Hepatitis E virus (HEV) is a viral infection primarily affecting the liver. It is transmitted through the fecal-oral route, usually from contaminated water or food. It is the fifth known form of viral hepatitis. Here is an overview of the epidemiology of the Hepatitis E virus: 

• Hepatitis E is endemic in many parts of the world, predominantly in low- and middle-income countries with inadequate sanitation systems. It is mainly found in Asia, Africa, the Middle East, and Central America. However, sporadic cases and outbreaks have also been reported in developed countries, including Europe and North America. 
• The primary transmission mode of Hepatitis E is ingesting fecally contaminated water or food. It can occur due to inadequate sanitation, undercooked or raw pork or game meat consumption, or contact with infected animals. Also, it can be transmitted via blood transfusions, although this is rare. 

Specific populations are at a high risk of contracting Hepatitis E, including: 

Individuals living in sectors with poor sanitation and limited access to clean water. 

• Travelers to regions where Hepatitis E is endemic. 
• People with weakened immune systems, like those with AIDS or undergoing organ transplantation. 
• Pregnant women, particularly in the third trimester, are at a greater risk of severe complications. 

Seasonality: Hepatitis E infections often exhibit a seasonal pattern in endemic regions. In many areas, the incidence is highest during the rainy seasons, as heavy rainfall can lead to water contamination and facilitate the spread of the virus. 

Kingdom: Viruses   

Phylum: Pisuviricota  

Class: Pisoniviricetes  

Order: Nidovirales  

Family: Hepeviridae  

Genus: Orthohepevirus  

Species: Hepatitis E virus  

Structure: 

• Virion: The HEV virion is spherical with a diameter of approximately 27 to 34 nm. It is synthesized of a single-stranded, positive-sense RNA genome enclosed within a protein shell called the capsid.
• Capsid: The capsid is the outermost layer of the virus and appears in icosahedral symmetry. It consists of 60 subunits arranged in a T=3 symmetry, forming a structure that resembles a soccer ball. The capsid proteins protect the viral RNA and play a role in viral attachment, entry, and immune recognition.
• Genome: The HEV genome is a positive-sense, single-stranded RNA molecule. It’s about 7.2 kb long and has three open reading frames (ORFs). These ORFs encode the viral proteins necessary for replication, and the assembly necessary that enables replica is encoded by these ORFs.
• ORF1: The largest ORF, or ORF1, encodes a polyprotein cleaved into non-structural proteins involved in viral replication and RNA synthesis. 
• ORF2: The second ORF encodes the viral capsid protein. It is responsible for forming the virus’s outer shell and plays a crucial role in viral entry and immune recognition. 
• ORF3: The third ORF encodes a small multifunctional protein called ORF3. It is involved in viral release, assembly, and modulation of host immune responses.
• Envelope: Unlike some other hepatitis viruses, HEV does not possess a lipid envelope. The capsid directly surrounds the viral RNA without an additional lipid bilayer. 

 (HEV) has been classified into four antigenic types.  

• Genotype 1 (HEV-1): This genotype is primarily associated with large outbreaks and epidemics of Hepatitis E in Asia and Africa. Subtypes of genotype 1 include 1a and 1b.   

• Genotype 2 (HEV-2): Genotype 2 is also predominantly found in developing countries, primarily in Africa and Mexico. It has been associated with sporadic cases and outbreaks, usually in areas with poor sanitation. Subtypes of genotype 2 include 2a and 2b.   

• Genotype 3 (HEV-3): Genotype 3 is the most prevalent genotype globally and has a wide distribution. It is reported in developing and developed countries and can infect humans and animals like pigs, wild boars, deer, and rabbits. Subtypes of genotype 3 include 3a to 3i.   

• Genotype 4 (HEV-4): Genotype 4 is primarily found in Asia, including China, Vietnam, and Japan. Like genotype 3, it can infect humans and various animal species, with pigs being an important reservoir. Subtypes of genotype 4 include 4a to 4g. 

• Entry and Replication: HEV enters the body through the oral route, primarily via ingesting contaminated food or water. The virus targets and infects hepatocytes, which are liver cells. The exact mechanism of viral entry into hepatocytes is not fully understood but likely involves receptor-mediated endocytosis.
• Viral Replication: Once inside hepatocytes, HEV releases its RNA genome, serving as a viral replication template. The viral RNA is translated into complex proteins, including non-structural proteins involved in viral RNA replication and synthesis.
• Immune Response: The immune system recognizes the presence of HEV and mounts an immune response to eliminate the virus. Both adaptive and innate immune responses are activated, involving various immune cells, such as macrophages, natural killer cells, and T lymphocytes.
• Liver Inflammation: The immune response triggers an inflammatory reaction in the liver, characterized by the infiltration of immune cells and the liberation of pro-inflammatory cytokines. This inflammation contributes to the liver damage observed in Hepatitis E.
• Hepatocyte Injury: The immune response and the direct cytopathic effect of the virus lead to injury and destruction of hepatocytes. This hepatocyte injury results in liver dysfunction, including impaired synthesis of proteins, bile flow disruption, and accumulation of toxins. 

