Alcohol abstinence in patients surviving an episode of ... · ALCOHOL ABSTINENCE IN PATIENTS SURVIVING AN EPISODE OF ALCOHOLIC HEPATITIS: PREDICTION AND IMPACT ON LONG-TERM SURVIVAL

ALCOHOL ABSTINENCE IN PATIENTS SURVIVING AN EPISODE OF ALCOHOLIC

HEPATITIS: PREDICTION AND IMPACT ON LONG-TERM SURVIVAL

José Altamirano1,§, Hugo López-Pelayo2§, Javier Michelena1, Patricia D. Jones5,

Lluisa Ortega2, Pere Ginès1,3, Juan Caballería1,3, Antoni Gual2, Ramón Bataller4,6*,

Anna Lligoña2*

Institutions:

1) Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona,

Spain. 2) Grup Recerca Addiccions Clinic (GRAC-GRE) Psychiatry Department,

Neurosciences Institute, Hospital Clínic of Barcelona, Red de Trastornos Adictivos

(RTA),Spain. 3) Liver Unit, CIBER de Enfermedades Hepáticas y Digestivas

(CIBERehd), Institució Catalana de Recerca i Estudis Avançats (ICREA), Universitat

de Barcelona, Barcelona, Spain. 4) Division of Gastroenterology and Hepatology.

Departments of Medicine and Nutrition. University of North Carolina at Chapel Hill,

Chapel Hill, NC. 5) Division of Gastroenterology and Hepatology, University of Miami

Miller School of Medicine, Miami, FL. 6) Pittsburgh Liver Research Center, Division of

Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Liver Center,

Pittsburgh, PA

§ Authors share first co-authorship.

* Authors share senior co-authorship.

Corresponding Authors:

Anna Lligoña, MD

Grup de Recerca Addiccions Clinic (GRAC-GRE)

Psychiatry Department, Neurosciences Institute,

Hospital Clínic, Barcelona, Spain

Email: [email protected]

Ramón Bataller, M.D., PhD.

University of Pittsburgh Medical Center (UPMC)

Division of Gastroenterology, Hepatology and Nutrition

Scaife Hall 8th floor, S844A

3550 Terrace St, Pittsburgh, PA 15261

+1(412)3834242

[email protected]

This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article asdoi: 10.1002/hep.29338

This article is protected by copyright. All rights reserved.

2

Main Manuscript Word Count: 4133 words

Number of Tables: 6

Number of Figures: 2

Conflict of interest: HLP has received honoraria as speaker from Lundbeck and

Janssen; and meeting grants from Lundbeck, Janssen, Pfizer, Otsuka, Esteve, Rovi

and Lilly. RB has received consulting fees from Echosens and Valyx. None of these

grants have relationship with the current manuscript. Other authors report no conflict

of interest.

Financial support: This work was supported by the National Institute on Alcohol Abuse

and Alcoholism (NIAAA)(1U01AA021908-01). JA wishes to express his gratitude to the

Mexican National Council of Science and Technology (CONACyT, Mexico City,

Mexico) for partially supporting his predoctoral stay at IDIBAPS.

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ABSTRACT :

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. Most studies

have focused on short-term prognosis, while factors associated with long-term survival

are largely unknown. The aims of our study were: 1) to determine the impact of

complete abstinence from alcohol on long-term survival and 2) to identify prognostic

factors at admission capable of predicting abstinence during long-term follow-up in

patients with AH. One hundred and forty-two patients with biopsy-proven AH that

survived the first episode were included. Demographic, psychiatric and biochemical

variables at admission and drinking status during follow-up were obtained. Cox

regression, logistic regression and classification and regression trees (CART) analyses

were used for statistical analysis. Overall mortality was 38% with a median follow-up of

55 months. During follow-up, complete abstinence was reported in 39% and was

associated with better long-term survival (HR 0.53; p=0.03). After adjustment for

baseline prognostic scoring systems (MELD and ABIC scores), complete abstinence

was independently associated with survival (p<0.05). Age and lack of prior alcoholism

treatments were independently associated with complete abstinence (p<0.001 and

p=0.02, respectively) during follow-up. CART analysis generated a simple and practical

algorithm based-on the combination of prior alcoholism treatments and age. Using

CART analysis we stratified 2 subgroups of patients with high (65%) and low (26-29%)

rates of complete abstinence after an episode of AH.

Conclusions: Complete abstinence after an episode of AH positively impacts long-

term survival. The combination of 2 variables easily obtained at admission might be

useful to predict long-term abstinence after an episode of AH. Strategies aimed at

promoting alcohol abstinence in these patients are mandatory.

Keywords: alcoholic liver disease; alcoholic hepatitis; survival; abstinence.

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INTRODUCTION

Alcoholic hepatitis (AH) is a severe clinical entity characterized by acute onset of

jaundice and liver-related complications in patients with severe alcohol use disorder. It

typically occurs in the setting of preexisting liver disease and most patients have

underlying cirrhosis.1 The short-term mortality of AH remains very high globally1-3 and

15-40% of patients die within the first 30 days.4 Short-term prognosis can be predicted

by prognostic models including Maddrey’s discriminant function (DF),5 Model for End-

Stage Liver Disease (MELD),6 Glasgow Alcoholic Hepatitis Score7 and the age-

bilirubin-INR-creatinine (ABIC).8 Moreover, the Lille model9 incorporates response to

prednisolone in determining the risk of death. The medical management of AH has not

evolved substantially in the last two decades. The first line therapy consists of

corticosteroids5,9-11. For patients that do not respond to first line therapy, there are no

effective alternative drugs 12-16. The only approach that improves survival in these

patients is "savage" liver transplantation.17-18 However, many patients with a severe

episode are unlikely to survive the six months of abstinence typically required prior to

consideration for transplant.

