trasplantehepático enpacientescon*...

Trasplante Hepático en pacientes con

Enfermedad Hepática AlcohólicaDr Santiago Tome

Hosp. Univ. Santiago de CompostelaSevilla,27 Mayo, 2016

Aspectos relevantes en EHA y Tx Hepático

üResultados generales de TX por Cirrosis Alcohólica

üEl alcohol y alcoholismo en el candidato a TxHepático

üSituación especial de la Hepatitis alcohólica como indicación de trasplante

ü Alcoholismo pos-‐trasplante

Datos de Registro Europeo

Datos del registro Americano

RXWFRPHV

OPTN SRTR Annual Data Report

OPTN SRTR Annual Data Report

Trasplante Hepático y Enfermedad Hepática Alcohólica

ToleranceDependence

Loss ofcontrol

Craving

Alcohol abuse

Alcoholic

DSM IVICD10

AUD ( DSM5)

Mild Moderate Severe

0%10%20%30%40%50%60%70%80%90%100%

With AWS Without AWS

Cirrhosis+alc.hepatitisCirrhosis

Alcoholic hepatitis

Steatosis

A series of 256 consecutive liver biopsies in heavy drinkers admitted to the hospital

ü Brien : We are all responsable for taking the first drink. Many alcoholics are probably not responsable for thesecond.Myths about the treatment of addiction. Lancet 1996

Perspectiva de especialistas en adicciones

Predictive factors of durable abstinence

9

Positivesü acknowledgment by the patient of his or her addictionü strong social support ü substitute activitiesü a source of improved self-‐esteem ü a rehabilitation relationshipü perception of negative consequences of alcohol relapse

Negatives• preexisting psychiatric comorbidities• unremitting multidrug abuse• repeated unsuccessful attempts of rehabilitation • social isolation

Vaillant liver transpl 1997

Que tiempo de abstinencia asegura ausencia de recaida ?

Valliant´s study: Recurrence (8-10 y follow up)

6 months of abstinence : 59%

24 months of abstinence : 41%

Vaillant GE. Liver Transpl Surg 1997

7 years better than 6 months

Valliant GE. A 60–year follow-up of alcoholic men. Addiction, 2003

A.Dimartini, 2006

“ No single factor seems to be of major importance as a predictor”

Dew et al Liver Transpl. 2008 .

54 studies

lack of consistent attendance, which created the perceptionthat patient decisions depended in part on which memberswere present. On the basis of the comments and our meet-ing observations, the 2 main barriers to effective groupdecision making were unwritten or unavailable policies andconfusion regarding advocacy versus stewardship.

In interviews and in meetings, we found numerous refer-ences to transplant center policies that were unclear or notwritten (“The new rule is that if someone is transplantedwithin 24 hours of intubation, it’s OK”; “So do we have apolicy then?” [from a transplant coordinator]; “I’m not advo-cating a position, I’m just trying to understand whether, whatour policy kinda is, I guess”). Unwritten policies were refer-enced at all 4 centers by both medical and nonmedical per-sonnel. These policies sometimes reflected decisions made byprogram leaders or past practices. Even when centers had writ-ten policies, some committee members reported being unableto locate them.

The physicians we interviewed reported a tendency toadvocate more strongly for patients with whom they have along-standing relationship, which was consistent with our ob-servations. Patient discussions in meetings with no physicianadvocate tended to be shorter and more negative in tone,which contributed to the perception of inconsistency ex-pressed by coordinators, social workers, and physicians. How-ever, at times advocacy also led to role confusion. In severalinstances, after a heated debate in a meeting, members wouldremark during interviews that they were only advocating forthe patient and did not actually believe that the patient was agood candidate. Members reported that they were never surewhether a physician was defending a firmly held position orassuming the role of patient advocate.

DISCUSSION

Our multicenter study of liver transplant committeesfound that structure varied substantially by center but thatfunction was relatively uniform. The process of determin-ing candidacy involves systematically searching for exclu-sion criteria and achieving an informal group consensus,primarily through inductive reasoning. Patients are ruledout on the basis of a well-defined group of reasons. Theyeither are too well to need a transplant or are predicted tohave poor outcomes despite receiving a transplant becauseof medical or psychosocial reasons. This practice followsthe time-honored rule of medical triage (13). Overall, theprocess seems to work well, and the general public shouldbe reassured that these committees take their organ stew-ardship responsibilities seriously.

However, our observations of decision making at the 4centers suggest some dominant themes that deserve furtherattention. The distinction between “unlikely to benefit”and “unlikely to benefit enough to justify use of a scarceorgan” is subtle but important. Although the simpler ver-sion may be easier when discussing this complex calculuswith patients, we contend that honesty should be main-

tained within committees. Although committee membersare forced to judge psychosocial factors, such as ability toadhere to a treatment plan, they must also be cognizant ofthe overlap with judgments about social worth. Finally,efforts should be made to minimize the influence of exter-nal forces on candidacy decisions, both at institutional andpublic policy levels. For example, decisions about whichperformance metrics to publicly report should consider notonly methodological factors but also the effect of thesemetrics on transplant center behavior (14, 15). Transplantcenters with poor performance metrics risk closure or lossof contracts with insurance companies. Because of currentconstraints, it may not be possible to eliminate such con-siderations from decision making. However, centers shouldattempt to follow what Rawls (16) calls a “lexical order-ing,” in which medical risks and benefits are addressedbefore external constraints are considered. The involve-ment of a medical ethicist, at least periodically, may helptransplant centers resolve these conundrums.

The problems noted by the committee members them-selves also deserve attention. On the basis of their comments,we propose 2 possible strategies for process improvement,which should be prospectively evaluated in future studies.First, as many transplant center policies as possible should bewritten down. Having accessible written policies may improveefficiency and consistency, particularly when the compositionof the committee varies or when a patient’s case is discussedon more than 1 occasion. Written protocols have been imple-mented successfully in such diverse areas of medicine as im-proving hospital safety and reaching end-of-life decisions (17)and could alleviate some of the committee members’ burden

Figure. Views of 45 transplant committee members on thefunctioning of their committee.

Respondents, n

Saw area as a problem

Saw area as a strength

15 10 5 0 5 10 15 20

Attendance at meetings

Climate and atmosphere

Consistency and fairness

Data and evidence

Decisiveness

Leadership

Organization and efficiency

Other

Professional roles and relations

Resources

Thoroughness

The scale reflects the number of times each topic was mentioned as aproblem or strength. Strengths and weaknesses were not formulated apriori but were constructed afterward on the basis of issues spontaneouslyvoiced by members in response to open-ended questions (a measure ofsalience [12]).

Original ResearchTransplant Committee Decision Making

www.annals.org 18 October 2011 Annals of Internal Medicine Volume 155 • Number 8 507

Downloaded From: http://annals.org/ by a Conselleria Sanidad Sergas User on 05/01/2016

Decision Making in Liver Transplant Selection CommitteesA Multicenter StudyMichael L. Volk, MD, MSc; Scott W. Biggins, MD, MAS; Mary Ann Huang, MD, MS; Curtis K. Argo, MD, MS; Robert J. Fontana, MD; andRenee R. Anspach, PhD, MSW

Background: To receive a liver transplant, patients must first beplaced on a waiting list—a decision made at most transplant centersby a multidisciplinary committee. The function of these committeeshas never been studied.

Objective: To describe decision making in liver transplant commit-tees and identify opportunities for process improvement.

Design: Observational multicenter study.

Setting: 4 liver transplant centers in the United States.

Participants: 68 members of liver transplant committees across the4 centers.

Measurements: 63 meetings were observed, and 50 committeemembers were interviewed. Recorded transcripts and field noteswere analyzed by using standard qualitative sociologic methods.

Results: Although the structure of the meetings varied by center,the process was uniform and primarily involved inductive reasoningto review possible reasons for patient exclusion. Patients were ex-cluded if they were too well, too sick (in the setting of advancedliver disease), or too old or had nonhepatic comorbid conditions,

substance abuse problems, or other psychosocial barriers. Dominantthemes in the discussions included member angst over decidingwho lived or died, a high correlation between psychosocial barriersto transplantation and the patient’s socioeconomic status, and theinfluence of external forces on decision making. Unwritten centerpolicies and confusion regarding advocacy versus stewardship roleswere consistently identified as barriers to effective group decisionmaking.

Limitations: The use of qualitative methods provides broad under-standing but limits specific inferences. The 4 centers may not reflectthe practices of every transplant center nationwide.

Conclusion: The difficult decisions made by liver transplant com-mittees are reasonably consistent and well-intentioned, but theprocess might be improved by having more explicit written policiesand clarifying roles. This may inform resource allocation in otherareas of medicine.

Primary Funding Source: The Greenwall Foundation and the Na-tional Institutes of Health.

Ann Intern Med. 2011;155:503-508. www.annals.orgFor author affiliations, see end of text.

Each year, more than 40 000 patients die of liver diseasein the United States (1), but only 6000 liver transplan-

tations are performed (2). The problem of fair allocation ofthe limited organ supply has interested transplant profes-sionals, ethicists, and the general public for years. How-ever, most of the literature has focused on determiningpriority on the waiting list. The necessary first step, accessto the list, has garnered considerably less attention.

To be placed on the waiting list for transplantation, apatient must first be referred to a transplant center. Atmost centers, a patient is evaluated in the clinic or as aninpatient, various tests are performed, and the patient isthen discussed in a weekly transplant selection committeemeeting. Despite the importance of these meetings, theirstructure and function have not been clearly delineated.The United Network for Organ Sharing has issued policiesregarding the composition of personnel at a transplant cen-ter (3), and the American Association for the Study ofLiver Diseases has guidelines on the criteria for determin-ing candidacy (4); however, no policy, guideline, or empir-ical research exists about the process by which candidacyfor liver transplantation is determined.

Understanding the actual decision-making process isimportant for several reasons. The first is transparency: Asstewards of a scarce resource, transplant professionals owesociety a clear view of their actions (5). The second isprocess improvement: Cognitive science has also demon-strated that decision making is often automatic and based

on previously constructed prototypes or images stored inour memories, which may not correspond to actual objects(6). Studying the process could help decision makers learnabout aspects of their decisions that may not have beenconscious, and developing a taxonomy of the types of de-cisions made in committee meetings might facilitate clearerdiscussions. In addition, transplantation remains one of thefew areas of U.S. medicine in which physicians explicitlyration care, and the lessons learned in this arena could beused to better understand resource allocation as a whole.For these reasons, we performed a multicenter study ofdecision making in liver transplant selection committees.Our goals were to use qualitative research methods to de-scribe the process of decision making for adult liver trans-plant candidacy and to identify potential opportunities forprocess improvement.

See also:

PrintEditors’ Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504

Web-OnlyAppendixConversion of graphics into slides

Annals of Internal Medicine Original Research

© 2011 American College of Physicians 503


Decision Making in Liver Transplant Selection CommitteesA Multicenter StudyMichael L. Volk, MD, MSc; Scott W. Biggins, MD, MAS; Mary Ann Huang, MD, MS; Curtis K. Argo, MD, MS; Robert J. Fontana, MD; andRenee R. Anspach, PhD, MSW

Background: To receive a liver transplant, patients must first beplaced on a waiting list—a decision made at most transplant centersby a multidisciplinary committee. The function of these committeeshas never been studied.

