内科学课件09-肝硬化和肝性脑病.ppt

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

2、es of cirrhosis: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

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

4、e in Cirrhosis 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 si

5、nusoidal 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 FlowSplanchnicvasodilatatio

6、nDistorted 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 i

7、ncrease 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 DISEASEDevelopm

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

9、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 InsufficiencyCirrh

10、osisAscitesEncephalopathyJaundicePortal 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 cirrhosis The

11、 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 Stigmata of chronic

12、 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(1.5 mg/dL)Portal hyper

13、tension 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 and any of the following:Varic

14、eal 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 functionRadiological findings:Small nodular li

15、ver 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 InsufficiencyCirrhosisAscitesEncephalopathyJaundicePortal

16、 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 according to the site of increased res

17、istanceCAUSES OF PORTAL HYPERTENSIONPortal Hypertension Is Classified According to the Site of Increased ResistanceTypeExamplePre-hepaticPortal or splenic vein thrombosisPre-sinusoidalSchistosomiasisSinusoidalCirrhosisPost-sinusoidalVeno-occlusive diseasePost-hepaticBudd-Chiari syndromeCLASSIFICATIO

18、N OF PORTAL HYPERTENSIONPortal venous inflowVariceal growthSplanchnic vasodilationVarices and Variceal HemorrhageVARICES AND VARICEAL HEMORRHAGEPortal Pressure MeasurementsThe hepatic venous pressure gradient(HVPG)is obtained by subtracting the free hepatic venous pressure(FHVP)from the wedged hepat

19、ic 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 al.J Hepatol 2003;3

20、8:266VARICES 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(spironolactone+furosemi

21、de)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 maximal diuretic therapy(4

22、00 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 mmHgSevere VasodilationHVPG 10 mmHgMode

23、rate 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 INDICATEDNORepeat ParacentesisYESPMN250

24、?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(uncomplicated SBP)avoid aminoglycosides Minimum

25、 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 bacteriaProbability of SBP recurrenceMonthsp=0.0063PlaceboNorf

26、loxacinPlacebop=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)Indications for Prophylactic Antibiotics to Prevent Spont

27、aneous 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 recommended(lower efficacy,development of quinolone-resistance)

28、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 failure and severe sinusoidal portal hypertension Absence of s

29、ignificant 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 HEPATORENAL SYNDROME(HRS)Two Types of Hepatorenal SyndromeType 1 Rapidly

30、 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 Absence of excessive gastrointestinal or renal fluid loss No improvement

31、 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 CRITERIA IN DIAGNOSING HEPATORENAL SYNDROMEUrine Sodium and Urine Volum

32、e 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 CRITERIA IN THE DIAGNOSIS OF HEPATORENAL SYNDROME(HRS)Activation of neuroh

33、umoral systemsSite of Action of Different Therapies for HRSAdvanced CirrhosisIntrahepatic resistanceArteriolar resistance(vasodilation)Sinusoidal pressureHepatorenal syndromeRenal vasoconstrictionTIPSTIPSTransplantEffective arterial blood volumeVaso-constrictorsAlbuminMECHANISM OF ACTION OF THE DIFF

34、ERENT THERAPIES FOR HEPATORENAL SYNDROME(HRS)Management of Hepatorenal SyndromeProven efficacy Liver transplantationUnder investigation Vasoconstrictor+albumin Transjugular intrahepatic portosystemic shunt(TIPS)Vasoconstrictor+TIPS Extracorporeal albumin dialysis(ECAD)Ineffective Renal vasodilators(

35、prostaglandin,dopamine)HemodialysisMANAGEMENT OF HEPATORENAL SYNDROMELiver insufficiencyVariceal hemorrhageComplications of Cirrhosis Result from Portal Hypertension or Liver InsufficiencyCirrhosisAscitesEncephalopathyJaundicePortal hypertensionSpontaneous bacterial peritonitisHepatorenal syndromeCO

36、MPLICATIONS OF CIRRHOSISHEPATIC ENCEPHALOPATHYHepatic EncephalopathyHepatic EncephalopathyNomenclature Type AAssociated with Acute liver failure Type BAssociated with porto-systemic Bypass without intrinsic hepatocellular disease Type CAssociated with Cirrhosis and porto-systemic shuntingFerenci et

