Richard Bendall

Hepatitis E: an emerging infection in developed countries

Hepatitis E is endemic in many developing countries where it causes substantial morbidity. In industrialised countries, it is considered rare, and largely confined to travellers returning from endemic areas. However, there is now a growing body of evidence that challenges this notion. Autochthonous hepatitis E in developed countries is far more common than previously recognised, and might be more common than hepatitis A. Hepatitis E has a predilection for older men in whom it causes substantial morbidity and mortality. The disease has a poor prognosis in the context of pre-existing chronic liver disease, and is frequently misdiagnosed as drug-induced liver injury. The source and route of infection remain uncertain, but it might be a porcine zoonosis. Patients with unexplained hepatitis should be tested for hepatitis E, whatever their age or travel history.

Hepatitis E Virus Antibodies in Blood Donors, France

Using a validated sensitive assay, we found hepatitis E virus (HEV) IgG in 52.5% of voluntary blood donors in southwestern France. This finding suggests HEV is highly endemic to this region. The high HEV prevalence may reflect local dietary practices, such as eating uncooked pork and game products.

A comparison of two commercially available anti-HEV IgG kits and a re-evaluation of anti-HEV IgG seroprevalence data in developed countries.

In developed countries, the incidence of hepatitis E virus (HEV) infection and the resulting seroprevalence are uncertain. Published estimates of seroprevalnce in these populations range from 0.26% to 31%, which may in part reflect the variety of assays used by different studies. This study compared the performance of two commercial assays (Genelabs [Singapore] and Wantai ‘Beijing, China’ HEV IgG EIA kits) and reviewed published estimates of anti‐HEV seroprevalence in developed countries. The assays were compared using the WHO anti‐HEV reference serum, sera from UK‐acquired cases of genotype 3 HEV infections and 500 UK blood donor sera. The PE2 assay was found to be more sensitive than the GL assay (lower limit of detection for HEV IgG 0.25 vs. 2.5 WHO units/ml); it was positive in more sera from proven cases (98% vs. 56%), remained positive for longer post infection and resulted in a substantially higher estimate of seroprevalence in blood donors (16.2% vs. 3.6%). these results suggest that published studies of HEV seroprevalence using the GL assay have underestimated the true figure and that a properly validated method is required to make meaningful comparisons of HEV seroprevalence between populations. J. Med. Virol. 82: 799–805, 2010.

Non–Travel-Associated Hepatitis E in England and Wales: Demographic, Clinical, and Molecular Epidemiological Characteristics

Between 1996 and 2003, 186 cases of hepatitis E were serologically diagnosed. Of these, 17 (9%) were not associated with recent travel abroad. Patients were >55 years old (range, 56-82 years old) and tended to be male (76%). Two patients presented with fulminant hepatitis. A total of 129 (69%) cases were associated with recent travel to countries where hepatitis E virus (HEV) is hyperendemic. Compared with patients with travel-associated disease, patients with non-travel-associated disease were more likely to be older, living in coastal or estuarine areas, not of South Asian ethnicity, and infected by genotype 3 strains of HEV. The genotype 3 subgenomic nucleotide sequences were unique and closely related to those from British pigs. Patients infected by HEV indigenous to England and Wales tended to belong to a distinct demographic group, there were multiple sources of infection, and pigs might have been a viral reservoir.

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.

Aims To report the natural history of autochthonous hepatitis E and hepatitis E virus (HEV) IgG seroprevalence in Southwest England. Methods Patients with unexplained hepatitis were tested for hepatitis E and cases followed until recovery or death. Five hundred blood donors, 336 individuals over the age of 60 years and 126 patients with chronic liver disease were tested for HEV IgG. Results Forty cases of autochthonous hepatitis E (genotype 3) were identified. Hepatitis E was anicteric in 25% of cases and usually caused a self-limiting hepatitis predominantly in elderly Caucasian males. Six of 40 had a significant complication and three patients died, two of who had previously undiagnosed cirrhosis. Hepatitis E shows a seasonal variation with peaks in the spring and summer and no cases in November and December. HEV IgG prevalence increases with age, is more common in men and is 16% in blood donors, 13% in patients with chronic liver disease and 25% in individuals over 60 years. Conclusion Autochthonous hepatitis E is more common than previously recognized, and should be considered in the differential diagnosis in patients with hepatitis, whatever their age or travel history. It carries a significant morbidity and when seen in the context of chronic liver disease carries an adverse prognosis.