Objective: To describe decision making in liver transplant commit-tees and identify opportunities for process improvement.

Design: Observational multicenter study.

Setting: 4 liver transplant centers in the United States.

Participants: 68 members of liver transplant committees across the4 centers.

Measurements: 63 meetings were observed, and 50 committeemembers were interviewed. Recorded transcripts and field noteswere analyzed by using standard qualitative sociologic methods.

Results: Although the structure of the meetings varied by center,the process was uniform and primarily involved inductive reasoningto review possible reasons for patient exclusion. Patients were ex-cluded if they were too well, too sick (in the setting of advancedliver disease), or too old or had nonhepatic comorbid conditions,

substance abuse problems, or other psychosocial barriers. Dominantthemes in the discussions included member angst over decidingwho lived or died, a high correlation between psychosocial barriersto transplantation and the patient’s socioeconomic status, and theinfluence of external forces on decision making. Unwritten centerpolicies and confusion regarding advocacy versus stewardship roleswere consistently identified as barriers to effective group decisionmaking.

Limitations: The use of qualitative methods provides broad under-standing but limits specific inferences. The 4 centers may not reflectthe practices of every transplant center nationwide.

Conclusion: The difficult decisions made by liver transplant com-mittees are reasonably consistent and well-intentioned, but theprocess might be improved by having more explicit written policiesand clarifying roles. This may inform resource allocation in otherareas of medicine.

Primary Funding Source: The Greenwall Foundation and the Na-tional Institutes of Health.

Ann Intern Med. 2011;155:503-508. www.annals.orgFor author affiliations, see end of text.

Each year, more than 40 000 patients die of liver diseasein the United States (1), but only 6000 liver transplan-

tations are performed (2). The problem of fair allocation ofthe limited organ supply has interested transplant profes-sionals, ethicists, and the general public for years. How-ever, most of the literature has focused on determiningpriority on the waiting list. The necessary first step, accessto the list, has garnered considerably less attention.

To be placed on the waiting list for transplantation, apatient must first be referred to a transplant center. Atmost centers, a patient is evaluated in the clinic or as aninpatient, various tests are performed, and the patient isthen discussed in a weekly transplant selection committeemeeting. Despite the importance of these meetings, theirstructure and function have not been clearly delineated.The United Network for Organ Sharing has issued policiesregarding the composition of personnel at a transplant cen-ter (3), and the American Association for the Study ofLiver Diseases has guidelines on the criteria for determin-ing candidacy (4); however, no policy, guideline, or empir-ical research exists about the process by which candidacyfor liver transplantation is determined.

Understanding the actual decision-making process isimportant for several reasons. The first is transparency: Asstewards of a scarce resource, transplant professionals owesociety a clear view of their actions (5). The second isprocess improvement: Cognitive science has also demon-strated that decision making is often automatic and based

on previously constructed prototypes or images stored inour memories, which may not correspond to actual objects(6). Studying the process could help decision makers learnabout aspects of their decisions that may not have beenconscious, and developing a taxonomy of the types of de-cisions made in committee meetings might facilitate clearerdiscussions. In addition, transplantation remains one of thefew areas of U.S. medicine in which physicians explicitlyration care, and the lessons learned in this arena could beused to better understand resource allocation as a whole.For these reasons, we performed a multicenter study ofdecision making in liver transplant selection committees.Our goals were to use qualitative research methods to de-scribe the process of decision making for adult liver trans-plant candidacy and to identify potential opportunities forprocess improvement.

See also:

PrintEditors’ Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504

Web-OnlyAppendixConversion of graphics into slides

Annals of Internal Medicine Original Research

© 2011 American College of Physicians 503


AAH Corticosteroid treatment.Early billirrubin response

Mathurin et al Hepatology 2003;38:1363-‐1369

ECBL: Decrease of the amount of BI at 7 days

83%

24%

Liver transplantation and Alcoholic Hepatitis concerns

Abstinence period less than 6 months(the six month rule)

Unknown outcome

Negative social impact

0

25

50

75

100

1 2 3 4 5 6Time (years)

Cumulativesurvivalrates(%)

Cirrhosis plus alcoholic hepatitis

Cirrhosis alone

Survival in LT patients with and without alcoholic hepatitis

Tome et al, J Hepatol2002

N:36

N:32

Patient survival -HAH and BAC

0

0.2

0.4

0.6

0.8

1

0 12 24 36 48 60 72 84 96 108

120 HAH

BAC

P=0.13

Months

Survival

HAH 32 31 29 28 27 27 24 21 15 12 10

BAC 110 94 90 87 84 78 71 60 53 43 34

Patient survival -ALD and Controls

0

0.2

0.4

0.6

0.8

1

0 12 24 36 48 60 72 84 96 108

120 ALD

Controls

P=0.53

Months

Survival

ALD 142 125 119 115 111 105 95 81 68 55 44

Controls 118 99 86 77 75 68 61 48 42 34 24

Survival analysis

Wells, liver transpl 2007

UNOS restrospective analysis. Singal et al Hepatology 2012

55 HAA en LE

165LT ALD

46Explcon HAA

138LT ALD

11 HAA

en LE y expl

33 LT ALD

Matching: Age, gender, ethnicity, MELD, DRI and year of LT

Cirrhotic

A Hepatitis

Proceso de selección

Nurses, oneresident, one fellow;; Addiction

specialist

seniorhepatologists

Anesthetistand

surgeons

Mathurin , NEJM 2011

Transplanted NRS Non-‐Transplanted NRs

Male gender 59% 59%

Age 47.5 [42.4 – 43.8] 50.8 [46 – 53]

Maddrey score 72.5 [61.2 – 92] 76.7 [66.4 – 88]

MELD 30.1(22-‐47) 29.1[19,1-‐40,2]

Lille score 0.88 [0.79 – 0.97] 0.81 [0.69 – 0.91]

MELD after 7 days MT

28.5(23-‐52) 29.4[19.4-‐60.2]

26 patientswith no response to corticosteroid therapy. First episode . Good psychosocial support

Mathurin , NEJM 2011

Early liver transplantation for severe Alcoholic HepatitisMathurin, NEJM, 2011

5/6 deaths related to infection. 4 invasive aspergillosis

Editorial

Liver Transplantation for Severe Alcoholic HepatitisCrosses the Atlantic

M. R. Lucey* and J. P. Rice

Division of Gastroenterology and Hepatology,Department of Medicine, University of Wisconsin Schoolof Medicine and Public Health, Madison, WI!Corresponding author: Michael R. Lucey,[email protected]

Received 21 September 2015, revised 10 October 2015and accepted for publication 14 October 2015

In 2011, Mathurin and colleagues demonstrated, in aground-breaking pilot study from France and Belgium, thatrescue liver transplantation could save the lives of carefullyselected patients with severe alcoholic hepatitis who hadfailed medical treatment (1). Their report challenged theview that patients with severe alcoholic hepatitis wereunsuitable candidates for liver transplantation, which hasprevailed for many years (2).

The reasons to deny liver transplantation to patients withsevere alcoholic hepatitis are complex. First, a significantproportion will recover with medical management thatincludes abstinence from alcohol (1,3). Therefore, in 1997,when a national conference organized by the AmericanSociety of Transplantation andAmericanAssociation for theStudy of Liver Diseases reviewed minimal criteria forplacement of candidates on the transplant waiting list, arequirement for 6 months’ abstinence had become thenorm for any patient with alcoholic liver disease in many USprograms (4). The conference recommendations were thatthe minimal criteria for listing of patients with alcoholic liverdisease should include ‘‘approval by the center evaluationcommittee. . . and favorable assessment by a substanceabuse professional and reported abstinence of at least6 months at time of listing’’ (2). The authors acknowledgedthat the last criterion excluded patients with severealcoholic hepatitis, and thus they left open the possibilityof exceptions (2). Since then, the application of a requiredabstinent period of 6 months has been challenged due tothe high early mortality rate of patients with severealcoholic hepatitis and the poor predictability of 6-monthsobriety on future alcohol relapse (5). The adoption inFrance of a more nuanced model to assess the risk ofalcohol relapse was an important step leading to theFrench–Belgian study of rescue liver transplantation for

patients with severe alcoholic hepatitis unresponsive tomedical management (6).

Perhaps the more fundamental reason in the United Statesfor the failure to offer liver transplantation to patients withsevere alcohol hepatitis is ambivalence among transplantprograms, insurance companies, and the public aboutalcohol use disorders. These views may be expressed asconcern that patients without extended sobriety willexperience poor outcomes due to alcohol relapse. How-ever, while patients with alcoholic liver disease whoundergo transplantation are at risk of alcohol relapse, andsevere alcohol relapse is associated with liver and otherpersonal injuries, the vast majority of alcoholic patientshave excellent outcomes after liver transplantation (7,8).These results have been achieved in transplant programsthat apply stringent selection criteria including requiring afixed interval of abstinence. It is unknown whether similarexcellent outcomes would be the norm were the selectionof candidates with short intervals of sobriety to becomecommonplace.

The decision to approve a patient with alcoholic liverdisease for transplantation is challenging for most pro-grams andmay be impacted by personal and programmaticbeliefs, rather than scientific evidence. Volk et al conducteda prospective of four US selection committees andobserved inconsistent judgments, lack of consensusbetween committee members, and expression of opinionsoutside committee members’ areas of expertise werecommon (9). Further, participants stated that alcoholicpatients posed to them the most difficult dilemmas. Aparticular area of contention is interpreting the significanceof consumption of small amounts of alcohol, typicallydescribed as ‘‘a slip’’ (6). Indeed, fear on the part of thecandidate that admission of any use of alcohol mayjeopardize their chances of transplantation may restrainhim or her from seeking appropriate assistance for theirunderlying addiction (10).

In the present issue of the American Journal of Transplan-tation, Im and colleagues provide an American experiencethat builds from the work of Mathurin and colleagues (11).Again, this is a prospective pilot study, with a matchedcontrol group, albeit from a single transplant center. Of 94patients with severe alcoholic hepatitis unresponsive tocorticosteroids recruited during the 3 years of the study,20 patients had acceptable psychosocial profiles, of whom

"C Copyright 2015 The American Society of Transplantationand the American Society of Transplant Surgeons

doi: 10.1111/ajt.13587

739

American Journal of Transplantation 2016; 16: 739–740Wiley Periodicals Inc.

Editorial

Liver Transplantation for Severe Alcoholic HepatitisCrosses the Atlantic

M. R. Lucey* and J. P. Rice

Division of Gastroenterology and Hepatology,Department of Medicine, University of Wisconsin Schoolof Medicine and Public Health, Madison, WI!Corresponding author: Michael R. Lucey,[email protected]

Received 21 September 2015, revised 10 October 2015and accepted for publication 14 October 2015

In 2011, Mathurin and colleagues demonstrated, in aground-breaking pilot study from France and Belgium, thatrescue liver transplantation could save the lives of carefullyselected patients with severe alcoholic hepatitis who hadfailed medical treatment (1). Their report challenged theview that patients with severe alcoholic hepatitis wereunsuitable candidates for liver transplantation, which hasprevailed for many years (2).

