Hepatitis A and Hepatitis E

Key Points

1
Infection by the nonenveloped, enterically transmitted viruses, hepatitis A virus (HAV) and hepatitis E virus (HEV), generally causes self-limited infection, but severe hepatitis may develop in some cases; chronic hepatitis E has been recognized in immunosuppressed patients and can result in hepatic fibrosis and cirrhosis.
2
HEV genotypes 1 and 2, involved in acute HEV infection, are transmitted by the fecal-oral route, whereas HEV genotypes 3 and 4 have been implicated in chronic HEV infection and are transmitted by a zoonosis with domestic swine, wild boar, or wild deer as intermediates.
3
HAV vaccination is effective protection against infection. An effective HEV vaccine has been developed but is not approved for use in most countries.
4
In addition to immunocompromised patients, pregnant women and patients with preexisting liver disease are at increased risk for developing severe complications of hepatitis E.
5
Antiviral therapy for HAV is not available, in contrast to HEV, which responds to ribavirin, which is indicated in severe acute or chronic HEV infection.

Hepatitis A Virus

Molecular Biology

1.
Classified as a picornavirus, subclassified as the only member of the subclass hepatovirus
2.
27 to 28 nm in diameter with cubic symmetry
3.
Positive single-stranded, linear RNA molecule, 7.5 kb in one open reading frame
4.
One serotype in human beings; at least 6 genotypes
5.
Although described as a nonenveloped virus, more recent evidence suggests that HAV may have enveloped and nonenveloped forms.
6.
Contains a single immunodominant neutralization site
7.
Contains four major virion polypeptides in a capsomere ( Fig. 3.1 )
8.
Replication in cytoplasm of infected hepatocytes through an RNA-dependent RNA polymerase; no definitive evidence of persistent replication in the intestine
9.
High degree of chemical and thermal resistance to inactivation, allowing HAV to persist in contaminated foods or fecal matter for weeks
10.
Can survive exposure to bile and other detergents
11.
Has been propagated in nonhuman primate and human cell lines
12.
Does not result in prolonged viremia or an intestinal carrier state
13.
Replicates in the liver and induces as yet unidentified immune responses

Epidemiology and Risk Factors

1.
Incubation period: 15 to 50 days (average, 30 days)
2.
Worldwide distribution; annual global incidence is 1.5 million cases; hyperendemic in developing countries
3.
In developed countries with improved water and sanitation systems, the majority of the population reach adulthood without acquiring HAV infection and developing immunity. In developing countries where areas with socioeconomic development and hygienic improvement have led to a reduction in HAV transmission and a higher average age at the time of initial infection, there has been a paradoxical increase in the incidence of symptomatic HAV with more severe consequences, such as fulminant hepatitis and prolonged hospital stays and death, reflecting the increased severity of HAV infection acquired after childhood ( Fig. 3.2 ).
4.
HAV is excreted in the stools of infected persons for 1 to 2 weeks before and at least 1 week after the onset of illness, usually shortly after the serum alanine aminotransferase (ALT) level begins to increase.
5.
Viremia is short lived, usually no longer than 3 weeks but occasionally up to 90 days in protracted or relapsing infection.
6.
Prolonged fecal excretion (for months) is reported in infected neonates; the frequency, concentration of virus in stool, and epidemiologic importance remain uncertain.
7.
Fulminant hepatitis A is increasingly uncommon since the advent of HAV vaccination.
8.
Enteric (fecal-oral) transmission occurs predominantly by person-to-person household spread or an infected food handler; occasional outbreaks are linked to a common source:
- ▪
  Contaminated food
- ▪
  Bivalve mollusks
- ▪
  Water
9.
Other risk factors for infection:
- ▪
  Daycare centers for infants, diapered children
- ▪
  Institutions for the developmentally disadvantaged
- ▪
  Travel to developing countries (the most common risk factor for Americans)
- ▪
  Oral-anal contact
- ▪
  Shared equipment or drugs in injection drug users
10.
No evidence for maternal-neonatal transmission
11.
The prevalence of HAV infection correlates with sanitary standards and larger households.
12.
Transmission by blood transfusion or blood products is very rare.
13.
No risk factors are identified in 30% to 40% of cases in the United States.
14.
The overall seroprevalence of HAV infection in the United States is <30% and is declining rapidly with expanded use of the HAV vaccine.
15.
Disease severity is increased in persons with preexisting liver disease or age ≥ 40 years.
16.
HAV cellular receptor 1 (HAVcr1), a polymorphic variant, has been associated with an increased risk of severe hepatitis, possibly secondary to more avid binding of the virus to hepatocytes, as well as a boost in the cytotoxicity of natural killer T cells against infected hepatocytes.

