Patient selection for LT for alcoholic liver disease:

1. Patient selection for LT for alcoholic liver disease: the present situation in Korea and recommendation - Controversial issues in LT for alcoholic liver disease of Korea TWO HEARTS ONE LIVER ONE LOVE FOREVER • Pusan National University Yangsan Hospital • HBP Surgery and LiverTransplant Team PNUYH HBP & LT TEAM

2. Safe Alcohol Use - 40 gm/day and 200gm/week for man

3. NO CRITERIANO SYSTEM

4. EU US REVIEW • KOREA 10 SURVEY • PNUYH EXPERIENCE

5. ALD remains the 2nd most common indication for LT, accounting for app. 40% of all primary LT in Europe and about 25% in US 20-45% of patients transplanted with ALD resume some degree of alcohol within 5 years of LT about half have harmful drinking. Transplantation 2013;95:755 The goal of 6 month rule (6 MoR) - current pre LT requirement at most centers To decrease the risk of recidivism To decrease the risk of graft loss

6. Recidivism risk decreases with increasing length of pre LT abstinence Retrospective Canadian study, n=170 LT recipients with ALD, LT between 1991-2007 Tandon et al, AJG, 2009 Compared to abstinent patients transplanted for non-alcoholic liver diseases, the survival rates in patients with recidivism to harmful drinking are similar initially but become worse after 5-10 years (45%-68% vs75%-86%). J Hepatol2012; 57: 306 Dig Dis Sci 2011; 56: 236

7. The patient survival rates after LT for ALD 81%-92%, 78%-86%, and 73%-86% at 1, 3, and 5 years respectively. Transplantation 2013; 95: 755 Am J Transplant 2010; 10: 138 No difference was seen when comparing the rate of graft loss from all causes after 90 postoperative days between ALD and PBC (hazard ratio 1.4; 95% CI 0.9–2.0). Eu So Or Transpl 2008; 21: 459 Patient loss is due to Ca and ASCVD rather than ALD Liver Transpl 2005;11:420 Declaration of Istanbul (2008); Organs should be equitably allocated to recipients without regard to gender, ethnicity, religion, or social or financial status. Do not discriminate against patients based on past behavior unless they have a clear impact on graft outcome.

8. No exceptions for ill patients with high MELDs 'Please help me Mum, I don't want to die': Last words of alcoholic, 22, who died after being refused liver transplantby JULIE MOULT for MAILONLINE and RYAN KISIEL for THE DAILY MAIL DATED: 16:26 GMT, 1 September 2009 A young alcoholic denied a liver transplant because he was too ill to prove he could stay. Gary Reinbach, 22, was terrified and pleaded with his mother to do something hours before his death. His last words to her were: 'Please help me Mum, I don't want to die.’ MrReinbach, who lived in Dagenham, Essex, began drinking at the age of 13 following the break-up of his parents' relationship. MrReinbach had the worst case of cirrhosis that doctors had ever seen in a man of his age but they refused to give him a new liver which could have saved his life. National guidelines dictate that to qualify for a donor organ, a potential recipient must prove he has the determination to stop drinking by remaining abstinent for six months.

9. Early Liver Transplantation for Severe Alcoholic Hepatitis N Engl J Med 2011;365:1790 SAH – not responding to medical Tx  6 mo survival rate 30% Prospective case control study French 7 centers SAH not responsive to medical Tx No prior episode of alcoholic hepatitis Having supportive family members Lille score ≥0.45 71% survival at 2 yrs vs 23% Almost 80% of deaths among control Pts occurred within 2 mo after identification of nonresponse to medical therapy An obvious ethical question is whether severe alcoholic hepatitis patients who do not respond to treatment should be left to their fate to die or should be considered for LT as suggested by the French consensus group.

10. There is some evidence that shows the duration of abstinence is correlated with less drinking after LT but there are many other factors that affect recidivism as well Some factors were found more often than not to be associated with abstinence: social stability, no alcohol problems among first-degree relatives, older age, no repeated alcohol treatment failures, good compliance with medical care, no current polydrug abuse, and no co-existing severe mental disorder. 6 MoR was a poor predictor of abstinence despite extensive research and wide usage. Need to develop a standardized multidisciplinary approach including not only 6 MoR but also other various predictors to minimize recidivism

11. Psychosocial Evaluation Although psychosocial evaluation is mandatory for all transplant candidates, it is more important in alcoholic cirrhotic. Psychosocial Assessment of Candidacy for Transplantation (PACT) scale is a common tool used at most centers for evaluating candidates for all types of transplants. JAMA 1989; 261: 2958 This scale is used to assess social support, psychological health, life style factors, and patients’ understanding of the transplant process including the follow up process after LT. Pts with intermediate risk for recidivism are recommended to undergo rehab. Txbefore being considered for LT.

