上海交通大学医学院内科学livercirrh课件

1、上海交通大学医学院内科学livercirrhARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCEHepatic cirrhosisMa Xiong, M.D., Associate ProfessorShanghai Institute of Digestive Disease, Renji HospitalShanghai Jiao Tong University School of Medicine上海交通大学医学院内科学livercir

2、rhHepatic 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 DecompensatedDEFINITION OF CIRRHOSIS上海交通大学医学院内科学livercirrhCirrhosisNormalNodulesIrregular surfaceGROSS

3、 IMAGE OF A NORMAL AND A CIRRHOTIC LIVER上海交通大学医学院内科学livercirrhCirrhotic liverNodular, irregular surfaceNodulesGROSS IMAGE OF A CIRRHOTIC LIVER上海交通大学医学院内科学livercirrhCirrhosisNormalNodules surrounded by fibrous tissueHISTOLOGICAL IMAGE OF A NORMAL AND A CIRRHOTIC LIVER上海交通大学医学院内科学livercirrhHISTOLOGICA

4、L IMAGE OF CIRRHOSISFibrosisRegenerative nodule上海交通大学医学院内科学livercirrhPATHOGENESIS OF LIVER FIBROSISHepatocytesSpace of DisseSinusoidal endothelial cellHepatic stellate cellFenestraeNormal Hepatic SInusoidRetinoid droplets上海交通大学医学院内科学livercirrhPATHOGENESIS OF LIVER FIBROSISAlterations in Microvascula

5、ture in Cirrhosis Activation of stellate cells Collagen deposition in space of Disse Constriction of sinusoids Defenestration of sinusoids上海交通大学医学院内科学livercirrhCompensatedcirrhosisDecompensatedcirrhosisDeathChronic liver diseaseNatural History of Chronic Liver DiseaseDevelopment of complications: Va

6、riceal hemorrhage Ascites Encephalopathy JaundiceNATURAL HISTORY OF CHRONIC LIVER DISEASE上海交通大学医学院内科学livercirrh604080100120140160040608020200100MonthsProbability of survivalAll patients with cirrhosisDecompensated cirrhosis180Decompensation Shortens SurvivalGines et. al., Hepatology 1987;7:122Median

7、 survival 9 yearsMedian survival 1.6 yearsSURVIVAL TIMES IN CIRRHOSIS10上海交通大学医学院内科学livercirrhLiver insufficiencyVariceal hemorrhageComplications of Cirrhosis Result from Portal Hypertension or Liver InsufficiencyCirrhosisAscitesEncephalopathyJaundicePortal hypertensionSpontaneous bacterial peritonit

8、isHepatorenal syndromeCOMPLICATIONS OF CIRRHOSIS上海交通大学医学院内科学livercirrhCirrhosis - 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 no

9、n-invasive testing, prior to liver biopsyDIAGNOSIS OF CIRRHOSIS上海交通大学医学院内科学livercirrhIn 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, va

10、scular spiders, palmar erythema) Palpable left lobe of the liver Small liver span Splenomegaly Signs of decompensation (jaundice, ascites, asterixis)DIAGNOSIS OF CIRRHOSIS CLINICAL FINDINGS上海交通大学医学院内科学livercirrhLaboratory Liver insufficiency Low albumin ( 1.3) High bilirubin ( 1.5 mg/dL) Portal hype

11、rtension Low platelet count ( 1In Whom Should We Suspect Cirrhosis?DIAGNOSIS OF CIRRHOSIS LABORATORY STUDIES上海交通大学医学院内科学livercirrhCT Scan in CirrhosisLiver with an irregular surfaceSplenomegalyCollateralsDIAGNOSIS OF CIRRHOSIS CAT SCAN上海交通大学医学院内科学livercirrhNoYesDiagnostic AlgorithmPatient with chron

12、ic liver disease and any of the following: Variceal hemorrhage Ascites Hepatic encephalopathyLiver biopsy not necessary for the diagnosis of cirrhosisPhysical findings:Enlarged left hepatic lobeSplenomegalyStigmata of chronic liver diseaseLaboratory findings:ThrombocytopeniaImpaired hepatic syntheti

