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MD Consult: Books: Goldman: Cecil Medicine: Chapter 151 – ACUTE VIRAL HEPATITIS

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 151 – ACUTE VIRAL HEPATITIS

Jay H. Hoofnagle

Definition

Acute viral hepatitis is a distinct clinical syndrome that can be caused by five separate, unrelated viruses. Clinically, acute viral hepatitis is marked by symptoms of malaise, nausea, poor appetite, vague abdominal pain, and jaundice; biochemically, by abrupt increases in serum bilirubin and aminotransferase levels; serologically, by the appearance of a hepatitis viral genome in the liver and serum followed by antibodies to viral antigens; and histologically, by varying degrees of hepatocellular necrosis and inflammation. Acute viral hepatitis is typically self-limited and resolves completely without residual liver injury or viral replication. A proportion of some forms of hepatitis, however, can result in persistent infection with chronic liver injury. The clinical manifestations of the five forms of viral hepatitis are quite similar, and the diseases can be distinguished only by serologic assays.

The five known causes of acute hepatitis are the hepatitis A (HAV), B (HBV), C (HCV), D or delta (HDV), and E (HEV) viruses ( Table 151-1 ). All except HBV are RNA viruses. Hepatitis A and E are forms of infectious hepatitis; they are spread largely by the fecal-oral route, are associated with poor sanitary conditions, are highly contagious, occur in outbreaks as well as sporadically, and cause self-limited hepatitis only. Hepatitis B, C, and D are forms of serum hepatitis, are spread largely by parenteral routes and less commonly by intimate or sexual exposure, and are not highly contagious but instead occur sporadically and rarely cause outbreaks. They are capable of leading to chronic hepatitis and, ultimately, to cirrhosis and hepatocellular carcinoma. Cases of an acute viral hepatitis–like syndrome that cannot be identified as being due to a known hepatitis virus occur and are termed acute non-A, non-B, non-C, non-D, non-E (non-A–E) hepatitis or acute hepatitis of unknown cause. Despite many attempts, the viral etiology of non-A–E hepatitis remains unproven.


TABLE 151-1   — 
FIVE CAUSES OF ACUTE VIRAL HEPATITIS

Hepatitis Virus Size (nm) Genome Spread Incubation Period (Days) Fatality Rate Chronic Rate Antibody
A 27 RNA Fecal-oral 15–45, mean of 25 1% None Anti-HAV
B 45 DNA Parenteral 30–180, mean of 75 1% 2–7% Anti-HBs
    Sexual       Anti-HBc
            Anti-HBe
C 60 RNA Parenteral 15–150, mean of 50 <0.1% 50–85% Anti-HCV
D (delta) 40 RNA Parenteral 30–150 2–10% 2–7% Anti-HDV
    Sexual     50%  
E 32 RNA Fecal-oral 30–60 1% None Anti-HEV
Epidemiology

Acute viral hepatitis is a common disease that affects 0.5 to 1% of persons in the United States each year. The annual incidence of acute hepatitis has been decreasing steadily since 1990, largely because of the use of hepatitis A and B vaccines and decreases in high-risk behaviors. In recent population-based surveys, viral causes of acute hepatitis were HAV in 37%, HBV in 45%, and HCV in 18% of cases. Hepatitis D is rare in the United States (<1% of acute cases), and most reported cases of hepatitis E have been imported. In up to 3% of cases, the cause of hepatitis cannot be ascertained even after extensive testing. In clinical practice, other nonviral forms of acute hepatitis must be considered, especially mononucleosis ( Chapter 400 ); secondary syphilis ( Chapter 340 ); drug-induced liver disease ( Chapter 153 ); acute cholecystitis (or acute biliary obstruction; Chapter 159 ); Wilson’s disease ( Chapter 230 ); and various forms of ischemic, malignant, or toxic hepatic injury ( Chapters 146 and 154 to 157 ).

Pathobiology

The pathogenesis of the liver injury in viral hepatitis is not well understood. None of the five agents seems to be directly cytopathic, at least at levels of replication found during typical acute and chronic hepatitis. The timing and histologic appearance of hepatocyte injury in viral hepatitis suggest that immune responses, particularly cytotoxic T-cell responses to viral antigens expressed on hepatocyte cell membranes, may be the major effectors of injury. Other pro-inflammatory cytokines, natural killer cell activity, and antibody-dependent cellular cytotoxicity may also play modulating roles in cell injury and inflammation during acute hepatitis virus infection. Recovery from hepatitis virus infection is usually accompanied by the appearance of rising titers of antibody against envelope antigens, such as anti-HAV, anti-HBs, anti-HCV-E1 and anti-HCV-E2, and anti-HEV; these antibodies may provide at least partial immunity to reinfection.

