2012-9-27 Characteristic of cirrhosis CIRRHOSIS AND ITS COMPLICATIONS Dr Jinsheng Guo Zhong Shan Hospital, Fu Dan University architecture Etiologies of Cirrhosis Factors that contribute to the risk of developing cirrhosis Regular(moderate)alcohol consumption Drug and chemicals e.g- PBC, AlH No Alcoholic Liver Cirrhosis older age, obesity, insulin resistance or type 2 diabetes pattis lipidemia(all Cryptogenic Genetic impact(single nucleotide polymorphisms DIsorders and brugs It Can cause DiSorders and brugs inat can cause panic ting hepatic blood flo g chronic hepatitis B or CI sitic (eg, echinococcosis) occlusive disease d antineoplastic agents
2012-9-27 1 CIRRHOSIS AND ITS COMPLICATIONS Dr. Jinsheng Guo Zhong Shan Hospital, Fu Dan University Characteristic of Cirrhosis Normal Liver Cirrhotic Liver A chronic, progressive, diffuse liver disease Fibrosis and disorganization of the lobular and vascular architecture histologically Chronic hepatitis with fibrosis 10-50 yrs Liver Cirrhosis Nonalcoholic steatohepatitis （NASH） Alcoholic Steatohepatitis (ASH) Long term, 80g/d, 10yr Drug and chemicals DILI Autoimmune e.g., PBC, AIH Biliary Schistosomiasis Chronic viral hepatitis HBV, HCV Etiologies of Cirrhosis Cryptogenic Inherited Circulation disturbance veno-occlusive disease, Budd-Chiari syndrome, constrictive pericarditis Wilson’s diseases hemochromatosis Factors that contribute to the risk of developing cirrhosis Regular (moderate) alcohol consumption age older than 50 years male gender older age, obesity, insulin resistance or type 2 diabetes hypertension, and hyperlipidaemia (all features of the metabolic syndrome) >= factors Genetic impact (single nucleotide polymorphisms) Disorders and Drugs That Can Cause Hepatic Fibrosis Infections Viral (e.g., chronic hepatitis B or C) Bacterial (eg, brucellosis) Parasitic (eg, echinococcosis) Drugs and chemicals Alcohol Amiodarone Chlorpromazine Isoniazid Methotrexate Methyldopa Oxyphenisatin Arsenicals Oral contraceptives (Buddi-Chiari) Pyrrolidizine alkaloids and antineoplastic agents Disorders affecting hepatic blood flow Budd-Chiari syndrome Heart failure Hepatic veno-occlusive disease Portal vein thrombosis (venoocclusive disease) Mechanical obstruction Biliary obstruction (chronic) Metabolic abnormality Nonalcoholic fatty liver disease Autoimmune Primary biliary cirrhosis Autoimmune hepatitis Primary sclerosing cholangitis Disorders and Drugs That Can Cause Hepatic Fibrosis
2012-9-27 Disorders and Drugs Inat can cau epatic Fibrosis Hepatic Fibrosis Copper storage diseases (eg, wilson's disease) Self-limited, acute liver injury (eg, acute viral hepatitis A) even architecture and hence does not cause fibrosis, despite o when fulminant, does not necessarily distort the scaffoldin In its initial stages, hepatic fibrosis can regress if the rouisomal disorders (eg, Zellweger syndrome) hronic or repeated injury, fibrosis becomes permanent Pathogenesis of Liver Cirrhosis Histopathologic Classification micronodular uniformly small nodules(< 3 mm in diameter) and regular ands of connective tissu fibrous septa formation macronodular nodules that vary in size(3 mm to 5 cm in diameter) Hepatitis B, C: Hem matosis. Wilsons disease mixed macro and micronodular micronodular and macronodular cirrhosis A1-AT deficiency, Wilson's disease; Hepatitis B rna surface of a normal liver The color is DO to 1600 grams
2012-9-27 2 Certain storage diseases and inborn errors of metabolism α 1-Antitrypsin deficiency Copper storage diseases (eg, Wilson's disease) Fructosemia Galactosemia Glycogen storage diseases (especially types III, IV, VI, IX, and X) Iron-overload syndromes (hemochromatosis) Lipid abnormalities (eg, Gaucher's disease) Peroxisomal disorders (eg, Zellweger syndrome) Tyrosinemia Congenital hepatic fibrosis Others Cystic fibrosis Graft-versus-host disease Jejunoileal bypass Sarcoidosis Disorders and Drugs That Can Cause Hepatic Fibrosis Self-limited, acute liver injury (eg, acute viral hepatitis A), even when fulminant, does not necessarily distort the scaffolding architecture and hence does not cause fibrosis, despite loss of hepatocytes. In its initial stages, hepatic fibrosis can regress if the cause is reversible (e.g., with viral clearance). After months or years of chronic or repeated injury, fibrosis becomes permanent. Fibrosis develops even more rapidly in mechanical biliary obstruction. Disorders and Drugs That Can Cause Hepatic Fibrosis Etiology Liver function Injury, Portal hypertension Diffuse, chronic liver injury Formation of diffuse fibrous septa regenerative nodules formation Hepato-cellular necrosis, collapse of hepatic lobules Complications Upper GI Bleeding, Hepatic coma, infections, Hepatocellular carcinoma; Functional renal failure Pathogenesis of Liver Cirrhosis FIBROSIS CIRRHOSIS Histopathologic Classification micronodular uniformly small nodules (< 3 mm in diameter) and regular bands of connective tissue Alcoholic, stasis macronodular nodules that vary in size (3 mm to 5 cm in diameter) Hepatitis B, C; Hemochromatosis, Wilson’s disease mixed macro and micronodular (incomplete septal cirrhosis) combines elements of micronodular and macronodular cirrhosis A1-AT deficiency, Wilson’s disease; Hepatitis B
