Hepatitis E: Symptoms, Types, Causes and Treatment

Hepatitis E is an underrecognized yet widespread liver disease caused by the hepatitis E virus (HEV). While most commonly associated with outbreaks in developing countries, it is increasingly being identified globally, including in developed nations. Hepatitis E can present with a wide range of symptoms, lead to acute or chronic illness, and affect not only the liver but other organs as well. Understanding its symptoms, types, causes, and treatment options is crucial for both public awareness and clinical care.

Symptoms of Hepatitis E

Hepatitis E can manifest in many ways, ranging from being entirely asymptomatic to causing severe, life-threatening illness. The clinical picture varies depending on the individual's age, immune status, and even the specific HEV genotype involved.

Symptom	Description	Severity/Notes	Source(s)
Jaundice	Yellowing of skin and eyes	Common in acute cases	1 7 8 10 11
Fatigue	Persistent tiredness	Nonspecific, frequent	1 10
Abdominal pain	Discomfort in upper right abdomen	Sometimes present	1 10
Fever	Elevated body temperature	Occasional	1 10
Nausea/Vomiting	Digestive upset	May occur in acute infection	7 10
Asymptomatic	No noticeable symptoms	Especially in chronic/immune cases	1 11
Extrahepatic	Neurological, renal, blood, etc.	Various, sometimes severe	2 3 5 10

Table 1: Key Symptoms

Common Liver-Related Symptoms

Most people with hepatitis E experience a short-lived illness resembling other forms of viral hepatitis:

• Jaundice is the hallmark symptom and is often accompanied by dark urine and pale stools.
• Fatigue and general malaise are very common, sometimes lasting for weeks.
• Abdominal pain, particularly in the upper right quadrant, is frequently reported.
• Nausea, vomiting, and fever can also appear, though not always.

These symptoms usually develop after an incubation period of 2–8 weeks 7 10.

Asymptomatic and Chronic Presentations

A significant number of people, especially those with compromised immune systems (e.g., transplant recipients, HIV-positive individuals), may have chronic HEV infections with little or no symptoms. This makes diagnosis challenging and allows the disease to progress unnoticed, potentially resulting in cirrhosis or liver failure 1 11.

Extrahepatic Manifestations

Hepatitis E is increasingly recognized as a systemic disease. In addition to classic liver symptoms, it can affect other organs and systems:

• Neurological: Guillain-Barré syndrome, neuralgic amyotrophy, and meningoencephalitis have all been reported. Neurological complications are among the most frequent extrahepatic issues 2 3 5 10.
• Renal: Acute kidney injury or glomerulonephritis can occur.
• Hematological: Cases of thrombocytopenia and other blood abnormalities have been described.
• Other: Pancreatitis, autoimmune reactions, and even rare endocrine or dermatological symptoms are possible 2 3.

Severity and At-Risk Groups

• Pregnant Women: Infection, especially during the third trimester, can be particularly severe and carries a high risk of fulminant liver failure and mortality rates of up to 25% 8 14.
• Immunocompromised Patients: Greater risk of chronic infection, cirrhosis, and severe liver disease 1 11.

Types of Hepatitis E

Understanding the different types of hepatitis E is essential, as the disease course, epidemiology, and risk factors vary by type and genotype.

Type/Genotype	Main Features	Host(s) Infected	Source(s)
Genotype 1	Epidemic, acute	Humans only	4 6 7 8 11 12
Genotype 2	Epidemic, acute	Humans only	4 6 7 8 11
Genotype 3	Zoonotic, chronic risk	Humans & animals	4 6 7 8 11 13 14
Genotype 4	Zoonotic, chronic risk	Humans & animals	4 6 7 8 11 13
Rare Types	Less common, emerging	Various (e.g., rabbits)	4 6 13

Table 2: Hepatitis E Types/Genotypes

Genotype 1 and 2

• Geographic Focus: These genotypes are primarily found in developing countries.
• Transmission: Almost exclusively human-to-human, typically through contaminated water.
• Clinical Course: Cause large outbreaks of acute hepatitis, especially during monsoon seasons or after natural disasters when sanitation is compromised.
• Severity: Can be severe in pregnant women and those with preexisting liver disease 7 8 13.

Genotype 3 and 4

• Geographic Focus: Found in both developing and developed countries.
• Transmission: Zoonotic—transmitted from animals (especially pigs, wild boar, and deer) to humans, commonly through consumption of undercooked meat or liver products. Can also be transmitted via blood products 13.
• Clinical Course: Often causes sporadic cases rather than outbreaks. Notably, these genotypes can result in chronic hepatitis in immunosuppressed individuals, leading to progressive liver disease 1 11 14.

Rare and Emerging Genotypes

Other, less common genotypes (such as those found in rabbits or camels) are being studied, but their significance for human disease is still being established 4 6 13.

Subtypes and Classification

HEV is a genetically diverse virus with many subtypes, but for clinical purposes, the four main genotypes above are most relevant. Standardized reference sequences have been established to aid research and diagnostics 4 6.

Causes of Hepatitis E

Hepatitis E is primarily caused by infection with HEV, but the route and context of transmission differ across regions and populations.

