Pre- and post-transplant Anti-alcoholic management 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철 Pre- and post-transplant Anti-alcoholic management Young-Chul Jung Yonsei University College of Medicine Department of Psychiatry

How much do we drink? Percentile

How much do we drink? Percentile

At-risk Drinking Addiction Drinking How much is too much? (Heavy drinking) Addiction (Alcohol Use Disorder) Neuroplastic changes Tolerance and Withdrawal Loss of Control Functional Impairment ≥ 4 drinks per day ≥ 14 drinks per week 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

Drinking At-risk Drinking Addiction Abstinence Spectrum of Alcohol Drinking Drinking At-risk Drinking (Heavy drinking) Addiction (Alcohol Use Disorder) Abstinence Return to heavy drinking (Relapse) Return to drinking (Lapse, Temporary Slip) 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

Liver transplantation for alcoholic liver disease: current concepts and length of sobriety. Lim and Keeffe. Liver Transpl. 2004 Oct;10(10 Suppl 2):S31-8. How often do patients with alcoholic liver disease experience relapse following liver transplantation? Are there reliable ways to predict relapse in patients prior to liver transplantation? Are 6-month mandated abstinence requirements justified by the evidence? 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

(20–30% of patients resume heavy alcohol drinking within 5 years) Liver transplantation for alcoholic liver disease: current concepts and length of sobriety. Lim and Keeffe. Liver Transpl. 2004 Oct;10(10 Suppl 2):S31-8. How often do patients with alcoholic liver disease experience relapse following liver transplantation? Are there reliable ways to predict relapse in patients prior to liver transplantation? Are 6-month mandated abstinence requirements justified by the evidence? Approximately 15% of patients started drinking within the first 6 months (20–30% of patients resume heavy alcohol drinking within 5 years) 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

Liver transplantation for alcoholic liver disease: current concepts and length of sobriety. Lim and Keeffe. Liver Transpl. 2004 Oct;10(10 Suppl 2):S31-8. How often do patients with alcoholic liver disease experience relapse following liver transplantation? Are there reliable ways to predict relapse in patients prior to liver transplantation? Are 6-month mandated abstinence requirements justified by the evidence? There are few reliable predictors of relapse in alcoholic patients, whether or not they undergo liver transplantation 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

Liver transplantation for alcoholic liver disease: current concepts and length of sobriety. Lim and Keeffe. Liver Transpl. 2004 Oct;10(10 Suppl 2):S31-8. How often do patients with alcoholic liver disease experience relapse following liver transplantation? Are there reliable ways to predict relapse in patients prior to liver transplantation? Are 6-month mandated abstinence requirements justified by the evidence? Although not supported by all studies, abstinence of fewer than 6 months prior to transplantation may be a reasonable predictor of relapse. 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

20% patients showed a relapse to alcohol drinking. Efficacy of pretransplant 6 month abstinence in 15 ALD patients who underwent LDLT Results 20% patients showed a relapse to alcohol drinking. The cumulative 1-, 3-, and 5-year relapse rates were 6.7%, 20%, and 20%. The relapse rates in patients who did and did not maintain 6 months of abstinence were 9.1% vs. 50% Efficacy of 6-month pretransplant abstinence for patients with alcoholic liver disease undergoing living donor liver transplantation. Hwang et al. Transplant Proc. 2006 Nov;38(9):2937-40.

Why is it so hard for an alcoholic to keep abstinence from alcohol for 6 months ? 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

Why is it so hard for an alcoholic to keep abstinence from alcohol for 6 months ? Chronic alcohol abuse leads to dysfunction of Prefrontal cortex Mesolimbic dopamine pathway 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

There are various types of “Alcohol-related Brain Damage” Frequent concomitants of alcoholism are liver disease (steatosis, hepatitis and cirrhosis), cardiovascular disease and malnutrition. Alcohol-related CNS disorders include hepatic encephalopathy, Wernicke encephalopathy, Korsakoff syndrome, Marchiafava–Bignami disease and central pontine myelinolysis. Zahr et al. Nature Reviews Neurology (2011)

Graded brain-volume deficits in Alcoholism and Korsakoff’s syndrome Healthy Control Alcohol Us Disorder AUD + Korsakoff

The Prefrontal cortex is vulnerable to Alcohol-related Brain Damage Healthy Control Young AUD (30s) Old AUD (50s) (Z score) -1 -2

“Sub-clinical” Frontotemporal dementia Frontotemporal dementia involve extreme changes in behavior & personality These include: Increasingly inappropriate actions Loss of empathy Lack of judgment and inhibition Apathy Repetitive compulsive behavior Lack of awareness of behavioral changes Frontotemporal dementia Alzheimer’s dementia

Why is it so hard for an alcoholic to keep abstinence from alcohol for 6 months ? Chronic alcohol abuse leads to dysfunction of Prefrontal cortex  Psychological test of Cognitive function Mesolimbic dopamine pathway 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

Why is it so hard for an alcoholic to keep abstinence from alcohol for 6 months ? Chronic alcohol abuse leads to dysfunction of Prefrontal cortex  Psychological test of Cognitive function Mesolimbic dopamine pathway 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

Healthy Control Drug Abuser Cocaine METH Heroine Alcohol Neural plastic changes of Mesolimbic dopamine pathway ① During Resting state Baseline striatal [11C] raclopride binding ▼ = Dopamine D2 receptors down regulation

Neural plastic changes of Mesolimbic dopamine pathway ② When Activated Placebo Methylphenidate Healthy Control Decrease in dopamine release by activation Cocaine Abuser

Mesolimbic Dopamine Reward Pathway is Shared by other Natural rewards Alcohol

Abnormal activation of Mesolimbic dopamine pathway Chronic alcohol abuse Abnormal activation of Mesolimbic dopamine pathway Neural plastic changes Dopamine receptor down-regulation Decrease in dopamine release by activation Tolerance of alcohol Apathy toward Natural rewards Compulsive use of alcohol

천원짜리 라면 vs. 10만원짜리 한정식 수라상

Disulfiram

Naltrexone Acamprosate Disulfiram μ Opioid antagonist NMDA antagonist GABA agonist Disulfiram

Nalterxone vs. Acamprosate Naltrexone Acamprosate Onset Rapid Slow Long term efficacy No Yes Maintain abstinence Reduce Heavy drinking Compliance /Side effects Variable Good Interaction with alcohol Hepatic impact high dose(>100mg) Dependence potential

How effective are anti-craving agents? Return to Any drinking (= Maintain Abstinence) Risk difference Naltrexone - 5% (- 0.10 ~ 0.00) P=0.02 Acamprosate - 9% (- 0.14 ~ - 0.04) P<0.001 Disulfiram - 4% (- 0.08 ~ +0.02) P=0.48 Return to Heavy drinking (= Prevent Relapse) - 9% (- 0.13 ~ - 0.04) - 1% (- 0.04 ~ +0.03) P=0.67 Jonas et al. JAMA. 2014 May 14;311(18):1889-900 Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis

Why is it so hard for an alcoholic to keep abstinence from alcohol for 6 months ? Chronic alcohol abuse leads to dysfunction of Prefrontal cortex  Psychological test of Cognitive function Mesolimbic dopamine pathway  Anti-craving agents 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철

Thank you for your attention Any Questions? 한국간담췌외과학회 제44차 춘계학술대회 2016년4월1일 연세의대 정신과학교실 정 영 철