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Treating and diagnosing hepatitis E

Case Study

A 57-year-old Filipino man attended the emergency department (ED) with recent onset of palpitations and breathlessness. He had a past history of hypertension, atrial fibrillation, myocardial infarction and a cerebrovascular accident.

The patient was a recent resident in Ireland, having left the Philippines four months previously and was currently living with his wife. He was an ex-smoker, drank no alcohol, denied recreational drug use and was not taking any over-the-counter medication or supplements.

In the ED a rapid, irregular pulse and hypertension were observed but otherwise his examination was normal. His BMI was also within normal range.

Applicable bloods, ECG and CXR were requested.

Results: Troponin 48ng/L (<14), ECG: fast atrial fibrillation with old MI changes, CXR: normal. Deranged liver function tests (LFTs) with a normal synthetic function were also noted (BR 19µmol/L (0-21) AST 82IU/L (0-40), ALT 135IU/L (0-41), ALP 63IU/L (40-129) GGT 98IU/L (0-71), albumin 41g/L (35-50) PT 10.5sec (9.9-13.0).

The patient was admitted for rate control of the atrial fibrillation and for further investigation of the hepatocellular damage (3:2 ALT:AST ratio).

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Discussion

Hepatitis E virus (HEV) was first postulated as the causative agent of an epidemic of hepatitis in Kashmir in 1978. The epidemic was water-borne and was particularly severe in pregnant women. Sera lacked markers of acute hepatitis A and hepatitis B.

In 1983, during an outbreak of hepatitis in a Russian military camp in Afghanistan, Dr Mikhail Balayan, a Russian virologist, succeeded in infecting himself with the virus by ingesting a pooled stool extract from nine patients. Thirty-six days later, he developed clinical hepatitis. A new spherical virus-like particle, 27-30nm in diameter, was demonstrated in his faeces by electron microscopy. Later, the virus was named HEV because of its enteric route of transmission and its ability to cause epidemics.

In recent years, there has been a paradigm shift in our understanding of HEV. The traditional view that HEV is only associated with travel to endemic regions in the developing world has changed, as it is now well established that HEV can be acquired indigenously. Since 15 December 2015, HEV is now a notifiable disease in Ireland

Virology

In 1990, Reyes et al cloned and sequenced the HEV genome. HEV is a single-stranded, positive-sense RNA virus of approximately 7.2Kb in size. It belongs to the genus orthohepevirus, the only member of the family hepeviridae. Its capsid is icosahedral and it does not possess an envelope.

Epidemiology

Phylogenetic analysis suggests that there are four genotypes (1-4) and up to 24 subtypes. Genotypes 1 and 2 exclusively affect humans and are often associated with large outbreaks and epidemics in developing countries and those with poor sanitation. Genotypes 3 and 4 infect humans, pigs, and other animal species and have been responsible for sporadic cases of disease in developed and developing countries  (see Table 1). During epidemic outbreaks, attack rates of 1-15 per cent (with a disproportionate number of cases in 15-40 year-olds) have been seen.

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Mode of transmission

Four major routes of HEV transmission have been reported. These are: (1) faecal-oral transmission due to contamination of water supplies (often cyclical, occurring with seasonal heavy rainfall); (2) food-borne transmission (consumption of undercooked/uncooked meat from an infected animal/domestic pigs, wild boar and wild deer have been found to be reservoirs of genotype 3 and 4, while consumption of shellfish was also found to be a risk factor in an outbreak on a cruise ship); (3) transfusion of infected blood products; and (4) vertical transmission.

Person-to-person transmission is uncommon.

Seroprevalence rates in UK and Ireland

Seroepidemiological studies indicate HEV-antibody (anti-HEV) seroprevalence rates in England to be approximately 13 per cent, with an annual attack rate of 0.1-0.2 per cent and an estimated 60,000 infections per year.

In a sentinel study published in The Lancet, November 2014, 225,000 blood donations (October 2012-September 2013) in South East England were screened for HEV. Of these, 79 donors (one in 2,848) were viraemic, with genotype 3 HEV. Most viraemic donors were seronegative at the time of donation. The 79 donations had been used to prepare 129 blood components, 62 of which had been transfused before identification of the infected donation. Follow-up of 43 recipients showed 18 (42 per cent) had evidence of infection, with an anti-HEV IgG prevalence of 16
per cent.

More recently, in Scotland, 4.7 per cent of 1,559 blood donors were found to be anti-HEV IgG positive. None tested positive for IgM. There is very little information about the true prevalence of HEV in Ireland. However, according to the Health Protection Surveillance Centre (HPSC), in 2016, in weeks one-to-16 there have been 34 notified cases of HEV.

Definition of acute and chronic HEV

Acute HEV is defined as the presence of anti-HEV IgM and anti-HEV IgG antibodies or evidence anti-HEV IgG seroconversion (ie, initially anti-HEV IgG negative and subsequently positive on later testing) or the presence of HEV RNA.

Chronic HEV is defined as the persistence of HEV RNA for at least three months (with or without detectable HEV antibodies).

