HEPATITIS VIRUSES

Introduction Viral hepatitis is a global health problem, the current scale of which is second only to that posed by HIV. This problem is associated particularly with chronic infections by hepatitis B and C viruses, which give rise to a huge problem of late onset liver disease. Hepatitis, meaning inflammation of the liver, is a major cause of morbidity in human populations. Although there are non-viral causes of hepatitis, viral infections represent the major cause of this disease. As with infections of other organs, there is a number of unrelated viruses that can infect the liver to cause hepatitis.

Introduction There are hepatitis viruses A, B, C, D and E, each of which is classified in a different virus family. Importantly, these can be divided into two groups, based on whether or not they can cause chronic infections. Those viruses that can do this routinely (hepatitis B and C viruses) are particularly associated with chronic or late-stage liver disease and with the emergence of liver cancer.

Major hepatitis viruses Genome Hepeviridae

The signs and symptoms of hepatitis Nutrient-enriched blood flows from the intestine to the liver via the portal vein where that nutrient is assimilated. Absorption of fats within the gut by synthesizing bile, which is then stored in the gall bladder and released into the gut via the bile duct. The liver is one of the main sites of glycogen storage and so is critical in energy homeostasis, maintaining blood glucose levels within a narrow range by taking up or releasing glucose in response to hormonal signals.

Functions of the Liver It is also a major site of biosynthesis for blood proteins, including albumin and clotting factors. The liver is a major site of blood detoxification. Aged RBCs cells are being continually destroyed in the spleen and this leads to the release of haem breakdown products, bilirubin and biliverdin, into the blood. The liver removes these, ultimately delivering them into the gut via the bile for excretion. The liver also removes other toxins, such as alcohol, that may be ingested.

Functions of the Liver During hepatitis, caused by virus infection or otherwise, some hepatocytes are lost. For all of the hepatitis viruses, pathology is immunemediated rather than through direct cytopathogenesis caused by virus replication. As a result, there is a diminution in all liver functions that is broadly speaking proportional to the scale of that loss. For as long as the infection or other inflammatory source persists, hepatocyte loss will continue, counterbalanced by liver regeneration. Once the source is eliminated, then both tissue and function will be restored.

The signs and symptoms of hepatitis Following virus infection, the appearance or not of any overt signs and symptoms of the infection will depend on the extent of the damage. Often, symptoms will extend only to mild fever or malaise, typical non-specific features of many infections. However, in more severe cases, the damage affects the production of bile to the point where haem degradation products build up in the blood to toxic levels. These then permeate other body tissues where they color the skin and whites of the eyes yellow, the characteristic of jaundice.

Hepatitis A virus infections Hepatitis A virus (picornavirus ) is transmitted by the faecal–oral route and is prevalent in areas with inadequate sanitation. Infection rarely results in disease in young children but acute signs and symptoms are more common in infected adults. Infections are normally resolved by the immune response, leading to lifelong immunity to the virus. A very effective vaccine is available. The virus is a close relative of the enteroviruses which infect the gut, and HAV can sometimes cause gastrointestinal symptoms that generally occur before hepatitis is seen.

Hepatitis A virus infections HAV replication does not appear to kill hepatocytes; instead, the damage to the liver that causes disease is mediated by the host immune response, particularly the cytotoxic T cell response. In most adults, HAV infection is self-limiting and virus is eventually cleared with resulting immunity to re-infection. There is no specific therapy; patients are advised to avoid other toxic insults to the liver (e.g. alcohol) to aid recovery. In a small number of people (less than 1%), rapid and extreme tissue destruction occurs, termed fulminant hepatitis. This results in liver failure which is fatal unless a transplant is available.

Hepatitis A virus infections Characteristics Spherical, RNA-containing particle, (+) ss-RNA 27-32 nm in diameter Icosahedral, naked HAV contains 4 capsid proteins “VP1, VP2, VP3, VP4” VP4 is required for attachment There is only one serotype but multiple genotypes exist Can be grown in certain monkey kidney and human diploid cells NCR: Non-Coding Region 

The genome has an attached protein VPg that acts as a primer for copying the genome (replication).

