Hepatitis A

Talal Adhami

William D. Carey

Definition and etiology

Hepatitis A virus (HAV) is a cause of acute liver inflammation or hepatitis. It can cause relapsing signs and symptoms but not a chronic infection. The virus is a 27-nm-diameter nonenveloped RNA virus. It belongs to the family Picornaviridae and the genus Hepatovirus, and it has characteristics of the enteroviruses.¹ Viral transmission occurs in a fecal-oral fashion. The genome is a positive-strand RNA, 7474 nucleotides long, 7.5 kb in length, that encodes a polyprotein with structural and nonstructural components. Viral replication and assembly occur in the hepatocyte cytoplasm of humans and nonhuman primates, the exclusive natural hosts. The virus is then secreted into the bile and serum.²

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Prevalence

HAV is found throughout the world and is the most common cause of symptomatic acute hepatitis in the United States (annual incidence, 9.1/100,000), occurring largely as sporadic rather than epidemic cases. This figure has been declining since vaccines have become available and given to high-risk persons. The virus is more prevalent in areas with poor sanitary conditions. The most common source of hepatitis A is direct person-to-person exposure and, to a lesser extent, direct fecal contamination of food or water. Consumption of raw or partially cooked shellfish raised in contaminated waterways is an uncommon but possible source of hepatitis A.³ Vertical transmission from mother to fetus and transmission from blood or blood products have been described on rare occasions. High-risk groups for acquiring HAV infection include travelers to developing nations, children in daycare centers, sewage workers, cleaning personnel, male homosexuals, intravenous drug users, hemophiliacs given plasma products, and persons in institutions. No identifiable source is found in 42% of all cases.⁴

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Pathophysiology

HAV is not directly cytopathic to the hepatocyte. Injury to the liver is secondary to the host's immune response. Replication of HAV occurs exclusively within the cytoplasm of the hepatocyte. Human leukocyte antigen (HLA)-restricted, HAV-specific CD8⁺ T lymphocytes and natural killer cells mediate hepatocellular damage and destruction of infected hepatocytes. Interferon gamma appears to have a central role in promoting the clearance of infected hepatocytes.^5,6

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Signs and symptoms

The clinical manifestations of HAV infection are widely variable, depending on the host response. They range from silent infection and spontaneous resolution to fulminant hepatic failure. The incubation period of HAV ranges from 15 to 49 days (mean, 25 days). The prodromal phase is characterized by nonspecific symptoms, such as fatigue, weakness, anorexia, nausea, vomiting, abdominal pain, and, less commonly, fever. Headache, arthralgias, myalgias, rash, or diarrhea can follow. Jaundice begins within 1 to 2 weeks from the onset of the prodrome. It occurs in 70% of adults infected with HAV, with or without pruritus, and in a far smaller proportion of children. Mild hepatomegaly, splenomegaly, and cervical lymphadenopathy are found in 85%, 15%, and 14% of infected patients, respectively.

The host is infective from 14 to 21 days before the onset of jaundice to 7 to 8 days after jaundice has resolved.⁷ The host serum and saliva are not nearly as infectious as stool, and urine does not transmit the virus. Anti-HAV antibody (immunoglobulin M [IgM], followed by immunoglobulin G [IgG]) appears shortly before the onset of symptoms and rises to high titers 3 to 4 months after exposure. IgM-specific anti-HAV persists for 4 to 12 months, and IgG-specific anti-HAV persists for life (Fig. 1 ). Extrahepatic manifestations are uncommon and include a leukocytoclastic vasculitis, glomerulonephritis, arthritis, immune complex disease, toxic epidermal necrolysis, myocarditis, optic neuritis, transverse myelitis, polyneuritis, thrombocytopenia, aplastic anemia, and red cell aplasia.⁸

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Diagnosis

Detecting IgM anti-HAV in the serum of a patient with the clinical and biochemical features of acute hepatitis usually confirms the diagnosis of acute hepatitis A.⁹ Figure 1 outlines the immune response to HAV infection. HAV antigen can be detected in the stool or body fluids, but there is no commercially available assay. Detecting viral RNA is highly specific but expensive and is rarely used to confirm the diagnosis. Liver biopsy is not indicated. Testing for anti-HAV IgG is not helpful in the diagnosis but is a means of assessing immunity to hepatitis A. When detected in the serum, this IgG remains positive for years.

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Treatment and prevention

Acute hepatitis A is usually a self-limited infection. Complete recovery is seen in most patients, and chronic disease does not occur. In rare cases, infection is complicated by fulminant disease, and fatalities occur. Treatment is mainly supportive. Attempts should be made to prevent transmission of the virus within the household and to close contacts. Boiling contaminated water for 20 minutes or exposing the virus to chlorine, formalin, or ultraviolet light reduces the risk of infection.¹⁰

A safe and effective hepatitis A vaccine is available and is recommended for patients at high risk of acquiring hepatitis A. Patients with chronic liver disease are more likely to develop severe or fulminant liver disease when infected with HAV and should be vaccinated. Hepatitis A vaccine is also recommended for patients with chronic immunodeficiency, those on dialysis, and those on chronic immunosuppressive therapies.

Two formulations of the HAV vaccine are available in the United States; both consist of inactivated hepatitis A antigen purified from cell culture. Havrix is recommended as two injections 6 to 12 months apart in an adult dose of 1440 U of enzyme-linked immunosorbent assay (ELISA; 1.0 mL) and a pediatric dose (ages 2-18 years) of 720 U (0.5 mL). A dose of 360 U administered three times over a 6-month period is an acceptable regimen for children. Travelers to high-risk areas should receive the first dose of vaccine at least 4 weeks before anticipated exposure. Vaqta is recommended for administration as two injections at least 6 months apart in an adult dose of 50 U (1.0 mL) and a pediatric dose (2 to 17 years) of 25 U (0.5 mL). Protection lasts for approximately 15 years.

Hepatitis A vaccines have an excellent safety record, with serious complications in less than 0.1% of recipients. Vaccines used are highly immunogenic, and seroconversion rates after the HAV vaccine is given are higher than 90% but lower in patients with chronic liver disease (possibly as low as 50%). At least 50% of patients who are vaccinated after transplantation have titers below the protective level 2 years after receiving the vaccination. Patients with liver disease should therefore be vaccinated as early in their illness as possible. Follow-up testing for anti-HAV antibody and booster inoculations are not currently recommended. Pooled human immune globulin, 2 mL/kg in adults and 0.02 mL/kg in children, given intramuscularly, is recommended for postexposure prophylaxis.⁹

These recommendations for the prevention of hepatitis A are advocated by the Centers for Disease Control and Prevention (CDC).

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Outcomes

The course of hepatitis A infection is benign in most of those infected. It is occasionally severe, or fulminant, in adults, particularly in those with chronic liver disease. Jaundice usually resolves in less than 2 weeks, and full recovery usually occurs in 2 months. The illness occasionally persists for several weeks or months, but it never leads to a chronic infection, chronic hepatitis, or cirrhosis. A chronic relapsing hepatitis has been noted to last for as long as 1 year. Hepatitis A can cause a cholestatic hepatitis that usually responds to a short course of prednisolone, 30 mg daily. Pregnancy does not affect the severity or outcome of acute hepatitis A infection. In the rare case of fulminant hepatitis, patients should be evaluated early for possible liver transplantation.¹¹

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Summary

• Hepatitis A (HAV) is an RNA virus and the most common cause of symptomatic acute hepatitis in the United States. The main mode of transmission is fecal-oral, but consumption of raw shellfish and direct contact with contaminated blood can cause infection.
• HAV causes acute and relapsing hepatitis. It does not cause chronic hepatitis.
• Treatment is usually supportive, and hospitalization may be needed for severe cases. Liver transplantation is recommended in case of fulminant HAV hepatitis.
• There is a safe and effective vaccine to prevent HAV infection. It is recommended for patients at high risk of acquiring hepatitis A and for patients with chronic liver disease.
• Intramuscular human immune globulin is recommended for postexposure prophylaxis.

