Hepatitis Viruses

Viral Hepatitis - Historical PerspectiveAInfectiousSerumViral hepatitisEntericallytransmittedParenterallytransmittedF, G,? otherENANBBDC

Viral Hepatitis - OverviewABCDESource ofvirusfecesblood/blood-derivedbody fluidsblood/blood-derivedbody fluidsblood/blood-derivedbody fluidsfecesRoute oftransmissionfecal-oralpercutaneouspermucosalpercutaneouspermucosalpercutaneouspermucosalfecal-oralChronicinfectionnoyesyesyesnoPreventionpre/post-exposureimmunizationpre/post-exposureimmunizationblood donorscreening;risk behaviormodificationpre/post-exposureimmunization;risk behaviormodificationensure safedrinkingwaterType of Hepatitis

THE MAJOR HEPATITIS VIRUSES VirusClassificationGenomeEnvelopeSpread HAVPicornaviridae, genus HepatovirusRNANonenvelopedFecal-oral HBVHepadnaviridaeDNAEnvelopedParenteral HCVFlaviviridae, genus HepacivirusRNAEnvelopedParenteral HDVUnclassifiedRNAEnveloped (from HBV)Parenteral HEVCaliciviridae, genus proposedRNANonenvelopedFecal-oral

Viral hepatitis is a systemic disease primarily involving the liver. Most cases of acute viral hepatitis in children and adults are caused by one of the following agents: hepatitis A virus (HAV), the etiologic agent of viral hepatitis type A (infectious hepatitis); hepatitis B virus (HBV), which is associated with viral hepatitis B (serum hepatitis);

hepatitis C virus (HCV), the agent of hepatitis C (common cause of posttransfusion hepatitis); or hepatitis E virus (HEV), the agent of enterically transmitted hepatitis. Other viruses are associated with hepatitis that cannot be ascribed to known agents, and the associated disease is designated non-AE hepatitis.

Hepatitis viruses produce acute inflammation of the liver, resulting in a clinical illness characterized by fever, gastrointestinal symptoms such as nausea and vomiting, and jaundice.

Hepatitis Type AHAV is a distinct member of the picornavirus family HAV is a 27- to 32-nm spherical particle with cubic symmetry, containing a linear single-stranded RNA genome with a size of 7.5 kb. Only one serotype is known. There is no antigenic cross-reactivity with HBV or with the other hepatitis viruses.

Although it was first provisionally classified as enterovirus 72, the nucleotide and amino acid sequences of HAV are sufficiently distinct to assign it to a new picornavirus genus, Hepatovirus. Genomic sequence analysis of a variable region involving the junction of the 1D and 2A genes divided HAV isolates into seven genotypes.

Heating food to > 85 C (185 F) for 1 minute and disinfecting surfaces with sodium hypochlorite (1:100 dilution of chlorine bleach) are necessary to inactivate HAV. The relative resistance of HAV to disinfection procedures emphasizes the need for extra precautions in dealing with hepatitis patients and their products.

HAV initially was identified in stool and liver preparations by employing immune electron microscopy as the detection system Sensitive serologic assays and polymerase chain reaction (PCR) methods have made it possible to detect HAV in stools and other samples and to measure specific antibody in serum.

Various primate cell lines will support growth of HAV, though fresh isolates of virus are difficult to adapt and grow. Usually, no cytopathic effects are apparent. Mutations in the viral genome are selected during adaptation to tissue culture.

Hepatitis Type BHBV is classified as a hepadnavirus HBV establishes chronic infections, especially in those infected as infants; it is a major factor in the eventual development of liver disease and hepatocellular carcinoma in those individuals.

A. STRUCTURE AND COMPOSITIONElectron microscopy of HBsAg-positive serum reveals three morphologic forms The most numerous are spherical particles measuring 22 nm in diameter and are made up exclusively of HBsAgTubular or filamentous forms, which have the same diameter but may be over 200 nm longand result from overproduction of HBsAg.

A: spherical Dane particle 42 nm (the infectious form of HBV)

B: pleomorphic spherical particles 20-22 nm

C: filamentous form

From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,, ABC

A: pleomorphic spherical particles 20 nmB: filamentous formC: spherical Dane particle 42 nm (the infectious form of HBV)

Larger, 42-nm spherical virions (originally referred to as Dane particles) are less frequently observed. The outer surface, or envelope, contains HBsAg and surrounds a 27-nm inner nucleocapsid core that contains HBcAg.The viral genome consists of partially double-stranded circular DNA, 3200 bp in length.

The virus also is stable at 37 C for 60 minutes and remains viable after being dried and stored at 25 C for at least 1 week. HBV (but not HBsAg) is sensitive to higher temperatures (100 C for 1 minute) or to longer incubation periods (60 C for 10 hours). HBsAg is stable at pH 2.4 for up to 6 hours, but HBV infectivity is lost.

Sodium hypochlorite, 0.5% (eg, 1:10 chlorine bleach), destroys antigenicity within 3 minutes at low protein concentrations, but undiluted serum specimens require higher concentrations (5%). HBsAg is not destroyed by ultraviolet irradiation of plasma or other blood products, and viral infectivity may also resist such treatment.

B. REPLICATION OF HEPATITIS B VIRUSThe infectious virion attaches to cells and becomes uncoated. In the nucleus, the partially double-stranded viral genome is converted to covalently closed circular double-stranded DNA (cccDNA).