Clinical Manifestations

The course of acute hepatitis is highly variable and ranges in severity from a transient, asymptomatic infection to severe or fulminant disease. The disease may be self-limited and resolve, run a relapsing course, or lead to chronic infection. In a typical, clinically apparent course of acute resolving viral hepatitis ( Fig. 151-1 ), the incubation period varies from 2 to 20 weeks, largely on the basis of the viral etiology and exposure dose. During this phase, virus becomes detectable in blood, but serum aminotransferase and bilirubin levels are normal, and antibody is not detected.

FIGURE 151-1  Typical course of acute viral hepatitis.

The preicteric phase of illness is marked by the onset of nonspecific symptoms such as fatigue, nausea, poor appetite, and vague right upper quadrant pain. Viral-specific antibody first appears during this phase. The preicteric phase typically lasts 3 to 10 days, but this phase may last longer and even constitute the entire course of illness in patients with subclinical or anicteric forms of acute hepatitis. Viral titers are generally highest at this point, and serum aminotransferase levels start to increase.

The onset of dark urine marks the icteric phase of illness, during which jaundice appears and symptoms of fatigue and nausea worsen. Typically, acute viral hepatitis is rarely diagnosed correctly before the onset of jaundice. If jaundice is severe, stool color lightens, and pruritus may appear. Anorexia, dysgeusia, and weight loss may also occur. Physical examination usually shows jaundice and hepatic tenderness. In more severe cases, hepatomegaly and splenomegaly may be present. Serum bilirubin levels (total and direct) rise, and aminotransferase levels are generally greater than 10 times the upper limit of normal, at least at the onset. During the icteric, symptomatic phase, levels of hepatitis virus begin to decrease in serum and liver.

The duration of clinical illness is variable; it typically lasts 1 to 3 weeks. Recovery is first manifested by return of appetite and is accompanied by resolution of the serum bilirubin and aminotransferase elevations and clearance of virus. Convalescence can be prolonged, however, before full energy and stamina return. Neutralizing antibodies usually appear during the icteric phase and rise to high levels during convalescence.

Complications of acute viral hepatitis include chronic infection, fulminant hepatic failure, relapsing or cholestatic hepatitis, and extrahepatic syndromes. Chronic hepatitis ( Chapter 152 ), generally defined as at least 6 months of illness, eventuates in approximately 2 to 7% of adults with hepatitis B and 50 to 85% of adults with hepatitis C. Hepatitis B, C, and D are said to be chronic if viremia persists for more than 6 months but can be suspected if viremia persists for 3 months after the onset of symptoms.

Acute liver failure or fulminant hepatitis occurs in 1 to 2% of patients with symptomatic acute hepatitis, perhaps most commonly with hepatitis B and D and least commonly with hepatitis C. The disease is called fulminant if hepatic encephalopathy appears; however, the initial symptoms (changes in personality, aggressive behavior, or abnormal sleep patterns) may be subtle or misunderstood. The most reliable prognostic factor in acute hepatic failure is the degree of prolongation of the prothrombin time; other signs of poor prognosis are persistently worsening jaundice, ascites, and decreases in liver size. Serum aminotransferase levels and viral titers have little prognostic value and often decrease with worsening hepatic failure.

In a proportion of patients with acute hepatitis, a cholestatic pattern of illness consisting of prolonged and fluctuating jaundice and pruritus develops. Patients may have one or more clinical relapses and may feel relatively good despite marked jaundice. Cholestatic hepatitis is generally benign and ultimately resolves.

In 10 to 20% of patients with acute hepatitis, a serum sickness–like syndrome marked by variable combinations of rash, hives, arthralgias, and fever develops during the preicteric phase. This immune complex–like syndrome is often mistakenly attributed to other illnesses until the onset of jaundice, at which time the fever, hives, and arthralgias quickly resolve. Other extrahepatic manifestations of acute hepatitis are uncommon but include severe headaches, encephalitis, aseptic meningitis, seizures, acute ascending flaccid paralysis, nephrotic syndrome, and seronegative arthritis.

Diagnosis

Serologic tests are adequate for the diagnosis of acute viral hepatitis (see later), so liver biopsy is not recommended unless the diagnosis remains unclear and a therapeutic decision is needed. If biopsy is required, the liver histology in acute viral hepatitis is characterized by widespread parenchymal inflammation and spotty necrosis. Inflammatory cells are predominantly lymphocytes, macrophages, and histiocytes. Fibrosis is absent. Immunohistochemical stains for hepatitis antigens are generally negative during the acute disease, and there are no reliably distinctive features that separate the five viral forms of acute hepatitis from each other.

