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Cirrosi Epatica Definizione Meccanismi della fibrogenesi epatica Fisiopatologia dellipertensione portale Complicanze maggiori della cirrosi Cenni di terapia.

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Presentation on theme: "Cirrosi Epatica Definizione Meccanismi della fibrogenesi epatica Fisiopatologia dellipertensione portale Complicanze maggiori della cirrosi Cenni di terapia."— Presentation transcript:

1 Cirrosi Epatica Definizione Meccanismi della fibrogenesi epatica Fisiopatologia dellipertensione portale Complicanze maggiori della cirrosi Cenni di terapia delle complicanze Management della cirrosi compensata/scompensata

2 CIRROSI Alterazione dellarchitettura del fegato caratterizzata da noduli e formazione di tessuto collagene CAUSE: Tutte le cause di danno epatico cronico

3 Causa iniziale Stadio finale Complicanze anni Cirrosi -Fibrosi -Distorsione dellarchitettura epatica Progressione del danno epatico cronico

4 Hepatic Artery Portal Vein Sinusoids Bile Duct Central Veins

5 NormalCirrhosis Changes of hepatic microcirculation in cirrhosis

6 Activation of HSC

7 LIVER CIRRHOSIS: from activation of HSC to cirrhotic nodules LIVER CIRRHOSIS : from activation of HSC to cirrhotic nodules

8 Spazio portale Fibrosi virale 1.– Necrosi a ponte porto-centrale 2. – Epatite da interfaccia e sviluppo di setti che circondano il parechima 3. – Perdita di connessioni vascolari con il sistema portale

9 fibrosi biliare fibrosi biliare Spazio portale Formazione di setti porto-portali Formazione di setti porto-portali La vena centrolobulare è conservata La vena centrolobulare è conservata Modello BDL CBP CB secondaria CSP

10 portal tract 1.– Secondary to venous outflow problems (e.g. chronic heart failure) 2. - Chronic ETOH consumption 3. – Development of central to central septa and reversed lobulation Centrolobular fibrosis fibrosis

11 CONSEQUENCES OF DEVELOPING PROGRESSIVE HEPATIC FIBROSIS structural & functional intrahepatic resistance splanchnic blood flow splanchnic blood flow (cirrhosis)HCC portal hypertension variceal bleeding hepatic encephalopathy hepatopulmonary syndrome portosystemic collaterals systemic hyperdynamic circulation ascites spontaneous bacterial peritonitis cardiac output cardiomyopathy decrease central volume HRS

12 Ipertensione portale Condizione fisiopatologica causata dallaumento della pressione venosa nel distretto portale Principale conseguenza della cirrosi epatica e principale meccanismo delle sue principali complicanze cliniche Riconosce anche cause extraepatiche, in cui le manifestazioni cliniche dominanti dipendono dalla sede di origine della ipertensione portale

13 Flusso epatico: 1.5 l/min (80% venoso, portale) Pressione portale: 7 mmHg (diretta o wedge) Pressione sovra- epatiche/atrio dx: 3-5 mmHg Gradiente porto-epatico (HVPG): 5 Anatomia e Fisiologia della circolazione portale Sistema venoso ad alta portata e bassa resistenza che drena il sangue dagli organi addominali per convogliarlo al fegato; da questo, attraverso i sinusoidi e le vene sovrepatiche, raggiunge la vena cava inferiore e la circolazione sistemica

14 Classificazione e cause Cause Pre-epatiche Trombosi portale Trombosi splenica Cause Intraepatiche Presinusoidali Sinusoidali Postsinusoidali Cause post-epatiche Membrana cavale Pericardite costrittiva Insufficienza tricuspidale Grave scompenso cardiaco destro

15 Cause di ipertensione portale intraepatica Pre-sinusoidali Schistosomiasi, sarcoidosi, tossici, fibrosi epatica congenita, malattie mielo proliferative Sinusoidali o miste Cirrosi, epatite alcolica, iperplasia nodulare rigenerativa Post-sinusoidali Malattia veno-occlusiva Sindrome di Budd-Chiari

16 PORTAL HYPERTENSION: pathophysiological sequelae structural & functional intrahepatic resistance splanchnic blood flow splanchnic blood flow (cirrhosis)HCC portal hypertension variceal bleeding hepatic encephalopathy hepatopulmonary syndrome portosystemic collaterals systemic hyperdynamic circulation ascites spontaneous bacterial peritonitis cardiac output cardiomyopathy decrease central volume HRS

