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1、ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE,Liver Cirrhosis,Natural History,Cirrhosis,End stage of any chronic liver diseaseCharacterized histologically by regenerative nodules surrounded by fibrous tissueClinically there are two types of c
2、irrhosis:CompensatedDecompensated,DEFINITION OF CIRRHOSIS,Cirrhosis,Normal,Nodules,Irregular surface,GROSS IMAGE OF A NORMAL AND A CIRRHOTIC LIVER,Cirrhotic liver,Nodular,irregular surface,Nodules,GROSS IMAGE OF A CIRRHOTIC LIVER,Cirrhosis,Normal,Nodules surrounded by fibrous tissue,HISTOLOGICAL IMA
3、GE 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
4、 in Microvasculature in Cirrhosis,Activation of stellate cellsCollagen deposition in space of DisseConstriction of sinusoidsDefenestration of sinusoids,Normal Liver,Hepatic vein,Sinusoid,Portal vein,Liver,Splenic vein,Coronary vein,THE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOW,Portal systemic
5、 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,AN INCREASE IN PORTAL VENOUS INFLOW SUSTAINS PORTAL HYPERTENSION,Mesenteric vei
6、ns,Flow,Splanchnicvasodilatation,Distorted sinusoidal architechure,Portal vein,An Increase in Portal Venous Inflow Sustains Portal Hypertension,Mechanisms of Portal Hypertension,Pressure(P)results from the interaction of resistance(R)and flow(F):,Portal hypertension can result from:increase in resis
7、tance to portal flow and/or increase in portal venous inflow,MECHANISMS OF PORTAL HYPERTENSION,Compensatedcirrhosis,Decompensatedcirrhosis,Death,Chronic liver disease,Natural History of Chronic Liver Disease,NATURAL HISTORY OF CHRONIC LIVER DISEASE,Development of Complications in Compensated Cirrhos
8、is,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,NATURAL HISTORY OF CIRRHOSIS,60,40,80,100,120,140,160,0,40,60,80,20,20,0,100,Months,Probability of survival,All patients with cir
9、rhosis,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,Liver insufficiency,Variceal hemorrhage,Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficien
10、cy,Cirrhosis,Ascites,Encephalopathy,Jaundice,Portal hypertension,Spontaneous bacterial peritonitis,Hepatorenal syndrome,COMPLICATIONS OF CIRRHOSIS,Cirrhosis-Diagnosis,Cirrhosis is a histological diagnosisHowever,in patients with chronic liver disease the presence of various clinical features suggest
11、s cirrhosisThe 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 diseaseChronic abnormal aminotransferases and/or alkaline phosphatasePhysical exam findingsStigm
12、ata of chronic liver disease(muscle wasting,vascular spiders,palmar erythema)Palpable left lobe of the liverSmall liver spanSplenomegalySigns of decompensation(jaundice,ascites,asterixis),DIAGNOSIS OF CIRRHOSIS CLINICAL FINDINGS,LaboratoryLiver insufficiencyLow albumin(1.3)High bilirubin(1.5 mg/dL)P
13、ortal hypertensionLow platelet count(1,In Whom Should We Suspect Cirrhosis?,DIAGNOSIS OF CIRRHOSIS LABORATORY STUDIES,CT Scan in Cirrhosis,Liver with an irregular surface,Splenomegaly,Collaterals,DIAGNOSIS OF CIRRHOSIS CAT SCAN,Diagnostic Algorithm,Patient with chronic liver disease and any of the f
14、ollowing: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 synthetic function,Radiological findings:
15、Small nodular liverIntra-abdominal collateralsAscitesSplenomegalyColloid shift to spleen and/or bone marrow,Yes,No,Yes,No,Liver biopsy,DIAGNOSTIC ALGORITHM,Liver insufficiency,Variceal hemorrhage,Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency,Cirrhosis,Ascites,Ence
16、phalopathy,Jaundice,Portal hypertension,Spontaneous bacterial peritonitis,Hepatorenal syndrome,COMPLICATIONS OF CIRRHOSIS,Cirrhosis is the most common cause of portal hypertensionThe site of increased resistance in cirrhosis is sinusoidalOther causes of portal hypertension are classified according t
