4, HBV-DNA is undetectable in the blood, HBsAg is negative, and HBsAb is positive.9

Hepatitis B Virus: Clinical Syndromes

Hepatitis D Virus

Hepatitis D (delta) virus (HDV) is a defective RNA virus that reproduces only in the presence of HBV. HDV occurs as a coinfection with acute HBV infection or as a superinfection in CHB. Superinfection in an HBV carrier occurs typically in an injection-drug user.35 HDV infection produces an unusually severe acute form of HBV that responds poorly to therapy. Almost half of the cases of fulminant (sudden) hepatitis B are associated with HDV coinfection.20 HDV varies widely geographically. It is rare in the United States, although intravenous drug users are at relatively high risk. There is no vaccine for HDV.9

Hepatitis C Virus

Many injection-drug users are HBcAb (+) and HCV-DNA (+) which indicates that they have been exposed to both hepatitis C virus (HCV) and HBV, but have recovered only from HBV.

Human Immunodeficiency Virus (HIV) and Hepatitis B Virus Coinfection

Unlike HCV, HBV infection does not alter the outcome of human immunodeficiency virus (HIV) infection, nor does HIV infection alter the evolution of HBV infection.34 Until recently, HBV and HCV infections were not treated in HIV (+) patients because of their limited life expectancy. Today, because of new drugs, treatment of coinfection is common.37

Fulminant Hepatitis B

Fulminant HBV infection is caused by a heightened immune response to the virus or HDV or HCV coinfection or superinfection.38 Fulminant HBV infection occasionally develops after withdrawal of immunosuppressive drugs (e.g., cancer chemotherapy drugs).39

HBeAg Status

CHB can be divided into two types based on HBeAg status of the blood:15,40

Hepatitis B e Antigen (+) Chronic Hepatitis B

Hepatitis B e antigen (+) chronic hepatitis (HBeAg (+) CHB) occurs during the early phases of infection when levels of HBeAg and HBV-DNA in the serum are high. When the body is infected with HBV, the immune system attempts to clear the virus by destroying infected hepatocytes. This process increases ALT levels. Most patients clear HBeAg and produce HBeAb which results in undetectable HBV-DNA and normal levels of ALT.

Hepatitis B e Antigen (-) Chronic Hepatitis B

Hepatitis B e antigen (-) chronic hepatitis B (HBeAg (-) CHB) develops in patients who lose HBeAg and seroconvert to HBeAb. HBeAg (-) CHB patients are HBsAg (+), HBeAg (-), and HBeAb (+). HBeAg (-) CHB occurs late in the course of infection.41 It is a potentially severe and progressive form of chronic liver disease and is characterized by very rare spontaneous remissions, frequent progression to cirrhosis, and increased risk of hepatocellular carcinoma.42 Severity of HBeAg (+) CHB depends on the age when the infection was contracted.

HEPATITIS B

Mutant Hepatitis B Viruses

Individuals with HBeAg (-) CHB are infected with mutant forms of HBV that have HBV-DNA polymerase that is unable to produce HBeAg. HBeAg (-) CHB patients have elevated liver enzymes, chronic liver disease, and are HBeAb (+) and HBV-DNA (+).15,40,43,44

The YMDD mutation HBV is a lamivudine-resistant virus. Patients with YMDD mutant HBV become HBV-DNA (-) while taking lamivudine (a generic antiviral drug), then later in the course of treatment become HBV-DNA (+) again. HBeAg (-) mutants are associated with fulminant HBV. The absence of HBeAg in the blood is responsible for this more aggressive disease course.45,46 Rare "vaccine escape" mutants are viral subtypes that can cause HBV infection in vaccinated persons.47 HBeAg seroconversion rates probably differ with different HBV genotypes and selection of certain mutations in the HBV genome. Patients with HBeAg (-) CHB tend to be older and male and to have severe cirrhosis and liver inflammation.9

Outcome

Outcome in HBV infection depends on numerous factors, including gender, ethnicity, exposure to aflatoxin, and HCV or HDV coinfection.48 CHB infections acquired in childhood are usually asymptomatic for many years, despite periods of active hepatitis.15 Chronic infections acquired in adulthood are more aggressive and frequently cause death within 7 to 10 years.48 Chronic carriers might develop CHB, cirrhosis, or primary hepatocellular carcinoma. CHB patients who develop cirrhosis are more likely to be older and alcohol abusers. Other risk factors for cirrhosis are infection with HCV, HDV, or HIV. More than twice the number of HBeAg (-) CHB patients progress to cirrhosis than do HBeAg (+) patients.9 HBV infection is a major risk factor for hepatocellular carcinoma, but risk diminishes considerably after CHB resolves.49,50 HBV-associated hepatocellular carcinoma typically occurs after 25 years or more of infection—and then, only in patients with cirrhosis. Cirrhotic patients who are older, male, abuse alcohol, or have liver failure are at a higher risk for hepatocellular carcinoma.9

Genotyping

HBV has a higher mutation rate than other DNA viruses.51 Consequently, natural variants have developed: HBV serological subtypes and genotypes.52 Some mutations have a replication advantage or they facilitate immune escape. A relationship exists between HBV genotype and development of cirrhosis and hepatocellular carcinoma and response to certain antiviral drugs which is not completely understood.

