Viral Hepatitis

Prodromal symptoms of nausea and anorexia, presence of pain in upper

abdomen together with characteristic laboratory features (elevated bilirubin,

elevated SGOT and SGPT > 500 with SGPT > SGOT and elevated alkaline

phosphates to < 3 times normal ) suggest the diagnosis of Viral Hepatits.

Virus Genome Replication Defective

DNA Polymerase in Virion

HBsAg in Envelope

Virus Family

HAV ssRNA No No No Picornavirus

HBV dsDNA1 No Yes Yes Hepadnavirus

HCV ssRNA No No No Flavivirus

HDV ssRNA2 Yes No Yes Deltavirus

HEV ssRNA No No No Calicivirus

Features HAV HBV HCV HDV HEV

INCUBATION (DAYS) AGE

15-45 DaysChildren , young adults

30-180 DaysYoung adults

15-160 DaysAny age but > in adults

30-180 Days Any age

14-60 DaysYoung adults

TRANSMISION •Fecal –oral •P.C•Perinatal •Sexual

+++ unusual --- +

--- +++ +++ ++

--- +++ + +

--- +++ + ++

+++ --- --- ---

CLINICAL•Severity

•Fulminant

•Progression to chronicity

•Carrier•Cancer •Prognosis

Mild

0.1%

None

None None Excellent

Occasionally severe 0.1- 1.0%

Occasional (1-10%)

0.1-%-30% + ntWorse with age

Moderate

0.1%

Common (50-70%)

1.5 to 3.2% +nt Moderate

Occasionally severe 5-20%

Common

variable variable Acute : goodChronic:poor

Mild

1-2%

None

None None Good

PROPHYLAXIS IgG vaccine HBIG Recombinant vaccine

None - Unknown

Hepatitis “A” Virus

CLINICAL CAPSULE:HAV is a non enveloped RNA Virus.It is classified in genus Hepatovirus under family Picornavirus.Originally called as enterovirus 72.

It is the only human hepatitis virus which can be cultivated in vitro.

M/C of hepatits in children. transmission by feco-oral route.

Virus is shed in feces during the late Incubation period & prodromal phase of illness.

LABORATORY DIAGNOSIS OF HAV• “Detection of IgM-specific

anti HAV in the blood of an acutely infected patient confirm the diagnosis of hepatitis A.”

• IgM appears in acute phase, peaking about 2 weeks after elevation of live enzymes and becomes undetectable withins 3-6 months.

• ELISA is the method of choice for measuring antibodies.

CLINICAL ASPECTS

• Fever, anorexia, and jaundice are common.

• ROT: is greatest 2 weeks before to 1 week after the onset of jaundice.

• HAV is excreted in clay-colored feces and dark urine for about 2 weeks before the onset of jaundice.

• Blood and serum are infective during the brief period of viremia.

• DIAGNOSISIgM-specific antibodydenotes acute infection.• TREATMENT And

PREVENTION No specific tx Passive immunization: Immune serum globulin

provides temporary about 80% to 90% protection.

Active immunization: Formalin-killed HAV, which

is grown in human cell culture, is almost 100% protective

HEPATITIS B VIRUS

• HBV belongs to hepadna viridae.

• HBV is the only has DNA viruses.

• Partial double strand DNA.

• HBV contains both DNA-dependent DNA polymerase and RNA-dependent reverse transcriptase.

• Found in cytoplasm of infected hepatocytes

Structure of HBV:• Serum form pt. of HBV shows 3

types of particle:1. Dane particle• Double walled spherical

structure,42 in diameter.• Complete HBV.• It contains:I. HBcAgII. HBsAgIII. HBeAg2.Spherical particle(MC)• 22nm • HBsAg3. Filamentous or tubular particle:• 22nm• Identical to spherical is HBs Ag.

Worldwide distribution of hepatitis B infection. Areas with high prevalence (>8% of population)

are in black, and areas with moderate prevalence (2% to 7%) are in gray.

Antigen HBs Ag

Actions :•1st virological marker•Elevation of SGOT/SGPT •Become undetectable 1-2 months after the onset of jaundice.•In chronic HBV infetcion HBsAg remain detectable beyond 6 months.

Antibodes :Anti HBsAg

Impact:•It become detectable in blood when HBsAgdisappears.•Protective AB.•Only marker present after immunization.

HBc Ag •It is not detectable because it is enclosed within HBsAg coat.