Treatment

Though not proven to be effective in prospective controlled trials, recent uncontrolled studies suggest that antiviral therapies may be effective in acute hepatitis B and C (see later). However, several recommendations are applicable to all patients with acute hepatitis. Bedrest and sensible nutrition are appropriate for patients who are symptomatic and jaundiced. Alcohol should be avoided until convalescence. Sexual contacts should be limited until partners receive prophylaxis. In hepatitis A, all household contacts should be given immune globulin, and initiation of HAV vaccination is appropriate. In hepatitis B, family members should be vaccinated, and hepatitis B immune globulin (HBIG) should also be given to recent sexual contacts. Patients in whom any signs of fulminant hepatic failure develop (prolongation of the prothrombin time, personality changes, confusion) should be considered for antiviral therapy and be evaluated quickly for possible liver transplantation ( Chapter 158 ). The success of transplantation for severe, acute viral hepatitis often depends on early referral and careful attention to all details of clinical management in the context of an experienced team of physicians. Follow-up of acute hepatitis should be adequate to show that resolution has occurred, particularly for patients with hepatitis C. Finally and importantly, all cases of acute hepatitis should be reported to the local or state health department as soon as possible after diagnosis.

HEPATITIS A

Epidemiology

Hepatitis A is highly contagious and is spread largely by the fecal-oral route, especially when sanitary conditions are poor. Hepatitis A has been decreasing in frequency in the United States but is still an important cause of acute liver disease worldwide. Acute hepatitis A can occur in sporadic as well as epidemic forms. Investigation of the source of hepatitis A cases reveals that most are due to direct person-to-person exposure and, to a lesser extent, to direct fecal contamination of food or water. Consumption of shellfish from contaminated waterways is a well-known, but quite uncommon source of hepatitis A. Rare instances of spread of hepatitis A from blood transfusions and pooled plasma products have been described. High-risk groups for acquiring hepatitis A include travelers to developing areas of the world, children in daycare centers (and secondarily their parents), men who have sex with men, injection drug users, hemophiliacs given plasma products, and persons in institutions.

Pathobiology

HAV is a small RNA virus that belongs to the family Picornaviridae (genus Hepatovirus). The viral genome is 7.5 kilobases (kb) in length and has a single, large open reading frame that encodes a polyprotein with structural and nonstructural components. The virus replicates largely in the liver and is assembled in the hepatocyte cytoplasm as a 27-nm particle with a single RNA genome and an outer capsid protein (HAVAg). The virus is secreted into bile and, to a lesser extent, serum. The highest titers of HAV are found in stool (106 to 1010 genomes per gram) during the incubation period and early symptomatic phase of illness.

Clinical Manifestations

The clinical course of typical acute hepatitis A ( Fig. 151-2 ) begins with an incubation period that is usually 15 to 45 days (mean of 25). Jaundice occurs in 70% of adults infected with HAV but in smaller proportions of children. Antibody to HAV (anti-HAV), which develops in all patients infected with the virus, is first detectable shortly before the onset of symptoms, then rises to high titer and persists for life. In contrast, IgM-specific anti-HAV arises early in the disease and persists for only 4 to 12 months. Severe and fulminant cases of hepatitis A can occur, particularly in the elderly and in patients with preexisting chronic liver disease. Hepatitis A is the most common cause of relapsing cholestatic hepatitis.

FIGURE 151-2  Serologic course of acute hepatitis A. ALT = alanine aminotransferase; HAV = hepatitis A virus.

Diagnosis

The diagnosis of acute hepatitis A is made by detection of IgM anti-HAV in the serum of a patient with the clinical and biochemical features of acute hepatitis. Testing for total anti-HAV is not helpful in diagnosis but is a means of assessing immunity to hepatitis A.

Prevention

A safe and effective HAV vaccine is available and recommended for all children 1 year of age and older and persons at increased risk of acquiring hepatitis A, including travelers to endemic areas of the world, men who have sex with men, and illicit drug users. HAV vaccine is also recommended for all patients with chronic liver disease and recipients of pooled plasma products, such as hemophiliacs.

Two formulations of HAV vaccine are available in the United States; both consist of inactivated hepatitis A antigen purified from cell culture. Havrix (GlaxoSmithKline, Philadelphia) is recommended as two injections 6 to 12 months apart in an adult dose of 1440 enzyme-linked immunosorbent assay (ELISA) units (1.0 mL) and a pediatric (2 to 18 years of age) dose of 720 ELISA units (0.5 mL). Vaqta (Merck, West Point, PA) is recommended as two injections 6 to 18 months apart in an adult dose of 50 U (1.0 mL) and a pediatric dose (1 to 18 years) of 25 U (0.5 mL). A combination HAV and HBV vaccine (Twinrix; GlaxoSmithKline) is also available; it is recommended for adults who require vaccination against both forms of hepatitis and is given in a three-injection schedule at 0, 1, and 6 months. HAV vaccines have an excellent safety record, with serious complications occurring in less than 0.1% of recipients. Seroconversion rates after HAV vaccine are greater than 95% but are lower in patients with chronic liver disease, human immunodeficiency virus (HIV) infection, and other immune-compromised conditions. Nevertheless, neither follow-up testing for anti-HAV nor late booster inoculations are currently recommended. Prevaccination serologic testing for anti-HAV is not recommended except perhaps for adults born in endemic countries and for older (>50 years of age) U.S.-born adults.

