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CARE OF THE ADVANCE CIRRHOTIC PATIENT AWAITING LIVER TRANSPLANTATION

CARE OF THE ADVANCE CIRRHOTIC PATIENT AWAITING LIVER TRANSPLANTATION. Professor Didier SAMUEL CENTRE HEPATOBILIAIRE HOPITAL PAUL BROUSSE VILLEJUIF, FRANCE. EVOLUTION OF LIVER TRANSPLANTATION IN USA. JF Trotter et al. NEJM 2002; 346: 1074-1082.

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CARE OF THE ADVANCE CIRRHOTIC PATIENT AWAITING LIVER TRANSPLANTATION

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  1. CARE OF THE ADVANCE CIRRHOTIC PATIENT AWAITING LIVER TRANSPLANTATION Professor Didier SAMUEL CENTRE HEPATOBILIAIRE HOPITAL PAUL BROUSSE VILLEJUIF, FRANCE

  2. EVOLUTION OF LIVER TRANSPLANTATION IN USA JF Trotter et al. NEJM 2002; 346: 1074-1082

  3. ALLOCATION OF GRAFTS3-Month Mortality according to Meld Score * R. Wiesner et al; Gastroenterology 2003; 124: 91-96

  4. Survival after Liver Transplantation in Relation with the MELD Score ONACA Liver Transplant 2003; 9: 117-123

  5. AIM OF THE CARE DURING THE WAITING PERIOD • Waiting time for transplantation varies between 3 and 18 months • The aims of the pre-transplant management are: • Avoid deterioration of liver function • Maintain the nutritional status of the patient • Avoid the appearance of contra-indications to transplantation: • Viral B Reactivation • Tumorous extension • Confirm the need for transplantation • Survey the appearance of contraindication to transplantation • Improve the results of transplantation

  6. CARE OF PATIENT DURING WAITING TIME • Required a regular follow-up • Every 2 to 4 weeks depending on severity of liver disease • Routine US doppler, surveillance of oesophagal varices, management of ascites • This follow-up can be done: • Directly by the transplant center • By the referring general physician or specialist • All therapeutic decisions should be made in accordance with the transplant physicians

  7. Prognosis of Patients with Cirrhosis after Onset of Ascites V Arroyo, J Colmenero J Hepatol 2003; 38: S69-S89

  8. Survival of Patients with Type 1-HRS A Gines Gastroenterology 1993; 105: 229-236

  9. REFRACTORY ASCITES • Paracentesis • Aim: • Avoid appearance of voluminous ascites • Avoid severe denutrition, hyponatremia and renal failure • Large volume 5-8 l compensated with albumine • Protection et surveillance of umbilical hernia: • Avoid the risk of umbilical rupture

  10. Probability of Rehospitalisation In Relation with the Treatment of Refractory Ascites Paracentesis + Diuretics Paracentesis + Alb + diurétics P<0.03 Gentilini J Hepatol 1999 30:639-45

  11. TIPS FOR REFRACTORY ASCITES Ochs et al. NEJM 1995; 332: 1192

  12. TIPS FOR REFRACTORY ASCITES Ochs et al. NEJM 1995; 332: 1192

  13. Effect of TIPS on Refractory Ascites Aj Sanyal Gastroenterology 2003; 124: 634-641

  14. TIPS or Paracentesis on Refractory Ascites Rössle et al. NEJM 2000; 342:1701

  15. TIPS FOR REFRACTORY ASCITES • Predictive factors of survival without transplantation (Rössle NEJM 2000; 342:1701) Age ≤ 60, female, bilirubin ≤ 3 mg/dl, Natremia ≥ 125 µmol/L • Predictive factors of survival (Ochs et al. NEJM 1995 ; 332:1192) • Age < 60, bilirubin < 22 µmol/L, complete response

  16. Probability of Development of De Novo-HRS after TIPS and Paracentesis P Gines Gastroenterology 2002; 123: 1839-1847

  17. COVER STENT TIPS : RANDOMIZED STUDY Probability of Survival Bureau Gastroenterology 2004; 126: 469-475

  18. MANAGEMENT OF REFRACTORY ASCITES • Transjugular portacaval shunt: TIPS • Effective on refractory ascites • More effective than paracentesis in control of ascites • More encephalopathy than paracentesis • Required the control of permeability of shunts • Same survival • Risk of liver failure in Child C patients • Well supported in patients with preserved liver function.

