Approach

The majority of patients with acute HEV infection are asymptomatic. In patients who develop an acute hepatitis (possibly less than 5% of all cases of HEV infection), the history should look for risk factors for potential exposure to HEV - most commonly, living in or recent travel to endemic areas such as Africa or Asia (transmission via the fecal-oral route due to genotype 1 or 2 infection), or via consumption of raw or undercooked pork, wild boar, or deer (foodborne/zoonotic transmission due to genotype 3 or 4), particularly in Europe.[1][2]​ Many patients in developed countries will not have a readily identifiable risk factor so, in these regions, any patient with an otherwise unexplained acute hepatitis could have HEV infection.[2]

If symptoms do occur with acute HEV infection, they are usually nonspecific and may be indistinguishable from other types of acute hepatitis.

  • Symptomatic infection is most common in those ages 44 years and younger in developing countries, where infection is usually acquired via the feco-oral route.[1]

  • In developed countries, symptomatic illness is most commonly seen in older men, which may indicate the presence of underlying liver disease.[11]

  • Progression to acute liver failure is rare, and is more of a concern in patients with existing chronic liver disease or patients who are pregnant; it is therefore important to have a high index of suspicion for HEV infection in pregnant patients who present with an acute hepatitis in endemic areas.[2]

  • HEV infection acquired via the feco-oral route is associated with high morbidity and mortality in pregnant patients.[1][2][17]

Extrahepatic manifestations of HEV infection can occur after acute infection and with chronic disease. Most significantly, there are a myriad of neurologic syndromes associated with HEV; an acute hepatitis with neurologic symptoms should raise suspicion for HEV infection.

All patients who present with signs and symptoms of acute hepatitis or acute liver failure, immunosuppressed patients, and patients with underlying liver disease with unexplained elevation of liver function tests should be tested for HEV infection.[2] The incubation period after exposure for HEV is 2-8 weeks; HEV RNA can be detected in stool about 3 weeks after infection and can last for approximately 6 weeks.[46][47]​​​ Biochemical and serologic markers start to increase just prior to symptom onset.[2]

Progression to chronic liver disease is most commonly associated with patients who are immunosuppressed, such as recipients of solid organ transplants, and has been defined as persistence of HEV replication for 3 or more months.[2][4][5]​​​​​​ Chronic infection has only been associated with infection with HEV genotypes 3 and 4.[4][48]​​​​ Solid organ transplant recipients infected with HEV have a greater than 50% risk of developing chronic HEV infection, which can progress to cirrhosis within several years.​[38][49]​​​ Chronic infection has less commonly been associated with other immunosuppressed groups, such as people with primary immunodeficiency, those with HIV who have low CD4 T lymphocyte counts, and those undergoing chemotherapy (especially due to hematologic malignancies).[2][38]

Any cause of acute hepatocellular injury is a differential for acute or chronic HEV infection. For chronic HEV infection, the differential diagnosis includes diseases seen in immunosuppressed patients, such as other viral causes of hepatitis. Several severe diseases seen in pregnancy are also differentials of acute HEV infection in pregnant individuals. See Differentials.

History

Acute HEV infection

If symptoms do occur with acute HEV infection they are usually nonspecific, and may include:

  • Malaise[2]

  • Fatigue[2]

  • Anorexia[2]

  • Nausea[2]

  • Vomiting[2]

  • Abdominal pain[2]

  • Pruritus[2]

  • Arthralgia/arthritis[2]

  • Diarrhea.

Enquire about potential exposure to HEV in patients who present with acute hepatitis, such as travel to or from endemic areas, or consumption of swine or deer, particularly in Europe.[1] Take a detailed history regarding travel, sources of drinking water, consumption of uncooked or undercooked food, and recent contact with any jaundiced people.[1]

  • Infection with HEV genotypes 1 and 2 is typically acquired by drinking fecally contaminated water in endemic areas, demonstrated by epidemic peaks during the rainy season.[1][7]

  • HEV genotypes 3 and 4 are acquired by ingestion of contaminated food or close association with the animal reservoir, such as by farm workers or veterinarians.[19][29]

  • Although much less common, HEV infection can occur after transfusion of blood products or following organ transplantation.[22][30][31][32]​​[33]​​ These risks are not applicable universally: for example, in the UK, blood donations are screened for HEV before transfusion.