Postexposure prophylaxis with immune globulin still is recommended for household and intimate contacts of persons with acute hepatitis A. The dose is 2 mL in adults and 0.02 mL/kg in children, given intramuscularly within 2 weeks of exposure. Concurrent HAV vaccination is appropriate.

Treatment

No specific therapies have been shown to shorten or ameliorate the course of illness in hepatitis A. An important element of management should be prophylaxis for contacts. Persons with fulminant hepatitis should be referred early for possible liver transplantation ( Chapter 158 ).

Prognosis

Acute hepatitis A is invariably a self-limited infection. The virus can persist for months, but it does not lead to a chronic infection, chronic hepatitis, or cirrhosis.

HEPATITIS B

Epidemiology

Hepatitis B is spread predominantly by the parenteral route or by intimate personal contact. It is endemic in many areas of the world, such as Southeast Asia, China, Micronesia, and sub-Saharan Africa. Lesser rates occur in the Indian subcontinent and Middle East. In the United States, hepatitis B is the most common cause of acute hepatitis, and chronic infection affects approximately 0.5% of the population. Investigations of the source of hepatitis B reveal that most adult cases are due to sexual or parenteral contact. Hepatitis B is common in injection drug users, heterosexuals with multiple sexual partners, and men who have sex with men. Blood transfusion and plasma products are now rarely infectious for hepatitis B because of the institution of routine screening of blood donations for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (HBcAg), anti-HBc. Maternal-infant spread of hepatitis B is another important mode of transmission not only in endemic areas of the world but also in the United States among immigrants from these endemic areas. Routine screening of pregnant women and prophylaxis of newborns are now recommended. Intrafamilial spread of hepatitis B can also occur, although the mode of spread in this situation is not well defined. Unfortunately, lack of attention to universal precautions and aseptic technique, especially the cleaning of shared medical devices, remains an important root cause of small outbreaks and sporadic cases of acute hepatitis B.

Pathobiology

HBV is a double-shelled, enveloped DNA virus belonging to the family Hepadnaviridae (genus Orthohepadnavirus). The viral genome consists of partially double-stranded DNA, is 3.2 kb in length, and possesses four partially overlapping open reading frames that encode the genes for HBsAg (S gene), HBcAg (C gene), HBV polymerase (P gene), and a small protein that seems to have transactivating functions (X gene, HBxAg). The S gene has three start codons and is capable of producing three different sizes of HBsAg (small, medium, and large S). The C gene has two start codons and can produce two antigenically distinct products: HBcAg, which is retained in hepatocytes until assembled and incorporated into HBV virions, and hepatitis B e antigen (HBeAg), which is secreted into serum as a small soluble protein. The virus infects only humans and higher apes and replicates predominantly in hepatocytes and perhaps to a lesser extent in stem cells in the pancreas, bone marrow, and spleen. During acute and chronic infection, patients with hepatitis B have large amounts of HBsAg in serum, most in the form of incomplete 20-nm virus-like spherical and tubular particles. The intact virion is a double-shelled particle with an envelope of HBsAg, an inner nucleocapsid of HBcAg, and an active polymerase enzyme that is linked to a single molecule of double-stranded HBV DNA. Persons who produce large amounts of HBV in serum also typically produce HBeAg, thus making HBeAg a surrogate marker for high levels of viral replication.

Clinical Manifestations

The typical course of acute, self-limited hepatitis B ( Fig. 151-3 ) begins with an incubation period of 30 to 150 days (mean of 75). During the incubation period, HBsAg, HBeAg, and HBV DNA become detectable in serum and rise to high titer, with the virus reaching titers of 108 to 1011 virions/mL. By the onset of symptoms, anti-HBc arises and serum aminotransferase levels are elevated. Jaundice appears in a third of adults with hepatitis B and lesser percentages of children. Generally, HBV DNA and HBeAg begin to fall at the onset of illness and may be undetectable at the time of peak clinical illness. HBsAg becomes undetectable and anti-HBs arises during recovery, several weeks to months after loss of HBsAg. Anti-HBs is a long-lasting antibody and is associated with immunity.

FIGURE 151-3  Serologic course of acute hepatitis B. HBc = hepatitis B core; HBeAg = hepatitis B e antigen; HBs = hepatitis B surface; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; PCR = polymerase chain reaction.

