Introduction 

Hepatitis E is a disease caused by a virus of the same name hepatitis E virus (HEV) that causes inflammation of the liver. The virus has 4 genetic types. Types 1 and 2 have been found in humans, while types 3 and 4 are found in animals such as wild boars, pigs, and deer. This disease does not affect these animals but is still transmissible to humans. It is estimated that there are approximately 20 million HEV infections worldwide each year, which result in around 3.3 million symptomatic cases of Hepatitis E.¹

Importance of diagnosing hepatitis E

Although it is true that under normal conditions hepatitis E causes an infection that resolves in 2 to 6 weeks, one of the greatest risks is that it can lead to fulminant hepatitis, which can be life-threatening. The individuals at higher risk of contracting Hepatitis E include recent travellers or those from endemic countries, as well as patients with acute hepatitis who may face severe complications, such as those with pre-existing liver diseases, pregnant women, and individuals with weakened immune systems.²

Modes of transmission and risk factors

The virus is excreted in the faeces of infected individuals and enters the human body through the intestinal tract. The main route of transmission is contaminated drinking water. Although hepatitis E is spread worldwide, it is more common in East and South Asia.^{1, 3}

Clinical presentation of hepatitis E

Common symptoms 

Several common symptoms of hepatitis E can sometimes be indistinguishable from other liver diseases. These typically include:  ¹ 

• An initial phase lasting several days with decreased appetite, mild fever, nausea, and vomiting
• Jaundice, dark urine, and pale stools
• Abdominal pain, itching, rash, or joint pain
• A slightly enlarged and tender liver (hepatomegaly)

Variation in symptoms by patient group 

This condition especially affects pregnant women and immunocompromised individuals:

Risks of hepatitis E in pregnant women

Pregnant women with Hepatitis E, especially those in the second or third trimester, are at a higher risk of foetal loss and acute liver failure. In severe cases, this can even lead to mortality. Pregnant women in the third trimester with Hepatitis E have a 20–25% chance of not surviving.¹

Chronic hepatitis E in immunocompromised individuals

Chronic infection cases have been reported in immunocompromised individuals. Although this is not common, the likelihood of it occurring increases if organ transplant recipients are being treated with immunosuppressive medications and have an infection with HEV genotypes 3 or 4.¹

Initial clinical evaluation

Physical examination 

In the physical examination, the doctor will focus on four areas, they will examine the patient's eyes, as jaundice, one of the most common symptoms of Hepatitis E, can cause the sclera to turn yellow.^5,6

A physical examination will be conducted to detect any tenderness or pain in the right upper quadrant. This quadrant contains the liver, the primary organ affected by hepatitis. An enlarged liver (hepatomegaly) in cases of disease is visible in 10%-85% of patients. The edges may be palpable, especially in children and thin adults. Typically, an enlarged liver expands downward or toward the left iliac fossa (LIF), which is located in the lower left part of the abdomen.^{6, 7}

Finally, the doctor will look for signs of advanced chronic liver disease, such as:

• Spider angioma
• Splenomegaly
• Ascites
• Caput medusae
• Palmar erythema

Diagnostic tests for hepatitis E

Blood tests

Liver function tests

Liver function tests measure substances produced by the liver in the blood, such as enzymes, proteins, and byproducts. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are enzymes that can help detect liver damage. When the liver is stressed, it tends to release one or both of these enzymes. When they are released equally, it indicates a likelihood of liver infection.⁸

Bilirubin levels

Bilirubin levels in the blood are also measured. When these levels are below the usual average, it generally indicates that the liver is not properly eliminating bilirubin and that there could be liver damage.⁹

Serological tests

Detection of anti-HEV IgM

For the diagnosis of hepatitis E infection, one of the most common tests is the detection of specific immunoglobulin M (IgM) antibodies against HEV in the blood. Antibodies are proteins produced by the immune system to fight off infections, and their presence helps confirm an active or recent infection. This test is especially useful as part of the differential diagnosis of acute hepatitis. These antibodies begin to be detected around 3 to 4 days after the onset of jaundice and can persist for up to 225 days.^1,10,11

Detection of anti-HEV IgG 

Following the detection of anti-HEV IgM, anti-HEV IgG can typically be identified within 3 to 4 days and may persist in the body for at least 7 years. It is important to emphasise that a positive test cannot confirm whether the disease is currently present or has already resolved. Therefore, an IgG avidity test is often necessary. 