The reasons to deny liver transplantation to patients withsevere alcoholic hepatitis are complex. First, a significantproportion will recover with medical management thatincludes abstinence from alcohol (1,3). Therefore, in 1997,when a national conference organized by the AmericanSociety of Transplantation andAmericanAssociation for theStudy of Liver Diseases reviewed minimal criteria forplacement of candidates on the transplant waiting list, arequirement for 6 months’ abstinence had become thenorm for any patient with alcoholic liver disease in many USprograms (4). The conference recommendations were thatthe minimal criteria for listing of patients with alcoholic liverdisease should include ‘‘approval by the center evaluationcommittee. . . and favorable assessment by a substanceabuse professional and reported abstinence of at least6 months at time of listing’’ (2). The authors acknowledgedthat the last criterion excluded patients with severealcoholic hepatitis, and thus they left open the possibilityof exceptions (2). Since then, the application of a requiredabstinent period of 6 months has been challenged due tothe high early mortality rate of patients with severealcoholic hepatitis and the poor predictability of 6-monthsobriety on future alcohol relapse (5). The adoption inFrance of a more nuanced model to assess the risk ofalcohol relapse was an important step leading to theFrench–Belgian study of rescue liver transplantation for

patients with severe alcoholic hepatitis unresponsive tomedical management (6).

Perhaps the more fundamental reason in the United Statesfor the failure to offer liver transplantation to patients withsevere alcohol hepatitis is ambivalence among transplantprograms, insurance companies, and the public aboutalcohol use disorders. These views may be expressed asconcern that patients without extended sobriety willexperience poor outcomes due to alcohol relapse. How-ever, while patients with alcoholic liver disease whoundergo transplantation are at risk of alcohol relapse, andsevere alcohol relapse is associated with liver and otherpersonal injuries, the vast majority of alcoholic patientshave excellent outcomes after liver transplantation (7,8).These results have been achieved in transplant programsthat apply stringent selection criteria including requiring afixed interval of abstinence. It is unknown whether similarexcellent outcomes would be the norm were the selectionof candidates with short intervals of sobriety to becomecommonplace.

The decision to approve a patient with alcoholic liverdisease for transplantation is challenging for most pro-grams andmay be impacted by personal and programmaticbeliefs, rather than scientific evidence. Volk et al conducteda prospective of four US selection committees andobserved inconsistent judgments, lack of consensusbetween committee members, and expression of opinionsoutside committee members’ areas of expertise werecommon (9). Further, participants stated that alcoholicpatients posed to them the most difficult dilemmas. Aparticular area of contention is interpreting the significanceof consumption of small amounts of alcohol, typicallydescribed as ‘‘a slip’’ (6). Indeed, fear on the part of thecandidate that admission of any use of alcohol mayjeopardize their chances of transplantation may restrainhim or her from seeking appropriate assistance for theirunderlying addiction (10).

In the present issue of the American Journal of Transplan-tation, Im and colleagues provide an American experiencethat builds from the work of Mathurin and colleagues (11).Again, this is a prospective pilot study, with a matchedcontrol group, albeit from a single transplant center. Of 94patients with severe alcoholic hepatitis unresponsive tocorticosteroids recruited during the 3 years of the study,20 patients had acceptable psychosocial profiles, of whom

"C Copyright 2015 The American Society of Transplantationand the American Society of Transplant Surgeons

doi: 10.1111/ajt.13587

739


than 32 not responding to medical therapy as defined by the Lille model

as a score of greater than 0.45 after 7 days of medical therapy (or ineligi-

ble for medical therapy) were described as nonresponders (4,12).

Patients with a Lille score of less than 0.45 were considered responders

to medical therapy. Patients hospitalized for less than 7 days (for whom a

Lille score could not be calculated) and with an early decline in serum

bilirubin of 25% or greater were also considered responders (15). Medical

therapy consisted of standard medical care for advanced liver disease at

a quaternary LT center in the United States and a variety of AH-specific

therapies by the referring providers and staff hepatologists. Severe AH

nonresponders have such limited therapeutic options and dismal prog-

noses that early LT was considered in select patients as a rescue option.

Candidate selection

After adopting a written policy outlining the candidate selection process

based on the European trial, our center began evaluating patients with

severe AH for early LT in January 2012 (Figure 1). Patients with severe

AH were selected as potential candidates for early LT based on the fol-

lowing criteria: nonresponse to medical therapy, severe AH as the

patient’s first liver-decompensating event, presence of good social sup-

port, and a favorable psychosocial profile suggesting a low risk of alcohol

relapse with a signed agreement to lifelong alcohol abstinence (12). We

excluded patients with concomitant chronic liver diseases like hepatitis

virus B or C infection and those with hepatocellular carcinoma, HIV, sev-

ere comorbid conditions, or psychiatric disorders. Patients with previously

controlled or newly diagnosed depression or anxiety disorders were not

excluded. Unlike the European trial, patients with recent infection and

gastrointestinal bleeding were still considered for early LT given their

common concurrence with severe AH and poor outcomes (16). Compre-

hensive medical, surgical, psychosocial, and financial evaluations of the

potential candidates were performed, as is routinely done for all potential

LT candidates at our center.

Psychosocial evaluations by a transplant psychiatrist and social worker

were promptly performed after identification of nonresponse to expedite

the LT evaluation. The social supports and health care providers of each

candidate were contacted to more accurately assess the candidate’s

insight into their alcoholism, including prior alcohol counseling and liver-

decompensating events. While based on methodology outlined by the

European trial, our candidate selection process differed in several

respects. Accounting for differences between residency training and LT

centers in Europe compared with the United States, the medical team

circles were adjusted to a committee comprising the staff hepatologist

and hepatology fellow active in the care of the candidate, the transplant

psychiatrist and social worker assessing the candidate, senior hepatolo-

gists, transplant surgeons, and financial coordinators in attendance at our

weekly candidate selection meetings. Our center’s written policy on early

LT for severe AH and its details were reiterated at each selection com-

mittee meeting (see Supporting Information). The candidate’s medical,

surgical, psychosocial, and financial histories were thoroughly presented

and reviewed. Decisions regarding candidate selection could be deferred

to gather more psychosocial data. Complete consensus of the committee

had to be reached before candidate acceptance for listing for early LT

(12,17). Ultimately, each patient’s candidacy was determined on a case-

by-case basis and reviewed retrospectively for this study.

Psychosocial evaluation study

Prospectively gathered psychosocial evaluation data of two cohorts—can-

didates provisionally accepted for early LT with favorable profiles and

those declined due to poor profiles—were compared by univariate and

multivariate logistic regression analyses to identify variables associated

with the determination of psychosocial profiles as favorable leading to

acceptance for early LT.

Case–control studyThe early LT for severe AH recipients were matched to control patients

with severe AH not responding to medical therapy, according to age,

sex, ethnicity, DF, and Lille score. The control patients were selected

from our center’s AH database over a 2-year period before the start of

our center’s strategy of early LT for severe AH that were not a part of

the prospectively identified study cohort.

Statistical analysis

Variables were compared between cohorts using the Student t-test and

two-tailed v2 test. These analyses were performed using Stata 12.0 (Sta-

taCorp, College Station, TX). In the case–control study, we estimated the

patient’s rate of survival by the Kaplan–Meier method and compared sur-

vival between the two cohorts by using the log-rank test. Time was mea-

sured from the first day of physical presentation to our center to the last

known date of follow-up or date of death from any cause.

Outcome

The primary end point was mortality at 6 months or early LT. This is com-

parable to the European trial and informs the likelihood of survival if the

6-month rule had been applied. After early LT, alcohol consumption and

enrollment in a program for AR when medically appropriate were

assessed at short intervals during outpatient follow-up visits with random

alcohol testing at the discretion of the AR program and/or hepatologist.

Figure 1: Early LT for severe AH candidate evaluation flow-chart. AH, alcoholic hepatitis; LT, liver transplantation.

842 American Journal of Transplantation 2016; 16: 841–849

Im et al

Early Liver Transplantation for Severe AlcoholicHepatitis in the United States—A Single-CenterExperience

G. Y. Im1,*, L. Kim-Schluger1, A. Shenoy1,E. Schubert3, A. Goel4, S. L. Friedman4,S. Florman1 and T. D. Schiano1

1Recanati/Miller Transplantation Institute,Division of LiverDiseases, Department of Medicine, The Icahn School ofMedicine at Mount Sinai,New York, NY2Department of Psychiatry,The Icahn School of Medicineat Mount Sinai,New York, NY3Social Work Services,The Mount Sinai Medical Center,New York, NY4Division of Liver Diseases,Department of Medicine, TheIcahn School of Medicine at Mount Sinai,New York, NY*Corresponding author: Gene Y. Im, [email protected]

Early liver transplantation (LT) in European centersreportedly improved survival in patients with severealcoholic hepatitis (AH) not responding to medicaltherapy. Our aim was to determine if a strategy ofearly LT for severe AH could be applied successfully inthe United States. We reviewed 111 patients with sev-ere AH at our center from January 2012 to January2015. The primary end point was mortality at 6 monthsor early LT, with a secondary end point of alcoholrelapse after LT. Survival was compared betweenthose receiving early LT and matched patients who didnot. Using a process similar to the European trial, 94patients with severe AH not responding to medicaltherapy were evaluated for early LT. Overall, 9 (9.6%)candidates with favorable psychosocial profiles under-went early LT, comprising 3% of all adult LT during thestudy period. The 6-month survival rate was higheramong those receiving early LT compared withmatched controls (89% vs. 11%, p<0.001). Eight recipi-ents are alive at a median of 735 days with 1 alcoholrelapse. Early LT for severe AH can achieve excellentclinical outcomes with low impact on the donor pooland low rates of alcohol relapse in highly selectedpatients in the United States.

Abbreviations: AH, alcoholic hepatitis; ALD, alcoholicliver disease; AR, alcohol rehabilitation; DF, discrimi-nant function; LT, liver transplantation

Received 04 June 2015, revised 16 August 2015 andaccepted for publication 31 August 2015

Introduction

Alcoholic hepatitis (AH) is an acute, inflammatory syn-drome of jaundice and liver injury that occurs in a subsetof patients after decades of heavy alcohol use (meanintake, approximately 100 g/day) (1–3). While mild formsof AH improve with conservative management, thosewith severe AH not responding to glucocorticoids as iden-tified by the Lille score (a score of >0.45 after 7 days ofmedical therapy) have a mortality rate that may exceed70% at 6 months (1,4). The recent STOPAH trial furthernarrowed the limited therapeutic options for severe AH toprimarily glucocorticoids, which carry substantial risks(5,6). Because most liver transplant centers require a mini-mum of 6 months of sobriety and participation in alcoholrehabilitation (AR) before candidate acceptance for listing,severe AH nonresponders are largely ineligible for livertransplantation (LT) (7). The validity of the “6-month rule”in predicting alcohol relapse is controversial, but there isincreasing recognition that certain patients may have alow risk of relapse after LT despite violation of the 6-month rule (7–11). In a prospective, multicenter trial,investigators in France and Belgium demonstrated thatearly LT performed for severe AH not responding to gluco-corticoids is feasible and improves survival with low ratesof alcohol relapse in highly selected candidates (12). Whilethis study generated significant interest, its approach hasnot been reported from other LT centers, especially inNorth America. To account for differences in population,social norms, access to medical care, organ allocation,and psychosocial evaluation performance, we sought toapply this strategy of early LT for patients with severe AHat an LT center in the United States.