Diagnosis

The diagnosis of acute hepatitis B can be made on the basis of finding HBsAg in the serum of a patient with the clinical and biochemical features of acute hepatitis. HBsAg may also be present as a result of chronic hepatitis B or the carrier state, however, and a patient with acute hepatitis and HBsAg in serum may actually have chronic hepatitis and a superimposed form of acute injury, such as acute hepatitis A or D or drug-induced liver disease. For this reason, testing for IgM anti-HBc is helpful because this antibody arises early and is lost within 6 to 12 months of the onset of illness. Testing for HBeAg, anti-HBe, HBV DNA, and anti-HBs is not generally helpful in the diagnosis of hepatitis B but may be valuable in assessing prognosis. Persons who remain HBV DNA or HBeAg positive (or both) 6 weeks after the onset of symptoms are likely to be developing chronic hepatitis B. Loss of HBeAg or HBV DNA is a favorable serologic finding. Similarly, loss of HBsAg plus the development of anti-HBs denotes recovery.

Hepatitis B is also an important cause of fulminant hepatitis. Factors associated with severe outcomes of acute hepatitis B include advanced age, female sex, and perhaps some strains of virus. There are variants of HBV that lack the ability to produce HBeAg because of a mutation in the precore region of the viral genome. These precore or HBeAg-negative mutants are associated with atypical forms of acute and chronic hepatitis B. Several clusters of severe or fulminant hepatitis B have been associated with infection with the HBeAg-negative forms of virus.

Prevention

Vaccination against HBV is recommended for all newborns, children, and adolescents, as well as adults at risk for acquiring HBV, including health care and public safety workers with exposure to blood, injection drug users, men who have sex with men, persons at risk for sexually transmitted infections, persons traveling internationally to endemic regions, and individuals with close contact with patients who have chronic hepatitis B. Two formulations of HBV vaccine are available in the United States; both are made from recombinant techniques using cloned HBV S gene expressed in Saccharomyces cerevisiae. For adults, the recommended regimen is three injections of 1.0 mL (20 μg of Energix-B [GlaxoSmithKline] or 10 μg of Recombivax HB [Merck]) given intramuscularly in the deltoid muscle at 0, 1, and 6 months. A combined HAV and HBV vaccine (GlaxoSmithKline) is given at the same schedule. The dose in newborns, children, and adolescents is less ( Table 151-2 ). The seroconversion rate is greater than 90% in healthy, young adults, but it may be lower in smokers, the obese, the elderly, and patients who are immunocompromised; these latter groups may require higher doses and more injections. Prevaccination screening for anti-HBs is not recommended except for adults in high-risk groups (e.g., persons born in endemic countries, injection drug users, men who have sex with men, and HIV-infected persons). Postvaccination testing for anti-HBs to document seroconversion is not recommended routinely except for persons whose subsequent clinical management depends on knowledge of their immune status, particularly health care and public safety workers. At present, booster doses are not recommended but they may be appropriate for high-risk individuals if titers of anti-HBs fall below what is considered protective (10 IU/mL).


TABLE 151-2   — 
HEPATITIS B VIRUS VACCINATION RECOMMENDATIONS

Group No. Doses Schedule (mo) Recombivax HB Energix-B
Infants 3 0, 1, and 6 5 μg (0.5 mL) 10 μg (0.5 mL)
Infants born to HBsAg-positive mothers 3 0[*], 1, and 6 5 μg (0.5 mL) 10 μg (0.5 mL)
Children (1–10 yr) 3 0, 1, and 6 5 μg (0.5 mL) 10 μg (0.5 mL)
Adolescents (11–19 yr)[] 3 0, 1, and 6 5 μg (0.5 mL) 10 μg (1 mL)
Adults 3 0, 1, and 6 10 μg (1 mL) 20 μg (1 mL)
Adults on dialysis[] 4 0, 1, 2, and 6 40 μg (1 mL) 40 μg (2 mL)

HBsAg = hepatitis B surface antigen.

* Hepatitis B immune globulin and initial vaccination should be given within 12 hours of birth.
Adolescents aged 11 to 15 years can receive an alternative regimen of two doses of 10 μg (1 mL) at 0 and 4 to 6 months.
Recombivax HB is available in a dialysis formulation of 40 μg/mL; Energix-B must be given as two 1-mL injections to achieve a dose of 40 μg.

Postexposure prophylaxis with HBIG is recommended at birth for infants born to infected mothers and for patients with percutaneous exposure to a patient with hepatitis B. A single dose of HBIG (0.5 mL in newborns of infected mothers, 0.06 mL/kg in other settings and in adults) should be given as soon as possible after exposure, and HBV vaccination should be started immediately. HBIG is unlikely to provide benefit if the time since exposure is longer than 14 days; vaccine alone can be used in these circumstances. For patients with sexual or household contact with a patient who has chronic hepatitis B, vaccination alone is appropriate; HBIG is recommended in addition for sexual exposure to a patient with acute hepatitis B.