Pathophysiology

After oral ingestion, HAV enters the portal circulation and reaches the liver after replication in intestinal cells. HAV enters hepatocytes, where further replication occurs resulting in a large amount of viral progeny released into the bile and intestinal lumen before being excreted in the feces Liver injury occurs via a host immune response.

Clinical Features

Self-Limited Disease ( Fig. 3.3 )

1.
Disease severity ranges from asymptomatic infection to fatal acute liver failure; severity is increased in those with preexisting liver disease or age ≥ 40 years.
- ▪
  The likelihood of symptomatic infection increases with age.
- ▪
  Children <6 years of age are typically asymptomatic.
- ▪
  Infectivity peaks between 2 weeks before and at least 1 week after symptoms begin.
- ▪
  Some infected persons develop one or more relapses after an apparent initial partial or complete resolution of symptoms. During relapse, there is ongoing viral replication, usually milder than the initial event, although prolonged cholestasis can occur, with eventual resolution (see discussion later in chapter).
2.
Fever in acute viral hepatitis is generally uncommon, although it can occur in acute hepatitis A.
3.
Prodromal symptoms abate or disappear with the onset of jaundice, although anorexia, malaise, and weakness may persist.
4.
Jaundice is heralded by the appearance of dark urine and lightening of stool color; pruritus (usually mild and transient) may also occur.
5.
Physical examination reveals mild hepatomegaly with tenderness.
6.
Mild splenomegaly and posterior cervical lymphadenopathy are noted in 15% to 20% of patients.

Acute Liver Failure

See Chapter 2 for information about acute liver failure.

Cholestatic Hepatitis

1.
Pruritus is prominent.
2.
Persistent anorexia and diarrhea are present in a few patients.
3.
Jaundice may persist for several months before eventual resolution.
4.
The prognosis is excellent, usually with complete resolution without specific therapy.

Relapsing Hepatitis

1.
Symptoms and liver biochemical test abnormalities recur weeks to months after apparent recovery.
2.
Immunoglobulin (Ig)M antibody to HAV (anti-HAV) may remain positive, and HAV may once again be shed in stool.
3.
Arthritis, vasculitis, and cryoglobulinemia may be observed.
4.
Prognosis is excellent with complete recovery even after multiple relapses (particularly common in children).

Extrahepatic Manifestations

Intracerebral hemorrhage has been reported as a complication of HAV infection, due mostly to aplastic anemia–induced thrombocytopenia. Other complications:

1.
Acute kidney injury
2.
Hemophagocytic lymphohistiocytosis
3.
Pure red cell aplasia
4.
Vasculitis with cutaneous manifestations
5.
Arthritis
6.
Autoimmune hemolytic anemia
7.
Guillain-Barré syndrome
8.
Pericarditis
9.
Cryoglobulinemia
10.
Myelopathy
11.
Mononeuritis
12.
Meningoencephalitis
13.
Acute pancreatitis

Laboratory Features

Self-Limited Disease

1.
Most prominent biochemical feature: Marked elevation of serum ALT and aspartate aminotransferase (AST) levels
2.
Peak aminotransferase (ALT and AST) levels vary from 500 to 5000 U/L; ALT levels are generally higher than AST levels.
3.
The serum bilirubin level is seldom >10 mg/dL, except in severe disease, acute liver failure, and cholestatic hepatitis.
4.
Serum alkaline phosphatase levels are normal or mildly elevated.
5.
The prothrombin time is normal or increased by 1 to 3 seconds.
6.
The serum albumin level is normal or minimally depressed.
7.
Peripheral blood counts are normal or mild leukopenia is present, with or without relative lymphocytosis.

Acute Liver Failure

See Chapter 2 for information about acute liver failure.

Cholestatic Disease

1.
Serum bilirubin levels may exceed 20 mg/dL.
2.
Serum aminotransferase levels are near normal despite cholestasis.
3.
Variable elevation of serum alkaline phosphatase
4.
Normal or nearly normal serum albumin
5.
A prolonged prothrombin time, if present, is usually responsive to vitamin K administration.

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