Acute viral hepatitis is a syndrome characterized by a constellation of clinical, biochemical, and pathological features following infection by viruses that primarily infect hepatocytes. Five hepatotrophic viruses (A, B, C, D, E) account for over 90% of cases. These hepatotrophic viruses are found worldwide (see Figures 47.1–47.5); their prevalence varies greatly from region to region and their geographical distribution is partly dependent on their mode of transmission. Hepatitis A virus (HAV) and hepatitis E virus (HEV) are transmitted enterically while hepatitis B, C, and D are transmitted via percutaneous/permucosal routes. The liver is the primary site of infection and replication of hepatotrophic viruses. Three (HAV, hepatitis C virus [HCV], and HEV]) are single‐stranded, positive‐sense RNA viruses, one, hepatitis D virus (HDV), is a single‐stranded, negative‐sense RNA virus, and hepatitis B virus (HBV) is a partially double‐stranded DNA virus.

The genomic organization of HAV is shown in Figure 47.6. The replication process of HAV has been inferred from studies of other picornaviruses. Entry of the virus into the host is mediated by a cell surface receptor, a mucin‐like class 1 integral membrane glycoprotein. Viral entry is followed by uncoating and initiation of viral protein synthesis (Figure 47.7). Viral RNA synthesis proceeds from negative to positive strand and occurs in the cytoplasm. Viral assembly follows a sequence similar to that of picornaviruses in a cellular membrane compartment.

The infectious HBV virion (Dane particle) has a 42 nm spherical, double‐shelled structure consisting of a lipid envelope containing HBsAg, which surrounds an inner nucleocapsid. The hepatitis B core antigen (HBcAg) complexes with viral‐encoded polymerase and viral DNA genome to form the nucleocapsid. The genome of HBV is a partially double‐stranded circular DNA of approximately 3.2 kbp. The viral genome encodes four overlapping open reading frames (ORF) from which four mRNA transcripts are derived and code for seven viral proteins (see Figure 47.8 for details). HBV replicates through a RNA intermediate and this process is summarized in Figure 47.9.

The HCV has a positive‐sense, single‐stranded RNA genome of approximately 9.6 kb in length with a single large ORF and highly conserved untranslated regions (UTR) at the 5′ and 3′ ends. The genomic organization is summarized in Figure 47.10. HCV replicates in the cytoplasm, in a membrane‐associated compartment. The replication process is illustrated in Figure 47.11.

HDV requires coinfection with HBV for replication. δ Antigen is the inner ribonucleoprotein component of a subviral particle that is enveloped by the HBV surface antigen. The ribonucleoprotein complex consists of small (SHDAg) and large (LHDAg) δ antigens and a single‐stranded circular RNA genome of 1.7 kb length, which has extensive self‐complementation to form a rod‐like structure (Figure 47.12). The HDV replication cycle is presented in Figure 47.13.

The HEV genome is a single‐stranded, positive‐sense RNA of approximately 7.5 kb. The genome is organized into three overlapping open reading frames (ORF 1–3) flanked by noncoding regions (Figure 47.14). The replication cycle of HEV is shown in Figure 47.15.

During primary infection, the initial pathway of the antiviral immune response is largely unknown. Acute viral infection is associated with activation of innate immunity in the liver. Recognition of infected hepatocytes by resident natural killer (NK) and/or natural killer T (NKT) cells leads to activation of these cells and induction of antiviral cytokines, including interferons. This phase of innate immunity leads to the initial control of viral replication. Since this antiviral response is likely associated with a noncytopathic mechanism, little or no hepatocellular injury is evident. The innate immune response also plays a critical role in the activation of adaptive immunity, including humoral and cellular responses. Induction of a humoral immune response with production of neutralizing antibodies prevents viral spread and leads to subsequent elimination of circulating viruses. For HBV, the antibody response to the envelope proteins is a T‐cell‐dependent process.

The other limb of the immune response, cell‐mediated immunity (CMI), is critical for the long‐term control of viral infections, including the hepatitis viruses. In acute HBV infection, individuals can mount a vigorous, multispecific, and polyclonal cellular immune response to HBV. In contrast, chronically infected patients have a weak or barely detectable anti‐HBV response. This is true for both CD4 and CD8 responses. During acute hepatitis B, a vigorous HLA class II‐restricted, CD4+, helper T‐cell response to multiple epitopes of HBc/eAg predominates in virtually all patients. By helping B cells produce neutralizing antienvelope antibodies and activating HBV‐specific cytotoxic T cells (CTLs), this CD4+ T helper population may direct the initial antiviral response.