Materials and Methods

Study population

Patients hospitalized at the Mount Sinai Medical Center through the

emergency department or via interhospital transfer and evaluated by a

hepatologist for severe AH were prospectively identified from January

2012 to January 2015. Patient electronic medical records were retrospec-

tively reviewed for demographic, medical, surgical, and psychosocial data

and outcomes. Severe AH was diagnosed on clinical grounds (some with

supporting liver biopsy results) and defined as a Maddrey’s discriminant

function (DF) greater than 32, the threshold for consideration of glucocor-

ticoid or other AH-specific therapies (13,14). Patients with DF greater

841

© Copyright 2015 The American Society of Transplantationand the American Society of Transplant Surgeons

doi: 10.1111/ajt.13586


Resultados

tions but no fungal infections (Table 2). There were fourreoperations, each occurring 1 day after early LT forbleeding and washout. Seven of nine recipients under-went perioperative hemodialysis with renal recovery andcessation of hemodialysis at a median of 3 days afterearly LT. Recipient 6 had recurrent Clostridium difficileinfections and developed chronic abdominal pain requir-ing chronic opioid treatment. Recipient 7 had prolongedrespiratory failure requiring tracheostomy and later diedof necrotizing pancreatitis with Citrobacter freundii–re-lated septicemia and multiorgan failure 16 weeks afterearly LT. All recipients received tacrolimus-basedimmunosuppression with no rejection episodes and weredischarged from our center at a median of 16 days afterearly LT.

In the case–control study, the early LT for severe AHrecipients and control patients were statistically wellmatched (Table S2). The 6-month survival rate was signif-icantly higher among patients undergoing early LT (89%)than among matched controls (11%, p<0.001) (Figure 2).Congruent with previous studies of severe AH nonre-sponders, the control patients acutely had high rates ofmortality. Two-thirds of the deaths in the control groupoccurred within 1 month after presentation to our center,highlighting the benefit of performing early LT for severeAH.

Burden of early LT for severe AHDuring the study period, 292 adult liver transplants wereperformed at our center, with alcoholic liver disease(ALD) as the indication in 10%. The nine early LT for sev-ere AH recipients comprised 3% of the total and 31% ofthose transplants for ALD overall. The non-AH, ALDrecipients had a median abstinence period of 25 monthsbefore LT. In total, 18 (90%) of 20 provisionally acceptedearly LT candidates, and seven (78%) early LT recipientswere referred from other hospitals via interhospital trans-fer, including three for second opinion evaluation fromother LT centers not performing early LT for severe AH.

Follow-up and assessment of alcohol relapseEight (89%) of nine early LT for severe AH recipients arealive at a median follow-up of 735 days (range, 181–1170days). All surviving recipients had liver enzyme and crea-tinine levels that returned to within normal range by 28days after early LT. Hepatology follow-up visits were fre-quent in the first 6 months after early LT, with a medianof 15 visits at a median interval of 11 days. All recipientsenrolled in AR programs when deemed medically feasi-ble by their hepatologist at a median of 130 days afterearly LT. Recipient 3 had self-reported slips of 60 and15 g of alcohol at 84 and 260 days after early LT, respec-tively, without further consumption based on self-report-ing and serial urine ethyl glucuronide testing (24–26).Neither episode was associated with symptoms orabnormal liver enzymes. Alcohol relapse was diagnosedin recipient 5 at 180 days after LT due to elevated livertests and positive urine ethyl glucuronide and confirmedby the presence of AH on liver biopsy. She has main-tained good graft function but likely has ongoing alcoholconsumption. There were no slips or relapses reportedor noted in the other recipients.

Discussion

In this early report of an initial US experience with a strat-egy of early LT for severe AH, we demonstrate that excel-lent clinical outcomes can be achieved with low burdenon the donor pool and low rates of alcohol relapse. Nonre-sponders to medical therapy for severe AH experienced adismal 6-month mortality rate of 70%, comparable to thatof previous studies (27–30). The high proportion of nonre-sponders was likely due to referral bias, as more thantwo-thirds of this cohort was composed of interhospitaltransfers, which increased over time for early LT consider-ation and highlights the key role of local providers. In addi-tion, concerns about potential denial of coverage byprivate or public insurers due to short sobriety durationlimiting access to early LT were unfounded, which is con-sistent with a recent survey of LT centers (21,32,32).

In practice, attempting to replicate the European methodol-ogy in the United States was not straightforward. Itrequired programmatic changes: revised policies,increased inpatient transfer and service volume, a dedi-cated addiction team, and candid multidisciplinary discus-sions of complex medical and psychosocial profiles ofpotential candidates. Despite these obstacles, our studyconfirms the findings of Mathurin and colleagues in a NorthAmerican patient cohort. Despite higher median MELDscores at the time of LT, the 6-month survival of early LTfor severe AH recipients (89%) was superior to that ofrecipients in the European trial (77%) and matched controlnonresponders (11%) (12). This former difference may berelated to a smaller study cohort, less glucocorticoid expo-sure, and local factors, particularly the presence of Asper-gillus infections described in France and Belgium (12,33).

Figure 2: Kaplan–Meier estimates of survival in nine earlyliver transplant recipients and nine matched controls.


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Im et al

tively in the group who relapsed and 100%, 92.4%(95% CI, 78.1%-97.5%), and 85.5% (95% CI,67.9%-93.9%) in the group of abstinent patients (P !0.006 when comparing survival curves with the Man-tel -Cox statistic). The risk of death resulting from alco-hol recidivism was represented by a crude hazard ratioof 4.36 (95% CI, 1.38-13.83) (P " 0.05), using a Coxproportional hazards model; when adjusted for age andsex, the hazard ratio was 5.65 (95% CI, 1.67-19.17)(P " 0.01). Figure 3 shows the survival curves of bothgroups assessed by the Kaplan-Meier method.

Discussion

We evaluated the long-term results of OLT for ALD,focusing on the occurrence of alcohol recidivism and itsrepercussion on the allograft, comorbidities, de novomalignancies, and survival. Interestingly, we observedexcellent and higher-than-expected 1- and 5-year patientsurvival rates in patients who underwent transplantationfor ALD. Although these rates were similar in patients whoresumed alcohol consumption (100% and 92.9%, respec-tively) and in those who remained abstinent (100% and92.4%, respectively), there was an abrupt and significantfall in the 10-year survival rate of the first group (45.1%)compared with that of the abstinent group (85.5%). Thisunexpected finding could be explained by the higher mor-tality rate observed in the first group, mainly because ofcancer and different cardiovascular events, which are dis-cussed in the following paragraphs.

Our study revealed a 25.9% alcohol relapse rate afterOLT, which falls within the range of relapse ratesreported in the literature and is consistent with thatpreviously reported by our group.2,4,7,8,16,19 Thus, it hasbeen estimated that between 20% and 50% of patientswho receive a liver transplant for end-stage ALDacknowledge some alcohol use in the first 5 years after

liver transplantation, and 10% to 15% will resumeheavy drinking.3,20,21 The alcoholic behavior is difficultto determine; several methods are used for this purpose:urine alcohol measurements, carbohydrate-deficienttransferrin, and information obtained from patientsand relatives about the resumption of alcohol use.22

The combination of different methods, a solid physi-cian–patient relationship, and a prolonged follow-upwould increase the sensitivity to detect sustained alco-hol use in these patients.23,24

As previously reported by our group, no differenceswere observed between abstinent patients and those whoresumed alcohol consumption—as indicated by patients’reports and monitoring of drug concentrations—con-cerning compliance with immunosuppressive drugs,which agrees with the limited recorded evidence that sug-gests that alcohol relapse leads to noncompliance in livertransplant recipients.1,25 We found no differences betweenabstinent patients and those who relapsed regarding theincidence of infections, which could be expected takinginto consideration previous reports that were not able todemonstrate any increased incidence of infections inpatients transplanted for ALD.15,17 Conversely, althoughwe observed a lower incidence of acute rejection in patientswith alcohol recidivism compared with those whoremained abstinent, this fact does not reach statistical sig-nificance and cannot be explained by poorer compliancewith therapeutic regimens. Certainly, our findings are inaccordance with previous reports, which showed thatALD recipients had a reduced risk of acute rejection com-pared with other indications, and appear to support thehypothesis suggested by these studies regarding an inhibi-tory effect of alcohol on various aspects of the immuneresponse.15,17,26

In accordance with the results of previous studies, nodifferences concerning graft evolution or metabolic dis-turbances were observed in abstinent patients com-pared with those who relapsed.2 However, our histo-logic study revealed only mild hepatic changes directlyattributable to alcohol in a few patients, which agreeswith our previous results in this cohort after a shorterperiod of follow-up. As reported by Pageaux et al.,2 fattychanges represented the most frequent finding relatedto alcohol injury in patients who resumed alcohol con-sumption. However, we could not demonstrate anystatistical difference with regard to patients whoremained abstinent. Finally, no differences in the inci-dence of other medical conditions, such as arterialhypertension or renal failure, were found when ana-lyzed together with metabolic disturbances.

The group of alcohol relapsers presented with ahigher incidence of de novo malignancies which, in

Figure 3. Kaplan-Meier survival curves from patientswith alcoholic liver disease, with or without alcoholrecidivism.

424 Cuadrado et al.Alcohol Recidivism Impairs Long-Term Patient SurvivalAfter Orthotopic Liver Transplantation for Alcoholic

Liver DiseaseAntonio Cuadrado, Emilio Fabrega, Fernando Casafont, and

Fernando Pons-Romero

The aim of this study was to evaluate the rate of alcoholrecidivism after orthotopic liver transplantation (OLT)for alcoholic liver disease (ALD) and its influence on theallograft and patient survival, as well as the developmentof comorbidities and de novo cancers. The study was per-formed on 54 subjects previously analyzed and trans-planted in our center for ALD, whose follow-up was pro-longed to a mean of 99.2 (SD 31.7) months (range,14-155). Medical records were reviewed, and data onalcohol consumption, therapeutic compliance, graft evo-lution, rejection, infections, comorbidities, rates of denovo malignancies and other clinical events, and survivalwere collected. Comparisons between groups were per-formed by the Fisher’s exact test, and survival was assessedby the Kaplan-Meier method. Survival curves were com-pared using the Mantel -Cox statistic. The risk of deathresulting from alcohol recidivism was analyzed with a Coxproportional hazards model. Fourteen patients whounderwent transplantation for ALD (25.9%) returned toalcohol use between 5.0 and 86.9 months after OLT(median, 47.5). There was no significant associationbetween the presence or absence of alcohol recidivism andthe occurrence of graft rejection, infections, associatedcomorbidities after OLT, or compliance. The 5- and10-year survival rates for patients with alcohol recidivismwere 92.9% and 45.1%, respectively, compared with92.4% and 85.5%, respectively, for patients without alco-hol recidivism. These figures show significantly lower sur-vival rates in recidivistic patients after 10 years (P < 0.01,Mantel -Cox). The fact that patients who resumed alcoholconsumption have a worse 10-year survival rate might beattributed to a higher frequency of deaths, primarily fromcancer and cardiovascular events. (Liver Transpl 2005;11:420-426.)

