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1、ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE,Liver Cirrhosis,XX医院,XX,ARCHITECTURAL LIVER DISRUPTION,Natural History,Natural History,Cirrhosis,End stage of any chronic liver diseaseCharacterized histologically by regenerative nodules surround
2、ed by fibrous tissueClinically there are two types of cirrhosis:CompensatedDecompensated,DEFINITION OF CIRRHOSIS,CirrhosisEnd stage of any chro,Cirrhosis,Normal,Nodules,Irregular surface,GROSS IMAGE OF A NORMAL AND A CIRRHOTIC LIVER,CirrhosisNormalNodulesIrregula,Cirrhotic liver,Nodular,irregular su
3、rface,Nodules,GROSS IMAGE OF A CIRRHOTIC LIVER,Cirrhotic liverNodular,irregu,Cirrhosis,Normal,Nodules surrounded by fibrous tissue,HISTOLOGICAL IMAGE OF A NORMAL AND A CIRRHOTIC LIVER,CirrhosisNormalNodules surrou,HISTOLOGICAL IMAGE OF CIRRHOSIS,Fibrosis,Regenerative nodule,HISTOLOGICAL IMAGE OF CIR
4、RHOSI,PATHOGENESIS OF LIVER FIBROSIS,Hepatocytes,Space of Disse,Sinusoidal endothelial cell,Hepatic stellate cell,Fenestrae,Normal Hepatic SInusoid,Retinoid droplets,PATHOGENESIS OF LIVER FIBROSIS,PATHOGENESIS OF LIVER FIBROSIS,Alterations in Microvasculature in Cirrhosis,Activation of stellate cell
5、sCollagen deposition in space of DisseConstriction of sinusoidsDefenestration of sinusoids,PATHOGENESIS OF LIVER FIBROSIS,Normal Liver,Hepatic vein,Sinusoid,Portal vein,Liver,Splenic vein,Coronary vein,THE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOW,Normal Liver Hepatic veinSinus,Portal systemi
6、c collaterals,Distorted sinusoidal architectureleads to increased resistance,Portal vein,Cirrhotic Liver,Splenomegaly,ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE,Portal systemic collateralsDis,AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PO
7、RTAL HYPERTENSION,Mesenteric veins,Flow,Splanchnicvasodilatation,Distorted sinusoidal architechure,Portal vein,An Increase in Portal Venous Inflow Sustains Portal Hypertension,AN INCREASE IN PORTAL VENOUS I,Mechanisms of Portal Hypertension,Pressure(P)results from the interaction of resistance(R)and
8、 flow(F):,Portal hypertension can result from:increase in resistance to portal flow and/or increase in portal venous inflow,MECHANISMS OF PORTAL HYPERTENSION,Mechanisms of Portal Hypertens,Compensatedcirrhosis,Decompensatedcirrhosis,Death,Chronic liver disease,Natural History of Chronic Liver Diseas
9、e,NATURAL HISTORY OF CHRONIC LIVER DISEASE,CompensatedDecompensatedDeathC,Development of Complications in Compensated Cirrhosis,Ascites,Jaundice,Encephalopathy,GI hemorrhage,Probability of developing event,0,20,60,80,100,0,60,40,20,40,80,100,120,140,160,Months,Gines et.al.,Hepatology 1987;7:122,NATU
10、RAL HISTORY OF CIRRHOSIS,Development of Complications,60,40,80,100,120,140,160,0,40,60,80,20,20,0,100,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
11、 years,SURVIVAL TIMES IN CIRRHOSIS,604080100120140160040608020200,Liver insufficiency,Variceal hemorrhage,Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency,Cirrhosis,Ascites,Encephalopathy,Jaundice,Portal hypertension,Spontaneous bacterial peritonitis,Hepatorenal synd
12、rome,COMPLICATIONS OF CIRRHOSIS,Liver insufficiencyVariceal he,Cirrhosis-Diagnosis,Cirrhosis is a histological diagnosisHowever,in patients with chronic liver disease the presence of various clinical features suggests cirrhosisThe presence of these clinical features can be followed by non-invasive t
13、esting,prior to liver biopsy,DIAGNOSIS OF CIRRHOSIS,Cirrhosis-DiagnosisCirrhosis,In Whom Should We Suspect Cirrhosis?,Any patient with chronic liver diseaseChronic abnormal aminotransferases and/or alkaline phosphatasePhysical exam findingsStigmata of chronic liver disease(muscle wasting,vascular sp
