Trajectories of Alcohol Consumption Following Liver Transplantation

Any use of alcohol in the years following liver transplantation (LTX) approaches 50% of patients transplanted for alcoholic liver disease (ALD). We collected detailed prospective data on alcohol consumption following LTX for ALD to investigate ongoing patterns of use. Using trajectory modeling we identified four distinct alcohol use trajectories. One group had minimal use over time. Two other groups developed early onset moderate‐to‐heavy consumption and one group developed late onset moderate use. These trajectories demonstrate that alcohol use varies based on timing of onset, quantity and duration. Using discriminant function analysis, we examine characteristics of recipient's pre‐LTX alcohol histories and early post‐LTX psychological stressors to identify the profile of those at risk for these specific trajectories. We discuss the relevance of these findings to clinical care and preliminarily to outcomes. Any use of alcohol in the years following liver transplantation (LTX) approaches 50% of patients transplanted for alcoholic liver disease (ALD). We collected detailed prospective data on alcohol consumption following LTX for ALD to investigate ongoing patterns of use. Using trajectory modeling we identified four distinct alcohol use trajectories. One group had minimal use over time. Two other groups developed early onset moderate‐to‐heavy consumption and one group developed late onset moderate use. These trajectories demonstrate that alcohol use varies based on timing of onset, quantity and duration. Using discriminant function analysis, we examine characteristics of recipient's pre‐LTX alcohol histories and early post‐LTX psychological stressors to identify the profile of those at risk for these specific trajectories. We discuss the relevance of these findings to clinical care and preliminarily to outcomes. Most reports of alcohol use after liver transplantation (LTX) identify the time to specific alcohol use outcomes (e.g. time to first drink) (1Berlakovich GA Windhager T Freundorfer E Lesch OM Steininger R Muhlbacher F Carbohydrate deficient transferrin for detection of alcohol relapse after orthotopic liver transplantation for alcoholic cirrhosis.Transplantation. 1999; 67: 1231-1235Crossref PubMed Scopus (46) Google Scholar, 2Everson G Bharadhwaj G House R et al.Long‐term follow‐up of patients with alcoholic liver disease who underwent hepatic transplantation.Liver Transplant Surg. 1997; 3: 263-274Crossref PubMed Scopus (67) Google Scholar) or set thresholds of use by which drinking groups are categorized (e.g. those who drank 140 g of ethanol/week) (3Kelly M Chick J Gribble R et al.Predictors of relapse to harmful alcohol after orthotopic liver transplantation.Alcohol Alcoholism. 2006; 41: 278-283Crossref PubMed Scopus (95) Google Scholar, 4Pageaux GP Bismuth M Perney P et al.Alcohol relapse after liver transplantation for alcoholic liver disease: Does it matter?.J Hepatol. 2003; 38: 629-634Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 5De Gottardi A Spahr L Gelez P et al.A simple score for predicting alcohol relapse after liver transplantation.Arch Intern Med. 2007; 167: 1183-1188Crossref PubMed Scopus (169) Google Scholar). We also reported on time to first alcohol use, binge use and frequency of use in our alcoholic liver disease (ALD) LTX recipients (6DiMartini A Day N Dew MA et al.Alcohol consumption patterns and predictors of use following liver transplantation for alcoholic liver disease.Liver Transplant. 2006; 12: 813-820Crossref PubMed Scopus (200) Google Scholar). We found those who take a drink can quickly transition to a binge (6 drinks) episode, with binge drinking occurring within the first year for over 40% of those who drank (6DiMartini A Day N Dew MA et al.Alcohol consumption patterns and predictors of use following liver transplantation for alcoholic liver disease.Liver Transplant. 2006; 12: 813-820Crossref PubMed Scopus (200) Google Scholar). Additionally, pre‐LTX alcohol history characteristics (diagnosis of alcohol dependence, short sobriety, alcoholism in a 1° biologic relative, other substance use and addiction rehabilitation) predicted time to these specific thresholds of use. There is great clinical and therapeutic utility in identifying the timing of onset of specific thresholds of alcohol use, specifically for planning appropriate timing of interventions. Over the long term, however, whether drinking is sustained, for how long, and whether specific patterns of use emerge may be most important for predicting outcome. Thus as the next step in our investigations of alcohol use in ALD LTX recipients we collected detailed, prospective post‐LTX alcohol consumption data allowing us to identify patterns of use far beyond basic thresholds of use. Using group‐based