Prise en charge de l hépatite alcoolique aiguë

Transcription

1 Prise en charge de l hépatite alcoolique aiguë Prof Christophe Moreno M.D. Ph.D. Clinical Director, Liver Unit Dept. of Gastroenterology, Hepato-Pancreatology and Digestive Oncology CUB Hôpital Erasme Christophe.moreno@erasme.ulb.ac.be DIU alcoologie, Module 2: aspects internistiques, 24 novembre 2017

2 CAS CLINIQUE Patient 56 ans Consulte pour ictère et dégradation état général en aggravation depuis 10 jours ATCDs: stéatose hépatique Ex clinique: at, ictère, pas d ascite, pas de signe d EH, érythème palmaire, angiomes stellaires MDV: OH: 80gr/j (arrêt depuis 7 jours) Pas de consommation de tabac Marié 2 enfants Actif professionnellement 2

3 QUESTION: QUE FAITES-VOUS? 1) Arrêt de l alcool, vitamines B1 et B6, à revoir dans 1 semaine 2) + Biologie et échographie et à revoir dans 3-5 jours 3) Hospitalisation d emblée (service des urgences) dans hôpital spécialisé dans les maladies hépatiques 3

4 CAS CLINIQUE: SUITE Consultation 5 jours plus tard Ictère aggravé bradypsychique Biologie Hb 12 g/dl Plaquettes: 95000/mm3 Leuco PTT 45% Bilirubine 18 mg/dl ALT 44 AST120 GGT90 Albumine 29 g/l creatinine 0.9 mg/dl Echographie du foie: Stéatose, dysmorphisme hépatique, lame d ascite péri-hépatique Veine porte perméable, voies biliaires non dilatées, pancréas normal 4

5 QUESTION: QUE FAITES-VOUS? 1) Poursuite de l arrêt de l alcool, à revoir dans 2 semaines avec contrôle biologie 2) + consultation Gastroentérologie 3) Hospitalisation dans hôpital spécialisé dans les maladies hépatiques 5

6 DEFINITION OF AH Clinical syndrome Recent (< 3 months) onset of jaundice (total bilirubin > 5 mg/dl) and liver failure Ongoing (or recent) alcohol misuse Histological features EASL Clinical Prac.ce Guidelines

7 -Steatosis -Hepatocyte ballooning -Inflammatory infiltrate with PMNs EASL Clinical Prac.ce Guidelines

8 Prognosis of AH 4.6 X (PT patient in sec - PT control in sec) + total bilirubin (mg/dl) Maddrey, et al. Gastroenterology 1978; 75:

9 Prognosis of AH 100 % 75 % 50 % 25 % n = 91 pts, M < 32 n = 96 pts, M 32 93±3% p < ±5% days Mathurin, et al. J Hepatol 2002; 36:

10 SEVERE AH ADMITTED TO ICU 55% of Severe AH were admitted to ICU: 60% with vasopressors, 52% with mechanical ventilation and 42% with RRT AH was frequently associated with a severe sepsis at the admission (26%) AH was frequently associated with AKI (28%) (prerenal, type 1 HRS) Gustot, et al. unpublished data; Louvet, et al. Gastroenterology 2009; Altamirano et al. Clin Gastroenterol Hepatol 2012

11 CorLcosteroids improve survival of palents with severe Alcoholic HepaLLs Individual Data Analysis Of The Last 5 RCTS (Mendenhall, Carithers, Ramond, Cabre*, Philipps*) 221 allocated to CorLcosteroids and 197 to controlled groups Survival (%) ±2.8% p= ±3.4% Pa.ents treated in the cor.costeroid group (n=221) Pa.ents treated in the non- cor.costeroid group (n=197) 0.00 Cor.costeroids Prednisolone 40 mg/d during 28 days days P Mathurin, J O Grady, RL CarithersJr, Philipps et al. Gut 2011