In most viral infections, the activation of virus‐specific CD8+ cytotoxic T lymphocytes is critical for viral clearance. Patients acutely infected with HBV develop a strong, polyclonal, HLA class I‐restricted CTL response that is directed against multiple epitopes in all viral proteins. This response appears to persist for many years after recovery from acute HBV infection.

The molecular and cellular mechanisms of viral clearance and hepatocellular injury have been studied in great detail for HBV infection (see Figure 47.16). CD8+, class I‐restricted HBsAg‐specific CTLs target the liver through interaction between the HBV‐specific T‐cell receptors and the antigen‐presenting HLA class I molecules on the hepatocytes and cause scattered apoptosis of hepatocytes. By secreting cytokines, including interferons, the CTLs recruit a variety of antigen‐nonspecific inflammatory cells into the liver, resulting in more extensive necroinflammatory injury of the liver. The predominant infiltrating effector cells are the macrophages, which probably mediate the majority of hepatocellular injury. The CTLs, although not primarily responsible for the majority of hepatocellular injury, initiate the cascade of immunological events leading to hepatitis. They also play a role in elimination of infected hepatocytes through noncytolytic inhibition of HBV gene expression and viral replication. The detection of virus‐specific CD4 and CD8 cells in the peripheral blood and liver of chronically infected individuals suggests a pathogenic relationship between the indolent cellular immune response and necroinflammatory liver disease associated with chronic hepatitis. Therefore, the CMI is a double‐edged sword: vigorous response leads to viral clearance, whereas ineffective response results in chronic hepatocellular injury.

Following infection, the hepatotrophic viruses give rise to similar clinical, biochemical, and pathological features. Serological testing is the only reliable way to determine the etiology of the infecting agent (see Figures 47.17–47.21). The incubation period differs for each virus, ranging from 2 weeks to 6 months. The clinical course ranges from an asymptomatic illness to fulminant hepatitis and is typified by three phases, prodromal, symptomatic and convalescent, lasting from 6 weeks to 6 months. Approximately 20% of cases present with jaundice. The primary biochemical abnormality is an acute rise in serum alanine and aspartate aminotransferases, markers of hepatocellular necrosis, to greater than 2.5 times the upper limit of normal, more commonly to greater than 10 times the upper limit of normal. The basic pathological lesion is an acute inflammation of the entire liver. The severity can range from mild, involving a few hepatocytes, to moderate, to massive necrosis, involving almost all hepatocytes (see Figures 47.22–47.25). The classic pathological features of acute viral hepatitis are swollen hepatocytes, apoptotic hepatocytes (acidophil bodies) and the presence of inflammatory cells within the hepatic lobule, predominantly lymphocytes and macrophages, which result in distortion of the normal liver architecture.

Hepatitis A virus and HEV generally do not lead to chronic infection in an immunocompetent host and development of antibody protects against reinfection for HAV. Persistent HEV infection has been noted in solid organ transplant patients receiving immunosuppression and human immunodeficiency virus (HIV)‐positive individuals. HBV, HCV, and HDV have the propensity to cause chronic infection and are associated with an increased risk of hepatocellular carcinoma. Effective and safe vaccines exist for the prevention of infection with HAV, HBV, and HEV. Vaccination against HAV and HBV is recommended in the pre‐ and postexposure setting and for persons with HCV‐related chronic liver disease. Institution of risk behavior modifications is the only effective way to prevent HDV superinfection in persons with chronic hepatitis B. No vaccine exists for HCV and strategies for preventing infection include screening of blood products and risk behavior modification. Improving hygiene, providing safe drinking water, and proper cooking of meats should lower the risk of HEV infection.

Treatment of acute viral hepatitis is supportive, with the goal being to maintain adequate nutrition, hydration, and monitoring for the development of fulminant hepatitis. Antiviral therapy is rarely indicated, especially for HAV and HEV where the course is benign and recovery the rule. Most adults with acute HBV infection recover spontaneously. Specific antiviral therapy can be considered in persons who fail to clear HBV after 12 weeks or who appear to be progressing to acute liver failure. Household and sexual contacts of persons with acute HBV infection should receive HBIG and HBV vaccine. Treatment of acute hepatitis C is recommended at diagnosis due to the high propensity to develop chronic hepatitis and to prevent person‐to‐person spread. Most acute HDV coinfection will resolve spontaneously but most superinfections progress to chronic infection. There is no effective therapy for acute HDV infection. Therapy can be considered in the chronic phase but there are no approved treatments.

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