17 Conseguenze dell ipertensione portale Splenomegalia ed ipersplenismo Circoli collaterali ed emorragie digestive Shunt porto-sistemici ed encefalopatia porto-sistemica Vasodilatazione splancnica ed alterazioni della emodinamica sistemica

18 Circoli collaterali Ligamento falciforme Gastro-esofagei Vene emorroidarie Gastro-esofagei Parete addome e retro peritoneo

19 Conseguenze degli shunts portosistemici Riducono il flusso portale Aumentano insufficienza epatica NON riducono significativamente la pressione portale Favoriscono la circolazione iperdinamica Favoriscono iperammoniemia Endotossinemia Encefalopatia porto sistemica

20 Complicanze maggiori della cirrosi

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23 Compensated cirrhosis Compensated cirrhosis Decompensated cirrhosis Decompensated cirrhosis Development of cirrhosis Death Chronic liver disease Orthotopic liver transplant (OLT) Development of complications: Variceal hemorrhage Ascites Encephalopathy HRS Variceal hemorrhage Ascites Encephalopathy HRS Natural History of Chronic Liver Disease

24 Mortalità per complicanze di cirrosi epatica - 384 Pts Fattovich G et al, Gastroenterology 1997;112:463 follow-up: 5 anni

25 Child-Turcotte-Pugh (CTP) Score Child A: 5-6 pts Child B: 7-9 pts Child C: 10-15 pts Points 123 Encephalopathy None Grade 1-2 Grade 3-4 (precipitant)(chronic) Ascites None Mild Moderate Bilirubin (mg/dl) 3 Albumin (g/dl) >3.5 2.8-3.5 <2.8 PT (seconds prolonged) 6 or INR 2.3 Points 123 Encephalopathy None Grade 1-2 Grade 3-4 (precipitant)(chronic) Ascites None Mild Moderate Bilirubin (mg/dl) 3 Albumin (g/dl) >3.5 2.8-3.5 <2.8 PT (seconds prolonged) 6 or INR 2.3 MINIMAL LISTING CRITERIA: CTP SCORE 7 POINTS

26 Predicts 3-month mortality among patients with chronic liver disease on the liver waiting list MELD = (0.957 x LN (creatinine) + 0.378 x LN (bilirubin) + 1.12 x LN (INR) + 0.643) x 10 Minimum score = 6 (risk of death on WL 20%) Maximum score = 40 (risk of death on WL 100%) Predicts 3-month mortality among patients with chronic liver disease on the liver waiting list MELD = (0.957 x LN (creatinine) + 0.378 x LN (bilirubin) + 1.12 x LN (INR) + 0.643) x 10 Minimum score = 6 (risk of death on WL 20%) Maximum score = 40 (risk of death on WL 100%) MELD (Model for End-Stage Liver Disease)

27 Diagnostica della cirrosi con ipertensione portale Clinico-semeiologica Misurazione invasiva emodinamica portale Eco-doppler Endoscopia digestiva

28 Diagnosi clinico-semeiologica Splenomegalia Circoli collaterali superficiali Gavoccioli emorroidari Spider Naevi Edema perimalleolare Ascite Asterixis

29 Semeiotica dellipertensione portale

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33 Definition of ascites Uncomplicated Grade 1 (mild) detectable only by US Grade 2 (moderate) moderate symmetrical abdominal distension Grade 3 (large) marked abdominal distension Refractory Ascites that cannot be mobilized or early recurrence of ascites not prevented by medical therapy Diuretic-resistant Diuretic-intractable

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35 Bed rest unproven benefit Dietary sodium restriction to 5.2 g/d (90 mmol) Diuretics Anti-Mineralocorticoids Spironolactone, Canrenoate, Canrenone Loop diuretics Furosemide, Torasemide, Ethacrynic Acid Other potassium-sparing diuretics Amiloride, Triamterene Treatment of Ascites

36 Treatment duration Intensive diuretic therapy (spironolactone 400 mg/d + furosemide 160 mg/d) for at least 1 wk Salt-restricted diet (< 90 mmol or 5.2 g of salt/d) Lack of response Weight loss < 0.8 kg over 4 days Urinary sodium output < sodium intake Early ascites recurrence Grade 2 or 3 ascites within 4 wks of initial mobilization Diuretic-induced complications Hepatic Encephalopathy, Renal Impairment, Hyponatremia, Hypo/Hyperkalemia Diagnostic Criteria of Refractory Ascites