Alcoholic liver disease (ALD) is the leading cause ofcirrhosis in Western countries and represents the

second most common indication for orthotopic livertransplantation (OLT) in the United States andEurope.1-3 Reported survival rates after liver transplan-tation appear to be similar among alcoholics and non-alcoholics, reaching up to 60% 7 years after OLT.1,4 Inview of patient and graft survival, rejection rates, andinfection rates, ALD appears to be a good indication forOLT.5

Nonetheless, this indication still remains controver-sial, based partly on concerns regarding alcohol relapseand functional outcome after transplantation in an eraof donor organ shortage and priority setting.1 In fact, itis common practice to establish a period of abstinencefrom alcohol (usually 6 months) before listing a patientwith ALD for OLT based on (1) patients in whomstabilization or improvement of liver function mayoccur, obviating the need for transplantation,3 and (2)higher reported rates of alcohol relapse in patients whohad been abstinent from alcohol for less than 6 monthsbefore transplantation.6

Several previous studies analyzed the rate of alcoholrelapse after OLT for ALD and its influence on patientand graft survival.2,4,7-18 Thus, reported rates of alcoholrelapse range from 11.5% to 49%, although this factwas rarely considered a reason for graft failure in recip-ients with ALD.2 Patients who resume alcohol con-sumption after OLT for ALD may damage their graftbecause of poor compliance with immunosuppressivedrugs and alcohol-related liver injury. Graft dysfunc-tion related to relapse ranged from 0% to 17%,although death related to relapse ranged from 0% to5%.2,4,8,9,11,14,15,17,18 The prognosis of liver transplan-tation in this setting after a more prolonged follow-uphas been seldom studied.

In a previous study from our group, 44 patients whounderwent an OLT for ALD and 17 control subjectswere included for study and followed for a mean of 39.5months; no deleterious effect of alcohol recidivism ontherapeutic compliance to treatment or on graft func-tion could be demonstrated.16 For the current study,the previous cohort of alcoholic patients was enlarged,

Abbreviations: OLT, orthotopic liver transplantation; ALD,alcoholic liver disease; 95% CI, 95% confidence interval.

From the Gastroenterology and Hepatology Unit, University Hospital“Marques de Valdecilla,” Faculty of Medicine, Santander, Spain.

Address reprint requests to Emilio Fabrega, MD, Gastroenterologyand Hepatology Unit, University Hospital “Marques de Valdecilla,”Faculty of Medicine, Avenida Valdecilla s/n, Santander 39008 Spain.Telephone: 073442202544; FAX: 073442202544; E-mail: [email protected]

Supported in part by FIS PI030330 and RNIHG from the SpanishMinistries of Health and Science and Technology.

Copyright © 2005 by the American Association for the Study ofLiver Diseases

Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/lt.20386

420 Liver Transplantation, Vol 11, No 4 (April), 2005: pp 420-426

Alcohol Recidivism Impairs Long-Term Patient SurvivalAfter Orthotopic Liver Transplantation for Alcoholic

Liver DiseaseAntonio Cuadrado, Emilio Fabrega, Fernando Casafont, and

Fernando Pons-Romero

The aim of this study was to evaluate the rate of alcoholrecidivism after orthotopic liver transplantation (OLT)for alcoholic liver disease (ALD) and its influence on theallograft and patient survival, as well as the developmentof comorbidities and de novo cancers. The study was per-formed on 54 subjects previously analyzed and trans-planted in our center for ALD, whose follow-up was pro-longed to a mean of 99.2 (SD 31.7) months (range,14-155). Medical records were reviewed, and data onalcohol consumption, therapeutic compliance, graft evo-lution, rejection, infections, comorbidities, rates of denovo malignancies and other clinical events, and survivalwere collected. Comparisons between groups were per-formed by the Fisher’s exact test, and survival was assessedby the Kaplan-Meier method. Survival curves were com-pared using the Mantel -Cox statistic. The risk of deathresulting from alcohol recidivism was analyzed with a Coxproportional hazards model. Fourteen patients whounderwent transplantation for ALD (25.9%) returned toalcohol use between 5.0 and 86.9 months after OLT(median, 47.5). There was no significant associationbetween the presence or absence of alcohol recidivism andthe occurrence of graft rejection, infections, associatedcomorbidities after OLT, or compliance. The 5- and10-year survival rates for patients with alcohol recidivismwere 92.9% and 45.1%, respectively, compared with92.4% and 85.5%, respectively, for patients without alco-hol recidivism. These figures show significantly lower sur-vival rates in recidivistic patients after 10 years (P < 0.01,Mantel -Cox). The fact that patients who resumed alcoholconsumption have a worse 10-year survival rate might beattributed to a higher frequency of deaths, primarily fromcancer and cardiovascular events. (Liver Transpl 2005;11:420-426.)

Alcoholic liver disease (ALD) is the leading cause ofcirrhosis in Western countries and represents the

second most common indication for orthotopic livertransplantation (OLT) in the United States andEurope.1-3 Reported survival rates after liver transplan-tation appear to be similar among alcoholics and non-alcoholics, reaching up to 60% 7 years after OLT.1,4 Inview of patient and graft survival, rejection rates, andinfection rates, ALD appears to be a good indication forOLT.5

Nonetheless, this indication still remains controver-sial, based partly on concerns regarding alcohol relapseand functional outcome after transplantation in an eraof donor organ shortage and priority setting.1 In fact, itis common practice to establish a period of abstinencefrom alcohol (usually 6 months) before listing a patientwith ALD for OLT based on (1) patients in whomstabilization or improvement of liver function mayoccur, obviating the need for transplantation,3 and (2)higher reported rates of alcohol relapse in patients whohad been abstinent from alcohol for less than 6 monthsbefore transplantation.6

Several previous studies analyzed the rate of alcoholrelapse after OLT for ALD and its influence on patientand graft survival.2,4,7-18 Thus, reported rates of alcoholrelapse range from 11.5% to 49%, although this factwas rarely considered a reason for graft failure in recip-ients with ALD.2 Patients who resume alcohol con-sumption after OLT for ALD may damage their graftbecause of poor compliance with immunosuppressivedrugs and alcohol-related liver injury. Graft dysfunc-tion related to relapse ranged from 0% to 17%,although death related to relapse ranged from 0% to5%.2,4,8,9,11,14,15,17,18 The prognosis of liver transplan-tation in this setting after a more prolonged follow-uphas been seldom studied.

In a previous study from our group, 44 patients whounderwent an OLT for ALD and 17 control subjectswere included for study and followed for a mean of 39.5months; no deleterious effect of alcohol recidivism ontherapeutic compliance to treatment or on graft func-tion could be demonstrated.16 For the current study,the previous cohort of alcoholic patients was enlarged,

Abbreviations: OLT, orthotopic liver transplantation; ALD,alcoholic liver disease; 95% CI, 95% confidence interval.

From the Gastroenterology and Hepatology Unit, University Hospital“Marques de Valdecilla,” Faculty of Medicine, Santander, Spain.

Address reprint requests to Emilio Fabrega, MD, Gastroenterologyand Hepatology Unit, University Hospital “Marques de Valdecilla,”Faculty of Medicine, Avenida Valdecilla s/n, Santander 39008 Spain.Telephone: 073442202544; FAX: 073442202544; E-mail: [email protected]

Supported in part by FIS PI030330 and RNIHG from the SpanishMinistries of Health and Science and Technology.

Copyright © 2005 by the American Association for the Study ofLiver Diseases

Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/lt.20386

420 Liver Transplantation, Vol 11, No 4 (April), 2005: pp 420-426

Figure 1.Specific Alcohol Use Trajectories From the Point of Transplant

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Trajectories of Alcohol Consumption Following LiverTransplantation

Andrea DiMartini, M.D.1,2,6, Mary Amanda Dew, Ph.D.1,3,4,5, Nancy Day, Ph.D.1,4, MaryGrace Fitzgerald, RN, MSN1,6, Bobby L. Jones, Ph.D.7, Michael deVera, M.D.2,6, and PauloFontes, M.D.2,6

1 Department of Psychiatry, University of Pittsburgh Medical Center2 Department of Transplantation Surgery, University of Pittsburgh Medical Center3 Department of Psychology, University of Pittsburgh Medical Center4 Department of Epidemiology, University of Pittsburgh Medical Center5 Department of Biostatistics, University of Pittsburgh Medical Center6 Starzl Transplant Institute7 Carnegie Mellon University

AbstractAny use of alcohol in the years following liver transplantation (LTX) approaches 50% of patientstransplanted for alcoholic liver disease (ALD). We collected detailed prospective data on alcoholconsumption following LTX for ALD to investigate ongoing patterns of use. Using trajectorymodeling we identified four distinct alcohol use trajectories. One group had minimal use overtime. Two other groups developed early onset moderate to heavy consumption and one groupdeveloped late onset moderate use. These trajectories demonstrate that alcohol use varies based ontiming of onset, quantity, and duration. Using discriminant function analysis, we examinecharacteristics of recipient’s pre-LTX alcohol histories and early post-LTX psychological stressorsto identify the profile of those at risk for these specific trajectories. We discuss the relevance ofthese findings to clinical care and preliminarily to outcomes.

Most reports of alcohol use after liver transplantation (LTX) identify the time to specificalcohol use outcomes (e.g. time to first drink) (1,2) or set thresholds of use by whichdrinking groups are categorized (e.g. those who drank 140gms of ethanol/week) (3,4,5). Wealso reported on time to first alcohol use, binge use, and frequency of use in our alcoholicliver disease (ALD) LTX recipients (6). We found those who take a drink can quicklytransition to a binge (6 drinks) episode, with binge drinking occurring within the first yearfor over 40% of those who drank (6). Additionally, pre-LTX alcohol history characteristics(diagnosis of alcohol dependence, short sobriety, alcoholism in a 1° biologic relative, othersubstance use, and addiction rehabilitation) predicted time to these specific thresholds ofuse.

There is great clinical and therapeutic utility in identifying the timing of onset of specificthresholds of alcohol use, specifically for planning appropriate timing of interventions. Overthe long-term, however, whether drinking is sustained, for how long, and whether specificpatterns of use emerge may be most important for predicting outcome. Thus as the next step

Address Correspondence to: Andrea DiMartini M.D., Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA15213, Phone (412) 383-3166, Fax (412) 383-4846, [email protected].

NIH Public AccessAuthor ManuscriptAm J Transplant. Author manuscript; available in PMC 2011 October 1.