trajectory models, designed to identify clusters of individuals who follow a similar progression in behavior or outcome over time (7Jones BL Nagin DS Advances in group‐based trajectory modeling and an SAS procedure for estimating them.Sociol Methods Res. 2007; 35: 542-571Crossref Scopus (794) Google Scholar), we modeled alcohol use based on the quantity, frequency and duration of consumption. Our second step was to examine the contribution of both pre‐ and early post‐LTX factors to these trajectories of drinking. Alcohol use is highly influenced by personal risk factors such as genetic predisposition, as well as environmental and psychological factors (8Schuckit MA Smith TL Danko GP et al.An evaluation of the full level of response to alcohol model of heavy drinking and problems in COGA offspring.J Stud Alcohol Drugs. 2009; 70: 436-445Crossref PubMed Scopus (50) Google Scholar, 9Trim RS Schuckit MA Smith TL The relationships of the level of response to alcohol and additional characteristics to alcohol use disorders across adulthood: A discrete‐time survival analysis.Alcohol: Clin Exp Res. 2009; 33: 1562-1570Crossref PubMed Scopus (60) Google Scholar). Thus we hypothesized that transplant‐specific events would be crucial to both the initiation and eventual pattern of alcohol use. As alcohol use can begin early post‐LTX (10DiMartini A Day N Dew M et al.Alcohol use following liver transplantation: A comparison of follow‐up methods.Psychosomatics. 2001; 42: 55-62Crossref PubMed Scopus (91) Google Scholar) we collected data on psychological and medical stressors within 3 months post‐LTX. We hypothesized these stressors would be associated with specific trajectories of alcohol use (i.e. those who experienced more stress early on would resume quickly and drink heavily). Using discriminant function analyses we identified key predictors of those who would advance along specific trajectories of alcohol use. At the Starzl Transplant Institute (STI) from May 1998 to August 2004, 265 patients underwent LTX for a primary or secondary diagnosis of ALD. We used standard research procedures for approaching and obtaining signed informed consent according to our IRB approved study protocol. During the period of recruitment, 208 (78%) of the 265 ALD LTX recipients participated; 38 (14%) died before enrollment, 4 (2%) were ineligible due to prolonged hospitalization/nursing home placement and 15 (6%) refused to participate. The pre‐LTX diagnosis of ALD was determined by consensus from interviews and examinations by our transplant surgeons (PF and MdV), hepatologists and psychiatry team (AD and MGF). Patients with ALD had prior excessive alcohol use, defined as ≥20 g of ethanol/day for women or ≥60 g ethanol/day for men (11Diehl AM Alcoholic liver disease.Liver Transplant Surg. 1997; 3: 206-211PubMed Google Scholar). The majority (>80%) had consumed these amounts for ≥10 years. Psychiatric diagnoses of alcohol dependence or abuse were made by the psychiatry team using a structured interview and the Diagnostic and Statistical Manual of Mental Disorders IV (12Michael F, ed. Diagnostic and statistical manual for mental disor-ders, 4th Ed. WDC, USA: APA Press, 1994.Google Scholar) criteria. Demographic and psychosocial information collected during the pretransplant evaluations and documented on a standardized evaluation form was extracted from the medical record including pretransplant length of sobriety, attendance at alcohol rehabilitation, family history of alcoholism (patient‐reported 1° biologic relative with an alcohol‐use disorder), history of other substances and injected drug use and psychiatric diagnosis and treatment for substance use, depressive or anxiety disorders. Medical variables including the patient's LTX MELD score, hepatitis C (HCV) infection, post‐LTX biopsy data and causes of death were collected from the medical record. Additional data were collected on episodes of biopsy proven acute rejection. All tissue pathology data are reviewed by trained evaluators in our STI Transplant Pathology department. Acute rejection required both a pathologist's descriptive report of acute rejection and a Rejection Activity Index score ≥3. Three prospective measures of posttransplant alcohol use were obtained during either face‐to‐face research assessments at a return clinic visit, by telephone with the research staff or by mail. First, every 3 months for the first posttransplant year and every 6 months thereafter, patients completed the Alcohol‐Timeline Follow‐back questionnaire (ATLFB) (13Sobell LC, Sobell MB. Timeline follow-back: A technique for assessing self-reported alcohol consumption. In: Measuring alcohol consumption. Totowa, NJ: The Humana Press, Inc, 1992.Google Scholar) (97% by mail). The ATLFB is a calendar instrument used in alcohol research that captures a daily profile of alcohol