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Hepatitis E virus infection
Renuka Umashanker, MD
Sanjiv Chopra, MD
UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on March 21, 2006. The next version of UpToDate (14.3) will be released in October 2006. INTRODUCTION — Hepatitis E virus (HEV) is a self-limited, enterically-transmitted acute viral hepatitis. Infection with this virus was first documented in 1955 during an outbreak in New Delhi, India [ 1 ] . THE VIRUS — HEV is an icosahedral, nonenveloped single stranded RNA virus that is approximately 27 to 34 nm in diameter and is structurally similar to viruses of the Caliciviradae family [ 2-4 ] . Three large opening reading frames (ORFs) of the positive-sense RNA of HEV have been described [ 5 ] :
- The largest ORF consists of 1693 codons; it codes for nonstructural proteins that are responsible for the processing and replication of the virus.
- The second ORF is composed of 660 codons and codes for structural proteins.
- The third ORF consists of 123 codons; although it may also be a structural protein, its function remains undetermined.
Although HEV structurally resembles viruses of the Caliciviridae family, genomic sequences by computer analysis show that portions of ORF1 are more akin to those of rubella virus [ 5 ] . Phylogenetic analysis suggests that there are four genotypes (1-4) and up to 24 subtypes [ 6 ] . The association of genotypes with clinical features is incompletely understood. However, genotype 1 and 2 appear to be confined to humans while genotype 3 and 4 infect humans and animals. Genotype 3 has been associated with less virulent disease [ 7 ] . EPIDEMIOLOGY — The epidemiology of HEV, previously known as waterborne or enterically transmitted non-A, non-B hepatitis, is similar to that of hepatitis A virus (HAV) [ 2,8 ] . However, HAV is more readily transmitted, causes more infections, and has a wider distribution worldwide, although HEV may be more widespread in industrialized countries than generally believed [ 9-18 ] . The highest incidence of HEV infection is in Asia, Africa, Middle East, and Central America [ 1,19-22 ] and HEV is the second most common cause of sporadic hepatitis in North Africa and the Middle East [ 23 ] . In the largest reported outbreak, over 100,000 individuals were afflicted in the Xinjiang region of China between 1986 and 1988 [ 24 ] . More recently, large outbreaks have been reported in refugee camps in Darfur, Sudan and Chad [ 25 ] . HEV is spread by fecally contaminated water in endemic areas [ 3,26 ] . Person-to-person transmission is uncommon. HEV can be transmitted by blood transfusion, particularly in endemic areas [ 27-29 ] . Sporadic cases that have been described in western countries have mostly been limited to visitors who have traveled to areas of the world that are endemic for HEV [ 30-33 ] . However, sporadic cases that were unassociated with travel have been reported [ 34 ] . HEV can infect pigs, suggesting that some cases of human transmission may be due to contact transmission across species [ 34,35 ] . Case series from Japan documented transmission from undercooked deer meat and from wild boar meat [ 36,37 ] . Rodents appear to serve as a reservoir in some regions [ 38 ] . Zoonotic transmission is also supported by the observation of high anti-HEV seroprevalence among people with occupational contact with animals [ 15,39,40 ] . Transmission during pregnancy — There is a paucity of data regarding the vertical transmission of HEV from infected mothers to their infants. One report evaluated eight babies born to mothers infected with hepatitis E in the third trimester [ 41 ] . Other causes of acute hepatitis were excluded. All eight mothers had vaginal deliveries. IgG anti-HEV was detected in all eight infants and HEV RNA was detected in five. Six infants had clinical, serologic, or virologic evidence of HEV infection. Two infants died within 24 hours of birth, one of whom had massive hepatic necrosis at autopsy. The authors concluded that HEV infection can be transmitted from mother to newborn with substantial perinatal morbidity and mortality. Similar conclusions have been reached in other reports [ 42 ] . CLINICAL MANIFESTATIONS — The incubation period of HEV infection ranges from 15 to 60 days [ 2,8,43,44 ] . High attack rates are found in adults between 15 and 40 years of age [ 8,45,46 ] . Secondary attack rates in susceptible household contacts are low due to the usual lack of person-to-person transmission, ranging from 0.7 to 2.2 percent [ 47 ] . The clinical signs and symptoms in patients with typical HEV infection are similar to those seen with other forms of acute viral hepatitis, although disease