Hepatitis E; Causes, Symptoms, Diagnosis, Treatment

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Hepatitis E is an enterically transmitted, self-limiting, acute, viral hepatitis. The disease causes large-scale, water-borne epidemics of viral hepatitis and is the most common cause of acute sporadic hepatitis and fulminant hepatic failure in such countries []. The disease has unique and as yet unexplained epidemiological characteristics, including repeated waves of large-scale epidemics, the occurrence of disease in the adult population and high incidence and severity of disease in pregnant women [].

Hepatitis E is a liver infection caused by the Hepatitis E virus (HEV). Hepatitis E is a self-limited disease that does not result in chronic infection. It is transmitted from the ingestion of fecal matter, even in microscopic amounts, and is usually associated with contaminated water supply in countries with poor sanitation. While Genotypes 1 and 2 (G1 and G2) are obligate human pathogens transmitted fecal-orally, leading to epidemics in developing countries. In contrast, genotypes 3 and 4 (G3 and G4) have a wider host range, including humans, but are primarily porcine viruses and are transmitted from animals to humans as a food-borne zoonosis when meat from an infected animal is consumed.

Types and Causes of Hepatitis E

Acute infection

  • There is substantial heterogeneity in the clinical presentation of HEV infection both between and within developing and developed countries. In resource-poor settings, the majority of cases, both sporadic and epidemic, involve either HEV1 (Asia) or HEV2.
  • The average incubation period of hepatitis E is 40 days, ranging from 2 to 8 weeks. After short prodromal phase symptoms may include jaundice, fatigue, and nausea, though most HEV infections are asymptomatic. The symptomatic phase coincides with elevated hepatic aminotransferase levels.[rx][rx][rx][rx]
  • Viral RNA becomes detectable in stool and blood serum during the incubation period. Serum IgM and IgG antibodies against HEV appear just before the onset of clinical symptom

Chronic infection

  • The chronic HEV infection can occur in immunosuppressed individuals, including transplant recipients, HIV-positive patients,, and patients receiving chemotherapy for hematological malignancies. While usually lasting weeks and then resolving, in people with weakened immune systems—particularly in people who have had solid organ transplant—hepatitis E may cause a chronic infection.[rx] Occasionally this may result in a life-threatening illness such as fulminant liver failure or liver cirrhosis.[rx][rx]All cases reported to date have involved HEV3 or HEV4. The bulk of the literature on chronic HEV infection concerns solid-organ transplant recipients, but the clinical presentation is similar in other immunocompromised cohorts.

Other Organs

Infection with the hepatitis E virus can also lead to problems in other organs. For some of these reported conditions such as musculoskeletal or immune-mediated manifestations, the relationship is not entirely clear, but for several neurological and blood conditions the relationship appears more consistent:[rx][rx]

  • Acute pancreatitis (HEV genotype 1[rx])
  • Neurological complications (though the mechanism of neurological damage is unknown at this point.[rx]) include Guillain-Barré syndrome (acute limb weakness due to nerve involvement), neuralgic amyotrophy (arm and shoulder weakness, also known as Parsonage-Turner syndrome), acute transverse myelitis and acute meningoencephalitis.
  • Glomerulonephritis with nephrotic syndrome and/or cryoglobulinemia
  • Mixed cryoglobulinemia, where antibodies in the bloodstream react inappropriately at low temperatures
  • Severe thrombocytopenia (low platelet count in the blood) which confers an increased risk of dangerous bleeding

2018 CDC article indicated the detection of rat HEV RNA in a transplant recipient and Distribution

  • Genotype 1 – has been isolated from tropical and several subtropical countries in Asia and Africa.[rx]
  • Genotype 2 – has been isolated from Mexico, Nigeria, and Chad.[rx]
  • Genotype 3 – has been isolated almost worldwide including Asia, Europe, Oceania, and North and South America.
  • Genotype 4 – appears to be limited to Asia and indigenous cases from Europe.[rx][rx][rx]

Genotypes 1 and 2 are restricted to humans and often associated with large outbreaks and epidemics in developing countries with poor sanitation conditions.[rx] Genotypes 3 and 4 infect humans, pigs, and other animal species and have been responsible for sporadic cases of hepatitis E in both developing and industrialized countries.[rx][rx]


Symptoms of Hepatitis E

When they occur, the signs and symptoms of hepatitis E are similar to those of other types of acute viral hepatitis and can include

The ratio of symptomatic to asymptomatic infection ranges from 1:2 to 1:13.

