New Pathways to Hepatitis E Infection
Abstract & Commentary
By Lin H. Chen, MD Dr. Chen is Assistant Clinical Professor, Harvard Medical School, Director, Travel Medicine Center, Mt. Auburn Hospital, Cambridge, MA.
Dr. Chen reports no financial relationships relevant to this field of study.
Synopsis: Hepatitis E virus (HEV) infections cause hepatitis outbreaks in developing countries, and travelers must exercise caution regarding food and water. HEV infection has also been increasingly identified in developed countries, associated with consumption of game meat or undercooked pork products, and infections can lead to chronic hepatitis in immunocompromised patients.
Source: Teshale EH, et al. The two faces of hepatitis E. Clin Infect Dis 2010;51:328-334.
Teshale and colleagues reviewed Hepatitis E Virus (HEV) infections and the two distinct presentations associated with this virus infection. HEV was initially recognized in the 1980s, but a number of outbreaks have been identified since the 1950s in India, Kashmir, Mexico, Ethiopia, China, Vietnam, Sudan, and Uganda. In comparison, only sporadic cases have occurred in industrialized countries. One presentation occurs during outbreaks in developing countries, predominantly caused by genotype 1 and sometimes genotypes 2 and 4; this syndrome is associated with high morbidity and mortality among pregnant women and young children. The other presentation is an asymptomatic infection, usually with genotype 3, and occurs in developed countries where the HEV seropositivity rate is 5-21%.
HEV belongs to the genus Hepevirus and is a non-enveloped RNA virus with at least 4 genotypes. HEV was initially considered a waterborne infection, but recent studies suggest additional transmission routes including transmission from person to person and via blood transfusions. Following exposure to the virus, the mean incubation period lasts 40 days (range 15-60 days), and infection leads to a wide range of presentations, from asymptomatic infection to fulminant hepatitis. Symptomatic HEV infection may present with jaundice, fever, hepatomegaly, malaise, and pruritus. Laboratory findings include elevated serum bilirubin, liver enzymes, and alkaline phosphatase levels. Case fatality rates in developing country epidemics range from 0.2-4%, but reach 10-25% in pregnant women, especially during the third trimester.
In industrialized countries, HEV genotype 3 appears to be prevalent, but only infrequently pathogenic. Some serological surveys have found high anti-HEV IgG seropositivity rates in the United States (21%) and Denmark, but much lower rates in other European countries and Japan. The disparity arises from variations in sensitivity and specificity of the assays used. HEV genotype 3 is considered a zoonosis of wild pigs, and consumption of wild or domestic pork seems to be associated with HEV infection in industrialized countries. However, numerous examples suggest additional modes of exposure, including the consumption of raw or undercooked shellfish.
Chronic HEV infection rarely occurs, yet cases have been reported in immunosuppressed patients such as transplant recipients, and chronic carriage may occur in HIV-infected patients. Reactivation of resolved HEV infection appears possible, as in a leukemia patient who underwent allogeneic stem cell transplantation. Severe disease from HEV may also be associated with underlying liver disease. Pregnant women and very young children are associated with high mortality in developing countries, in particular Central Asia and Africa.
The diagnosis of acute HEV infection can be established most reliably by nucleic acid amplification to identify HEV RNA in blood or stool specimens. Blood samples showed HEV RNA from about 2 weeks before to 1 week after the onset of jaundice, whereas stool samples are positive later than blood but last 2 weeks after blood samples become negative. Diagnosis can also be obtained serologically by the detection of anti-HEV IgM, which disappears over 4-6 months, or anti-HEV IgG, which may persist for more than a decade. Currently no antibody assay is approved by the U.S. Food and Drug Administration (FDA).