Cause/Route	Description	Risk Factors/Notes	Source(s)
Fecal-oral route	Contaminated water/food	Main route in endemic areas	5 7 8 10 11
Zoonotic	Undercooked meat (pork, game)	Genotypes 3 & 4, developed areas	5 7 8 13 14
Blood transfusion	Contaminated blood products	Immunosuppressed at higher risk	10 11 13
Maternal-fetal	Perinatal transmission	Rare, but observed	8 10
Parenteral	Needles, medical procedures	Less common	8 10

Table 3: Causes and Transmission Routes of Hepatitis E

Fecal-Oral Transmission

• Contaminated Water: The most common mode of spread in developing countries. Outbreaks often follow flooding or infrastructure failure, leading to mixing of sewage and drinking water 7 8 10.
• Food-Borne: Less common, but possible if food is handled with contaminated water or hands.

Zoonotic Transmission

• Undercooked Animal Products: Particularly pork, wild boar, or deer meat, as well as sausages or liver products, are major sources in developed countries 5 7 13.
• Animal Reservoirs: Pigs, wild boar, and deer are the primary reservoirs for genotypes 3 and 4. Other animals like rabbits and camels may also harbor HEV 13.

Blood and Blood Products

• Transfusion Transmission: Documented cases have shown HEV can be transmitted via blood transfusions, especially in immunocompromised recipients. Screening of blood products for HEV is under consideration in several countries 10 11 13.

Maternal-Fetal and Parenteral Routes

• Vertical Transmission: From mother to fetus during pregnancy, though rare, can lead to severe outcomes for both 8 10.
• Medical Procedures: Transmission via contaminated needles or medical equipment has been reported but is not the main route 8 10.

Risk Factors

• Poor Sanitation: Living in or traveling to areas with poor water treatment.
• Dietary Habits: Eating undercooked pork or game meat.
• Immunosuppression: Higher susceptibility to chronic infection and severe disease.
• Pregnancy: Especially in the third trimester, increases risk of severe complications 8 10 14.

Treatment of Hepatitis E

The management of hepatitis E varies depending on whether the infection is acute or chronic, the patient’s immune status, and the presence of complications.

Treatment	Indication	Efficacy/Notes	Source(s)
Supportive care	Acute, self-limiting	Most cases resolve without treatment	7 10 11 14
Ribavirin	Chronic, severe cases	Main antiviral, effective in most	1 5 11 15 17 18
Pegylated interferon	Chronic (non-transplant)	Alternative, caution in transplants	1 11 18
Sofosbuvir	Add-on in chronic	Experimental, additive with ribavirin	16
Silvestrol	Experimental, chronic	Inhibits replication in vitro	15
Immunosuppression reduction	Chronic, transplant pts	May promote viral clearance	1 11 18
Vaccination	Prevention (China)	Licensed in China, not globally	8 11 13

Table 4: Current Treatment Options

Supportive Care for Acute Hepatitis E

• Most Cases: Acute hepatitis E in healthy individuals is self-limiting and requires only rest, hydration, and monitoring 7 10 14.
• Severe Acute Cases: In rare, severe cases (such as fulminant hepatitis), ribavirin may be considered, though this is still under investigation 17.

Antiviral Therapy for Chronic Hepatitis E

• Ribavirin: The mainstay of therapy for chronic HEV infection, especially in immunocompromised patients (e.g., organ transplant recipients, HIV-positive individuals). Ribavirin is generally effective and well-tolerated, though anemia is a common side effect 1 5 11 15 18.
• Pegylated Interferon: Sometimes used, particularly in non-transplant patients, but carries a risk of transplant rejection and is less favored in these cases 1 11 18.
• Sofosbuvir and Silvestrol: Experimental agents. Sofosbuvir (an antiviral used in hepatitis C) shows additive effects with ribavirin in vitro and may be considered in difficult-to-treat cases 15 16. Silvestrol is also a promising compound in early studies 15.

Immunosuppression Management

• Immunosuppression Reduction: In transplant recipients, reducing immunosuppression can allow the immune system to clear the virus in some cases 1 11 18.

Prevention and Vaccination

• Vaccination: The HEV 239 vaccine (Hecolin®) is licensed and available in China, with high efficacy. No vaccine is available elsewhere yet, but it represents a major step forward in prevention 8 11 13.
• Preventive Measures: Include ensuring safe drinking water, practicing good hygiene, and thoroughly cooking pork and game meats.

Special Considerations

• Pregnant Women: There is no specific antiviral therapy proven safe in pregnancy; supportive care and close monitoring are critical 8 14.
• Relapse and Resistance: Some HEV variants may be resistant to ribavirin, and relapses can occur, particularly in those unable to reduce immunosuppression 12 18.

Conclusion

Hepatitis E is a complex, global disease with diverse presentations and significant public health implications. Early recognition, understanding of transmission routes, and appropriate treatment are key to managing and preventing its impact.

Key Takeaways:

• Symptoms range from no symptoms to severe liver and extrahepatic disease; jaundice and fatigue are common, but neurological and kidney issues can also occur.
• Types/Genotypes: Four main genotypes affect humans, with types 1 and 2 causing epidemics in developing regions and types 3 and 4 causing sporadic, often zoonotic, cases and chronic disease in developed countries.
• Causes: Infection occurs mainly via contaminated water in endemic areas and undercooked pork or game meat in developed regions; blood transfusion and maternal-fetal transmission are less common.
• Treatment: Most acute cases resolve without intervention, but chronic or severe disease requires antiviral therapy, primarily with ribavirin. Vaccination is available in China.

Staying informed about hepatitis E contributes to better prevention, early detection, and improved outcomes for those affected.