 Extrahepatic manifestations of hepatitis E

Neurological

    Haematological

    • Thrombocytopenia
    • Monoclonal immunoglobulin
    • Cryoglobulinaemia

      Nephrological

      • Glomerulonephritis

      Miscellaneous

      • Acute pancreatitis
      • Arthritis
      • Autoimmune thyroiditis
      • Myocarditis


        Diagnosis of Hepatitis E

        In terms of the diagnosis of hepatitis E, only a laboratory blood test that confirms the presence of HEV RNA or IgM antibodies to HEV can be trusted.[rx][rx] The World Health Organization has developed an international standard strain for the detection and quantification of HEV RNA.[rx] In acute infection, the viremic window for the detection of HEV RNA closes 3 weeks after symptoms begin.[rx]

        • Blood tests – Doctors suspect hepatitis based on typical symptoms, such as jaundice.
        • Liver Function Test – Testing for hepatitis usually begins with blood tests to determine how well the liver is functioning and whether it is damaged (liver function tests). Liver function tests involve measuring the levels of liver enzymes and other substances produced by the liver. These tests may help establish or exclude the diagnosis of hepatitis, identify the cause, and determine the severity of liver damage.
        • Because cases of hepatitis E – are not clinically distinguishable from other types of acute viral hepatitis, diagnosis can be confirmed only by testing for the presence of antibodies against HEV or HEV RNA.
        • No serologic tests to diagnose HEV infection – have been approved by the FDA for use in the United States. Several tests are available for research purposes and some commercial laboratories use commercially available assays from other countries.
        • HEV infection – should be considered in any person with symptoms of viral hepatitis who has traveled to a hepatitis E endemic region, recently travelled from an endemic area, or from an outbreak afflicted region and who is negative for serologic markers of Hepatitis A, B, C, and other hepatotropic viruses.
        • A detailed history regarding sources – of drinking water, uncooked food, and contact with jaundiced persons should be obtained to aid in diagnosis. There are increasing numbers of domestically acquired cases of hepatitis E and diagnosis should be suspected when no etiology can be identified on thorough evaluation.
        • The initial test method is an anti-HEV IgM assay -The presence of IgM anti-HEV antibodies is suggestive of recent HEV infection
        • If the initial test is positive – confirmatory testing should be performed when available since no single EIA method achieves high specificity. Confirmatory testing may include an alternate anti-HEV IgM, evidence of rising anti-HEV IgG titers (greater than fivefold change over two weeks), or detection of HEV RNA in serum or stool [RX].
        • If initial EIA testing –  is negative, and there is still a high suspicion for HEV infection, repeat testing should be performed, preferably with an HEV RNA assay. The use of RNA testing is particularly important in immunocompromised hosts with suspected HEV due to a high rate of false-negative antibody testing [rx,rx,rx].
        • Testing for IgG anti-HEV antibodies – is of limited utility in the diagnosis of chronic HEV infection. The presence of IgG (or total) anti-HEV antibodies is a marker of exposure to HEV, which can be either recent or remote. In addition, the decline in IgG anti-HEV titers with time might adversely affect its sensitivity for detecting remote infection.
        • Anti-HEV – There are no commercial tests for HEV licensed in the United States; however, there are research laboratories that can test for anti-HEV by EIA or Western blot of serum, and for HEV genomes by a polymerase chain reaction of blood or feces [rx].
        • Antibody testing — The timing of the appearance of HEV markers is important for interpreting the results of serologic testing in the setting of acute hepatitis (.
        • IgM anti-HEV  – appears during the early phase of clinical illness and disappears rapidly over four to five months  [rx]. Although IgM anti-HEV has been detected in the serum by EIA in more than 90 percent of patients in some outbreak settings when samples were obtained within one week to two months after the onset of illness, serology may be negative in a substantial proportion of patients with acute infection [rx].  In another report, the sensitivity and specificity for IgM anti-HEV were 27 and 92 percent, respectively. HEV RNA was detected in 23 percent of patients followed by the detection of specific IgM in 17 percent and IgG in 13 percent of patients [rx].
        • The IgG response appears shortly after the IgM response – and its titer increases throughout the acute phase into the convalescent phase. It is unclear how long IgG anti-HEV antibodies persist. In one report, antibodies were detected as long as 14 years after the acute phase of illness; however, a booster effect due to reinfection could not be excluded [rx,rx,rx-rx]. In other follow-up studies, IgG antibody titers showed a rapid decline but were detectable 14 to 20 months after an acute HEV infection. Discordance between assays of IgG anti-HEV antibody is even higher as compared with assays for IgM anti-HEV antibody [rx].
        • HEV RNA assay — HEV can be detected in stool approximately one week before the onset of illness and can persist for as long as two weeks thereafter [rx,rx-rx]. In serum, HEV may be detected two to six weeks after infection and can persist for two to four weeks in those who resolve the acute infection. Although HEV viremia is short-lived in most patients with acute infection, it can persist for years in those who develop chronic infection[rx].


