Hepadnaviridae Notes

NOTES NOTES HEPADNAVIRIDAE MICROBE OVERVIEW ▪ Hepadnaviridae: family of DNA viruses, causes liver disease ▪ Produces DNA polymerase with reverse transcriptase, RNAse activity Replication/multiplication ▪ Reverse transcription (RNA intermediate) Structure ▪ Enveloped ▪ Icosahedral capsid ▪ Partially double stranded, partially single stranded circular DNA COMPLICATIONS ▪ Chronic hepatitis, acute liver failure (fulminant hepatitis), liver cirrhosis, hepatocellular carcinoma (HCC) HEPATITIS B VIRUS osms.it/hepatitis-b-virus PATHOLOGY & CAUSES ▪ Hepatitis B virus (HBV) ▫ DNA virus: can cause acute/chronic liver disease ▫ Member of Hepadnaviridae family (only human pathogenic species) ▪ Target: hepatocytes, zone I (periportal area) ▪ Incubation period: six weeks to six months Antigens ▪ Hepatitis B surface antigen (HBsAg/ Australia antigen) ▫ Key infection marker ▪ Hepatitis B core antigen (HBcAg) ▫ Not detectable in serum; found in liver with acute/chronic hepatitis B ▪ Hepatitis B e antigen (HBeAg) ▫ Secreted by infected cells; indicates active infection, replication Transmission ▪ Perinatal (childbirth), parenteral (e.g. IV drug use, blood transfusions), sexual ▪ HBV survives ≥ seven days in environment Highest prevalence ▪ Parts of sub-Saharan Africa, mainly due to perinatal transmission ▪ Lower prevalence areas have greater association with parenteral, sexual transmission TYPES Acute hepatitis ▪ Liver inflammation for < six months) ▪ HBV penetrates hepatocytes → CD8+ T-lymphocyte activation → cytotoxic killing → hepatocyte apoptosis → liver damage, inflammation ▪ Phases ▫ Early, window (antigens undetectable), recovery OSMOSIS.ORG 417

▪ Acute liver failure progression: < 1% ▪ Chronic hepatitis progression (in adults): < 5% ▪ Acute liver failure ▫ Acute liver injury (severe hepatocyte necrosis), hepatic encephalopathy, coagulopathy ▫ Excessive immune response → massive hepatocyte lysis ▫ Preexisting liver disease absence ▫ Associated with HBV genotype D Chronic hepatitis ▪ HBsAg persistent for > six months ▪ Pathogenesis ▫ HBV penetrates hepatocytes → insufficient CD8+ T-lymphocyte activation → “immune tolerance” → HBV persistence ▪ Progression to HCC ▫ HBV integrates to host DNA → oncogene activation → oncogenesis ▪ Chronicity depends highly on age at time of infection ▫ Younger age, ↑ chronicity risk ▫ Immunosuppressed, elderly people also more susceptible ▪ Phases ▫ Immune tolerant: no liver inflammation/ fibrosis ▫ Immune active: liver damage, inflammation, possible fibrosis ▫ Immune inactive: ↓ inflammation ▫ Reactivation: liver damage, inflammation, possible fibrosis ▫ “Recovery”: occult HBV, HBsAg negative; still infected, disease inactive (best prognosis) RISK FACTORS ▪ IV drug use ▪ Healthcare workers ▫ Frequent contact with blades, needles, body fluids ▪ High-risk sexual behavior ▪ Anal intercourse ▪ Previous HIV/hepatitis C infection 418 OSMOSIS.ORG COMPLICATIONS ▪ HCC, fulminant hepatitis, liver cirrhosis Hepatic encephalopathy ▪ Excessive nitrogen load, electrolyte disturbances → altered neurologic functions in individuals with severe liver disease Hepatorenal syndrome ▪ Portal hypertension → splanchnic vasodilation → ↓ effective circulatory volume → ↑ renin-angiotensin-aldosterone system → renal vasoconstriction → hepatorenal syndrome (liver dysfunction → kidney failure) Bleeding diathesis ▪ Hypocoagulability → ↑ hemorrhage risk SIGNS & SYMPTOMS Acute hepatitis ▪ Can be anicteric (not accompanied by jaundice) with non-specific symptoms (e.g. fever, malaise, nausea, vomiting) ▪ Some progress to icteric hepatitis with hepatomegaly, right upper-quadrant pain, jaundice (30%), dark-colored urine (due to conjugated hyperbilirubinemia), pale stool Chronic hepatitis ▪ Mostly asymptomatic/non-specific symptoms until late disease stages ▪ Exacerbations may present as acute hepatitis ▪ Jaundice, ascites, splenomegaly, encephalopathy (e.g. personality changes, ↓ level of consciousness, intellectual impairment, asterixis) may present ▪ Extrahepatic manifestations (occasionally) ▫ Fever, rash, arthralgia, arthritis, glomerulonephritis DIAGNOSIS LAB RESULTS ▪ HBV DNA detection ▫ Polymerase chain reaction (PCR), in-situ hybridization, Southern hybridization

