内科学：肝硬化和肝性脑病课件.ppt

1、ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCELiver CirrhosisNatural HistoryCirrhosis End stage of any chronic liver disease Characterized histologically by regenerative nodules surrounded by fibrous tissue Clinically there are two types of ci

2、rrhosis: Compensated DecompensatedDEFINITION OF CIRRHOSISCirrhosisNormalNodulesIrregular surfaceGROSS IMAGE OF A NORMAL AND A CIRRHOTIC LIVERCirrhotic liverNodular, irregular surfaceNodulesGROSS IMAGE OF A CIRRHOTIC LIVERCirrhosisNormalNodules surrounded by fibrous tissueHISTOLOGICAL IMAGE OF A NORM

3、AL AND A CIRRHOTIC LIVERHISTOLOGICAL IMAGE OF CIRRHOSISFibrosisRegenerative nodulePATHOGENESIS OF LIVER FIBROSISHepatocytesSpace of DisseSinusoidal endothelial cellHepatic stellate cellFenestraeNormal Hepatic SInusoidRetinoid dropletsPATHOGENESIS OF LIVER FIBROSISAlterations in Microvasculature in C

4、irrhosis Activation of stellate cells Collagen deposition in space of Disse Constriction of sinusoids Defenestration of sinusoidsNormal Liver Hepatic veinSinusoidPortal veinLiverSplenic veinCoronary veinTHE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOWPortal systemic collateralsDistorted sinusoid

5、al architectureleads to increased resistancePortal veinCirrhotic Liver SplenomegalyARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCEAN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSIONMesenteric veins FlowSplanchnicvasodilatationDisto

6、rted sinusoidal architechurePortal veinAn Increase in Portal Venous Inflow Sustains Portal HypertensionMechanisms of Portal Hypertension Pressure (P) results from the interaction of resistance (R) and flow (F):P = R x FPortal hypertension can result from: increase in resistance to portal flow and/or

7、 increase in portal venous inflowMECHANISMS OF PORTAL HYPERTENSIONCompensatedcirrhosisDecompensatedcirrhosisDeathChronic liver diseaseNatural History of Chronic Liver DiseaseDevelopment of complications: Variceal hemorrhage Ascites Encephalopathy JaundiceNATURAL HISTORY OF CHRONIC LIVER DISEASEDevel

8、opment of Complications in Compensated Cirrhosis AscitesJaundiceEncephalopathyGI hemorrhageProbability of developing event020608010006040204080100120140160MonthsGines et. al., Hepatology 1987; 7:122NATURAL HISTORY OF CIRRHOSIS604080100120140160040608020200100MonthsProbability of survivalAll patients

9、 with cirrhosisDecompensated cirrhosis180Decompensation Shortens SurvivalGines et. al., Hepatology 1987;7:122Median survival 9 yearsMedian survival 1.6 yearsSURVIVAL TIMES IN CIRRHOSISLiver insufficiencyVariceal hemorrhageComplications of Cirrhosis Result from Portal Hypertension or Liver Insufficie

10、ncyCirrhosisAscitesEncephalopathyJaundicePortal hypertensionSpontaneous bacterial peritonitisHepatorenal syndromeCOMPLICATIONS OF CIRRHOSISCirrhosis - Diagnosis Cirrhosis is a histological diagnosis However, in patients with chronic liver disease the presence of various clinical features suggests ci

11、rrhosis The presence of these clinical features can be followed by non-invasive testing, prior to liver biopsyDIAGNOSIS OF CIRRHOSISIn Whom Should We Suspect Cirrhosis? Any patient with chronic liver disease Chronic abnormal aminotransferases and/or alkaline phosphatase Physical exam findings Stigma

12、ta 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 FINDINGSLaboratory Liver insufficiency Low albumin ( 1.3) High bilirubin

