Background
Since 1980, hepatitis E virus (HEV) is recognized as a causative agent of acute viral inflammation of the human liver [
1]. The clinical features resemble those of infection with hepatitis A virus (HAV), and both are transmitted by the fecal-oral route or by contaminated water [
2]. Unlike HAV, secondary transmission appears to be of minor significance [
3,
4]. HEV infection is usually self-limited, and its severity may range from subclinical infection to fulminant liver failure, probably depending on genotype. The risk for a fulminant disease course is particularly high in pregnant women, with an increased risk for adverse pregnancy outcomes and a maternal mortality rate up to 20 % in case of a genotype 1 infection [
5‐
7]. In addition, an increased risk for complications is observed in immunosuppressed persons, especially in transplant patients who may develop chronic hepatitis [
8,
9].
HEV, a non-enveloped single-stranded RNA virus, is classified as a unique member of genus
Hepevirus in the family of
Hepeviridiae, of which only one serotype is known [
10]. Four human HEV genotypes have been identified, each having distinct geographical distributions. Genotypes 1 and 2 are responsible for large water-borne HEV outbreaks in humans in tropical and sub-tropical parts of Asia, Africa and Central America due to poor hygiene. In these areas HEV infection is considered an important cause of acute clinical hepatitis in adults [
11,
12]. In developed Western countries HEV genotypes 3 and 4 are thought to be zoonotic as they are found in domestic pigs and cows and also in wild animals such as swine, deer, and mongoose [
13]. The exact route of transmission of genotypes 3 and 4 is still unknown, but it may be by eating contaminated undercooked food such as meat from domestic pigs, or from wild animals [
12‐
15].
In the Netherlands, the incidence of HEV is unknown, and representative data on the seroprevalence of HEV antibodies in the general Dutch population are scarce. In 2011 it was estimated that on average 27 % of Dutch blood donors were anti-HEV IgG positive, with an age-dependent increase from 13 % in teenagers to 42 % in those of 50 years and older [
16].
This study investigated a representative sample of the general adult population of Amsterdam, the Netherlands, on the presence of antibodies against HEV in relation to demographic data. Amsterdam has large migrant communities, mainly from Morocco and Turkey, but also from people originating from various tropical countries such as Surinam, Netherlands Antilles and Indonesia. This allowed us to look for determinants for anti-HEV seropositivity in different migrant groups using data and samples from a study that was performed in 2004, the Amsterdam Health Monitor (AHM). Furthermore, we looked whether anti-HEV seropositivity was related to the seroprevalence of hepatitis A virus (HAV) in the same AHM population [
17]. The resulting data offers new insights into the sero-epidemiology of HEV infection in an urbanized area with mixed ethnicities.
Discussion
In this cross-sectional study among the adult population of Amsterdam, we found clear differences in HEV seroprevalence between those born in the Netherlands and first generation migrants. This has not been reported before within one multi-ethnic population. Also new in this study is that weighted calculations could be made in the AHM study. The overall weighted seroprevalence of HEV-IgG in the adult Amsterdam population was 26.7 % in 2004, which is comparable to an estimate made in 2011 among Dutch blood donors (27 %) by Slot et al. [
16]. Yet the blood donor population likely reflects a more autochthonous Dutch population with certainly less Moroccans and Turkish participants, as in the AHM study a deliberate oversampling on these ethnicities was performed. Similar to the blood donor population our study demonstrated an age related increase of anti-HEV seroprevalence of 10 % in those younger than 35 years, to 55 % in persons of 65 years and older. This association of HEV-IgG seropositivity with increasing age has also been reported in other studies [
20‐
23]. In the Netherlands, the anti-HEV seroprevalence in blood donor populations declined over time from 46.6 % in 1988 to 20.9 % in 2011 among comparable age groups, indicating that the HEV infection pressure is not constant. Indeed, in the Netherlands a recent rise of anti-HEV IgG prevalence among young blood donors indicates that the HEV incidence is increasing again [
21].