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Hepatitis B

Robert S. O'Shea

Epidemiology

Liver disease related to hepatitis B remains an important public health concern and a major cause of morbidity and mortality. It also presents a common challenging problem for practicing physicians.

Hepatitis B is found throughout the world, but its prevalence varies greatly; it is especially high in Asia, sub-Saharan Africa, and the South Pacific, as well as in specific populations in South America, the Middle East, and the Arctic.¹ Prevalence in the United States varies, based on the population makeup, including the extent of the immigrant population from endemic areas, and on risk factors and behavior, such as the prevalence of intravenous drug use and homosexual practices. Public health agencies estimate that there are about 1.25 million people infected in the United States, but 2 billion people infected worldwide, with approximately 5% of the world's population (or 350 million people) being carriers of chronic hepatitis B.² In a typical year, 70,000 Americans become infected with chronic hepatitis B virus (HBV), and approximately 5000 patients with chronic hepatitis B die of complications caused by the disease. Worldwide, chronic hepatitis B is the tenth leading cause of death.

Hepatitis B was first discovered in 1963 by Dr. Baruch Blumberg and colleagues, who identified a protein (the “Australia antigen” that reacted to antibodies from patients with hemophilia and leukemia. The association of this protein with infectious hepatitis was discovered 3 years later by several investigators, and the virus was specifically seen by electron microscopy in 1970.³

HBV is a double-stranded hepatotropic DNA virus belonging to the family Hepadnaviridae. The virus infects only humans and some other nonhuman primates. Viral replication takes place predominantly in hepatocytes and, to a lesser extent in the kidneys, pancreas, bone marrow, and spleen. The viral genome is 3.2 kb in length and possesses four partially overlapping open-reading frames that encode various antigens.⁴ The intact virion is a spherical double-shelled particle with an envelope of hepatitis B surface antigen (HBsAg), an inner nucleocapsid of core antigen (HBcAg), and an active polymerase enzyme linked to a single molecule of double-stranded HBV DNA. Significant variability of the nucleotide sequence exists, and the virus can be subdivided into eight different genotypes, based on the degree of variation. The clinical importance of these is still uncertain, however.

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Natural history

Although HBV can survive outside the body for up to 1 week—and therefore, might be transmitted via indirect contact, such as from open sores—hepatitis B is spread predominantly parenterally, through intimate personal contact, and perinatally. Persons at risk include intravenous drug users, children of mothers with HBV, men who have sex with men, patients on hemodialysis, and those exposed to blood or blood products.

The incubation period of HBV ranges from 45 to 160 days (mean, 100 days). The acute illness is usually mild, particularly in children. In adults, as many as 30% to 50% present with jaundice, and hepatitis may be fulminant in 0.1% to 0.5% of those with acute hepatitis B infection. Symptoms therefore range widely in severity, from asymptomatic subclinical infection to fulminant fatal disease. An insidious onset of nausea, anorexia, malaise, and fatigue, or flulike symptoms, such as pharyngitis, cough, coryza, photophobia, headache, and myalgias, can precede the onset of jaundice. Fever is uncommon, unlike with hepatitis A infection. These symptoms abate with the onset of jaundice, although anorexia, malaise, and weakness can persist. Physical examination features are nonspecific but can include mild enlargement and slight tenderness of the liver, mild splenomegaly, and posterior cervical lymphadenopathy in 15% to 20% of patients. Fulminant disease (acute liver failure) manifests with a change in mental status (encephalopathy) and coagulopathy.⁵

The risk of developing chronic infection, or the carrier state, defined as the persistence of HBsAg in the blood for longer than 6 months, depends on the age and immune function of the patient at the time of initial infection. Ninety percent of infected newborns, 30% of children younger than 5 years, and 10% of adults progress to chronic infection. Of these carriers, 15% to 40% develop hepatitis B-related sequelae in their lifetimes. Patients with chronic infection spontaneously clear surface antigen at a rate of 0.5% per year.⁶ Patients with chronic hepatitis B can develop extrahepatic manifestations, including arthralgias, mucocutaneous vasculitis, glomerulonephritis, and polyarteritis nodosa. The glomerulonephritis of hepatitis B occurs more commonly in children than in adults and is usually characterized by the nephrotic syndrome, with little decrease in renal function. Polyarteritis nodosa occurs primarily in adults and is marked by a sudden and severe onset of hypertension, renal disease, and systemic vasculitis with arteritis in the vessels of the kidneys, gallbladder, intestine, or brain. Other rare extrahepatic manifestations are mixed essential cryoglobulinemia, pericarditis, and pancreatitis.

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Diagnosis

Viral and immune markers are detectable in blood, and characteristic antigen-antibody patterns evolve over time. The first detectable viral marker is HBsAg, followed by hepatitis B e antigen (HBeAg) and HBV DNA. Titers may be high during the incubation period, but HBV DNA and HBeAg levels begin to fall at the onset of illness and may be undetectable at the time of peak clinical illness.⁷ Core antigen does not appear in blood, but antibody to this antigen (anti-HBc) is detectable with the onset of clinical symptoms.

The IgM fraction is used in an important diagnostic assay for acute hepatitis B infection. Before current molecular assays were available, it was the only marker detectable in the window period, the time between the disappearance of HBsAg and the appearance of anti-HBs. Patients who clear the virus lose HBsAg and develop anti-HBsAb, a long-lasting antibody associated with immunity. The presence of anti-HBsAb and anti-HBcAb (IgG) indicates recovery and immunity in a previously infected person, whereas a successful vaccination response produces antibody only to HBsAg (Box 1 ).

HBeAg is another viral marker detectable in blood. It correlates with active viral replication and therefore high viral load and infectivity. The antigen is synthesized from a strand of DNA immediately preceding the area that codes for the core antigen.⁸ A mutation in this area can occur, preventing the production of the HBeAg. Such viruses are present throughout the world, particularly in Asia and the Mediterranean, and are known as precore mutants. The presence of a precore or core mutant, causing HBeAg-negative chronic hepatitis, typically implies disease of longer standing and therefore a higher risk of cirrhosis.

The hepatitis B virus is not cytopathic, and liver injury in chronic hepatitis B is believed to be immunologically mediated. Thus, the severity and course of disease do not correlate well with the level of virus in serum or the amount of antigen expressed in the liver. Antigen-specific cytotoxic T cells are believed to play a role in the cell injury in hepatitis B, but they ultimately account for viral clearance. Specific cytokines produced by cytotoxic and other T cells also have antiviral effects, contributing to viral clearance without cell death. The lack of a vigorous and specific CD8⁺ cytotoxic T cell and CD4⁺ helper T cell response can allow chronic infection to develop. Recruitment of nonspecific T cells then results in low-level chronic inflammation and liver damage. Similarly, spontaneous seroconversion from HBeAg to anti-HBeAb during chronic hepatitis B is also immunologically mediated, as is suggested from the transient flare of disease that often immediately precedes clearance of HBeAg.⁷

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Clinical course

Acute hepatitis B is diagnosed by detecting HBsAg and IgM core antibody, or core antibody alone, in the window period. IgM core antibodies are lost within 6 to 12 months of the onset of illness. Biochemically, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels can increase to between 500 to 5000 U/L and fall after the acute phase of infection. Serum bilirubin levels seldom increase above 10 mg/dL, the alkaline phosphatase level and prothrombin time are usually normal or mildly elevated (e.g., 1 to 3 seconds), and the serum albumin level is normal or minimally depressed. Peripheral blood counts may show mild leukopenia, with or without relative lymphocytosis. Loss of HBsAg and the development of HBsAb signify recovery from the acute infection and the development of immunity (Fig. 2 ).