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Trajectories of Alcohol Consumption Following LiverTransplantation

Andrea DiMartini, M.D.1,2,6, Mary Amanda Dew, Ph.D.1,3,4,5, Nancy Day, Ph.D.1,4, MaryGrace Fitzgerald, RN, MSN1,6, Bobby L. Jones, Ph.D.7, Michael deVera, M.D.2,6, and PauloFontes, M.D.2,6

1 Department of Psychiatry, University of Pittsburgh Medical Center2 Department of Transplantation Surgery, University of Pittsburgh Medical Center3 Department of Psychology, University of Pittsburgh Medical Center4 Department of Epidemiology, University of Pittsburgh Medical Center5 Department of Biostatistics, University of Pittsburgh Medical Center6 Starzl Transplant Institute7 Carnegie Mellon University

AbstractAny use of alcohol in the years following liver transplantation (LTX) approaches 50% of patientstransplanted for alcoholic liver disease (ALD). We collected detailed prospective data on alcoholconsumption following LTX for ALD to investigate ongoing patterns of use. Using trajectorymodeling we identified four distinct alcohol use trajectories. One group had minimal use overtime. Two other groups developed early onset moderate to heavy consumption and one groupdeveloped late onset moderate use. These trajectories demonstrate that alcohol use varies based ontiming of onset, quantity, and duration. Using discriminant function analysis, we examinecharacteristics of recipient’s pre-LTX alcohol histories and early post-LTX psychological stressorsto identify the profile of those at risk for these specific trajectories. We discuss the relevance ofthese findings to clinical care and preliminarily to outcomes.

Most reports of alcohol use after liver transplantation (LTX) identify the time to specificalcohol use outcomes (e.g. time to first drink) (1,2) or set thresholds of use by whichdrinking groups are categorized (e.g. those who drank 140gms of ethanol/week) (3,4,5). Wealso reported on time to first alcohol use, binge use, and frequency of use in our alcoholicliver disease (ALD) LTX recipients (6). We found those who take a drink can quicklytransition to a binge (6 drinks) episode, with binge drinking occurring within the first yearfor over 40% of those who drank (6). Additionally, pre-LTX alcohol history characteristics(diagnosis of alcohol dependence, short sobriety, alcoholism in a 1° biologic relative, othersubstance use, and addiction rehabilitation) predicted time to these specific thresholds ofuse.

There is great clinical and therapeutic utility in identifying the timing of onset of specificthresholds of alcohol use, specifically for planning appropriate timing of interventions. Overthe long-term, however, whether drinking is sustained, for how long, and whether specificpatterns of use emerge may be most important for predicting outcome. Thus as the next step

Address Correspondence to: Andrea DiMartini M.D., Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA15213, Phone (412) 383-3166, Fax (412) 383-4846, [email protected].

NIH Public AccessAuthor ManuscriptAm J Transplant. Author manuscript; available in PMC 2011 October 1.

Published in final edited form as:Am J Transplant. 2010 October ; 10(10): 2305–2312. doi:10.1111/j.1600-6143.2010.03232.x.

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Figure 1.Specific Alcohol Use Trajectories From the Point of Transplant

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Figure 2.A. Causes Death Overall, N=327. B. Non-Hepatic Causes of Deaths, N=207.CV=Cardiovascular.

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HR 8.5). Retransplantation within the first year of primary transplant was not associatedwith an increased risk of death long term (>1 year). This may reflect the era oftransplantation and may not be applicable to the current era as survival afterretransplantation has improved since the early 1990’s (10).

Liver-related deaths accounted for almost 1/3 of all deaths. Risk factors for liver-relateddeath included underlying hepatitis C, an established risk factor, as well as posttransplantdiabetes, hypertension, and renal insufficiency, which have not previously been associatedwith liver related deaths. It should be noted that this cohort of patients were transplanted inthe early 1990s which preceded the likelihood of early antiviral treatment for their recurrenthepatitis C after transplant. The impact of HCV on longterm outcomes in this cohort hasbeen described previously(17). The association of diabetes with liver related mortality fitswith the current knowledge that insulin resistance posttransplant has been shown to beassociated with more rapidly progressive fibrosis and hepatitis C recurrence, intuitivelyincreasing the risk of liver-related mortality(18).

Malignancy is the second most common cause of death in the long term followup of thesepatients. It is no surprise that patients transplanted with HCC or CCA are at higher risk ofdeath from a malignancy. Protocols and allocation policies are different from 1990-94 andtherefore this data may not apply to the current transplant era. However, more patients diedof denovo than recurrent malignancy and risk factors exist including ALD and older patientswhich are unrelated to the era of transplant. Interestingly, PSC and smoking history were notstatistically associated with increased malignancy-related death despite a higher frequencyof malignancy in PSC patients (20). A detailed analysis of malignancy posttransplant in thispopulation is now published elsewhere (20). Rigorous screening programs for preventionand early detection of malignancy in the post transplant should be studied.

Renal insufficiency/failure occurred in over 68% of patients in the posttransplant period andwas shown to be an important risk factor for late death. Renal failure is an important causeof death in a small but increasing number of patients late posttransplant. Older age, pre-LTRI, pre and post-LT diabetes and ALD are strongly associated with renal related death andshould be factored into identifying recipients who may benefit from combined liver kidneytransplantation.

An obvious limitation of this study is its historical nature. The lack of clarity on the specificcauses of liver related deaths (recurrence of disease vs rejections or other cause) or renaldeaths is a limitation and allows for only generalizations regarding risk factors for thesedeaths. We must also keep in mind that the risk factors identified may be associated withcontributing causes of death and not necessarily the listed cause. Certainly survival afterprimary transplantation or retransplantation has improved over the years. While this impactsthe interpretability of some of the data presented, it is also the driving factor to understandmore about long term mortality. This study, allows insight into cause-specific risk factors,helping us to identify those risk factors that may or may not change within multiple eras oftransplant. Metabolic complications after transplant arise in a large percentage of thetransplant population in every era and this study provides awareness into the impact of thesecomplications on longterm survival. Continued data of cause-specific risk factors forlongterm mortality are needed.

SummaryHepatic etiologies are the most frequent cause of death in the late posttransplant setting.Immunosuppression changes and antiviral treatments in the current era of transplantationmay impact the frequency of liver related deaths. In addition to malignancy andcardiovascular disease, renal failure is an important and escalating cause of death in the late

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HR 8.5). Retransplantation within the first year of primary transplant was not associatedwith an increased risk of death long term (>1 year). This may reflect the era oftransplantation and may not be applicable to the current era as survival afterretransplantation has improved since the early 1990’s (10).

Liver-related deaths accounted for almost 1/3 of all deaths. Risk factors for liver-relateddeath included underlying hepatitis C, an established risk factor, as well as posttransplantdiabetes, hypertension, and renal insufficiency, which have not previously been associatedwith liver related deaths. It should be noted that this cohort of patients were transplanted inthe early 1990s which preceded the likelihood of early antiviral treatment for their recurrenthepatitis C after transplant. The impact of HCV on longterm outcomes in this cohort hasbeen described previously(17). The association of diabetes with liver related mortality fitswith the current knowledge that insulin resistance posttransplant has been shown to beassociated with more rapidly progressive fibrosis and hepatitis C recurrence, intuitivelyincreasing the risk of liver-related mortality(18).

Malignancy is the second most common cause of death in the long term followup of thesepatients. It is no surprise that patients transplanted with HCC or CCA are at higher risk ofdeath from a malignancy. Protocols and allocation policies are different from 1990-94 andtherefore this data may not apply to the current transplant era. However, more patients diedof denovo than recurrent malignancy and risk factors exist including ALD and older patientswhich are unrelated to the era of transplant. Interestingly, PSC and smoking history were notstatistically associated with increased malignancy-related death despite a higher frequencyof malignancy in PSC patients (20). A detailed analysis of malignancy posttransplant in thispopulation is now published elsewhere (20). Rigorous screening programs for preventionand early detection of malignancy in the post transplant should be studied.

Renal insufficiency/failure occurred in over 68% of patients in the posttransplant period andwas shown to be an important risk factor for late death. Renal failure is an important causeof death in a small but increasing number of patients late posttransplant. Older age, pre-LTRI, pre and post-LT diabetes and ALD are strongly associated with renal related death andshould be factored into identifying recipients who may benefit from combined liver kidneytransplantation.

An obvious limitation of this study is its historical nature. The lack of clarity on the specificcauses of liver related deaths (recurrence of disease vs rejections or other cause) or renaldeaths is a limitation and allows for only generalizations regarding risk factors for thesedeaths. We must also keep in mind that the risk factors identified may be associated withcontributing causes of death and not necessarily the listed cause. Certainly survival afterprimary transplantation or retransplantation has improved over the years. While this impactsthe interpretability of some of the data presented, it is also the driving factor to understandmore about long term mortality. This study, allows insight into cause-specific risk factors,helping us to identify those risk factors that may or may not change within multiple eras oftransplant. Metabolic complications after transplant arise in a large percentage of thetransplant population in every era and this study provides awareness into the impact of thesecomplications on longterm survival. Continued data of cause-specific risk factors forlongterm mortality are needed.

SummaryHepatic etiologies are the most frequent cause of death in the late posttransplant setting.Immunosuppression changes and antiviral treatments in the current era of transplantationmay impact the frequency of liver related deaths. In addition to malignancy andcardiovascular disease, renal failure is an important and escalating cause of death in the late

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underestimation as it is quite likely that some deaths characterized as ‘unknown’ includedsudden cardiac deaths. Patients followed closely in a transplant center would be unlikely tohave an ‘unknown’ liver or malignancy related death.

A novel observation in this multicentered study is the surge in renal related deaths withlonger follow up. Other reviews have found renal failure to be a cause of 1–2% of deathsoverall (4–6). Our study suggests that, with longer follow-up, renal failure is a major causeof death, with the inflection point for increasing frequency occurring at the sixthpostoperative year. A weakness in this observation is the lack of clear definitions of renalfailure as a cause of death. We are limited by the documentation of primary cause of deathbeing simply “renal failure”. Supporting this finding, and even more importantly, is theanalysis showing the risk of death from any cause is substantially impacted by renalinsufficiency, with increased risk associated with later onset (>1 year post transplant) ofrenal insufficiency compared to early (<1 year) onset.

This study confirms a lower risk of death for cholestatic liver disease patients. It is thoughtthat fulminant hepatic failure patients have an increased risk of mortality posttransplant, butour data suggests that if the patient survives the first year, they experience a lower risk ofdeath thereafter. Alcoholic liver disease and metabolic liver disease are risk factors for longterm mortality. A diagnosis of HCC or CCA at the time of transplant, whether previouslyidentified or found incidentally on explant, portended a worse prognosis in this cohort ofpatients. The risk was higher when analyzed with all incidental malignancies includedcompared to only previously known malignancies, suggesting incidental cancers have animpact on long term mortality. This risk appears to be predominantly associated withmalignancy related deaths, as they were not independent variables associated with othercauses of death (although CCA had a HR 2.6 for liver related death suggesting a type 2error). Care must be taken in interpreting this data as the difference in selection criteria forpatients with malignancy as well as therapeutic management before and after transplant inthe present era have undoubtedly affected the outcome in these patients.

