上海交通大学医学院内科学课件 liver cirrh.ppt

ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE Hepatic cirrhosis Ma Xiong, M.D., Associate Professor Shanghai Institute of Digestive Disease, Renji Hospital Shanghai Jiao Tong University School of Medicine Hepatic Cirrhosis End stage of any chronic liver disease Characterized histologically by regenerative nodules surrounded by fibrous tissue Clinically there are two types of cirrhosis: Compensated Decompensated DEFINITION OF CIRRHOSIS CirrhosisNormal Nodules Irregular surface GROSS IMAGE OF A NORMAL AND A CIRRHOTIC LIVER Cirrhotic liver Nodular, irregular surface Nodules GROSS IMAGE OF A CIRRHOTIC LIVER CirrhosisNormal Nodules surrounded by fibrous tissue HISTOLOGICAL IMAGE OF A NORMAL AND A CIRRHOTIC LIVER HISTOLOGICAL IMAGE OF CIRRHOSIS Fibrosis Regenerative nodule PATHOGENESIS OF LIVER FIBROSIS Hepatocytes Space of Disse Sinusoidal endothelial cell Hepatic stellate cell Fenestrae Normal Hepatic SInusoid Retinoid droplets PATHOGENESIS OF LIVER FIBROSIS Alterations in Microvasculature in Cirrhosis Activation of stellate cells Collagen deposition in space of Disse Constriction of sinusoids Defenestration of sinusoids Compensated cirrhosis Decompensated cirrhosis Death Chronic liver disease Natural History of Chronic Liver Disease Development of complications: Variceal hemorrhage Ascites Encephalopathy Jaundice NATURAL HISTORY OF CHRONIC LIVER DISEASE 604080100120140160 0 40 60 80 20 200 100 Months Probability of survival All patients with cirrhosis Decompensated cirrhosis 180 Decompensation Shortens Survival Gines et. al., Hepatology 1987;7:122 Median survival 9 years Median survival 1.6 years SURVIVAL TIMES IN CIRRHOSIS 10 Liver insufficiency Variceal hemorrhage Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency Cirrhosis Ascites Encephalopathy Jaundice Portal hypertension Spontaneous bacterial peritonitis Hepatorenal syndrome COMPLICATIONS OF CIRRHOSIS Cirrhosis - Diagnosis Cirrhosis is a histological diagnosis However, in patients with chronic liver disease the presence of various clinical features suggests cirrhosis The presence of these clinical features can be followed by non- invasive testing, prior to liver biopsy DIAGNOSIS OF CIRRHOSIS In Whom Should We Suspect Cirrhosis? Any patient with chronic liver disease Chronic abnormal aminotransferases and/or alkaline phosphatase Physical exam findings Stigmata of chronic liver disease (muscle wasting, vascular spiders, palmar erythema) Palpable left lobe of the liver Small liver span Splenomegaly Signs of decompensation (jaundice, ascites, asterixis) DIAGNOSIS OF CIRRHOSIS CLINICAL FINDINGS Laboratory Liver insufficiency Low albumin ( 1.3) High bilirubin ( 1.5 mg/dL) Portal hypertension Low platelet count ( 1 In Whom Should We Suspect Cirrhosis? DIAGNOSIS OF CIRRHOSIS LABORATORY STUDIES CT Scan in Cirrhosis Liver with an irregular surfaceSplenomegalyCollaterals DIAGNOSIS OF CIRRHOSIS CAT SCAN No Yes Diagnostic Algorithm Patient with chronic liver disease and any of the following: Variceal hemorrhage Ascites Hepatic encephalopathy Liver biopsy not necessary for the diagnosis of cirrhosis Physical findings: Enlarged left hepatic lobe Splenomegaly Stigmata of chronic liver disease Laboratory findings: Thrombocytopenia Impaired hepatic synthetic function Radiological findings: Small nodular liver Intra-abdominal collaterals Ascites Splenomegaly Colloid shift to spleen and/or bone marrow YesNo YesNo Liver biopsy DIAGNOSTIC ALGORITHM Mechanisms of Portal Hypertension Pressure (P) results from the interaction of resistance (R) and flow (F): P = R x F Portal hypertension can result from: increase in resistance to portal flow and/or increase in portal venous inflow MECHANISMS OF PORTAL HYPERTENSION Normal Liver Hepatic vein Sinusoid Portal vein Liver Splenic vein Coronary vein THE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOW Portal systemic collaterals Distorted sinusoidal architecture leads to increased resistance Portal vein Cirrhotic Liver Splenomegaly ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION Mesenteric veins Flow Splanchnic vasodilatation Distorted sinusoidal architechure Portal vein An Increase in Portal Venous Inflow Sustains Portal Hypertension 20 Small varicesLarge varicesNo varices 7-8%/year7-8%/year Varices Increase in Diameter Progressively Merli et al. J Hepatol 2003;38:266 VARICES INCREASE IN DIAMETER PROGRESSIVELY A Threshold Portal Pressure of 12 mmHg is Necessary for Varices to Form P 50 mEq/day Diuretics Should be spironolactone-based A progressive schedule (spironolactone furosemide) requires fewer dose adjustments than a combined therapy (spironolactone + furosemide) MANAGEMENT OF UNCOMPLICATED ASCITES Sodium Restriction 2 g (or 5.2 g of dietary salt) a day Fluid restriction is not necessary unless there is hyponatremia (0.5 kg/day in patients without edema and 1 kg/day in those with edema Side effects Renal dysfunction, hyponatremia, hyperkalemia, encephalopathy, gynecomastia Management of Uncomplicated Ascites MANAGEMENT OF UNCOMPLICATED ASCITES: DIURETIC THERAPY Definition and Types of Refractory Ascites Occurs in 10% of cirrhotic patients Diuretic-intractable ascites Therapeutic doses of diuretics cannot be achieved because of diuretic-induced complications Diuretic-resistant ascites No response to maximal diuretic therapy (400 mg spironolactone + 160 mg furosemide/day) 20% 80% Arroyo et al. Hepatology 1996; 23:164 DEFINITION AND TYPES OF REFRACTORY ASCITES Peritoneo-Venous Shunt (PVS) is Useful in the Treatment of Refractory Ascites Use of jugular vein will hinder TIPS placement Intraabdominal adhesions may complicate liver transplant surgery One-way valve PERITONEO-VENOUS SHUNT (PVS) IS USEFUL IN THE TREATMENT OF REFRACTORY ASCITES Treatment of Ascites Hepatorenal Syndrome Refractory Ascites Uncomplicated Ascites Portal Hypertension No Ascites 1) LVP + albumin 2) TIPS 3) PVS (in non-TIPS, non-transplant candidates) LVP = large volume paracentesis TIPS = transjugular intrahepatic portosystemic shunt TREATMENT OF REFRACTORY ASCITES 44 Spontaneous Bacterial Peritonitis (SBP) Complicates Ascites and Can Lead to Renal Dysfunction SBP HVPG 10 mmHg Extreme Vasodilation HVPG 10 mmHg Severe Vasodilation HVPG 10 mmHg Moderate Vasodilation HVPG 250/mm3 Rimola et al., J Hepatol 2000; 32:142 EARLY DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS (SBP) TREATMENT INDICATED Diagnosis and Management of Spontaneous Bacterial Peritonitis Diagnostic Paracentesis PMN250? Culture Positive? TREATMENT NOT INDICATED NO Repeat Paracentesis YES PMN250? Culture Positive? NO NO YES YES YESNO MANAGEMENT ALGORITHM IN SPONTANEOUS BACTERIAL PERITONITIS (SBP) Treatment of Spontaneous Bacterial Peritonitis Recommended antibiotics for initial empiric therapy i.v. cefotaxime, amoxicillin-clavulanic acid oral nofloxacin (uncomplicated SBP) avoid aminoglycosides Minimum duration: 5 days Re-evaluation if ascitic fluid PMN count has not decreased by at least 25% after 2 days of treatment Rimola et al., J Hepatol 2000; 32:142 TREATMENT OF SPONTANEOUS BACTERIAL PERITONITIS (SBP) All SBPs SBP caused by gram- negative bacteria Probability of SBP recurrence Months p=0.0063 Placebo Norfloxacin Placebo p=0.0013 Norfloxacin 0 1.0 .8 .4 .2 .6 481220 0 16048122016 Months Norfloxacin Reduces Recurrence of Spontaneous Bacterial Peritonitis Gines et al., Hepatology 1990; 12:716 NORFLOXACIN REDUCES RECURRENCE OF SPONTANEOUS BACTERIAL PERITONITIS (SBP) Indications for Prophylactic Antibiotics to Prevent Spontaneous Bacterial Peritonitis Cirrhotic patients hospitalized with GI hemorrhage (short-term) Norfloxacin 400 mg p.o. BID x 7 days Patients who have recovered from SBP (long-term) Norfloxacin 400 mg p.o. daily, indefinitely Weekly quinolones not recommended (lower efficacy, development of quinolone-resistance) INDICATIONS FOR PROPHYLACTIC ANTIBIOTICS TO PREVENT SPONTANEOUS BACTERIAL PERITONITIS (SBP) 50 Characteristics of Hepatorenal Syndrome Renal failure in patients with cirrhosis, advanced liver failure and severe sinusoidal portal hypertension