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| معلومات للمرضى | فيروس |
Research |
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Pathology of Viral Hepatitis
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What is Viral Hepatitis?
vIt is the response of the patient’s immune system to viral antigens displayed on cells v Which viruses? Hepatotropic viruses Acute Viral Hepatitis Clinic pathological syndromes v 0Classic (icteric) acute type v0Subclinical anicteric v0Cholestatic v0Fulminent v0Neonatal v0Atypical variants
Liver Response to Acute Viral Hepatitis
v0Inflammatory cell infiltrate 0macrophage activity 0Hepatocellular damage 0Liver cell regeneration
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0Inflammatory infiltrate- 0Composition 0Lymphocytes CD8, CD20 0Plasma cells 0macrophages 0Location- 0Portal tracts 0Interface 0parenchyma
Inflammatory infiltrate
0Hepatocellular damage-
00Types of necrosis 0Focal necrosis or apoptosis fundamental lesion of acute viral hepatitis 0Confluent necrosis comprises groups of adjacent hepatocytes, often perivenular (zone 3) Bridging necrosis: necrosis linking vascular structures Pan acinar: extensive necrosis involving zone 1 and 2 in addition to zone3 0Interface hepatitis (piece-meal necrosis
Focal spotty necrosis
apoptosis
Zone 3 necrosis Central vein with surrounding congestion and necrotic hepatocytes
Interface hepatitis
Bridging necrosis v0Activated Kupffer cell, circulating macrophage expression of I CAM, ELAM, VCAM Perl’s +ve iron rich lymphoid follicles v0Liver cell regeneration distortion of cell plate mitotic figures liver cell rosettes v0Other pathological findings: cholestasis bile duct damage liver fibrosis (condensation of reticulin) 0Evolution of the lesion- 0Regression (few weeks or months decrease inflammation, necrosis increase phagocytic activity ductular proliferation 0Chronicity inflammation of the liver continues >6m 0Residual stage non specific reaction unconnected to VH
slight alteration in architecture, fibrous septa
focal liver cell regeneration cholestasis kupffer cell activation
0Differential Diagnosis of AH-
v0Infectious mononucleosis (EBV) atypical lymphocytes in sinusoids v0CMV, herpes confluent necrosis, minimal inflammation
v0Drugs (herbal remedies) neutrophils, eosinophils, granuloma , perivenular necrosis, duct damage v0PBC v0AIH v0Chronic liver diseases 0Sequelae of Acute Hepatitis- v0Restitution to normal morphology 0Death from severe liver damage 0Post-hepatitic scarring 0Viral carrier state 0Chronic hepatitis and cirrhosis 0Hepatocellular carcinoma 0Chronic Viral hepatitis- 0Definition: a pattern of clinical, biochemical and histological findings in association with one of at least three viral infection namely hepatitis B, C 0 and D viruses v0Clinical definition: persistent inflammation of the liver in the setting of an identifiable hepatotropic viral infection of 6 months or longer evidenced clinically by symptoms &/or biochemical abnormalities 0Pathogenetic mechanisms-
v0gene products that inhibit apoptosis of infected or reacted cell population v0gene products that interfere with cell mediated immunity and cytokine action v0mutations of the virus may lead to escape from both humoral and cell mediated immunity v0infection of extra hepatic sites, may encourage viral persistence v0Direct cytotoxicity 0Pathogenetic mechanisms2- Host Response Humoral immune response: viral antibodies Cell mediated immune response: v0Interferons inhibit all phases of viral-cell interaction induce production of host proteins (HLA-I,II, components of complement, Fc receptor stimulate CD8, macrophage, NK cells v0TNFalpha Stimulate chemotaxis Activation of macrophage, T cell Acute phase protein transcription 0IL-1 Proliferation of lymphocytes & fibroblasts
0Pathological Features- 0Inflammatory cell infiltration 0Hepatocyte death 0Hepatocyte atrophy 0Hepatocyte regeneration 0Hepatic fibrosis 0Hepatic fibrosis- Start by extension of portal stroma Contains collagen I, III, reticulin, elastin produced by Hepatic Stellate Cell Activated by: oxidant stress lipid peroxidation products Respond to: TGF-β, IL-1, IL-4 Fibrosis follows from portal tracts towards zone1 Eventually lead to linking one portal tract to another Ductular reaction starts to appear at the interface Proliferating duct-like structures produce collagen V (scarring)
Portal tract expansion by fibrosis 
Fibrous septa, ductular proliferation
Bridging fibrosis Fibrosis linking vascular channels, Porto-portal, Porto-central
cirrhosis Differential Diagnosis of Chronic Viral Hepatitis- . autoimmune hepatitis auto antibodies.