All seven known HBV genotypes are found in the United States. Genotype A is most common in the United States and Western Europe. Genotype D is associated with higher risk of developing decompensated cirrhosis.53 Genotype C is associated with a greater risk of hepatocellular carcinoma.54

Liver Function Tests

Diagnostic tests for viral hepatitis assess liver function and damage and identify type and amount of virus.55,56 Alanine transaminase (ALT), serum glutamate pyruvate transaminase (SGPT), aspartate aminotransferase (AST), and serum glutamic-oxaloacetic transaminase (SGOT) are enzymes produced in the liver that are used as rough indicators (markers) of the degree of liver cell inflammation.57 Although elevations of these liver enzymes are frequently seen in acute and chronic hepatitis,57 they are not related to disease severity or outcome58,59 or to inflammatory changes or degree of fibrosis.55,56 ALT can be normal even in individuals with liver damage and can be elevated in diseases other than hepatitis.60

In acute viral hepatitis, ALT levels are typically very high in the early phases and decline slowly during the recovery phase. White blood cell count is normal or slightly low; there might be a few atypical lymphocytes.20 In chronic hepatitis, laboratory findings typically show active hepatocellular inflammation. ALT levels are elevated. Usually bilirubin and alkaline phosphatase values increase, and gamma globulin (IgG) is detectable.

Treatment Goals

Replication of HBV virus by hepatocytes causes liver injury.61 The primary treatment goal is long-term eradication of HBV-RNA from the blood; secondary goals are reversal of liver tissue damage and preservation of overall health and quality of life. Ideally, long-term suppression of viral replication should lead to reversal of liver disease and slow or stop development of hepatocellular carcinoma. In typical Stage 1 infection, patients with normal ALT levels do not progress to cirrhosis.62,63 Practically speaking, the goal of treatment is to move quickly from Stage 2—where the infection can progress to cirrhosis—62,63 to Stage 3—where there is no need for treatment.61,64

Current treatment strategy is three-pronged: antiviral medication, complications management, and liver transplant.20 Success is measured in terms of virological, biochemical, and histological responses.65,66 Virological response measures decrease in viral load. Criterion for a cure is “sustained virological response” which indicates that a patient is free of virus a certain number of months after stopping treatment.65 A biochemical response is evaluated by changes in the levels of enzymes produced by the liver. Biochemical response is a less reliable improvement indicator than virological response because levels fluctuate during treatment.67,68 Histological response is measured by improvement in the condition of liver tissue. Improvement in liver histology is directly related to a slowing of the disease and prevention of cirrhosis and liver cancer.66

PHARMACOLOGY

• Treatment Options

Treatment Options

In principle, all patients with chronic viral hepatitis are candidates for antiviral drugs. The likelihood of cirrhosis and hepatocellular carcinoma development—and consequently a need for treatment63—depends on age, immune status, viral load, geography, and genetics.62,69

Two categories of drugs are used to treat CHB infection: nucleoside analogs and immunomodulators. Immunomodulators include interferon-a, thymosin-a,1 and therapeutic vaccines. Lamivudine (3TC) and adefovir dipivoxil are the most well-known nucleoside analog drugs. Only interferon-a, lamivudine, and adefovir are approved by the FDA. Immunomodulators promote destruction of infected liver cells and stimulate cytokine production to suppress HBV replication. Nucleoside analogs suppress HBV-DNA synthesis and might accelerate clearance of infected cells.

Interferon-a

Interferon is an antiviral protein produced naturally by cells that have been invaded by pathogens. Interferon has a vital role in regulation of the immune system: by controlling the body’s reaction to viruses. Interferon increases the activity of natural killer cells and blocks production of genetic material produced by a virus. The body makes three types of interferon (a, ß, and y). Synthetic interferon-a is genetically engineered and used as a treatment for HBV infection. Today, interferon is an integral part of most treatment regimes for CHB. Patients with CHB have inadequate responses to interferon made by their own body. Recombinant interferon-a has immunomodulatory, antiproliferative, and antiviral activities.21,70 It alters the course of CHB infection by activation of immune system cells and stimulation of antibody production.71 Successful interferon-a treatment decreases HBV viral load, normalizes liver enzymes, and decreases risks of hepatocellular carcinoma and cirrhosis.72-74

Interferon has some advantages over other available treatments. Treatment time with interferon is shorter than with some other drugs. Patients who manage to sustain an initial response to interferon-a have a better chance for a complication-free survival.75,76 No viral resistance is developed with interferon-a. It produces a relatively long-lasting response in a moderate proportion of patients. At the end of 12 months of therapy, between 50% and 70% of patients treated with interferon-a have normal ALT values and have cleared HBV-DNA.74-76 However, only a very small number of patients respond to treatment with interferon; there are frequent relapses after treatment has ended. Sustained response rates are highly variable—18 months after therapy has ended, a patient’s chance of maintaining a sustained response is between 6% and 24%.75,76 Sometimes longer treatment produces higher response rates, but sustained response to treatment is maintained in less than a third of patients.77

Because of cost, side effects, and lengthy treatment time, it would be useful to know the likelihood of response before beginning treatment with interferon. Unfortunately, no factors are sufficiently predictive to accurately identify responsive patients.78 The best identifier of a patient who will respond positively is reduction in viral load during the first month of treatment.79 High pre-treatment ALT and low serum HBV-DNA levels—factors that indicate that the patient is already in the immune clearance phase—increase the likelihood of response to interferon.71,80 A greater likelihood of response is associated with younger age, female gender, low body weight, absence of cirrhosis,81 and viral genotype B.82 Men and individuals with certain types of HBV mutations and HIV coinfection are less likely to respond. Interferon is generally less effective in Asian patients, particularly patients with normal ALT levels.49 Interferon-a treatment for patients with decompensated cirrhosis or combined HBV and HDV infections has not been useful.83,84 Clinical trials of interferon as a treatment of HBeAg (-) mutant viruses have achieved high rates of remissions, but have been followed by equally high rates of relapse.85,86

Nucleoside Analogs

Nucleoside analogs are antiviral drugs that mimic natural nucleosides. They inhibit viral replication by incorporating themselves into newly replicating viral DNA which causes the chain to terminate. Nucleoside analogs cannot eradicate HBV completely.