The recent STOPAH19 trial only showed a beneficial effect of prednisolone at day 28,

while neither prednisolone nor pentoxifylline was effective after that period. Importantly,

half of the patients died in one year and only one third remained abstinent. This high

rate of recidivism has been confirmed in other studies.20 This seminal study suggests

that alcohol abstinence is only achieved in a minority of patients and that persistent

alcohol intake could influence long-term survival. There are no studies assessing the

predictors of alcohol abstinence in this patient population, and there is limited data on

the influence of alcohol intake on patient outcome. The current study was undertaken

to fill this gap.

Although abstinence from alcohol is routinely recommended after an episode of AH,

there are no studies assessing motivational or pharmacological therapies to promote

abstinence. Similarly, no studies have identified parameters at admission that predict

long-term abstinence. The risks of resuming alcohol use should not be understated. In

one study, a significant proportion of patients with recidivism developed a subsequent

episode of AH that was more severe than the index episode with ≈60% mortality.21

Identification of patients with high risk of recidivism is relevant because it can be used

to select patients for salvage transplantation and to identify those patients needing

more intense alcohol therapy.22-23 However, there are no studies evaluating factors

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associated with long-term abstinence after an episode of AH. We hypothesize that

persistent alcohol use is associated with poorer long-term survival. The aims of our

study were: 1) to determine impact of complete abstinence from alcohol on long-term

survival and 2) to investigate the predicting factors associated with long-term

abstinence in patients with AH.

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PATIENTS AND METHODS

Study Cohort

We included patients admitted to the Liver Unit (Hospital Clínic, Barcelona, Spain) from

1999 to 2012 with biopsy-proven AH included in several prospective studies 2,4,8,24. The

inclusion criteria were presence of heavy drinking (alcohol consumption >60 g/day for

more than 1 year) prior to admission, moderately elevated aminotransferases,

aspartate aminotransferase (AST) levels higher than alanine aminotransferase (ALT),

high gamma-glutamyl transpeptidase (GGT) and abrupt arise in bilirubin serum levels.

In all cases, AH was confirmed histologically by the presence of hepatocellular damage

(hepatocellular ballooning and presence of Mallory bodies), inflammatory infiltrate

(predominantly polymorphonuclear cells) and pericellular fibrosis. Patients with

hepatocellular carcinoma, any other potential cause of liver disease and those who

died during index hospitalization were excluded from the study. In our hospital, the vast

majority of physicians use the ABIC score to stratify patients with severe AH, given that

it was generated in our center and accurately identifies patients with high short-term

mortality Accordingly, severe AH was defined as Maddrey’s discriminant function (DF)

>32 and/or ABIC score >6.71 at admission. All patients with AH received general

support measures and severe cases were treated with 40 mg of prednisone orally

every 24 hours for 4 weeks followed by a taper period of 2 weeks. Treatment was

discontinued in non-responding patients as assessed by Lille score >0.45, according to

the center’s guidelines during the patients’ admission. All patients underwent bacterial

infection screening at admission. During hospitalization, patients with clinical

complications, such as ascites, spontaneous bacterial peritonitis, renal dysfunction,

overt hepatic encephalopathy or gastrointestinal bleeding associated with portal

hypertension, as well as bacterial infections non-related to portal hypertension, were

diagnosed and treated according to international guidelines and the clinical protocol of

the Liver Unit in effect when the patients were admitted. As a part of the protocol for

patients with alcoholic liver disease admitted to our liver unit, a team composed of a

psychiatrist, psychologist, and social worker carefully evaluated patients. After hospital

discharge, patients were referred to the Addiction Unit (AU) and the liver unit of our

center for subsequent evaluation and follow-up. The Ethics Committee of the Hospital

Clinic approved the study and all patients gave written informed consent (CEIC

2011/707).

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Clinical and Psychosocial Evaluations at Admission

The demographic and analytical parameters, assessed within 48 hours from hospital

admission, included: age, gender, serum glucose, creatinine, sodium, bilirubin, AST,

ALT, GGT, albumin, international normalized ratio (INR), leukocyte count, platelet

count, hematocrit and hemoglobin levels. The different AH scoring systems were

calculated based on the laboratory values at admission and or within 48 hours of

admission. For purposes of this study, a psychiatrist from our AU performed a full

interview of every included patient and, when needed to close relatives. This interview

included: psychiatric and social parameters, such as alcohol dependency (DSM IV-

TR), cognitive deficits (Mini Mental State Examination), presence/absence of an

underlying psychiatric disease (DSM IV-TR), tobacco consumption, amount of alcohol

consumption, years of heavy alcohol consumption and previous treatments for

alcoholism. When reports of alcohol consumption variables conflicted, the highest

estimate was used. Diagnosis of alcohol abuse and dependence was made according

to the criteria detailed in the Diagnostic and Statistical Manual of Mental Disorders, IV

Edition. For each patient, alcohol consumption was classified using the High-Risk

Alcoholism Relapse (HRAR) scale. The HRAR scale was originally developed from a

cohort of male US Veterans and includes 3 parameters (duration of heavy drinking,

usual number of daily drinks, and number of prior alcoholism treatment experiences)

empirically evaluated to estimate the risk of alcoholism recidivism.25 The HRAR scale

has recently shown good accuracy to predict harmful drinking in patients undergoing

liver transplantation for alcoholic cirrhosis.25 We adapted the number of drinks to the

amount of alcohol of one standard drink (SD) in Europe (e.g. 1 SD=10 g of pure

ethanol). Each item can be scored 0, 1, or 2 for a total possible score ranging from 0 to

6 (Supplementary Table 1).