        Virological Markers

        • Assuming that vaccination has not occurred, tests may show [rx]

        If the person’s immune system is normal, then

        • If IgM anti-HEV – is negative, then there is no evidence of recent HEV infection
        • If IgM anti-HEV – is positive, then the person is likely to have a recent or current HEV infection. If the person’s immune system is weakened by disease or medical treatment, as in the case of a person who has received a solid organ transplant then
        • If IgM anti-HEV – is negative, then if additional blood testing reveals > positive HEV RNA then the person has HEV infection > negative HEV RNA then there is no evidence of current or recent infection
        • If IgM anti-HEV – is positive, then the person is likely to have a recent or current HEV infection, and HEV RNA may be useful to track resolution.

        Diagnosis of hepatitis E virus infection

        TestMethodUsesComments
        IgM anti-HEVELISAAcute infectionAssays vary in performance, issue of genotype applicability, poor performance in immune disorders, cross-reactive with other viral infections
        ICT (POCT)
        IgG anti-HEVELISASeroprevalenceAssays vary in performance
        ICT (POCT)Acute infection
        Natural protection
        Vaccine efficacy
        HEV RNANATAcute infectionViremia short-lasting, in-house assays vary in performance, advantage immune disorders
        Confirm chronicity
        Anti-viral response
        Donor screening
        HEV antigenEIAAcute infection81% concordance with HEV RNA

        Adopted from Khuroo et al[], 2016. HEV: Hepatitis E virus; ICT: Immunochromatographic test; POCT: Point of care test; NAT: Nucleic acid test; EIA: Enzyme immunoassay.

        TestClinical Use and Interpretation
        Elevated liver indicators; aspartate aminotransferase (AST) alanine aminotransferase (ALT) bilirubins, alkaline phosphataseMarkers of hepatic injury; not specific to HEV but indicate hepatitis is present
        Hepatitis E IgMUsed for primary diagnosis; positive early in infection, but may not be positive on presentation; declines slowly after acute infection over a period of months
        Hepatitis E IgGBecomes positive shortly after HEV IgM; stays positive for years; HEV IgM should turn positive in infected patients with positive HEV IgM
        Hepatitis E RNA by PCRLimited availability; usually positive on presentation; the virus can be detected in either serum or stool; useful for acute diagnosis in critically-ill patients and for assessment of immunosuppressed patients with positive serology and ongoing hepatic disease
        Extrahepatic manifestations of acute and chronic hepatitis E infection
        Organ systemClinical syndrome
        Neurological
        • Neuralgic amyotrophy
        • Guillain–Barré syndrome
        • Meningoencephalitis
        • Mononeuritis multiplex
        • Myositis
        • Bell’s palsy
        • Peripheral neuropathy
        • Vestibular neuritis
        Kidney
        • Membranoproliferative and membranous glomerulonephritis
        • Immunoglobulin A nephropathy
        Haematological
        • Thrombocytopaenia
        • Monoclonal immunoglobulin
        • Cryoglobulinaemia
        • Aplastic anemia
        Other
        • Acute pancreatitis
        • Arthritis
        • Myocarditis
        • Autoimmune thyroiditis
        Reproduced and adapted with permission from the European Association for the Study of the Liver guidelines[rx]