Lamivudine. Lamivudine (3TC) is a nucleoside analog that suppresses HBV replication by inhibiting viral polymerase.70 Lamivudine inhibits HIV replication.93 Unlike interferon, which is only effective in patients who can mount an immune response, lamivudine can, in some cases, overcome poor T-cell response seen in chronically infected patients.90 The pre-treatment ALT level is an important predictor of response to lamivudine—the higher the ALT, the higher the rate of HBeAg seroconversion.91 Lamivudine has advantages of being a relatively safe drug that has mild side effects and a relatively low cost.92 Results of lamivudine studies vary widely. In a number of trials, a 12-month course of lamivudine lowered ALT levels and cleared HBV-DNA from the blood in more than 70% of patients during treatment.42 The number of patients who were able to maintain HBeAg seroconversion after lamivudine treatment was finished varied between studies.92,93 Reversion to HBeAg (+) status when lamivudine treatment is ended is common.94 After 12 months of treatment, only 20% of patients achieved seroconversion (disappearance of HBeAg and appearance of anti-HBe) on average.92,93,95-97 Overall, the sustained HBeAg seroconversion rate after lamivudine seems to be slightly lower than interferon-a.97 HBeAg seroconversion rates increase with treatment length, 42,98 but only 35% of patients treated with lamivudine remain in remission after the third year due to viral resistance. Response rates to lamivudine in HBeAg (-) patients are the same as those in HBeAg (+) patients, but about 65% of HBeAg (-) patients relapse 2 years after treatment.99 Emergence of drug-resistant HBV after treatment termination is common. With prolonged treatment, escape mutants develop in approximately 15% of patients after 1 year.101 Viral resistance ultimately has an adverse effect on liver histology42 and can cause acute liver disease.102

Adefovir dipivoxil (Hepsera®). Adefovir has been approved by the FDA as treatment for CHB infection. This nucleoside analog inhibits HBV replication103 by terminating the HBV-DNA chain. It probably stimulates natural killer cell activity and induces endogenous interferon production.104 Two weeks of treatment with adefovir results in a rapid decline in HBV-DNA levels,105 but like other nucleoside analogs, it does not eradicate HBV-DNA completely.106 The drug is active against lamivudine-resistant mutants105—no resistance has been seen in patients treated for 60 weeks.107

Famciclovir. Famciclovir is a nucleoside analog that inhibits HBV replication by incorporating itself into HBV-DNA and terminating the chain.108 It has shown some success in liver transplantation patients.109,110 Prolonged treatment with famciclovir causes drug resistance.111 Resistance to lamivudine occurs earlier in patients sequentially treated with famciclovir followed by lamivudine.110 Although it is unlikely to become an established treatment for CHB, some experts think famciclovir has some potential in combination therapies.113

Emtricitabine. Emtricitabine (Coviracil®) is a derivative of lamivudine with antiviral activity similar to lamivudine. Because of cross-resistance between lamivudine and emtricitabine, it cannot be used to treat patients with lamivudine-resistant variants.120

Combination Therapy

Several combinations of nucleoside analogs have been studied. Some synergistic effects between lamivudine and famciclovir occur.115 Relapses after treatment in patients who received only lamivudine were considerably higher than in patients who received a combination of lamivudine and famciclovir.116 Adding interferon-a to the lamivudine and famciclovir combination produced no better results than combination of the two nucleoside analogs.117 Treatment with a combination of interferon-a and lamivudine is only slightly more effective than either drug alone.95 Even if some synergic antiviral effects occur, relapse rates after combined interferon-a and lamivudine are high.118

New Drugs in Development

Entecavir. Entecavir blocks all three HBV replication steps119 and suppresses lamivudine-resistant mutants in laboratory experiments.120 Entecavir reduced viral load in CHB patients more effectively than lamivudine.121 Some patients who abruptly discontinued entecavir experienced hepatic flares.119

Ganciclovir. In clinical trials, ganciclovir suppressed HBV and lowered ALT in most patients. However, HBV-DNA rebounded in 60% of patients when treatment was discontinued, causing serious side effects.122

Antisense oligodeoxynucleotides. Antisense oligodeoxynucleotides are synthetic DNA molecules that inhibit gene expression in cells by binding to mRNA to prevent translation.123 Effectiveness depends on successful delivery of oligodeoxynucleotides to the liver.124

Ribozymes. Ribozymes (ribonucleic acid enzymes; HepBzyme™) are naturally occurring RNA molecules that appear to disrupt the HBV lifecycle of HBV by cleaving RNA.125 HepBzyme™ significantly reduced HBV in animal studies and is as effective as lamivudine. Combinations of HepBzyme™ and interferon or HepBzyme™ and lamivudine resulted in additive down-regulation of HBV antigen production.126

Vaccination

A safe and effective HBV vaccine with minimal side effects that provides long-term protection has been widely available for more than 20 years. HBV vaccination has created dramatic reductions in infection rate.9 Overall infection rates in infants and children have decreased dramatically worldwide—in some areas by as much as 90%.127 Rates of hepatocellular carcinoma in children have declined commensurately.127 Universal infant immunization is the most effective method to prevent HBV infection,4,128 but anyone who has increased risk of contracting HBV should be vaccinated. Vaccination programs should include children and adolescents, healthcare workers, and pregnant women.4 Vaccination gives an almost universal HBsAb (anti-HBs) response in almost all normal recipients. Immunocompromised recipients respond poorly to standard HBV vaccine. Individuals with chronic liver disease have lower than average rates of seroconversion after HBV vaccination. However, many who do not respond to a standard dose of vaccine, do respond to a higher dose.129 Currently HBV escape mutants do not threaten effectiveness of immunization.9

Hepatitis B Immune Globulin

Hepatitis B immune globulin (HBIG) is a highly effective “post-exposure” treatment that prevents HBV infection and provides short-term protection.20 Vaccination is recommended in conjunction with HBIG for neonates of HBsAg (+) mothers, in needle-stick accidents, and for regular sexual contacts of individuals with acute HBV.20