13、c functionRadiological findings: Small nodular liver Intra-abdominal collaterals Ascites Splenomegaly Colloid shift to spleen and/or bone marrowYesNoYesNoLiver biopsyDIAGNOSTIC ALGORITHM上海交通大学医学院内科学livercirrhMechanisms of Portal Hypertension Pressure (P) results from the interaction of resistance (R

14、) and flow (F):P = R x FPortal hypertension can result from: increase in resistance to portal flow and/or increase in portal venous inflowMECHANISMS OF PORTAL HYPERTENSION上海交通大学医学院内科学livercirrhNormal Liver Hepatic veinSinusoidPortal veinLiverSplenic veinCoronary veinTHE NORMAL LIVER OFFERS ALMOST NO

15、 RESISTANCE TO FLOW上海交通大学医学院内科学livercirrhPortal systemic collateralsDistorted sinusoidal architectureleads to increased resistancePortal veinCirrhotic Liver SplenomegalyARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE上海交通大学医学院内科学livercirrhAN INC

16、REASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSIONMesenteric veins FlowSplanchnicvasodilatationDistorted sinusoidal architechurePortal veinAn Increase in Portal Venous Inflow Sustains Portal Hypertension20上海交通大学医学院内科学livercirrhSmall varicesLarge varicesNo varices7-8%/year7-8%/yearVarices Inc

17、rease in Diameter ProgressivelyMerli et al. J Hepatol 2003;38:266VARICES INCREASE IN DIAMETER PROGRESSIVELY上海交通大学医学院内科学livercirrhA Threshold Portal Pressure of 12 mmHg is Necessary for Varices to Form P 50 mEq/dayDiuretics Should be spironolactone-based A progressive schedule (spironolactone furosem

18、ide) requires fewer dose adjustments than a combined therapy (spironolactone + furosemide)MANAGEMENT OF UNCOMPLICATED ASCITES上海交通大学医学院内科学livercirrhSodium Restriction 2 g (or 5.2 g of dietary salt) a day Fluid restriction is not necessary unless there is hyponatremia (125 mmol/L) Goal: negative sodiu

19、m balance Side effect: unpalatability may compromise nutritional statusManagement of Uncomplicated AscitesMANAGEMENT OF UNCOMPLICATED ASCITES: SODIUM RESTRICTION40上海交通大学医学院内科学livercirrhDiuretic TherapyDosageSpironolactone 100-400 mg/day Furosemide (40-160 mg/d) for inadequate weight loss or if hyper

20、kalemia develops Increase diuretics if weight loss 1 kg in the first week and 0.5 kg/day in patients without edema and 1 kg/day in those with edema Side effectsRenal dysfunction, hyponatremia, hyperkalemia, encephalopathy, gynecomastiaManagement of Uncomplicated AscitesMANAGEMENT OF UNCOMPLICATED AS

21、CITES: DIURETIC THERAPY上海交通大学医学院内科学livercirrhDefinition and Types of Refractory AscitesOccurs in 10% of cirrhotic patientsDiuretic-intractable ascitesTherapeutic doses of diuretics cannot be achieved because of diuretic-induced complicationsDiuretic-resistant ascitesNo response to maximal diuretic t

22、herapy (400 mg spironolactone + 160 mg furosemide/day)20%80%Arroyo et al. Hepatology 1996; 23:164DEFINITION AND TYPES OF REFRACTORY ASCITES上海交通大学医学院内科学livercirrhPeritoneo-Venous Shunt (PVS) is Useful in the Treatment of Refractory AscitesUse of jugular vein will hinder TIPS placement Intraabdominal

23、adhesions may complicate liver transplant surgeryOne-way valvePERITONEO-VENOUS SHUNT (PVS) IS USEFUL IN THE TREATMENT OF REFRACTORY ASCITES上海交通大学医学院内科学livercirrhTreatment of AscitesHepatorenalSyndromeRefractoryAscitesUncomplicatedAscitesPortal HypertensionNo Ascites1) LVP + albumin2) TIPS3) PVS (in