        Treatment of Hepatitis E

        Non-Pharmacological

        • Eating a varied, balanced diet
        • Drinking plenty of liquids, especially water
        • Planty of resting
        • Avoiding things that irritate the liver, such as alcohol
        • Slow down. Cut back on daily activities until all of your energy returns. As you start to feel better, take your time in getting back to your regular routine. If you try to do it too fast, you may get sick again.
        • Drink plenty of water to avoid dehydration. Fruit juices and broth are other good choices if you can tolerate them.
        • Eat a healthy mix of foods. Even though food may not appeal to you, it’s important for you to get good nutrition.
        • Don’t drink alcohol or use illegal drugs. They can make liver problems worse.
        • Make sure your doctor knows all the medicines you’re taking, including herbal products. Don’t start or change any medicines without talking to your doctor first.

        Pharmacological Treatment

        • Ribavirin – is effective against a wide range of RNA viruses. As such, several antiviral mechanisms have been proposed, one of which is lethal mutagenesis. RNA virus intra-host populations have high levels of variation due to rapid RNA replication and the lack of proof-reading capability in RNA-dependent RNA polymerase. This means that these viruses run close to the genomic error threshold, the point at which the burden of mutation is incompatible with the transmission of the virus’ master sequence.
        • Ribavirin – is incorporated into newly synthesized viral RNA, introducing mutations. By increasing the error rate, ribavirin pushes the virus over this threshold and induces extinction.Ribavirin has been observed to exert this effect on HEV. Higher rates of mutation increase the likelihood of acquiring mutations associated with the development of hepatic failure, progression to chronic infection and reduced immunoreactivity. Mutations that confer resistance to ribavirin have also been reported. It has been suggested that the selection of such variants that increase viral fitness may explain the treatment failure seen in some patients.
        • Pegylated interferon-α (IFNα) – has been used to good effect in a small number of chronically infected liver transplant recipients,, and one hemodialysis patient. In general IFNα is not recommended in patients who have received transplants however, because the risk of acute rejection is increased. In other immunocompromised patients, this is not an issue. A handful of case reports and small case series have described effective treatment with IFNα, ribavirin and a combination of the two in patients with hematological malignancies being treated with chemotherapy and HIV-positive patients.,,
        • Sofosbuvir – Although developed as a treatment for hepatitis C, it has been reported that sofosbuvir has some activity against HEV RNA replication in vitro and has an additive antiviral effect with ribavirin[rx]. However, when a hepatitis C/HEV co-infected patient received a 12-week course of sofosbuvir and daclatasvir, they did not achieve virologic clearance of HEV[rx]. Therefore, it remains unknown if the observations made in vitro will translate into clinical efficacy in vivo.

        Effect of drugs on hepatitis E virus replication and their use and impact on immunosuppressant therapy during chronic hepatitis E virus infection in solid organ transplant patients

        ClassDrugEffect on HEV replicationClinical use
        Calcineurin inhibitorsCyclosporine, tacrolimusStimulates HEV replication with an increase in HEV load and promotes HEV persistenceReduce dose
        mTOR inhibitorsRapamycin, everolimusStimulates HEV replication with an increase in HEV loadReduce dose
        Antimetabolite immunosuppressantMycophenolate mofetilInhibits HEV replication and helps HEV clearanceContinue the drug
        Guanosine analogRibavirinInhibits HEV replication and causes HEV clearancePrimary drug for therapy
        CytokinesPegylated interferon αInhibits HEV replication and causes HEV clearanceIndicated if Ribavirin therapy fails
        Nucleotide analogSofosbuvirInhibits HEV replication in vitroUnclear, clinical trials indicated

        HEV: Hepatitis E virus.