Immunotherapy

Vaccination cannot eliminate an established HBV infection.20 However, therapeutic vaccination might decrease tolerance and stimulate T-cell immune responses in CHB carriers. Animal studies and clinical trials have shown that standard HBV vaccination could decrease HBV replication in CHB patients.130 However, in a therapeutic vaccination study, the gap between participants who seroconverted and those who did not was an unimpressive 6%. No patient lost HBsAg.131

DNA-based vaccines are in early stages of development. DNA-based vaccines involve injection of plasmids (a small genetic particle removed from a chromosome) encoding HBV antigens. Plasmid DNA immunization causes generation of humoral immune responses.132

Ursodeoxycholic Acid

Ursodeoxycholic acid (ursodiol) is a bile acid that limits hepatocyte injury,133 lowers elevated liver enzymes, and alleviates symptoms in certain liver diseases. In the laboratory, ursodeoxycholic acid protected hepatocytes from apoptosis induced by alcohol.134 Ursodeoxycholic acid reduced ALT levels in the absence and presence of interferon in clinical trials. It potentiates 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.135 Although ursodeoxycholic acid produces no anti-viral effect, it does reduce disease activity135,136 and appears to be a suitable substitute for patients who cannot tolerate interferon137 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.138

NUTRITIONAL THERAPY

• Nutritional Supplements
• Botanicals
• New Directions in Botanicals

For many patients, the primary goal for CHB, i.e., complete eradication of the HBV virus, is not realistic. Many can achieve secondary endpoints, such as lower viral load and liver enzymes and delayed cirrhosis and hepatocellular carcinoma, with alternative therapies. A recognized group of nutritional supplements and medicinal herbs have proven antiviral and biochemical actions and have been used safely worldwide in liver disease—some for thousands of years.

Nutritional Supplements

Antioxidant defenses might not provide adequate protection against the oxidative molecules produced by the immune system during inflammatory processes. Slowing cytokine production and maintaining antioxidant defenses depends on nutrient intake. Nutrients absorbed from dietary sources influence inflammatory aspects of the immune system by altering cytokine production and limiting responsiveness of target tissues to cytokines. Alterations in intake of fats, antioxidant nutrients, protein, and certain amino acids reduce inflammation by biologically interacting with cytokines and reactive oxygen species.139

Intake of metallic trace nutrients such as copper, zinc, and selenium influences antioxidant enzyme activity. Constituents for defense are acquired from intake of nutrients with antioxidant properties: 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.140

Antioxidant Vitamins

Components of antioxidant defenses interact directly and indirectly to maintain antioxidant capacity in tissues. Vitamin E, vitamin C, and glutathione are interlinked in antioxidant defense.41 Vitamin E influences inflammatory and immune function. Vitamin E deficiency impairs cellular and humoral immunity, whereas supplementation lowers incidence of infectious disease.142,143 Vitamin C is a key component of antioxidant defense.144 B vitamins have widespread effects on immune function and indirectly contribute to antioxidant defenses. Vitamins B12 and B6 are cofactors in the metabolic pathway for biosynthesis of cysteine which is necessary for glutathione synthesis.144 Deficiencies in B vitamins and vitamin E create abnormalities in cell-mediated immune responses. Supplementation with vitamins C, A, E, and the B vitamins improve lymphocyte function.141

Glutathione

Glutathione, a molecule composed of glycine, glutamate, and cysteine, is key to the regulation of cellular activity. Depletion of glutathione below a critical level causes cell death. Glutathione is synthesized and highly concentrated in the liver where it has 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 which is important in the manufacture of lymphocytes.145 Cytokine production in response to inflammatory stimuli depends on the ability of the body to produce glutathione.146 Attack by free radicals depletes glutathione.

Low levels of glutathione are linked to many diseases. Aging alters glutathione status by lowering levels of reduced glutathione and raising levels of oxidized glutathione.147 Malnutrition148 and alcoholism149 lead to deficiencies of glutathione precursors, limiting glutathione synthesis.150 Liver damage is related to production of free radicals during inflammatory processes. In viral hepatitis, liver damage is attributed to an imbalance in reduction/oxidation (redox) processes and glutathione depletion. Altered glutathione status is a feature of cirrhosis and nonalcoholic liver disease.149,151,152

Nutrients that Raise Glutathione Levels

Glutathione stimulation is a primary immune-modulating mechanism. Amino acid precursors to glutathione increase glutathione concentration in relevant tissues and stimulate immunity.153 Supplementary glutathione and its precursors (e.g., glutamine, glutamate, alpha-lipoic acid, N-acetyl-cysteine, cysteine, and S-adenosylmethionine or SAMe) increase glutathione levels.

Glutamine. Glutamine is the most abundant amino acid in the body.154 Although it is considered a non-essential amino acid, cells cannot grow without glutamine.155,156 Glutamine is organ-specific—it is produced mostly in skeletal muscle and then delivered where it is needed157 in times of stress.158 Catabolic stress can cause plasma glutamine to drop by as much as 30%.159 Glutamine has immunoregulatory capabilities.154,160 Growth and proliferation of lymphocytes is closely related to cellular glutathione and glutamine content.161 Glutamine is necessary for the production of cytokines;162 certain killer cell activity is reduced when it is depleted.163 Glutamine is associated with a number of pathologic conditions. Glutamine depletion slows wound healing and increases the risk of sepsis and organ failure.164

Glutamine is a glutathione precursor.145,165 Glutamine depletion down-regulates the intracellular glutathione level in the body;166 dietary supplementation increases it.154 Alterations of glutathione metabolism have been identified in pathological conditions, including liver disease.167,168 Supplemental glutamine protects the liver and enhances hepatic detoxification.169 Glutamine preserves hepatic glutathione levels in rats poisoned with acetaminophen.169 In cirrhosis of the liver patients, glutamine increases serum glutathione and decreases cytokine production.170

