Journal of Hepatology
Volume 48, Issue 3 , Pages 494-503, March 2008

Hepatitis E: An emerging awareness of an old disease☆

Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 50 South Drive MSC 8009, Bethesda, MD 20892-8009, USA

published online 03 January 2008.

Associate Editor: M. Colombo

Article Outline

Although hepatitis E was recognized as a new disease in 1980, the virus was first visualized in 1983 and its genome was cloned and characterized in 1991, the disease is probably ancient but not recognized until modern times. Hepatitis E is the most important or the second most important cause of acute clinical hepatitis in adults throughout Asia, the Middle East and Africa. In contrast, hepatitis E is rare in industrialized countries, but antibody (anti-HEV) is found worldwide. HEV is a small round RNA-containing virus that is the only member of the genus Hepevirus in the family Hepeviridae. Although similar to hepatitis A virus in appearance, there are significant differences between the two viruses. Hepatitis E is principally the result of a water-borne infection in developing countries and is thought to be spread zoonotically (principally from swine) in industrialized countries. Because diagnostic tests vary greatly in specificity, sensitivity and availability, hepatitis E is probably underdiagnosed. At present, control depends upon improved hygiene; a highly efficacious vaccine has been developed and tested, but it is not presently available.

Abbreviations: HAV, hepatitis A virus, IEM, immune electron microscopy, HEV, hepatitis E virus, ORFs, open reading frames

Keywords: Water-borne, Zoonosis, Acute hepatitis

 

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1. Introduction: modern history 

Until 1980 hepatitis A virus (HAV) was the only type of water-borne viral hepatitis recognized [1], [2]. The discovery of hepatitis E resulted from application of recently developed assays for antibody to HAV (anti-HAV) to paired sera collected from Indian water-borne hepatitis outbreaks [1], [2]. Similar epidemics were subsequently identified in Central and Southeast Asia, the Middle East and North Africa, but the inability to identify the etiologic agent serologically or virologically made it impossible to determine if one or multiple viruses were involved. In 1983, Mikhail Balayan, a Russian virologist, experimentally ingested a faecal suspension from Asian patients and collected his faeces during the incubation period [3]. He identified the virus in his faeces by immune electron microscopy (IEM) and successfully transmitted the virus to cynomolgus monkeys. Thus, the etiologic agent was identified in precisely the same way that HAV had been identified a decade earlier [4].

Because the new agent could not be grown in cell culture and because the quantity of virus in acute phase faeces was relatively limited, diagnosis of cases was difficult and limited to analysis by IEM, a tedious and labor-intensive serologic test. Nevertheless, based upon limited serology augmented by serologic exclusion of HAV infections, sporadic cases not associated with outbreaks were also identified [5]. In fact, studies of the epidemiology of HAV worldwide demonstrated that clinical hepatitis A was virtually non-existent in developing countries and that most disease previously thought to be hepatitis A was actually the newly diagnosed hepatitis [6]. In 1991, Tam et al. succeeded in cloning and sequencing the genome of the virus and it was named “hepatitis E virus” (HEV) [7]. Because of a superficial physical and molecular resemblance to the caliciviruses, it was classified within the Caliciviridae. However, a more extensive analysis revealed HEV to be genetically more closely related to rubella virus, although physically, the two viruses are quite different [8]. Ultimately, HEV was accorded its own genus (Hepevirus) and its own family (Hepeviridae) [9].

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2. The disease: comparison with hepatitis A 

Hepatitis A virus and hepatitis E virus cause disease that is indistinguishable without serologic testing [10], [11], [12], [13]. Both cause an acute, self-limiting infection that may vary in severity from inapparent to fulminant. However, hepatitis A and hepatitis E do differ in a few respects: (1) the incubation period of hepatitis E is, on average, 10 days longer than that of hepatitis A (Table 1); (2) a single infectious dose of HAV can initiate a full-blown case of hepatitis A. In contrast, the clinical response to HEV, at least in non-human primate models, is dose-dependent, and a low dose of virus usually results in an inapparent infection. (3) The mortality of hepatitis A, like its clinical attack rate, is age dependent: most infections of infants and young children are inapparent or subclinical, whereas infections of older children and adults are more likely to be clinically significant and this is reflected in the mortality rate of 0.1–2%. It is not as clear that the severity of hepatitis E is age dependent and it has been reported that hepatitis E has a mortality of 1–4%, considerably higher than that of hepatitis A. (4) Whereas the mortality of hepatitis A is approximately the same in pregnant versus non-pregnant cases, for unknown reasons the mortality of hepatitis E is much higher (approximately 20%) in pregnant women, compared to non-pregnant individuals. Transmission of HEV from the pregnant mother to her fetus, resulting in fetal wastage, is also common. (5) Bimodal and relapsing hepatitis is relatively common in hepatitis A, whereas it is rare in hepatitis E. However, neither type of hepatitis progresses to chronicity, except in the rare event of infection of the immunologically compromised host [14], [15].