17、o the site of increased resistance,Causes of Portal Hypertension,CAUSES OF PORTAL HYPERTENSION,Portal Hypertension Is Classified According to the Site of Increased Resistance,TypeExamplePre-hepaticPortal or splenic vein thrombosisPre-sinusoidalSchistosomiasisSinusoidalCirrhosisPost-sinusoidalVeno-oc
18、clusive diseasePost-hepaticBudd-Chiari syndrome,CLASSIFICATION OF PORTAL HYPERTENSION,Vasodilation and Hyperdynamic Circulation in Cirrhosis-Multiple Organ Involvement,Splanchnic vasodilation,Peripheral vasodilation,Pulmonary vasodilation,Cerebral vasodilation,VASODILATION AND HYPERDYNAMIC CIRCULATI
19、ON IN CIRRHOSIS MULTIPLE ORGAN INVOLVEMENT,Splanchnic vasodilation,Varices and Variceal Hemorrhage,VARICES AND VARICEAL HEMORRHAGE,Portal Pressure Measurements,Definitive method to establish the diagnosis of portal hypertensionDirect methods(percutaneous,transjugular)are cumbersome and may be associ
20、ated with complicationsThe safest and most reproducible method is measurement of the hepatic venous pressure gradient(HVPG),PORTAL PRESSURE MEASUREMENTS,Portal Pressure Measurements,The 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-FHVP,PORTAL PRESSURE MEASUREMENTS,Small varices,Large varices,No varices,7-8%/year,7-8%/year,Varices Increase in Diameter Progressively,Merli et
22、al.J Hepatol 2003;38:266,VARICES INCREASE IN DIAMETER PROGRESSIVELY,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),A THRESHOLD
23、 PORTAL PRESSURE OF 12 mmHg IS NECESSARY FOR VARICES TO FORM,Variceal rupture,Cirrhosis,PROGRESSION OF PORTAL HYPERTENSION LEADS TO VARICEAL GROWTH AND VARICEAL RUPTURE,Predictors of hemorrhage:Variceal size Red signs Child B/C,NIEC.N Engl J Med 1988;319:983,Variceal hemorrhage,Varix with red signs,
24、PROGNOSTIC INDICATORS OF FIRST VARICEAL HEMORRHAGE,Prophylaxis of Variceal Hemorrhage,MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE-SUMMARY,Treatment of Acute Variceal Hemorrhage,General Management:IV access and fluid resuscitationDo not overtransfuse(hemoglobin 8 g/dL)Antibiotic p
25、rophylaxisSpecific therapy:Pharmacological therapy:terlipressin,somatostatin and analogues,vasopressin+nitroglycerinEndoscopic therapy:ligation,sclerotherapyShunt therapy:TIPS,surgical shunt,TREATMENT OF ACUTE VARICEAL HEMORRHAGE,Endoscopic Variceal Band Ligation,Bleeding controlled in 90%Rebleeding
26、 rate 30%Compared with sclerotherapy:Less rebleedingLower mortalityFewer complicationsFewer treatment sessions,ENDOSCOPIC VARICEAL BAND LIGATION,Transjugular Intrahepatic Portosystemic Shunt,Hepatic vein,Portal vein,Splenic vein,Superior mesenteric vein,TIPS,THE TRANSJUGULAR INTRAHEPATIC PORTOSYSTEM
27、IC SHUNT,Evolution of Varices,Level of Intervention,Management Recommendations,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 i
28、n 2-3 yearsNo specific therapy,Small varicesRepeat endoscopy in 1-2 yearsNo 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 t
29、herapy,Beta-blockers+nitrates or EVLBeta-blockers+EVL?TIPS or shunt surgery as rescue therapy,SUMMARY OF MANAGEMENT OF VARICES AND VARICEAL HEMORRHAGE,Liver insufficiency,Variceal hemorrhage,Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency,Cirrhosis,Ascites,Encephalo
30、pathy,Jaundice,Portal hypertension,Spontaneous bacterial peritonitis,Hepatorenal syndrome,COMPLICATIONS OF CIRRHOSIS,Cirrhosis,Ascites,PATHOGENESIS OF ASCITES,Ultrasound is the Most Sensitive Method to Detect Ascites,Liver,ULTRASOUND IS THE MOST SENSITIVE METHOD TO DETECT ASCITES,Diagnostic Paracent
31、esis,Indications,Contraindications,New-onset ascitesAdmission to hospitalSymptoms/signs of SBPRenal dysfunctionUnexplained encephalopathy,None,DIAGNOSTIC PARACENTESIS,Cirrhotic ascites,Cardiac ascites,Peritoneal malignancy,1.1,4.0,3.0,2.0,1.0,0,Serum ascites albumin gradient(g/dL),Serum-Ascites Albu
32、min 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,Activation of neurohumoral systems,Site of Action of Different Therapies for Ascites,Cirrhosis,Intrahepatic resistance
