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Prof M J Hale  Division of Anatomical Pathology

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HEPATITIS A: typically a disease of children Spread by faecal oral route Institutional settings  Water borne epidemics in overcrowded and unsanitary conditions Relatively short incubation period Sporadic or epidemic Directly cytopathic virus No carrier state Mild illness; usually full recovery Can be severe in adults

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HEPATITIS B:   Can cause: Acute hepatitis Non progressive chronic hepatitis Progressive chronic hepatitis ending in cirrhosis Fulminant hepatitis with hepatic necrosis Asymptomatic carrier state with or without progressive subclinical disease Backdrop for HDV Important role in development of HCC

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HBV –present in all physiologic and pathologic body fluids, with the exception of stool. Spread by blood and blood products, as well as body secretions – saliva, semen, sweat, tears, breast milk & pathologic effusions. Primary risk categories for HBV infection: Transfusion, blood products, dialysis, needle stick injuries, IV drug abuse & homosexual community.

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Vertical Transmission (In endemic regions such as Africa and SE Asia spread from an infected mother to a neonate during birth is common) These neonatal infections can result in a carrier state for life. Horizontal Transmission Peer to peer, eg adult to adult (blood products, contaminated needles, sexual tx etc)

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HBV produces liver injury via host immune response ( not  by direct   cytopathic effect) Viral Ag’s – HBsAg appears on the cell surface  - recognised by the body’s immune system –activation of cytotoxic CD8+ T lymphocytes  →  destruction of hepatocytes(apoptosis) If immunity is impaired the virus can survive in liver cells without causing damage →  asymptomatic carriers Liver biopies – hepatocytes – ground glass appearance due to abundance of viral particles

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B756-10 Liver Hepatitis B Ground glass hepatocytes Tv3

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B756-10 Liver Hepatitis B Ground glass hepatocytes Surface antigen Tv6

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The carrier state – defined by the presence of HBsAg in serum for 6 months or longer after initial detection. The presence of the ‘e’ Ag of HBV indicates active liver disease.

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HEPATITIS C: Major cause of liver disease worldwide Main routes of transmission: Inoculations Blood transfusions Sexual transmission & vertical transmissions – rare High incidence in haemophiliacs, IV drug abusers, haemodialysis patients & homosexual community

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HCV – high rate of progression to chronic liver disease or eventual cirrhosis > 50%. Probably leading infectious cause of chronic liver disease in the west Inherently unstable virus –multiple types & subtypes Characterised by repeated bouts of hepatic damage as a result of reactivation of an existing strain or emergence of an endogenous newly mutated strain. Antiviral therapy available (USD80 000) but generics being developed.

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HEPATITIS D: Delta agent – RNA virus unable to replicate on it’s own. Requires HBV for replication Acute co-infection – after exposure to serum containing both HDV & HBV Superinfection – chronic carrier of HBV with a new inoculum of HDV Common in drug addicts, haemophiliacs, homosexual community & health care workers.

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Characterised by : Acute hepatitis – mild or fulminant Chronic progressive disease culminating in cirrhosis

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HEPATITIS E: Enterically transmitted waterborne infection Self limiting disease  Not associated with chronic liver disease

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CLINICOPATHOLOGIC SYNDROMES: CARRIER STATE: Patients without symptoms Harbour the virus & can therefore transmit the virus ASYMPTOMATIC INFECTION: Patients only identified by minimally elevated serum transaminases  OR Antiviral antibodies

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ACUTE VIRAL HEPATITIS: - non specific symptoms – fever, chills, RUQ pain & jaundice Jaundice CHRONIC VIRAL HEPATITIS: Symptomatic, biochemical or serologic evidence of continuing or relapsing hepatic disease for  ≥6/12,  histologically documented inflammation and necrosis The hepatitis viruses are the most common causes of chronic hepatitis

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Other causes of chronic hepatitis include : Wilsons disease  A1 antitrypsin deficiency Chronic alcoholism Drugs (isoniazid, methyldopa, methotrexate) Autoimmune hepatitis May or may not progress to cirrhosis FULMINANT HEPATITIS: Submassive or massive necrosis

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MORPHOLOGY OF ACUTE AND CHRONIC HEPATITIS: The morphologic features of both acute & chronic hepatitis are shared among the hepatotropic viruses These features can be mimicked by drug reactions Most viruses do not impart specific cytopathic changes HBV infection  →  ground glass hepatocytes

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Acute hepatitis: Portal tracts – mixed inflammatory cell infiltrate Interface hepatitis – spillover of the inflammatory infiltrate into the periportal hepatocytes Lobular inflammation (spotty inflammation) Ballooning degeneration of hepatocytes Hepatocyte necrosis (Apoptosis/Councilman bodies) Steatosis (HCV) Cholestasis Kupffer cell hyperplasia  Bridging necrosis

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Portal inflammation & Interface hepatitis Mild ductular proliferation

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Chronic hepatitis: Portal tract inflammation, most conspicous feature  Mainly lymphoplasmacytic with few neutrophils & eosinophils  Lymphoid aggregates (HCV) Ground glass hepatocytes(HBV); proliferation of the ER synthesising HBsAg particles Interface hepatitis(piecemeal necrosis) Portal fibrosis – bridging fibrosis → Cirrhosis

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Portal tract inflammation & interface hepatitis

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Histology report : Aetiology  Degree of fibrosis Degree of activity Various grading and staging systems

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DNA lymphotropic virus of the herpes group Liver involved in >90% of cases Infects B-lymphocytes Latent infection in immunocompromised patients (post transplant pts – B cell lymphomas)

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Portal tract: marked atypical lymphocytic infiltrate Atypical lymphocytes in the sinusoids

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DNA virus (Herpes group) Virus acquired early in life – incorporated into the host cells as a latent infection; reactivated in immunosuppressed states Common infective agent in congenital infections Portal tract – prominent lymphocytic infiltrate

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Intranuclear amphophilic viral inclusions in hepatocytes, Kupffer cells, endothelial cells and duct epithelium. Viral inclusions can elicit an inflammatory response – granulomatous/microabscess

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TJA15323-12 liver transplant CMV & rejection Tv7

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TJA15323-12 liver transplant CMV & rejection Tv8

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Hepatic lesions only occur in immunocompromised patients, malnourished children and pregnant females Usually associated with disseminated infections Patchy to confluent coagulative necrosis Intranuclear inclusions

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Liver disease is secondary to associated infections or neoplasms Chronic viral hepatitis – HBV, HCV & CMV Patients with HIV co-infected with HBV & HCV have more progressive liver disease with a higher risk for development of cirrhosis & HCC Mild macrovesicular & microvesicular steatosis seen in 25-50%

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Progressive bile duct damage and bile duct loss (HIV associated cholangiopathy) Frequently secondary to CMV and/or  Cryptosporidium  infection Often minimal inflammation

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Angioproliferative lesions secondary to  Bartonella henselae  (bacillary angiomatosis) Opportunistic infections – CMV,MAI complex & various fungal infections Other infections – TB Neoplastic conditions – Kaposi’s sarcoma, B cell NHL

PATHOLOGY OF VIRAL HEPATITIS

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