Alpha-lipoic acid. Alpha-lipoic acid (ALA, thioctic 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.145,172 It is soluble in both lipids and water and acts as an antioxidant in both mediums.173 It is active in its oxidized and in its reduced form (dihydrolipoic acid or DHLA).171 Alpha-lipoic acid can regenerate vitamins C174 and E175 and significantly raise intracellular glutathione levels.176

Alpha-lipoic acid is used extensively for liver disease and is an accepted antidote to poisons (e.g., Amanita mushroom poisoning) and drugs that are metabolized in the liver.171 It has an ability to chelate copper, manganese, mercury, and zinc;177 reduce cadmium-induced hepatotoxicity;172 and protect from arsenic poisoning.178

N-acetyl-cysteine. N-acetyl-cysteine (NAC) has anti-mutagenic and anti-carcinogenic properties and is a powerful scavenger of free radicals. It is a precursor of glutathione. Conversion of NAC to two of its major metabolites, cysteine and inorganic sulfite, accounts for its protective effects and its role as a precursor to glutathione.179-181 NAC 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. NAC may only concentrate in tissues where it is required.182,183 NAC can modulate concentrations of certain cytokines. In laboratory studies, it increases IL-1 and IL-2 levels when they are low and decreases these cytokines at higher concentrations.184

NAC is used for hepatotoxic conditions that increase oxidative stress or decrease glutathione.182 It is an established antidote for acetaminophen overdose,185 a condition known to deplete liver glutathione.186 NAC may have a role in liver cancer treatment. It inhibits cell growth and proliferation in cancer cell lines187-189 and prevents transformation of carcinogens into more toxic compounds.

Conjecture is that the relative ineffectiveness of interferon for treatment of chronic viral hepatitis is due to a glutathione imbalance. Supplementing interferon with a glutathione precursor may increase its effectiveness and antioxidants may act in synergy with interferon. Trials have tested this theory using a combination treatment of interferon with NAC. One study reported that supplementation of interferon with NAC enhanced the response to interferon, but had no effect when taken alone.190 In patients with acute viral hepatitis A and B, NAC had no effect on liver enzyme or total bilirubin levels.191

S-adenosylmethionine. S-adenosylmethionine (SAMe) is an amino acid derivative found in cells of all mammals.192 SAMe is formed by a reaction between methionine and ATP, an important energy source in the body.193 SAMe participates in detoxification reactions and the manufacture of antioxidants. It is a major glutathione precursor that provides methyl groups for biosynthesis.145 Hypomethylation is strongly associated with carcinogenesis.194 Methyl-deficient diets have caused liver cancer in animals. SAMe reduced hepatic necrosis in rats with methyl-deficient diets.152 Folic acid and vitamin B12 are necessary for resynthesis of SAMe.195-196 Evidence indicates that folate deprivation contributes to methyl insufficiency.197

SAMe has been used worldwide for liver198 and gallbladder disease.199 SAMe is highly concentrated in a normal liver;196 low levels are a feature of cirrhosis.193 SAMe supplementation significantly restores glutathione depletion in chronic liver disease patients. Animal and human studies show SAMe lessens symptoms of liver disease caused by alcohol,200 toxic chemicals197 and prescription and over-the-counter drugs.197 In a clinical trial, SAMe, taken over a period of 2 years, lowered the death rate of patients with alcoholic cirrhosis.201

Note: See Appendix C for Cautions and Contraindications.

HEPATITIS B

Whey Protein

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.202 Whey contains several biological components with immune-enhancing properties. For example, ß-lactoglobulin modulates lymphatic responses.203 a-Lactalbumin directly effects B- and T-lymphocyte function and its iron chelating properties reduce oxidative stress. Lactoperoxidase catalyzes reduction of hydrogen peroxide.204,205 Approximately 15% of whey proteins are immunoglobulins, the antibodies that confer immunity.206

Lactoferrin

A major component of whey protein is an iron-binding antioxidant glycoprotein—apolactoferrin, the iron-depleted form of lactoferrin.207 Lactoferrin has far-reaching antiviral and immunomodulatory properties.208 It activates natural killer cells and neutrophils, enhances macrophage cytotoxicity,209,210 and decreases inflammation through certain cytokines (TNF, IL-6).211 Lactoferrin inhibits metastasis of primary tumors in mice.212 When a high-lactoferrin whey concentrate and an anticancer drug were combined, cytotoxicity increased.213 In a small study in HBV and HCV patients, lactoferrin decreased ALT and lipid peroxide levels and increased glutathione, IL-2, and natural killer activity in the HBV group.214 Clinical trials in immune compromised populations (where low glutathione levels are common) revealed significantly elevated glutathione levels after whey. 215-218

Phosphatidylcholine

Phosphatidylcholine provides the main structural support for cell membranes and has a role in regulation of membrane fluidity. It is an essential nutrient and is a reservoir of choline.219 Phosphatidylcholine offered antioxidant protection in animal studies and clinical trials.220,221 It protects against chemical toxins and pharmaceuticals. Phosphatidylcholine is an excellent source of methyl groups (crucial for hepatic detoxification).222

Liver disease enhances lipid peroxidation and depletes phosphatidylcholine and glutathione.223 Phosphatidylcholine administration benefits liver damage. Clinical trials show significantly lower liver enzyme levels, improvement in liver tissue, and mortality rate decrease using phosphatidylcholine. Because phosphatidylcholine breaks down collagen, it may benefit liver fibrosis.224 Baboons 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.225 In a clinical trial in patients with CHB and CHC, treatment with a combination of interferon and phosphatidylcholine did not accelerate elimination of HBV-DNA or HBeAg or alter the response to interferon in CHB patients.226

Selenium

Selenium is a trace mineral227 essential for the proper immune system function.228,229 It has antioxidant properties and is a cofactor in several metabolic pathways.230 Glutathione peroxidase, an enzyme that uses glutathione, is selenium-dependent. Certain breakdown products of selenium enhance immune cell activity.231

Plant food is the major dietary source of selenium. For example, garlic is rich in selenium. Selenium amounts in plants depend on the selenium content of the soil where they are grown.232 Human selenium deficiency is seen in areas where soil content is low.233,234 Epidemiological investigations associate low nutritional selenium status and increased risk of disease.235,236 Selenium deficiency does not cause serious disease, but it can make the body more susceptible to illness.237

Note: See Appendix C for Cautions and Contraindications.