37 Infezione del liquido ascitico PMN > 250/mm 3 e colturale + su liquido ascitico Microbiologia: G-: E. Coli, K. Pneumoniae (60%) G+: Strepto (25%) Anaerobi: rari Non evidente sorgente di infezione addominale trattabile chirurgicamente 10-25% dei cirrotici ospedalizzati con ascite Mortalità elevata (17-50%) Alto rischio di recurrence: 43-70% (6-12 mesi) PERITONITE BATTERICA SPONTANEA: definizione ed epidemiologia

38 PERITONITE BATTERICA SPONTANEA: forme cliniche 1.Classic 2.CNNA (culture negative neutrocytic ascites) 3.MNB (monomicrobial non-neutrocytic bacterascites) carcinosi peritoneale, pancreatite, peritonite TBC ClassicaCNNAMNB PMN> 250 < 250 Colturale+-+

39 Cefotaxime: 2g/12 hrs per 5-10 gg Ciprofloxacina: 400 mg/12 hrs per 5 gg, poi orale Se non risposta: Stafilo? + Albumina: 1.5 g/kg alla diagnosi, 1 g/kg dopo 48 hrs (prevenire HRS!) Chinolonico long-term (Norfloxacina 400 mg/die) soprattutto se proteine < 1 g/dl nel liquido ascitico PERITONITE BATTERICA SPONTANEA: terapia e profilassi

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41 Definition of Hepatorenal Syndrome (HRS) Type I HRS Rapid and progressive renal failure with a doubling of serum creatinine to a level greater than 2.5 mg/dl or a halving of the creatinine clearance to less than 20 ml/min in less than 2 wks Type II HRS More chronic form with a slowly progressive increase in serum creatinine level to greater than 1.5 mg/dl or a creatinine clearance of less than 40 ml/min

42 DIFFERENCES BETWEEN TYPE-1 AND TYPE-2 HRS Renal failure Type-2Type-1 Consequence Survival Moderate and steady Refractory ascites Months Severe and progressive Terminal hepatorenal failure Days SpontaneousPrecipitated Onset

43 Definition of Hepatorenal Syndrome: Major Criteria Chronic or acute liver disease with liver failure and portal hypertension Low glomerular filtration rate (serum creatinine > 1.5 mg/dl or creatinine clearance < 40 ml/min) Absence of shock, excessive fluid loss, ongoing bacterial infection and recent treatment with nephrotoxic drugs No sustained improvement in renal function following expansion with 1.5 l of isotonic saline Proteinuria < 0.5 g/dl No US evidence of renal tract disease

44 Definition of Hepatorenal Syndrome: Minor Criteria Urine volume < 500 ml/d Urine sodium < 10 mmol/d Urine osmolality < plasma osmolality Urine red cell count < 50/high power field Serum sodium < 130 mmol/l

45 The Pathophysiology of HRS

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47 Varici esofagee Varici fondo Diagnosi e classificazione endoscopica

48 Gastropatia ipertensiva GAVE

49 Dilation and Rupture of Varices Varix P Flow Risk increases in portal pressure and collateral blood flow caused by: Meals Alcohol Exercise Increased intra-abdominal pressure

50 Acute variceal bleeding Sclerotherapy + Drugs vs Sclerotherapy alone Mortality

51 (profilassi secondaria) PREVENZIONE RISANGUINAMENTO (profilassi secondaria) BB + nitratifallimentoLEV(+ BB) successo fallimento successo Malattia epatica avanzata Malattia epatica stabile Continuare + follow up continuare TIPS (DSSR) TIPS OLT D´Amico, 2004

52 Hepatic Encephalopathy Nomenclature Type A Associated with Acute liver failure Type B Associated with porto-systemic Bypass without intrinsic hepatocellular disease Type C Associated with Cirrhosis and porto- systemic shunting Type A Associated with Acute liver failure Type B Associated with porto-systemic Bypass without intrinsic hepatocellular disease Type C Associated with Cirrhosis and porto- systemic shunting Ferenci et al., Hepatology 2002; 35:716 HEPATIC ENCEPHALOPATHY – NOMENCLATURE