24、non-TIPS, non-transplant candidates)LVP = large volume paracentesisTIPS = transjugular intrahepatic portosystemic shuntTREATMENT OF REFRACTORY ASCITES44上海交通大学医学院内科学livercirrhSpontaneous Bacterial Peritonitis (SBP) Complicates Ascites and Can Lead to Renal Dysfunction SBPHVPG 10 mmHgExtreme Vasodilat

25、ionHVPG 10 mmHgSevere VasodilationHVPG 10 mmHgModerate VasodilationHVPG 250/mm3Rimola et al., J Hepatol 2000; 32:142EARLY DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)上海交通大学医学院内科学livercirrhTREATMENTINDICATEDDiagnosis and Management of Spontaneous Bacterial PeritonitisDiagnostic ParacentesisPM

26、N250?Culture Positive?TREATMENT NOT INDICATEDNORepeat ParacentesisYESPMN250?Culture Positive?NONOYESYESYESNOMANAGEMENT ALGORITHM IN SPONTANEOUS BACTERIAL PERITONITIS (SBP)上海交通大学医学院内科学livercirrhTreatment of Spontaneous Bacterial Peritonitis Recommended antibiotics for initial empiric therapy i.v. cef

27、otaxime, 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 treatmentRimola et al., J Hepatol 2000; 32:142TREATMENT OF SPONTANEOUS BACTERIAL PERITONI

28、TIS (SBP)上海交通大学医学院内科学livercirrhAll SBPsSBP caused by gram-negative bacteriaProbability of SBP recurrenceMonthsp=0.0063PlaceboNorfloxacinPlacebop=0.0013Norfloxacin01.0.8.4.2.6481220016048122016MonthsNorfloxacin Reduces Recurrence of Spontaneous Bacterial PeritonitisGines et al., Hepatology 1990; 12:7

29、16NORFLOXACIN REDUCES RECURRENCE OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)上海交通大学医学院内科学livercirrhIndications for Prophylactic Antibiotics to Prevent Spontaneous Bacterial Peritonitis Cirrhotic patients hospitalized with GI hemorrhage (short-term) Norfloxacin 400 mg p.o. BID x 7 daysPatients who have

30、 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上海交通大学医学院内科学livercirrhCharacteristics of Hep

31、atorenal 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 vasoconstrict

32、ion leading to reduced glomerular filtration rateCHARACTERISTICS OF HEPATORENAL SYNDROME (HRS)上海交通大学医学院内科学livercirrhTwo Types of Hepatorenal SyndromeType 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/

33、dL or creatinine clearance 40 ml/min Absence of shock, bacterial infection, or nephrotoxic drugs Absence of excessive gastrointestinal or renal fluid loss No improvement in renal function after plasma volume expansion with 1.5 L of isotonic saline Urinary protein 500 mg/dL and normal renal ultrasoun

34、dMajor Criteria in the Diagnosis of Hepatorenal SyndromeArroyo et al., Hepatology 1996; 23:164MAJOR CRITERIA IN DIAGNOSING HEPATORENAL SYNDROME上海交通大学医学院内科学livercirrhUrine Sodium and Urine Volume are Minor Criteria in the Diagnosis of HRSMinor criteriaUrine sodium plasma osmolalitySerum sodium 130 mE

35、q/LUrine volume 500 ml/dayUrine RBCs 50/HPFArroyo et al., Hepatology 1996; 23:164URINE SODIUM AND URINE VOLUME ARE MINOR CRITERIA IN THE DIAGNOSIS OF HEPATORENAL SYNDROME (HRS)上海交通大学医学院内科学livercirrhActivation of neurohumoral systemsSite of Action of Different Therapies for HRSAdvanced CirrhosisIntra