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13 28-DAY SURVIVAL P=0.06 Thursz M et al, NEJM

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15 NO SURVIVAL BENEFIT AT M3 AND 1 YEAR IN PREDNISOLONE GROUPS Thursz M et al, NEJM

16 NO SURVIVAL BENEFIT AT M3 AND 1 YEAR IN PREDNISOLONE GROUPS More infections in prednisolonetreated patients (13% vs 7%) Thursz M et al, NEJM

17 Impact of infection development under steroids 23.7% of severe AH patients treated with steroids will develop infection under therapy Pulmonary infections are the most frequent (40%) Louvet et al, Gastroenterology 2009

18 16% of severe AH patients were diagnosed with invasive aspergillosis MELD score 24 and ICU admission were predictive of invasive aspergillosis 18

19 Infection diagnosed before initiation of steroids does not impact survival 25.6% of severe AH patients were diagnosed with infection prior to initiation of steroids Sites of infection: SBP (44.4%), UTI (31.7%), pulmonary infections (12.7%) Louvet et al, Gastroenterology 2009

20 PTX 400 mg 3 times daily P = Placebo Akriviadis et al, Gastroenterology 2000;119:

21 Combination corticosteroids + PTX are not better than corticosteroids alone 100 p= ±3.1% (40 deaths) Survival (%) 50 Group A: prednisolone + PTX Group B: prednisolone + placebo 67.8±4.2% (42 deaths) Mathurin, Louvet et al, JAMA 2013 Time (days)

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23 28-DAY SURVIVAL P=0.69 Thursz M et al, NEJM

24 IS N-ACETYLCYSTEINE USEFUL? NAC 14 days NAC 7 days C Moreno et al, J Hepatol 2010 S Stewart et al, J Hepatol

25 Combination corticosteroids + NAC seems to be better than corticosteroids alone NAC 150 mg/kg in 30 min 50 mg/kg in 4 hrs 100 mg/kh in 16 hrs D2 100 mg/kg/24hrs during 5 days p=0.006 p=0.06 p=0.07 Nguyen- Khac et al, N Engl J Med 2011

26 Nutrition? 26

27 MALNUTRITION IS A FREQUENT COMPLICATION IN ALCOHOLIC HEPATITIS Malnutrition, both protein energy malnutrition, and deficiencies in individual nutrients, is a MAJOR complication of ALD Virtually every patient with AH has some degree of malnutrition Mendenhall,

28 SEVERE ALCOHOLIC HEPATITIS: NUTRITION ESPEN Guidelines on Enteral Nutrition: Liver disease $ Summary of statements: Alcoholic steatohepatitis Subject General Application Route Recommendations Use simple bedside methods such as the Subjective Global Assessment (SGA) or anthropometry to identify patients at risk of undernutrition. Recommended energy intake: kcal/kg BW/d ( kj/bw Kg/d) Recommended protein intake: g/kgbw/d Use supplementary enteral nutrition when patients cannot meet their caloric requirements through normal food. In general, oral nutritional supplements are recommended. Use tube feeding if patients are not able to maintain adequate oral intake (even when oesophageal varices are present) PEG placement is associated with a higher risk of complications and is not recommended. Clinical nutri.on 2006

29 Cabré et al, Hepatology 2000;32:36-42 Survival rate (%) TEN CORTIC Mortality 28 day 31% 25% Mortality M1-12 8% * 37% * Death by infection M1- M12 50% 90% TEN: 2000 kcal/day, 72 g prot/day

30 Benefit of enteral nutrition in association with steroids? Mul.center, randomized, controlled trial (18 Belgian and 2 French hospitals) Biopsy- proven severe AH pa.ents (mdf>32) Screening period 14 days after admission Active arm Control arm Intensive enteral nutrition using a feeding tube Méthylprednisolone 32 mg/d Randomisation 1:1 Conventional nutrition Méthylprednisolone 32 mg/d Follow-up Day In the Active arm, patients received Fresubin HP Energy (1.5 kcal/ml, 7.5 g prot/ 100 ml) as it follows: 1L/day if body weight (BW) < 60 kgs,1.5l if BW between 60 and 90 kgs, 2L if BW>90 30 kgs