53 Encephalopathy of acute liver failure (Type A) Rapid deterioration in the level of consciousness Increased intracranial pressure (ICP) Reduced cerebral perfusion pressure Neuropathologically, there is brain edema Pathogenesis is multifactorial with ammonia playing a major role Rapid deterioration in the level of consciousness Increased intracranial pressure (ICP) Reduced cerebral perfusion pressure Neuropathologically, there is brain edema Pathogenesis is multifactorial with ammonia playing a major role

54 Type C Hepatic Encephalopathy is the Encephalopathy of Cirrhosis Neuropsychiatric complication of cirrhosis Results from spontaneous or surgical / radiological portal-systemic shunt + chronic liver failure Failure to metabolize neurotoxic substances Alterations of astrocyte morphology and function (Alzheimer type II astrocytosis) Neuropsychiatric complication of cirrhosis Results from spontaneous or surgical / radiological portal-systemic shunt + chronic liver failure Failure to metabolize neurotoxic substances Alterations of astrocyte morphology and function (Alzheimer type II astrocytosis) TYPE C HEPATIC ENCEPHALOPATHY IS THE ENCEPHALOPATHY OF CIRRHOSIS

55 Treatment: rarely effective short of liver transplant Characteristics of Type A vs. Type C Hepatic Encephalopathy Gradual onset Rarely fatal Main cause: shunting / toxin Precipitant Treatment: usually effective Gradual onset Rarely fatal Main cause: shunting / toxin Precipitant Treatment: usually effective Rapid onset Frequently fatal Main cause: cerebral edema Rapid onset Frequently fatal Main cause: cerebral edema Type A Type C CHARACTERISTICS OF TYPE A VS. TYPE C ENCEPHALOPATHY

56 Pathophysiology of Hepatic Encephalopathy Ammonia Upregulation of astrocytic peripheral benzodiazepine receptors (PBR) Neurosteroid production Modulation of GABA A receptor Hepatic encephalopathy Ammonia Upregulation of astrocytic peripheral benzodiazepine receptors (PBR) Neurosteroid production Modulation of GABA A receptor Hepatic encephalopathy PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY

57 Hepatic Encephalopathy Pathogenesis Bacterial action Protein load Bacterial action Protein load Failure to metabolize NH 3 NH 3 Shunting GABA-BD receptors GABA-BD receptors Toxins PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY

58 Pathogenesis of Hepatic Encephalopathy: role of GABA-BD receptors

59 Hepatic 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 EEG 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 EEG HEPATIC ENCEPHALOPATHY IS A CLINICAL DIAGNOSIS

60 StageMental stateNeurologic signs 1Mild confusion: limited attention Incoordination, tremor, span, irritability, inverted sleep impaired handwriting pattern 2Drowsiness, personality changes,Asterixis, ataxia, intermittent disorientation dysarthria 3Somnolent, gross disorientation,Hyperreflexia, muscle marked confusion, slurred speechrigidity, Babinski sign 4ComaNo response to pain, decerebrate posture 1Mild confusion: limited attention Incoordination, tremor, span, irritability, inverted sleep impaired handwriting pattern 2Drowsiness, personality changes,Asterixis, ataxia, intermittent disorientation dysarthria 3Somnolent, gross disorientation,Hyperreflexia, muscle marked confusion, slurred speechrigidity, Babinski sign 4ComaNo response to pain, decerebrate posture Stages of Hepatic Encephalopathy STAGES OF HEPATIC ENCEPHALOPATHY

61 Ong et al., Am J Med 2003; 114:188 Poor Correlation of Ammonia Levels With Presence or Severity of Encephalopathy Venous total ammonia mol/L Venous total ammonia mol/L 0 0 400 350 300 250 200 150 100 50 Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Severity of Hepatic Encephalopathy

62 Blood ammonia levels cause as much confusion in those requesting the measurement as in the patients in whom they are being measured Adrian Reuben Hepatology 2002;35:983 Adrian Reuben Hepatology 2002;35:983 BLOOD AMMONIA LEVELS ONLY LEAD TO CONFUSION

63 Minimal 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) Predicts overt 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) Predicts overt encephalopathy MINIMAL HEPATIC ENCEPHALOPATHY

64 Treatment 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) 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 ENCEPHALOPATHY

65 Actions of Lactulose Lactulos e Lactic acid Decreased pH NH 3 Urease- producing bacteria Increase cathartic effect NH 3 NH 4 + ACTIONS OF LACTULOSE