14、iders,palmar erythema)Palpable left lobe of the liverSmall liver spanSplenomegalySigns of decompensation(jaundice,ascites,asterixis),DIAGNOSIS OF CIRRHOSIS CLINICAL FINDINGS,In Whom Should We Suspect Cirr,LaboratoryLiver insufficiencyLow albumin(1.3)High bilirubin(1.5 mg/dL)Portal hypertensionLow pl
15、atelet count(1,In Whom Should We Suspect Cirrhosis?,DIAGNOSIS OF CIRRHOSIS LABORATORY STUDIES,LaboratoryIn Whom Should We Su,CT Scan in Cirrhosis,Liver with an irregular surface,Splenomegaly,Collaterals,DIAGNOSIS OF CIRRHOSIS CAT SCAN,CT Scan in CirrhosisLiver with,Diagnostic Algorithm,Patient with
16、chronic liver disease and any of the following:Variceal hemorrhageAscitesHepatic encephalopathy,Liver biopsy not necessary for the diagnosis of cirrhosis,Physical findings:Enlarged left hepatic lobeSplenomegalyStigmata of chronic liver disease,Laboratory findings:ThrombocytopeniaImpaired hepatic syn
17、thetic function,Radiological findings:Small nodular liverIntra-abdominal collateralsAscitesSplenomegalyColloid shift to spleen and/or bone marrow,Yes,No,Yes,No,Liver biopsy,DIAGNOSTIC ALGORITHM,NoYesDiagnostic AlgorithmPatie,Liver insufficiency,Variceal hemorrhage,Complications of Cirrhosis Result f
18、rom Portal Hypertension or Liver Insufficiency,Cirrhosis,Ascites,Encephalopathy,Jaundice,Portal hypertension,Spontaneous bacterial peritonitis,Hepatorenal syndrome,COMPLICATIONS OF CIRRHOSIS,Liver insufficiencyVariceal he,Cirrhosis is the most common cause of portal hypertensionThe site of increased
19、 resistance in cirrhosis is sinusoidalOther causes of portal hypertension are classified according to the site of increased resistance,Causes of Portal Hypertension,CAUSES OF PORTAL HYPERTENSION,Cirrhosis is the most common c,Portal Hypertension Is Classified According to the Site of Increased Resis
20、tance,TypeExamplePre-hepaticPortal or splenic vein thrombosisPre-sinusoidalSchistosomiasisSinusoidalCirrhosisPost-sinusoidalVeno-occlusive diseasePost-hepaticBudd-Chiari syndrome,CLASSIFICATION OF PORTAL HYPERTENSION,Portal Hypertension Is Classif,Portal venous inflowVariceal growth,Splanchnic vasod
21、ilation,Varices and Variceal Hemorrhage,VARICES AND VARICEAL HEMORRHAGE,Portal venous inflowSplanchni,Portal Pressure Measurements,The hepatic venous pressure gradient(HVPG)is obtained by subtracting the free hepatic venous pressure(FHVP)from the wedged hepatic venous pressure(WHVP):The FHVP acts as
22、 an internal zero to correct for extravascular,intraabdominal pressure increases(e.g.ascites),HVPG=WHVP-FHVP,PORTAL PRESSURE MEASUREMENTS,Portal Pressure MeasurementsTh,Small varices,Large varices,No varices,7-8%/year,7-8%/year,Varices Increase in Diameter Progressively,Merli et al.J Hepatol 2003;38
23、:266,VARICES INCREASE IN DIAMETER PROGRESSIVELY,Small varicesLarge varicesNo v,A Threshold Portal Pressure of 12 mmHg is Necessary for Varices to Form,P0.01,5,10,12,15,25,30,35,20,HepaticVenousPressureGradient(mmHg),Garcia-Tsao et.al.,Hepatology 1985;5:419,Varices Present(n=72),Varices Absent(n=15),
24、A THRESHOLD PORTAL PRESSURE OF 12 mmHg IS NECESSARY FOR VARICES TO FORM,A Threshold Portal Pressure of,Variceal rupture,Cirrhosis,PROGRESSION OF PORTAL HYPERTENSION LEADS TO VARICEAL GROWTH AND VARICEAL RUPTURE,Variceal GrowthVariceal ruptur,Predictors of hemorrhage:Variceal size Red signs Child B/C
25、,NIEC.N Engl J Med 1988;319:983,Variceal hemorrhage,Varix with red signs,PROGNOSTIC INDICATORS OF FIRST VARICEAL HEMORRHAGE,Predictors of hemorrhage:NIEC.,Prophylaxis of Variceal Hemorrhage,MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE-SUMMARY,Prophylaxis of Variceal Hemorr,Treatme