Follow-Up and Definitions

After hospital discharge from the index AH episode, patients were referred to the AU

for regular follow-up. Our AU has extensive experience in the psychological and

psychiatric treatments of patients with alcoholic liver disease.26-28 Data about prior

alcohol consumption, consumption of psychotropic drugs, alcohol abstinence, time

since last alcohol consumption and the number of previous alcohol detoxifying

treatments were carefully collected. All collected data from patients was always

compared with reports from with relatives or accompanying persons. In the event

of recidivism, information about the number of standard drinks consumed was

collected. For the purpose of this study, data about long-term abstinence and alcohol

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recidivism were retrospectively collected by: a) telephone survey to the patient and/or

patient’s relatives (See Supplementary Information for Survey) (n=98), b) in-person

interviews (n=15) and/or c) review of clinical records from hospital and primary care

medicine units (n=29). All data recorded from the telephonic interviews were also

contrasted with data from electronic charts of the primary care centers (shared

electronic charts). Data about clinical decompensations after index admission for AH

and liver transplantation during follow-up were also recorded retrospectively. Alcohol

abstinence was evaluated on the basis of patient's self-report, family member

interviews, and/or the presence of alcohol in the urine in those attending the hospital

AU. Alcohol recidivism was defined as any amount of regular alcohol use (consumption

at least once a week) after index hospitalization for AH. Overall survival was calculated

from the date of hospitalization for the initial episode of AH until the date of death or the

date the patient was last known to be alive. Those undergoing LT were censored alive

at the date of transplantation. Current hospital protocols for LT consider only those

patients having >6 months of alcohol abstinence to candidates. None of the patients in

this cohort underwent "salvage liver transplantation".

Statistical Analysis

Continuous variables were described as median (25-75 interquartile range).

Categorical variables were described by means of counts and percentages.

Comparisons between groups were performed using the Student´s t-test or Mann-

Whitney U test, when appropriate. Differences between categorical variables were

assessed by the chi-square test or Fisher´s exact test, when necessary. To investigate

variables with prognostic information for long-term survival and alcohol recidivism,

those that were statistically significant (p<0.05), and those considered clinically

relevant at univariate analyses were entered into multivariate analysis. The p-values for

the univariate tests were not corrected for multiple testing, because those tests were

exploratory. The results of the multivariate logistic regression and Cox regression

analyses (odds ratios -OR- and hazard ratios –HR-, respectively) determined those

variables independently associated with the main outcomes survival and recidivism

(after adjusting for the contributions of other variables). In order to avoid co-linearity,

those variables included in a prognostic score (e.g. ABIC score and MELD score) were

not included separately in the multivariate models. To avoid over-fitting, a pre-defined

ratio of candidate prognostic variables to the number of observed events (eg. deaths or

alcohol recidivism [y/n]) was set at 1:10. In order to evaluate the influence of

abstinence in long-term survival, comparative risk analysis using the Kaplan-Meier

method compared by the log-rank test was performed. The SPSS statistical package

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(SPSS Inc., version 15.0, Chicago, IL.) was used for all analyses. A p-value <0.05 was

required for significance. Finally, to evaluate the interaction of variables independently

associated with alcohol recidivism after an index episode of AH a classification and

regression tree (CART) analysis was performed. We used the CART Pro v6.0 software

(Salford systems, San Diego, CA), based on the original Breinman´s code. See

Supplementary Data for detailed explanation on CART analysis.

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RESULTS

Clinical Characteristics of the Study Cohort

One hundred and sixty two patients comprised the original cohort admitted for AH, with

one hundred forty two patients surviving index hospitalization of AH and finally included

in this study. Study participants were predominantly male (69%) and the median age at

admission was 50 years. Almost one-third of patients (30%) had a psychiatric

comorbidity, predominantly depression, however some patients had anxiety and/or

personality disorders. Median reported daily alcohol intake at time of admission was

100 g/day (25-75 IQR: 80-130 g/day). Most patients were long-time drinkers and 28 out

of 142 (20%) of patients reported over twenty daily alcoholic drinks. From the whole

cohort, 46% patients had previously been diagnosed with liver disease and 81% were

cirrhotic at admission. Patients had severe liver disease on presentation, with a median

MELD of 16, Maddrey DF of 35 and ABIC score of 7.2. As expected, total median

bilirubin was elevated at admission (7 mg/dL), AST was elevated and median AST/ALT

ratio at admission was 2.7. Median platelet count was 120 x 109/L and median INR

1.57. The majority of patients presented with jaundice, hepatomegaly, ascites and

edema. Infection at admission was present in 18% of patients and 30% of patients

developed an infection during the index hospitalization. Fifteen percent of patients

developed acute kidney injury (AKI, according to AKIN criteria2) during admission,

10.6%, and 17% of patients required admission to the intensive care unit. Clinical,

demographic and biochemical data at admission are shown in Supplementary Table 2.