31 RESULTS 3 patients were lost to follow-up during the study period Intensive arm Control arm p value Average kcal/day 2206 ± ± Average gr protein/day 106 ± ± Average kcal/kg/day 27.9 ± ± Nutrition intake was recorded during 14 days in both arms Moreno C et al, Gastroenterology

32 RESULTS: SURVIVAL 32

33 SAFETY OF ENTERAL FEEDING IN SEVERE AH PATIENTS Serious adverse events (SAEs) considered related to enteral nutrition were reported in 5 patients in the intensive arm (3 had aspiration pneumonia, 1 had decompensated diabetes, 1 had a severe worsening of encephalopathy) Aspiration pneumonia rapidly led to death in 1 patient Premature enteral feeding tube withdrawal (before the 14 days of intensive enteral nutrition) was reported in 33 patients (48.5%) Moreno C et al, Gastroenterology

34 Early identification of non-response: Lille model 1, severe AH Survival probability 0,750 0,500 0,250 Lille model < % of patients p < Lille model % of patients 0,000 0,0 50,0 100,0 150,0 200,0 Time in days Louvet, et al. Hepatology 2007; 45:

35 How to improve survival in severe AH patients who do not respond to corticosteroids? New molecules and/or strategies Ø Ø Ø Ø Ø Ø Enteral nutrition Antioxydants Anti-TNF Pentoxifylline MARS Liver Transplantation Louvet et al, J Hepatol 2008;48: ; Boitard, et al. AASLD 2007

36 Liver transplantation (LT)? Con: No alcohol abstinence Higher risk of alcohol reccurence? Natural recovery after alcohol abstinence Higher risk of mortality related to Transplantation? Pro: Advantaged by the system (MELD) Often young patients and first liver decompensation High risk of 6-month mortality

37 The 6-month rule of abstinence Bad exclusion criteria AbsLnence < 6 months before LT Good inclusion criteria AbsLnence > 6 months before LT AbsLnent aver LT Not abslnent aver LT TOTAL ,6 % Foster PF et al, Hepatology 1997

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39 Protocol for LT in NR severe AH 7 Transplant centers (6 French, 1 Belgian) Non-response to medical therapy was determined based on the Lille model or based on early worsening of liver function Selection criteria: 1. Non-response to medical therapy 2. Severe AH as the first decompensating event 3. Presence of close supportive family members 4. Absence of severe co-morbidities or psychiatric disorders 5. Agreement by patients and family members to adhere to lifelong total alcohol abstinence 6. Absolute consensus of medical and paramedical staff Mathurin et al, N Engl J Med 2011

40 Liver Transplantation: option in non-responders Survival % Months Mathurin et al, N Engl J Med 2011

41 Take home messages (1) AH is a severe disease, the diagnosis is based on clinical findings and histology Corticosteroids are the first line of treatment in severe forms. NAC could have an additive effect. Patients have to be hospitalized (at least one week) in specialized centers (transjugular liver biopsy, experience) Adequate nutritional intake (>21.5 kcal/kg/day) should be targeted. Favor oral route. Screening, early indentification and treatment of infection are crucial in the management

42 Take home messages (2) Identification of non-response to corticosteroids is possible at Day 7 of therapy and associated with very poor prognosis (25-30% survival at 6 months). STOP steroids in null-responders (Lille score > 0.56) Early liver Transplantation may be an appropriate rescue option for highly selected patients with severe alcoholic hepatitis not responding to medical therapy Alcohol abstinence improve mid- and long-term survival (>6 months) and is crucial for long term prognosis New therapeutic options are urgently needed

43 Thanks for your attention!