26、nt of Acute Variceal Hemorrhage,General Management:IV access and fluid resuscitationDo not overtransfuse(hemoglobin 8 g/dL)Antibiotic prophylaxisSpecific therapy:Pharmacological therapy:terlipressin,somatostatin and analogues,vasopressin+nitroglycerinEndoscopic therapy:ligation,sclerotherapyShunt th
27、erapy:TIPS,surgical shunt,TREATMENT OF ACUTE VARICEAL HEMORRHAGE,Treatment of Acute Variceal He,Endoscopic Variceal Band Ligation,Bleeding controlled in 90%Rebleeding rate 30%Compared with sclerotherapy:Less rebleedingLower mortalityFewer complicationsFewer treatment sessions,ENDOSCOPIC VARICEAL BAN
28、D LIGATION,Endoscopic Variceal Band Ligat,Transjugular Intrahepatic Portosystemic Shunt,Hepatic vein,Portal vein,Splenic vein,Superior mesenteric vein,TIPS,THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT,Transjugular Intrahepatic Port,Evolution of Varices,Level of Intervention,Management Recommend
29、ations,Cirrhosis with no varices,Small varicesNo hemorrhage,Medium/large varicesNo hemorrhage,Variceal hemorrhage,Recurrent variceal hemorrhage,Pre-primary prophylaxis,Primary prophylaxis,Secondary prophylaxis,Repeat endoscopy in 2-3 yearsNo specific therapy,Small varicesRepeat endoscopy in 1-2 year
30、sNo specific therapy?beta-blocker to prevent enlargementMedium/Large varicesNon-selective beta-blockersEVL in those intolerant to drugs,Endoscopic/pharmacologic therapyAntibiotics in all patientsTIPS or shunt surgery as rescue therapy,Beta-blockers+nitrates or EVLBeta-blockers+EVL?TIPS or shunt surg
31、ery as rescue therapy,SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL HEMORRHAGE,Evolution of VaricesLevel of I,Liver insufficiency,Variceal hemorrhage,Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency,Cirrhosis,Ascites,Encephalopathy,Jaundice,Portal hypertension,Sponta
32、neous bacterial peritonitis,Hepatorenal syndrome,COMPLICATIONS OF CIRRHOSIS,Liver insufficiencyVariceal he,Cirrhosis,Ascites,PATHOGENESIS OF ASCITES,CirrhosisActivation of neurohu,Ultrasound is the Most Sensitive Method to Detect Ascites,Liver,ULTRASOUND IS THE MOST SENSITIVE METHOD TO DETECT ASCITE
33、S,Ultrasound is the Most Sensiti,Diagnostic Paracentesis,Indications,Contraindications,New-onset ascitesAdmission to hospitalSymptoms/signs of SBPRenal dysfunctionUnexplained encephalopathy,None,DIAGNOSTIC PARACENTESIS,Diagnostic ParacentesisIndicat,Cirrhotic ascites,Cardiac ascites,Peritoneal malig
34、nancy,1.1,4.0,3.0,2.0,1.0,0,Serum ascites albumin gradient(g/dL),Serum-Ascites Albumin Gradient is High in Portal Hypertensive Causes of Ascites,Runyon,Ann Intern Med 1992;117:215,SERUM-ASCITES ALBUMIN GRADIENT(SAAG)IS HIGH IN PORTAL HYPERTENSIVE CAUSES OF ASCITES,Cirrhotic ascitesCardiac ascit,Acti
35、vation of neurohumoral systems,Site of Action of Different Therapies for Ascites,Cirrhosis,Intrahepatic resistance,Arteriolar resistance(vasodilation),Sinusoidal pressure,Ascites,Sodium and water retention,Diuretics,Effective arterial blood volume,MECHANISM OF ACTION OF THE DIFFERENT THERAPIES FOR A
36、SCITES,Activation of neurohumoral sys,Management of Uncomplicated Ascites,Definition:Ascites responsive to diuretics in the absence of infection and renal dysfunction,Sodium restrictionEffective in 10-20%of casesPredictors of response:mild or moderate ascites,Urine Na excretion 50 mEq/dayDiureticsSh
37、ould be spironolactone-basedA progressive schedule(spironolactone furosemide)requires fewer dose adjustments than a combined therapy(spironolactone+furosemide),MANAGEMENT OF UNCOMPLICATED ASCITES,Management of Uncomplicated As,Definition and Types of Refractory Ascites,Occurs in 10%of cirrhotic pati
