Hepatitis E, a (relatively) little-known virus

Of all the types of hepatitis that have been characterised up until now, hepatitis “E” is undoubtedly the least well known among both the general public and scientists. While it sometimes causes death, it is asymptomatic in the majority of cases. In industrialised countries, it affects humans but above all, it affects animals, especially pigs. Is it really the same virus? And who infects who? How is it transmitted? The laboratory of veterinary virology at the University of Liège, led by Etienne Thiry, is endeavouring to answer these questions.  

Most people have already heard of hepatitis A, B or C. However, very few people are familiar with the different forms of hepatitis beyond the first three letters of the alphabet. For instance, there is hepatitis D, which is quite virulent but mostly unknown to the general public because it develops in the shadow of hepatitis B, from which it is indissociable. But the list doesn’t end here because there is a new addition to this virus family: hepatitis E. A recent arrival that is completely unknown. At least on this side of the planet. In Asia and developing countries, it has made much more of a name for itself. According to the World Health Organisation (WHO), this disease causes the majority of the 20 million new infections and 3.3 million acute cases recorded every year in these countries. 

In Belgium, as in other industrialised countries, hepatitis E is present but its incidence is probably under-estimated. Few scientific studies have been carried out on the subject, and few public authorities have subsidised this type of research. Undoubtedly because the infection it causes is far less devastating than those of its “cousins”: 56,600 deaths recorded very year compared with 780,000 for B and 500,000 for C, according to the WHO. 

Almost everywhere in Europe, however, researchers are starting to cotton on to this theme. In Belgium, this is the case at the Institut Scientifique de Santé Publique (ISP - Public Health Scientific Institute), which is a reference laboratory in terms of human hepatitis viruses, but also… the faculty of veterinary medicine at ULg. How come? “It may well seem strange that vets are involved in this human disease”, admits Étienne Thiry, director of the Laboratory of Veterinary Virology and Viral Animal Diseases. “This is where the international "One Health" concept comes in, which aims to explore the interactions between animal and human diseases when they are transmitted to humans. Like bird flu for instance”. 

In the beginning, everyone thought that hepatitis E was only transmitted from human to human by the faecal-oral route, mainly through contaminated water. But then doubts were raised. What if animals were responsible for it? Was it a human virus or an animal virus?

It all depends on which genotype we are talking about. Hepatitis E has four different genotypes. 1 and 2 only infect humans, mainly in Asia and Africa. They cause severe illness, which is particularly aggressive in pregnant women and can lead to death. On the other hand, 3 and 4 seem to be more inoffensive, with far less serious clinical signs. Genotype 3 is found in humans, mainly in Europe and North America. In Belgium, a study carried out in Flanders (but on a restricted sample) showed that 14 % of people were infected.  

A troubling fact: genotype 3 has also been identified in the same geographic areas in pigs and, to a lesser degree, in wild boar and deer. So could there be a potential zoonotic reservoir of the virus, allowing transmission from animals to humans? This remains to be seen...  

“What happens between pigs and humans? That’s the question we’ve been trying to answer for the past five years, in collaboration with the ISP”, Étienne Thiry continues. “For the time being, we don’t know exactly if the virus first appeared in humans or pigs”. With the help of an American specialist, the laboratory in Liège analysed phylogenetic data to establish the virus’ family tree, based on current knowledge, in order to go back as far as possible in time. It wasn’t easy because it belongs to the very complex Hepeviridae family, which is found in camels, rodents, and bats. The researchers nevertheless managed to go back approximately 1 million years to find an ancestor common to hepevirus in mammals and birds. The dichotomy occurred later, but no-one knows whether pig or humans were infected first.   

One thing is certain, genotype 3 hepatitis E also affects pigs. The team from Liège carried out a survey among Belgian pig farmers, in order to determine how many animals were infected. The verdict: 93 % of pig farms tested positive and 73 % of pigs were affected. “We weren’t expecting such a high prevalence! Especially compared with 14 % seropositivity in humans according to the Flemish study”, Étienne Thiry points out. “As for pigs, the virus is found almost everywhere, compared with a low incidence in humans. How does this virus pass from animals to humans?”