Factors Associated with Long-Term Survival after Index Admission

Overall, median follow-up was 55 months (IQR 17-84 months). At the end of follow up,

62% of the patients were alive (n= 88) and 38% were deceased (n= 54). The specific

cause of death during follow-up was obtained in 95% of the 54 deceased patients.

Main causes of death were liver related causes in 47 patients (80%), non-liver related

in 11 (15%) and unknown in 3 (4%). From liver-unrelated death, 3 patients had an

upper aerodigestive tract cancer, 4 lethal cardiovascular events and 1 perforated

appendicitis. Patients deceased at follow-up were older at baseline, median age of 52

years compared to 48 years in those alive at follow-up (p<0.05). Gender was

associated with survival and of those deceased at follow-up, 80% were men compared

to 62% of those alive at follow-up (p=0.02). Importantly, a higher proportion of those

deceased at follow-up had a long duration of heavy drinking (>11 years)(Table 1)

There were no significant differences in the number of patients with psychiatric

comorbidities or current smokers or cirrhosis when comparing those alive vs. deceased

at follow-up. Importantly, complete abstinence after the index admission was

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associated with better survival. Of those alive at follow-up, 55% had resumed active

drinking, compared to 70% of those deceased at follow-up.

In order to explore those factors associated with long-term survival we conducted

univariate and multivariate Cox survival analyses. In univariate analysis, age (p=0.01),

gender (p=0.02), duration of heavy drinking ≥25 years (p=0.01), INR (p=0.004),

baseline ABIC score (p=0.001), MELD score (p=0.03), and presence of liver

decompensations during follow-up (p<0.001) were associated with poor survival.

Conversely, WBC (p=0.03) and complete abstinence (p=0.03) were associated with

improved long-term survival (Table 2). After adjusting for all variables by univariate

analysis and stratifying by the presence of decompensations during follow-up, 2

multivariate Cox survival models were fitted. On separate multivariate analyses,

baseline ABIC score with complete abstinence, and age along with baseline MELD and

complete abstinence, were independently associated with long-term survival (Table 3).

Finally, we analyzed the subset of patients with a serum bilirubin >4.7 mg/dL at

admission (n=88), confirming that complete abstinence was the main factor influencing

long-term survival (Supplementary Tables 3, 4 and 5).

Impact of Alcohol Abstinence on Long-Term Survival

We next compared the impact of alcohol recidivism on long-term survival. The overall

mortality of patients with alcohol recidivism vs those that remain completely abstinent

was 44% vs. 29% (p=0.06), respectively. The Kaplan-Meier analysis shows that the

presence of alcohol recidivism after an episode of AH negatively influenced long-term

survival (Figure 1). As expected, the median follow-up of patients with alcohol

recidivism was significantly shorter when compared with those completely abstinent

(46 vs 63 months; p=0.008). When analyzing time frames, we did not found significant

differences on survival between abstinent and patients that recidivate at 3, 6 and 12

months of follow-up (p>0.05, for all cases). However, differences in survival became

significant after 18 months of follow-up (p=0.045; Supplementary Figure 1). Finally,

36% of patients with complete abstinence presented at least 1 liver decompensation

requiring admission during follow-up, compared with 58% of patients with alcohol

recidivism (p=0.009, Supplementary Figure 2).

Factors Influencing Long-Term Abstinence after the Index Admission.

Based on our criteria to define recidivism (see Methods), 60% were considered

recidivists during the follow-up. Recidivist patients were younger at admission (47 vs

51 years; p=0.004), reported a higher number of daily drinks (p=0.03) and more prior

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alcoholism treatments before the index hospitalization (p=0.006) (Table 4). Importantly,

patients that achieved complete abstinence during follow-up had a lower median

HRAR scale (2 vs 3 points; p=0.007). However, when comparing the proportion of

patients with HRAR scale >3 points (e.g. high risk for alcohol recidivism) at baseline

between the 2 groups, no significant differences were found (p=0.08). In addition, there

were no significant differences in the proportion of smokers, presence and type of

psychiatric comorbidity and baseline MELD score when comparing abstinent patients

vs. those that reported recidivism. We found a significantly higher baseline ABIC score

among abstinent patients (p=0.009). However, we found that this difference was

related to the inclusion of age as a variable of the ABIC scoring system. Time to

recidivism was available for 120 patients; 62 (52%) recidivated 1 year after the index

episode and 85 (71%) after 24 months.

In order to identify factors associated with long-term abstinence, we next performed

univariate and multivariate logistic regression analyses including variables obtained at

the index hospitalization. In univariate analysis, age (p=0.005), number of daily drinks

≥11 (p=0.02), no prior alcoholism treatments (p=0.007), HRAR scale (p=0.006) and

ABIC score (p=0.01) were associated with complete abstinence during follow-up.

Importantly, when categorizing HRAR scale we did not find any significant association

with long-term abstinence. This last finding likely reflects the lack of associative effect

of one of the parameters included in this scale (e.g. duration of heavy drinking) with

long-term abstinence (Table 5). After including variables significant after univariate

analysis and adjusting for baseline liver function (e.g. baseline ABIC and MELD

scores), 4 multivariate logistic regression models for predict abstinence were fitted. On

multivariate models, only age and lack of prior alcoholism treatments were

independently associated with long-term abstinence (Table 6). We also analyzed the

subset of patients with serum bilirubin >4.7 mg/dL at admission (n=88), confirming the

association of age and lack of previous alcoholism treatments with complete

abstinence (Supplementary Tables 6, 7 and 8).