Chronic hepatitis B is defined as the persistence of HBsAg in serum for at least 6 months. Patients with chronic infection may be divided into those with evidence of active replication, typically associated with abnormal transaminase levels and higher viral loads, and those in the nonreplicative state, associated with decreased markers of liver inflammation and damage and lower viral loads. Transaminase levels may be normal, or they may be increased anywhere from 1 to 10 times the upper limit of normal. Levels of HBV DNA are usually in the range of 10⁵ genome copies/mL, which are readily detectable by hybridization techniques, but the absolute level can fluctuate.

HBeAg in serum reflects active viral replication, and the clinical outcome of infection is correlated with HBeAg status. Conversion to HBeAg-negative and HBeAb-positive status in patients with chronic hepatitis B typically leads to decreased inflammation, with normalizing transaminase levels and decreased levels of HBV DNA in serum: the inactive carrier state. The e antigen marker is also absent in patients with core or precore mutants. Using conventional hybridization assays, HbsAg carriers do not have detectable HBV DNA in serum. Testing for HBV DNA with more sensitive techniques, such as the polymerase chain reaction (PCR) assay, however, usually demonstrates low levels of viral DNA in serum in these carriers (Fig. 3 ).

The course of chronic hepatitis B is variable. Spontaneous loss of HBeAg occurs at a rate of 8% to 12% per year, associated with a decrease in HBV DNA below levels detected by hybridization techniques. Loss of HBsAg occurs less often (<1%/year). Chronically infected patients without active liver disease or viral replication (inactive carriers) generally have a benign course, with a smaller likelihood of progressing to cirrhosis. Patients who continue to have active viral replication with high levels of HBV DNA and HBeAg in serum have progressive liver injury, and cirrhosis and end-stage liver disease can develop. A transient flare of disease often precedes remission. Loss of HBeAg is not always followed by permanent resolution of disease and disease flares can occur, particularly if a patient is treated with steroids or other immunosuppressive medications. Patients who revert to chronic HBeAg-positive status tend to develop cirrhosis at a substantially increased rate compared with those who remain HBeAg-negative.⁹ Patients infected with a core or precore mutant strain, who continue to have high DNA levels and evidence of ongoing hepatic inflammation, tend to have a higher risk of disease progression than patients who are HBeAg-positive.

Chronic HBV infection is associated with a ten-fold increase in the risk of developing hepatocellular carcinoma (HCC). This risk is further magnified in the setting of ongoing inflammation: In patients with both HBsAg and HBeAg, the risk increases to 60-fold compared with the general population.¹⁰ Older men with cirrhosis and those coinfected with hepatitis C are at greatest risk. In regions where HBV is endemic, HCC is the leading cause of cancer-related death. It is therefore recommended that HBV carriers, particularly those at highest risk (men older than 45 years, patients with cirrhosis, and those with a family history of liver cancer) should be screened with ultrasound and alpha-fetoprotein testing for HCC at 6-month intervals.¹¹

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Treatment and immunization

Effective vaccines for HBV, defined as inducing better than 90% protection against HBV, have been available in the United States since 1982. Hepatitis B vaccine has been described as the first effective anticancer vaccine, and its use has been promoted by the World Health Organization as routine care worldwide since 1997. Early strategies targeted high-risk groups, but they were not successful in materially decreasing incidence rates. Therefore, universal vaccination for HBV has been recommended for infants by the American Academy of Pediatrics since 1991. For patients with a documented exposure, postexposure prophylaxis consists of a single dose of hepatitis B immunoglobulin (HBIg) injected intramuscularly, followed immediately by HBV vaccination. Two recombinant hepatitis B vaccines are available in the United States, Engerix-B. and Recombivax HB. For adults, the recommended regimen is three injections (20 µg of Engerix-B or 10 µg of Recombivax HB) intramuscularly in the deltoid muscle at 0, 1, and 6 months. The seroconversion rate is greater than 90% in adults but may be lower in certain persons, depending on comorbid diseases or genetic factors, as well as in smokers, the obese, older adults, or patients who are immunocompromised. These patients might require higher doses and more injections.

Prevaccination screening for anti-HBs is not recommended except for adult patients who are likely to have been previously exposed, including those in high-risk groups (e.g., injection drug users, male homosexuals). Postvaccination testing for anti-HBs to document seroconversion is not routinely recommended, except for persons who are at risk for lack of response or continued exposure. Booster doses may be appropriate for high-risk patients if titers of anti-HBs fall below what is considered protective (10 IU/mL). The vaccine should be routinely administered to everyone younger than 18 years and to adults at risk of exposure. It should be given to neonates of HBV-infected mothers together with HBIg.¹²

In acute hepatitis B, treatment is supportive. Although several case series have been published, there is no clear evidence that early therapy with antiviral agents for acute hepatitis B decreases the risk of chronicity or speeds recovery. Most patients with acute icteric hepatitis B recover without residual injury or chronic hepatitis. Patients should be followed with repeat testing for HBsAg and ALT levels to determine whether seroconversion and clearance of surface antigen have occurred.¹³

In chronic hepatitis B, therapy is administered to suppress viral replication and prevent progression of liver disease. Although several end points are therefore important, the ability of any medication to prevent liver damage may be related to specific targets, including the prevention of inflammation (leading to decreased liver enzyme levels, a biochemical end point), or the ability of a drug to induce seroconversion (from HBeAg-positive to HBeAg-negative) or a change in fibrosis (i.e., a decrease in scar tissue on repeat liver biopsy). Because the likelihood of developing anti-HBs, and therefore recovery with long-term protection from hepatitis B, is fairly low, measured outcomes of treatment focus on rates of normalization of liver enzyme levels, decreases in viral DNA levels, or seroconversion—that is, from HBeAg-positive to HBeAg-negative, with a positive HBeAb.

In the absence of cirrhosis, therapy is not routinely recommended for patients with normal enzyme levels whether they are chronic inactive carriers or based on their HBeAg status.¹⁴ Therapy is recommended for patients with evidence of active damage to the liver, such as those with abnormal transaminase levels (an ALT level more than twice the upper limit of normal). A liver biopsy before therapy is the gold standard to assess the degree of necroinflammatory activity and fibrosis. Although the data are still evolving, the most recent recommendations of the American Association for the Study of Liver Diseases (AASLD) also include treatment of patients with compensated and decompensated cirrhosis and measurable HBV DNA (>2000 IU/ml) regardless of HBeAg status or degree of elevation of ALT level.¹⁴ This approach is supported by several studies that have shown a decreased rate of development of progressive liver disease or complications in treated patients.

Six agents have been approved by the U.S. Food and Drug Administration (FDA) to treat hepatitis B. Interferon alfa, available since 1992 and injected subcutaneously at a dosage of 5 MU daily, has direct antiviral activity as well as effects on the host immune system. The major side effects of interferon include fatigue, muscle aches, fever, depression, and irritability. Uncommon severe side effects include exacerbation of depression, psychosis, renal and cardiac failure, bacterial infections, and induction of autoimmunity. The FDA approved the use of long-acting interferon (peginterferon alfa-2a, at a dose of 180 µg for 48 weeks) in 2005 for treating patients with chronic hepatitis B; the side-effect profile of peginterferon alfa-2a is very similar to that of shorter-acting interferon. Other treatments available are oral agents and include nucleoside or nucleotide analogues, which interfere with the replication of the hepatitis B virus. The advantages of these medications include a relatively more benign side effect profile compared with interferon; however, the durability of response after treatment might not be as reliable as that of interferon. The first of these was lamivudine, approved by the FDA in 1998. Other medications available for treating HBV include adefovir, approved by the FDA in September 2002, entecavir, approved in March 2005, and telbivudine, approved in October 2006.