13、 ( 1.5 mg/dL) Portal hypertension Low platelet count ( 1In Whom Should We Suspect Cirrhosis?DIAGNOSIS OF CIRRHOSIS LABORATORY STUDIESCT Scan in CirrhosisLiver with an irregular surfaceSplenomegalyCollateralsDIAGNOSIS OF CIRRHOSIS CAT SCANNoYesDiagnostic AlgorithmPatient with chronic liver disease an

14、d 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 synthetic functionRadiologi

15、cal findings: Small nodular liver Intra-abdominal collaterals Ascites Splenomegaly Colloid shift to spleen and/or bone marrowYesNoYesNoLiver biopsyDIAGNOSTIC ALGORITHMLiver insufficiencyVariceal hemorrhageComplications of Cirrhosis Result from Portal Hypertension or Liver InsufficiencyCirrhosisAscit

16、esEncephalopathyJaundicePortal hypertensionSpontaneous bacterial peritonitisHepatorenal syndromeCOMPLICATIONS OF CIRRHOSIS Cirrhosis is the most common cause of portal hypertension The site of increased resistance in cirrhosis is sinusoidal Other causes of portal hypertension are classified accordin

17、g to the site of increased resistanceCAUSES OF PORTAL HYPERTENSIONPortal Hypertension Is Classified According to the Site of Increased ResistanceTypeExamplePre-hepaticPortal or splenic vein thrombosisPre-sinusoidalSchistosomiasisSinusoidalCirrhosisPost-sinusoidalVeno-occlusive diseasePost-hepaticBud

18、d-Chiari syndromeCLASSIFICATION OF PORTAL HYPERTENSIONVasodilation and Hyperdynamic Circulation in Cirrhosis - Multiple Organ InvolvementSplanchnic vasodilationPeripheral vasodilationPulmonary vasodilationCerebral vasodilationVASODILATION AND HYPERDYNAMIC CIRCULATION IN CIRRHOSIS MULTIPLE ORGAN INVO

19、LVEMENTPortal venous inflowVariceal growthSplanchnic vasodilationVarices and Variceal HemorrhageVARICES AND VARICEAL HEMORRHAGEPortal Pressure MeasurementsDefinitive method to establish the diagnosis of portal hypertensionDirect methods (percutaneous, transjugular) are cumbersome and may be associat

20、ed with complicationsThe safest and most reproducible method is measurement of the hepatic venous pressure gradient (HVPG)PORTAL PRESSURE MEASUREMENTSPortal Pressure MeasurementsThe hepatic venous pressure gradient (HVPG) is obtained by subtracting the free hepatic venous pressure (FHVP) from the we

21、dged hepatic venous pressure (WHVP):The FHVP acts as an internal zero to correct for extravascular, intraabdominal pressure increases (e.g. ascites)HVPG = WHVP - FHVPPORTAL PRESSURE MEASUREMENTSSmall varicesLarge varicesNo varices7-8%/year7-8%/yearVarices Increase in Diameter ProgressivelyMerli et a

22、l. J Hepatol 2003;38:266VARICES INCREASE IN DIAMETER PROGRESSIVELYA Threshold Portal Pressure of 12 mmHg is Necessary for Varices to Form P 50 mEq/dayDiuretics Should be spironolactone-based A progressive schedule (spironolactone furosemide) requires fewer dose adjustments than a combined therapy (s

23、pironolactone + furosemide)MANAGEMENT OF UNCOMPLICATED ASCITESDefinition 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 m

24、aximal diuretic therapy (400 mg spironolactone + 160 mg furosemide/day)20%80%Arroyo et al. Hepatology 1996; 23:164DEFINITION AND TYPES OF REFRACTORY ASCITESSpontaneous Bacterial Peritonitis (SBP) Complicates Ascites and Can Lead to Renal Dysfunction SBPHVPG 10 mmHgExtreme VasodilationHVPG 10 mmHgSev