use for the intervals between follow‐up interviews providing information on the quantity, frequency, patterns and duration of use. The ATLFB has good psychometric characteristics (high test–retest reliability and validity across clinical and general population samples) (14Sobell LC, Sobell MB. Timeline followback: A calendar method for assessing alcohol and drug use (User’s Guide). Toronto, Canada: Addiction Research Foundation, 1996.Google Scholar). Participants were told the ATLFB was strictly confidential and would not become a part of their medical record or be revealed to any LTX team member. We felt that ensuring participants’ anonymity would improve the yield in reporting alcohol use. Completion rates were high at all time points (range 75–94%, average 81% with >81% average at 5 years and beyond). Second, over the same time points, a caregiver who knew the patient best and typically lived with the patient (usually a spouse or family member) completed an alcohol quantity–frequency questionnaire that asked about the patient's alcohol use. The caregiver questionnaire patterned after the NIAAA Quantity‐Frequency measure (15Armor, DJ, Polich JM, Stambul HB. Alcoholism and treatment. New York: Wiley, 1978.Google Scholar) asks about the number of drinking days and the amounts consumed. This information was transcribed onto a calendar form similar to the ATLFB. Third, during routine posttransplant clinic appointments, clinical interviews were performed by the transplant psychiatrist (AD) who was blinded to the data obtained by other methods. Responses to questions about alcohol use from the psychiatrist's interview were compared with information given by the patient to the transplant coordinators and surgeons during the same clinic visit in independent interviews. The highest amount reported by the patient was recorded as quantity/frequency of alcohol use with specific dates and amounts of use on a monthly calendar form (similar to the ATLFB). Patients are seen in the transplant clinic as medically indicated. However, when possible, most patients are seen twice weekly for the first month after LTX discharge, then monthly until 3 months post‐LTX, then typically every 3 to 6 months thereafter (see reference 10DiMartini A Day N Dew M et al.Alcohol use following liver transplantation: A comparison of follow‐up methods.Psychosomatics. 2001; 42: 55-62Crossref PubMed Scopus (91) Google Scholar for comparison of alcohol reporting methods) (10DiMartini A Day N Dew M et al.Alcohol use following liver transplantation: A comparison of follow‐up methods.Psychosomatics. 2001; 42: 55-62Crossref PubMed Scopus (91) Google Scholar). As part of routine clinical care, blood alcohol levels are checked at transplant clinic appointments. These data were extracted from patients’ medical records and used in combination with alcohol calendars to identify the onset of use (if discrepant from other methods) or to quantify the amount used. At 3 months post‐LTX or later if still hospitalized, we assessed symptoms of depression (Beck Depression Inventory‐BDI), anxiety (Zung Anxiety Scale‐ZAS), perceived stress (Cohen's and of transplant‐specific of The of transplantation on and New NJ: Scholar, MA et in patterns of following Clin in 3: PubMed Scopus Google Scholar) were also patients were also asked to how experienced about their rejection for for a second transplant and about were also asked whether felt would transplant if At follow‐up clinic patients are to from alcohol use is the patient would from the transplant psychiatrist with to alcohol if indicated. Thus the study was not a study in which alcohol use was clinical we the same standard of care as would most transplant is and clinical is when alcohol use is Our standard is with or as indicated. We to the levels to as as for from the alcohol use calendar caregiver and clinic were a drinking outcome for was a between consumption amounts or frequency we the highest reported amount to alcohol use that a would not on the of The between the alcohol use in the analyses and the was highest for the clinic report patient report and caregiver report to the the patients’ reported use on their calendar and revealed during clinic interviews good Statistical for rates and Ed. New York: and Scholar). of comparison between of alcohol alcohol consumption was reported in standard alcohol drink (i.e. one of or a one of modeling is a analysis, which groups within a population to patterns or trajectories. examine patterns of the daily amounts of alcohol consumption over the SAS procedure BL Nagin DS A SAS procedure based on for estimating Methods Res. 2001; Scopus Google Scholar) to was used. This procedure trajectories of and level of alcohol use for the groups as a function of time from are the trajectories of the number of consumption reported from the of from the