Paul Martin, MD, FACG. University of Miami. 30,000 deaths from cirrhosis per annum, alcohol implicated in 48%

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1 Paul Martin, MD, FACG University of Miami 30,000 deaths from cirrhosis per annum, alcohol implicated in 48% Second commonest indication for liver transplant NIAA 2007 Page 1 of 26

2 Risk Factors Medical Therapy Liver Transplantation One drink (USA) 12 ounces of beer 4-5 ounces of wine (1/2 glass, 125 ml) 1.5 ounces of liquor (1 shot) All approximately grams of ethanol One drink (Europe) 10 grams of ethanol! Page 2 of 26

3 50-60 g alcohol/day for men, > 20 g/day for women Low risk for alcoholic cirrhosis even at this level of consumption ( % in Italy, Denmark) Binge drinking, drinking between meals and alcohol type ( wine risk less?) implicated Reuben 2006 CAGE questionnaire: a Have you ever felt you ought to cut down on your drinking? b Have people annoyed you by criticizing your drinking? c Have you ever felt bad or guilty about your drinking? d Have you ever had a drink first thing in the morning (eye opener) Page 3 of 26

4 Clinical Features Fatty Liver Fibrosis Cirrhosis HCC Alcoholic Hepatitis Page 4 of 26

5 Paul Martin, MD, FACG Concomitant HCV Obesity? Etoh increases penetrance of primary hemochromatosis Gene polymorphisms: PNPLA, TNF α etc. Yeluru 2016 Acetate ADH Acetaldehyde CYP 2E1 ALCOHOL DAMPs (ex. LPS, HMB1) Decreased gut mucosal integrity Adduct s Hepatocyte injury and necrosis ROS Stellate cell activation TLR4 activation Endotoxemia Kupffer cell activation FA synthesis, FA oxidation STEATOSIS SIRS ALCOHOLIC HEPATITIS INFLAMMATION LIVER FAILURE IL-1, TNFa and other proinflammatory cytokines FIBROSIS MULTI-ORGAN FAILURE REGENERATION Decreased NK cells Malnutrition Yeluru et al Page 5 of 26

6 Hepatic Steatosis: present in 90% of heavy drinkers, rapidly reversible with abstinence Alcoholic Hepatitis: occurs in 10-35% of heavy drinkers, precursor of cirrhosis Cirrhosis: develops in subset of heavy drinkers HCC Page 6 of 26

7 Treatment Abstinence Fat resolves in several weeks to several months Natural history Can progress to cirrhosis if patients continue to drink alcohol Women at higher risk of cirrhosis than men Long history of alcohol use Decades, >6 drinks per day Abstinence for <6 weeks Jaundice Fever Tender hepatomegaly, hepatic bruit Ascites AST>ALT; AST <200 (usually) INR prolonged Leukocytosis (WBC>10,000; PMN s > 6000) Page 7 of 26

8 Discriminate Function (Maddrey) Bilirubin (mg/dl) + [4.6 x prothrombin time] (seconds prolonged) > 32 has high short term mortality >55 has very high mortality MELD ( Creatinine, bilirubin, INR (prothrombin) MELD > 22 predicts high 30-day mortality Sensitivity 0.75; specificity 0.75 Dunn Hepatology 2005;41:353 Hospitalize patients with DF>32 or MELD > 20 Exclude infection Norfloxacin if ascites albumin <1.0 g/dl Adequate nutrition >2000 Cal/day (enteral feeding if necessary) Multivitamins (thiamine, etc) Page 8 of 26

9 Pharmacological Therapy Cumulative Survival 100% 75% 50% 25% Predictors of Survival Age (p<0.0001) Creatinine (p<0.002) Prednisolone (p<0.002) Pred 85% P=0.001 Placebo 65% Days Mathurin 2002 Page 9 of 26

10 Paul Martin, MD, FACG PTX Probability of Survival Placebo 0.6 P< Death with HRS Placebo: 22/24 (92%) PTX: 6/12 (50%) Multivariate Predictors of Survival Age Creatinine PTX treatment Time (Days) Akriviatis Gastroenterology 2000;119: patients, Maddrey DFS > 32 Randomized to PTX or Steroids Mortality at 3 months significantly lower in PTX (14.7%) compared to Steroid group (35.2%) 6 patients in steroid group developed HRS, none in PTX group De BK 2009 Page 10 of 26

11 Large UK trial, 1103 patients randomized Patients randomized to pred or ptx placebo controlled arms Endpoints were mortality at 28 days, 90 days and 1 year Thursz 2015 Proportion Surviving 1.0 Prednisolone No Prednisolone P= Days since Start of Treatment Thursz 2015 Page 11 of 26

12 Proportion Surviving No Pentoxifylline Pentoxifylline NS Days since Start of Treatment Thursz 2015 Proportion Surviving Placebo-placebo 0.1 Prednisolone-placebo 0.5 Pentoxifylline-placebo 0.2 Prednisolone-pentoxifylline Days since Start of Treatment Thursz 2015 Page 12 of 26