Laboratory criteria

Laboratory criteria for diagnosis of acute HEV infection include the presence of both anti-HEV IgM and IgG in serum. The IgM response is rapid, occurring about a month after infection and peaking at the onset of biochemical abnormalities and/or symptoms and disappears rapidly over four-to-five months. The IgG response remains long-term. In addition, the presence of HEV RNA in serum confirms acute HEV in a patient with symptoms of
acute infection.

Testing for anti-HEV IgM antibody can give false negative results in immunocompromised individuals. Therefore, HEV RNA testing in serum is recommended.

HEV RNA testing on faeces may also be performed.

Clinical manifestations of acute HEV infection

The average time between exposure to HEV and infection is 40 days (range 10-to-63 days). Approximately 95 per cent of people do not develop symptoms. The risk of symptomatic illness may depend on age of infection. Research among non-human primates has shown a direct association between infective dose and disease severity, but an inverse relationship to the incubation period.

The symptoms typically last one-to-two weeks and include anorexia, dark urine, nausea and vomiting, abdominal pain, and eventually jaundice and last one-to-two weeks. HEV is self-limiting and, like hepatitis A, resolution generally confers protective immunity.

Virus excretion in stool has been demonstrated from one week prior to onset to up to 30 days after the onset of jaundice.

Chronic HEV infection

It is now recognised that HEV infection can also evolve to chronic hepatitis in immunosuppressed patients (patients with a solid-organ transplant (SOT) especially if on tacrolimus, haematological patients and HIV-positive patients, CD4 <250mm¯³). They commonly present with extreme fatigue.

LFTs tend to be raised but much less than in an immunocompetent patient. In these patients, HEV-induced extra-hepatic manifestations have been noted. Chronic HEV infection to date has only been described in patients infected by genotype 3.

Extra-hepatic manifestations

As with other viral hepatitis, extra-hepatic manifestations can occur and the spectrum of clinical disorders is still emerging. They occur in acute and chronic HEV infections.

These include rheumatological symptoms, arthralgia and rash, which may be linked with cryoglobulinaemia, renal disease, including glomerulonephritis with or without cryoglobulinemia and membranous glomerulonephritis. Acute pancreatitis, haematological disorders, myocarditis, and thyroiditis have also been reported. Neurologic manifestations (Guillain-Barré syndrome, neuralgic amyotrophy, acute transverse myelitis, encephalitis) are also an emerging extra hepatic manifestation of genotype 3 infection.

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Case fatality

Most people with hepatitis E recover completely. However, fulminant hepatitis is more likely in those who are pregnant, in those who are malnourished or who have pre-existing liver disease.

During HEV outbreaks, the overall case-fatality rate is about 1 per cent but higher in pregnant women (10-30 per cent) in the third trimester.

Of note, high mortality rate in pregnancy is associated with genotype 1 but is not evident with genotype 3. There is also a high mortality rate in patients with pre-existing chronic liver disease and solid organ transplant recipients on immunosuppression.

Prevention

Travellers to endemic areas (Asia, Africa, Middle East and Central America) should engage in practices that may prevent infection, such as avoiding drinking water of unknown purity, uncooked shellfish and uncooked fruits or vegetables.

Current recommendations by the Food Safety Authority of Ireland (FSAI) suggest that cooking pork and pork products (eg, sausages) to a minimum of 75ºC at the centre of the thickest part is sufficient to protect consumers. Normal grilling of frying of sausages until they are well browned and firm inside, with no traces of pink meat, usually results in centre temperatures of 85ºC. However, it is recommended to use a thermometer to check the temperature.

An effective vaccine against HEV has been developed in China, ‘HECOLIN’, but to date is not available elsewhere. It is a recombinant vaccine derived from a genotype 1 Chinese strain. The efficacy has been shown to be >95 per cent for genotype 4, there is limited data for genotype 1 and it is not available for genotypes 2 and 3.

Treatment

Treatment is supportive. However, in the transplant patient with chronic HEV infection, in addition to supportive therapy, viral clearance is desirable. The first step is to reduce the immunosuppressive therapy, as reduction of immunosuppression results in viral clearance in 30 per cent of patients.

In addition to supportive treatment, severe acute HEV and fulminant hepatitis, as well as chronic HEV, may require treatment with an antiviral agent. Antiviral therapy, ribavirin for at least three months, should be considered in patients for whom immunosuppressive therapy cannot be reduced and for those who do not achieve viral clearance after reducing immunosuppression. Ribavirin is contraindicated in pregnancy as it is teratogenic, however the risks of HEV transmission to the foetus may outweigh the risks of administration of ribavirin.

Conclusion

The Filipino man in the case report had been resident in Ireland approximately 120 days, which is outside the incubation period of 10-63 days, and it is likely, therefore, that the HEV infection was acquired while living in Ireland.

Furthermore, HEV RNA was shown to be genotype 3 subtype on sequencing, which is known to be associated with food-borne transmission. This case highlights the importance of considering HEV infection in any patient with biochemical evidence of hepatitis for which there is no other virological or immunological cause.

Clinical learning point

Since 15 December 2015, HEV is now a notifiable disease in Ireland under the infectious diseases regulations.

All medical practitioners and laboratories are required to notify HEV to the Medical Officer of Health.  

References available on request

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