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| معلومات للمرضى | فيروس |
Research |
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Pathology of Chronic Hepatitis
Pathological Types of Chronic Hepatitis
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vViral Hepatitis vAlcoholic Hepatitis vNon alcoholic steatohepatitis vWilson’ s Disease vHaemochromatosis vAlpha 1 Anti-trypsin deficiency vDrug-induced hepatitis
Alcoholic Hepatitis.- Metabolism of Alcohol Alcohol is absorbed from GIT, distributed to the tissues, oxidized predominantly in liver: Alcohol dehydrogenase pathway: acetaldehyde + H2 which reduces NAD (nicotineamide adenine dinucleotide) into NADH + acetaldehyde, The excess NADH in the cytosol leads to increase lactate:pyruvate ratio The microsomal ethanol-oxidizing system: cytochrome P-450 dependant pathway Catalase pathway: plays a minor role
Metabolic disturbances ass. with alc. metabolism .- Increase lactate:pyruvate ratio: lactic acidosis, decrease renal capacity for uric acid excretion Impaired carbohyd. metabolism:↓gluconeogenesis from a.a., may produce hypoglycaemia Impaired fat metabolism:H+ ions replace 2 carbon fragments derived from fatty acids as the main energy source of hepatocyte mitochondria, ↓fatty acid oxidation, ↑αglycerophosphate which leads to ↑trapping of fatty acids, ↑synthesis of triglycerides, retention of lipoproteins Impaired metabolism of serotonin, galactose Fatty Change.- Fatty change(Steatosis)occurs mainly in perivenular zone, can be seen in all zones as the injury progress Initially fat droplets are membrane bound, as the droplets enlarge, they fuse forming non-membrane bound vesicles Rupture of distended hepatocyte leads to release of fat and inflammatory response Microvesicular steatosis (foamy degeneration) describes severe liver injury occurring in fatty liver in the absence of alcoholic hepatitis Alcoholic Hepatitis .- Non specific digestive symptoms, hepatomegaly, raised liver enzymes Histopathology: fatty change (steatosis), liver cell necrosis, neutrophil infiltrate, mallory bodies, minimal pericellular fibrosis Other features: lipogranuloma, bile stasis, Kupffer cell proliferation Sclerosing hyaline necrosis: perivenular liver cell necrosis associated with deposition of fibrous tissue, occluded hepatic vein, portal hypertension
Alcoholic Cirrhosis.- Features at risk of progression to cirrhosis: severity of fatty change and hepatic necrosis, widespread obliteration of hepatic venules and Mallory bodies. WHO definition: diffuse process characterized by fibrosis and the conversion of liver architecture into structurally abnormal nodules Micronodular cirrhosis: nodules less than 3mm in diameter in a background of alcoholic hepatitis. Hepatic veins are not recognized but new vessel formation is apparant Non Alcoholic Steatohepatitis .- NASH: alcoholic hepatitis like pattern of injury occurring in livers of non drinkers Risk factors: F gender, obesity, hyperlipidaemia, rapid weight loss, type II DM, some drugs Histopathology: macrovesicular steatosis, focal inflammatory infiltrate (monocytes, polymorphs), pericellular fibrosis, Mallory bodies, focal hepatocyte necrosis, fibrosis Pathogenesis of NASH.- Induction of CYP2E1, lipid peroxidation, endotoxins, cytokines are involved in the pathogenesis Oxidative stress due to lipid peroxidation products Activated Kupffer cell by endotoxins, is chemoattractant for neutrophil Increase production of proinflammatory cytokines: TNF alpha, IL-1, IL-6 Humoral immunity: increase gamma globulins, perisinusoidal deposition of IgA, low titre of autoantibodies IgG, IgA LMA Antibodies
Wilson’s Disease.- What is Wilson’s disease It is a genetic disorder in which copper builds in the body mainly in the liver, named after Dr. Samual Wilson (1912). It is an autosomal recessive disease, the defective gene is an ATP-ase dependent, P-type copper transporter localized to chromosome 13q-14.3 The symptoms & signs are the result of copper overload in various tissues and organs.