66 Córdoba, J Hepatology 2004; 91:38 Day 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 11 12 13 14 Hepatic encephalopath y stage 0 0 1 1 2 2 3 3 4 4 Hypoproteic diet Normoproteic diet Protein Restriction Is Not Necessary in Hepatic Encephalopathy PROTEIN RESTRICTION IS NOT NECESSARY IN HEPATIC ENCEPHALOPATHY

67 Variceal Bleed Monitor Liver Function PT, Alb, Bili q 3-6 months Hepatoma Surveillance U/S, AFP q 6 months Varices Surveillance Compensated Decompensated Encephalopathy Treatment Recommendations - Cirrhosis SBP Ascites HRS (Garcia-Tsao G, 2003)

68 Maintain nutrition/reduce salt intake Maintain nutrition/reduce salt intake Prevent bone loss Prevent bone loss Prevent bleeding Prevent bleeding Prevent encephalopathy Prevent encephalopathy High index suspicion for sepsis High index suspicion for sepsis Close control diabetes Close control diabetes Management of complications Management of complications Early diagnosis and therapy of HCC Early diagnosis and therapy of HCC (Selected antiviral therapy) (Selected antiviral therapy) Appropriate referral to transplant centres Appropriate referral to transplant centres Management of cirrhosis

69 Natural History of Cirrhosis in 2008: Altered by What We Do More aggressive screening HCC identified earlier Ablative therapies for HCC (down- staging) Obliteration of varices/beta-blockade TIPSS Liver Transplantation

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71 Hepatic Encephalopathy Treatment: Summary Decrease ammonia production in gut: Lactulose Antibiotics Adjustment in dietary protein Decrease ammonia production in gut: Lactulose Antibiotics Adjustment in dietary protein Increase ammonia fixation in liver: Ornithine aspartate Benzoate Increase ammonia fixation in liver: Ornithine aspartate Benzoate Shunt occlusion or reduction HEPATIC ENCEPHALOPATHY – TREATMENT SUMMARY

72 Liver Transplant Decompensated cirrhosis - all causes (hepatitis C most common indication) Intrahepatic malignancy Acute liver failure Metabolic disease Decompensated cirrhosis - all causes (hepatitis C most common indication) Intrahepatic malignancy Acute liver failure Metabolic disease Extrahepatic malignancy Active infection Active substance abuse Advanced cardiopulmon-ary disease Extensive portal venous thrombosis Extrahepatic malignancy Active infection Active substance abuse Advanced cardiopulmon-ary disease Extensive portal venous thrombosis Indications Contraindications

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74 Child score and survival in 424 patients Days 16001400120010008006004002000 Cum Survival 1.0.8.6.4.2 0.0 CPT - A CPT - B CPT - C OLT 1-yr survival OLT 2-yr survival Heumann et al

75 100 60 0 0 80 40 20 0 0 2 2 4 4 6 6 8 8 10 Months from listing Probabilit y of survival (%) Probabilit y of survival (%) 12 <15 15 - 20 20 - 29 30+ 92.3% 90.7% 66.0% 33.8% MELD and Survival on Transplant Waiting List

76 Organ Allocation for Liver Transplant Fulminant hepatic failure has highest priority MELD score determines priority in cirrhosis Amongst patients with same blood type, highest MELD score determines priority Waiting time used only to break ties with identical MELD scores MELD scores are updated at regular intervals Fulminant hepatic failure has highest priority MELD score determines priority in cirrhosis Amongst patients with same blood type, highest MELD score determines priority Waiting time used only to break ties with identical MELD scores MELD scores are updated at regular intervals

77 United Network for Organ Sharing (UNOS) Regions 2 2 9 9 1 1 11 3 3 10 7 7 8 8 4 4 5 5 6 6

78 Current 1- and 3-year survival rates are 90% and 80%, respectively During 2005, ~6,000 liver transplantations were performed During 2005, ~17,000 patients were on the waiting list and ~2,000 died on it or were removed from it because they became too sick for transplant Main problem is the shortage of donors Expansion of donor pool: marginal livers, split-livers, live donors Current 1- and 3-year survival rates are 90% and 80%, respectively During 2005, ~6,000 liver transplantations were performed During 2005, ~17,000 patients were on the waiting list and ~2,000 died on it or were removed from it because they became too sick for transplant Main problem is the shortage of donors Expansion of donor pool: marginal livers, split-livers, live donors Liver Transplantation in the U.S.