vMetabolic liver disease alpha antitrypsin deficiency1 .
vWilson’s Disease copper acc fatty change Mallory bodies.
Scoring in Chronic Viral Hepatitis. Drug induced hepatitis α methyl dopa, isoniazid, nitrofurantoineosinophils. v.The purpose of scoring the necroinflammatory process (HAI) was to follow the course of chronic hepatitis in asymptomatic patients Historical background
Knodell et al., 1981 Scheuer et al., 1991 Desmet et al., 1994 Batto and Ludwig 1995 Ishak et al., 1995 Metavir, 1996
Modified Knodell Ishak (et aln.-
vScoring
the necroinflammatory activity
Interface
hepatitis 0-4.
Confluent
necrosis 0-6.
Focal
spotty necrosis 0-4.
Portal
inflammation 0-4.
Total score
of 18
Modified Knodell
Ishak et al.-
v.Scoring the architectural changes No fibrosis 0 . Fibrous expansion of some p.t. 1 . fibrous expansion of most p.t. without septa 2 . fibrous expansion with occasional p-p links 3 fibrous expansion with marked bridging 4 Incomplete cirrhosis 5 . cirrhosis 6 . Type A Viral Hepatitis.- vRNA hepatovirus . .Spread by oral-faecal route . Viral Ag:cytoplasm of Kupffer cells, hepatocytes . Viral antibodies in serum (IgM: current infection, IgG: past infection . Pathogenetic mechanisms: . Hum oral immune response: B lymphocytes . Cell mediated CD45RO (memory Tcell), NK . Cellular cytotoxicity . Histopathology (acute hepatitis) . Periportal inflammation & necrosis . Cholestatic hepatitis . Type B Viral Hepatitis.- vDNA hepatovirus . vSpread by parental route mainly . HBV antigens . HBs preS1: for attachment of virus to hepatocytes preS2 X: interact with promoters of cell growth HBc HBe HBV antibodies . HBs anti HBc anti HBe HBV cycle in the liver.- vViral attachment to hepatocytes . The virus uncoats . Viral DNA travels to the nucleus, where it is converted to a closed circular (cc) viral DNA with the formation of viral mRNA (long, short forms) The long form of viral mRNA serves a a template for minus strand DNA & is packaged to cytoplasm The core particles thus formed, containing double stranded viral DNA Assembly into complete virions Release from the cell Meantime, integration of segments of viral DNA into host cell genome takes place
Serological Pattern .-
vHBsAg: appear in the serum of 8 w average . may disappear before the onset of symptoms may persist into the symptomatic phase may persist after symptoms abate HBsAb: . may persist for the entire life of patient may decline over years & eventually disappear HBeAg: . IgM anti-HBcAg . Anti-HBe: develop in acute self limiting infection . IgG anti-HBc (hallmark of exposure or ongoing HBV infection) .
Histopathology
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vAcute hepatitis B . arying number of apoptotic bodies perivenular confluent necrosis parenchymal collapse vChronic hepatitis B . interface hepatitis lobular activity lymphoplasmacytic infiltrate ground glass hepatocytes (HBsAg) vFibrosing cholestatic hepatitis .
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