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
2012-9-27 BIOCHEMISTRY OF LIVER FUNCTION Metavir Scoring System for Fibrosis Centrel vi F3 F4 Scoring Systems for fibrosis Progression Histological“母“ F4(Cirrhosis) Non-cirmhotk Compensated Compensated Decompensated None(no varices) None varices G, magI Biological Fibrogenesis Scar and Thick (acelluar ngiogenesis X-linking Stage Pathophysiology Portal Hvpertension -Pathogenesis Pressure Flow x Resistance estruction of hepatocytes ncreased flow Flbrockyecarming (Splanchnic Vasculature) ncreased pressure in the venous and sinusoidal channel Modulable function injury contraction
2012-9-27 6 Metavir Scoring System for Fibrosis F1 F3 F2 F4 Modified from Poynard Scoring Systems for fibrosis Progression METAVIR Knodell Ishak F4 F4 F6 F3-F4 F3-F4 F5 F3 F3 F4 F2 F1-F3 F2-F3 F1 F1 F2 F0-F1 F0-F1 F1 F0 F0 F0 Friedman SL. Gastroenterology, 2008 Classification of chronic liver disease based on hisptological, clinical, hemodynamic, and biological parameters. Pathophysiology Etiology Alcohol abuse, Malnutrition, infection, drugs, Fatty infiltration, biliary obstruction… Portal hypertension Destruction of hepatocytes Fibrosis/scarring Liver function Injury Obstruction of blood flow Increased pressure in the venous and sinusoidal channel
2012-9-27 Consequences of portal hypertension Consequences of portal hypertension Formation and open of portal-systemic collateral's Formation and open of portal Esophageallgastric varices systemic collateral short gastric/coronary veins Splenomegaly Rectal collaterals uphemorrhoidal/middle inf Hemorrhoidal umbilical/epigastric bdominal wall varices
2012-9-27 7 Consequences of portal hypertension Formation and open of portalsystemic collateral’s Splenomegaly Ascites Consequences of portal hypertension Formation and open of portal-systemic collateral’s Esophageal/gastric varices short gastric/coronary veins Rectal collateral‘s Suphemorrhoidal/middle & inf. Hemorrhoidal Caput medusae umbilical/epigastric abdominal wall varices Portal system and left renal Esophageal varices Gastric varices Normal Gastro-esophageal varices bleeding Caput medusae ( umbilical)
2012-9-27 Consequences of portal hypertension Ascites Overflow theory abdominal wall varices Ascites enin angiotension aldosterone system RAAS Kallikrein-kinin system, Adenosine onal synthesis of PGs(PGE2 ? Renal tubular RAAS, Angiotension ll 一ET ↑ Plasma re Consequences of portal hypertension Pathology of Liver Cirrhosis Splenomegaly Other Organs vein varices: mucosal edema and stasis hypersplenism: anemia, leukopenia, peptic ulcer formation thrombocytopenia glomerulonephritis(membranous, anti-glumerulat ne, mesangial proliferative ilation of spenic sinus; proliferation of splenic pulp dilation of spleen artery, varicosity of splenic vein lomerulosclerosis, kidney tubules degenerative endophlebitis atrophy and degeneration
2012-9-27 8 abdominal wall varices Consequences of portal hypertension Ascites Theories of ascites formation • Underfilling theory • Overflow theory • Arterial vasodilation theory Ascites • Sodium retention --- Renin angiotension aldosterone system (RAAS) --- sympathetic nerve system , norepinephrine --- Intrarenal factors Kallikrein-kinin system, Adenosine • Water retention --- Antidiuretic hormone (ADH) --- Impaired renal synthesis of PGs (PGE2 ) • Renal vasoconstriction -- RAAS, Angiotension II -- SNS -- ADH -- ET Consequences of portal hypertension Splenomegaly Splenomegaly hypersplenism: anemia, leukopenia, thrombocytopenia spleen：splenomegaly; congestion; blood stasis, dilation of spenic sinus; proliferation of splenic pulp; dilation of spleen artery; varicosity of splenic vein; endophlebitis Pathology of Liver Cirrhosis Other Organs Gastrointestinal vein varices；mucosal edema and stasis； peptic ulcer formation Renal： glomerulonephritis（membranous, anti-glumerular basement membrane, mesangial proliferative glomerulonephritis） Glomerulosclerosis, kidney tubules degenetative necrosis Endocrine gland atrophy and degeneration