Treatment

The use of antiviral therapy for acute hepatitis B is controversial. Interferon alfa and lamivudine are established therapies for chronic hepatitis B ( Chapter 152 ), but they have not been adequately evaluated for acute infection. In a small study, interferon alfa did not decrease the rate of chronicity or speed recovery. Uncontrolled observations using lamivudine in patients with fulminant and severe hepatitis B, however, suggest that this therapy may ameliorate the course of infection. Because of the safety of lamivudine therapy and the unpredictable and potentially serious outcome of severe cases of acute hepatitis B, therapy with lamivudine (100 mg daily until the disease has resolved and HBsAg has become negative) is prudent for patients with symptoms or signs of fulminant liver disease (rising prothrombin time, severe jaundice), particularly if high levels of HBV DNA are present. Management of acute hepatitis B should also focus on avoidance of further hepatic injury and prophylaxis of contacts. The patient should be monitored by repeat testing for HBsAg and alanine aminotransferase levels 3 to 6 months later to determine whether chronic hepatitis B has developed ( Chapter 152 ).

Prognosis

Chronic hepatitis B ( Chapter 152 ) develops in 2 to 7% of adults infected with HBV, more commonly in men and in immunosuppressed individuals. The risk for chronic infection also correlates with age: it occurs in 90% of newborns infected with HBV, in approximately 30% of infants, but in less than 10% of adults. Chronic hepatitis B is still the third or fourth most common cause of cirrhosis ( Chapter 157 ) in the United States and is an important cause of liver cancer ( Chapter 206 ).

HEPATITIS C

Epidemiology

Hepatitis C is spread predominantly by the parenteral route. At highest risk are injection drug users and persons with multiple parenteral exposures. Sexual transmission of hepatitis C occurs but is not common. Prospective follow-up of spouses and sexual partners of patients with chronic hepatitis C shows the risk for sexual transmission to be low (<1% per year of exposure). Maternal-infant spread occurs in approximately 5% of cases, usually to infants whose mothers have high levels of HCV RNA in serum and a protracted delivery or early rupture of membranes. Other potential sources of HCV are needlestick accidents and either contamination or inadequate sterilization of reusable needles and syringes. Unfortunately, outbreaks of hepatitis C in health care settings continue to be identified from reuse of syringes and other failures in appropriate aseptic technique. Since the introduction of routine screening of blood for anti-HCV, post-transfusion hepatitis C has become rare. Inactivation procedures performed on plasma products have made transmission of HCV from clotting factor concentrates uncommon. There remain, however, many persons with chronic hepatitis C who were infected with this virus by these means in the past. Current studies of acute hepatitis C indicate that more than 60% of cases are attributable to injection drug use; 15 to 20% to sexual exposure (usually involving multiple sexual partners); and only a small proportion to maternal-infant spread, needlestick accidents, and iatrogenic causes. Approximately 10% of cases are not associated with any history of potential exposure and remain unexplained.

Pathobiology

HCV is an RNA virus that belongs to the family Flaviviridae (genus Hepacivirus). HCV was originally identified by molecular techniques, and the virus has not been well visualized. HCV probably circulates as a double-shelled enveloped virus, 50 to 60 nm in diameter. The genome is a positively stranded RNA molecule; it is approximately 9.6 kb in length and contains a single large open reading frame that encodes a large polyprotein that is post-translationally modified into three structural and several nonstructural polypeptides. The structural proteins include two highly variable envelope antigens (E1 and E2) and a relatively conserved nucleocapsid protein (C). HCV replicates largely in the liver and is detectable in serum in titers of 105 to 107 virions/mL during acute and chronic infection.

Clinical Manifestations

The clinical course of acute hepatitis C ( Fig. 151-4 ) begins with an incubation period that ranges from 15 to 120 days (mean of 50). During the incubation period, often within 1 to 2 weeks of exposure, HCV RNA can be detected by sensitive assays such as reverse transcriptase polymerase chain reaction (PCR). HCV RNA persists until well into the clinical course of disease. Antibody to HCV (anti-HCV) arises late in the course of acute hepatitis C and may not be present at the time of onset of symptoms and serum aminotransferase elevations. If the hepatitis is self-limited, HCV RNA soon becomes undetectable in serum; in this situation, titers of anti-HCV are generally modest and may eventually fall to undetectable levels as well.

FIGURE 151-4  Serologic course of acute hepatitis C. HCV = hepatitis C virus; PCR = polymerase chain reaction.