  19. SPONTANEOUS BACTERIAL PERITONITIS • Treatment • Improvement of prognosis • Urgent care +++: • Antibiotherapy effective, non nephrotoxic • Associated with Perfusion of albumin (Sort NEJM 1999) • Secondary prophylaxis +++ • Long-term therapy with Norfloxacin (Gines Hepatology 1990, Inadomi Gastroenterology 1997, Younossi, J Hepatol 1997) • Primary prophylaxis if protide concentration < 10g/l in ascites • Improvement of survival, risk of selection of resistant bacterias?

  20. SURVIVAL AFTER TRANSPLANTATION IN RLATION WITH RENAL FUNCTION AT TRANSPLANTATION S Nair Hepatology 2002; 35: 1179

  21. PREVENTION OF HRS AND OF RENAL FAILURE • Albumin compensation after large volume paracentesis • Prévention of spontaneous bacterial peritonitis (PBS): primary or secondary antibioprophylaxis • Antibiotherapy + albumin infusion in PBS (Sort et al. NEJM 1999; 341: 203) • Avoid nephrotoxic drugs (aminosides)

  22. TREATMENT OF HEPATORENAL SYNDROME • Treatment of the cause (sepsis, haemorrage) • Pharmacologic treatment • Albumin + ornipressine (Guevara Hepatology 1998; 1: 35) • Albumin + terlipressine (Urtiz J Hepatol 2000, Moreau Gastro 2002) • Albumin + midoridine + Octreotide (Angeli Hepatology 1999; 29: 1690) • Noradrenalin (Duvoux Hepatology 2002) • TIPS • Can reverse HRS (Guevara Hepatology 1998, Brensing Gut 2000 ) • SHR Type 2+++ • MARS • Can restore diuresis, improve survival (Mitzner Liver Transpl 2000)

  23. Survival in relation with the Renal Response to Terlipressine 1 Probability of survival 0,5 Responders p<0.0001 Non-responders 0 0 180 360 Days Moreau et al. Gastroenterology 2002 ; 122: 923-930

  24. TERLIPRESSIN+ ALBUMIN IN HRS Uriz J Hepatol 2000;33:43-18

  25. Effect of Noradrenalin on Type 1-HRS C Duvoux Hepatology 2002; 36: 374-380

  26. “LONG-TERM“ USE OF ORNIPRESSINE + DOPAMINE Renal Function Improvement In Relation With Treatment Duration Gulberg Hepatology 1999.30:870 -75

  27. TIPS AND HEPATORENAL SYNDROME Brensing et al. Gut 2000; 47:288

  28. TIPS AND HEPATORENAL SYNDROME • Operative mortality : 1/31 • Improvement of renal function • (increase of créatinin clearance and of renal sodium excretion) • Survival: • .10 patients without TIPS: 3 months survival: 10% • . Patients with TIPS: • Survival: 81%, 71%, 48%, 35% at 3, 6, 12, 18 mois • Predictive factors of survival : bilirubin and SHR type Brensing et al. Gut 2000; 47:288

  29. TIPS - • REFRACTORY ASCITES , HEPATORENAL SYNDROME • TIPS for ascites • Child B or “early“ C • Age < 60 • Maintained liver function, no jaundice • No spontaneous encephalopathy • TIPS for Hepatorenal Syndrome • After failure of medical treatment • As a bridge for transplantation • Mostly for HRS-type 2 patients

  30. EXTRACORPOREAL ALBUMIN DIALYSIS MARS U Heemann et al. Hepatology 2002; 36: 949-958

  31. Effect of MARS on Hepatorenal Syndrome Natremia PT MAP Urinary Volume MARS CVVHD MARS CVVHD MARS CVVHD MARS CVVHD • 13 cirrhotic patients with HRS type 1 • 8 treated with MARS system 5.2 ±3.6 treatments SR Mitzner, Liver Transplantation2000; 6: 277

  32. 3-Year Survival after Transplantation of Patients with HRS Treated with Vasopressin Analogues and those without HRS T Restuccia J Hepatol 2004; 40: 140-146

  33. Risk of Post-Transplant Renal Failure in Patients with HRS Treated with Vasopressin Analogues and Patients without HRS T Restuccia J Hepatol 2004; 40: 140-146

  34. Transplant-Free Survival in Patients with HRS Treated with Vasopressin Analogues According to Reponse to Therapy T Restuccia J Hepatol 2004; 40: 140-146

  35. PATIENTS WITH ALCOOLIC CIRRHOSIS • Routine follow-up +++: • Evaluation of the compliance of the patients • Assessment of abstinence • Evaluation of liver function • Possible improvement of liver function after 6 months • Disappearance of ascites • Improvement of Child-Pugh Score • Possibility of removal from the waiting list