To find out, the laboratory first studied the presence of hepatitis E in wildlife (1) in collaboration with the Department of Wildlife Health and Pathology under Prof. A. Linden. It established that 34 % of wild boars were positive, compared with 1 to 3 % of deer and roe deer. “We therefore – quite confidently – suggested that there were two identified animal reservoirs in Belgium: domestic pigs and wild boar”. Once again, it is impossible to accurately determine who infected who in the beginning. “Even if it is very difficult to demonstrate, we can put forward the hypothesis that this virus, which has existed for hundreds of thousands of year, must have initially been present in wildlife. In the beginning, pigs were practically all wild. In fact, the pig is a sort of domesticated wild boar. But does this virus come from pigs or was it transmitted to them by humans? We can’t answer this question”, Étienne Thiry repeats.  

He and his team nevertheless wanted to determine whether the wild boar virus could inoculate pigs. Considering the prevalence of the disease in farms, it was no mean feat to find “clean” animals. They had to go to France, to the Breton commune of Ploufragan, where ANSES (Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail) has an adjoining animal house, with biosecurity level 3, where a herd of pigs can live protected from infection. “We carried out two series of experiments”, the professor explains. “First to show that the wild boar virus is transmitted to pigs, and then transmitted from pig to pig. It isn’t enough to demonstrate a probability of introduction, it is also necessary to ensure that once the virus has multiplied, it can be infectious again for the others and thus establish itself in a pig population. This is where we are currently at”.  

In nature, transmission is faecal-oral between animals. Deer are undoubtedly collateral victims, contaminated by wild boar excrement, although there is no real continuation of the infection afterwards, as shown by it low presence among these animals. But how does hepatitis E pass from pigs to humans? Even if every part of a pig is good to eat, its waste is one part that doesn’t reach the table…

“The next step is to continue with the One Health collaboration and o find out how the disease is transmitted”, Étienne Thiry reckons. International studies have already revealed a few possibilities. For instance, people who are professionally exposed to pigs (breeders, vets, abattoir workers, etc.) seem to test positive more often than others. For the moment, these results haven’t been confirmed in Belgium, owing to a lack of subsidies to finance the research. 

Other scientific works, especially in Japan, have demonstrated that the infection can be caused by eating raw liver. Normally, the virus is inactivated at 70 degrees and above but sometimes, game is undercooked. In the south of Corsica and in France, it is a cured sausage that is to blame: the figatelli, a cured sausage made from raw pigs’ liver. In Belgium, food habits are different and we still have to determine which factors could play a role in contagion. “In the future, we’ll have to take a closer look at pork-based food”, the professor believes. “Logically, this is the main source to which people might be exposed. Epidemiological studies need to be carried out on a human level. As for vets, we shall focus more on virological aspects. By using new generation sequencing techniques, we’ll be able to characterise the virus much more thoroughly, so that we can specify the relationship between the virus isolated in pigs and wild boar, and the one in humans. For the time being, we believe they are almost identical, based on the knowledge we have. But we haven’t yet explored the whole genome”.

These in-depth analyses will perhaps indirectly allow us to understand the transmission from animal to human. And to develop a vaccine? “There is already a human vaccine in China”, Étienne Thiry explains. “We’re prepared to investigate this problem in animals. A vaccine would be possible, but I don’t think this will be the preferred approach because it would be very expensive. Health and hygiene inspections would be the more likely methods. We suggested this to the Walloon Region, which clearly isn’t ready yet and didn’t accept our project”. 

Because it is an asymptomatic disease, funding isn’t forthcoming… At most, there may be a few signs of inflammation in pigs’ livers. Otherwise, the disease is harmless. Only the “best” viruses manage to find such a good balance between themselves and their host, because it isn’t in their interest to kill the latter. However, this doesn’t mean that a far more virulent strain won’t emerge one day, or that the virus may become more serious after contact with other infections. Despite its inoffensive appearance, it would be worth learning more about hepatitis E…

(1)Belgian Wildlife as Potential Zoonotic Reservoir of Hepatitis E virus, in Transboundary and Emerging Diseases (2015).