25、ere VasodilationHVPG 10 mmHgModerate VasodilationHVPG 250/mm3Rimola et al., J Hepatol 2000; 32:142EARLY DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)TREATMENTINDICATEDDiagnosis and Management of Spontaneous Bacterial PeritonitisDiagnostic ParacentesisPMN250?Culture Positive?TREATMENT NOT INDI

26、CATEDNORepeat ParacentesisYESPMN250?Culture Positive?NONOYESYESYESNOMANAGEMENT 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 (uncompli

27、cated 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 PERITONITIS (SBP)All SBPsSBP caused by gram-negative bacteriaProbabili

28、ty of SBP recurrenceMonthsp=0.0063PlaceboNorfloxacinPlacebop=0.0013Norfloxacin01.0.8.4.2.6481220016048122016MonthsNorfloxacin Reduces Recurrence of Spontaneous Bacterial PeritonitisGines et al., Hepatology 1990; 12:716NORFLOXACIN REDUCES RECURRENCE OF SPONTANEOUS BACTERIAL PERITONITIS (SBP)Indicatio

29、ns 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 recovered from SBP (long-term) Norfloxacin 400 mg p.o. daily, indefinitely Weekly quinolones not recommen

30、ded (lower efficacy, development of quinolone-resistance)INDICATIONS FOR PROPHYLACTIC ANTIBIOTICS TO PREVENT SPONTANEOUS BACTERIAL PERITONITIS (SBP)Hepatorenal SyndromeASCITES AND HEPATORENAL SYNDROMECharacteristics of Hepatorenal Syndrome Renal failure in patients with cirrhosis, advanced liver fai

31、lure 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 rateCHARACTERISTICS OF HEPATORENA

32、L SYNDROME (HRS)Two 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/dL or creatinine clearance 40 ml/min Absence of shock, bacterial infection, or nephrotoxic drugs Abs

33、ence 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 ultrasoundMajor Criteria in the Diagnosis of Hepatorenal SyndromeArroyo et al., Hepatology 1996; 23:164MAJOR

34、CRITERIA IN DIAGNOSING HEPATORENAL SYNDROMEUrine Sodium and Urine Volume are Minor Criteria in the Diagnosis of HRSMinor criteriaUrine sodium plasma osmolalitySerum sodium 130 mEq/LUrine volume 500 ml/dayUrine RBCs 50/HPFArroyo et al., Hepatology 1996; 23:164URINE SODIUM AND URINE VOLUME ARE MINOR C

35、RITERIA IN THE DIAGNOSIS OF HEPATORENAL SYNDROME (HRS)Activation of neurohumoral systemsSite of Action of Different Therapies for HRSAdvanced CirrhosisIntrahepatic resistanceArteriolar resistance(vasodilation)Sinusoidal pressureHepatorenal syndromeRenal vasoconstrictionTIPSTIPSTransplantEffective ar

36、terial blood volumeVaso-constrictorsAlbuminMECHANISM OF ACTION OF THE DIFFERENT THERAPIES FOR HEPATORENAL SYNDROME (HRS)Management of Hepatorenal SyndromeProven efficacy Liver transplantationUnder investigation Vasoconstrictor + albumin Transjugular intrahepatic portosystemic shunt (TIPS) Vasoconstr

37、ictor + TIPS Extracorporeal albumin dialysis (ECAD)Ineffective Renal vasodilators (prostaglandin, dopamine) HemodialysisMANAGEMENT OF HEPATORENAL SYNDROMELiver insufficiencyVariceal hemorrhageComplications of Cirrhosis Result from Portal Hypertension or Liver InsufficiencyCirrhosisAscitesEncephalopa

38、thyJaundicePortal hypertensionSpontaneous bacterial peritonitisHepatorenal syndromeCOMPLICATIONS OF CIRRHOSISHEPATIC ENCEPHALOPATHYHepatic EncephalopathyHepatic EncephalopathyNomenclature Type AAssociated with Acute liver failure Type BAssociated with porto-systemic Bypass without intrinsic hepatoce