        Prevention of Hepatitis E


        Prevention is the most effective approach against the disease. At the population level, the transmission of HEV and hepatitis E disease can be reduced by

        • Maintaining quality standards for public water supplies, and
        • Establishing proper disposal systems for human feces.
        • For people with hepatitis E, the exclusion period from childcare, preschool, and work is not clear but it is reasonable to recommend the same exclusion period as for hepatitis A: 7 days after the onset of jaundice or illness
        • Follow good personal hygiene practices, especially thorough hand washing
        • Always follow good food handling procedures.
        • In areas of the world where food and water are less safe than in Australia care is needed to minimize your chances of getting hepatitis E infection. In such areas, the following are recommended:
        • Do not eat raw fruit and raw vegetables unless you can peel them yourself
        • Cooked food that is served hot is usually safe
        • Only drink water that has been boiled or drink sealed bottled water
        • Do not use tap water to clean your teeth. Use water that has been boiled or use sealed bottled water
        • Do not eat ice or add ice to your drinks
        • Carbonated drinks from sealed containers are usually safe if no ice is added.
        • Maintaining hygienic practices;
        • Avoiding consumption of water and ice of unknown purity.

        In 2011, a recombinant subunit vaccine to prevent hepatitis E virus infection was registered in China. It has not yet been approved in other countries.

        Or

        At the population level, the risk of hepatitis E infection and transmission can be reduced by:

        • Maintaining quality standards for public water supplies.
        • Establishing proper disposal systems to eliminate sanitary waste.

        Maintain good personal hygiene

        • Perform hand hygiene frequently, wash hands thoroughly especially before handling food or eating, and after using the toilet or handling vomitus or fecal matter. Wash hands with liquid soap and water, and rub for at least 20 seconds. Then rinse with water and dry with a disposable paper towel or hand dryer. If hand washing facilities are not available, or when hands are not visibly soiled, hand hygiene with 70 to 80% alcohol-based hand rub is an effective alternative.
        • Wear gloves and a mask while disposing of or handling vomitus and feces, and wash hands thoroughly afterward.
        • Use serving chopsticks and spoons at mealtime. Do not share food and drinks with others.
        • Refrain from work or school, and seek medical advice when suffering from vomiting or diarrhea.
        • Exclude infected persons and asymptomatic carriers from handling food and from providing care to children, elderly and immunocompromised persons.

        Maintain good food hygiene

        • Adopt the 5 Keys to Food Safety in handling food, i.e. Choose (Choose safe raw materials); Clean (Keep hands and utensils clean); Separate (Separate raw and cooked food); Cook (Cook thoroughly); and Safe Temperature (Keep food at a safe temperature) to prevent foodborne diseases.
        • Drink only boiled water from the mains or bottled drinks from reliable sources.
        • Avoid drinks with ice of unknown origin.
        • Purchase fresh food from hygienic and reliable sources. Do not patronize illegal hawkers.
        • Clean and wash food thoroughly. Cook food, especially seafood (e.g. shellfish), pork and pig offal, thoroughly before consumption. Avoid raw food or undercooked food.
        • Store food properly or in the refrigerator, do not place food at ambient temperature for a long time.
        • Slice raw meat and offal into thin strips to allow thorough cooking, especially during hotpot or congee cooking.
        • For sliced pig liver, depending on thickness and quantity, boil at 100°C or stir-fry in hot skillet/wok for at least three to five minutes.
        • Heating to an internal temperature of 90°C for 90 seconds is required for the cooking of molluscan shellfish. If possible, remove the shells before cooking as they impede heat penetration. Otherwise, boil at 100°C until their shells open; boil for an additional three to five minutes afterward. Discard any shellfish that do not open during cooking.
        • For meat and offal, make sure that juices are clear, not red, blood is not visible when you cut the cooked meat and offal.
        • When having hotpot, use separate chopsticks and utensils for handling raw and cooked foods to prevent cross-contamination.
        • Eliminate sources of food and nesting places for rodents in the living environment. Store food in covered containers and handle pet food properly to avoid it becoming food for rodents;
        • Store all refuse and food remnants in dustbins with well-fitted cover. Dustbins must be emptied at least once a day;
        • Keep premises, especially refuse rooms and stairways clean. Avoid accumulation of articles;
        • Inspect all flowerbeds and pavements for rodent infestation regularly; and
        • Avoid high-risk activities below to reduce rodent contact:
          • Avoid rodent contact and places dirtied with rodent excreta;
          • Avoid handling rodents with bare hands;
          • Wash hands with liquid soap and water immediately after handling animals, and disinfect contaminated areas; and
          • If wound appears, clean broken skin immediately and cover it properly with waterproof adhesive dressings.


        References

        Hepatitis E


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