Patients who are HBeAg-positive and have evidence of liver disease should be treated. The choice among treatment options is dictated by considerations of the likelihood of response, cost, length of treatment, and side-effect profile, as well as the likelihood of developing resistance. There are some data regarding the likelihood of treatment response in patients treated with interferon, with a higher chance of success in patients with high ALT levels but low HBV DNA levels. Analogously, lamivudine is more likely to be effective in patients with increased ALT levels or inflammation on liver biopsy. Comparable predictors of response for the other antivirals have not been established.

The response rate for these different therapies in this population, defined as seroconversion (from HBeAg-positive to HBeAg-negative, with a positive HBeAb) is variable; published rates are 12% (with adefovir), 16% to 18% with lamivudine, 21% with entecavir, 26% with telbivudine, and 32% to 33% with peginterferon alfa-2a or interferon. Other end points (normalization of liver enzyme levels or improvement in liver histology) are typically seen in 50% to 70% of treated patients. Patients with a beneficial response to interferon therapy often develop a flare of disease, with elevations of serum ALT to levels two to three times the baseline before normalization occurs. Because of the possibility that a flare of liver disease can lead to decompensation, the use of interferon in cirrhotic patients is not recommended. Disease flares, by comparison, are not typically seen in patients treated with lamivudine or adefovir. Preliminary data have suggested that entecavir might also be safe in cirrhotic patients.

Treatment for patients with HBeAg-negative disease is also possible. Several studies have shown efficacy with each of the various approved therapies, in terms of loss of hepatitis B viral DNA or normalization of liver enzyme levels (in approximately 60%-70%). Unfortunately, the response rates are often not sustained, with very high relapse rates after therapy is stopped. As a result, the optimal duration of therapy is not defined in this population.

An important consideration in patients treated with any of the nucleoside or nucleotide analogues is the possibility of emergence of resistant mutants, which increases with increasing duration of treatment. This is particularly true with lamivudine treatment, for which rates of resistance range from 24% at 1 year to 42% by year 2 of continued therapy. Lamivudine resistance is manifested by the reappearance of HBV DNA in serum, most commonly with the YMDD mutant, characterized by an amino acid substitution in the HBV DNA polymerase. The outcomes in these patients are variable, but the emergence of a mutant virus can lead to a serious flare of liver disease. Patients therefore should be monitored for the development of resistance and considered for treatment with another antiviral. Other antivirals are associated with a much lower rate of resistance, but none of them is immune from this possibility. Combination therapy with several agents is likely more effective in preventing the development of resistance, but optimal combinations to improve response rates and clinical outcomes have not yet been defined.

Thus, although the introduction of nucleotide or nucleoside analogues represents a significant advance in the management of chronic hepatitis B, many questions remain regarding optimal dosing, duration, and possible combinations to prevent resistance, increase long-term suppression, or promote eventual clearance. A number of other drugs, including emtricitabine, clevudine, famciclovir, and tenofovir, have also shown some efficacy, often in patients coinfected with HIV, and are therefore being further studied in a number of clinical trials. These emerging therapies, including newer and more potent antiviral agents, coupled with aggressive worldwide vaccination policies, lend promise to the hope that hepatitis B will one day be controlled.

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Summary

• Hepatitis B is found throughout the world. Its incidence is especially high in Asia, sub-Saharan Africa, the South Pacific, South America, the Middle East, and the Arctic.
• The most common mode of transmission of hepatitis B worldwide is from mother to infant. Hepatitis B is spread predominantly parenterally, through intimate personal contact, and perinatally.
• Persons at risk include intravenous drug users, children of mothers with HBV, men who have sex with men, patients on hemodialysis, and those exposed to contaminated blood or blood products.
• Most acute infections produce no symptoms. When present, symptoms range widely in severity, from asymptomatic subclinical infection to fulminant fatal disease.
• The risk of developing chronic infection (or the carrier state) depends on the age and immune function of the patient at the time of initial infection.
• Viral and immune markers are detectable in blood, and characteristic antigen-antibody patterns evolve over time. The first detectable viral marker is HBsAg, followed by HBeAg and HBV DNA.
• Effective vaccines for HBV, defined as inducing better than 90% protection against HBV, have been available in the United States since 1982. Hepatitis B vaccine has been described as the first effective anticancer vaccine, and its use has been promoted by the World Health Organization for routine care worldwide since 1997.
• In acute hepatitis B, treatment is supportive. Although several case series have been published, there is no clear evidence that early therapy with antiviral agents for acute hepatitis B decreases the risk of chronicity or speeds recovery. In chronic hepatitis B, therapy is administered to suppress viral replication and prevent progression of liver disease. Many treatment programs have been shown to be effective and have been approved by the FDA and other governmental health agencies around the world.

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Hepatitis C

Robert S. O'Shea

Despite rapid scientific progress in understanding the biology of viral illnesses, viral liver disease remains a common and challenging problem for physicians and their patients. Six viruses, designated hepatitis A, B, C, D, E, and G, primarily target the liver and produce inflammation, or hepatitis, as their primary clinical manifestation. Other viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), can cause hepatitis as part of their clinical presentation, but the liver is usually not the primary infected organ. Of the typical hepatitis viruses, chronic infection with hepatitis C remains one of the most important clinical and public health problems. In the Western world, chronic damage from hepatitis C is the primary cause for the end-stage liver disease requiring liver transplantion.

The discovery of the hepatitis C virus (HCV) in 1989 was a major breakthrough. Before that point, it was clear that a major cause of acute hepatitis after a blood transfusion was neither related to hepatitis A nor to hepatitis B—hence the early name for this disease, non-A, non-B hepatitis. After extensive testing of serum from experimentally infected animals, the virus was cloned using molecular biology techniques. It was found to be an RNA virus classified in the Flaviviridae family and genus Hepacivirus.¹ It is a double-shelled, enveloped, single-stranded RNA virus, 50 to 60 nm in diameter. HCV replicates in the liver, and it is detectable in serum during acute and chronic infection.

The HCV genome codes for the synthesis of a single large polyprotein of about 3000 amino acids that is then cut by specific enzymes into structural and nonstructural proteins. A schematic of the hepatitis C viral structure is shown in Figure 4, along with the proteins that each section encodes. Based on differences in the amino acid sequence of specific proteins, hepatitis C can be classified into a number of different subtypes, known as genotypes. Because of the high error rate in the production of daughter RNA viruses, infected patients typically harbor a heterogeneous group of viruses, with multiple mutations in specific proteins. This variability can be used to divide the HCV infection further in a given patient into subtypes and, beyond that, into specific quasispecies.² This has considerable importance in determining the outcome of treatment, although it probably does not affect the natural history of the disease. Although the virus is found throughout the world, the various genotypes of hepatitis C are distributed differently; for example, genotype 4 infection is common in Egypt, but relatively rare in the United States (Fig. 5 ).

Prevalence

Some patients exposed to hepatitis C do not develop chronic infection, perhaps as many as 20%. Similarly, although the remainder develop chronic infection, only a percentage ultimately develop cirrhosis and its complications, usually over a 10- to 20-year time frame.

Because patients who develop a new infection with hepatitis C are usually asymptomatic for many years, the true prevalence is probably underestimated. It is estimated that approximately 170 million people are infected worldwide, equivalent to 3% of the world's population. Based on antibody testing on blood samples from the National Health and Evaluation Nutrition Surveys from 1999 through 2002 in the United States, it was estimated that as many as 4.1 million people were exposed to HCV. Because most patients are unable to clear the infection spontaneously, experts have estimated that between 2.7 and 3.9 million people—or about 1.3% of the U.S. population—have chronic hepatitis C infection.³

In the past, a major route of infection was via blood transfusion; after implementing polymerase chain reaction (PCR) assays to screen blood donations, the risk of transfusion-associated HCV fell to less than 1 per 100,000 units transfused. Although the incidence of new infection dropped dramatically, the prevalence of infection (the total population of patients still infected) continues to rise. The most common route of transmission is now believed to be related to intravenous drug use, responsible for perhaps as many as 50% of new infections.