39、llular disease Type CAssociated with Cirrhosis and porto-systemic shuntingFerenci et al., Hepatology 2002; 35:716HEPATIC ENCEPHALOPATHY NOMENCLATURETreatment: rarely effective short of liver transplantCharacteristics of Type A vs. Type C Hepatic EncephalopathyGradual onsetRarely fatalMain cause: shu

40、nting / toxinPrecipitantTreatment: usually effectiveRapid onsetFrequently fatalMain cause:cerebral edemaType AType CCHARACTERISTICS OF TYPE A VS. TYPE C ENCEPHALOPATHYType C Hepatic Encephalopathy is the Encephalopathy of Cirrhosis Neuropsychiatric complication of cirrhosisResults from spontaneous o

41、r 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 CIRRHOSISHepatic Encephalopathy PathogenesisBacter

42、ial actionProtein loadFailure to metabolize NH3NH3 ShuntingGABA-BD receptorsToxinsPATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHYHepatic Encephalopathy Is A Clinical Diagnosis Clinical findings and history important Ammonia levels are unreliable Ammonia has poor correlation with diagnosis Measurement of a

43、mmonia not necessary Number connection test Slow dominant rhythm on EEGHEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSISSTAGES OF HEPATIC ENCEPHALOPATHYConfusionDrowsinessSomnolenceComa1234StageStages of Hepatic Encephalopathy12345678910111213141516171819202122232425BeginEndTime to complete_Number Conn

44、ection Test (NCT)Sample handwritingDraw a starNUMBER CONNECTION TEST70Electroencephalogram in Hepatic EncephalopathyELECTROENCEPHALOGRAM IN HEPATIC ENCEPHALOPATHYMinimal Hepatic Encephalopathy Occurs in 30-70% of cirrhotic patients without overt hepatic encephalopathy Detected by psychometric and ne

45、uro-psychological testing May improve with lactulose or synbiotics (probiotics and fermentable fiber)MINIMAL HEPATIC ENCEPHALOPATHYMinimal Hepatic EncephalopathyAbnormalities on testing Attention and cognitive deficits Visual-spacial perception impaired Defects in visual constructive ability Impaire

46、d driving ability Evoked potentials and spectral electro-encephalography abnormalMINIMAL HEPATIC ENCEPHALOPATHY ABNORMALITIES ON TESTINGTreatment of Hepatic Encephalopathy Identify and treat precipitating factor Infection GI hemorrhage Prerenal azotemia Sedatives Constipation Lactulose (adjust to 2-

47、3 bowel movements/day) Protein restriction, short-term (if at all)TREATMENT OF HEPATIC ENCEPHALOPATHYHepatic Encephalopathy PrecipitantsGI bleedingExcess proteinSedatives / hypnoticsTIPSDiureticsSerum K+Plasma volume AzotemiaTempInfectionsHEPATIC ENCEPHALOPATHY PRECIPITANTSActions of LactuloseLactul

48、oseLactic acidDecreased pHNH3Urease-producing bacteriaIncrease cathartic effectNH3NH4+ACTIONS OF LACTULOSEHepatic EncephalopathyTreatment: SummaryDecrease ammonia production in gut: Lactulose Antibiotics Adjustment in dietary proteinIncrease ammonia fixation in liver: Ornithine aspartate BenzoateShu

49、nt occlusion or reductionHEPATIC ENCEPHALOPATHY TREATMENT SUMMARYFlumazenilRifaximinpA minimally absorbed oral antimicrobial agent that is concentrated in the gastrointestinal tractpBroad-spectrum in vitro activity against gram-positive and gram-negative aerobic and anaerobic enteric bacteriapA low

50、risk of inducing bacterial resistance Liver insufficiencyVariceal hemorrhageComplications of Cirrhosis Result from Portal Hypertension or Liver InsufficiencyCirrhosisAscitesEncephalopathyJaundicePortal hypertensionSpontaneous bacterial peritonitisHepatorenal syndromeCOMPLICATIONS OF CIRRHOSISNew The