C.H.B. ACUTE LIVER FAILURE Guidelines and Consensus for Management Professor Didier SAMUEL Dr. Philippe ICHAI Centre Hépatobiliaire Hôpital Paul Brousse Faculté de Médecine Paris Sud Unité Inserm-Paris Sud Villejuif, France

Outcome of ALF A: Spontaneous recovery before encephalopathy B: Spontaneous recovery after encephalopathy C: Late regeneration (duration unknown): not avoiding death except with the help of auxiliary liver transplantion or liver support D: Total destruction of hepatocytes = death or transplantation Functional hepatocytes time (days) < 10 % ? 0 % 100 % ? D B A C Encephalopathy

C.H.B. Management of fulminant hepatitis

Fulminant (FH) hepatitis : acute hepatitis complicated by the occurrence of encephalopathy 2 weeks after the onset of jaundice Subfulminant hepatitis (SFH): acute hepatitis complicated by the occurrence of encephalopathy 2 to 12 weeks after the onset of jaundice DEFINITION* * Bernuau et al. Semin Liver Dis 1986 * Bismuth, Samuel et al. Ann Int Med 1987

Hyperacute liver failure: acute hepatitis complicated by encephalopathy < 7 days after onset of jaundice Acute liver failure: acute hepatitis complicated by encephalopathy days after onset of jaundice Subacute liver failure: acute hepatitis complicated by encephalopathy days after onset of jaundice DEFINITION* * O'Grady et al. Lancet 1993

Type of ALF and Outcome * Bernal Lancet 2010

C.H.B. Management of fulminant hepatitis

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Etiology and Prognosis of Fulminant Hepatitis in Adults First Step: Find the Cause of FH Emergency investigations  Virological tests : HAV, HBV,HCV  Toxicological screening: paracetamol, amphetamine, tricyclic antidepressants, salicylates, ecstasy  Imaging medical: liver ultrasound, computed tomography Second line tests  Virological tests: HSV, VZV, HEV Serological tests but PCR +++  Biochemical / Immunological tests Cupremia, cupruria, caeruloplasmin, Gammaglobulin, Autoantibodies  Cardiac / Pulmonary exploration: Echocardiography, Swann-Ganz  Histological examination: Transjugular liver biopsy + immunohistochemical staining

C.H.B. (Hôpital Paul Brousse ) Etiology of Acute Liver Failure in Adults Changes over Time in France (Hôpital Paul Brousse ) (198 patients) 38 % 4 % 25 % 3 % 8 % 22 % (285 patients) 12 % 10 % 13 % 32 % 19 % 14 % AcetaminophenDrugs HAVHBV Indeterminateother * p<0.05 Ichai P, Samuel D, Liver Transplant 2008

C.H.B. Etiology of Fulminant Hepatitis in Adults Changes over time in US Shakil, Liver Transplant 2000; Ostapowicz G, Ann Intern Med 2002 Pittsburgh (177 patients) 20 % 7 % 12 % 19 % 15 % 28 % USA* (308 patients) 7 % 15 % 7 % 5 % 6 % 61 % * 17 tertiary care centers AcetaminophenDrugs HAVHBV Indeterminateother

C.H.B. Ostapovicz Ann Int Med 2002;137: Etiology and Outcome of FHF in 17 US Centers 308 Patients

C.H.B. Management of fulminant hepatitis

C.H.B. To identify contra- indications to OLT Past history Malignant infiltration (liver metastases, lymphoma, acute leukemia): Transjugular liver biopsy Uncontrolled sepsis Intractable hypotension Respiratory failure Neurological complications

C.H.B. Management of Fulminant hepatitis

C.H.B. Criteria of LT King’s College and Clichy-Villejuif Bernal Lancet 2010

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Management of fulminant hepatitis

C.H.B. Control Factors of deterioration ICU Management Infection (antibiotics) Hypoglycemia (defective glycogenolysis, gluconeogenesis, insulin metabolism): administration of a daily dose of 200 g carbon hydrates Hypophosphoremia Hyponatremia Hepatotoxic drugs, sedative drugs

C.H.B. Management of Fulminant Hepatitis

C.H.B. N-acetylcystein paracetamol overdose, non paracetamol overdose Prednisolone autoimmune hepatitis * ? Acyclovir (10 mg/kg x 3/d) IV HSV hepatitis** ? Ganciclovir (5mg/kg x 2/d) FH due to cytomegalovirus Lamivudine, Tenofovir, Entecavir HBV reactivation. Not in primoinfection *** Silibinin, penicillin Amanita phalloides poisoning ? Specific Treatments * Ichai P et al, Liver Transpl 2007; ** Norvell J Liver Transpl 2007; *** Kumar M, Hepatology 2007,

C.H.B. Management of fulminant hepatitis

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Fulminant Hepatitis Brain Oedema M, 16 Years FH Undeterminate cause Stage 3 Coma before LT LT 5/2/00 Mydriasis during Surgery Immediate post -transplant Brain Death

C.H.B. Bernal W, Semin Liver Dis 2008 Aggarwal S, Liver Transpl 2008

C.H.B. PaCO2: mmHg * 0.5g/kg IV X 4-6/j Phenobarbital 3-5 mg/kg then 1-3mg/kg/j Thiopental: 5-10mg/kg then 3-5 mg/kg/j 25 mg IV boluses Dehydration Hyperosmol. Renal toxicity Rebound Hypotension Prolonged coma No ICP decrease Renal, Gastric toxicity?