Other potential avenues of infection include having multiple sexual partners, tattooing, body piercing, and sharing straws during intranasal cocaine use, all of which are linked to an increased risk of infection. Maternal-fetal transmission occurs in approximately 10% of cases and is more likely to occur in a mother who is coinfected with HIV. The rate of infection after an HCV-contaminated needle-stick injury has ranged from 0% to 10% in various studies. Although possible, viral transmission to a sexual partner in a monogamous relationship is rare, with a less than 5% risk. The Centers for Disease Control and Prevention (CDC) does not advocate any change in sexual practice for partners engaging in a long-term, monogamous, sexual relationship.

Based on epidemiologic studies of transmission and prevalence rates, the CDC recommends screening patients with specific risk factors, including the following:⁴

• Patients who have previously used drugs
• Patients with HIV or hemophilia
• Patients on dialysis in the past, or those who received transplants or transfusions before 1992
• Health care workers after a needle stick injury
• Possibly children of HCV-infected mothers or sexual partners of HCV-infected persons

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Pathophysiology

Although HCV can be found in multiple sites throughout the body, including the liver, peripheral blood mononuclear cells, dendritic cells, epithelium, and even the central nervous system, HCV replicates in the hepatocytes. However, in the person with a normal immune system, it is not directly hepatotoxic.

Viral replication occurs through an RNA-dependent RNA polymerase process. Lymphocytes recognize infected cells and initiate an immune response to control the virus. Viral clearance is associated with the development and persistence of strong, virus-specific responses by cytotoxic T lymphocytes and helper T cells. Because of the rapid evolution of diverse quasispecies within an infected person, even a brisk B cell (e.g., antibody) response to hepatitis C has been inadequate to clear the infection, because the virus represents a moving target to the immune system. For the same reason, progress in the development of a vaccine to protect patients from an initial infection has been slow.

Damage to the liver parenchyma is mediated by inflammatory cytokines. Persistent inflammatory mediators activate stellate cells in the liver parenchyma, leading to varying degrees of hepatic fibrosis. Why some patients develop progressive fibrosis and eventually cirrhosis, and others do not, is unknown, but some predictors of progression have been identified, including male sex, age at onset of infection, and use of alcohol.

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Signs and symptoms

Acute HCV infection is uncommonly recognized because it is usually accompanied by mild flulike symptoms. Although the vast majority of patients with acute HCV infection are asymptomatic, weight loss, fatigue, muscle or joint pain, irritability, nausea, malaise, anorexia, and jaundice have been reported to occur rarely in the 2- to 26-week incubation period. In chronic symptomatic HCV infection, fatigue is a common complaint, but the degree of fatigue is unrelated to the severity of liver disease. Other complaints can include depression, nausea, anorexia, abdominal discomfort, and difficulty with concentration. Symptoms might first appear only with the onset of more-advanced liver disease. Common extrahepatic manifestations of HCV infection include mixed cryoglobulinemia and porphyria cutanea tarda. Membranoproliferative glomerulonephritis, leukocytoclastic vasculitis, focal lymphocytic sialadenitis, and idiopathic pulmonary fibrosis occur in rare cases and are believed to be secondary to immune-complex deposition in association with intact virus or viral proteins. Many patients have no specific symptoms, and the finding of abnormal hepatic transaminase levels on routine testing often prompts specific testing for hepatitis C.

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Diagnosis

Serologic assays for HCV are based on detecting HCV antibodies or HCV RNA. The most commonly used serologic test for detecting antibodies to hepatitis C is ELISA, with a sensitivity and specificity of 95%. Some laboratories automatically confirm a positive ELISA test by a supplemental recombinant immunoblot assay (RIBA) to increase the specificity of the test (e.g., to decrease the number of false positives). In the 15% of infected persons who clear the virus spontaneously, these antibody test results remain positive and thus cannot be used to confirm active infection. This also applies to treated patients who clear the virus, who maintain a positive HCV antibody indefinitely. A very small percentage of patients infected with HCV are unable to mount an immune response to the viral protein and do not produce antibody. These false negatives occur in those with HIV infections, renal failure, or HCV-associated mixed cryoglobulinemia. Confirmation of ongoing infection therefore requires the detection of HCV RNA by PCR using a qualitative or quantitative assay. These assays can detect a viral count as low as 9.6 IU/L. A negative qualitative test result argues strongly against active viral infection. The quantitative HCV RNA test reflects the viral load, which is an important variable to predict the outcome of anti-HCV therapy but not the likelihood of disease progression.⁴

Patients commonly come to medical attention based on elevated alanine aminotransferase (ALT) levels, which are indirect markers of liver cell necrosis. Although ALT measurements have been used to monitor HCV infection and the efficacy of therapy, the recognition that many infected patients have normal ALT levels has limited their usefulness. Furthermore, the normalization of ALT levels with antiviral therapy is not proof of successful virus eradication. Viral quantification has replaced ALT levels, therefore, in monitoring treatment response.

In patients with documented HCV infection, a liver biopsy is often helpful in determining the need for therapy. Although not considered mandatory before initiating treatment, it documents the amount of ongoing destruction (grade) and degree of fibrosis (stage) of disease. Patients with more-advanced fibrosis are at high risk for progressive liver disease and therefore should be considered for therapy. Significant fibrosis may be present in up to 25% of patients with normal transaminase levels. Conversely, patients with minimal fibrosis can choose to forgo immediate therapy, weighing the likelihood of progressive scar tissue development against the side effect profile of current treatment, as well as the likelihood of response.

Viral load and viral genotype help predict the outcome of treatment, because response rates are most strongly linked to these two variables. In addition, they influence the length of therapy: Patients with genotype 1, the most common form in North America, and a high viral load are more resistant to therapy, with response rates of approximately 40%, even after 1 year of combination treatment. By comparison, patients with genotype 2 or 3 may be expected to achieve sustained virologic response rates of almost 80% after 6 months of treatment.⁴

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Treatment

Treatment outcomes depend on many factors, including whether a patient is being treated for acute or chronic disease. Acute HCV infection is uncommonly diagnosed, because it often manifests with nonspecific flulike symptoms. Available evidence suggests that interferon-based therapy given early in the course of infection decreases the risk of progression to chronic disease.⁵ Health care workers, for example, who are accidentally exposed to HCV-infected blood via a needle stick injury, should be followed carefully for evidence of ongoing infection, and if they are unable to clear the infection spontaneously, they should be treated early.

The more common situation facing clinicians is that of patients with chronic hepatitis C, for whom the goal of treatment is elimination of the virus. This is associated with stabilization or even improvements in liver histology and clinical course. Secondary aims are symptom control, improvement in liver function, and prevention of complications of progressive liver disease, including cirrhosis, decompensated liver disease, and hepatocellular carcinoma.

Complete abstinence from alcohol is an extremely important behavioral modification and has been shown to affect the likelihood of progression as well as the efficacy of therapy. The usefulness of other therapies, including dietary supplements, herbs, and unconventional treatments, have not been rigorously studied, and the results are extremely varied.⁶ Apart from interferon-based therapy, most interventions have only marginal benefit. Regardless of whether a patient elects to be treated or not, practice guidelines recommend that all patients with hepatitis C and no evidence for immunity be vaccinated for hepatitis A and, if risk factors exist, for hepatitis B as well.