Anti HBcAg•IgM•IgG

•IgM: acute or recent infection.•IgG: remote or chronic infection.

HBe Ag •Appears shortly after HBsAg.•Indicator of active intraheptic replication and infectivity.

Anti HBeAg •Disappearance of HBeAg followed by anti HBe Ag.•It pesence indicates low infectivity & virus infection.

HBxAg HCC No A/B

Serologic and Virologic Markers of HBV

Management

• High carbohydrate diet.• Domperidome • Silymarin • i.v ornithine (it is amino acid reduced the swelling) • f/u 6 months Anti HBsAg =0• Liver start regressing --- fulminant hepatic failure(0.1-1%).• Bleeding • Amonia >> in blood >hepatic encephalopathy>comaTx : Orthoptic liver transplantation.Anti HBsAg + <10 5 copies/ml then wait and watch.>10 5 copies/ml Tx:alfa interferone+lamividine

Hepatitis “C” Virus

• Classified as a new genus Hepacivirus in the family flaviviridae.

• The virus can’t be cultured.• Positive-sense RNA genome that

encodes three structural and five nonstructural proteins .

• Highly heterogeneous virus, hypervariable regions in E2.

• Eleven genotypes with multiple subtypes have different geographic distribution.

• Genotypes important for therapy response.

• HCV replicates in the cytoplasm via negative-sense RNA intermediates

• It is the commonest cause of post transfusion hepatitis and chronic hepatitis.

Laboratory diagnosis of HCV:• The most sensitive and gold

standard test in establishing diagnosis is assay for HCV RNA.

• HCV-RNA can be detected within a few days of exposure of HCV well before the appearance of A/B ( IgG class)

Test for HCV-RNA assays are:• PCR• TMA • B DNA hybridization.• A/B detection by ELISA.The type of A/B are detected:Anti NS-5 (TGA)Anti C22/C33( SGA)Anti C100(FGA)

• Hepatitis C is the MCC of Chronic Hepatitis.

• 50-80% patients.• Long term prognosis is benign.• Fatigue is the MC symptom.• Immune complex mediated extra

hepatic complication are less common than chronic hepatitis B with the exception of essential mixed cryoglobulinemia which is more common in chronic hepatitis C.

• Autoimmune play a role in the pathogenesis of chronic hepatitis c.

• Lab findings:Characteristics episodic pattern ofAminotransferase activity>aminotransferaselevel tend to fluctuate. ALT> AST ( after cirrhosis AST>ALT)Presence of Anti LKM1 anti body against

p450 2 D6.( HCV microsomal A/B).Anti LKM2 --- (Drug induced A/B)Anti LKM3---(Chronic Hepatits D)

Inflammation in chronic hepatitis C virus (HCV) infection. Chronic inflammation of the portal area with a lymphoid aggregate in the center can be seen. At the edges of the

portal area, the interface between the parenchyma and portal connective tissue, inflammation spreads outward, destroying hepatocytes and expanding the portal tract

by piecemeal necrosis.

TREATMENT:• Pegulated IFN-a + ribavirin• Chronic hepatits is the most common indication for liver

transplantation.• MCC of chronic carrier state is HCV. About 50-70% of patients

progress to chronic hepatitis.• Chronicity----HCV>HDV>HBV Remember---in HBV infection there are two types of carriers:1.Super carriers-high titre of HBsAg, HBeAg DNA polymerase and HBV in the circulation.-highly infective.2.Simple carriers-low titre of HBsAg with negative HBeAg DNA polymerase and HBV.-have low infectivity. HOWEVER• HCV may cause co infection with HBV and co-infection of HCV with

HBV increases the rate of development of cirrhosis and the risk of HCC compared with infection. With either virus alone.

• HCV can cause liver carcinoma.

Hepatitis E

• Also known as enterically transmitted non-A non-B(NANB) virus or epidemic NANB.

• Classified in the genus HERPES virus under the family CALIVIRIDAE.

• Single stranded +sense RNA virus.• The viral particles in stool are

spherical, 27 to 34 nm in diameter with icosahedral symmetry, and unenveloped, and they exhibit spikes on their surface.

• A unique feature is the clinical severity and high case fatality rate of 20-40% in pregnant women, especially in the last trimester of pregnancy.

• Characteristically associated with cholestasis.

SIMILARITIES IN HAV & HEV:Both have acute onset with mild

illness.Both are transmitted by feco-oral

route.DIFFERENCES IN HAV & HEV:HAV is more common in children.