Innate Immune Response: 

• RLRs (RIG-I-like receptors): RLRs are cytoplasmic pattern-recognizing receptors that recognize viral RNA in infected cells’ cytoplasm. MDA5 (melanoma differentiation-associated protein 5), RIG-I (retinoic acid-inducible gene I), and LGP2 (Laboratory of Genetics and Physiology 2) are the three primary RLRs. These receptors recognize various viral RNA structures and stimulate innate immune responses targeting HEV, including HEV. 
• TLRs (Toll-like receptors) are transmembrane receptors that lie on the exteriors of immune cells such as dendritic and macrophage cells. TLRs recognize pathogen-associated molecular patterns (PAMPs), molecular patterns of HEV. TLRs are essential in triggering innate immune responses from recognizing PAMPs and regulating downstream signaling pathways. 
• PRRs initiate signaling cascades that culminate in NF-B activation. When PRRs are activated, a sequence of intracellular signaling events occurs, culminating in activating the IB kinase (IKK) complex. The protein IKK complex phosphorylates the NF-B inhibitor (IB), causing its ubiquitination and destruction. Degradation of IB allows NF-B dimers, which generally consist of p50 subunits and p65 (RelA), to translocate into the nucleus. 

Adaptive Immune Response: 

• T Cells: The potential epitopes can be triggered in mononuclear cells from peripheral blood (PBMCs) or distinct T-cell subsets from persons affected with HEV or immunized against HEV.
• Antibodies: B cells produce virus-specific antibodies that neutralize HEV and prevent its spread. Antibodies are crucial in clearing the virus from the bloodstream and preventing reinfection. 

Role of Gut Mucosal Immunity: HEV is primarily transmitted through the oral route, and gut mucosal immune responses are critical in preventing HEV entry and replication in the intestinal tract. These responses include the production of secretory IgA antibodies, as well as the presence of specific immune cells in the gut. 

Clinical manifestations of Hepatitis E virus (HEV) infection can vary from mild, self-limiting illness to severe forms of hepatitis. Most HEV infections are asymptomatic or cause only mild symptoms, especially in healthy individuals. However, specific populations, such as pregnant women and those with pre-existing liver disease, are at higher risk of developing severe manifestations. 

Here are the main clinical manifestations of Hepatitis E:  

Acute Hepatitis: The majority of HEV infections result in acute hepatitis. Symptoms usually occur after an incubation period of 2 to 6 weeks and can last several weeks. Common symptoms include: 

• Fatigue and Loss of appetite 
• Nausea and vomiting 
• Abdominal pain or discomfort 
• Jaundice 
• Dark urine and Pale stools 
• Joint and Muscle pain 

Fulminant Hepatitis: In rare cases, particularly in individuals with pre-existing liver disease or pregnant women, Hepatitis E can progress to fulminant hepatitis. It is a severe and life-threatening condition characterized by rapid liver failure.

Symptoms may include: 

• Severe jaundice
• Coagulopathy (bleeding or clotting disorders) 
• Hepatic encephalopathy (confusion, altered consciousness) 
• Ascites (fluid accumulation in the abdomen) 
• Kidney dysfunction 
• Multi-organ failure 

Chronic Hepatitis: Chronic HEV infection is rare but can occur in individuals with compromised immune systems, such as solid organ transplant recipients or those with underlying immunosuppressive conditions. Chronic hepatitis E may lead to persistent or relapsing hepatitis, with ongoing liver inflammation and potential progression to cirrhosis. 

It’s worth noting that Hepatitis E can also have extrahepatic manifestations, affecting organs outside the liver. These extrahepatic manifestations are uncommon and may include neurological symptoms (such as Guillain-Barré syndrome) or kidney-related problems (such as membranoproliferative glomerulonephritis). 

Serology: 

• Anti-HEV IgM: This test detects immunoglobulin M (IgM) antibodies specific to the Hepatitis E virus. The presence of IgM antibodies indicates recent or acute HEV infection. 
• Anti-HEV IgG: This test detects immunoglobulin G (IgG) antibodies specific to the Hepatitis E virus. IgG antibodies are produced later during infection and can persist long, indicating previous or ongoing HEV infection.
• Reverse Transcription Polymerase Chain Reaction (RT-PCR): It determines and amplifies the Hepatitis E virus’s genetic material (RNA). It is sensitive and specific for detecting acute HEV infection. The extracted RNA is subsequently reverse-transcribed, in which a reverse transcriptase enzyme creates a complementary DNA (cDNA) replica from the viral RNA template. This step transforms the RNA to a stabilized DNA form that PCR may amplify. TaqMan probes or SYBR Green are fluorescent dyes used in the PCR reaction. When these dyes bind to amplified DNA, they exhibit fluorescence, enabling continuous PCR activity
• Liver Function Tests: These tests measure various markers of liver health, including liver enzymes (such as alanine aminotransferase and aspartate aminotransferase) and bilirubin levels. Elevated liver enzymes and abnormal bilirubin levels indicate liver inflammation and dysfunction. 

• Particular attention should be given to high-risk populations, such as pregnant women, individuals with compromised immune systems, and those living in poor sanitation, to ensure appropriate preventive measures and access to healthcare.
• Ensuring access to safe drinking water: Promoting clean, potable water for drinking and cooking can help reduce HEV transmission through contaminated water sources.
• Encouraging proper sanitation practices, including adequate waste disposal and safe sewage systems, can minimize HEV contamination of the environment.
• Food Safety: Promoting good food hygiene practices, such as thoroughly cooking meat (especially pork), proper handwashing before food handling, and avoiding cross-contamination of raw and cooked foods, can help prevent HEV transmission through contaminated food.
• Screening donated blood and organ/tissue donations for HEV can help prevent transmission through transfusions or transplantation. 

• Hepatitis E – StatPearls – NCBI Bookshelf (nih.gov) 
• Frontiers | Host Innate Immunity Against Hepatitis Viruses and Viral Immune Evasion (frontiersin.org)