Absence of significant histological changes in the kidney (“functional” renal failure) Marked arteriolar vasodilation in the extra-renal circulation Marked renal vasoconstriction leading to reduced glomerular filtration rate CHARACTERISTICS OF HEPATORENAL SYNDROME (HRS) Two Types of Hepatorenal Syndrome Type 1 Rapidly progressive renal failure (2 weeks) Doubling of creatinine to 2.5 or halving of creatinine clearance (CrCl) to 1.5 mg/dL or CrCl 1.5 mg/dL or creatinine clearance plasma osmolality Serum sodium 130 mEq/L Urine volume 500 ml/day Urine RBCs 50/HPF Arroyo et al., Hepatology 1996; 23:164 URINE SODIUM AND URINE VOLUME ARE MINOR CRITERIA IN THE DIAGNOSIS OF HEPATORENAL SYNDROME (HRS) Activation of neurohumoral systems Site of Action of Different Therapies for HRS Advanced Cirrhosis Intrahepatic resistance Arteriolar resistance (vasodilation) Sinusoidal pressure Hepatorenal syndrome Renal vasoconstriction TIPS TIPS Transplant Effective arterial blood volume Vaso- constrictors Albumin MECHANISM OF ACTION OF THE DIFFERENT THERAPIES FOR HEPATORENAL SYNDROME (HRS) Management of Hepatorenal Syndrome Proven efficacy Liver transplantation Under investigation Vasoconstrictor + albumin Transjugular intrahepatic portosystemic shunt (TIPS) Vasoconstrictor + TIPS Extracorporeal albumin dialysis (ECAD) Ineffective Renal vasodilators (prostaglandin, dopamine) Hemodialysis MANAGEMENT OF HEPATORENAL SYNDROME HEPATIC ENCEPHALOPATHY Hepatic Encephalopathy 60 Hepatic Encephalopathy Nomenclature Type A Associated with Acute liver failure Type B Associated with porto-systemic Bypass without intrinsic hepatocellular disease Type C Associated with Cirrhosis and porto-systemic shunting Ferenci et al., Hepatology 2002; 35:716 HEPATIC ENCEPHALOPATHY NOMENCLATURE Treatment: rarely effective short of liver transplant Characteristics of Type A vs. Type C Hepatic Encephalopathy Gradual onset Rarely fatal Main cause: shunting / toxin Precipitant Treatment: usually effective Rapid onset Frequently fatal Main cause: cerebral edema Type AType C CHARACTERISTICS OF TYPE A VS. TYPE C ENCEPHALOPATHY Type C Hepatic Encephalopathy is the Encephalopathy of Cirrhosis Neuropsychiatric complication of cirrhosis Results from spontaneous or surgical / radiological portal-systemic shunt + chronic liver failure Failure to metabolize neurotoxic substances Alterations of astrocyte morphology and function (Alzheimer type II astrocytosis) TYPE C HEPATIC ENCEPHALOPATHY IS THE ENCEPHALOPATHY OF CIRRHOSIS Hepatic Encephalopathy Pathogenesis Bacterial action Protein load Failure to metabolize NH3 NH3 Shunting GABA-BD receptors Toxins PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY Hepatic Encephalopathy Is A Clinical Diagnosis Clinical findings and history important Ammonia levels are unreliable Ammonia has poor correlation with diagnosis Measurement of ammonia not necessary Number connection test Slow dominant rhythm on EEG HEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSIS StageMental stateNeurologic signs 1Mild confusion: limited attention Incoordination, tremor, span, irritability, inverted sleep impaired handwriting pattern 2Drowsiness, personality changes,Asterixis, ataxia, dysarthria intermittent disorientation 3Somnolent, gross disorientation,Hyperreflexia, muscle marked confusion, slurred speechrigidity, Babinski sign 4ComaNo response to pain, decerebrate posture Stages of Hepatic Encephalopathy STAGES OF HEPATIC ENCEPHALOPATHY STAGES OF HEPATIC ENCEPHALOPATHY Confusion Drowsiness Somnolence Coma 123 4 Stage Stages of Hepatic Encephalopathy Asterixis ASTERIXIS IS THE HALLMARK IN THE DIAGNOSIS OF HEPATIC ENCEPHALOPATHY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1516 17 18 1920 21 22 23 24 25 Begin End Time to complete_ Number Connection Test (NCT) Sample handwriting Draw a star NUMBER CONNECTION TEST 70 Electroencephalogram in Hepatic Encephalopathy ELECTROENCEPHALOGRAM IN HEPATIC ENCEPHALOPATHY Minimal Hepatic Encephalopathy Occurs in 30-70% of cirrhotic patients without overt hepati