79 Compensated cirrhosis Compensated cirrhosis Decompensated cirrhosis Decompensated cirrhosis Development of cirrhosis Orthotopic liver transplant (OLT) Death Median survival ~ 9 years Median survival ~ 9 years Median survival ~ 1.6 years Median survival ~ 1.6 years Chronic liver disease Development of complications : Variceal hemorrhage Ascites Encephalopathy Jaundice Variceal hemorrhage Ascites Encephalopathy Jaundice Natural History of Chronic Liver Disease NATURAL HISTORY OF CHRONIC LIVER DISEASE – SUMMARY

80 Liver biopsy Clinical/LSS Liver biopsy Clinical/LSS Large varices beta-blockers Small varices EGD in 1-2 yrs No varices EGD in 2-3 yrs Large varices beta-blockers Small varices EGD in 1-2 yrs No varices EGD in 2-3 yrs Ultrasound and AFP q 6 mos Measures to stop alcohol use Hep A and B vaccination Measures to stop alcohol use Hep A and B vaccination Compensated cirrhosis Compensated cirrhosis Decompensated cirrhosis Decompensated cirrhosis Orthotopic liver transplant (OLT) Orthotopic liver transplant (OLT) Death Chronic liver disease Diagnosis: Screen for varices (EGD): Screen for HCC: Management of Compensated Cirrhosis MANAGEMENT OF COMPENSATED CIRRHOSIS – SUMMARY

81 Compensated cirrhosis Compensated cirrhosis Decompensated cirrhosis Decompensated cirrhosis Orthotopic liver transplant (OLT) Orthotopic liver transplant (OLT) Death Chronic liver disease Diagnosis: Treatment: Early diagnosis of SBP: Clinical US or CAT scan Clinical US or CAT scan Spironolactone-based No NSAIDs Spironolactone-based No NSAIDs Paracentesis q admission or with symptoms No aminoglycosides in SBP Paracentesis q admission or with symptoms No aminoglycosides in SBP Ascites Management of Ascites MANAGEMENT OF ASCITES – SUMMARY

82 Compensated cirrhosis Compensated cirrhosis Decompensated cirrhosis Decompensated cirrhosis Orthotopic liver transplant (OLT) Orthotopic liver transplant (OLT) Death Chronic liver disease Diagnosis / Treatment: Other Treatment: Prophylaxis of rebleed: Variceal Bleed Endoscopy within 12 hrs Prophylactic antibiotics Beta-blockers prior to d/c or Serial ligation post d/c Beta-blockers prior to d/c or Serial ligation post d/c Management of Variceal Bleeding MANAGEMENT OF VARICEAL BLEEDING – SUMMARY

83 Compensated cirrhosis Compensated cirrhosis Decompensated cirrhosis Decompensated cirrhosis Orthotopic liver transplant (OLT) Orthotopic liver transplant (OLT) Death Chronic liver disease Diagnosis Treatment: Encephalopathy Clinical D/C diuretics D/C sedatives Dx paracentesis D/C diuretics D/C sedatives Dx paracentesis No long-term protein restriction Management of Encephalopathy MANAGEMENT OF HEPATIC ENCEPHALOPATHY - SUMMARY

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85 Cenni di terapia dellipertensione portale Farmaci antifibrotici: una promessa ancora non mantenuta Lunica terapia in grado di modificare la progressione è, al momento, il trattamento del fattore etiologico di base (es no Et-OH) Il target della terapia è quello di ridurre, farmacologicamente o chirurgicamente il gradiente venoso porto-epatico Lend-point clinico è la prevenzione primaria o secondaria del sanguinamento da varici

86 Terapia dellipertensione portale Vasocostrittori arteriolari splancnici Beta bloccanti non selettivi Vasopressina ed analoghi Somatostatina ed analoghi Terapia Endoscopica Scleroterapia Legatura Terapia Chirurgica H shunt (mesocavale) Splenorenale distale TIPS

87 Mediatori vasoattivi nella ipertensione portale VASODILATATORI Glucagone Prostaciclina Adenosina Fattore Natriuretico Atriale VIP Endotossine TNF NO VASOCOSTRITTORI Norepinefrina Serotonina Endotelina Angiotensina II Vasopressina