Commentary
Autochthonous HEV infections are increasingly reported in Europe. In southwest England, testing for HEV IgG in patients with unexplained hepatitis and among blood donors identified 40 cases of autochthonous HEV (genotype 3). The disease affected predominantly elderly Caucasian males, was anicteric in 25% of the cases, and typically was self-limiting. Complications occurred in 6/40 patients, and 3 patients died, including 2 with previously unrecognized cirrhosis.1 In this population, HEV peaked in the spring and summer and was silent in November-December. Seroprevalence increased with age and was 16% in blood donors, 13% in patients with chronic liver disease, and 20% in persons older than 60 years.1
A challenge in the diagnosis of HEV infection is the lack of standardization and accuracy among some diagnostic tests. A study that was published in the same issue of CID reported the performance of six immunoassays for detecting IgM antibodies to HEV. Drobeniuc et al. tested sera from patients with acute infection against each of the 4 genotypes and also those with nonacute HEV infections. They found wide variations in sensitivities, specificities, and lack of interassay consistency.The two in-house assays that were tested performed well. Among the commercial assays, the best performers were Diagnostics Systems with a sensitivity of 98% and specificity of 95.2%, and Mikrogen with a sensitivity of 92% and specificity of 95.6%.2 The commercial assays from Immuno-Diagnostics and MP Biomedicals had lower sensitivities (82% and 72%, respectively) mainly due to poor detection of genotypes 2, 3, and 4.2 These data indicate that a clinician evaluating a traveler for possible acute hepatitis E infection must consider the reliability of the diagnostic test being used. In the United States, HEV PCR is performed in some research settings, but this could be a confirmatory test to the immunoassays, if available.
We have learned much about HEV, but more questions remain. As summarized by Teshale et al., there are two distinct clinical pictures of HEV. The first is that of outbreaks in developing countries leading to high morbidity and mortality among pregnant women and young children, and the second is that of subclinical infections in developed countries whose sources of exposure await further elucidation.
Recently, Colson et al. conducted a case-control study in France on three cases of autochthonous hepatitis E and 15 family members. They found that figatellu, a traditional pig liver sausage dish often served raw and consumed widely in France, was a source of HEV infection. Tests for HEV IgG and IgM antibodies and HEV RNA were positive in 7 of 13 individuals who ate raw figatellu and 0 of 5 individuals who did not eat raw figatellu (P = 0.041).3 HEV genotype 3 RNA was identified in 7 of 12 figatelli purchased in supermarkets, and statistically significant genetic links were found between the RNA sequences obtained from both patients and the figatelli.
Because of its association with chronic disease in immunocompromised hosts, a case-control study among solid-organ transplant recipients sought to identify risk factors for HEV infection and to characterize the infections through serological tests, virus quantification, and viral genotyping. Among 38 consecutive patients, all with genotype 3 infection, 22 (58%) developed a chronic infection. Serum liver enzymes were higher in the patients who cleared the virus than in those who developed chronic infections, but the anti-HEV IgG and IgM profiles and HEV RNA levels were similar. A logistic regression analysis found the only positive association with HEV infection was the consumption of game meat (68% of case patients vs 47% of control participants; odds ratio, 2.32; 95% confidence interval, 1.04-5.15).4
These recent data suggest that consumption of game meat or undercooked pork products is one route of exposure to HEV. Because HEV can lead to chronic hepatitis in immunocompromised patients, these individuals should avoid eating game meat or undercooked pork products to prevent the acquisition of HEV infection and the development of chronic hepatitis.
References
- Dalton HR, Stableforth W, Thurairajah P, et al. Autochthonous hepatitis E in Southwest England: Natural history, complications and seasonal variation, and hepatitis E virus IgG seroprevalence in blood donors, the elderly and patients with chronic liver disease. Eur J Gastroenterol Hepatol 2008;20(8):784-90.
- Drobeniuc J, Meng J, Reuter G, et al. Serologic assays specific to immunoglobulin M antibodies against hepatitis E virus: Pangenotypic evaluation of performances. Clin Infect Dis 2010;51(3):e24-7.
- Colson P, Borentain P, Queyriaux B, et al. Pig liver sausage as a source of hepatitis E virus transmission to humans. J Infect Dis 2010;202(6):825-34.
- Legrand-Abravanel F, Kamar N, Sandres-Saune K, et al. Characteristics of autochthonous hepatitis E virus infection in solid-organ transplant recipients in France. J Infect Dis 2010;202(6):835-44.
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