Dehydroepiandrosterone

DHEA (dehydroepiandrosterone) 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%.238 DHEA production peaks around age 25, then declines approximately 2% yearly until the end of life.239-242 DHEA-S (sulfate) is an inactive metabolite of DHEA that represents storage of about 98% of the hormone. DHEA and DHEAS are converted into several active metabolites.239,243,244 They are precursors of about half the androgens in men, 75% of active estrogens in premenopausal women, and all active estrogens after menopause.239,241,242 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 DHEA-S. It is 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.245 DHEA levels decline with ageing. Preliminary studies of DHEA replacement show encouraging results, especially in immune system enhancement.246-248

Note: See Appendix C for Cautions and Contraindications.

Botanicals

Antioxidants discussed in this section have a broad spectrum of biological, pharmacological, and therapeutic activities and defend against free radicals and oxidative stress caused by hepatitis viral infections.

Grape Seed Skin Extract

The proanthocyanidins contained in grape seeds are polyphenols closely related to flavonoids.249 Proanthocyanidins increase the activity of endogenous antioxidants such as glutathione and superoxide dismutase.250 They are twice as potent as vitamin E and four times as potent as vitamin C.251-253 Their impressive list of actions include inhibition of lipid oxidation and platelet aggregation, promotion of nitric oxide production, arrest of tumor growth, and inhibition of carcinogenesis. Proanthocyanidins exert an immunomodulatory effect. In the laboratory, proanthocyanidins increase the cytotoxicity of natural killer cells, enhance production of IL-2, and decrease production of IL-6.254 A diet supplemented with proanthocyanidins increases T- and B-cell activity in mice with age-associated immune deficits.255 Dosing animals with grape seed extract before giving them hepatotoxic doses of acetaminophen significantly attenuated DNA damage and liver cell damage.256 Today grape seed extract is commonly used for edema and chronic venous insufficiency.257

Milk Thistle

Silybum marianum (commonly know as milk thistle) has been used for liver diseases for more than 2000 years.258 Silymarin, milk thistle’s hepatoprotective component,259,261 reduces free radical production and lipid peroxidation in the liver and slows glutathione depletion.261 Silymarin is used for chronic inflammatory liver disorders, including cirrhosis, hepatitis, alcohol-related fatty liver disease,262 and liver damage caused by toxic chemicals.263,264 Silymarin reduces hepatic necrosis in rats caused by toxic doses of acetaminophen265 and protects liver cell membranes exposed to an array of hepatotoxins,266,267 regenerates hepatic tissue,268 and enhances liver detoxification.269

Licorice Root

Licorice root has been used for thousands of years. Its active component, glycyrrhizin, is converted into glychyrrhetic acid by an enzymatic reaction. Glycyrrhizin has immune-modulating,270 anti-inflammatory,271 antioxidant,272 antiviral,273,274 and anti-tumor activity.275 In the laboratory, glycyrrhizin has stabilized lysosomal membranes.276 Glycyrrhizin modifies the expression of HBV antigens on hepatocytes and suppresses secretion of HBsAg.277 It inhibits the enzyme that breaks down cortisol, prolonging its anti-inflammatory effects.278 Glycyrrhetic acid inhibits the complement cascade.279

An intravenous glycyrrhizin preparation is used for CHB In Japan.274 The antiviral mechanism of glycyrrhizin is twofold: a direct inhibitory action on viral replication and function and stimulation of the host immune system T-cells to produce interferon-y.278 This is demonstrated in several animal studies in which glycyrrhizin improved resistance to herpes simplex and influenza viruses280 and increased production of IL-10 in cells infected with hepatitis virus.270

Glycyrrhizin improves liver function in CHB patients with occasional complete recovery from hepatitis.277 It lowers ALT levels.281 and has hepatoprotective effects against cirrhosis and carcinogens.282,283 A Chinese study evaluated glycyrrhizin as a treatment for CHB patients with serum ALT more than two times higher than normal. Glycyrrhizin given intravenously for 4 weeks, followed by oral glycyrrhizin for an additional 4 weeks revealed ALT levels in 77% of the study group dropped to 1.5 times normal and 57% dropped to normal (2% withdrew from side effects).284 There is growing interest in glycyrrhizin and pharmaceutical combinations. Oral lamivudine plus intravenous glycyrrhizin effectively treats CHB infection.285 In a small trial in CHB carriers (HBsAg+, HBeAg+, HBV-DNA polymerase +), IV glycyrrhizin for 4 weeks followed by interferon for 4 weeks resulted in loss of HBeAg in 60% of patients at the 6-month follow-up. ALT levels decreased in half of the patients, but only 20% seroconverted; viral titers were not reported.286

Note: See Appendix C for Cautions and Contraindications.