Chapter 78 Hepadnaviridae Laboratory testing ▪ ↑ alanine aminotransferase (ALT), aspartate aminotransferase (AST) ▫ ALT > AST ▫ Usually ALT in acute hepatitis > 1000 U/L (may be ↓ in chronic hepatitis) ▫ ALT levels take longer than AST to return to normal ▪ ↑ ALT for > six months indicates chronicity ▪ ↑ alpha-fetoprotein (AFP) in HCC ▪ Liver fibrosis ▫ ↓ leukocytes, platelets ▫ AST/ALT > 1 (normal ≈ 0,8) ▫ ↑ total bilirubin ▫ ↓ serum albumin ▫ Delayed prothrombin time, ↑ international normalized ratio (INR) Serologic marker detection through enzyme immunoassay ▪ Hepatitis B surface antigen (HBsAg) ▫ Indicates infection (acute/chronic) ▪ Hepatitis B surface antibodies (Anti-HBs) ▫ Provides HBV infection immunity appears after vaccination/resolved acute hepatitis ▪ IgM antibodies against hepatitis B core antigen (IgM anti-HBc) ▫ Acute infection/chronic hepatitis reactivation phase ▪ IgG antibodies against hepatitis B core antigen (IgG anti-HBc) ▫ Non-specific antibody; may be ↑ during acute, resolved, chronic hepatitis ▪ Hepatitis B e antigen ▫ Active replication, high infectivity ▪ Hepatitis B e antibodies ▫ Low replication, infectivity Liver biopsy ▪ Acute hepatitis ▫ Mononuclear infiltrate ▫ Pericentral inflammation, necrosis ▫ Eosinophilic hepatocytes ▪ Chronic hepatitis ▫ Fibrosis ▫ Nodule formation ▫ Mononuclear portal infiltrate ▫ Some hepatocytes have uniformly dull cytoplasm due to endoplasmic reticulum swelling (“ground glass” hepatocytes) OSMOSIS.ORG 419

Figure 78.1 Ground glass hepatocytes seen in the liver of an individual with hepatitis B infection. TREATMENT MEDICATIONS ▪ Antiviral monotherapy ▫ Severe acute hepatitis, pre-existing liver disease, concomitant hepatitis C/D infection, immunocompromised, elderly Acute hepatitis ▪ Post-exposure prophylaxis ▫ HBV vaccine and immunoglobulin Chronic hepatitis ▪ Combination therapy (e.g. lamivudine, interferon) 420 OSMOSIS.ORG Prevention ▪ HBV vaccine ▪ Recombinant type most commonly used ▫ HBsAg inserted in yeast cells ▪ HBsAg → development of anti-HBsAg → HBV infection immunity ▪ Intramuscular administration ▪ Three doses for coverage (very effective) ▪ Administration regime: 0, 1–2 months, 6–12 months ▫ Infant immunization: first dose at birth ▫ Does not require booster dose (longterm protection) SURGERY ▪ Acute liver failure ▫ Consider liver transplantation OTHER INTERVENTIONS ▪ Acute liver failure ▫ Fluid resuscitation, early nutritional support, antiviral therapy (nucleoside/ nucleotide analogues) Acute hepatitis ▪ Supportive treatment (e.g. fluid therapy, nutrition)

Chapter 78 Hepadnaviridae HEPATITIS D VIRUS osms.it/hepatitis-d-virus PATHOLOGY & CAUSES SIGNS & SYMPTOMS ▪ Hepatitis D virus (HDV/delta virus): incomplete RNA virus; contributes to acute liver failure development, chronic hepatitis exacerbation in people coinfected/ previously infected with HBV ▪ HDV not member of Hepadnaviridae family ▪ HDV infection inhibits HBV replication due to HBV, HDAg interaction during viral replication ▫ Coinfected individuals: HDV predominant ▫ ↑ inflammatory response (compared to HBV alone) ▫ Poor response to existing HBV treatment ▪ Incubation period ▫ 6–24 weeks Coinfection ▪ Biphasic course with acute hepatitis symptoms Structure ▪ Outer envelope made of HBsAg, inner HDV RNA, delta antigen (HDAg) LAB RESULTS Transmission ▪ Parenteral, sexual, perinatal (very rare) Satellite virus ▪ Can only infect if host also infected with HBV ▫ Coinfection: simultaneous infection ▫ Superinfection: HDV infection after established HBV infection; more severe RISK FACTORS ▪ IV drug use, high-risk sexual behavior, HBV presence Acute liver failure ▪ Systemic symptoms ▫ E.g. fever, malaise, nausea, vomiting) ▫ Hepatomegaly, right upper quadrant pain; sometimes jaundice, dark colored urine, pale stool ▪ Hepatic encephalopathy ▫ Personality changes, ↓ level of consciousness, intellectual impairment, asterixis DIAGNOSIS ▪ Serologic marker detection ▫ IgM/IgG anti-HDV ▪ PCR assays ▫ HDV RNA detection TREATMENT MEDICATIONS ▪ Pegylated interferon alpha ▪ Prevention ▫ HBV vaccine SURGERY ▪ Consider liver transplantation for chronic hepatitis D, acute liver failure OSMOSIS.ORG 421