Risk factors known to be associated with death early after LT include age, pre-LT renalinsufficiency, and pre-LT diabetes are incorporated into survival adjustment calculations bythe Scientific Registry of Transplant Recipients for center specific 1 year outcomes. Theserisk factors as well as hypertension also contribute independently to an increase the risk ofdeath in the late posttransplant period. This is the first large multi-centered study to identifypatient related risk factors for death and cause specific death. It has been suggested thatpatients transplanted with pre-existing diabetes have worse 1, 3, and 5 year survival after atransplant (11,12). New onset diabetes is reported in 10–35% of liver transplant patients(13–15). One case control study suggested no increased risk of 1, 3, or 5 year mortality forpatients with sustained new onset diabetes after transplant (15) whereas anotherretrospective study with 10 year analysis suggested increased mortality for patients withsustained new onset diabetes (13). In our study, both pretransplant and posttransplantdiabetes (whether new onset or sustained diabetes), in addition to posttransplanthypertension and renal insufficiency, were predictors of longterm death, as well asspecifically cardiovascular and renal deaths. Body mass index at the time of transplant wasnot associated with longterm mortality, consistent with previous findings(16). Surprisingly,smoking was a risk factor for overall death, but not cardiovascular or malignancy deathsspecifically, but this may be due to small numbers of smokers in the cause specific analysis.Regardless of the era of transplant, these risk factors remain major issues in the care of posttransplant patients and may be targets to improve overall outcomes.

Retransplantation > 1 year from the primary transplant is associated with increased risk ofdeath overall, primarily due to markedly increased risk of liver related death (independent

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Evolution of Causes and Risk Factors for Mortality Post LiverTransplant: Results of the NIDDK Long Term Follow-up Study

Kymberly DS Watt1, Rachel A Pedersen2, Walter K Kremers2, Julie K Heimbach3, andMichael R Charlton1

Mayo Clinic Transplant Center, Rochester, MN, United States1Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester,Minnesota, USA.2Division of Biomedical Statistics and Informatics, Mayo Clinic and Foundation, Rochester,Minnesota, USA.3Department of Surgery, Mayo Clinic and Foundation, Rochester, Minnesota, USA.

AbstractAlthough mortality rates following liver transplantation (LT) are well described, there is a lack ofdetailed, prospective studies determining patterns of and risk factors for long term mortality. Weanalyzed the multi-center, prospectively obtained NIDDK Liver Transplantation Database of 798transplant recipients from 1990–1994 (followup 2003). Overall, 327 recipients died. Causes ofdeath >1 year: 28% hepatic, 22% malignancy, 11% cardiovascular, 9% infection, 6% renal failure.Renal related death increased dramatically over time. Risk factors for death >1 year (univariate):male gender, age/decade, pre-LT diabetes, post-LT diabetes, post-LT hypertension, post-LT renalinsufficiency, retransplantation >1 year, pre-LT malignancy, alcoholic (ALD) disease andmetabolic liver disease, with similar risks noted for death >5 years. Hepatitis C, retransplantation,post-LT diabetes, hypertension and renal insufficiency were significant risk factors for liverrelated death. Cardiac deaths associated with age, male gender, ALD, cryptogenic disease, pre-LThypertension and post-LT renal insufficiency. In summary, the leading causes of late deaths aftertransplant were graft failure, malignancy, cardiovascular disease and renal failure. Older age,diabetes, and renal insufficiency identified patients at highest risk of poor survival overall.Diligent management of modifiable post-LT factors including diabetes, hypertension and renalinsufficiency may impact long term mortality.

IntroductionAdvances in medical management and surgical technique have resulted in step-wiseimprovements in early posttransplant survival rates. In the current transplant era, the overall1 and 5 year survival rates after a liver transplant (LT) are 85% and 68% respectively, with a10 year survival rate closer to 50% (http://www.unos.org). Improvement in earlyposttransplant patient survival has increased the importance of understanding the causes andrisk factors for late posttransplant mortality. The few reports that have described longtermpost-LT mortality of have been limited by a retrospective, single center design, small cohortsize and/or inclusion of pediatric patients. (1–6)

Corresponding Author: Dr. Kymberly DS Watt, M.D., Division of Gastroenterology and Hepatology, Mayo Clinic and FoundationCH-10, 200 First St. S.W., Rochester, MN. 55905, Phone 507-266-1580, Fax 507-266-1856, [email protected] conflicts of interest for any of the authorsFunding: none

NIH Public AccessAuthor ManuscriptAm J Transplant. Author manuscript; available in PMC 2011 June 1.

Published in final edited form as:Am J Transplant. 2010 June ; 10(6): 1420–1427. doi:10.1111/j.1600-6143.2010.03126.x.

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Table 3. IRRs were significantly elevated for LT recipientsaged 50 years or older at transplant (IRR=2.7), for thosewith a transplant period equal to or >2 years (IRR=2.2),and for those with ALD (IRR=7.4). Among 1298 LT recipi-ents with smoking information (46.9% of the whole studygroup), the combination of cigarette smoking and ALD

conferred a very high risk of HN and esophageal cancers(IRR=35.1, 95% CI: 11–107), as compared to recipientswho were either nonsmokers, or smokers without ALD, ornonsmokers with ALD. All cases of HN or of esophagealcancer underwent CNI treatment, whereas none of themwas treated with mTORi (Table 3).Overall, the estimated median time of survival after LT

was 24.3 years for recipients without a DNC, 8.6 years forthose with HN cancer, and 6.2 years for those who devel-oped an esophageal carcinoma. After 10 years from LT, thesurvival probability was 0.48 for recipients with HN and0.44 for recipients with esophageal cancers (Fig. 3). Themedian time from transplant to cancer was 37.5 monthsfor HN cancers and 57.7 months for esophageal carcinoma,while the 5-year survival probability after cancer diagnosis

Cum

ulat

ive

inci

denc

e (%

)

Time since trasplantation (years)

0

1

2

3

0 2 4 6 8 10

Head & neck

Esophagus

Cancer type Cumulative incidence (%)

5 years 10 years

Head & neck 1.32 1.77

Esophagus 0.31 0.75

Figure 1 Cumulative incidence of de novo malignancies after liver

transplant, according to cancer type and time since transplant. Italy,

1990–2010.

Table 1. Baseline characteristics of 2770 patients who underwent liver

transplantation: Italy, 1990–2010.

All patients

(n = 2770)

Patients with de

novo cancers

(n = 178)

N. (%) N. (%)

Sex

Male 2069 (74.7) 140 (78.7)

Female 701 (25.3) 38 (21.3)

Age at transplant (years)

<45 610 (22.0) 33 (18.5)

45–54 931 (33.6) 68 (38.2)

55–59 619 (22.4) 44 (24.7)

60+ 610 (22.0) 33 (18.5)

Baseline disease/s*

Cirrhosis 2411 (87.0) 155 (87.1)

Liver cancer 970 (35.0) 62 (34.8)

Cholestatic liver disease 128 (4.6) 9 (5.1)

Acute liver failure 114 (4.1) 6 (3.4)

Metabolic liver disease 70 (2.5) 4 (2.2)

Miscellaneous 11 (0.4) 0 (0)

History of HBV infection

No 1605 (57.9) 99 (55.6)

Yes 1165 (42.1) 79 (44.4)

History of HCV infection

No 1391 (50.2) 102 (57.3)

Yes 1379 (49.8) 76 (42.7)

History of alcohol abuse†No 2024 (73.1) 113 (63.5)

Yes 746 (26.9) 65 (36.5)

Ever smoker‡No 502 (18.1) 18 (10.1)

Yes 796 (28.7) 51 (28.7)

Unknown 1472 (53.1) 109 (61.2)

Calendar year at transplant

≤2000 708 (25.6) 80 (44.9)

2001–2005 1020 (36.8) 57 (32.0)

≥2006 1042 (37.6) 41 (23.0)

Area of origin

Northern Italy 602 (21.7) 45 (25.3)

Central Italy 504 (18.2) 36 (20.2)

Southern Italy 1560 (56.3) 96 (53.9)

Abroad 104 (3.8) 1 (0.6)

Status of the donor

Living 107 (3.9) 5 (2.8)

Deceased 2663 (96.1) 173 (97.2)

Use of CNI§No 40 (1.4) 0 (0)

Yes 2730 (98.6) 178 (100)

Table 1. continued

All patients

(n = 2770)

Patients with de

novo cancers

(n = 178)

N. (%) N. (%)

Use of mTORi§No 2718 (98.1) 178 (100)

Yes 52 (1.9) 0 (0)

Follow-up

Total person years (PYs) 16 349.9 –Length of follow-up (years)¶ 4.6 (2.3–8.9) –

*The sum does not add to the total because of overlapping conditions.

†Clinically defined as a cause of the disease that led to liver transplant.

‡Data on smoking were collected in 4 of 9 transplant centers.

§Considered as initial immunosuppressive therapy (CNI: Calcineurin

Inhibitors; mTORi: mTOR inhibitors).

¶The data are presented as medians and IQRs.

844 © 2015 Steunstichting ESOT 28 (2015) 841–848

Alcoholic liver disease and cancers after liver transplant Piselli et al.

was 35.2% for HN patients, and 14.5% for patients diag-nosed with esophageal carcinoma (data not shown intables). Of the 30 ALD recipients of liver transplant whodeveloped HN cancers or esophageal carcinoma, alcoholconsumption after liver transplantation was documented infour (13.3%) (two cases of oral cavity and two cases ofcancer of the esophagus). In these ALD LT recipients, thetime between transplant and cancer diagnosis was similar(range: 21–104 months) to that of the remaining 26 ALDLT recipients (range: 14–133 months) (data not shown intables).

Stage at cancer diagnosis was available for 20 of these 41LT recipients with HN cancers or esophageal carcinoma:

Eight cases (40.0%) were early stages (i.e., stage I-II), and12 (60.0%) cases had advanced disease (i.e., stage III-IV).With regard to the treatment of these 41 neoplasms, che-motherapy was administered in 10 (24.4%), surgery in 18(43.9%), and radiotherapy in 23 (56.1%). Combinations ofthese therapeutical approaches were documented in 20 LTrecipients (48.8%) with these cancers (e.g., eight casesunderwent both surgery and radiotherapy).

Discussion

In this cohort of over 2700 Italian recipients of LT followedfor up to 20 years, we quantified the strong impact of heavy

Table 2. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) for alcohol-related malignancies with at least five observed cases fol-

lowing liver transplantation. Italy, 1990–2010.

Cancer site ICD-10

No. of cancer cases

SIR (95% CI)Observed Expected

Head & Neck C00-C14, C30-C32 32 6.83 4.69 (3.21–6.62)Tongue C01-C02 6 0.75 8.04 (2.95–17.49)Oral cavity, others C00, C03-C10 10 3.01 3.32 (1.59–6.11)Larynx C32 16 3.08 5.19 (2.97–8.43)

Esophagus C15 9 0.99 9.07 (4.14–17.21)

Cancer type ALD Obs SIR (95% CI)

Head & neckYes 23 11.83 (7.50–17.75)*

No 9 1.84 (0.84–3.50)

TongueYes 5 22.99 (7.47–53.65)*

No 1 1.89 (0.05–10.53)

Oral cavityYes 6 7.06 (2.59–15.37)*

No 4 1.96 (0.54–5.03)

LarynxYes 12 13.73 (7.09–23.97)*

No 4 1.81 (0.49–4.64)

EsophagusYes 7 23.70 (9.53–48.83)*

No 2 2.87 (0.35–10.36)

NoYes Standardized incidence ratio (SIR)ALD: alcoholic liver * = P < 0.05

disease

0.1 1 10 100 1000

Figure 2 SIRs for selected cancer sites according to history of Alcoholic Liver Disease. Italy, 1990–2010.