2012-9-27 g that fatty change (also caused by Micronodular cirrhosis with Wilson' s disease, primary biliary cirrhosis, and hemachromato an 3 mm and, hence, this is an example of Histological Patterns of Fibrosis hronic viral hepatitis, chronic cholestatic diseases (e.g, steatohepatitis, and chronic venous outflow Porto-portal(e.g, cholestatic liver injuries) 市Rmp则m he tver can be divided nto three Central-portal (e. g, alcoholic liver disease)
2012-9-27 3 Histological Patterns of Fibrosis Portal-based fibrosis (e.g., chronic viral hepatitis, chronic cholestatic diseases, and hemachromatosis) Central-based fibrosis (e.g., steatohepatitis, and chronic venous outflow obstruction) Distribution pattern of the fibrotic septae Porto-portal (e.g., cholestatic liver injuries) Portal-central (e.g., viral hepatitis) Central-portal (e.g., alcoholic liver disease)
2012-9-27 Chronic viral hepatitis C portal-portal fibrotic septa and formation(Trichrome staining proliferation of bile ductules(H&E) Acute alcoholic hepatitis Deposition of extracellular matrix around Trichrome staining)Osis portal-central vein bridging necr hepatocytes(so called ch Nonalcoholic steatohepatitis which there is ib osis bridaging between central zonal p Macrovesicular steatosis and pericellular fibrosis (Trichrome staining use. unlike a true cirrhosis. there is minimal lar regeneration
2012-9-27 4 Chronic viral hepatitis C portal-central fibrotic septa and nodule formation(Trichrome staining) Courtesty of Dr. M. Isabel Fiel, Mount Sinai School of Medicine Biliary cirrhosis portal-portal fibrotic septa and proliferation of bile ductules (H&E) Courtesty of Dr. M. Isabel Fiel, Mount Sinai School of Medicine Autoimmune hepatitis portal-central vein bridging necrosis (Trichrome staining) Courtesty of Dr. M. Isabel Fiel, Mount Sinai School of Medicine Acute alcoholic hepatitis Deposition of extracellular matrix around hepatocytes (so called chicken wire pattern) and ballooning degeneration of hepatocytes Courtesty of Dr. M. Isabel Fiel, Mount Sinai School of Medicine Nonalcoholic steatohepatitis Macrovesicular steatosis and pericellular fibrosis (Trichrome staining) Courtesty of Dr. M. Isabel Fiel, Mount Sinai School of Medicine
2012-9-27 Pathogenesis Pathogenesis with positional signals and a mechanical scaffold Guo and Friedman. Senn L/ Dis, 2007 Pathways of Stellate cell Activation Hepatic Stellate cell Activation A Central Event in Liver Fibrosis INJURY Normal Liver with Fibro REVERSAON2 RESOLUTON THE HEPATIC PERISINUSOIDAL (DISSE)SPACE ③999 Sinusoid LIPOCYTE一一 MYOFIBROBLAST
2012-9-27 5 Pathogenesis Fibrogenic stimuli from injured liver Oxidative stress; Hypoxia; Inflammation and immune responses; Apoptosis; Steatosis; Senecense and autopathy Imbalance between the accumulation and degradation of ECM Tissue inhibitors of metalloproteinases (TIMPs) The biologic activity of ECM in fibrogenesis Dramatic changes of ECM components in the quality, quantity, and distribution provides cells with positional signals and a mechanical scaffold Provide “biological signals” with a resultant fibrogenic response and angiogenesis Cellular responses and behavior Capillarization of the sinusoids, Angiogenesis vascularized fibrotic septa intrahepatic shunts between afferent (portal vein and hepatic artery) and efferent (hepatic vein) vessels of the liver Cirrhosis may lead to liver failure, portal hypertension, or development of hepatocellular carcinoma Injured hepatocytes Kupffer cell activation Stellate cell activation Inflammation Matrix production, degradation and remodeling Fibrosis ROS/NOS, cytokines (PDGF TGF-1, MCP-1) Cytokines (MCP- 1, MIP-2, IL-1 ) Cytokines (MCP-1, TNF-, IL-1 MIP-2) Denatured proteins ROS apoptotic bodies ROS/NOS Degraded collagen, hyaluronic acid MMPs/TIMPs Endothelial cells EIIIA isoform, ET-1, VEGF PDGF Type IV collagen, laminin Lipid peroxides, apopttoic bodies, cytokines (VEGF, IGF-1) Endothelial cells Pathogenesis Guo and Friedman, Senim Liv Dis, 2007 Hepatic Stellate cell Activation - A Central Event in Liver Fibrosis Normal Liver Activated HSC with Fibrosis Friedman SL and Arthur, Science and Medicine, 2002 RESOLUTION APOPTOSIS? REVERSION? INJURY PDGF ET-1 TGF-1 PDGF, MCP-1 PDGF, Serum MCP-1 Proliferation Fibrogenesis HSC Chemotaxis Retinoid Loss WBC Chemoattraction Matrix Degradation Oxidative Stress, cFn MMP-2 Initiation Perpetuation Contractility Pathways of Stellate cell Activation Friedman SL, J Biol Chem, 2000