88 No specific treatment, only reduction of dietary sodium intake Treatment of ascites: Grade 1 Ascites

89 Bed rest unproven benefit Dietary sodium restriction to 5.2 g/d (90 mmol) Diuretics Anti-Mineralocorticoids Spironolactone, Canrenoate, Canrenone Loop diuretics Furosemide, Torasemide, Ethacrynic Acid Other potassium-sparing diuretics Amiloride, Triamterene Treatment of ascites: Grade 2 Ascites

90 Spironolactone: alone at first, 100-200 mg/d once Adequate response: weight loss = - 0.5 kg/d (1 kg/d if peripheral edema) If not adequate response: stepwise increase If failure to spironolactone 200 mg/d after 2-3 wks: + Furosemide (20-40 mg/d) If failure: maximal doses of spironolactone 400 mg/d + furosemide 160 mg/d Canrenoate, Amiloride (5-30 mg/d), or Torasemide may be used alternatively Treatment of ascites: use of Diuretics in Grade 2 Ascites

91 Electrolyte imbalance (hyponatremia, hypo/hyperkalemia, metabolic acidosis, metabolic hypochloremic alkalosis) if hyperkalemia > 6 mmol/l: stop spironolactone if hypokalemia < 3.5 mmol/l: stop furosemide Renal impairment Hepatic Encephalopathy Gynecomastia Testis hypotrophia Muscle cramps (also related to effective hypovolemia): may benefit from albumin, Zn sulfate Treatment of ascites: Complications of diuretic therapy

92 Severe hyponatremia (< 120 mmol/l) Renal impairment (serum creatinine > 150 umol/l) Active bacterial infection Treatment of ascites: Contraindications of diuretic therapy

93 Paracentesis, followed by Sodium restriction Diuretic therapy to reduce the risk of recurrence within 4 wks (90% vs 20%) Treatment of ascites: Grade 3 Ascites

94 Effective and safe in single session All ascitic fluid may be removed, even though in large amount Plasma volume expansion once paracentesis has been completed Plasma substitute if paracentesis < 5 l Albumin if paracentesis > 5 l (6-8 g/l of ascites removed) Treatment of ascites: use of Paracentesis in Grade 3 Ascites

95 Severe coagulopathy or marked thrombocytopenia (< 50.000/ml) Previous surgery or peritoneal adhesions (risk of bowel perforations) Bleeding (may be fatal) Leakage of ascitic fluid Renal impairment Treatment of ascites: Contraindications and complications of paracentesis

96 Repeated total paracentesis, followed by Sodium restriction Diuretic therapy (if tolerated; stop when urine sodium output < 30 mmol/d) TIPS (if paracentesis are not tolerated any more) Treatment of ascites: Refractory Ascites

97 No published controlled trials Water restriction is ineffective Plasma volume expansion with colloids may have some benefit Vasopressin-2 receptor antagonists seem to be promising Treatment of dilutional hyponatremia

98 Therapy of Hepatorenal Syndrome: present and future Liver Transplantation Vasopressin Analogues α-Adrenergic Agonists Molecular Adsorbent Recirculating System

99 Therapy of Hepatorenal Syndrome: Vasopressin Analogues (Ornipressin, Terlipressin) Rationale: increase of splanchnic and systemic vascular resistance, resulting in a redistribution of the circulating blood volume, via suppression of the RAA and sympathetic activities Useful in combination with albumin and low-dose dopamin

100 Therapy of Hepatorenal Syndrome: α-Adrenergic Agonists (midodrine) Rationale: improvement of systemic vasoconstriction and urinary sodium excretion Effective in combination with plasma volume expansion and octreotide (an inhibitor of the release of endogenous vasodilators)

101 HE:FATTORI PRECIPITANTI ABUSO DI FARMACI (diuretici, sedativi, oppiati) INFEZIONI INTERCORRENTI ECCESSO DI ALCOL / PROTEINE EMORRAGIA DIGESTIVA INTERVENTI CHIRURGICI COPROSTASI IPERAZOTEMIA ALCALOSI IPOKALIEMICA HCC

102 HE: TERAPIA MEDICA IDENTIFICARE FATTORE PRECIPITANTE LIMITARE INTROITO PROTEICO LATTULOSIO (attenzione meteorismo!) ANTIBIOTICI TOPICI (Paromomicina, Rifaximina) CLISTERINI MEDICATI sistematicamente!!!


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