Hepatitis E Virus and Neurologic Disorders

Information about the spectrum of disease caused by hepatitis E virus (HEV) genotype 3 is emerging. During 2004-2009, at 2 hospitals in the United Kingdom and France, among 126 patients with locally acquired acute and chronic HEV genotype 3 infection, neurologic complications developed in 7 (5.5%): inflammatory polyradiculopathy (n = 3), Guillain-Barre syndrome (n = 1), bilateral brachial neuritis (n = 1), encephalitis (n = 1), and ataxia/proximal myopathy (n = 1). Three cases occurred in nonimmunocompromised patients with acute HEV infection, and 4 were in immunocompromised patients with chronic HEV infection. HEV RNA was detected in cerebrospinal fluid of all 4 patients with chronic HEV infection but not in that of 2 patients with acute HEV infection. Neurologic outcomes were complete resolution (n = 3), improvement with residual neurologic deficit (n = 3), and no improvement (n = 1). Neurologic disorders are an emerging extrahepatic manifestation of HEV infection.

The role of hepatitis E virus testing in drug‐induced liver injury

Background  Locally acquired hepatitis E is an emerging infection in developed countries and can be misdiagnosed as drug‐induced liver injury.

Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus–host recombinant

The RNA virus, hepatitis E virus (HEV) is the most or second-most important cause of acute clinical hepatitis in adults throughout much of Asia, the Middle East, and Africa. In these regions it is an important cause of acute liver failure, especially in pregnant women who have a mortality rate of 20–30%. Until recently, hepatitis E was rarely identified in industrialized countries, but Hepatitis E now is reported increasingly throughout Western Europe, some Eastern European countries, and Japan. Most of these cases are caused by genotype 3, which is endemic in swine, and these cases are thought to be zoonotically acquired. However, transmission routes are not well understood. HEV that infect humans are divided into nonzoonotic (types 1, 2) and zoonotic (types 3, 4) genotypes. HEV cell culture is inefficient and limited, and thus far HEV has been cultured only in human cell lines. The HEV strain Kernow-C1 (genotype 3) isolated from a chronically infected patient was used to identify human, pig, and deer cell lines permissive for infection. Cross-species infections by genotypes 1 and 3 were studied with this set of cultures. Adaptation of the Kernow-C1 strain to growth in human hepatoma cells selected for a rare virus recombinant that contained an insertion of 174 ribonucleotides (58 amino acids) of a human ribosomal protein gene.

Autochthonous hepatitis E in southwest England

Summary.  Although autochthonous hepatitis E has been reported in developed countries, its extent and nature in the United Kingdom are unclear. The aim of the present study was to report the natural history, lifestyle risk factors and molecular epidemiology of autochthonous hepatitis E infection in southwest England. Three hundred and thirty‐three patients with unexplained hepatitis were tested for markers of hepatitis E virus (HEV) infection over a 7‐year period. HEV RNA isolated from the cases was amplified and characterized. Of the 333 patients, 21 had autochthonous hepatitis E. Patients were middle‐aged or elderly and males were more commonly affected. Clinical manifestations ranged from asymptomatic infection to severe hepatitis. Of the 21 patients, 20 recovered within 6 weeks. None of the cases had travelled to an area endemic for HEV. None of the patients were vegetarian and all ate pork. Of the 21 cases, 20 occurred in the spring, summer and autumn months. All polymerase‐chain‐reaction‐confirmed cases carried HEV genotype 3, which bore close sequence homology to HEV circulating in UK pigs. In the United Kingdom, autochthonous hepatitis E may be more common than previously recognized. Although the mode of transmission remains to be determined, it may be a zoonosis with pigs as a reservoir. Hepatitis E should be considered a public health issue in the United Kingdom.

Human and Porcine Hepatitis E Virus Strains, United Kingdom

We describe a case of acquired infection of a strain of hepatitis E virus (HEV)with a 100% amino acid identity to the analogous region in strains of HEV circulating in a United Kingdom pig herd. This case further supports the theory that autochthonous HEV infection in industrialized countries is zoonotic.