First generation migrants of Moroccan ethnic origin were 3 times more likely to be anti-HEV-seropositive compared to the autochthonous Dutch population. A recent review reported that the anti-HEV seroprevalence in the general population in countries of the Middle East and the Northern African-region, where also Morocco is situated, ranges from 2 to 38 % [
24]. This is lower than the 44 % weighted prevalence that we found among first generation Moroccans in Amsterdam.
There was a significant difference in age of migration between those who were HEV positive versus HEV negative in the ‘younger’ Turkish and ‘other’ ethnicity migrants, but not for the Moroccans. This could indicate that those who migrated at an older age from Turkey or the other countries had got infected in the country of origin. Those who were older than 40 to 45 years at the time of study participation had been at least 20 years in the Netherlands (Table
2) and had experienced an equal infection pressure as the Dutch, as shown by the same chance of being HEV positive or HEV negative.
Surprisingly, first generation migrants from Turkey had a lower weighted seroprevalence compared to the Dutch, although this difference was not significant; yet it was also significantly lower than that of first generation Moroccans. This difference is not easily understood. It indicates that exposure to HEV in Turkey differs from that in Morocco, however it might also be that the higher prevalence in Moroccans relative to that of Turkish first generation migrants in Amsterdam reflects a more rural versus a more urban descent of these migrants, respectively. The seroprevalence (20.3 %) that we found in the Turkish group is higher compared to the seroprevalence estimated in a Turkish study (of 2002) showing a geographical range of 3.8 % in the city of Ankara up to more than 15 % in rural Eastern Turkey [
25]. Because the assays that were used differ, study results are not fully comparable and the Turkish study possibly underestimated the true prevalence.
Other sero-epidemiological studies in developed countries reported a wide variety of anti-HEV IgG seroprevalence, from 5 % in Japan, to 22 % in France, Germany, and Denmark and also in the United States [
20,
22,
23,
26,
27]. Next to differences in exposure to HEV, an important issue is also the variation in assays with different performances that were used [
28‐
31]. In this study the Wantai HEV IgG test was used, with a high specificity (99 %) and sensitivity (98 %) [
16,
28,
29,
31‐
33]. Using this assay the anti-HEV seroprevalence in many developed countries was higher than previously anticipated [
11,
25,
34].
A limitation of our study is that HEV genotypes are not known. HEV seropositivity in first generation Moroccans may be based on immunity against HEV genotypes 1 or 2, since these types predominantly circulate in African countries. Also water-borne HEV outbreaks with these genotypes have been described in several parts of Morocco [
3,
12,
35]. It might thus well be that first generation Moroccan participants experienced a HEV infection before they migrated to the Netherlands, whereas others got infected in the Netherlands. Due to small numbers, we were only able to create two age strata in the analysis of the median age of immigration. Possibly, residual confounding of age may have influenced our findings.
In the Netherlands it was previously shown that both humans and pigs harbor the same HEV genotype 3, so transmission is probably food-related [
14,
15]. Because Muslims do not eat pork meat or other pork products and because Surinamese people are known not liking to eat raw or undercooked meat, these groups may be protected from acquiring HEV genotype 3 in the Netherlands.
We hypothesized that because HAV and HEV are both fecal-orally transmitted infections, there might have been a relation between the seroprevalence of HEV and HAV. Almost all first-generation migrants from Morocco and Turkey had natural immunity to HAV, regardless of their HEV status. Also within the Dutch population there was no difference in HAV status between the anti-HEV IgG positive and negative groups. Our data showed thus no such relation between hepatitis E and hepatitis A virus infection and therefore we think that the transmission of both hepatitis viruses occurred independently. This was also previously shown in many other studies. In most of the countries also the HAV seroprevalence was higher than the HEV seroprevalence, in similar age groups [
36‐
40].
Acknowledgements
The authors would like to thank H.J. Fennema, J.A.R. van den Hoek and A.P. Verhoef for their contribution to the realization of the Amsterdam health monitor 2004 study. We also thank D. Uitenbroek and J. Ujcic-Voortman for enabling the data collection process. F. Zethof is acknowledged for help with the hepatitis E serological testing.