Finally, in order to evaluate the interactions between the two significant variables and

aiming to generate a more intuitive and practical model for accurate prediction of long-

term abstinence, we fitted a CART model. The generated decision tree discriminated

two sub-populations with different rates of long-term abstinence: a high-rate abstinence

group (65% complete abstinence rate at follow-up) composed by those patients without

history of prior alcoholism treatments and greater than 48 years old at baseline and a

low-rate abstinence group (26-29% complete abstinence rate at complete follow-up)

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composed by those with prior alcoholism treatments and those without prior alcoholism

treatments but 48 years old or less (Figure 2). This CART model showed good

usefulness estimated by an AUROC of 0.71.

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DISCUSSION

Most clinical and translational research on AH focuses on short-term prognosis,

while studies assessing the main determinants of long-term prognosis are scarce.

Based on our clinical experience, we hypothesized that the alcohol drinking status

heavily determines the long-term outcome of patients surviving an episode of AH. We

followed-up a cohort of well characterized biopsy-proven cohort of patients with AH for

4.6 years. We confirmed that the main parameter influencing mortality in the long term

was resuming alcohol consumption. Interestingly, we found that alcohol recidivism after

the index episode of AH strongly predicted survival. Whether the pattern of drinking or

occasional drinking (i.e. “slips”) also influence survival was not assessed in our study

and deserves further investigation. Likewise, the prognostic value of previous

admissions to hospitalization and parameters at discharge have not been assessed in

this study. Other scoring systems such as the alcoholic hepatitis histological score or

the presence of systemic inflammatory response syndrome predicted short-term

survival in our series of patients with AH4,24, but not alcohol relapse or long-term

survival, indicating that parameters from the index hospitalization other than age, do

not play a role in the long-term outcome of patients surviving an episode of AH. Larger

studies should investigate if genetic factors or ethnicity (given that 95% of our cohort

was Caucasian) influence the deleterious effects of alcohol intake on long-term

outcome.

Our results strongly indicate that maneuvers aimed at promoting alcohol

abstinence should be initiated as early as possible in patients hospitalized with AH.

Ideally, multidisciplinary teams including addiction therapists should contribute in the

integral treatment of these patients. According to previous research, alcohol recidivism

prevention in patients with cirrhosis caused by ALD depends on multidisciplinary

collaboration including psychological treatment based on Cognitive-Behavior Therapy

(CBT), Motivational Enhancement Therapy (MET), Comprehensive Medical Care

(CMC) and pharmacological treatments. 29-32 In addition, a recent open-label study

using baclofen (a GABA receptor agonist) seems promising in the prevention of alcohol

recidivism of patients with AH 33. Other psychological treatments (e.g. CBT, MET, CMC

or their combination) have not been prospectively evaluated for abstinence

maintenance in the treatment of patients with AH.

Besides determining the key role for alcohol consumption in the outcome of these

patients, our study attempted to identify factors that predict alcohol recidivism. In our

center, addiction specialists assess all patients during the index hospitalization as part

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of the clinical protocol. We routinely collect data on the type and amount of alcohol

consumption and previous detoxification attempts. These parameters are included in

the HRAR score, which was initially designed to predict the recidivism in patients

undergoing a liver transplantation. We have also data on smoking status and use of

illicit drugs, however employment status and other psychosocial variables were not

collected. Interestingly, we found that neither the amount of daily consumption nor the

duration of alcohol intake, current smoking status and use of illicit drugs predicted

recidivism in patients that survive an episode of AH. This can be partially explained

because all these patients were heavy drinkers (defined as > 60 g / day) constituting a

homogeneous sample with only slight differences in daily amount of alcohol intake

(IQR 80-130 and < 20% taking > 20 SDU) which do not allow predict any change in the

recidivism risk in this population. In contrast, age and previous detoxification attempts

heavily predicted alcohol recidivism. By combining these two parameters we were able

to build a simple algorithm to identify patients with high and low risk of recidivism. In

this study we found that age greater than 48 years was associated with higher rate of

abstinence, which goes in line with previous literature. In previous studies, age has

been inversely associated with lower response to alcohol treatment because of lack of

adherence, and was also inversely associated with more relapse in alcohol use

disorders (AUD)34. The reason for this might be the presence of higher craving in

younger people. In fact, there are studies demonstrating that some anticraving drugs

such as ondansertron were successfully tested in adolescents and adults with early-

onset of AUD, being ineffective in adults with late-onset AUD35-36. In this context, it

seems that two types of alcoholism exist according to age, and craving plays a role as

mediator. Finally, age at onset is an essential element to differentiate two types of

alcoholism according to the classical classification of Cloninger37. However, a

physiological explanation of increased craving in young alcohol dependants is still

lacking; further prospective studies in patients with AH, taking into account craving,

tools for craving assessment, and other psychological phenomena, are required.

With regards to the importance of previous AUD treatments, our algorithm shows

that those patients with previous AUD treatments had a higher risk for long-term

alcohol recidivism. Previous literature has shown that the probability of success of any

given treatment decreases with each previous failures38. This means that the patient’s

expectancy to achieve treatment goals decreases as the number of treatments

increases, suggesting an altered role in self-efficacy39-40.