C.H.B. « New therapies of Cerebral oedema » 1 2

C.H.B. Changes In ICP After Moderate Hypothermia (32-33°C) In FHF Jalan Gastroenterology 2004; 127: patients with FHF

C.H.B. Larsen, EASL 2011 Prophylactive Effect of Mild Hypothermia (MH) to Prevent Brain Œdema in Patients with Acute Liver Failure Hypothermia (33- 34°C) SMTp N pts2133_ T° _ ICH (ICP>25 mmHg)12/21 (57%)15/33 (45%)0.58 Deaths 10 (48%)19 (58%)NS Multicenter, randomized controlled trial groups: MH vs SMT No significantly difference of baseline characteristics in the 2 groups

C.H.B. Hepatology, 2004

C.H.B. Rolando N, Liver Transpl Surgery 1996, Vaquero J, Gastroenterology 2003; Sepsis Most common cause of death Commonly precipates MOF Risk factor with SIRS for developing cerebral edema Site of infection Pneumonia (50%) Urosepsis (22%) IV catheter-induced bacteremia (12%) Spontaneous bacteremia (16%) Infecting organisms Gram-negative bacilli Gram-positive cocci Candida species

C.H.B. Prophylactic Strategy Limitation of IV lines, Strict aseptic technique Chest radiograph, cultures of blood, urine, sputum Prophylactic antibiotics No benefit of enteral decontamination versus prophylactic therapy with parenteral antibiotics Prophylactic therapy for Who ? In patients with high risk of infection: Progression to high grade encephalopathy Renal failure SIRS Prophylactic parenteral broad-spectrum antibiotic/antifungal regimens Ceftazidime Piperacillin + tazobactam Antifungal

C.H.B. Hemodynamic Disturbances PathophysiologyHemodynamic support Sheron N, Clin Intensive Care 2002, Harry R, Hepatology 2002

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Harrisson PM, Wendon J et al, NEJM 91, Lee Gastro 2009

C.H.B. * OutcomeComa at randomization Traitement grouppOR PlaceboNAC Overall survival 21 days I-II75%79%0.292 III-IV53%48%0,64 Transplant-free survival 21 days I-II30%52% III-IV22%9% Total27%40% Gastroenterology 2009

C.H.B. Artificial Liver Support

C.H.B. 85.0% 68.5% 84.9% 82.0% Paracetamol Saliba F et al, AASLD 2009 Randomized Controlled Multicentre Trial Evaluating Efficacy and Safety of MARS® in Patients with Fulminant and Subfulminant Hepatic Failure Non Paracetamol

C.H.B. Management of Fulminant Hepatitis

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Management for ALF AASLD Position Paper Polson, Lee Hepatology 2005

C.H.B. LIVER TRANSPLANTATION Liver transplantation (LT) is the treatment of patients with ALF who will not recover with medical treatments. Most medical treatments are performed to gain time during the waiting period for transplantation Early referral is essential The need for LT should be evaluated as soon as possible Liver transplantation in ALF is an emergency When a liver graft is available –The indication for transplantation should be reevaluated –If indication confirmed, LT should be performed immediately

C.H.B. Indication of liver Transplantation for ALF Europe ( ELTR) Germani J Hepatol 2012

C.H.B. Survival after Transplantation for ALF Europe (ELTR) Germani J Hepatol 2012 Patient SurvivalGraft Survival

C.H.B. Risk of 3 or 12 Month Mortality or Graft Loss in patients Older than 50 Transplanted for ALF (ELTR) Germani J Hepatol months12 months

C.H.B. HIP/PAP : properties for tissue regeneration and protection against cellular stress in transgenic mice. - HIP/PAP: significantly improved survival in Fas-intoxicated mice - Primary hepatocytes were efficiently protected against multiple cell death signals by HIP/PAP

C.H.B. Conclusion Rapid transfert to a transplantation center is required Identification of aetiology is urgent: paracetamol, HAV, HBV, drug- induced and indeterminate are the main causes Evaluation of prognosis, indication for LT should be given early Cerebral edema and sepsis are the main complications of ALF Overall specialised ICU management is essential NAC in non-Paracetamol ALF is recommended Intracranial pressure (ICP) monitoring, remains controversial. Noninvasive monitoring of ICP is promising. Emergency LT is the treatment of patients with poor prognosis