Table 1. Enterically-transmitted hepatitis viruses
HAVHEV
Incubation period∼30 days∼40 days
Dose-dependent severityNoYes
Mortality0.1–2%1–4%
Mortality in pregnancyNo differenceUp to 20%
Bimodal diseaseCommonRare
Chronicity(No)(No)
In developed regionsEpidemic, endemicAntibody, but rare disease
In developing regionsAntibody, but rare diseaseEpidemic, endemic
AgeOlder children, younger adultsOlder children, younger adults
SexNo differenceNo difference (except in pregnancy)

These differences probably reflect, in part, differences in the nature of the two viruses (Table 2, Table 3). Although both are “small round viruses,” they differ in some important characteristics. (1) HAV is very stable in the environment compared to HEV. For example, HAV can withstand a temperature of 60°C, whereas HEV is inactivated at temperatures 5–10°C lower [16], [17]. (2) Excreted titers of virus in the faeces are a hundred-fold greater for HAV than for HEV. (3) The host ranges also differ: HAV is exclusively a virus of humans and certain other non-human primates, whereas HEV can infect humans, chimpanzees and certain species of macaques, but in addition, certain HEV strains are endemic in swine herds worldwide and are believed to be one source of human infection [18], [19]. Chickens harbor a separate HEV type that is believed not to infect mammals [20]. Antibody to HEV has been detected in a number of other animal species, including rats, dogs, cattle, sheep, camels, etc., and it is not known whether these HEV strains are transmissible to humans [19]. (4) Naturally attenuated strains of HAV have never been identified, whereas strains of HEV, especially those that can also infect swine, appear to be less virulent for humans than the strains that infect humans only [10], [21]. This may be a separate phenomenon from the dose-dependency of HEV.

Table 2. Taxonomy
CharacteristicHAVHEV
FamilyPicornaviridaeHepeviridae
GenusHepatovirusHepevirus
GenotypesSix (1,2,3: human; 4,5,6: simian)Five (1,2: human; 3,4: human, swine; 5: avian)
SerotypesOneOne (1–4)
Table 3. Enterically-transmitted hepatitis viruses: biology (molecular and classical)
HAVHEV
Size (nm)2832–34
GenomePositive sense, single-stranded RNAPositive sense, single-stranded RNA
Genome size7.5kb7.2kb
5′ non-coding regionComplex, IRESSimple, capped
Open reading frames1 (polyprotein)3 (different reading frames)
3′ non-coding regionPoly A tailPoly A tail
Growth in cell culturePoorPoor
Stability of virusesVery stableLess stable (?)
Infectious titer in faeces106–109104–107
Host rangePrimatesPrimates, pigs, rats, chickens, cattle, sheep, etc.
Naturally attenuated strainsNo (?)Yes (?)

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3. The virus: taxonomy and comparison with HAV 

HAV and HEV are both small, non-enveloped viruses that contain positive sense, single-stranded RNA genomes of 7.5 and 7.2kb, respectively. In addition, they have similarities and differences in their taxonomic status. (1) Whereas HAV has its own genus (Hepatovirus) within the large (at least six genera) virus family Picornaviridae, HEV is the sole member of genus Hepevirus and family Hepeviridae [9], [22]. (2) HAV is comprised of six (formerly seven) genotypes: genotypes 1–3 are of human derivation and genotypes 4–6 are of simian origin. HEV is comprised of at least five genotypes: genotypes 1 and 2 are strictly human (but see below), genotypes 3 and 4 are probably of swine origin but infect humans also and the 5th (provisional at this time) is of avian origin and is endemic in many chicken flocks. The avian virus probably does not infect humans [23]. (3) All genotypes of HAV belong to one serotype. Thus, only one hepatitis A vaccine is needed for broad protection. Similarly, the four recognized mammalian HEV strains all belong to one serotype. It is not known whether avian HEV belongs to a different serotype, but it is likely.