33、,Arteriolar resistance(vasodilation),Sinusoidal pressure,Ascites,Sodium and water retention,Diuretics,Effective arterial blood volume,MECHANISM OF ACTION OF THE DIFFERENT THERAPIES FOR ASCITES,Management of Uncomplicated Ascites,Definition:Ascites responsive to diuretics in the absence of infection
34、and renal dysfunction,Sodium restrictionEffective in 10-20%of casesPredictors of response:mild or moderate ascites,Urine Na excretion 50 mEq/dayDiureticsShould be spironolactone-basedA progressive schedule(spironolactone furosemide)requires fewer dose adjustments than a combined therapy(spironolacto
35、ne+furosemide),MANAGEMENT OF UNCOMPLICATED ASCITES,Definition and Types of Refractory Ascites,Occurs in 10%of cirrhotic patients,Diuretic-intractable ascitesTherapeutic doses of diuretics cannot be achieved because of diuretic-induced complicationsDiuretic-resistant ascitesNo response to maximal diu
36、retic therapy(400 mg spironolactone+160 mg furosemide/day),Arroyo et al.Hepatology 1996;23:164,DEFINITION AND TYPES OF REFRACTORY ASCITES,Spontaneous Bacterial Peritonitis(SBP)Complicates Ascites and Can Lead to Renal Dysfunction,SPONTANEOUS BACTERIAL PERITONITIS(SBP)COMPLICATES ASCITES AND CAN LEAD
37、 TO RENAL DYSFUNCTION,Early Diagnosis of SBP,Diagnostic paracentesis: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 BACTERIA
38、L PERITONITIS(SBP),TREATMENTINDICATED,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 PERITO
39、NITIS(SBP),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
40、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,Months,Norfloxacin Reduces Recurrence of Spontaneous Bacterial Peritonitis,Gines et al.,Hepatology 1
41、990;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 daysPatients who have recovered from
42、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),Hepatorenal Syndrome,ASCITES AND HEPATORENAL SYNDROME,Characteristic
43、s of Hepatorenal Syndrome,Renal failure in patients with cirrhosis,advanced liver failure and severe sinusoidal portal hypertensionAbsence of significant histological changes in the kidney(“functional”renal failure)Marked arteriolar vasodilation in the extra-renal circulationMarked renal vasoconstri
44、ction leading to reduced glomerular filtration rate,CHARACTERISTICS OF HEPATORENAL SYNDROME(HRS),Two Types of Hepatorenal Syndrome,Type 1Rapidly 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 refra
45、ctory ascites,Arroyo et al.,Hepatology 1996;23:164,TYPES OF HEPATORENAL SYNDROME(HRS),SURVIVAL IN THE DIFFERENT TYPES 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.,Lanc
46、et 2003;362:1819,Type 1,Cirrhosis,Arteriolar resistance(vasodilation),Effective arterial blood volume,Ascites,Sodium and water retention,Activation of neurohumoral systems,NSAIDs,DiureticsDiarrheaHemorrhage,VasodilatorsLVP w/o albuminInfection,THERE ARE MANY CONDITIONS OTHER THAN HEPATORENAL SYNDROM
47、E THAT CAN LEAD TO RENAL FAILURE IN PATIENTS WITH CIRRHOSIS,Cirrhosis,Arteriolar resistance(vasodilation),Effective arterial blood volume,Ascites,Sodium and water retention,Activation of neurohumoral systems,NSAIDs,DiureticsDiarrheaHemorrhage,VasodilatorsLVP w/o albuminInfection,HEPATORENAL SYNDROME
48、(HRS)IS A DIAGNOSIS OF EXCLUSION,Advanced hepatic failure and portal hypertensionCreatinine 1.5 mg/dL or creatinine clearance 40 ml/minAbsence of shock,bacterial infection,or nephrotoxic drugsAbsence of excessive gastrointestinal or renal fluid lossNo improvement in renal function after plasma volum
49、e expansion with 1.5 L of isotonic salineUrinary protein 500 mg/dL and normal renal ultrasound,Major Criteria in the Diagnosis of Hepatorenal Syndrome,Arroyo et al.,Hepatology 1996;23:164,MAJOR CRITERIA IN DIAGNOSING HEPATORENAL SYNDROME,Urine Sodium and Urine Volume are Minor Criteria in the Diagno
50、sis of HRS,Minor criteriaUrine sodium plasma osmolalitySerum sodium 130 mEq/LUrine volume 500 ml/dayUrine 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