Hepatitis A virus infections Pathogenesis Acute, self-limiting, incubation period: 15-50 days HAV multiplies within hepatocytes and Kupffer cells Virions are secreted into the bile and released in stool Symptoms: fever, nausea, vomiting, jaundice, liver cell necrosis Infection provides life long immunity while vaccine protects for 20 years Kupffer cells: specialized macrophages located in the liver, lining the walls of the sinusoids .

Hepatitis A virus infections Laboratory Diagnosis Bilirubin Transaminases Virus in feces: Immune-electron microscopy RIA, ELISA for specific IgM Control of HAV infections Interrupt fecal-oral transmission Chlorination of drinking water as the virus can survive in fresh and salt water Human immunoglobulin (passive immunization) Vaccination

Hepatitis B Virus “HBV” Characteristics Belongs to the Hepadnaviridae family Spherical, double-shelled particles, the complete virions or “Dane particles” are 42 nm in diameter Other forms include spheres or tubules of 20-22 nm in diameter Consist of excess surface antigen (HBsAg = Hepatitis B surface antigen, a glycoprotein) The core is icosahedral nucleocapsid Enveloped

Hepatitis B Virus “HBV” Characteristics The nucleocapsid contains: The DNA genome A DNA-dependent DNA polymerase Hepatitis B core antigen (HbcAg) Hepatitis B e antigen (HBeAg) Hepatitis B X antigen There are 4 major serotypes and 8 genotypes Differences between genotypes affect the disease severity, course and likelihood of complications and response to treatment

Hepatitis B Virus “HBV” Replication The replication of HBV is a “Retroviruslike replication” The (-) DNA strand (the complete strand) is about 3200 nucleotides in length, (+) strand is shorter (about 700 nucleotides) Upon infection, viral DNA polymerase is activated and completes the synthesis of (+) DNA strand using the (-) strand as a template A full length RNA strand “pregenome” is transcribed from (-) DNA strand Pregenome is packaged within the cell to form an immature core (-) DNA is synthesized from RNA via reverse transcriptase”virus-coded” (+) DNA is synthesized using (-) DNA as template by viral DNA polymerase Degradation of (+) DNA to form gaps

covalently closed circular form called CCC DNA

Schematic representation of HBV life cycle Attachment Movement to nuclear membrane Entry of genome completes (+) DNA strand Full length RNA strand “pregenome” is transcribed Viral mRNAs leave nucleus & 8 Translation of proteins & 10 Viral reverse transcriptase, is also produced & packaged DNA replication is primed Reverse transcription of the pregenome occurs within the capsid core particles are transported to the nucleus core particles acquire envelopes as they bud into the ER & 16 Assembly and release

Hepatitis B Virus “HBV” HBV Markers HbsAg – Anti-HBs HbcAg – Anti-HBc HbeAg – Anti-Hbe HBXAg – Anti-HBX Ag All, with the exception of HbcAg could be found in blood, HbcAg is detectable only in the hepatocyte nuclei.

Hepatitis B Virus “HBV” Immunology of HBV infection Ag   Ab HBsAg present in acute and chronic infections and in carriers Anti-HBs are protective antibodies, indicates recovery, present during convalescence HBeAg Anti-Hbe its presence indicates little or no infectivity, present during convalescence HBXAg may contribute to the pathogenesis of chronic infection and development of liver cancer Anti-HBX Abs appear when other markers are undetectable

Hepatitis B Virus “HBV” Epidemiology of HBV Infections The prevalence of HBV in a community can be estimated by the presence of antiHBs or HBsAg-positive carriers It is estimated that there are 240 million HBV carriers in the world High risk groups include: Patients who receive repeated blood transfusion Hospital staff: surgeons, nurses, laboratory technichians Drug addicts Neonatal transmission during delivery of mothers whose blood contains HBeAg Sexual transmission, “HBsAg is found in breast milk, semen, vaginal secretions, saliva and urine” the branch of medicine that deals with the incidence, distribution, and possible control of diseases and other factors relating to health.