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4. Epidemiology: the old and the new 

The cloning of the HEV genome was a major breakthrough in HEV virology. This led to the sequencing of the HEV genome and the expression of recombinant HEV proteins. Each, in turn, took the field of HEV virology in a different direction.

One was the development of serologic and diagnostic tests [24]. These revealed that hepatitis E virus was the single most important cause of acute clinical hepatitis among adults throughout Central and Southeast Asia and the second most important cause, behind hepatitis B virus, throughout the Middle East and North Africa (Fig. 1) [25], [26], [27]. In contrast, HEV was responsible for a vanishingly small number of cases of such hepatitis in the United States and other industrialized countries [28]. In the United States, HAV has been the single most important cause of acute clinical hepatitis.

In contrast to the geographic incidence of HEV disease, the geographic prevalence of antibody to HEV was worldwide, although the highest prevalences were found mostly in countries where the disease was endemic. Furthermore, the prevalence of anti-HEV in countries, such as India, where the disease was endemic, did not fit the usual pattern for an enterically-transmitted virus, such as HAV, where infection occurs early in life and involves most of the population (Fig. 2) [29]. To add to the confusion, in Egypt, where sporadic cases of hepatitis E have occurred but where water-borne epidemics have not been reported, the age-specific prevalence of anti-HEV more closely resembled that of anti-HAV in developing countries [30]. And finally, the age-specific prevalence of anti-HEV in the United States was much higher than expected, considering that fewer than a dozen cases of hepatitis E have been reported from that country [31]. In fact, in some states, the prevalence of antibody to HEV was higher than the prevalence of antibody to HAV (Fig. 3).

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  • Fig. 3. 

    Surprisingly, in the United States, the prevalence of anti-HEV is equal to or greater than the prevalence of anti-HAV in some regions, especially in states that are large producers of swine [31].

The second direction in which the cloning and sequencing of the HEV genome took the field was into its molecular biology and molecular epidemiology. The four mammalian genotypes of HEV were found to have unique geographic distributions (Fig. 4, Fig. 5) [32]. Human genotype 1, found throughout Asia and North Africa, has been the major cause of water-borne epidemics and significant sporadic disease. Human genotype 2 has been recovered from a single epidemic in Mexico and from several epidemics in central Africa. Genotype 3 has been recovered from humans in North and South America, several countries of Europe, Japan and a few Pacific Rim countries. Genotype 4 has been recovered from humans in parts of China, Japan, Taiwan and Vietnam.

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  • Fig. 5. 

    HEV genotypes 3 and 4, which infect both humans and swine, have been recovered from pigs in regions that roughly parallel the distribution of these viruses in human infections. However, there are exceptions.

HEV genotype 3 has been recovered from swine principally in the same regions that genotype 3 was recovered from humans and the same is true for genotype 4 recovered from swine. With few exceptions [33], genotypes 3 and 4 appear not to produce disease in swine. These two genotypes also appear to be less virulent for humans than genotypes 1 and 2. Thus, in developing countries, where virulent genotypes 1 and 2 are present, these are the viruses that are recovered most frequently from human cases of hepatitis E, even though genotypes 3 or 4 are present in the local swine herds [34], [35]. In contrast, in industrialized countries, where virulent genotypes 1 and 2 are not present or cannot sustain themselves in the environment, the less virulent genotypes 3 and 4 are responsible for the occasional case of clinical hepatitis E in these settings. This suggests that the relatively high prevalence of anti-HEV in industrialized countries may result from inapparent infections with attenuated strains of HEV derived from swine or other domestic or wild animals and that the strains only rarely cause clinical disease.

The Delhi epidemic is believed to have been caused by genotype 1 virus, the only recognized cause of human clinical hepatitis E in India. In this epidemic, the age-specific clinical attack rate of HEV was in older children and young adults (Fig. 6) [36]. Virtually all water-borne epidemics of hepatitis E have had a similar age pattern. Sporadic hepatitis E caused by genotypes 1 and 2 in developing countries has occurred most frequently in older children and young adults also. In contrast, hepatitis E caused by genotypes 3 and 4, principally (but not exclusively) in industrialized countries, has occurred on average at a much older age and, in some cases, in individuals who are also infected with human immunodeficiency virus. This suggests that these attenuated strains of HEV may infect humans but are more likely to cause disease in those who are elderly or otherwise immunologically compromised. Since none of the HEV genotypes spread readily from person to person, it is likely that they are acquired from an animal reservoir, such as swine.

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  • Fig. 6. 