  • Vertical transmission can occur, but this is a less common mode of transmission.[34]

  • People living in crowded camps or temporary housing, such as refugees or people who are internally displaced, or those living in military camps, are at greater risk of contracting HEV infection.[1][40]

Ask about previous medical history as well as symptoms of extrahepatic manifestations of HEV, which can occur after acute infection and with chronic disease. As there are myriad neurologic syndromes associated with HEV infection, an acute hepatitis with neurologic symptoms should raise suspicion for the condition. Conditions that have been observed in the context of hepatitis E are numerous, and include:[2][9]

  • Neurologic

    • Guillain-Barré syndrome

    • Neuralgic amyotrophy

    • Meningitis

    • Cranial nerve palsies

  • Renal

    • Glomerulonephritis

  • Hematologic

    • Cryoglobulinemia

    • Thrombocytopenia

    • Hemolysis

    • Aplastic anemia

  • Other

    • Acute pancreatitis

    • Thyroiditis

    • Myocarditis.

Acute liver failure/acute-on-chronic liver failure

Although the definition of acute liver failure varies globally, the most commonly used definition in the US and Europe is: an illness duration of <26 weeks in a patient with no evidence of prior liver disease or cirrhosis with any degree of mental status alteration (encephalopathy) and coagulopathy (international normalized ratio [INR] ≥1.5).[50]

Acute liver failure is a rare sequela of acute HEV infection and is more of a concern in patients with existing chronic liver disease (when symptoms occur in a patient with preexisting liver disease, the term "acute-on-chronic liver failure" is used).[2][11]​ However, it is important to note that acute HEV infection in pregnancy in endemic areas can lead to acute liver failure in upwards of 20% of women.[10]

Patients who progress to acute, or acute-on-chronic, liver failure may present with symptoms including:[51][52][53]​​​​​

  • Abdominal pain

  • Nausea

  • Vomiting

  • Malaise

  • Confusion, changes in personality, or somnolence (due to hepatic encephalopathy).

See Acute liver failure.

Chronic HEV infection

Clinical presentation of chronic HEV infection has largely been found in patients with solid organ transplantation, but has also been associated with other immunosuppressed groups, such as individuals with HIV, patients with primary immunodeficiencies, and patients undergoing chemotherapy.[2][13]​ Chronic HEV infection is frequently asymptomatic in people who are immunosuppressed, and is typically identified during investigation following abnormal biochemical liver function tests.

Solid organ transplant recipients infected with HEV have between a 50% and 70% risk of developing chronic HEV infection, which can progress to cirrhosis within several years.[2][38][49][54]​​​​​ Note that in some countries, including the UK and Ireland, and some parts of Europe, blood samples from solid organ donors are screened for HEV infection; this is performed post transplant to help inform clinical management decisions in recipients. Chronic HEV infection that is untreated or fails treatment can cause liver fibrosis and progress to cirrhosis. See Complications.

Physical exam

Acute HEV infection

In patients with acute HEV infection, exam may reveal jaundice, scleral icterus, and, in some patients, right upper quadrant tenderness. Also be alert for signs of neurologic syndromes associated with acute HEV (see above).

[Figure caption and citation for the preceding image starts]: Patient with jaundiceGarry Watson/Science Photo Library [Citation ends].com.bmj.content.model.Caption@140cbfe

Chronic HEV infection

The physical exam in most patients with chronic HEV will be normal. Note that patients with chronic disease may progress to cirrhosis of the liver, and may develop stigmata of chronic liver disease. See Complications.

Acute liver failure/acute-on-chronic liver failure

Patients who present with acute liver failure/acute-on-chronic liver failure may have similar signs to those presenting with acute hepatitis infection; patients with acute liver failure may also have features of hepatic encephalopathy evident on exam. Hepatic encephalopathy encompasses a spectrum of neurologic and psychiatric changes; initial signs and symptoms may be subtle.[55] Signs that may be present on exam due to encephalopathy include:[55]

  • Asterixis

  • Hypertonia

  • Hyperreflexia

  • Clonus

  • Rigidity.

Patients with acute hepatic failure may also have hepatomegaly, as well as right upper quadrant tenderness. Less commonly patients may present with features of coagulopathy. See Acute liver failure.

