Hepatitis E virus (HepE) is the most common form of acute viral hepatitis worldwide, being more common in low- and middle-income countries. The transmission of HepE happens when contaminated water is consumed, known as the faecal-oral route of entry. Once a person is infected, HepE affects the liver and can lead to hepatitis, which is the inflammation of the liver resulting in symptoms such as weight loss, fatigue and fever-like states, but can result in death if left untreated.¹ The World Health Organisation (WHO) estimates 20 million cases of infection worldwide, with 3.3 million being symptomatic. 

Fortunately, in most cases, the virus is ‘self-limiting’, meaning it resolves itself without requiring medical intervention. However, people who are pregnant and contract HepE, especially during the second and third trimesters, are at an increased risk of acute liver failure, loss of foetus (miscarriage), and increased mortality.² 

Understanding hepatitis E

Hepatitis E is known as an RNA virus, meaning, unlike human DNA, which has two strands (i.e., double-stranded), it only has one strand of genetic material to help it make more viruses. There are four genotypes (a.k.a. variants with slightly altered genetic makeup) of HepE:³

• Genotypes 1 and 2: These variants are ‘human viruses’ that only infect humans. These are endemic to regions in Asia, Africa, Central America, and the Middle East
• Genotypes 3 and 4: These are called zoonotic (a disease that is transmitted from animals to humans) and first infect animals such as pigs and deer. The virus is transmitted to humans through undercooked meat

How does the virus enter the body? 

Once the virus is ingested, it crosses the intestinal mucosa (a protective layer in the gut) and enters the blood. Once in the blood, the virus enters portal circulation. Portal circulation is a nutrient-rich flow of blood from the gut to the liver. Once the virus infiltrates the blood, it has a one-way ticket to the liver, where it goes on to infect liver cells (known as hepatocytes).⁴ 

It takes approximately. 28 to 40 days for it to start showing symptoms. This period is known as the incubation period when the virus ‘settles’ and makes more of itself. The reason symptoms are not showing during this time is that the immune system has not detected the virus and activated the inflammation needed to remove it.⁵ 

Viruses are sneaky. They have ways of evading the immune system (i.e., our body's security force). They do this by making proteins that help them evade immune detection. They do this by dampening their presence and detection by making proteins that mimic anti-inflammatory signals used by the body to control the immune system. 

HepE is only found in the liver and not found in other tissues (cells that have the same function, e.g., skin, brain, and kidneys). This is known as ‘tropism’: the ability of a virus to infect specific cells of the body. 

What does the virus do once it's in the liver? 

The virus can change the structure of the liver. The liver is a highly specialised organ and has important functions that allow the body to work at its best. These include:⁶

• Bile production: Bile is an alkaline fluid that helps to digest and absorb fats, vitamins and cholesterol
• Regulating blood clotting: Using vitamin K, the liver helps produce proteins that allow normal blood clotting
• Bilirubin metabolism: Bilirubin (pronounced bil.e.ru.bin) is a yellow-orange pigment formed when the liver breaks down the component of blood known as haemoglobin. Bilirubin is excreted in bile
• Vitamin storage: vitamins such as A, B12, D, E and K, as well as minerals such as copper and iron are stored in the liver 
• Detoxification: special types of immune cells in the liver called Kupffer cells are vital in breaking down toxins and invading bacteria/viruses/parasites 

When the virus invades and the immune system finally detects the invader, immune cells start to produce a very powerful immune-activating molecule called interferon-gamma (INF-𝛄). This molecule tells immune cells that a virus is in the body and it's time to get it out. This molecule also causes infected liver cells (hepatocytes) to be killed.¹

The death of hepatocytes impacts the function of the liver, which is highly specialised and changes to its structure cause severe consequences. When a person experiences hepatitis, they would start to feel⁴:

• Nausea
• Vomiting and diarrhoea
• Jaundice: liver damage prevents the normal function of the liver involved in bilirubin clearance. This leads to yellowing of the white pigments of the eyes and skin since bilirubin will not be cleared and will build up
• Abdominal pain

Unfortunately, pregnant patients experience more severe forms of these symptoms. 