LTX were modeled by a the can data from individuals with of who or died over the of follow‐up not to be data until the of were and the number of groups in the until the G the of a Google Scholar) are the number of to the in time post‐LTX are for We used discriminant function to whether pre‐LTX alcohol use history variables as well as participants’ medical and psychosocial characteristics early post‐LTX between trajectory groups and to the relative of these predictors in individuals the to the group the full set of variables not be used in the discriminant and a of variables were First, based on our prior clinical and research (6DiMartini A Day N Dew MA et al.Alcohol consumption patterns and predictors of use following liver transplantation for alcoholic liver disease.Liver Transplant. 2006; 12: 813-820Crossref PubMed Scopus (200) Google Scholar), we four pre‐LTX variables a from the alcohol history to length of sobriety, psychiatric diagnosis of alcohol dependence, 1° biologic relative with alcoholism and use of other substances was not used due to high with other Second, we variables medical pre‐LTX MELD score and early post‐LTX with was not used due to high with other substance Third, we the contribution of symptoms of and stress and and the perceived stress a measure of due to between these We also were in of the transplant and felt questions on whether recipient's would to and whether had about transplant if to their liver best the early post‐LTX with their One recipients had data on all of the variables and were in the discriminant function Participants all variables the study later when the psychological measures were not These individuals were similar on medical and psychological variables that were more to be and histories of other substance use. Demographic characteristics of are similar with to and to for ALD LTX recipients of Scholar). Patients are and with a years. Most were high and in psychiatric and medical M high and psychiatric heavy M of sobriety, M to prior to statistical and are to M to prior to statistical and are to rehabilitation, history of dependence substance use, C infection, score, M to prior to statistical and are to rejection within 3 post‐LTX psychiatric stress M depression M anxiety M to prior to statistical and are to in a to LTX most patients had years of heavy drinking were years for men for amounts of alcohol consumed not by 15 standardized had a 1° biologic relative with Most had or year of pre‐LTX sobriety, had addiction to had used other including and was in of patients The MELD score at the time of LTX was of the patients experienced acute rejection within 3 months and had or more episodes of rejection. the post‐LTX for the and are not of levels of depression or of patients reported symptoms on of these of is and compared to the general for general mental and population for the (range for are in the high and not of the patients were about a rejection and over 50% had about their and about a However, felt that would LTX if the 208 had reported alcohol use post‐LTX on any measure the we identified four distinct trajectories of alcohol consumption. The majority group drank amounts However, other distinct alcohol‐use trajectories early onset moderate use that over time group later onset moderate use that over time group and an early onset, pattern of use group The trajectories are as the of the number of standard for intervals to the of the with intervals trajectory The amounts of consumption consumption during of the time over a period of years Our not of use more consumption during these time the characteristics of had minimal use the 3 had a moderate use pattern that at years and by year 4 had minimal use until year 3 then use that during the the drinking had a onset heavy use that at year 3 and year the average across group 5 was were individuals in group who at to a of or a of characteristics of alcohol use of use after LTX of consumption at of comparison between of alcohol alcohol consumption is standard drink (i.e. one of or a of of level of standard onset moderate standard to moderate use after 3 years standard a at year onset heavy standard a at year of comparison between of alcohol alcohol consumption is standard drink (i.e. one of or a of in a We preliminarily outcomes between the We that alcohol would to be to we the early onset moderate‐to‐heavy use groups 3 and to to all The use of group 4 not until beyond 3 years and would not such a on early outcomes. We found groups 3 and 5 from all by more or rejection on biopsy and more to All who died of ALD were in groups 3 and There was in between groups were those in groups 3 and 5 more to of (see of outcomes between early onset 3 and are reported the of are of with not of with acute score of number to more as died of a combination of and alcohol liver liver causes of liver and