Patients treated with interferon are classified into those who do not respond (i.e., fail to clear HCV from their blood), relapsers (i.e., those who cleared the virus on treatment, but afterward had detectable virus), and those who develop a sustained virologic response (SVR), defined as undetectable virus in the serum 6 months after treatment completion, which correlates well with long-term absence of virus. Although any patient with hepatitis C infection can be considered for therapy, the decision must be individualized, based on the overall risks and benefits of therapy. Patients with chronic HCV infection and evidence of damage, including elevated serum aminotransferase levels, chronic hepatitis on liver biopsy, absence of decompensation, and no contraindications, should be considered for treatment. Specific contraindications include severe concurrent disease, previous solid organ transplantation, autoimmune hepatitis, hyperthyroidism, pregnancy, or uncontrolled depression. Previous contraindications, such as HIV infection or AIDS or otherwise immunocompromised status, are no longer considered obstacles to treatment. Often, HIV-positive patients are coinfected with hepatitis C, because the viruses can share a similar epidemiology. The most recent studies have demonstrated response rates to therapy of 14% to 73% in these patients, depending on genotype, which are somewhat better than those seen with previous treatments. These rates, however, are less than those expected in HIV-negative patients.⁷

A pretreatment neuropsychiatric assessment should be performed in all patients. If depression, anxiety, or other psychiatric illness is evident by history, a psychiatric consultation should be sought for evaluation, treatment, and follow-up during the interferon treatment period. Psychosis and homicidal or suicidal ideation are strong contraindications to therapy.

Factors predicting a therapeutic response include low pretreatment HCV RNA level, genotype 2 or 3, female sex, low body mass index (BMI), and low hepatic iron load. Patients with advanced liver disease or decompensated cirrhosis are also unlikely to respond and often are unable to tolerate treatment.⁴

Treatment of hepatitis C infection has evolved since the 1990s. It remains based on interferon alfa as an immune modulator. Response rates were modest when it was used as monotherapy (10% in genotype 1 and 30% at best in genotypes 2 and 3). Side effects remain a significant problem and are typically described as flulike symptoms, including fever, arthralgia, headache, depression, injection site inflammation, and bone marrow suppression. The addition of ribavirin, a nucleoside analogue and an inhibitor of viral replication, has improved the SVR rate to approximately 50% (46% in genotype 1 and 76% in genotypes 2 and 3; Table 1 ). There is some evidence for a dose-response effect, with generally increased response rates in higher doses (usually 1000-1200 mg in divided doses). Ribavirin is cleared by the kidneys and therefore is contraindicated in patients with significant renal dysfunction (a creatinine clearance <50 mL/min). It also has been shown to be teratogenic and is therefore strictly contraindicated in pregnancy. The most common side effect is fatigue in about 15% of patients, resulting partly from hemolytic anemia.

The most recently introduced treatment is pegylated interferon, a form of interferon covalently bound to a large inert polyethylene glycol molecule. The combination serves to prolong the serum half-life by decreasing the excretion rate, thereby increasing the duration of action. Enhanced response rates have been demonstrated for pegylated interferons in combination therapy with ribavirin.⁸ If patients are able to complete a full course of treatment at optimal doses (e.g., without dose adjustments for side effects or toxicity), SVR rates may be as high as 88% in genotypes 2 and 3 patients and up to 50% in those with genotype 1 (see Table 1). Side effects, such as injection site reaction and bone marrow suppression, may be more pronounced with different formulations and doses.

Although the usual duration of treatment for patient with genotype 1 is 48 weeks, data from multiple studies have suggested that it is possible to predict the outcome of therapy by 12 weeks of therapy. If a patient fails to clear infection or has at least a 2-log decline in the viral load (measured with the same PCR assay as used at baseline), it is unlikely that the patient will develop a SVR.⁹ Studies are ongoing to define new and earlier stopping rules.

Patients on therapy need to be monitored closely for complications or symptoms of the adverse reactions of combination therapy. This should include evaluation for depression, symptoms of irritability, sleep disturbance, and visual disturbances, as well as evidence of hyper- or hypothyroidism. Blood counts should be monitored frequently at the beginning of treatment and at least monthly afterward, if stable. An emerging literature suggests that support of the bone marrow with erythropoietin for anemia and granulating cell-stimulating factor (GCSF) for neutropenia can allow continuation of therapy, even in patients with significantly affected counts. The cost effectiveness of this approach, however, is uncertain.

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Complications

Chronic HCV infection is the most common indication for liver transplantation in the United States, and, as complications related to the epidemic continue, a significant impact on the U.S. health care system is expected. It has been estimated that over the next 20 years, the ppercentage of infected patients with cirrhosis will increase from 16% to 32%, and other complications will also increase dramatically, including hepatic decompensation (up 106%), hepatocellular carcinoma (up 81%), and liver-related deaths (up 180%).¹⁰

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Conclusions

HCV infection typically progresses to chronic infection in more than 60% of patients, and it can lead to cirrhosis in as many as 20% over a 20-year period. Serum aminotransferase levels reflecting hepatocellular injury can fluctuate, as does the viral load.

As the disease evolves, hepatocytes are progressively destroyed and replaced by fibrosis, insidiously leading to the development of bridging fibrosis and ultimately cirrhosis. The course of any individual patient is affected by various factors, such as age at onset of infection, sex, coinfection with other viruses (HAV, HBV or HIV), or other medical conditions, as well as risk behavior, such as alcohol consumption. Interferon-based treatment has a varying success rate in clearing the virus, as noted earlier. Careful selection and monitoring of patients are essential in undertaking therapy. In patients without cirrhosis, hepatitis C–related mortality is only slightly increased. Severe complications usually occur only in those with established cirrhosis. The risk of developing hepatocellular carcinoma (HCC) in chronic HCV patients with cirrhosis is as high as 4% per year. HCV-infected patients with cirrhosis should be screened at intervals with ultrasound and alpha-fetoprotein testing. Some retrospective studies have shown that treatment with interferon is associated with a lower rate of development of HCC, even without an SVR.

Although HCV remains a major global health problem, significant advances in the understanding of its basic biology have allowed significant improvements in treatment since the turn of the 21st century. Treatment, although difficult, has been shown to prolong life, and the pace of discovery in this field gives hope that patients will be able to be treated even more effectively in the future.

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Summary

• It is estimated that approximately 170 million people are infected worldwide (3% of the world's population). It has been estimated that as many as 4.1 million Americans were exposed to HCV; from 2.7 to 3.9 million people in the United States have chronic hepatitis C infection.
• Chronic HCV infection is the most common indication for liver transplantation in the United States and, as its complications continue, a significant impact on the U.S. health care system is expected. It has been estimated that over the next 20 years, the percentage of infected patients with cirrhosis will increase from 16% to 32% and other complications will also increase dramatically.
• In the past, a major route of infection was via blood transfusion; after implementing the use of polymerase chain reaction (PCR) assays to screen blood donations, the risk of transfusion-associated HCV fell to less than 1/100,000 units transfused. However, the prevalence of infection continues to rise. The most common route of transmission is now believed to be related to intravenous drug use, responsible for perhaps as many as 50% of new infections. Maternal-fetal transmission occurs in approximately 10% of cases.
• Acute HCV infection is uncommonly recognized. Although most patients with acute HCV infection are asymptomatic, fatigue, depression, nausea, anorexia, abdominal discomfort, and difficulty with concentration can occur in chronic symptomatic HCV infection. Common extrahepatic manifestations of HCV infection include mixed cryoglobulinemia and porphyria cutanea tarda. Many patients have no specific symptoms, and the finding of abnormal hepatic transaminase levels on routine testing often prompts specific testing for hepatitis C.
• Serologic assays for HCV are based on detecting HCV antibodies or HCV RNA. Viral load and viral genotype help predict the outcome of treatment, because response rates are most strongly linked to these two variables.
• Treatment of hepatitis C infection is based on interferon alfa administration over many months. Combined with ribavirin, a sustained virologic response rate of approximately 50% (46% in genotype 1 and 76% in genotypes 2 and 3) can be anticipated. Higher response rates may be seen when the patient is younger, thinner, or female and has a low viral load and absence of hepatic fibrosis.