Hepatitis E in pregnant women

Pregnant people have the highest mortality rate among those who are infected with HepE, with approximately 25% of cases in the third trimester being associated with fatality due to acute liver failure.³ 

HepE can be transmitted from an infected mother to the infant whilst pregnant, which can lead to increased risk of perinatal mortality and foetal loss. Whether or not HepE can be transmitted by breast milk is not fully known, but the virus has been isolated in the breast milk of mothers infected with the virus.² 

Mechanisms behind the increased risk in pregnancy

The virus itself is not ‘cytotoxic' and does not lead to death of human cells once it infects. But, as mentioned earlier, the immune system kills any cells that are infected. Research shows that once infected, it is the immune response to the virus that leads to liver damage. The mechanism remains unclear, but several immune cells and inflammatory pathways are thought to play a role:⁴

• T-helper 1 (Th1) and T helper 2 (Th2) immune cells: these specialised immune cells are involved in the detection (Th1) and attack (Th2) of invading viruses (and other pathogens)
• Natural killer cells: as the name suggests, these immune cells directly and indirectly kill cells that are infected to reduce the spread of the disease-causing agent
• Type 1 interferon signalling pathway: as mentioned earlier, this small molecule with a big role results in inflammation

During pregnancy, the immune system is changed to ensure the foetus is protected. A foetus is considered ‘foreign’ by the person's body since it is genetically different. Therefore, the body adapts to treat it as a transplanted organ, reducing the immune response to tolerate this. There are a number of ways it does this:

• Pregnancy-related increases in progesterone, oestrogen, and human gonadotropin hormone: the actions of these suppress other pro-inflammatory pathways under normal circumstances, drive the immune response leading to inflammation and immune-attack of material recognised as ‘foreign’
• The placenta (tissue surrounding the foetus, providing nutrients and blood supply) secretes molecules that act to further suppress the immune system

Though the research can be contradictory, it is thought that the immunosuppression during pregnancy, combined with the immune evading tactics of the virus, is thought to explain increased chances of contracting HepE.³ Also, the hormonal changes during pregnancy are thought to allow the virus to make more of itself easily. Combined, the hormonal changes and immunosuppression impact hepatocytes that are both overwhelmed by the virus and the hormones produced during pregnancy, leading to damage.⁷ 

Diagnosis and treatment

If suspected of infection, or due to increased chances, such as living in areas of high incidence, clinical testing can be undertaken. This involves laboratory analysis of blood for.⁸

• Bilirubin amount in the serum of the blood. When levels are higher than normal, this can be a sign of liver impairment
• Alanine aminotransferase: increased levels of this enzyme is an indication of liver damage
• HepE IgM presence in the blood. IgM is a type of antibody first used by the adaptive immune system (a branch of the immune system that orchestrates an attack on specific pathogens). When these levels are high, an infection is likely. Further analysis of this antibody can allow specific diagnoses of HepE

Testing will also be undertaken for other types of hepatitis: A, B and C

If, however, the patient is immunocompromised (e.g., due to HIV/AIDS), then there will be a lack of immune response. Therefore, the testing of antibodies is not a sufficient diagnostic tool by itself. The use of PCR (polymerase chain reaction; a lab technique that multiplies DNA to a detectable level using a sample) can be used alongside blood tests to detect the presence of viral genetic material. This can test whether or not viral genetic material is present in the patient after 6 months of initial infection.⁹ 

Unfortunately, there is no ideal treatment for HepE during pregnancy. Use of antivirals such as ribavirin is not suitable for pregnant patients since it can lead to the development of teratogenicity: defects in the developing feotus. The best cure remains prevention. 

Prevention strategies for pregnant women

Since the primary way the virus enters is through oral consumption, avoiding contaminated water and food sources (e.g., unclean water/tap water from endemic countries, and uncooked meats) will reduce the chances of HepE infection. Pregnant people should avoid travel to areas where the hepatitis E virus is endemic.⁴ 

Public education and an increase in health and safety standards (through the assistance of international aid and charities) can help reduce incidence. 

Global impact and epidemiology

The impact of HepE is large, with 20 million people each year being infected worldwide, with 3.4 million having symptomatic infections. Pregnant people living in low-income countries are thought to be more susceptible to serious HepE infection. There is a 100% ‘vertical transfer’ rate from mother to baby.^1,2 

FAQs

What is a virus? 

A virus is neither living nor dead, it is a very small ‘germ’ that needs a host to survive. It replicates (makes more of itself) in cells of its host before spreading to others. 

Why is hepatitis E common during pregnancy?

During pregnancy, the immune system changes to accommodate the baby, making a person more susceptible to infection. 

Does hepatitis A cause the same symptoms?

No. If contracted during pregnancy, the symptoms do not tend to be severe. 

Summary

Hepatitis E is a type of single-stranded DNA virus that causes large-scale epidemics worldwide. It is mostly contracted through drinking contaminated water. This virus only affects the liver, and due to the immune response against it, leads to liver damage known as hepatitis. Normally, the virus is self-limiting and people get better without the need of medical intervention. However, during pregnancy, the body's adaptation to the foetus can result in severe symptoms if HepE is contracted, leading to miscarriage. The best form of cure remains prevention through public education and increased health and safety standards.