2012-9-27 Endocrine system Pulmonary manifestations Hepatic hydrothorax(肝性胸水 Telangiectases(毛细血管扩张症 nary syndrome(HPs,肝肺综合征) Spider nevi(嶼蛛痣 riad of pulmonary vascular dilatation Palmar erythema(肝掌) arterial hypoxemia Testicular atrophy(睾丸委缩 in the setting of advanced liver disease Menstrual irregularities(月经失调) Hepatorenal syndrome( HRs) Mechanisms of HRS Hypotension due to Arterial vasodilation AAS. AVP endothelin advanced hepatic failure Reduced cardiac Portal Reduced ked abnormalities in arterial circulation hypertension sensitivity to nous vasoactive system ↓ HRS ction of LTC4 gressive Often results in mild renal insufficiency causing LTD4 and F2 oprostane PGI2 and PGE2 Symptoms and signs Clinical Features Compensated cirrhosis Decompensated cirrhosis brosis itself does not cause distinct symptoms. Symptoms may develop secondary to the primary disorder with splenomegaly is often ss complications, such as variceal GI d loss of e bleeding. portal-systemic encephalopath develop. gastro-esophageal varices, Splemegaly, ascit
2012-9-27 9 Endocrine system Gynecomastia (男性乳房发育), Telangiectases (毛细血管扩张症) Spider nevi (蜘蛛痣) Palmar erythema (肝掌) Testicular atrophy (睾丸萎缩) Menstrual irregularities (月经失调) Pulmonary manifestations Hepatic hydrothorax (肝性胸水) Hepatopulmonary syndrome (HPS, 肝肺综合征) triad of pulmonary vascular dilatation arterial hypoxemia in the setting of advanced liver disease Hepatorenal syndrome ( HRS) Occurred in the setting of: -- chronic liver disease -- advanced hepatic failure -- portal hypertension characterized by: -- impaired renal function -- marked abnormalities in arterial circulation -- activation of endogenous vasoactive system Classified into 2 different types: -- Type I: Rapidly progressive -- Type II: Not rapidly progressive Often results in mild renal insufficiency causing diuretic resistant ascites Mechanisms of HRS Renal cortical ischemia HRS Hypotension due to: Arterial vasodilation, Reduced cardiac output Portal hypertension Increased local production of LTC4, LTD4 and F2 isoprostane Activation of SNS, RAAS, AVP, endothelin and neuropeptide Y Reduced sensitivity to NO and ANP renal production of PGI2 and PGE2 Symptoms and Signs Hepatic fibrosis itself does not cause distinct symptoms. Symptoms may develop secondary to the primary disorder or to portal hypertension. Portal hypertension with splenomegaly is often asymptomatic unless complications, such as variceal GI bleeding, ascites, or portal-systemic encephalopathy, develop. Eventually, cirrhosis supervenes. Clinical Features Compensated cirrhosis Many people experience few symptoms at the onset of cirrhosis, symptoms are typically vague and nonspecific. -- Fatigue and loss of energy -- Loss of appetite and nausea -- Spider angiomas -- liver function is normal Decompensated cirrhosis Hepatocellular insufficiency Symptoms caused by loss of functioning liver cells --- System： fatigue, weakness, weight loss, malnutrition --- Digestive System: Loss of appetite, nausea, diarrhea Portal hypertention gastro-esophageal varices, Splemegaly, ascites…