Of note, our study was done in the Barcelona area and it is well know that

alcohol consumption varies among different geographical areas and is influenced by

socioeconomic and cultural factors. Traditionally, two cultural patterns have been

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proposed: 1) that based on binge drinking (e.g UK or Ireland with > 30% prevalence of

heavy episodic drinkers among drinkers vs <20% in Sourthern countries such us Spain

or Italy) and 2) the regular drinking pattern (mainly seen in Southern Europe). Although

these patterns are quickly evolving due to globalization, our predicting algorithm should

be externally validated in these two populations.

This study has important clinical and research implications. First, it highlights

the crucial role of alcohol consumption in the long-term prognosis of this disease.

Specialized liver centers should prioritize early interventions and close follow-up of

these patients to assist in the alcohol use disorder. Second, it suggests that any clinical

trial assessing the impact of medications on long-term survival after an episode of

alcoholic hepatitis should take into account the presence/absence of alcohol

consumption. This is important since medications aimed at improving liver function

could also affect alcohol behavior. This is a topic of recent interest in the field of alcohol

addiction since experimental and human data suggest that systemic inflammation

could play a role in alcohol use disorder (both in the etiology and prognosis)41-42.

Whether this link is present in patients with AH deserves future translational studies.

Finally, the identification of those with higher risk of recidivism might allow for testing

and implementation of specific pharmacological strategies to promote abstinence

during the follow-up of these patients.

In conclusion, the current study investigates the main determinants of long-term

prognosis in patients with biopsy-proven AH. We found that continued alcohol

consumption is associated with a poorer long-term survival after an episode of AH,

which has important implications in the management of these patients. Moreover, we

developed a simple algorithm capable of identifying patients with low and high risk of

alcohol recidivism. Future prospective studies including patients with more severe AH

should validate this system and, most importantly, test pharmacological and

psychological interventions to promote alcohol abstinence among these patients.

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FIGURE LEGENDS

FIGURE 1. Impact of Complete Alcohol Abstinence on Long-term Survival of

Patients that Survive an Episode of Alcoholic Hepatitis.

The Kaplan-Meier analysis shows that the presence of alcohol recidivism after an

episode of AH negatively influenced long-term survival

FIGURE 2. Prognostic Algorithm for Complete Abstinence Prediction on Long-

term Follow-up of Patients that Survived an Episode of AH.

The CART analysis discriminated two sub-populations: 1) a high-rate abstinence group

(65% complete abstinence rate at complete follow-up) including those patients without

prior alcoholism treatments and older than 48 years old and 2) a low-rate abstinence

group (26-29% complete abstinence rate at complete follow-up) composed by those

with prior alcoholism treatments and those without prior alcoholism treatments but

younger than 48 years old.

Page 17 of 43

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18

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Table 1. Baseline Characteristics of Patients with Alcoholic Hepatitis, Stratified by Outcome after

Index Hospitalization (n=142).

Variable Alive

n=88

Deceased

n=54 p value

Clinical and epidemiological variables

Age (years) 48 (40-53) 52 (47-57) 0.014

Gender (male) 62.5 (55) 79.6 (43) 0.032

Alcohol intake at admission (grams/day) 100 (80-130) 100 (80-130) 0.476

Duration of heavy drinking

≤11 years

12-24 years

≥25 years

19.3 (17)

64.8 (57)

15.9 (14)

3.7 (2)

70.4 (38)

25.9 (14)

0.019

Active smoking 67.0 (59) 74.1 (40) 0.442

Psychiatric comorbidity 27.3 (24) 33.3 (18) 0.486

Cirrhosis 78.4 (69) 85.2 (46) 0.318

Follow-up (months) 66 (46-99) 14 (6-50) <0.001

Biochemical variables at admission

Hemoglobin (g/dL) 11.2 (8.9-12.3) 11.1 (9.7-12.6) 0.552

WBC (x109/L) 8.7 (6.4-13.2) 7.8 (5.0-12.5) 0.091

Platelets (x109/L) 136 (86-213) 103 (56-167) 0.156

Creatinine (mg/dL) 0.8 (0.6-1.0) 0.8 (0.7-1.0) 0.520

Bilirubin (mg/dL) 6.6 (2.6-13.6) 8.8 (4.1-16.5) 0.384

AST (IU/L) 119 (78-172) 138 (92-202) 0.771

ALT (IU/L) 41 (31-57) 52 (36-73) 0.457

GGT (IU/L) 379 (149-799) 394 (166-655) 0.615

Albumin (g/L) 27 (23-30) 26 (23.5-31) 0.765

INR 1.56 (1.33-1.74) 1.63 (1.43-1.90) 0.180

Sodium (mEq/L) 134 (130-137) 134 (131-137) 0.561

Scoring systems

Baseline ABIC 7.02(5.94-8.04) 7.48 (6.85-8.48) 0.014

Baseline MELD 14.4 (9.8-20.9) 17.5 (13.5-22.1) 0.122 Data shown as median(interquartile range) or %(n). WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine

aminotransferase; GGT, gamma glutamyl transpeptidase; INR, international normalized ratio; ABIC, age, serum bilirubin,

INR and serium creatinine score; MELD, model for end-stage liver disease score. Psychiatric comorbidity defined as the

presence of at least one of the following: depressive syndrome, anxiety disorder, bipolar disorder, type A or B cluster

personality disorder.

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Table 2. Univariate Analysis of Variables Associated with Survival after Index Hospitalization in

Patients with Alcoholic Hepatitis.

