SUPPLEMENT

Natural History of Alcohol Use Disorders in LiverTransplant PatientsAndrea DiMartiniUniversity of Pittsburgh Medical Center, Starzl Transplant Institute, Pittsburgh, PA

1) WHAT IS ALCOHOL DEPENDENCE?

A. Liver transplantation (LT) patients with alcoholicliver disease (ALD) often have the comorbid psychiatricdisorder of alcohol dependence (AD).

1. Not all patients with AD will develop ALD.2. Most, but not all patients, with ALD will be AD.3. Approximately 75-80% of ALD LT patients have

AD.B. Diagnostic criteria of alcohol use disorders.1. Alcohol abuse.a. Clinically important impairment or distress repeat-

edly in one or more of the following items in a 12-monthperiod.

i. Failure to fulfill major obligations (e.g., absences/suspension from work, neglecting household duties).

ii. Physically hazardous (e.g., driving while intoxi-cated).

iii. Legal problems (e.g., disorderly conduct, arrest fordriving while intoxicated).

iv. Social/interpersonal problems (e.g., argumentswith spouse about drinking, physical fights).

b. Approximately 60% continue with abuse; only 10%go on to develop AD.

2. Diagnostic criteria of AD.a. Clinically important impairment or distress in 3 or

more of the following in a 12-month period.i. Tolerance (e.g., increased amount needed for effect,

diminished effect).ii. Withdrawal (e.g., autonomic hyperactivity, tremor,

or use to avoid withdrawal).iii. Larger amounts/longer period than intended.iv. Persistent desire/unsuccessful attempts to cut

down.v. Excessive time spent with alcohol (e.g., spending

all of spare time at bar or recovering from effects ofalcohol).

vi. Activities given up as a result of alcohol (social,occupational, recreational activities give up to use al-cohol instead—e.g., preferring to drink instead of at-tending son’s baseball game).

vii. Continued use despite problems (e.g., knowing ofphysical disease such as liver disease or psychologicalproblem such as depression caused or worsened byalcohol use).

b. Most LT candidates with ALD meet diagnostic cri-teria for AD (�75-80%).

c. Nearly 70% of our alcohol-dependent LT cohortendorsed �4 of these criteria (when they were active intheir addiction before LT).

d. Lifetime prevalence of AD is approximately 4%.

2) NATURAL HISTORY OF AD: A CHRONICMEDICAL ILLNESS

A. First use of alcohol typically begins early with thedevelopment of dependence by early adulthood.

1. AD remains stable over years (unless a patientabstains).

2. Associated with a 10-15-year decrease in life spanfor a variety of health reasons (including, trauma, sui-cide).

3. Most (nearly 75%) of those with AD never receivetreatment.

4. Physicians need to screen for alcohol consumptionand refer AD patients for treatment.

B. AD is a chronic medical disorder.1. Heritability estimates from twin studies indicate

that a 60% variance of risk is genetic (heterogeneousand polygenic).

Abbreviations: LT, liver transplantation; ALD, alcoholic liver disease; AD, alcohol dependence; HCV, hepatitis C virus.Supported by grant K23 AA0257 from the National Institute of Alcohol Abuse and Alcoholism and an R01 DK066266 from the NationalInstitute of Digestive Disorders and Kidney Diseases. Additional information comes from the monograph Alcoholism: UnderstandingIts Developmental Trajectory, Treatment, and Recovery by Ting-Kai Li, MD, Director, National Institute on Alcohol Abuse andAlcoholism, NIH, DHHS, at the 27th Annual Leadership Conference National Association of Addiction Treatment Providers, Scottsdale,Arizona, May 27, 2005, and also information from the Alcohol Medical Scholars Web site at http://www.alcoholmedicalscholars.org/.Address reprint requests to Andrea DiMartini, MD, Department of Psychiatry, University of Pittsburgh Medical Center, Starzl Transplant Institute,Pittsburgh, PA.

DOI 10.1002/lt.21342Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 13:S76-S78, 2007

S76 Liver Transplantation, Vol 13, No 11, Suppl 2 (November), 2007: pp S76-S78

2. Risk factors reflect familial/genetic factors and en-vironment and personal choice.

3. Dependence has a distinct pathophysiology.4. Effects on brain circuitry.a) Alcohol/drugs either directly or indirectly acutely

activate mesolimbic dopamine-rich reward system.b) Prolonged use3changes in brain function.i. Brain metabolic activity.ii. Receptor availability.iii. Gene expression.iv. Responsiveness to environmental cues.c. Unclear whether changes return to normal with

abstinence.5. Changes in brain circuitry3increased difficulty

changing alcohol behavior.a. Pairing of person/places/things/specific emo-

tions3rapid and entrenched learning/conditioning.b. May elicit cravings even after long abstinence.C. Treatment is effective.1. Goals.a. Minimize symptoms/exacerbations.b. Maximize function (physical, social, and role func-

tion).c. Treatment requires chronic care and monitoring.i. Insurance restrictions often limit covered services.ii. Emphasis is on acute care rather than ongoing

treatment or on the process of relapse to prevent recur-rence.