  36. PATIENTS WITH HBV CIRRHOSISTreatment of viral replication • Viral B replication associated with: • Before transplantation • Deterioration of liver function • Decrease survival • Increased risk of HCC development • After transplantation • Risk of HBV reinfection • Decrease survival • Antiviral treatment is necessary

  37. 100 Compensated HBV cirrhosis (n=77) Lamivudine (n=27) 80 40 Decompensated HBV cirrhosis (n=21) % Survival 40 20 0 4 5 3 2 1 0 Years Lamivudine in Decompensated HBV Cirrhosis Patients with HBV decompensated cirrhosis treated with lamivudine compared to non-treated historical control patients (Adapted from De Jongh et al and Perillo et al) Fontana et al, Seminars in Liver Disease 2003;23:89-100.

  38. X Survival of HBV Cirrhotic Patients on Lamivudine 100 X X X X X 129 patients X X X X X X 80 X X X X X X X X X X X 60 40 NS SURV 20 All 25 patients 0 42 24 30 36 18 12 6 0 Kaplan-Meier plot of patient survival in the entire cohort (n=154), NS patients surviving <6 months (n=25), and SURV patients, which includes patients surviving ³6 months and those with less than 6 months of follow-up (n=129). The actuarial 3-year survival in the SURV group was 88% and 73% in the overall group. R Fontana. Gastroenterology 2002;123:719-727.

  39. 169 161 156 149 116 88 57 43 27 24 15 Post- transplant Pré- transplant 103 98 91 84 52 28 13 2 2 2 0 ADEFOVIR GS 435: Median Decline of HBV DNA * 0.0 Group B : Patients waiting for Transplantation -1.0 Group A : Transplant Patient -2.0 * PCR Roche Amplicor LLQ 1000 copies/mL ** 48 weeks pre- et post-transplantation and 96 weks post-transplantation p <0.001 compared to inclusion p <0.001 ** -3.0 log10 copies/mL -4.0 -5.0 0 4 4 8 8 12 12 24 24 36 36 48 48 60 60 72 72 84 84 96 96 Schiff Hepatology 2003; 38: 1419-1427

  40. HBV DNA <400 copies/ml Normalisation 81% ALT Albumin 76% 81% Bilirubin 50% Prothrombin 83% CPT Score stable or improved 92%* ADEFOVIR IN 128 HBV CIRHOTIC PATIENTS WAITING FOR LIVER TRANSPLANTATION Efficacy at week 48 Schiff Hepatology 2003; 38: 1419-1427 *at 24 weeks

  41. PREVENTION OF HBV RECURENCE ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION • The treatment with lamivudine or adefovir is effective • Some patients will die without transplantation despite antiviral response • These patients should be individualized • Some patients will improve and can be removed from the waiting list • This last issue is still open

  42. PREVENTION OF HCV RECURENCE ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION • Interferon + Ribavirin before transplantation • Difficult to manage in decompensated cirrhotic patients • Risk of deterioration of liver function • Poor antiviral effect at this stage • Recent promising study (Everson AASLD 2002) • Low increase of Peg IFN + ribavirin • SVR: 30% in genotype 3, 11% in genotype 1 • No HCV recurrence in sustained responders.

  43. PREVENTION OF HCV RECURENCE ANTIVIRAL TREATMENT BEFORE LIVER TRANSPLANTATION • Interferon + Ribavirin before transplantation • 30 HCV Cirrhotic pts; Child A: 15, Child BC: 15; Genotype 1b: 25 • IFN 3MU/day Ribavirin 800 mg/day until LT • 9 (30%) virologic response • 11 patients required filgrastim and 8 required EPO • No change in LFTs • Variables associated with response: low viral load, low ALT, non-1 genotype • 6/9 responders remained HCV RNA Neg after LT, 3 relapsed Forns et al J Hepatol 2003 ; 39: 389-396

  44. PATIENTS WITH HCV CIRRHOSISTreatment of viral replication before transplantation • The treatment is difficlut • Mostly reserved to Child A and B patients • Almost impossible in Child C patients • Duration before LT to be determined • No improvement in liver function despite clearance of HCV RNA • However should be considered since SVR patients will not recur

  45. MANAGEMENT OF PATIENTS BEFORE TRANSPLANTATIONCONCLUSION • The care of the patients before transplantation is essential • To avoid deaths in the waiting time period • To improve the results and survival post-transplantation.

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