and and or are reported the of are not Rejection score number to more as died of a combination of and alcohol liver and and and in a We used discriminant function to whether recipients in the trajectories be from other across an of factors pre‐LTX characteristics and post‐LTX The discriminant function compared all trajectories on a of these characteristics (see The trajectory groups along in the discriminant function for a of the A of of the was for by these function analyses using alcohol psychological characteristics and early of use function level onset moderate onset moderate onset heavy and psychiatric of sobriety, to prior to statistical and are to of either of the first of the second history of dependence substance use, post‐LTX of and psychological (high M (high compared to year about not LTX if knew stress M to prior to statistical and are to of either of the first of the second in a The first function between and those who The second function those who had early onset of moderate‐to‐heavy alcohol use from those who drank in amounts or later post‐LTX. was in a on (see for the of group and The discriminant function are in the of These are in the same as in and that the most important risk those with at or for the first function were length of family history of alcoholism and alcohol dependence diagnosis the second function those with early onset moderate to heavy alcohol use 3 and were by reporting post‐LTX compared to one year prior more more perceived stress a pre‐LTX history of other substance use and not that would liver if it The utility of these discriminant can be their to their trajectory One were their trajectory was and for groups This was by by would be and The of the group was also by the of alcohol use, our trajectories important patterns that emerge along the post‐LTX most patients or drink distinct patterns of moderate‐to‐heavy consumption Two were patterns of early onset use, one moderate and one to heavy use. These trajectories demonstrate that for early following transplantation and recipients can quickly over their drinking. the of moderate‐to‐heavy alcohol use can begin years post‐LTX. Thus clinical well beyond the early years post‐LTX. We as in our prior reports (6DiMartini A Day N Dew MA et al.Alcohol consumption patterns and predictors of use following liver transplantation for alcoholic liver disease.Liver Transplant. 2006; 12: 813-820Crossref PubMed Scopus (200) Google Scholar), that pre‐LTX variables of the alcohol history dependence, short length of sobriety, family history of alcoholism and the use of other compared to as in our prior length of is the most of return to alcohol use with the highest discriminant The discriminant function analyses identified additional characteristics of those who would return to a moderate or heavy pattern of alcohol use. it be that early post‐LTX would or a return to alcohol use, we hypothesized that following LTX would the risk of alcohol use. We found that those more to drink in the early patterns 3 and were more problems were more reported had more and and felt would liver if it was a of the of their the of the transplant not more quickly to felt their was and that felt would not be that alcohol use was how and to drinking in response to the of the early post‐LTX and treatment of stress as it to early post‐LTX to of and as well as of addiction may in the of these in groups and 4 who drank and the early post‐LTX had characteristics of groups 3 and were a year were to be in felt more not their to LTX and felt more would liver if those patients who be as well in the early post‐LTX may be more about their and the of their liver and that drinking early on is not a A of the study is the of our trajectory However, to alcohol use beyond outcomes we to groups from which these distinct patterns of alcohol consumption As a study the was not to in LTX is both to that the trajectories are and to for a number of predictors to be the we the number of predictors to that the be Using Ed. Scholar). in the study may This was not a study as we preliminarily early outcomes between in we to examine these trajectories in to late onset medical As we trajectories using the period of we outcome data these to whether the trajectories and medical Thus we found patterns in the of alcohol consumption that emerge after LTX for ALD. These patterns demonstrate that alcohol use can be early or and can at minimal levels or heavy patterns of use. We also identify the predictors of those who drink and also those who advance along specific trajectories. these findings we can our and treatment to these specific individuals at risk at specific time points of The of of to as by the of This research is by from the Institute of Alcohol and Alcoholism and from the Institute of Disorders and

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