37、al.,Hepatology 2002;35:716HEPATIC ENCEPHALOPATHY NOMENCLATURETreatment:rarely effective short of liver transplantCharacteristics of Type A vs.Type C Hepatic EncephalopathyGradual onsetRarely fatalMain cause:shunting/toxinPrecipitantTreatment:usually effectiveRapid onsetFrequently fatalMain cause:cer

38、ebral edemaType AType CCHARACTERISTICS OF TYPE A VS.TYPE C ENCEPHALOPATHYType C Hepatic Encephalopathy is the Encephalopathy of Cirrhosis Neuropsychiatric complication of cirrhosisResults from spontaneous or surgical/radiological portal-systemic shunt+chronic liver failureFailure to metabolize neuro

39、toxic substancesAlterations of astrocyte morphology and function(Alzheimer type II astrocytosis)TYPE C HEPATIC ENCEPHALOPATHY IS THE ENCEPHALOPATHY OF CIRRHOSISHepatic Encephalopathy PathogenesisBacterial actionProtein loadFailure to metabolize NH3NH3 ShuntingGABA-BD receptorsToxinsPATHOPHYSIOLOGY O

40、F HEPATIC ENCEPHALOPATHYHepatic 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 EEGHEPATIC ENCEPHALOPATHY IS A

41、CLINICAL DIAGNOSISSTAGES OF HEPATIC ENCEPHALOPATHYConfusionDrowsinessSomnolenceComa1234StageStages of Hepatic Encephalopathy12345678910111213141516171819202122232425BeginEndTime to complete_Number Connection Test(NCT)Sample handwritingDraw a starNUMBER CONNECTION TEST70Electroencephalogram in Hepati

42、c EncephalopathyELECTROENCEPHALOGRAM IN HEPATIC ENCEPHALOPATHYMinimal Hepatic Encephalopathy Occurs in 30-70%of cirrhotic patients without overt hepatic encephalopathy Detected by psychometric and neuro-psychological testing May improve with lactulose or synbiotics(probiotics and fermentable fiber)M

43、INIMAL HEPATIC ENCEPHALOPATHYMinimal Hepatic EncephalopathyAbnormalities on testing Attention and cognitive deficits Visual-spacial perception impaired Defects in visual constructive ability Impaired driving ability Evoked potentials and spectral electro-encephalography abnormalMINIMAL HEPATIC ENCEP

44、HALOPATHY ABNORMALITIES ON TESTINGTreatment of Hepatic Encephalopathy Identify and treat precipitating factor Infection GI hemorrhage Prerenal azotemia Sedatives Constipation Lactulose(adjust to 2-3 bowel movements/day)Protein restriction,short-term(if at all)TREATMENT OF HEPATIC ENCEPHALOPATHYHepat

45、ic Encephalopathy PrecipitantsGI bleedingExcess proteinSedatives/hypnoticsTIPSDiureticsSerum K+Plasma volume AzotemiaTempInfectionsHEPATIC ENCEPHALOPATHY PRECIPITANTSActions of LactuloseLactuloseLactic acidDecreased pHNH3Urease-producing bacteriaIncrease cathartic effectNH3NH4+ACTIONS OF LACTULOSEHe

46、patic EncephalopathyTreatment:SummaryDecrease ammonia production in gut:Lactulose Antibiotics Adjustment in dietary proteinIncrease ammonia fixation in liver:Ornithine aspartate BenzoateShunt occlusion or reductionHEPATIC ENCEPHALOPATHY TREATMENT SUMMARYFlumazenilRifaximinpA minimally absorbed oral

47、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 risk of inducing bacterial resistance Liver insufficiencyVariceal hemorrhageComplications of Cirrhosis Result f

48、rom Portal Hypertension or Liver InsufficiencyCirrhosisAscitesEncephalopathyJaundicePortal hypertensionSpontaneous bacterial peritonitisHepatorenal syndromeCOMPLICATIONS OF CIRRHOSISNew Therapeutic Paradigm for Patients With CirrhosisCompensatedCirrhosisStatins Non-selective beta-blockersLife style changesSpecific therapy for etiologyAntibioticsprobioticsAnticoagulantsFuture therapiesImmune regulation?