2. Treatment does not cure but reduces symptoms/improve functioning.

3. Longer treatment course more effective.i. Marked decrease in alcohol use in persons in treat-

ment �3 months.Alcohol: long-term residential program lowered 35%,

outpatient lowered 65%.ii. Much lowered use if in treatment �6 months.Alcohol: long-term residential program/outpatient

lowered 75%-80%.

3) ARE AD LT PATIENTS DIFFERENT FROMAD PATIENTS IN THE GENERALPOPULATION?

A. The percentage of those receiving LT for ALD with orwithout hepatitis C virus (HCV) has been relatively sta-ble, if not slightly decreasing over the past decade rep-resenting 15-20% of all U.S. LTs.

B. Patients with ALD are not proportionally repre-sented among LT recipients. ALD accounts for:

1. Thirty percent of all liver deaths in United States.2. Only 15% of all LTs in the United States.C. AD is a chronic medical illness that spans decades.1. After �10 years of AD, as few as 20-35% will be

abstinent for 1 year.2. Patients with ALD often drink in a heavy, sustained

pattern for 10-20 years.3. Patients referred for transplant often, but not al-

ways, have a sustained period of sobriety.D. Patients with AD have greater odds of having:1. Mood disorder (mostly depression)—4� risk.

2. Drug dependence—37� risk.3. Nicotine dependence—6.4� risk.E. Our cohort of 208 ALD LT patients.1. Predominately white men, average age 51 years.2. Nearly 75% AD.3. Approximately 60% family history of alcohol use

disorder.4. Seventeen percent depressive disorder.5. Forty-one percent used drugs in addition to alcohol

(38% used intravenous drugs).6. Nearly 75% used nicotine (smoked or smokeless).7. Eight percent sober for �1 year.8. Forty-five percent attended addiction rehabilita-

tion.9. Many similarities to the AD population in general.

4) DOES LT CHANGE THE COURSE OF AD?

A. Time to specific alcohol use outcomes by 5 years afterLT in a cohort.

1. Any alcohol use—43% had had at least one drink.2. Binge use—27% had at least a single binge episode

(defined as �6 drinks per occasion).3. Frequency use—20% had at least a 1-week period

that included 4 days of drinking.4. Drinking most often began within the first post-LT

year but could begin even after �4 years of post-LTsobriety.

B. Those who took a first drink were at very high riskto continue drinking and to escalate to other, moreserious patterns of use. Sixty percent who took a firstdrink eventually went on to have a binge episode. Ad-ditionally, for 20%, their first drink was a binge episode,highlighting the quick loss of control over drinking. Forthis reason, we recommend no alcohol at all, not even asingle drink for a special occasion.

C. Drinking trajectories—demonstrating the quan-tity, frequency, and duration of alcohol consumption.

1. Seventy-one percent either were complete abstain-ers or drank very minimally on 1-2 occasions.

2. Sixteen percent drank minimally to moderatelyrarely to occasionally.

3. Only 7% developed an escalating heavy drinkingpattern.

4. Five percent drank moderately over time.D. Predictors of post-LT alcohol use—predicted the

time to onset of specific alcohol outcomes and the mod-erate to high drinking trajectories.

1. Diagnosis of AD was associated with a 2.8� greaterlikelihood of alcohol use.

2. Each month of pre-LT sobriety conferred a lesserrisk to drink (21% less risk for each month sober).

3. Addiction rehabilitation was associated with a 2�greater likelihood to use alcohol. We interpreted this tomean that patients who required addiction rehabilita-tion in order to stop drinking before LT (compared withthose who stopped on their own) had a more severeform of the addiction.

4. First-degree biologic relative with an alcohol usedisorder was associated with a 1.5� greater risk.

E. There was no specific clinical cutpoint for pre-LT

NATURAL HISTORY OF ALCOHOL USE DISORDERS S77

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length of sobriety that would have high sensitivity andspecificity in determining those unlikely to drink.