appears to be relatively severe compared with hepatitis A [ 48 ] . Prolonged cholestasis has been described in up to 60 percent of patients [ 48 ] . Jaundice is usually accompanied by malaise, anorexia, nausea, vomiting, abdominal pain, fever, and hepatomegaly. Other less common features include diarrhea, arthralgia, pruritus, and urticarial rash [ 30,49-51 ] . Some patients have asymptomatic infection. Fulminant hepatitis can occur, resulting in an overall case fatality rate of 0.5 to 3 percent [ 52 ] . For reasons that are not understood, fulminant hepatic failure occurs more frequently during pregnancy, resulting in an inordinately high mortality rate of 15 to 25 percent, primarily affecting women in the third trimester [ 3,53,54 ] . Infection with HEV can also lead to hepatic decompensation in patients with preexisting liver disease and those who are malnourished [ 55 ] . As noted above, certain genotypes have also been associated with more severe disease. Laboratory findings include elevated serum concentrations of bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) [ 30,56 ] . Resolution of the abnormal biochemical tests generally occurs within one to six weeks after the onset of the illness. Chronic hepatitis does not develop after acute HEV infection [ 57 ] . Pathology — Morphological features of HEV include those noted with cholestatic and classic types of acute viral hepatitis. Cholestatic forms are characterized by bile stasis in canaliculi and gland-like transformation of hepatocytes. In the classic presentation, the biopsy reveals focal necrosis, ballooned hepatocytes, and acidophilic degeneration of hepatocytes [ 1,54 ] . In fatal cases submassive as well as massive hepatic necrosis is present [ 8,49 ] . DIAGNOSIS — The diagnosis of HEV is based upon the detection of the HEV genome in serum or feces by PCR or by the detection of IgM antibodies to HEV [ 58 ] . Simultaneous assessment of anti IgA HEV has been proposed to increase specificity, especially in patients with IgM rheumatoid factor in serum, which can cause a false-positive result on the IgM based assay [ 58 ] . Persistence of IgG anti-HEV has been noted in different studies for 6 to 12 months, 1 to 4 years, and as long as 14 years [ 32,43,56,59 ] . At present, only research-based tests are available for the specific detection of hepatitis E virus antigen (HEVAg) in the serum. HEVAg has also been detected in liver tissue using an immunofluorescent probe [ 4 ] . Rapid immunochromatographic assays for serologic diagnosis are under development [ 60,61 ] . Commercially available antibody-based tests are available in Europe, Canada and Asia. In the United States, testing for HEV is available only in research laboratories, which can be located through the Centers for Disease Control (800-311-3435; www.cdc.gov ). Differential diagnosis — The differential diagnosis mainly includes other forms of viral hepatitis, drug or toxic hepatitis, ischemic hepatitis and other infectious diseases in areas where they are endemic such as leptospirosis, dengue fever, malaria, and typhoid fever. PREVENTION AND TREATMENT — Vaccines against HEV are in development [ 62-65 ] . Little information exists regarding the efficacy of pre- or post-exposure immune globulin (IG) prophylaxis for the prevention of HEV [ 66 ] . There is at present no proof that immune globulin, including lots produced in countries where HEV is endemic, confers protection against hepatitis E [ 67 ] . Travelers to endemic areas should engage in practices that may prevent infection, such as avoiding drinking water of unknown purity, uncooked shellfish, and uncooked fruits or vegetables. Treatment of infection remains supportive. SUMMARY —
- Hepatitis E virus (HEV) is a single stranded RNA virus that causes a self-limited, enterically-transmitted acute viral hepatitis. Phylogenetic analysis suggests that there are 4 genotypes (1-4) and up to 24 subtypes. The association of genotypes with clinical features is incompletely understood, although genotype 3 has been associated with milder disease.
- The clinical features of acute HEV infection are similar to those seen with other forms of acute viral hepatitis, although disease appears to be relatively severe compared with hepatitis A.
- The diagnosis of HEV is based upon the detection of the HEV genome in serum or feces by PCR or by the detection of IgM antibodies to HEV.
- A vaccine against HEV is not yet commercially available. Travelers to endemic areas should engage in practices that may prevent infection, such as avoiding drinking water of unknown purity, uncooked shellfish, and uncooked fruits or vegetables.
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