    The age-related clinical attack rate of hepatitis E differs by genotype. In the famous Delhi epidemic of 1955 (presumably caused by a genotype 1 virus), the highest incidence of disease was in those 20–29 years of age [36]. Similarly, endemic disease associated with HEV genotype 1 or 2 infections in developing countries also peaks in the 20–29 year age group. In contrast, clinical hepatitis E associated with infection with genotypes 3 or 4, often in industrialized countries, peaks in those 60 years of age or older.

Indeed, such appears to be the case. There is support for a zoonotic source of HEV infection in industrialized countries. Genotypes 1 and 2 can be experimentally transmitted to certain species of non-human primates but not to other animals [37]: the few reports of the transmission or recovery of genotype 1 in other animals may reflect laboratory contamination [38], [39], [40], [41]. In contrast, isolates of genotype 3 (and probably 4) whether from humans or swine are transmissible not only to non-human primates but to other diverse animal species [37], [42], [43] and in the United States, as well as in Europe, those with exposure to swine have a higher prevalence of antibody to HEV than matched blood donors [28], [44]. Avian HEV is not transmissible to non-human primates [20]. Thus this virus probably does not pose a threat to man.

Direct evidence for a zoonotic transmission of hepatitis E virus from Sika deer to human beings has been reported from Japan and, also from Japan, consumption of wild boar meat has been linked to cases of hepatitis E [45], [46], [47].

What about other potential animal sources of HEV? HEV is endemic in feral and wild rat species, but this virus is not transmissible to non-human primates, so it probably is not a potential source of human infection [48], [49], [50]. More interesting are cows, sheep and goats. These species, particularly the first two, have high prevalences of anti-HEV in some populations, but HEV has not been isolated and characterized from these domestic species [17], [51]. Thus, not only swine but perhaps one or another of the other major meat sources in the human food chain may be sources of zoonotic infections of humans. Indeed, HEV sequences have been recovered from commercially available pork liver purchased in butcher shops in Japan, the Netherlands and the United States, and viable HEV was recovered from such livers in the United States [52], [53], [54]. It has been shown that HEV would survive temperatures reached when meat is cooked to the rare state [14]. It is likely that some meat other than pork is involved in the transmission of HEV in Islamic countries and the recovery of HEV from other meat sources in the human food chain might help us to understand the perplexing epidemiology of this human pathogen.

The origin of hepatitis E is unknown. It has been suggested that it is an emerging disease. However, historical records suggest that hepatitis E may be ancient. Two features of the epidemiology of hepatitis E appear to be unique for an enterically-transmitted hepatitis agent in a developing country: peak incidence of infection and clinical attack rate in older children and young adults and high incidence of fulminant hepatitis and death among infected pregnant women. The former was instrumental in recognizing hepatitis E as a new disease because the populations in which it occurred were virtually 100% immune to HAV by ages 5–10 years. Thus, adults in such populations would not be expected to develop clinical hepatitis A. Nevertheless, epidemic and endemic hepatitis with the epidemiologic characteristics of water-borne and enterically-transmitted disease, and associated with a high mortality in pregnant women, occurred regularly in adults throughout Europe and elsewhere in the latter half of the 19th century [55]. Was this disease hepatitis A? Probably not. A number of studies of the prevalence of anti-HAV in Europe, the United States and Australia have revealed that HAV has diminished in importance in those populations over the past 70 years, from a seroprevalence of almost 100% in those born early in the 20th century to single-digit percentages today [56], [57], [58]. It is likely that the epidemiology of HAV infection in endemic areas was the same then as it is now: Infection with this enterically-transmitted virus early in life when such infections typically are clinically inapparent. Thus, much of the epidemic and endemic hepatitis A-like disease occurring in what are now industrialized countries, as well as elsewhere, before the 20th century was probably hepatitis E.

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5. Diagnosis 

Hepatitis E can be diagnosed by the demonstration of IgM anti-HEV in the serum by ELISA (generally present when the patient is first seen by a physician) or by detection of viral genomic RNA in the serum or faeces by nested or real-time PCR [21], [32]. Unfortunately, both serologic tests and molecular tests vary greatly in sensitivity, making diagnosis, and especially seroepidemiological studies, less reliable than for the other human hepatitis viruses.

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6. Prevention 

Improved public hygiene (treatment of water and sewage) is the first line of defense against hepatitis E, as well as other enterically-transmitted diseases, especially in developing countries. In industrialized countries prevention of zoonotic spread may also be important. However, even in industrialized countries, such diseases generally persist, albeit at a lower level, and vaccines provide a second, usually more effective mode of prevention.