Variable HR 95% CI p value

Clinical and epidemiological variables

Age (years) 1.04 1.00 – 1.10 0.014

Gender (male) 2.13 1.10 – 4.16 0.026

Alcohol intake at admission (grams/day) 1.00 0.99 – 1.00 0.716


≤11 years

12-24 years

≥25 years

Ref

3.94

6.03

-

0.95 – 16.32

1.36 – 26.62

-

0.059

0.018

Active smoking 1.37 0.75 – 2.51 0.310

Psychiatric comorbidity 1.12 0.64 – 1.96 0.701

Cirrhosis 0.97 0.75 – 1.26 0.820


Hemoglobin (g/dL) 1.02 0.92 – 1.14 0.679

WBC (x109/L) 0.94 0.88 – 1.00 0.036

Platelets (x109/L) 0.99 0.99 – 1.00 0.134

Creatinine (mg/dL) 0.99 0.73 – 1.34 0.926

Bilirubin (mg/dL) 1.02 0.99 – 1.04 0.193

AST (IU/L) 1.00 0.99 – 1.00 0.822

ALT (IU/L) 1.00 0.99 – 1.01 0.547

GGT (IU/L) 1.00 1.00 – 1.00 0.598

Albumin (g/L) 0.99 0.94 – 1.04 0.712

INR 1.39 1.11 – 1.75 0.004

Sodium (mEq/L) 0.99 0.94 – 1.04 0.682

Scoring systems at admission

Baseline ABIC 1.34 1.13 – 1.58 0.001

Baseline MELD 1.03 1.00 – 1.07 0.031

Follow-up variables

Decompensations during follow-up 4.45 2.34 – 8.49 <0.001

Complete abstinence during follow-up 0.53 0.29 – 0.95 0.034

HR, hazard ratio; 95% CI, 95% confidence interval; WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine

aminotransferase; GGT, gamma glutamyl transpeptidase; INR, international normalized ratio; ABIC, age, serum bilirubin,

INR and serium creatinine score; MELD, model for end-stage liver disease score. Psychiatric comorbidity defined as the

presence of at least one of the following: depressive syndrome, anxiety disorder, bipolar disorder, type A or B cluster

personality disorder.

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Table 3. Multivariate Cox Regression Analyses of Variables Associated with Survival after Index

Hospitalization in Patients with Alcoholic Hepatitis.

Model #1 Multivariate Cox regression analysis

HR (95% CI) p value

Baseline ABIC 1.35 (1.14 – 1.59) <0.001

Complete abstinence during follow-up 0.51 (0.27 – 0.96) 0.038

Model #2 Multivariate Cox regression analysis

HR (95% CI) p value

Age (years) 1.06 (1.02 – 1.09) 0.002

Baseline MELD 1.04 (1.01 – 1.07) 0.015

Complete abstinence during follow-up 0.43 (0.22 – 0.82) 0.011

HR, hazard ratio; 95% CI, 95% confidence interval. ABIC, age, serum bilirubin, INR and serum

creatinine score.

Variables included in Model #1 were high-risk alcoholism relapse scale, ABIC at admission,

abstinence during follow-up, gender and white blood cell count. Variables included in Model #2 were

high-risk alcoholism relapse scale, MELD at admission, age, abstinence during follow-up, gender and

white blood cell count. Analysis was stratified by the presence of decompensations during follow-up

for both models.

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Table 4. Baseline Characteristics of Patients with Alcoholic Hepatitis, Stratified by Abstinence

during Follow-up (n=142).

Variable Complete Abstinence

n=56

Alcohol Recidivism

n=86 p value

Clinical, epidemiological and psychiatric variables

Age (years) 51 (47 – 56) 47 (41 – 54) 0.004

Male gender 66.1 (37) 70.9 (61) 0.541

Follow-up (months) 63 (37-104) 46 (14-71) 0.008


≤11 years

12-24 years

≥25 years

16.1 (9)

66.1 (37)

17.9 (19)

11.6 (10)

67.4 (58)

20.9 (18)

0.446

Number of daily drinks

≤11

12-19

≥20

39.3 (22)

44.6 (25)

16.1 (9)

20.9 (18)

57 (49)

22.1 (19)

0.039

Prior alcoholism treatments

0

1

>1

73.2 (41)

19.6 (11)

7.1 (4)

50 (43)

31.4 (27)

18.6 (16)

0.006

HRAR 2 (1 - 3) 3 (2 - 4) 0.007

HRAR

0-2

3-4

5-6

62.5 (35)

32.1 (18)

5.4 (3)

46.5 (40)

41.9 (36)

11.6 (10)

0.049

HRAR (>3 points) 9 (16) 26 (30) 0.08

Active smoking 66.1 (37) 72.1 (62) 0.445

Psychiatric comorbidity 30.4 (17) 30.2 (26) 0.987

Type of psychiatric comorbidity (n=43)

Anxiety and depression

Personality disorders

82.4 (14)

17.6 (3)

73.1 (19)

26.9 (7)