38、ents,Diuretic-intractable ascitesTherapeutic doses of diuretics cannot be achieved because of diuretic-induced complicationsDiuretic-resistant ascitesNo response to maximal diuretic therapy(400 mg spironolactone+160 mg furosemide/day),Arroyo et al.Hepatology 1996;23:164,DEFINITION AND TYPES OF REFRA
39、CTORY ASCITES,Definition and Types of Refrac,Spontaneous Bacterial Peritonitis(SBP)Complicates Ascites and Can Lead to Renal Dysfunction,SPONTANEOUS BACTERIAL PERITONITIS(SBP)COMPLICATES ASCITES AND CAN LEAD TO RENAL DYSFUNCTION,Spontaneous Bacterial Peritoni,Early Diagnosis of SBP,Diagnostic parace
40、ntesis:If symptoms/signs of SBP occurUnexplained encephalopathy and/or renal dysfunctionAt any hospital admissionDiagnosis based on ascitic fluidPMN count 250/mm3,Rimola et al.,J Hepatol 2000;32:142,EARLY DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS(SBP),Early Diagnosis of SBPDiagnost,TREATMENTIND
41、ICATED,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,YES,NO,MANAGEMENT ALGORITHM IN SPONTANEOUS BACTERIAL PERITONITIS(SBP),TREATMENTDiagnosis a
42、nd Managem,Treatment of Spontaneous Bacterial Peritonitis,Recommended antibiotics for initial empiric therapyi.v.cefotaxime,amoxicillin-clavulanic acidoral nofloxacin(uncomplicated SBP)avoid aminoglycosidesMinimum duration:5 daysRe-evaluation if ascitic fluid PMN count has not decreased by at least
43、25%after 2 days of treatment,Rimola et al.,J Hepatol 2000;32:142,TREATMENT OF SPONTANEOUS BACTERIAL PERITONITIS(SBP),Treatment of Spontaneous Bacte,All SBPs,SBP caused by gram-negative bacteria,Probability of SBP recurrence,Months,Months,Norfloxacin Reduces Recurrence of Spontaneous Bacterial Perito
44、nitis,Gines et al.,Hepatology 1990;12:716,NORFLOXACIN REDUCES RECURRENCE OF SPONTANEOUS BACTERIAL PERITONITIS(SBP),All SBPsSBP caused by gram-neg,Indications for Prophylactic Antibiotics to Prevent Spontaneous Bacterial Peritonitis,Cirrhotic patients hospitalized with GI hemorrhage(short-term)Norflo
45、xacin 400 mg p.o.BID x 7 daysPatients who have recovered from SBP(long-term)Norfloxacin 400 mg p.o.daily,indefinitelyWeekly quinolones not recommended(lower efficacy,development of quinolone-resistance),INDICATIONS FOR PROPHYLACTIC ANTIBIOTICS TO PREVENT SPONTANEOUS BACTERIAL PERITONITIS(SBP),Indica
46、tions for Prophylactic A,Hepatorenal Syndrome,ASCITES AND HEPATORENAL SYNDROME,Hepatorenal SyndromeASCITES AN,Characteristics of Hepatorenal Syndrome,Renal failure in patients with cirrhosis,advanced liver failure and severe sinusoidal portal hypertensionAbsence of significant histological changes i
47、n the kidney(“functional”renal failure)Marked arteriolar vasodilation in the extra-renal circulationMarked renal vasoconstriction leading to reduced glomerular filtration rate,CHARACTERISTICS OF HEPATORENAL SYNDROME(HRS),Characteristics of Hepatorenal,Two Types of Hepatorenal Syndrome,Type 1Rapidly
48、progressive renal failure(2 weeks)Doubling of creatinine to 2.5 or halving of creatinine clearance(CrCl)to 1.5 mg/dL or CrCl 40 ml/minAssociated with refractory ascites,Arroyo et al.,Hepatology 1996;23:164,TYPES OF HEPATORENAL SYNDROME(HRS),Two Types of Hepatorenal Syndr,SURVIVAL IN THE DIFFERENT TY
49、PES OF HEPATORENAL SYNDROME(HRS),0,2,4,6,8,12,10,Months,1,0.2,0.4,0.6,0.8,Survival probability,0,Type 2,p=0.001,Survival in Different Types of Hepatorenal Syndrome(HRS),Gines et al.,Lancet 2003;362:1819,Type 1,SURVIVAL IN THE DIFFERENT TYPE,Cirrhosis,Arteriolar resistance(vasodilation),Effective art
50、erial blood volume,Ascites,Sodium and water retention,Activation of neurohumoral systems,NSAIDs,DiureticsDiarrheaHemorrhage,VasodilatorsLVP w/o albuminInfection,THERE ARE MANY CONDITIONS OTHER THAN HEPATORENAL SYNDROME THAT CAN LEAD TO RENAL FAILURE IN PATIENTS WITH CIRRHOSIS,CirrhosisIntrahepatic r