Green Tea Extract

The Chinese have used the leaves of Camellia sinensis for many diseases for over 4000 years. Green tea contains flavonoids and B and C vitamins287,288 and is rich in polyphenols and gallic acid and catechin and their derivatives.289 Epigallocatechin-3-gallate (EGCG) is the major and the most active polyphenol in green tea extract.280 The potent antioxidant activity of green tea catechins has been well researched. Green tea has a positive influence on lipid metabolism and exerts antimutagenic and anticancer effects. Polyphenols in green tea can influence the proliferative processes of cells.291 Dozens of epidemiological studies report the positive effects of green tea on cancer292-293

Hepatoprotective effects of green tea are modulation of inflammatory processes and protection against DNA damage.294 Studies in mice showed that green tea inhibited chemical-induced hepatotoxicity.295 Green tea is effective for hepatitis.296 Oxidative stress activates hepatic stellate cells during hepatic fibrogenesis. Polyphenols from green tea scavenge oxygen radicals and prevent activation of stellate cells, thereby minimizing liver fibrosis.290 Polyphenols from green tea are potent free radical scavengers.297 In the laboratory, epigallocatechin-3-gallate protected against oxidative stress and hepatotoxin toxicity created by cytochrome P450 enzymes.298

Note: See Appendix C for Cautions and Contraindications.

Phyllanthus

The phyllanthus plant is found in tropical and subtropical countries. It is used in kidney and bladder disease, diabetes, jaundice, and dysentery.299 It is touted as antiviral, especially for HBV infection, and a treatment for hepatic cancer.300,301 Chemical compounds isolated from phyllanthus (e.g., niranthin, nirtetralin, hinokinin, and geraniin) have the greatest ability to suppress HBsAg and HBeAg at non-cytotoxic concentrations,302-306 possibly the key to phyllanthus’ antiviral activity. In laboratory experiments, Phyllanthus amarus and closely related species307 down-regulate transcription of HBV mRNA,304 inhibit HBV polymerase,308 decrease HBV-DNA, and suppress HBV secretion.304,305,309-311 P. amarus has anti-inflammatory activity.312 Extracts inhibited induction of pro-inflammatory enzymes, attenuated secretion of tumor necrosis factor, and inhibited induction of IL-1b, IL-10, and interferon-y.312

P. amarus positively affects liver biochemistry313 and significantly increases survival of animals with hepatocellular carcinoma.314,315 Clinical trial data are conflicting.316-318 P. amarus, P. niruri, and P. urinaria have HBV-suppressing effects in clinical trials.319 A review of phyllanthus for HBV treatment identified seven trials with positive results and seven trials with negative results.320 Another review identified 22 trials, but only 5 had methodologies rigorous enough for consideration.313 Phyllanthus had positive effects on serum HBeAg levels321 and cleared HBeAg from the blood better than placebo. Interferon and phyllanthus acted equally well to clear HBeAg and HBV-DNA.313-322 There was difference in P. amarus and interferon-y as treatment for CHB. Phyllanthus had a seroconversion rate for HBeAg and HBV-DNA similar to interferon-a. The normalization rates for ALT in the phyllanthus group were higher than the interferon-y group.323

There are more than 700 species of phyllanthus.308 Not all have equal antiviral activity against HBV.307-324 Opinions of investigators as to which species is more active against HBV-DNA have changed over the years,307,324,325 perhaps due to genetic variability across species for the trait inhibiting DNA polymerase.308

Picrorhiza

Picrorhiza kurroa is used for disorders of lungs and liver,326 dysentery, nausea, anorexia, dyspepsia, and fever.327 Current research interests include acute viral hepatitis, drug-induced liver damage, and other liver diseases.328

Biologically active principles have been isolated from picrorhiza. Its major constituents include the iridoid glycosides picroside I, II, III, pikuroside, kutkoside and 6-feruloyl catalpol, cucurbitacin glycosides, androsin, and apocynin.329,330 Picroliv (a standardized iridoid glycoside fraction of P. kurroa composed of the iridoid glycosides, picroside-I and kutkoside) is used in animal experiments and clinical trials.329-331 Picroliv has hepatoprotective332 and anti-inflammatory properties,329,335,336 and antioxidant activity similar to superoxide dismutase.331 Antioxidant properties of picrorhiza might cause its hepatoprotective effect as a result of reducing lipid peroxidation and free radical damage.329,337,338 Picrorhiza has a hepatoprotective action similar to silymarin.339,340 It restores glutathione levels in animals by decreasing damage to liver cells poisoned with hepatotoxic chemicals, such as Amanita mushrooms,339,341 carbon tetrachloride,342-344 galactosamine,345,346 alcohol,347 aflatoxin,348 acetaminophen,349 and other toxic substances. In some induced liver-injury experiments in rats, picrorhiza reduced liver enzymes and lipid levels.331 Unfortunately, no trials of picrorhiza as a treatment for CHB have been published in peer-reviewed journals.

New Directions in Botanicals

The literature search for this protocol uncovered a long list of botanicals and functional foods used for HBV infection worldwide, including andrographis, astragalus, boswellia, bupleurum, Curcuma longa, Wilkstroemia indica, Larch Arabinogalactan, red peony root, algae, three kinds of mushrooms, and several patent medicines of largely unknown composition. These products are in various stages of research. Several showed promise as antivirals with activity against HBV.350,351

Sho-saiko-to (TJ-9), an extract of scutellaria, glycyrrhiza, bupleurum, ginger, ginseng, and other botanicals, contains major active compounds structurally similar to silibinin.352 In the laboratory, this compound has antioxidant,353,354 anti-tumor,355 and hepatoprotective activity.356 A small clinical trial for cirrhosis showed no decrease in mortality for patients who were HBsAg (+).357 Compound 861 is an extract of ten herbs based on traditional Chinese medicine with Salvia miltiorrhiza, Astragalus membranaceous, and Spatholobus suberectus as chief components. In a 2000-patient study, Compound 861 improved symptoms and normalized ALT in 82% of participants. In a smaller controlled study in patients with HBV-related diseases, the fibrosis reversal rate after 6 months was more than 75%.319

Not all herbal medicine is beneficial or even harmless. LIV-52, an Ayurvedic extract of several plants, caused disastrous results in a 1997 clinical trial. The death rate of enrollees with alcoholic cirrhosis was 81% in the LIV 52-treated group, compared with 40% in the placebo group.358

FUNCTIONAL AND PRACTICAL MEDICINE

The liver is the primary metabolic organ in the body. It is intermediary in metabolism of nutrients and bile salts. The liver significantly influences absorption, storage, and metabolism. Damage to the liver leads to vitamin and mineral deficiencies and malnutrition.359 Nutrition can have a critical role in the management of HBV infection at all disease stages.