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Hepatitis D

Talal Adhami

William D. Carey

Virology

Hepatitis D or delta virus (HDV) is a defective single-stranded RNA virus requiring the presence of hepatitis B virus (HBV) for its expression and replication. HDV is a 35- to 37-nm spherical particle enveloped by a lipoprotein coat derived from HBsAg. HDV-RNA consists of 1680 nucleotides, and replication is limited to hepatocytes. It is considered to be the smallest RNA genome among the animal viruses.

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Prevalence

HDV has a worldwide distribution. It is endemic in the developing world, with a high prevalence in South America. HDV infection is limited to patients who have HBV infection and, like hepatitis B, is acquired parenterally. Worldwide, about 5% of HBV carriers are anti-HDV-positive. Delta hepatitis remains a common problem among intravenous drug users.

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Pathophysiology

Patients may be infected with HDV at the same time that they acquire the hepatitis B virus (acute coinfection) or they can acquire the virus after infection with hepatitis B (superinfection). It is still not clear whether the virus is directly cytotoxic or whether an immune-mediated response is responsible for the pathology. An immune response may be the predominant mediator in chronic disease, whereas direct viral cytotoxicity can predominate in acute infection. Necroinflammatory activity is severe, but histologic features are nonspecific for chronic HDV infection.¹

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Signs and symptoms

Symptoms of HDV infection are nonspecific, and most patients have subclinical illness. Most patients who acquire HDV and HBV simultaneously clear the delta virus, whereas 70% to 90% of those superinfected develop chronic delta infection. Superinfection produces more-severe acute illness than HBV alone and carries a higher risk for fulminant hepatic failure, which occurs in 5% to 20% of cases.²

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Diagnosis

The diagnosis of delta hepatitis should only be considered if positive HBV infection is present. This is usually reflected by finding a positive serum HBsAg or HBV DNA, or both. Measuring antibodies to delta antigen using ELISA can make the diagnosis. However, it may be positive after viral clearance, especially in case of HBV-HDV coinfection. IgM antibodies are increased when there is liver damage and not just in the acute illness; they apparently disappear when the hepatitis resolves. Presence of HDV antigen in the serum confirms the diagnosis, as does HDV RNA, which is only available in a research setting. Anti-HDV antibody (IgG) can appear in high titers in chronic HDV infection, whereas lower titer may be detected after viral resolution.

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Treatment

Delta hepatitis can be prevented by vaccination against hepatitis B. At this time, there is no effective vaccine to prevent delta hepatitis in chronic hepatitis B carriers. Delta hepatitis can be treated with high-dose interferon as high as 9 million U three times per week for 1 year. Although as many as 70% of patients clear the virus and normalize liver enzyme levels, almost all patients relapse at some point after therapy. Orthotopic liver transplantation is considered for decompensated patients. Interestingly, patients who have HDV and who receive a liver transplant have a higher chance of graft survival than those who receive a transplant for hepatitis B alone. This phenomenon may be a result of the inhibitory effect of HDV on HBV replication. Hepatitis B immunoglobulin is administered to these patients.

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Outcomes

Coinfection with HDV and HBV can result in a severe fulminant hepatitis and liver failure or can persist as a chronic infection, resulting in cirrhosis or hepatocellular carcinoma. Chronic infection can persist in an inactive phase, and some patients go into complete remission. The chance of progression to cirrhosis is higher in patients with delta hepatitis than in patients solely infected with hepatitis B, as is the risk for hepatocellular carcinoma. Patients coinfected with human immunodeficiency virus or hepatitis C have a worse outcome.^3,4

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Summary

• Hepatitis D or delta virus (HDV) is a defective single-stranded RNA virus requiring the presence of hepatitis B virus (HBV) for its expression and replication. HDV has a worldwide distribution. It is endemic in the developing world.
• HDV infection is limited to patients who have HBV infection and, like hepatitis B, is acquired parenterally.
• Infection with HDV produces more severe acute illness than HBV alone and carries a higher risk for fulminant hepatic failure, which occurs in 5% to 20% of cases.
• The chance of progression to cirrhosis is higher in patients with delta hepatitis than in patients solely with hepatitis B, as is the risk for hepatocellular carcinoma.
• Delta hepatitis can be prevented by vaccination against hepatitis B.

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Hepatitis E

Talal Adhami

William D. Carey

Definition

Hepatitis E virus (HEV) is a 32-nm nonenveloped single-stranded RNA virus. It belongs to the family Calciviridae and genus Calcivirus. It is largely a waterborne epidemic disease (Fig. 6 ). Increasing evidence has suggested that animals, especially swine, represent an important reservoir for HEV.¹

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Prevalence and risk factors

HEV is distributed in endemic and epidemic forms in Southeast and Central Asia, the Middle East, Africa, and Mexico (Fig. 7 ). Seroprevalence studies have indicated that the incidence of hepatitis E is increasing in 8 of 11 countries surveyed. Up to 30% of persons ages 16 to 30 years test positive for anti-E antibodies in most participating countries, except for Spain, Japan, and the United States, where the incidence remains very low.² The incidence may be increasing in the United Kingdom.³ In Nepal, 56% of acute hepatitis is associated with IgM anti–hepatitis E. It is rare in the United States, except in immigrants and travelers returning from endemic regions. Less than 1% of reported cases of acute viral hepatitis in the United States are attributed to hepatitis E. Infection requires ingestion of fecally contaminated water or foods.

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Pathophysiology and natural history

HEV replicates in the hepatocytes and is excreted in stool. Transmission is predominantly by the fecal-oral route, usually through contaminated water. Although person-to-person transmission is rare, maternal-neonatal transmission has been documented. Outbreaks occur in conditions of crowding and poor sanitation. A report of hepatitis E among displaced populations in Darfur, Sudan, has indicated an attack rate as high as 3% and a case-fatality rate of 1.7%. Forty-two percent of the deaths occurred in pregnant women.⁴

The incubation period ranges from 15 to 60 days. The virus is detected in stool as early as 1 week before the onset of clinical illness and persists for 1 to 2 weeks afterward, during which stools are highly infectious. Anti-HBE antibody (IgM) appears soon after the onset of the clinical infection, and IgG appears soon after that; IgG remains detectable for as long as 20 months.

Like hepatitis A, HEV is most often a self- limited disease; immunity develops, and no second attacks occur. Hepatitis E occurs, on average, in older persons than those who acquire hepatitis A infection. Severe disease, including fulminant hepatitis and death, occur more often in hepatitis E.⁵

The course of HEV is usually more severe than that seen in other forms of epidemic jaundice. The fatality rate is generally lower than 1%. It is, however, an illness of great concern in pregnant women because it can cause liver failure, with a mortality rate of 20%. Prolonged viremia or fecal shedding are unusual, and chronic infection does not occur.

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Signs and symptoms

HEV causes acute hepatitis. Nonspecific constitutional and gastrointestinal symptoms are similar to those found in other types of viral hepatitis. The onset of symptoms tends to be abrupt, and fever is uncommon. Prodromal symptoms improve or disappear with the onset of jaundice, although anorexia, malaise, and weakness can persist. Without the presence of jaundice, most sporadic episodes are probably misdiagnosed. Nevertheless, in most reported outbreaks, jaundice is present in 90% to 100% of cases, suggesting that HEV may be more likely than hepatitis A, B, or C to produce jaundice.