2012-9-27 Clinical Features Jaudice oration of skin, Com membranes insufficiency hypertension trunk and face degradation in liver hard surface on Splenomegaly pertension Palmar erythema Proteinaceous fluid in dusa Cruveilhier- A variety of metabolic from umbilicus vein that shunts blood Epigastric vascular andular male breast pattern tissue oestradiol, yndrome erythemia entral portion of th ed oestradiol orizonal white bands Hypoalbuminaemia oxime white t Foetor hepaticus swe ubad aons of disinhitonof motor afa atile dimethylsulfide, Hypertrophic Painful proliferative Hypoxaemia due to right-to- especially in portosyst Anorexia, fatigue, Occurs in >50% of steoarthropathyfing osteoarthropathy of ed liver, secondary to ibrosis and chanced oxidative stress Type 2 diabetes Occurs in of Catabolic metabolism by ontraction of palmar patients with cirrhosis diseased liver, secondary to 腱膜桡侧字缩 fascia exposure or diabeties) Clinical features( Hepatocellular Insufficiency -Reduced synthesis of coagulation factors(Il,V,VIL, IX, X Hypersplenism: low platelet count, poor absorption Gastrointestinal bleeding Hormonal abnormalities Gynecomastia Spider nevi Jaundice 10
2012-9-27 10 Clinical Features Jaundice Edema Coagulopathy Spider angiomata Palmar erythema A variety of metabolic abnormalities Gastroesophageal varices Splenomegaly Ascites Hepatic encephalopathy Caput medusae, CruveihierBaumgarten syndrome hepatocellular insufficiency portal hypertension Description Cause Jaudice Yellow discoloration of skin, cornea, and mucous membranes Compromised hepatocyte excretory function, occurs when serum bilirubin>20mg/L Spider amgiomata Central arteriole with tiny radiating vessels, mainly on trunk and face Raised oesotradiol, decreased oestradiol degradation in liver Nodular liver Irregular, hard surface on palpation Fibrosis, irregular regeneration Splenomegaly Enlarged on palpation or in ultrasound Portal hypertension, splenic congestion Ascites Proteinaceous fluid in abdominal cavity, clinical detected when≥1.5L Portal hypertension Caput medusae Prominent veins radiating from umbilicus Portal hypertension, reopening of umbilical vein that shunts blood from portal vein CruveilhierBaumgarten syndrome Epigastric vascular murmur Shunts from portal vein to umbilical vein branches, can be present without Caput medusae Palmar erythemia Erythema sparing central portion of the palm Increased oestradiol, decreased oestradiol degradation in liver White nails Horizonal white bands or proximal white nail plate Hypoalbuminaemia Hypertrophic Painful proliferative Hypoxaemia due to right-toleft shunting Osteoarthropathy/fing er clubbing Osteoarthropathy of long bones Portopulmonary hypertension Dupuytren’s contracture 掌腱膜桡侧挛缩 Fibrosis and contraction of palmar fascia Enhanced oxidative stress, increased inosine (alcohol exposure or diabeties) Gynecomastia, loss of male hair pattern Benign proliferation of glandular male breast tissue Enhanced conversion of androstenedione to oestrone and oestradiol, reduced oestradiol degradation in liver Hypogonadism Mainly in alcoholic cirrhosis and haemochromatosis Direct toxic effect of alcohol or iron Flapping tremor (asterixis) Asynchronous flapping motions of dorsiflexed hands Hepatic encephalopathy, disinhibition of motor neurons Foetor hepaticus Sweet, pungent smell Volatile dimethylsulfide, especially in portosystemic shunting and liver failure Anorexia, fatigue, weight loss, muscle wasting Occurs in >50% of patients with cirrhosis Catabolic metabolism by diseased liver, secondary to anorexia Type 2 diabetes Occurs in 15-30% of patients with cirrhosis Catabolic metabolism by diseased liver, secondary to anorexia Tendency to hemorrhage and anaemia --Reduced synthesis of coagulation factors (II,V,VII,IX,X) -- Hypersplenism: low platelet count, poor absorption -- Gastrointestinal bleeding Hormonal abnormalities -- Gynecomastia -- Telangiectases -- Spider nevi -- Palmar erythema Jaundice Hepatocellular Insufficiency Clinical features (I) spider nevi