1. Months of pre-LT sobriety conferred less risk in alinear fashion.

2. Similar to what is seen in the general AD popula-tion, the longer the sobriety, the less risk to drink.

3. In the general AD population, stable sobriety ismeasured in years, not months.

F. Survival up to 7 years after LT was not differentbetween groups based on drinking outcomes. Our sur-vival data are comparable to United Network for OrganSharing survival data.

G. Causes of death.1. For recurrent diseases, 48% of our cohort was

infected with hepatitis B virus and/or HCV. Fifteen diedof recurrent HCV, with a mean survival of 3.3 years.

2. Thirteen died of cancer; mean survival was 3.5years. Seven cancer deaths were most likely from to-bacco exposure (lung and throat cancers in smokers/chewers).

3. Five died of alcohol-related causes; mean survivalwas 4 years.

5) CONCLUSIONS

A. AD LT recipients share the same general character-istics of those with AD in the general population.

1. We have patients with complex histories, early on-set, family histories of AD, comorbid drug use, depres-sion, and tobacco use histories.

a. We are selecting patients for LT with long sobriety.b. In the general AD population, this represents only

a small percentage: 20-35% who had AD for 10-20years and were 1 year sober.

c. Members of our cohort were more likely to haveattended addiction rehabilitation before LT.

B. Outcomes are very good.1. Most (71%) were completely or nearly completely

abstainers.2. Only 12% returned to a pattern of repeated drink-

ing (only 7% in the heaviest repeated pattern of use).Many of these patients sought help for their addiction.

3. Few died as the result of alcohol consumption.4. Patients in our cohort were more likely to die of

recurrent HCV or cancer.C. Suggest considering recruiting patients from the

still alcohol-dependent population if they can.1. Begin active addiction treatment.2. Have adequate support (family and LT team) for

ongoing addiction treatment.3. Demonstrate abstinence.4. Recall that 75% of AD population never get treat-

ment for their addiction. We could improve the courseof their AD and medical outcome by identifying thesepatients and referring them for assessment and addic-tion treatment.

BIBLIOGRAPHY

The materials below can be ordered from the NIAAAPublications Distribution Center, P.O. Box 10686,Rockville, MD 20849-0686; phone 301-443-3860. Theyare also available in full text on NIAAA’s Web site(http://www.niaaa.nih.gov/). NIAAA continually devel-ops and updates materials for practitioners and pa-tients; please check the Web site for new offerings.

For Practitioners

Helping Patients with Alcohol Problems: A Health Prac-titioner’s Guide. (Includes A Pocket Guide: AlcoholScreening and Brief Intervention.) Available at: http://www.niaaa.nih.gov/publications/Practitioner/Helpin-gPatients.htm.

Alcohol and Disease Interaction 2001;25(4). Availableat: http://www.niaaa.nih.gov/publications/arh25-4/toc25-4.htm.

What Is Moderate Drinking? 1999;23(1). Available at:http://www.niaaa.nih.gov/publications/arh23-1/toc23-1.htm

Alcohol’s Effect on Organ Function, 1997;12(1).Available at: http://www.niaaa.nih.gov/publications/arh21-1/toc21-1.htm.

Alcohol-Medication Interactions—Alcohol Alert No.27-1995. Available at: http://www.niaaa.nih.gov/pub-lications/aa27-text.htm.

For Patients

Alcohol: A Women’s Health Issue—Describes the effectsof alcohol on women’s health at different stages in theirlives. NIH Publication 02-5152. Also available: a 12-minute video, with the same title, that describes thehealth consequences of heavy drinking in women.

Alcohol: What You Don’t Know Can Harm You—Pro-vides information on drinking and driving, alcohol-medi-cation interactions, interpersonal problems, alcohol-re-lated birth defects, long-term health problems, andcurrent research issues. English version: NIH Publication99-4323; Spanish version: NIH Publication 99-4323-S.

Alcoholism: Getting the Facts—Describes alcoholismand alcohol abuse and offers useful information on whenand where to seek help. English version: NIH Publication96-4153; Spanish version: NIH Publication 99-4153-S.

Drinking and Your Pregnancy—Briefly conveys thelifelong medical and behavioral problems associatedwith fetal alcohol syndrome and advises women not todrink during pregnancy. Revised 2001 English version:NIH Publication 96-4101; Spanish version: NIH Publi-cation 97-4102.

Frequently Asked Questions About Alcoholism andAlcohol Abuse—English version: NIH Publication 01-4735; Spanish version: NIH Publication 02-4735-S.

Tips for Cutting Down—Provides patients with a self-evaluation and tips for cutting down on drinking. In En-glish and Spanish. NIH Publication No. 07-3769.

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