Hepatitis E: The nonendemic perspective

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Abbreviations

HEV

hepatitis E virus

HIV

human immunodeficiency virus

IgG

immunoglobulin G

IgM

immunoglobulin M

NHANES

National Health and Nutrition Examination Survey.

Hepatitis E virus (HEV) is a nonenveloped, single‐stranded, positive sense RNA virus that measures ∼7.2 kb.1 It was the last of the human hepatotropic viruses to be discovered and is classified within the genus Hepevirus of the Hepeviridae family.2 Four major genotypes of the virus have been identified, which may contribute to the observed epidemiological differences between endemic and nonendemic areas of the world.2, 3 Hepatitis E genotypes 1 and 2 predominate in endemic regions, where infection is characterized by major epidemics and sporadic cases of acute hepatitis usually related to consumption of fecally contaminated water.4 Young adult males are affected more than females, but mortality is higher in pregnant women. In contrast, genotypes 3 and 4 predominate in nonendemic regions, where hepatitis E is rare and is associated with sporadic acute hepatitis. The mode of transmission is unknown, but zoonosis is suspected. Swine appear to be the primary host, but other animals such as deer, rabbits, mongeese, chicken, and fish may serve as vectors.5, 6 Humans are thought to be accidental hosts, and in contrast to endemic regions, older males are more commonly affected than younger persons. Hepatitis E has been considered an emerging infection in developed countries because of a growing number of reports of human infection with genotypes 3 and 4 from the United States, Europe, and Japan.

Epidemiology in Nonendemic Areas

In nonendemic areas, most cases of acute HEV are sporadic and have been associated with travel to endemic countries (so‐called “imported or travel‐associated hepatitis E infection”7). This is mostly due to infection with HEV genotypes 1 and 2. Recently, however, several cases of hepatitis E have been reported that are unrelated to travel in an endemic region (e.g., “autochthonous” or locally acquired infection). Most of these cases are due to infection with genotypes 3 and 4. The routes of transmission of autochthonous hepatitis E are unknown. There is weak evidence for environmental transmission based on drinking untreated water as a risk factor from Spain and France8, 9 and from detection of HEV RNA in strawberry fields irrigated with contaminated river water in Canada.10 However, there are also reports of transmission from consumption of undercooked pig, wild boar, and deer meat products, which together with a high seroprevalence of anti‐HEV among veterinarians and other individuals who work with pigs suggests zoonotic transmission. Elderly males, immunocompromised individuals, and individuals with chronic liver disease are more commonly affected in contrast to endemic HEV infection.

The seroprevalence of anti‐HEV varies widely in developed countries. In Europe, it ranges from a low of 2% in Germany to 21% in Denmark and a high of 52% in southern France, a hyperendemic area.11, 12, 13 This wide variability may in part be due to the assay used. In the United States, the seroprevalence was reported to be 21% based on a population‐based survey of the noninstitutionalized population participating in National Health and Nutrition Examination Survey (NHANES) III (1988‐1994).14 Among United States‐born subjects, anti‐HEV positivity was associated with being male, non‐Hispanic white, and residing in the Midwest.14 However, data from the most recent NHANES study (2009‐2010) showed a much lower rate of 6.9%.15 The cause for this large decline is unknown but again may be related to different anti‐HEV assays.

Despite the high seroprevalence, the incidence of acute HEV is reported to be very low, at seven infections per 1000 susceptible persons per year based on modeling of NHANES III data.16 Accordingly, in the last 14 years, of 123 suspected cases reported to the Centers for Disease Control and Prevention, only 33 (27%) were confirmed to have hepatitis E infection; approximately two thirds were autochthonous cases, and one quarter were organ transplant recipients. The presumed high prevalence and low incidence of HEV in the United States suggests that most cases of autochthonous HEV infection are subclinical.15

Clinical Presentation

Similar to endemic regions, hepatitis E infection in nonendemic regions presents as self‐limiting acute hepatitis. It usually causes an anicteric, asymptomatic hepatitis. Cases of symptomatic acute or fulminant hepatitis with liver failure are uncommon. This is substantiated by an analysis from the Acute Liver Failure Study group of 699 cases without a known diagnosis, which reported a very low incidence of acute HEV infection (0.4%) based on anti‐HEV immunoglobulin M (IgM) testing.¹⁵