36、hepatic resistanceArteriolar resistance(vasodilation)Sinusoidal pressureHepatorenal syndromeRenal vasoconstrictionTIPSTIPSTransplantEffective arterial blood volumeVaso-constrictorsAlbuminMECHANISM OF ACTION OF THE DIFFERENT THERAPIES FOR HEPATORENAL SYNDROME (HRS)上海交通大学医学院内科学livercirrhManagement of

37、Hepatorenal SyndromeProven efficacy Liver transplantationUnder investigation Vasoconstrictor + albumin Transjugular intrahepatic portosystemic shunt (TIPS) Vasoconstrictor + TIPS Extracorporeal albumin dialysis (ECAD)Ineffective Renal vasodilators (prostaglandin, dopamine) HemodialysisMANAGEMENT OF

38、HEPATORENAL SYNDROME上海交通大学医学院内科学livercirrhHEPATIC ENCEPHALOPATHYHepatic Encephalopathy60上海交通大学医学院内科学livercirrhHepatic EncephalopathyNomenclature Type AAssociated with Acute liver failure Type BAssociated with porto-systemic Bypass without intrinsic hepatocellular disease Type CAssociated with Cirrho

39、sis and porto-systemic shuntingFerenci et al., Hepatology 2002; 35:716HEPATIC ENCEPHALOPATHY NOMENCLATURE上海交通大学医学院内科学livercirrhTreatment: rarely effective short of liver transplantCharacteristics of Type A vs. Type C Hepatic EncephalopathyGradual onsetRarely fatalMain cause: shunting / toxinPrecipit

40、antTreatment: usually effectiveRapid onsetFrequently fatalMain cause:cerebral edemaType AType CCHARACTERISTICS OF TYPE A VS. TYPE C ENCEPHALOPATHY上海交通大学医学院内科学livercirrhType C Hepatic Encephalopathy is the Encephalopathy of Cirrhosis Neuropsychiatric complication of cirrhosisResults from spontaneous

41、or surgical / radiological portal-systemic shunt + chronic liver failureFailure to metabolize neurotoxic substancesAlterations of astrocyte morphology and function (Alzheimer type II astrocytosis)TYPE C HEPATIC ENCEPHALOPATHY IS THE ENCEPHALOPATHY OF CIRRHOSIS上海交通大学医学院内科学livercirrhHepatic Encephalop

42、athy PathogenesisBacterial actionProtein loadFailure to metabolize NH3NH3 ShuntingGABA-BD receptorsToxinsPATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY上海交通大学医学院内科学livercirrhHepatic Encephalopathy Is A Clinical Diagnosis Clinical findings and history important Ammonia levels are unreliable Ammonia has poo

43、r correlation with diagnosis Measurement of ammonia not necessary Number connection test Slow dominant rhythm on EEGHEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSIS上海交通大学医学院内科学livercirrhStageMental stateNeurologic signs1Mild confusion: limited attention Incoordination, tremor,span, irritability, inver

44、ted sleep impaired handwritingpattern2Drowsiness, personality changes,Asterixis, ataxia, dysarthriaintermittent disorientation3Somnolent, gross disorientation,Hyperreflexia, musclemarked confusion, slurred speechrigidity, Babinski sign4ComaNo response to pain, decerebrate postureStages of Hepatic En

45、cephalopathySTAGES OF HEPATIC ENCEPHALOPATHY上海交通大学医学院内科学livercirrhSTAGES OF HEPATIC ENCEPHALOPATHYConfusionDrowsinessSomnolenceComa1234StageStages of Hepatic Encephalopathy上海交通大学医学院内科学livercirrhAsterixisASTERIXIS IS THE HALLMARK IN THE DIAGNOSIS OF HEPATIC ENCEPHALOPATHY上海交通大学医学院内科学livercirrh12345678910111213141516171819202122232425BeginEndTime to complete_Number Connection Test (NCT)Sample handwritingDraw a starNUMBER CONNECTION TEST70上海交通大学医学院内科学livercirrhElectroencephalogram in Hepatic EncephalopathyELECTROENCEPHALOGRAM IN HEPATIC ENCEPHALOPATHY上海交通大学医学院内科学live