The cccDNA serves as template for all viral transcripts, including a 3.5-kb pregenome RNA. The pregenome RNA becomes encapsidated with newly synthesized HBcAg. Within the cores, the viral polymerase synthesizes by reverse transcription a negative-strand DNA copy.

The polymerase starts to synthesize the positive DNA strand, but the process is not completed. Cores bud from the pre-Golgi membranes, acquiring HBsAg-containing envelopes, and may exit the cell. Alternatively, cores may be reimported into the nucleus and initiate another round of replication in the same cell.

DISEASEIncubation period is 4 to 12 weeks, followed by the acute infection phase, icteric, or anicteric course Hepatic cell damage is not primarily due to cytopathic activity of the virus, but rather to a humoral and cellular immune response against the virus-induced membrane antigens (HBs, HBc) on the surface of the infected hepatocytes

0.51% of those infected experience a fulminant, often lethal, hepatitis. In 8090% of cases the infection runs a benign course with complete recovery and elimination of the HBV from the body. A chronic infection develops in 510%

Three forms are differentiated, but mixed forms are possible:Healthy HBV carriers,Chronic persistent hepatitis (CPH) without viral replicationChronic aggressive hepatitis (CAH) with viral replication and a progressive course.

A chronic infection can result in development of a carcinoma (hepatocellular carcinoma, HCC) or cirrhosis of the liverThe delta agent appears to have an unfavorable influence on the clinical course, usually making the disease more aggressive, increasing the number of complications and worsening the prognosis.

Epidemiology and PreventionHumans are the sole reservoir of HBV. Transmission is parenteral, either with blood or body fluids containing HBV (sexual intercourse) that come into contact with mucosa, lesions, or microlesions in the skin. In transmission by blood, the tiniest amounts contaminating syringe needles, ear-piercing needles, tattooing instruments, etc. suffice to produce an infection.

Hepatitis B infections from blood transfusions have been greatly reduced by thorough screening of blood donors for HBs antigens, despite which patients receiving multiple transfusions or dialysis remain a highrisk group.Since no effective chemotherapy against HBV has been developed to date,the WHO recommends general hepatitis B prophylaxis in the form of active immunization with HBs antigen.

In response to a sudden high-level infection risk (accidental inoculation with infectious material), persons whose immune status is uncertain should also be passively immunized with human anti-HBs antiserumif possible within hours of pathogen contact.Periodic booster shots, especially for persons at high risk, were recommended for some time to maintain sufficient immune protection

Hepatitis Type CClinical and epidemiologic studies and cross-challenge experiments in chimpanzees had suggested that there were several non-A, non-B (NANB) hepatitis agents which, based on serologic tests, were not related to HAV or HBV. The major agent was identified as hepatitis C virus (HCV).

HCV is a positive-stranded RNA virus, classified as family Flaviviridae, genus Hepacivirus. Various viruses can be differentiated by RNA sequence analysis into at least six major genotypes (clades) and more than 70 subtypes.

The genome is 9.4 kb in size and encodes a core protein, two envelope glycoproteins, and several nonstructural proteins. The expression of cDNA clones of HCV in yeast led to the development of serologic tests for antibodies to HCV. Most cases of posttransfusion NANB hepatitis were caused by HCV.

Most new infections with HCV are subclinical. The majority (7090%) of HCV patients develop chronic hepatitis, and many are at risk of progressing to chronic active hepatitis and cirrhosis (1020%). In some countries, as in Japan, HCV infection often leads to hepatocellular carcinoma.

About 25,000 individuals die annually of chronic liver disease and cirrhosis in the United States; HCV appears to be a major contributor to this burden (approximately 40%).HCV displays genomic diversity, with different genotypes (clades) predominating in different parts of the world.

The virus undergoes sequence variation during chronic infections. This complex viral population in a host is referred to as quasi-species. This genetic diversity is not correlated with differences in clinical disease, although differences do exist in response to antiviral therapy according to viral genotype.

Hepatitis Type D (Delta Hepatitis)An antigen-antibody system termed the delta antigen (delta-Ag) and antibody (anti-delta) is detected in some HBV infections. The antigen is found within certain HBsAg particles. In blood, HDV (delta agent) contains delta-Ag (HDAg) surrounded by an HBsAg envelope.

It has a particle size of 3537 nm and a buoyant density of 1.241.25 g/mL in CsCl. The genome of HDV consists of single-stranded, circular, negative-sense RNA, 1.7 kb in size. It is the smallest of known human pathogens and resembles subviral plant pathogens, ie, viroids.

No homology exists with the HBV genome. HDAg is the only protein coded for by HDV RNA and is distinct from the antigenic determinants of HBV. HDV is a defective virus that acquires an HBsAg coat for transmission. It is often associated with the most severe forms of hepatitis in HBsAg-positive patients.

Hepatitis Type EHepatitis E virus (HEV) is transmitted enterically and occurs in epidemic form in developing countries, where water supplies are sometimes fecally contaminated. Pregnant women may have a high (20%) mortality rate.

The viral genome has been cloned and is a positive-sense, single-stranded RNA 7.6 kb in size. The virus resembles caliciviruses but is unclassified. Animal strains of HEV are common throughout the world.