Extrahepatic neurological manifestations have been reported in association with HEV infection, including Guillain‐Barre syndrome, Bell's palsy, acute transverse myelitis, and acute meningoencephalitis.17 A unique feature of autochthonous hepatitis E is the capability to develop chronic HEV infection, which may progress to cirrhosis. Chronic infection has been reported in immunocompromised patients such as organ transplant recipients,18, 19, 20, 21 post‐hematopoietic stem cell transplant recipients,22 patients receiving chemotherapy,23, 24 and patients infected with human immunodeficiency virus (HIV).25, 26 A large case series of acute HEV infection among 85 recipients of renal, liver, and combined renal and pancreatic transplants in France reported that two thirds of the cases progressed to chronic hepatitis E; the remainder resolved spontaneously. Strikingly, 16% of the chronic cases progressed to cirrhosis over a period of 2 to 3 years.27 Chronic infection has reportedly occurred in HIV‐positive subjects, particularly those with low CD4 counts, but is uncommon. There are rare reports of chronic infection among recipients of stem cell or bone marrow transplants for hematological malignancy.28 The true incidence and prevalence of chronic HEV infection among the immunosuppressed or immunocompromised populations are unknown, but current data suggest that it is low and presently does not warrant screening these populations for presence of HEV. Testing, however, is indicated for unexplained hepatitis in this population.29 Interestingly, all cases of chronic infection have been associated with HEV genotype 3 infection. It is unknown whether the other genotypes can cause chronic infection.

Diagnosis

There is no gold standard test for the diagnosis of HEV infection. Diagnosis and interpretation of results are problematic due to issues of sensitivity and specificity with currently available serologic assays (Table 1, Fig. 1). A number of assays are commercially available, but none are approved by the US Food and Drug Administration. In the clinical setting, diagnosis of acute hepatitis E depends on demonstration of anti‐HEV IgM in serum and/or HEV RNA (Fig. 2). In chronic infection, HEV RNA has been reported to persist with HEV immunoglobulin G (IgG) (Fig. 3). All current HEV RNA assays are performed in‐house, and their validity is unknown. In immunocompromised patients, anti‐HEV IgG may be undetectable, and HEV RNA alone may confirm hepatitis E infection.

Table 1.

Performance of 12 Tests for Detection of Antibody to HEV

Test	Limit of Detection	Sensitivity (%)	Specificity (%)
1	1:80	96	98
2	1:160	98	93
3	1:20	98	79
4	1:10	83	98
5	1:20	89	100
6	1:40	67	100
7	1:160	91	95
8	1:20	72	98
9	Unknown	15	84
10	1:0	24	100
11	1:5	24	100
12	1:10	57	98

Adapted from Hepatology.34 Copyright 1998, Wiley.

Figure 1.

Antibody to HEV reactivity in serum samples that were positive by two or more tests, serum samples that showed prior discrepant results, and serum samples that were negative by two or more tests. The 12 tests correspond to the 12 tests shown in Table 1. Adapted from Hepatology.34 Copyright 1998, Wiley.

Figure 2.

Acute hepatitis E infection. HEV RNA becomes detectable in serum and stool during the incubation period followed by appearance of anti‐HEV IgG and anti‐HEV IgM. IgM levels peak early and become undetectable after resolution of symptoms, whereas IgG levels rise slowly and continue to increase and persist after recovery. HEV RNA becomes undetectable in the serum after recovery. HEV RNA is detected in the stool longer than in the serum. Adapted with permission from New England Journal of Medicine.35 Copyright 2012, Massachusetts Medical Society.

Figure 3.

Chronic hepatitis E infection in a patient who received a kidney transplant in March 2005. (A) Liver enzyme pattern along with serologic and virologic markers of hepatitis E infection. Hepatitis E infection was diagnosed when anti‐HEV IgM was tested in September 2006 for elevated liver enzymes. Anti‐HEV IgM and HEV RNA remained positive for more than 6 months. Anti‐HEV IgG was undetectable throughout the course of infection. (B) Liver biopsy specimen obtained in September 2007 with portal inflammation and mononuclear cells extending beyond the limiting plate and surrounding individual or small clusters of hepatocytes (hematoxylin and eosin stain). (C) Sirius red staining of collagen, indicating cirrhosis, with an advancing fibrosing phenomenon isolating parenchymal nodules. Adapted with permission from New England Journal of Medicine.36 Copyright 2008, Massachusetts Medical Society.

Treatment

Acute hepatitis E infection usually resolves spontaneously. However, if chronic infection ensues, treatment should be considered due to the possibility of development of cirrhosis. In immunocompromised subjects, reducing immunosuppression alone can result in clearance of the infection in up to one third of patients.27 If HEV RNA persists despite weaning of immunosuppression, peginterferon alone, ribavirin alone, or the combination of both for 3‐12 months have been used to treat chronic hepatitis E with varying success (66%‐82% based on small case series).30, 31, 32 Initial doses of pegylated interferon (peginterferon alfa‐2a, 135 μg/week) and ribavirin (600‐1000 mg/day in divided doses) are generally lower than those used for chronic hepatitis B or C.30, 33 Ribavirin monotherapy is preferred over pegylated interferon or combination therapy in renal transplant subjects because of the risk of graft rejection.27, 30