Initial investigations

Test the patient for hepatitis E infection if they:[1][2]

  • Present with an acute hepatitis and have traveled from an area in which there is a hepatitis E outbreak or where hepatitis E is endemic

  • Have unexplained symptoms of liver injury, regardless of travel history, and test negative for serologic markers of hepatitis A, hepatitis B, hepatitis C, other hepatotropic viruses, and all other causes of acute liver injury; see Hepatitis A, Hepatitis B, Hepatitis C

  • Present with suspected drug-induced liver injury

  • Are immunosuppressed and have unexplained abnormal liver function tests

  • Have unexplained flares of chronic liver disease

  • Present with neuralgic amyotrophy or Guillain-Barré syndrome

  • Have abnormal liver function tests after receiving blood products (note this does not apply to those who have received blood transfusions in countries where there is routine nucleic acid testing of blood donations for HEV: for example, in the UK).

Also consider testing for HEV infection in patients with:[2]

  • Encephalitis

  • Myelitis.

Tests for HEV

Use a combination of nucleic acid amplification techniques (NAATs) and serologic testing to confirm HEV infection.[1][2][56]​​​

HEV antibody (anti-HEV) and HEV RNA polymerase chain reaction (PCR) tests are the basic tests for diagnosis of HEV infection and subsequent monitoring. However, availability of these tests may be limited in some regions - follow your local protocol. In the US, for example, these tests can be ordered from the Centers for Disease Control and Prevention. CDC: hepatitis E information - laboratory testing requests Opens in new window​ Rapid tests for HEV infection detection are also available.[15]

Always request anti-HEV immunoglobulin M (IgM) screening in immunocompetent patients with suspected HEV.[2][15][56]

  • Definitive diagnosis of HEV infection in endemic areas is usually based on serum anti-HEV IgM antibody detection in immunocompetent patients.[15][56] Anti-HEV IgM is usually detectable from 1 week to 2 months after exposure to the virus and typically persists for 3-4 months.[2][56]

  • Some organizations, such as the European Association for the Study of the Liver (EASL), also recommend anti-HEV IgG screening alongside anti-HEV IgM.[2] Bear in mind, however, that anti-HEV IgG positivity may reflect past infection. Anti-HEV IgG is detectable later in the clinical course than anti-HEV IgM; the titer increases throughout the illness, and can persist for many years.[2]

If the patient is immunosuppressed, use other tests, such as reverse transcriptase polymerase chain reaction (RT-PCR) for hepatitis E virus RNA detection in serum and stool (note these tests require specialized testing facilities).[2][15]​​[25][41][56]​​​​ Antibody detection is unreliable in transplant recipients and other people who are immunosuppressed, due to delayed or impaired humoral response (which may lead to false negative results).[2]​​[25][41][56][57]​​​ These approaches may also be helpful for diagnosis in areas where HEV infection is less common, and to detect chronic HEV infection.[15]

  • HEV RNA present in serum or stool indicates HEV infection and is often the only positive test in immunosuppressed patients with chronic HEV infection.[56]

  • HEV RNA is detectable around 3 weeks after onset of infection, and may persist for several weeks after infection has cleared.[2][17]

  • Chronic HEV infection is defined by the persistence of HEV RNA for 3 or more months.[2][4][5]

  • In practice, serum HEV RNA testing is often used in preference to stool analysis due to availability and ease of testing; however, stool testing may be useful following treatment of chronic infection as a negative stool HEV RNA is helpful to confirm treatment success.

Characterization of liver status

Perform the following laboratory tests in all patients to characterize liver disease status:

  • Complete blood count

  • Basic metabolic panel

  • Coagulation profile

  • Liver biochemistry, including:

    • Aspartate aminotransferase (AST)

    • Alanine aminotransferase (ALT)

    • Alkaline phosphatase

    • Total bilirubin (direct and indirect)

    • Albumin.

Consider abdominal ultrasound as a first imaging test in patients who may have underlying liver disease, are immunocompromised, or have chronic infection to evaluate the liver for the presence of fibrosis, cirrhosis, and portal hypertension, and to exclude hepatocellular carcinoma.

Other investigations

Triphasic contrast computed tomography or contrast magnetic resonance imaging may be considered, particularly in patients with advanced fibrosis or cirrhosis. Noninvasive methods of assessing liver fibrosis (e.g., transient elastography using magnetic resonance or Fibroscan, fibrosis biomarkers) or liver biopsy can be obtained in situations where there is a diagnostic dilemma, but should not be routinely required.

​Consider specialist nephrology review for further renal investigation if the patient has recent deterioration of renal function or significant proteinuria.[2] Renal manifestations of HEV infection include prerenal failure, glomerular disorders, and tubular and interstitial injury.[58]

Consider referral to a neurologist for further investigations if the patient presents with neurologic manifestations related to HEV infection.

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