The impact of alcohol and malnutrition on any liver disease is recognized. Preventive measures such as a healthy diet and no alcohol reduce progression of liver disease. In cirrhotic men, a high-fat, low-protein, low-carbohydrate diet significantly increased cirrhosis risk; alcohol further increased risk.231,360 Excessive weight is strongly associated with elevated ALT levels and increases risk of liver disease. Weight reduction and exercise can improve liver function in patients with fatty liver disease361 and may reduce steatosis and fibrosis. Healthy eating increases treatment response, decreases side effects, and improves quality of life for patients with chronic viral hepatitis. A healthy diet is composed of foods from all food groups, including enough calories and protein to fight infection and regenerate the liver and ample amounts of vegetables and fruit to maximize free radical-fighting antioxidants. Limit high-fat and high-sugar foods. Ideally, meals should be small, spread out over the day.

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 liver disease. In particular, Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen should be avoided. (See the Acetaminophen Poisoning or OTC Drug Toxicity Protocol).

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 and can help relieve fatigue, stress, and depression; improve appetite; build up the immune system; and in general improve quality of life.360

LIFE EXTENSION’S INTEGRATED PROTOCOL

• Conventional Therapy
• Lifestyle Modification
• Nutritional Supplements

Conventional Therapy

• Conventional drug therapy for HBV is evolving. If your physician prescribes a drug, it will probably be one of three approved by the FDA: interferon-a, lamivudine, or adefovir.
• If you are taking interferon, high levels of iron could interfere with treatment. If your physician thinks you can benefit from lower iron levels, he might prescribe calcium citrate, lactoferrin, or green tea extract to block iron absorption. Do not undertake an iron-lowering regime without a physician's supervision.

Lifestyle Modifications

• Avoid drinks containing alcohol. Hepatitis patients are especially vulnerable to the damaging effects of alcohol.
• Eat plenty of fresh fruits and vegetables for natural sources of minerals, vitamins, and essential fatty acids.
• Reduce stress on and off the job.
• Exercise regularly and keep weight within normal limits.
• If your physician prescribes medicine to treat your HBV infection, follow his directions precisely. Be sure he is aware of all prescribed and over-the-counter medicines that you take.
• Avoid non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. All medications, including over-the-counter preparations and herbal remedies, are potentially hepatotoxic. Use them with caution.

Nutritional Supplements

• R-Dihydro-lipoic acid: 300 mg daily. R-dihydro-lipoic acid is the biologically active form of alpha-lipoic acid.
• N-acetyl-cysteine: 600 mg daily
• Whey protein: 20–30 grams daily
• Glutathione: 500 mg daily on an empty stomach
• Silibinin extract: One capsule three times daily
• L-glutamine: 500-1000 mg daily.
• SAMe: 1200–1600 mg daily
• Trimethylglycine (TMG): 1000 mg twice daily
• Folic acid: 800 mcg three times daily
• Methylcobalamin (vitamin B12): 1–5 mg once daily (dissolve tablets in mouth)
• Polyenylphosphatidylcholine (PPC): 1800–2700 mg daily in divided doses
• Green tea polyphenols: 1–2 green tea extract capsules (725 mg, 93% polyphenols) early in the day, either from green tea extract capsules or from drinking 5–10 cups of green tea
• Garlic: 1200 mg of aged garlic extract
• Grape seed-skin extract: (85–95% proanthocyanidin), 100 mg, two to three times daily
• Selenium: 200–400 mcg daily
• DHEA tablets (dissolve in mouth): 15–45 mg daily (See the DHEA Replacement Therapy protocol for specific information and precautions.)
• Life Extension Mix and Life Extension Herbal Mix: Use standard recommended doses of both products.

Note: Do not take glutamine if you have been diagnosed with hepatic encephalopathy or liver failure, if you are undergoing cancer chemotherapy, or if you take anticonvulsant drugs.

Note: If liver enzyme levels rise when you take Life Extension Mix, you might not be able to tolerate the moderate doses of vitamin A, niacin, and beta carotene that it contains. Stop taking Life Extension Mix, but continue to take all the nutrients in Life Extension Mix, except vitamin A, niacin, and beta carotene.

Note: Many suggested nutrients may be found in the Life Extension Mix.

For More Information

• 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
• American Association for the Study of Liver Diseases, (703) 299-9766; E-mail: aasld@aasld.org http://www.aasld.org/
• Hepatitis B Foundation Drug Watch. Compounds in Development for Hepatitis B. www.hepb.org

Products Available

Silibinin Plus, HepatoPro (PPC) capsules, Kyolic Reserve Garlic capsules, Se-Methyl-selenocysteine, R-dihydro-lipoic acid, DHEA, N-acetyl-cysteine, SAMe, Life Extension Mix, Life Extension Herbal Mix, grape seed-skin extract, folic acid, methylcobalamin (B12), TMG, whey protein isolate with lactoferrin, L-glutathione, green tea extract capsules (regular and decaffeinated) are available by calling (800) 544-4440 or by ordering online at www.lef.org. Prescription drugs cited should be prescribed by a physician who treats hepatitis.

Janice Roma Kane, D.O. 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.

Sections were written and edited by Randall Lee Kohl, Ph.D., R.Ph., F.C.P., Senior Editor for LE Publications, Inc. Please direct only your comments to rkohl@lef.org. Direct your questions to the Life Extension Health Advisory staff at (800) 544-4440.

Hepatitis B

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