Considerable progress has been made in the immunoprophylaxis of hepatitis E. As noted, ORF 1 encodes the non-structural proteins (Fig. 7). Although immunogenic, these proteins are not part of the virion and are not known to elicit protection. ORF 3 encodes a small, heterogeneous protein of unknown function and antibody to it is short-lived and it does not neutralize the virus. In contrast, the capsid protein encoded by ORF2 is highly conserved, highly immunogenic and antibody to it neutralizes and is protective. Furthermore, it is a major target of cell-mediated immunity [59], [60], [61]. Thus the capsid antigen is the preferred protein for vaccine development.

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  • Fig. 7. 

    The genome of HEV consists of single-stranded, positive sense RNA with a size of 7.2kb. There are three open reading frames (ORFs) that encode the non-structural proteins, a small protein of unknown function and the capsid protein, respectively. The genome also encodes putative phosphorylation and glycosylation sites and contains a cis-reactive element (CRE). Two subgenomic RNAs were reported previously; the smaller of the two has been shown to express both ORF2 and ORF3 [7], [68].

The 72kDa capsid antigen was expressed in Escherichia coli as a complete protein and in truncated variations [62]. While the complete protein is relatively insoluble, truncated forms are much more soluble, and some, when used as vaccines, have protected rhesus monkeys from challenge with virulent HEV in studies from China. Even more impressive has been progress in vaccine development with capsid protein expressed from baculovirus in insect cells [62]. In insect cells, endogenous proteases cleave the 72kDa capsid protein in a cascade to progressively smaller sizes. The first cleavage removes the 111aa signal sequence-like portion from the amino-terminal part of the molecule and this is followed by subsequent carboxy-terminal cleavages, resulting in proteins of 63, 62, 56 and 53kDa size. From a vaccine standpoint, the 62 and 56kDa proteins have proven to be the most protective and the 56kDa protein has proven to be the most stable. It is necessary to maintain the native structure of these proteins because the most important (perhaps only) neutralization epitope is conformational in nature [63], [64]. Extensive testing in monkeys of the 56kDa protein led to its selection by GlaxoSmithKline (GSK) for clinical testing and a lot of the vaccine was prepared by Novavax under contract with GSK. In preclinical evaluation of the vaccine in rhesus monkeys, it was found to be 83% efficacious in preventing infection and 100% efficacious in preventing hepatitis when the monkeys were challenged with virulent HEV genotypes 1, 2 or 3 (genotype 4 had not been discovered at that time) [65].

The vaccine was subsequently tested for safety and immunogenicity in US Army volunteers at Walter Reed Army Medical Hospital and in Nepalese Army volunteers in Nepal and, subsequently, in an efficacy trial in Nepalese Army volunteers in the Kathmandu Valley of Nepal [66], [67]. Nepal was chosen because surveillance studies carried out over a number of years in the Kathmandu Valley demonstrated an ongoing problem with hepatitis E, both in the Kathmandu civilian population and in the Royal Nepal Army. The vaccine was administered in a double-blind, randomized study in 2000 susceptible adults. The vaccine was administered in three doses, at 0, 1 and 6 months and the volunteers were followed for clinical hepatitis and adverse events.

Adverse events were minimal and virtually identical in the vaccine and placebo groups. Vaccine efficacy following three doses of vaccine was 95.5%, with only three cases occurring in the vaccine group compared to 66 in the placebo group. Vaccine efficacy following only two doses of vaccine was still 87%. Thus, hepatitis E vaccines hold the promise of preventing significant illness in developing countries where the disease is endemic.

Despite the success of this vaccine in a field trial, it is not yet known whether it will be marketed, because, in spite of the apparent need for such a vaccine, the potential market in industrialized countries is quite small and probably limited to the military and other travelers to endemic regions. In developing countries, such a vaccine could be widely used, especially in children between birth and adolescence, but its cost would have to be low enough to be affordable by those most at risk and still provide a profit for pharmaceutical companies. Optimally, a vaccination program that would fit into WHO vaccination schedules of the Expanded Programme on Immunization would be the most useful. By extrapolation from vaccination programs against other enterically-transmitted viruses, universal pediatric vaccination would probably be necessary for effective control of hepatitis E.

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☆ The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript. This is a NIH funded study; the authors are NIH employees.

PII: S0168-8278(07)00686-1

doi:10.1016/j.jhep.2007.12.008

Journal of Hepatology
Volume 48, Issue 3 , Pages 494-503, March 2008

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