13 Not all patients respond to prednisolone Check bilirubin level after 7 days of treatment If bilirubin at Day 7 is higher, then STOP prednisolone If bilirubin at Day 7 is lower, then CONTINUE prednisolone for 28 days Avoid Steroid Autopilot Louvet 2007 Clinical features of AH mimic sepsis ( fever, leukocytosis, hypotension etc.) 25.6% of patients already infected prior to steroids Infection treated for mean of 8 days prior to steroids Infection occurred in 11% of steroid responders vs 43% in non-responders Prior infection not contraindication to steroids Louvet 2009 Page 13 of 26

14 Combination of prednisolone (40 mg/day x 28 days) and pentoxifylline (400 mg TID): group A versus prednisone and placebo: group B DFS > 32, 278 patients Biopsy proven alcoholic hepatitis Endpoints Primary endpoint was six-month survival Secondary endpoint was development of a hepatorenal syndrome Findings Six month survival is identical in two groups: 67.8% versus 68.5% Rate of hepatorenal syndrome was the same: 9.1% versus 10.3% No clear benefit from combination therapy! Louvet patients randomized to steroids with and without NAC infusion 1 month but not 6 month survival better with combination regimen Less HRS with NAC arm Nguyen-Khac 2011 Page 14 of 26

15 No therapy reduces long term mortality Benefit of cortictosteroids confirmed Pentoxyifylline benefit suggested Corticosteroids plus NAC promising Mortality has diminished overall Singh 2015 Large UK study No benefit with PTX Short benefit only with steroids Thursz NEJM 2015 Page 15 of 26

16 Consider therapy with corticosteroids or pentoxifylline Corticosteroids improve liver function in responders Pentoxifylline may prevent hepatorenal syndrome Colchicine PTU Silymarin SAME Probiotics Page 16 of 26

17 Paul Martin, MD, FACG Yeluru et al Pharmacological Therapy: Newer Approaches Page 17 of 26

18 Alcoholic Liver Disease Li et a Preventing Alcohol Relapse Page 18 of 26

19 Cumulative production (%) No. at Risk Placebo Baclofe n Relapse Placebo Active P= Time since randomisation (days) Addolorato 2007 Calculate MELD/Maddrey DF MELD < 20 Maddrey DF < 32 MELD > 20 Maddrey DF > 32 Supportive care Start PTX or steroids HRS Octreotide midodrine, IV albumin Bilirubin decreases, Cr stable Discharge at bili <10 Consider Baclofen Cr improves Choi 2012 Page 19 of 26

20 Role of Liver Transplant Appropriate Patient Selection Outcomes for Patient and Graft Impact of Alcohol Resumption Comorbidities Page 20 of 26

21 Depression Lack of Stable Partner ("Family and friends") Tobacco Use Lack of Insight Grams of Alcohol consumed prior to eval. Multivariate model correctly predicted post- OLT outcome in 89% of recipients Length of abstinence not predictive Kelly 2006 Prospective Study Patients enrolled 3 months post-olt 167 patients enrolled ( 95% of eligible patients) DiMartini 2006 Page 21 of 26

22 > 60 g/day for men, > 20 g/day for women > 88% had consumed this amount for at least 10 years Pre-OLT diagnosis of alcohol dependence or alcohol abuse DiMartini Alcohol-Timeline Follow-Back questionnaire q 3 mos for first year and then q 6 mos. 2. Caregiver questionnaire 3. Routine followup by psychiatrist blinded to results of questionnaires Page 22 of 26

23 1.0 Alcohol Use post-olt Proportion free from alcohol consumption Frequency outcome Binge outcome First alcohol use Number remaining from 167 at time 0: First Drink 123 Binge 144 Frequency Years DiMartini % recipients consumed Etoh by 4.5 yrs post-olt 26% binged ( 6 drinks for men, 4 for women) 20% frequent alcohol ( 4 days a week) No specific length of pre-olt sobriety predicted abstinence, relatively few patients with < 6 mos DiMartini 2006 Page 23 of 26

24 100% 80% 60% 40% 20% 0% All Diagnoses Alcoholic FHF Ch viral hep HCC PBC 1 year survival 5 year survival Role of Liver Transplant Page 24 of 26

25 100 Responder controls Survival (%) Patients undergoing transplantation Nonresponder controls P< No. at Risk Responder controls 92 Patients undergoing 26 transplantation Nonresponder controls Months Mathurin NEJM 2011 Comorbidities Page 25 of 26

26 Incidence of orophayngeal squamous cell carcinoma increased in recipients transplanted for alcoholic cirrhosis Followup of 45 mos, 26% in alcoholic recipients vs 5% in other cirrhotics ( p < 0.05) Cigarette exposure implicated in increased risk Duvoux 1999 Treatment of Severe Alcoholic Hepatitis Indicated Established Role for Liver Transplant Possible Role for Baclofen to Prevent Alcohol Relapse Page 26 of 26