Diagnosis

Diagnosis of acute hepatitis C is generally based on detection of anti-HCV in serum in a patient with the clinical and biochemical features of acute hepatitis. In some patients, however, detectable levels of anti-HCV do not develop until weeks or months after the onset of illness, so retesting for anti-HCV during convalescence or direct tests for HCV RNA are necessary to exclude the diagnosis of acute hepatitis C in a patient who tests negative for all serologic markers. Several commercial tests for HCV RNA are now licensed and are reliable in detecting HCV RNA at levels greater than 100 copies/mL. Tests that quantify the HCV RNA level are also available, but measuring viral levels is not clinically useful in diagnosis or monitoring of acute hepatitis C.

Prevention

At present, there are no means of prevention of hepatitis C other than avoidance of high-risk behaviors and appropriate use of universal precautions. Injection drug use is currently the most common cause of newly acquired cases of hepatitis C. In this regard, needle exchange programs and education regarding the risks of drug use, including intranasal cocaine, and the risk of transmission from shared injection equipment are important.

Accidental needlestick exposure is perhaps the most frequent issue in prevention of transmission. At present, neither immune globulin nor preemptive therapy with antiviral agents or interferon is recommended in this situation. Monitoring by means of aminotransferase levels, HCV RNA, and anti-HCV testing (at baseline and 1 and 6 months after exposure) is appropriate. This approach allows for early intervention and treatment.

Treatment

Therapy with peginterferon alfa and ribavirin has been shown to be beneficial in chronic hepatitis C ( Chapter 152 ); such therapy leads to sustained clearance of virus and resolution of disease in slightly more than 50% of cases. The role of therapy during acute infection is still unresolved. Because 50 to 85% of patients with acute disease progress to chronic infection, the issue of early therapy often arises. Several studies have now documented that more than 90% of patients with acute hepatitis C treated with peginterferon with or without ribavirin for 24 weeks experience resolution of disease and sustained loss of HCV RNA.[1] Importantly, initiation of therapy can be delayed for 2 to 3 months after the onset of infection without a decrease in the high response rate. For these reasons, patients with acute hepatitis C should be treated only if HCV RNA remains detectable for 2 to 3 months after the onset of infection. An appropriate regimen is either peginterferon alfa-2a (180 μg) or alfa-2b (1.5 μg/kg) once weekly for 24 weeks in combination with ribavirin (1000 mg/day if body weight <70 and 1200 mg if >70 kg). The possible roles of HCV genotyping in guiding therapy and limiting therapy to 12 to 16 weeks in patients who become HCV RNA negative within 4 weeks of starting therapy are currently under investigation ( Chapter 152 ).

Prognosis

The major complication of acute hepatitis C is the development of chronic hepatitis. The clinical course depicted in Figure 151-4 is not typical because hepatitis C does not resolve in 50 to 85% of cases but rather progresses to chronic infection ( Chapter 152 ). In this situation, HCV RNA remains detectable, and aminotransferase levels generally remain elevated, though often in a fluctuating pattern. In some instances, aminotransferase levels become normal despite persistence of viremia. Other complications include the development of immune complex phenomena and cryoglobulinemia, although these complications are more typical of chronic disease. Fulminant hepatitis resulting from HCV is rare; in several large surveys of acute liver failure, none of the cases could be attributed to HCV.

HEPATITIS D

Epidemiology

Hepatitis D is linked to hepatitis B, and consequently its epidemiology is similar. HDV can be spread by the parenteral route and sexually. Persons at greatest risk are chronic carriers of hepatitis B and persons who have repeated parenteral exposures. In the United States and western Europe, delta hepatitis is most common in injection drug users and, before routine screening of blood donations, recipients of blood products, including persons with hemophilia and thalassemia. Delta hepatitis is endemic in the Amazon basin and central Africa and is common in some European and Mediterranean countries, including southern Italy, Greece, and eastern Europe.

Pathobiology

The hepatitis delta virus is a unique RNA virus that requires HBV for replication. The viral genome is a short, 1.7-kb circular single-stranded molecule of RNA that has a single open reading frame and a highly conserved nontranslated region that resembles the self-replicating element of viroids. The single open reading frame encodes delta antigen, and RNA editing can vary the size of the molecule to produce either a small (195 amino acids) or large (214 amino acids) delta antigen. The small delta antigen promotes the replication of HDV RNA; the large delta antigen promotes viral assembly and secretion into serum as the mature 36-nm delta viral particle.

Clinical Manifestations

Delta hepatitis occurs in two clinical patterns, termed coinfection and superinfection. Delta coinfection is the simultaneous occurrence of acute HDV and acute HBV infection. It resembles acute hepatitis B but may manifest a second elevation in aminotransferase levels associated with the period of delta virus replication. The diagnosis of acute delta coinfection can be made in a patient with clinical features of acute hepatitis who has HBsAg, anti-HDV, and IgM anti-HBc in serum. Immunoassays for anti-HDV are commercially available and reliable, although antibody may appear late during the illness. In patients suspected of having delta hepatitis, repeat testing for anti-HDV during convalescence is appropriate.

