Management of Acute Decompensation of Cirrhosis JOHN O GRADY KING S COLLEGE HOSPITAL

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1 Management of Acute Decompensation of Cirrhosis JOHN O GRADY KING S COLLEGE HOSPITAL

2 Terminology Acute decompensation of cirrhosis - stable patient with sudden deterioration Acute-on-chronic liver failure - stable patient with sudden deterioration and evidence of organ failure

3 Acute-on-chronic Liver Failure Has been described as a new discrete entity APASL definition is acute illness leading to organ failure in patients with cirrhosis American and European concept is a precipitating event leading to failure of one or more organs and a short-term mortality in region of 15-30%.definitions differ greatly from each other and were developed in a theoretical rather than experimental basis.

4 EASL-CLIF Consortium Moreau R, et al, Gastroenterology 2013;144: patients hospitalised with acute decompensation of cirrhosis 415 were deemed to have acute-on-chronic liver failure 928 were deemed not to have acute-on-chronic liver failure A series of analyses were performed and statistical differences were used to define the entity

5 Results Distinguishing Features Organ failure defined as: - renal failure in isolation, - one organ failure with serum creatinine in range, - any two organs other than kidney, - one organ failure with encephalopathy. No precipitating event identified in 44% of cases Gastrointestinal bleeding not considered relevant Inflammatory markers with considerable overlaps for white cell count and c-reactive protein

6 Triggers for decompensation Gastrointestinal bleeding Infection may be relatively trivial and include spontaneous bacterial peritonitis Dehydration and renal dysfunction

7 ACLF & Practical Management Futile Critical Care? Mortality of cirrhotic patients admitted to LITU, King s College Hospital n=971 p<0.001 Log-rank for comparison of eras McPhail et al Clin Gastro Hep 2015;13:

8 Antibiotic Therapy All patients with hepatic encephalopathy All patients with variceal bleeding All patients with WCC in ascites >400 Patients undergoing paracentesis >5 litres

9 Fig. 1 Journal of Hepatology , DOI: ( /j.jhep ) Copyright 2015 BMJ Publishing Group Ltd, British Society of Gastroenterology and European Association for the Study of the Liver Terms and Conditions

10 HRS Vasopressors Vs Albumin or Placebo Meta-analysis of 12 RCTs and 700 patients Noradrenaline effective in reversing HRS but trials small Terlipressin better than albumin or palcebo with RR 2.54 reversal of HRS and 0.79 for mortality Terlipressin more adverse events but infusion safer

11 Terlipressin versus midodrine and octreotide in HRS (Cavallin et al, 2015;62:567-74) 27 patients received terlipressin in escalating doses from 3mg to 12mg daily 22 patients received midodrine (7.5mg to 12.5 mg TDS) and octreotide µg Intravenous albumin standard of care Recovery of renal function 70.4% Vs 28.6% (p = 0.01) 3 month survival 59% Vs 43% (NS)

12 Terlipressin Vasopressin agonist that increases GFR 196 patients with type 1HRS randomised to terlipressin or placebo Intravenous albumen was standard of care Primary end-point was reversal of HRS with serum creatinine <1.5mg/dl for >40 hours Secondary end-point survival and transplant free survival Negative study but only 6% completed 14 days of treatment (Boyer at al Gastro 2106)

13 Encephalopathy and Precipitating Factors Overt Hepatic Encephalopathy Normal Ammonia Load (TIPSS; constipation) Gastrointestinal bleeding Infection Hyponatremia Dehydration/Diarrhoea Renal Dysfunction Metabolic Alkalosis Sedative Drugs e.g. benzodiazepines

14 Overview of Therapies in HE LOLA Ornithine Phenylacetate Lactulose Neomycin/Rifaximin Vancomycin Norfloxacin Probiotics Protein Restriction

15 Management of Hyponatraemia Intravenous saline 5% dextrose is fluid of choice Fluid restrict at 1.5 litres or lower Consider filtration if less that mmol/l

16 Hyponatremia and risk of other complications Angeli et al. Patient population survey. Hepatology 2006

17 Prednisolone or pentoxifylline for alcoholic hepatitis 1026 patients projected enrollment 1053 patients with assessable primary end-point data 2 X 2 factorial design Assumption that mortality would be reduced from 30% to 21% in the active limbs Mean DF 63 and MELD 21; 27% encephalopathic and <1% renal failure

18 Mortality at 28 Days, 90 Days, and 1 Year. Thursz MR et al. N Engl J Med 2015;372:

19 Kaplan Meier Curves Showing Overall Survival Thursz MR et al. N Engl J Med 2015;372:

20 Conclusions Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28- day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year.

21 Secondary analysis Baseline adjustment to correct for 7 variables that influenced mortality Prednisolone Vs no prednisolone OR 0.61 p = 0.02 Pentoxifylline Vs no pentoxifylline OR 1.1 p =0.62 Conclusion that this may be a chance finding OR a benefit of prednisolone on short-term mortality

22 Alternative interpretations Negative study with p >0.05 Recruiting the planned 1200 patients might have dipped under p <0.05 threshold Recruited population did not match projections in study design Medium- and long-term survival only meaningful metrics Short-term survival needs to be bridged to another intervention

23 Systematic review and network meta-analysis Singh s, et al, Gastroenterology 2015;149: patients in 22 RCTs with ranked analysis Corticosteroids and N-Acetylcysteine most likely to reduce short-term mortality Corticosteroids + pentoxifylline significantly reduce shortterm mortality Pentoxifylline helpful if corticosteroids contraindicated

24 RR for short-term mortality Pentoxifylline Steroids Both CS & N-AC

25 Conclusions Entity of acute-on-chronic liver failure gaining increasing attention Gastrointestinal bleeding, infection are main triggers Jaundice, ascites, encephalopathy, renal dysfunction and hyponatraemia main clinical manifestations Antibiotics, volume expansion and vasopressors main therapies Role of corticosteroids in acute alcoholic hepatitis remains uncertain