© 2015 Steunstichting ESOT 28 (2015) 841–848 845

Piselli et al. Alcoholic liver disease and cancers after liver transplant

ORIGINAL ARTICLE

Head and neck and esophageal cancers after liver transplant:results from a multicenter cohort study. Italy, 1997–2010Pierluca Piselli,1 Patrizia Burra,2 Augusto Lauro,3 Umberto Baccarani,4 Giuseppe M. Ettorre,5

Giovanni B. Vizzini,6 Maria Rendina,7 Massimo Rossi,8 Giuseppe Tisone,9 Fausto Zamboni,10

Ilaria Bortoluzzi,2 Antonio D. Pinna,3 Andrea Risaliti,4 Laura Galatioto,6 Giovanni Vennarecci,5 AlfredoDi Leo,7 Francesco Nudo,8 Daniele Sforza,9 Giovanni Fantola,10 Claudia Cimaglia,1 Diana Verdirosi,1

Saverio Virdone,11 and Diego Serraino11 for the Italian Transplant and Cancer Cohort Study*

1 Department of Epidemiology and Pre-Clinical Research, National Institute for Infectious Diseases “L. Spallanzani”, Rome, Italy

2 Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy

3 Liver and Multiorgan Transplant Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy

4 Liver Transplant Unit, Department of Medical and Biological Sciences, University of Udine, Udine, Italy

5 Division of General Surgery and Liver Transplantation, S. Camillo Hospital, Rome, Italy

6 Department of Gastroenterology and Hepatology, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT), University of

Pittsburgh Medical Center, Palermo, Italy

7 Department of Emergency and Organ Transplantation, Section of Gastroenterology, University Hospital, Bari, Italy

8 Department of General Surgery and Organ Transplantation, Umberto I Policlinic, Sapienza University, Rome, Italy

9 UOC Transplant Unit, Department of Surgery, Tor Vergata University, Rome, Italy

10 Department of Surgery, General and Hepatic Transplantation Surgery Unit, A.O.B. Brotzu, Cagliari, Italy

11 Epidemiology and Biostatistics Unit, Centro di Riferimento Oncologico IRCCS, Aviano, Pordenone, Italy

Keywords

aerodigestive cancers, cancer risk,

immunosuppression, liver cirrhosis, liver

diseases, oncogenic viruses, organ

transplantation.

Correspondence

Diego Serraino MD, SOC Epidemiologia e

Biostatistica, IRCCS Centro di Riferimento

Oncologico – Via F Gallini 2, 33081 Aviano,

Italy.

Tel.: +39-0434-659354;

fax: +39-0434-659231;

e-mail: [email protected]

*Other members of the Italian Transplant and

Cancer Cohort Study: Zanus G. (Padua

University Hospital, Padua, Italy); Chiala’ C.,

Rizzi S.F., Tucci A. (University Hospital, Bari,

Italy); Di Gioia P., Pellegrini S., Zanfi C. (“S.

Orsola-Malpighi” Hospital, Bologna, Italy);

Adani G.L., Lorenzin D. (University of Udine,

Udine, Italy); Colasanti M., Coco M., Miglioresi

L., Santoro R. (S. Camillo Hospital, Rome,

Italy); Mennini G. (Umberto I Policlinic, Rome,

Italy); Casella A., Fazzolari L., Toti L. (Tor

Vergata University, Rome, Italy); Agresta A.,

Ippolito G., Puro V. (INMI “L. Spallanzani”,

Rome, Italy); Dal Maso L., Fratino L., Gini A.,

Petrara R.M., Taborelli M., Vaccher E. (Centro

Summary

This study quantified the risk of head and neck (HN) and esophageal cancers in2770 Italian liver transplant (LT) recipients. A total of 186 post-transplant cancerswere diagnosed—including 32 cases of HN cancers and nine cases of esophagealcarcinoma. The 10-year cumulative risk for HN and esophageal carcinoma was2.59%. Overall, HN cancers were nearly fivefold more frequent in LT recipientsthan expected (standardized incidence ratios - SIR=4.7, 95% CI: 3.2–6.6), whileesophageal carcinoma was ninefold more frequent (SIR=9.1, 95% CI: 4.1–17.2).SIRs ranged from 11.8 in LT with alcoholic liver disease (ALD) to 1.8 for LT with-out ALD for HN cancers, and from 23.7 to 2.9, respectively, for esophageal carci-noma. Particularly elevated SIRs in LT with ALD were noted for carcinomas oftongue (23.0) or larynx (13.7). Our findings confirmed and quantified the largecancer excess risk in LT recipients with ALD. The risk magnitude and the preva-lence of ALD herein documented stress the need of timely and specifically orga-nized programs for the early diagnosis of cancer among LT recipients, particularlyfor high-risk recipients like those with ALD.

© 2015 Steunstichting ESOT 28 (2015) 841–848 841

Transplant International ISSN 0934-0874

Table 3. IRRs were significantly elevated for LT recipientsaged 50 years or older at transplant (IRR=2.7), for thosewith a transplant period equal to or >2 years (IRR=2.2),and for those with ALD (IRR=7.4). Among 1298 LT recipi-ents with smoking information (46.9% of the whole studygroup), the combination of cigarette smoking and ALD

conferred a very high risk of HN and esophageal cancers(IRR=35.1, 95% CI: 11–107), as compared to recipientswho were either nonsmokers, or smokers without ALD, ornonsmokers with ALD. All cases of HN or of esophagealcancer underwent CNI treatment, whereas none of themwas treated with mTORi (Table 3).Overall, the estimated median time of survival after LT

was 24.3 years for recipients without a DNC, 8.6 years forthose with HN cancer, and 6.2 years for those who devel-oped an esophageal carcinoma. After 10 years from LT, thesurvival probability was 0.48 for recipients with HN and0.44 for recipients with esophageal cancers (Fig. 3). Themedian time from transplant to cancer was 37.5 monthsfor HN cancers and 57.7 months for esophageal carcinoma,while the 5-year survival probability after cancer diagnosis

Cum

ulat

ive

inci

denc

e (%

)

Time since trasplantation (years)

0

1

2

3

0 2 4 6 8 10

Head & neck

Esophagus

Cancer type Cumulative incidence (%)

5 years 10 years

Head & neck 1.32 1.77

Esophagus 0.31 0.75

Figure 1 Cumulative incidence of de novo malignancies after liver

transplant, according to cancer type and time since transplant. Italy,

1990–2010.

Table 1. Baseline characteristics of 2770 patients who underwent liver

transplantation: Italy, 1990–2010.

All patients

(n = 2770)

Patients with de

novo cancers

(n = 178)

N. (%) N. (%)

Sex

Male 2069 (74.7) 140 (78.7)

Female 701 (25.3) 38 (21.3)

Age at transplant (years)

<45 610 (22.0) 33 (18.5)

45–54 931 (33.6) 68 (38.2)

55–59 619 (22.4) 44 (24.7)

60+ 610 (22.0) 33 (18.5)

Baseline disease/s*

Cirrhosis 2411 (87.0) 155 (87.1)

Liver cancer 970 (35.0) 62 (34.8)

Cholestatic liver disease 128 (4.6) 9 (5.1)

Acute liver failure 114 (4.1) 6 (3.4)

Metabolic liver disease 70 (2.5) 4 (2.2)

Miscellaneous 11 (0.4) 0 (0)

History of HBV infection

No 1605 (57.9) 99 (55.6)

Yes 1165 (42.1) 79 (44.4)

History of HCV infection

No 1391 (50.2) 102 (57.3)

Yes 1379 (49.8) 76 (42.7)

History of alcohol abuse†No 2024 (73.1) 113 (63.5)

Yes 746 (26.9) 65 (36.5)

Ever smoker‡No 502 (18.1) 18 (10.1)

Yes 796 (28.7) 51 (28.7)

Unknown 1472 (53.1) 109 (61.2)

Calendar year at transplant

≤2000 708 (25.6) 80 (44.9)

2001–2005 1020 (36.8) 57 (32.0)

≥2006 1042 (37.6) 41 (23.0)

Area of origin

Northern Italy 602 (21.7) 45 (25.3)

Central Italy 504 (18.2) 36 (20.2)

Southern Italy 1560 (56.3) 96 (53.9)

Abroad 104 (3.8) 1 (0.6)

Status of the donor

Living 107 (3.9) 5 (2.8)

Deceased 2663 (96.1) 173 (97.2)

Use of CNI§No 40 (1.4) 0 (0)

Yes 2730 (98.6) 178 (100)

Table 1. continued

All patients

(n = 2770)

Patients with de

novo cancers

(n = 178)

N. (%) N. (%)

Use of mTORi§No 2718 (98.1) 178 (100)

Yes 52 (1.9) 0 (0)

Follow-up

Total person years (PYs) 16 349.9 –Length of follow-up (years)¶ 4.6 (2.3–8.9) –

*The sum does not add to the total because of overlapping conditions.

†Clinically defined as a cause of the disease that led to liver transplant.

‡Data on smoking were collected in 4 of 9 transplant centers.

§Considered as initial immunosuppressive therapy (CNI: Calcineurin

Inhibitors; mTORi: mTOR inhibitors).

¶The data are presented as medians and IQRs.

844 © 2015 Steunstichting ESOT 28 (2015) 841–848

Alcoholic liver disease and cancers after liver transplant Piselli et al.

1. Cual es la herramienta fundamental en la evaluación de la recidiva alcohólica pos-‐trasplante: tiempo de abstinencia pre trasplante, evaluación psiquiátrica o evaluación social.

R. Un periodo de abstinencia pre-‐trasplante como herramienta única de la valoración del alcoholismo es inadecuada. Esta debe descansar en la evaluación de la adicción por especialistas en adicciones y psiquiatras. Recomendación IA

2.-‐Que medidas deberíamos de implementar para reducir la recaída en el consumo alcohólico y tratar de mejorar la mortalidad?

R. En el manejo del paciente alcohólico el trabajar estrechamente con unidades y especialistas en adicciones reduce la recaída en el consumo y disminuye la mortalidad. Recomendación IA

3.-‐Deberíamos considerar el trasplante hepático en aquellos enfermos con Hepatitis alcohólica aguda grave que no responden al tratamiento medico?

R.-‐El trasplante hepático se encuentra indicado en Hepatitis alcohólica aguda grave en pacientes cuidadosamente seleccionados y que no responden al tratamiento medico. Recomendación IB.

4.-‐En el seguimiento del trasplantado por enfermedad hepática alcohólica que otras medidas se deben implementar con el objetivo de reducir la mortalidad.

R. El paciente trasplantado alcohólico presenta mayor riesgo cardiovascular que otros trasplantes y especialmente propenso a desarrollar cáncer de cabeza y cuello y pulmón. Factores de riesgo especialmente modificables como el tabaco, obesidad y sedentarismo deben ser evitados. Recomendación IB.

Muchas gracias!

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