Immunoglobulin G (IgG) avidity is defined as the strength with which IgG binds to an antigen and how this strength changes as it gradually matures after primary infection. Early in the infection (within the previous 3 months), the binding strength is weak, which will be reflected in this serological test. When the infection has lasted more than 6 months, high avidity begins to be reflected.^10,12

Molecular tests

HEV RNA PCR testing (for detecting viral genetic material)

Polymerase chain reaction (PCR) tests are a reliable way to detect viral infections and make a diagnosis. These tests examine small amounts of genetic material from a pathogen. In the case of the HEV virus, the process is complicated because the clinical signs of this disease are identical to those of other types of acute hepatitis. Therefore, it is vital to first exclude the possibility of any other type of acute hepatitis. 

Once this is done, the diagnosis will depend either on the detection of anti-HEV antibodies or the detection of HEV nucleic acid. This test also helps identify which of the four types of HEV the patient has and the amount of virus present. The viral load is important as it allows professionals to monitor how the patient responds to treatment.^{13, 14}

Importance in immunocompromised patients or severe cases

Patients with reduced immunocompetence have a higher risk of developing a chronic HEV infection, especially of genotype 3. These cases are often due to prior ineffective viral clearance, which consequently increases the likelihood of the disease progressing to liver fibrosis or even liver cirrhosis. To prevent this, it is necessary to conduct a thorough diagnosis, followed by screening for HEV in immunocompromised patients who present with elevated liver transaminases. Transaminases are a type of enzyme whose levels increase in the blood when the liver is under stress.^15,16

Differential diagnosis

Exclusion of other causes of hepatitis 

One of the major challenges with hepatitis E is that, as previously mentioned, it is impossible to clinically distinguish it from other types of acute viral hepatitis. To differentiate it, a clinical history must be obtained to identify risk factors and symptoms, along with laboratory tests.

A highly relevant aspect of this disease is the epidemiological settings in which the patient has been or currently resides. This includes areas with a risk of water contamination. Laboratory tests are also crucial, especially the aforementioned serological tests and HEV RNA PCR testing, which is particularly important in areas where hepatitis E is uncommon and in rare cases of chronic HEV infection.^1,17

Role of diagnostic imaging if necessary

Although the diagnosis is primarily made based on clinical features and serological tests, imaging manifestations of viral hepatitis on ultrasound can help identify unexpected findings such as hepatomegaly, thickening of the gallbladder wall, fluid accumulation around the portal vein, or generalised hypoechogenicity. All these findings can contribute to future diagnoses and should not be dismissed.^18,19

The most commonly used imaging tests for liver diseases are Computed Tomography (CT) scans, FibroScan, and Magnetic Resonance Imaging (MRI).

Summary

Hepatitis E is a disease caused by the HEV virus, which affects the liver. Although it typically resolves within 2 to 6 weeks, it can lead to severe complications, especially in people with preexisting liver conditions, pregnant women, and immunocompromised individuals. It is mainly transmitted through contaminated water and is more prevalent in Asia.

The most common symptoms include fever, loss of appetite, nausea, jaundice, dark urine, and pale stools. In pregnant women, especially during the third trimester, the mortality rate can reach up to 25%. Immunocompromised individuals are at higher risk of developing chronic infections.

Diagnosis includes blood tests to measure liver enzymes (ALT and AST) and bilirubin levels, serological tests to detect IgM antibodies (acute infection) and IgG antibodies (past or chronic infection), and PCR tests.

To make a differential diagnosis from other types of hepatitis, it's essential to consider whether the patient has been in an endemic area, their medical history, and lab results.