Diagnosis

Acute delta superinfection is the occurrence of acute HDV infection in a person with chronic hepatitis B or the HBsAg carrier state. The diagnosis of acute delta superinfection can be made in a patient with clinical features of acute hepatitis who has HBsAg and anti-HDV but no IgM anti-HBc in serum. Superinfection with HDV is more frequent than coinfection and is far more likely to lead to chronic delta hepatitis. Other tests that are helpful in making the diagnosis of ongoing HDV infection are serum HDV RNA (detectable by PCR) and HDV antigen (detectable by immunoblot); both of these tests are currently research assays and not standardized. Delta antigen can also be detected readily in liver biopsy specimens with immunohistochemical stains.

Prevention

Delta hepatitis can be prevented by preventing hepatitis B. The severity of delta hepatitis is another compelling rationale for routine hepatitis B vaccination in areas of the world where delta hepatitis is endemic. There are no means of prevention of delta hepatitis in a person who is already an HBsAg carrier; in this situation, avoidance of further exposure is important.

Treatment

No specific therapies are available for acute delta hepatitis. Lamivudine and other anti-HBV agents are ineffective against HDV replication. Most cases of acute coinfection resolve; patients with superinfection should be treated when it is clear that chronic delta hepatitis has supervened.

Prognosis

Delta hepatitis tends to be more severe than hepatitis B alone and is more likely to lead to fulminant hepatitis and to cause severe chronic hepatitis and ultimately cirrhosis.

HEPATITIS E

Epidemiology

Hepatitis E is responsible for epidemic and endemic forms of non-A, non-B hepatitis that occur in lesser developed areas of the world. Large outbreaks have been described from India, Pakistan, China, northern and central Africa, and Central America. In studies from India and Egypt, hepatitis E has accounted for a high proportion of cases of sporadic acute hepatitis. In the United States and western Europe, hepatitis E is rare, with most cases being imported or caused by zoonotic spread from swine or rats that harbor a similar virus. HEV is spread by the fecal-oral route, and most cases can be traced to exposure to contaminated water under poor hygienic conditions. Hepatitis E seems to be less contagious than hepatitis A, the other form of infectious hepatitis, and secondary cases are rare.

Pathobiology

HEV is a small nonenveloped, single-stranded RNA virus that is currently unclassified. The viral genome is 7.5 kb in length and encodes three open reading frames, the first (ORF1) for the nonstructural proteins responsible for viral replication, the second (ORF2) for the capsid protein (HEV antigen), and the third (ORF3) for a short protein of unknown function. The virus and HEV antigen can be detected in hepatocytes during acute infection. The highest levels of virus are detectable in stool during the incubation period of the disease. Viruses similar to HEV are found in other species, and strains found in domesticated swine may be infectious in humans.

Clinical Manifestations

The clinical course of hepatitis E resembles that of other forms of hepatitis. The incubation period is 15 to 60 days (mean of 35). The disease is frequently cholestatic, with prominence of bilirubin and alkaline phosphatase elevations. Hepatitis E also tends to be more severe than other forms of epidemic jaundice, with a fatality rate of 1 to 2% and a particularly high rate of acute liver failure in pregnant women. HEV virions and antigen can be detected in stool and liver during the incubation period and early symptomatic phase, but these tests are not practical means for diagnosis. ELISAs for IgM and IgG antibody to HEV (anti-HEV) have been developed and are reactive in at least 90% of patients at the onset of clinical illness. These tests are neither generally available nor standardized, however. In addition, anti-HEV is found in 1 to 2% of the normal population, which may represent resolved subclinical cases of hepatitis E acquired during travel or as a result of exposure to livestock or other infected animals.

Diagnosis

The diagnosis of hepatitis E should be considered in a patient with acute hepatitis who has recently traveled to an endemic area, particularly if tests for other forms of hepatitis are nonreactive. The finding of anti-HEV, particularly of the IgM subclass, is sufficient to make the diagnosis in this situation. Hepatitis E is rare in the United States and Western world, however, so testing for anti-HEV is rarely necessary.

Prevention and Treatment

There are no known means of prevention or treatment of hepatitis E. Immune globulin, even when prepared from the plasma of populations with a high rate of hepatitis E, does not seem to be effective. No specific means of treatment have been evaluated.

Travelers to areas of the world (particularly pregnant women) where hepatitis E is endemic should be cautioned regarding drinking water and uncooked food. Recombinant vaccines against HEV have been developed and shown to be effective in animal models of hepatitis E. Efficacy trials of an HEV vaccine are now under way in endemic areas.

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