Common Findings in WD.- Liver findings: Signs of chronic liver disease, Hepatospleenomegaly, rash, +ve antinuclear or anti smooth muscle antibodies Brain findings: Neuropsychiatric signs, irritability, tremors, gait disturbance Other findings: ↑ g-globulin levels, arthropathy, cardiac complications, gallbladder stones, renal tubular disease, gynaecomastia, ammenorrhoea, Kayser-Fleisher rings Diagnosis of WD .- Serum caeruloplasmin below 20mg/dl v24h urine copper excretion >100µg Liver copper concentration over 250µg/g dry weight
Copper Metabolism.- Dietary copper is taken up by intestinal cells Transported to copper-containing cellular proteins including metallothionin or exported from the cell by P-type ATPase Copper is rapidly transported to the liver via albumin from the intestinal cells Following uptake by hepatocytes, copper is either secreted via caeruloplasmin into the blood stream or excreted into the bile Both physiological mechanisms are defective in WD
Liver Histopathology in WD.- Acute hepatitis: ballooning of hepatocytes, spotty necrosis, apoptotic bodies, cholestasis, steatosis, periportal cholangiolar proliferation, fibrosis. Chronic hepatitis: portal inflammation, interface hepatitis, steatosis, presence of Mallory bodies in periportal hepatocytes, +ve copper associated protein granules in hepatocytes, cirrhosis
Haemochromatosis .- Two specific iron binding proteins Ferritin: the major storage protein that sequesters iron in tissues (plasma ferritin is a reliable indicator of body iron stores Transferrin: iron binding protein which maintains iron in a non toxic form during its transport via blood Haemosiderin: water insoluble deposit of hydrated iron oxide micelles associated with varying amount of denatured protein
Normal iron metabolism.- Iron absorption: body’s needs for iron is exerted at intestinal level, depending on total body iron content, rate of erythropoiesis Iron transport: iron bound to transferrin is transported from intestine to liver, BM, others Iron delivery to tissue: binding of iron-transferrin to transferrin receptor, internalization into cell, release of iron in intracelular organelle Iron storage: Normally iron is stored in the liver as ferritin, few haemosiderin
Classification of Iron Overload.- Genetic disorders: associated with elevated absorption from a normal diet: heriditary haemochromatosis, autosomal dominant pattern heriditary haemochromatosis Haematological disorders: thalassaemia major, sideroblastic anaemia Increased dietary iron: (african iron overload Iron via parental route: blood transfusion, parental iron medications Miscellaneous: end stage cirrhosis, neonatal iron overload, porphyria cutanea tarda
Histological assessment of iron overload.- The grade (amount) of stainable iron (0-4 Its distribution in various cell types of parenchyma (0-4 The presence or absence of fibrosis or cirrhosis (0-4 Alpha 1 antitrypsin deficiency.- Mutation in the gene encoding for A1A protein with no inhibitory activity accumulation of A1AT in hepatocytes vreduced serum level of A1AT 75alleles (A-Z) according to their isoelectric points have been described. S (migrate slowly), Z (migrate towards cathode), M (middle). Histologically, giant cell hepatitis, PAS+, diastase resistant inclusions
Drug- Induced Hepatitis.- Intrinsic Hepatotoxins (true hepatotoxins High incidence of hepatic injury in individuals exposed to it Produce similar lesions in experimental animals Dose-dependence of the phenomenon Direct and indirect hepatotoxins Idiosyncratic (their toxicity is not predictable, produce hepatic injury in small proportion of exposed individuals
Pathogenesis .-
CYP3A7,the major cytochrome in the liver is able to metabolize potential hepatotoxins. Mechanisms of drug reactions: oxidative stress, chemicals producing free radicals can cause hepatocyte apoptosis and can induce lipid peroxidation of cellular membranes (CCl4, mushroom intoxication) immunologic alteration (aflatoxin, sulfonamides, amoxicillin, halothane, chloroflurocarbons) Pathological Findings .- Steatosis: defective disposal of lipids by the liver or impaired oxidation of fatty acids by hepatocytes, defective assembly of triglycerides with apoproteins Cholestasis: interference with sinusoidal-hepatic uptake, inhibition of excretion of substances into the canaliculus (rifampicin, contraceptive steroids) Hepatic injury (idiosyncratic): hypersensitivity (immunological) production of antibodies to hepatic proteins, sensitized T cell, metabolic aberration of the host (metabolic) Morphological forms of toxic hepatitis.- Acute Hepatitis Cytotoxic: necrosis, degeneration, steatosis Cholestatic Chronic Hepatitis Inflammatory infiltrate: eosinophils, lymphoid aggregates, granuloma Cholestasis: hepatocanalicular, canalicular, ductular Steatosis: mainly microvesicular Necrosis: bile duct injury, chronic hepatitis injury
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