Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis A

Abstract

Hepatitis A virus (HAV) is transmitted by the fecal-oral route and is a major cause of acute viral hepatitis. The clinical manifestations of HAV infection range from asymptomatic infection to acute liver failure (ALF), but do not include progression to chronic hepatitis. Risk factors for severe acute hepatitis A are older age (>40 years) and preexisting liver disease. Some patients may show atypical clinical features such as relapsing hepatitis, prolonged cholestasis, or extrahepatic manifestations. Almost all hepatitis A patients spontaneously recover with supportive care. However, in the case of ALF (<1%), intensive care and urgent decision on liver transplantation are required. Liver injury during hepatitis A is not directly caused by HAV but is known to be caused by immune-mediated mechanisms. In this review, the natural history and clinical manifestations of hepatitis A are described. In addition, mechanisms of immunopathogenesis in hepatitis A are discussed.

Figure 1.

A typical course of hepatitis A. After a 3- to 5-week incubation period following hepatitis A virus (HAV) infection, patients develop symptoms of hepatitis with elevation of serum alanine aminotransferase (ALT) levels. Fecal virus shedding and viremia are present and peak during the incubation period. Anti-HAV antibodies appear in serum first as immunoglobulin (Ig)M and subsequently as IgG. Virus-specific T-cell responses coincide with the elevation of serum ALT levels.

Figure 2.

The clinical outcomes of hepatitis A virus (HAV) infection. Clinical manifestations of HAV infection depend on the age of patients. Most adult patients develop symptomatic hepatitis, whereas most young children do not. Common hepatitis symptoms are fever, malaise, nausea or vomiting, abdominal discomfort, and dark urine and jaundice. Reported extrahepatic complications include acute kidney injury, acalculous cholecystitis, pancreatitis, pleural or pericardial effusion, hemolysis, hemophagocytosis, pure red-cell aplasia, acute reactive arthritis, skin rash, and neurological manifestations such as mononeuritis, Guillain–Barré syndrome, and transverse myelitis.

Figure 3.

Radiological findings of hepatitis A. (A) Transabdominal ultrasonography shows diffuse wall thickening of the gallbladder (arrows) measuring ∼10 mm. (B) Transverse computed tomography (CT) scan depicts low attenuating halo around the right portal vein indicating periportal tracking (arrowheads). Perihepatic lymph node enlargement is also noted (arrow).

Figure 4.

Two different forms of infectious hepatitis A virus (HAV) virions. Quasi-enveloped HAV (eHAV) is detected in serum and plasma of the infected host, whereas nonenveloped, naked HAV is shed in feces. New replicated progeny virus is released from hepatocytes in the quasi-enveloped form and subsequently loses its lipid envelope following exposure to bile salts in the biliary canaliculus. The viral capsid within the quasi-enveloped eHAV virion is protected from neutralizing antibodies. Nonenveloped, naked HAV is highly stable. It is shed in feces via the intestinal tract and maintains infectivity in the environment. LSECs, Liver sinusoidal endothelial cells.

Figure 5.

Mechanism of CXC-chemokine ligand (CXCL)10 expression in Hepatitis A virus (HAV)-infected hepatocytes. HAV RNA is sensed by MDA5 in the cytosol or TLR3 in the endosome. However, downstream signaling is interrupted by HAV proteins as described in the text. Nonetheless, interferon λ (IFN-λ) and CXCL10 are produced from HAV-infected cells, particularly at an early stage of HAV infection. CXCL10 is produced in HAV-infected cells in a MAVS- and IRF3-dependent but IFN-independent manner. CXCL10 can contribute to liver inflammation and hepatocyte injury by recruiting CXCR3⁺ immune cells to the HAV-infected liver.