WhileHEV is more common in young adult.HEV can cause fulminant hepatitis in

pregnant women ( not HAV).Secondary attack rate of HEV is very

low (2-3%) as against 10-20% in HAV.

Hepatitis D or Delta virus

• It has been classified in genus Delta virus.

• Delta core of HDV is encapsulated by an outer envelope of HBsAg, so require co-operative function of HBV.

• Intracellular replication of HDV RNA can occur without HBV but liver injury requires the presence of HBV.

• It is defective RNA virus depend on the helper function of HBV for its replication and expression.

• It contains defective ssRNA.

• It has no independent existence and can survive and replicate only as long as HBV infection persists in the host .

HDV infection

Superinfection• Infected with HBV

• Has grave course with more chances of fulminant hepatitis & chronic infection.

• IgM anti HDV (+)ve & IgM anti HBc(+)ve

Coinfection• Infection occurs

simultaneously with HBV.

• Comparatively mild course.

• IgM anti HDV(+)ve & IgG anti HBc(+)ve.

• There is no association between HDV and hepatocellular carcinoma

• HDV antigen ( Delta antigen) is primarily expressed in liver cell nuclei, where it can be demonstrated by immunofluroscence.

Distribution of hepatitis E virus infection, among countries in which outbreaks have

been identified (shown in black).

HEPATITIS G• Blood born virus.• It resembles HCV.• Also k/s GB virus C.HGV RNA has been found in patients with:• Acute hepatitis• Chronic hepatitis• Fulminant hepatitis• Hemodialysis• i.v drug addicts.• Blood donor.• Its genome resembles HCV genome except, it lacks a protein

corresponding to the core protein of HCV that forms the nucleocapsid.

• HGV infection occur independently, it does not require co-infection of HCV.

Treatment of Hepatitis

• Treatment of patients with hepatitis is supportive and directed at allowing hepatocellular damage to resolve and repair itself.

• Only HBV and HCV have specific treatments, and those are only partially effective.

• Recombinant interferon- and pegylated interferon- are currently the therapy of proven benefit in the treatment of patients chronically infected with HBV or HCV.

• With nucleoside and nucleotide analogs, such as lamivudine, HBV DNA levels are reduced, but the virus is rarely eliminated and viral replication resumes in the majority of patients when treatment is stopped. The emergence of drug-resistant virus mutants in long-term therapy is a major problem.

• Combination therapy ofinterferon- and ribavirin against chronic hepatitis C gives a sustained response rate of up to 50%, though that therapy is less successful in patients with genotype 1.

• Orthotopic liver transplantation is a treatment for chronic hepatitis B and C end-stage liver damage. However, the risk of reinfection on the graft is at least 80% with HBV and 50% with HCV, presumably from extrahepatic reservoirs in the body.

Drug Nucleoside analogue MOA Viral Spectrum

Entecavir Yes Reverse transcriptase inhibitor

HBV

Foscarnet No Viral polymerase inhibitor

HBV

Ribavirin Yes Perhaps blocks capping of viral mRNA

Respiratory syncytial virus, influenza A and B, Lassa fever, hepatitis C, other

Lamivudine (3TC) Yes Reverse transcriptase inhibitor

HIV-1, HIV-2, HBV

Zalcitabine (ddC) Yes Reverse transcriptase inhibitor

HIV-1, HIV-2, HBV

Examples of Antiviral Compounds Used for Treatment of Viral Infections

Clinical and Laboratory Features of Chronic Hepatitis

Type of hepatitis Diagnostic test(s) Autoantibodies Therapy

Chronic hepatitis B HBsAg, IgG anti-HBc, HBeAg, HBV DNA

Uncommon IFN- , PEG;IFN- lamivudine ;adefovirentecavir ;telbivudine ;tenofovir

Chronic hepatitis C Anti-HCV, HCV RNA Anti-LKM1a PEG IFN-  plus;ribavirin;Telaprevir;Boceprevird

Chronic hepatitis D Anti-HDV, HDV RNA, HBsAg, IgG anti-HBc

Anti-LKM3 IFN- , PEG ; IFN- c

Autoimmune hepatitis

ANAb (homogeneous), anti-LKM1 (±) Hyperglobulinemia

ANA, anti-LKM1 anti-SLAe

Prednisone, azathioprine

Drug-associated — Uncommon Withdraw drug

Cryptogenic All negative None Prednisone (?),azathioprine (?)

Will be grateful for advice. Blossom Sabi