Lectures 12-13: Hepatitis Viral Diseases

Hepatitis

Inflammation of the liver

Hepatitis A

Positive ssRNA

Source: Feces

Common in restaurants, daycare centers, shellfish, food irrigated with contaminated water

Capsid protein binds to receptors on hepatocytes followed by viral replication

Viral shedding into stool ~2 weeks before symptom onset and ~1 week after symptom resolution

Non-permanent liver damage from CD8+ T cell or ADCC-mediated elimination of infected cells

~1 week of fever, headache, malaise, fatigue, GI symptoms followed by dark urine and a few days later, clay-colored, pale stool (bile gives stool its color)

Self-limited- No chronic state

IgM anti-HAV detectable by symptom onset, IgG shows up later confers lifelong protection

RT-PCR of blood or stool to detect viral RNA

Hepatitis A Vaccine

Whole virus, formaldehyde inactivated

Children 1st dose at 12 months; then 6 months after 1st dose

At risk, unvaccinated adults (travelers to endemic area, chronic liver disease, MSM, IVDU)

Hepatitis B

Gapped positive dsDNA

Source: Blood

Perinatal or early childhood transmission in endemic areas

IVDU, healthcare workers, sex

Intact virion = Dane particle

HBsAg particles - an excess of surface protein sequester HBsAb

HBV is non-cytolytic—does not cause cell death

Acute and chronic infection

Acute symptoms develop due to the cytotoxic T cell response directed against infected hepatocytes

Antigen excess leads to small immune complexes forming, facilitating a Type III hypersensitivity response

Age at transmission is a major determinant of chronicity

Perinatal infection → Almost always chronic

For chronic active HBV: oral reverse transcriptase inhibitors

Hepatitis B Replication

Gapped dsDNA genome undergoes repair by host enzymes to form covalently closed circular (cccDNA) - persists as a stable episome in the nucleus

cccDNA serves as a template to make pre-genomic RNA and mRNA

Pregenomic (pg)RNA undergoes reverse transcription to synthesize negative-sense ssDNA, which is then copied to form the genomic gapped dsDNA

Hepatitis Labs

HBsAg = hepatitis B surface antigen (envelope and surface proteins)

HBsAg = infection

HBsAb = protective immunity and can take over 6 months to be detectable in the blood → resolved infection or prior vaccination

HBcAg = hepatitis B core antigen capsid, DNA, polymerase

HBcAb = first antibody to appear during acute infection; not protective

HBcAb IgM indicates acute disease (< 6 mo); IgG persists for years

HBsAg positive + HBcAb IgM positive = Acute HBV Diagnosis

HBeAg = hepatitis B e antigen (proteolytic process of viral core)

HBeAg formed during the proteolytic processing of the viral core and correlates with higher levels of circulating viral DNA; detectable soon after HBsAg → High replication, high infectivity

IgM HBcAb is the only positive marker during the window period

Hepatitis B Vaccine

Active multi-dose vaccine - recombinant subunit vaccine: HBsAg

1st dose recommended for all newborns within 24 hours of birth

Hepatitis C

Enveloped positive ssRNA

Source: Blood

In US, IVDU and sexual transmission are primary risk factors

HCV is non-cytolytic

Acute: hepatocyte death is mediated by cytotoxic T cells

Chronic: Ongoing inflammation leading to liver cirrhosis and Hepatocellular carcinoma (HCC)

Infection triggers antibodies that are non- protective; particles precipitate leading to immune complex disease, cryoglobulinemia, vasculitis

HCV establishes a chronic state in most infected patients

Risk for factors for progression to cirrhosis and/or cancer include: Older age at infection, Alcohol use, Co-infection with HIV or HBV

Large genetic variability

Viral RNA encodes a polyprotein that is proteolytically cleaved into 10 proteins by a viral protease and is replicated by RdRp

HCV RNA PCR can be detected as early as 2 weeks post-infection

Enzyme immunoassay (EIA) is able to detect anti-HCV Abs 4-12 weeks after infection

Hepatitis D

Circular, (-) sense ssRNA surrounded by the delta antigen (HDAg)

Source: Blood

Requires HBV to replicate → Requires HBsAg for its envelope

Co-infection: HBV + HDV transmitted together, more severe acute symptoms than HBV alone

Superinfection: HDV acquired after HBV → severe hepatitis (mortality)

Vaccinate against HBV confers protection against HDV

Hepatitis E

Positive ssRNA

Source: Feces

Severe disease can occur in following groups:

Mortality in pregnant women in 3rd trimester

Underlying liver disease

Immunosuppressed

Chronic carrier state only in immunocompromised

Elevated anti-HEV IgM corresponding with onset of symptoms for acute disease

Diagnosed by serology - IgM and -IgG anti-HEV antibodies

RT-PCR blood/stool to confirm

Acute Viral Hepatitis

Asymptomatic in majority

Fever, headache, muscle aches, fatigue, anorexia, nausea & vomiting

Abdominal pain often in right upper quadrant

Bilirubinuria and then jaundice appear often as other symptoms begin to resolve

Tenderness and swelling over liver

Acute Viral Hepatitis Pathogenesis

Viral infection of hepatocytes disrupts ability to conjugate bilirubin, causing unconjugated bilirubin to accumulate in serum

Inflammation within the liver impairs bile flow (intrahepatic cholestasis), reducing excretion of conjugated bilirubin into the gut

Rising serum bilirubin—both unconjugated from impaired processing and conjugated from impaired excretion—accumulates in tissues

Acute Viral Hepatitis Lab Findings

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) released from dying (infected) hepatocytes

Rise early in course of infection, often > 1000 IU/L

Gamma-glutamyl transferase (GGT) and alkaline phosphatase (AlkPhos) reside in cells of the biliary tree

Often (near)-normal in early infection

Liver swelling causes biliary obstruction, which prevents bile from leaving the liver → increase in serum bilirubin = jaundice

Inflammation damages bile duct cells → moderate increases in AlkPhos and GGT

Chronic Viral Hepatitis

Cirrhosis

Immune complex disease

Hepatocellular carcinoma (HCC)

May be asymptomatic for years

LFTs normal or mildly abnormal

Complications develop anywhere from 15-40 years after infection