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Diagnosis

In the United States, hepatitis E infection should be considered in patients who present with acute hepatitis and have recently traveled to endemic areas. The disease is often cholestatic, with elevated bilirubin and alkaline phosphatase levels. The presence of anti-HBE antibody (IgM) in the serum confirms the disease and persists for at least 6 weeks after the peak of the illness. IgG antibody peaks soon after that and remains detectable for as long as 20 months. Laboratory diagnosis is based on antibody testing. IgM anti–hepatitis E denotes recent infection, although the IgM can remain positive for more than 1 year. IgM anti–hepatitis E is usually present for years.⁶

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Treatment and prevention

Persons traveling to endemic areas should be aware of the virus and avoid water, uncooked food, and contact with contaminated substances. Vaccination and immune globulin are not currently available, but tests have been conducted in human volunteers. Treatment of the acute infection is supportive.

Common sense dictates that societal commitment to good public health, clean water supplies, and personal sanitation will reduce the incidence of HEV, as it has with hepatitis A. However, evidence is meager that such measures have had an impact on HEV infection rates. Passive immunization with gamma globulin is not recommended for protection against hepatitis E, in part because gamma globulin produced in countries where the prevalence of HEV is low is expected to have low anti-HEV activity. Even when gamma globulin is produced in high-endemic areas, evidence of benefit of passive immunization is equivocal. No active immunization is currently available.

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Summary

• Hepatitis E is an RNA virus that infects humans through oral contamination of water. It spreads both from person to person and through animal intermediaries, such as swine.
• Hepatitis E is seen principally in Southeast and Central Asia, the Middle East, and Africa, and in travelers returning from endemic areas.
• Illness caused by hepatitis E might be asymptomatic, but is much more likely to produce jaundice than other forms of acute viral hepatitis. The case-fatality rate is 1.7%, but pregnant women seem especially susceptible to severe disease and a fatal outcome.
• There is no chronic form of hepatitis E. One attack appears to confer immunity.
• Management of acute hepatitis E is similar to that for other forms of acute viral hepatitis. Patients who can maintain hydration and nutrition can be treated at home; those with severe symptomatic disease can require hospitalization. No antiviral agents have yet been shown to affect the course of acute hepatitis E.

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Suggested Readings - Hepatitis A

• Advisory Committee on Immunization Practices (ACIP). Prevention of hepatitis A through active or passive immunization. MMWR Morb Mortal Wkly Rep. 1999, 48: (RR-12):1-37.
• Younossi ZM. Viral hepatitis guide for practicing physicians. Cleve Clin J Med. 2000, 67: (Suppl 1): SI6 -SI45.

Suggested Readings - Hepatitis B

• Blumberg BS, Alter HJ, Visnich S. A “new” antigen in leukemia sera. JAMA. 1965, 191: 541 -546.
• Centers for Disease Control and Prevention. Prevention of perinatal transmission of hepatitis B virus: Prenatal screening of all pregnant women for hepatitis B surface antigen. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Morb Mortal Wkly Rep. 1988, 37: 341 -346.
• Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med. 2004, 350: 1118 -1129.
• Hsu YS, Chien RN, Yeh CT, et al: Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology. 2002, 35: 1522 -1527.
• Keefe EB, Dieterich DT, Han SH, et al: A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol. 2004, 2: 87 -106.
• Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment and current and emerging prevention and control measures. J Viral Hepatol. 2004, 11: 97 -107.
• Liang TJ, Ghany M. Hepatitis B e antigen—the dangerous end game of hepatitis B. N Engl J Med. 2002, 347: 208 -210.
• Lok AS, McMahon BJ. Chronic hepatitis B. AASLD practice guidelines. Hepatology. 2007, 45: 507 -539.
• Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD). Chronic hepatitis B: Update of recommendations. Hepatology. 2004, 39: 857 -861.
• McMahon BJ, Holck P, Bulkow L, Snowball M. Serologic and clinical outcomes of 1536 Alaska Natives chronically infected with hepatitis B virus. Ann Intern Med. 2001, 135: 759 -768.
• Nair S, Perrillo RP. Hepatitis B and D. In: Zakim D, Boyer TD (eds): Hepatology: A Textbook of Liver Diseases. 4th ed. Philadelphia: WB Saunders, 2003, 959 -1017.
• Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev. 2000, 64: 51 -68.
• World Health Organization: Geographic Prevalence of Hepatitis B, 2004. Available at http://www.who.int/vaccines-surveillance/graphics/htmls/hepbprev.htm (accessed March 9, 2009)
• Yang H, Lu SN, Liaw YF, et al: Hepatitis B e antigen and the risk of hepatocelluar carcinoma. N Engl J Med. 2002, 347: 168 -174.

Suggested Readings - Hepatitis C

• Choo QL, Kuo G, Weiner AJ, et al: Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989, 244: 359 -362.
• Chung RT, Andersen J, Volberding P, et al: Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004, 351: 451 -459.
• Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003, 9: 331 -338.
• Davis GL, Wong JB, McHutchison JG, et al: Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003, 38: 645 -652.
• Fried MW, Shiffman ML, Reddy KR, et al: Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002, 347: 975 -982.
• Jaeckel E, Cornberg M, Wedemeyer H, et al: German Acute Hepatitis C Therapy Group: Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med. 2001, 345: 1452 -1457.
• Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002, 36: (Suppl 1): S30 -S34.
• Liu J, Manheimer E, Tsutani K, Gluud C. Medicinal herbs for hepatitis C virus infection: A Cochrane hepatobiliary systematic review of randomized trials. Am J Gastroenterol. 2003, 98: 538 -544.
• Penin F, Dubuisson J, Rey FA, et al: Structural biology of hepatitis C virus. Hepatology. 2004, 39: 5 -19.
• Strader DB, Wright T, Thomas DL, Seeff LB. American Association for the Study of Liver Diseases: Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004, 39: 1147 -1171.

Suggested Readings - Hepatitis D

• Chu CM, Yeh CT, Liaw YF. Viral superinfection in previously unrecognized chronic carriers of hepatitis B virus with superimposed acute fulminant versus nonfulminant hepatitis. J Clin Microbiol. 1999, 37: 235 -237.
• Huo TI, Wu JC, Lai CR, et al: Comparison of clinico-pathological features in hepatitis B virus-associated hepatocellular carcinoma with or without hepatitis D virus superinfection. J Hepatol. 1996, 25: 439 -444.
• Mendez L, Reddy KR, Di Prima RA, et al: Fulminant hepatic failure due to acute hepatitis B and delta co-infection: Probable bloodborne transmission associated with a spring-loaded fingerstick device. Am J Gastroenterol. 1991, 86: 895 -897.
• Polish LB, Gallagher M, Fields HA, Hadler SC. Delta hepatitis: Molecular biology and clinical and epidemiological features. Clin Microbiol Rev. 1993, 6: 211 -229.

Suggested Readings - Hepatitis E

• Abe K, Li TC, Ding X, et al: International collaborative survey on epidemiology of hepatitis E virus in 11 countries. Southeast Asian J Trop Med Public Health. 2006, 37: 90 -95.
• Chau TN, Lai ST, Tse C, et al: Epidemiology and clinical features of sporadic hepatitis E as compared with hepatitis A. Am J Gastroenterol. 2006, 101: 292 -296.
• Guthmann JP, Klovstad H, Boccia D, et al: A large outbreak of hepatitis E among a displaced population in Darfur, Sudan, 2004: The role of water treatment methods. Clin Infect Dis. 2006, 42: 1685 -16891.
• Myint KS, Endy TP, Shrestha MP, et al: Hepatitis E antibody kinetics in Nepalese patients. Trans R Soc Trop Med Hyg. 2006, 100: 938 -941.
• Sadler GJ, Mells GF, Shah NH, et al: UK acquired hepatitis E-an emerging problem? J Med Virol. 2006, 78: 473 -475.
• Zheng Y, Ge S, Zhang J, et al: Swine as a principal reservoir of hepatitis E virus that infects humans in eastern China. J Infect Dis. 2006, 193: 1643 -1649.