12. Medical Evaluation A careful assessment should be made of the effects of alcohol on other organs including the presence of cardiomyopathy, chronic pancreatitis, Wernicke’s encephalopathy, alcohol-related dementia, peripheral neuropathy, and upper aero-digestive malignancies as these can affect LT candidacy. ClinLiver Dis 2012; 16: 851 These issues need to be addressed as they have a negative impact on LT outcome. Therefore, detailed cardiac, neurological, and aero-digestive assessment should be done in alcoholic cirrhotic to assure their LT candidacy.

13. Immediate Listing for Liver Transplantation Versus Standard Care for Child–Pugh Stage B Alcoholic Cirrhosis - A Randomized Trial Ann Intern Med 2009 150: 153 Patients with Child–Pugh stage B alcoholic cirrhosis were randomly assigned in a 1:1 ratio to immediate listing for liver transplantation (60) or standard care (60). The average Child–Pugh score and MELD score were 8.1 and 14.5, respectively. The incidence of de novo tumors  at least twofold higher in ALD AJT 2010;10:138 Upper aero-digestive cancers  10-fold higher risk compared to other indications GE 2009; 137: 2010 TP 2003; 35: 1900 When we consider LT in ALD MELD score might be greater than 15

14. Liver Transplantationfor Alcoholic Liver Disease KOREA KONOS registry From 2000 to 2015 Total 12662 patients

15. Annual Status of ALD patients in KOREA (2000~2015) * According to KONOS registry

16. Annual Status of ALD patients in KOREA (2000~2015) * According to KONOS registry

17. Etiology of LT patients in KOREA (2000~2015) 42% 17.7% 9.3% 3.9% 3.7%

18. The SURVEY: Patients Selection for LT for Alcoholic Liver Disease March 2016 10 LT centers in KOREA

19. Question 1. • Do you strictly apply the 6-month rule in your • center?

20. Question 2. • How many cases have kept the 6-month rule • among ALD patients?

21. Question 3. • What is your diagnostic method for alcohol • recidivism?

22. Question 4. • How do you make a decision to proceed LT for acute hepatic failure due to alcoholic hepatitis ?

23. Question 5. • Do you enforce the prohibition commitment to your patients? If yes, how?

24. Question 6. • Do you consult to psychiatrist about alcoholic abuse?

25. Question 7. • Is there any differences of alcohol recidivism between the patients who kept the 6-month rule and the others?

26. PNUYH EXPERIENCES Liver Transplantation for ALD From May 2010 to June 2015 Total 229 cases ALD 56 cases H O P E Helping Outside Patients Everywhere • Pusan National University Yangsan Hospital • HBP Surgery and LiverTransplant Team

27. Annual Status of LT for ALD patients in PNUYH (2010. May~2015.June)

28. Demographics of the ALD Patients

29. POD 30days Mortality • Total patients 6.5% (15/229) Non-alcoholic patients 5.8% (10/173) ALD patients 8.9% (5/56) Overall Survival Rate P=0.321 Non-alcoholics ALD patients

30. The Cause of Death in ALD patients

31. pRBC Transfusion during Transplantation P=0.004

32. Morbidity of the Recipients P=0.174 P=0.008 P=0.030 * All Complication according to ClavienDindo Classification (above IIIA)

33. Correlation with LT type P=0.051

34. Overall Survival Rate LT type P<0.001 P=0.009 LDLT DDLT

35. Overall Survival Rate Alcohol Relapse None Alcoholic recidivism P=0.705

36. Overall Survival Rate 6-month Rule P<0.001 P=0.056 Keeping 6-month rule Not keeping 6-month rule

37. Correlation between Alcohol Recidivism and 6-month rule 20.0% 3.8% P=0.068

38. Correlation between Alcohol Recidivismand Multidisciplinary treatment 28.6% 10.2%

39. SUMMARY • Although Korea LT society doesn’t have any official rule to select patients in ALD for LT, most centers have strictly applied 6 month rule as much as possible. • In the context of steadily increased ALD in LT, we definitely need a standardized multidisciplinary approach including not only 6 month rule but also other various predictors such as social stability, no family history, older age, good compliance with alcohol Tx, no current polydrug abuse, no severemental disorderto minimize recidivism and to maximize abstinence.

40. SUMMARY • SAH not responsive to medical Tx with no prior episode of alcoholic hepatitis and having supportive family members should be considered for LT. • Psychosocial evaluation and support are mandatory especially in ALD. • When we consider to perform LT for ALD, MELD score might be ≥ 15 considering high incidence of upper aero-digestive cancer. • Based on our primitive experience in ALD PNUYH need more strict selection criteria for ALD patients especially in severely deteriorated cases to enhance organ sparing.