0.714

0.714


Haemoglobin (g/dL) 11.2(9.2-12.8) 11.2(9.1-12.4) 0.214

WBC (x109/L) 8.7(6.4-13.2) 8.4(6.1-12.8) 0.687

Platelets (x109/L) 134(84-204) 115(69-181) 0.528

Creatinine (mg/dL) 0.80(0.62-1.00) 0.80(0.60-0.96) 0.991

Bilirubin (mg/dL) 8.0(3.1-15.0) 6.1(3.0-10.9) 0.161

AST (IU/L) 117(82-175) 132(85-195) 0.359

ALT (IU/L) 45(32-57) 46(33-67) 0.259

GGT (IU/L) 376(147-671) 432(162-834) 0.253

Albumin (g/L) 26(24-30) 27(23-31) 0.800

INR 1.59(1.41-1.89) 1.57(1.35-1.80) 0.897

Sodium (mEq/L) 134(130-137) 135(131-137) 0.882


Baseline ABIC 7.69 (6.76 – 8.74) 7.03 (6.09 – 7.81) 0.009

Baseline MELD 17.87 (12.53 – 22.28) 15.38 (10.35 – 20.77) 0.450 Data shown as median(interquartile range) or %(n). 1 daily drink = 10 grams of alcohol. Alcoholism treatments refer to any outpatient or inpatient

treatment for alcoholism. HRAR, high-risk alcoholism relapse scale; ABIC, age, serum bilirubin, INR and serium creatinine score; MELD, model

for end-stage liver disease score. Psychiatric comorbidity defined as the presence of at least one of the following: depressive syndrome, anxiety

disorder, bipolar disorder, type A or B cluster personality disorder.

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Table 5. Univariate Logistic Regression Analysis of Variables Associated with Alcohol Recidivism

in Patients with Alcoholic Hepatitis.

Variable OR 95% CI p value

Clinical, epidemiological and psychiatric variables

Age (years) 0.94 0.90 – 0.98 0.005

Male gender 1.25 0.61 – 2.58 0.541


≤11 years

12-24 years

≥25 years

Ref

1.41

1.62

-

0.52 – 3.80

0.49 – 5.31

-

0.496

0.426


≤11

12-19

≥20

Ref

2.40

2.58

-

1.09 – 5.27

0.94 – 7.07

-

0.030

0.065

Number of daily drinks (≥11 daily drinks) 2.44 1.16 – 5.16 0.019

Prior alcoholism treatments

0

1

>1

Ref

2.34

3.81

-

1.03 – 5.32

1.18 – 12.37

-

0.042

0.026

Prior alcoholism treatments (≥ 1 treatment) 2.73 1.32 – 5.66 0.007

HRAR (points) 1.46 1.12 – 1.91 0.006

HRAR (points)

0-2

3-4

5-6

Ref

1.75

2.92

-

0.85 – 3.61

0.74 – 11.45

-

0.130

0.125

Modified HRAR (>3 points) 2.26 0.97 – 5.29 0.06

Active smoking 1.33 0.64 – 2.74 0.446

Psychiatric comorbidity 1.08 0.52 – 2.27 0.832


Baseline ABIC 0.72 0.56 – 0.93 0.013

Baseline MELD 0.99 0.95 – 1.03 0.449 OR, odds ratio; CI, confidence interval. 1 daily drink = 10 grams of alcohol. Alcoholism treatments refer to any outpatient or

inpatient treatment for alcoholism. HRAR, high-risk alcoholism relapse scale; ABIC, age, serum bilirubin, INR and serium

creatinine score; MELD, model for end-stage liver disease score. Psychiatric comorbidity defined as the presence of at least

one of the following: depressive syndrome, anxiety disorder, bipolar disorder, type A or B cluster personality disorder.

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Table 6. Multivariate Logistic Regression Analyses of Variables Associated with Alcohol

Recidivism in Patients with Alcoholic Hepatitis.

Model #1 Multivariate logistic regression analysis

OR (95% CI) p value

Baseline ABIC 0.71 (0.54 – 0.94) 0.015


≤11

12-19

≥20

-

1.97 (0.86 – 4.52)

1.59 (0.53 – 4.75)

0.275

0.108

0.404

Number of prior alcohol treatments

0

1

>1

-

2.23 (0.93 – 5.32)

3.90 (1.14 – 13.37)

0.038

0.072

0.030


OR (95% CI) p value

Baseline ABIC 0.72 (0.55 – 0.95) 0.019

Number of daily drinks (≥11 daily drinks) 1.89 (0.86 – 4.17) 0.114

Number of prior alcohol treatments (≥ 1

treatment) 2.59 (1.21 – 5.57) 0.015


OR (95% CI) p value

Baseline MELD 0.98 (0.93 – 1.02) 0.257

Age (years) 0.94 (0.90 – 0.98) 0.008


≤11

12-19

≥20

-

1.99 (0.87 – 4.59)

1.75 (0.58 – 5.30)

0.263

0.105

0.322

Number of prior alcohol treatments

0

1

>1

-

2.20 (0.91 – 5.30)

3.61 (1.04 – 12.52)

0.054

0.079

0.043


OR (95% CI) p value

Baseline MELD 0.97 (0.94 – 1.02) 0.293

Age (years) 0.94 (0.90 – 0.99) 0.008

Number of daily drinks (≥11 daily drinks) 1.95 (0.88 – 4.33) 0.101

Number of prior alcohol treatments (≥ 1

treatment) 2.51 (1.16 – 5.47) 0.020

Model #1 AUROC: 0.71 (95% CI 0.63 – 0.80); Model #2 AUROC: 0.71 (95% CI 0.63 – 0.80); Model #3

AUROC: 0.71 (95% CI 0.62 – 0.80); Model #4 AUROC: 0.72 (95% CI 0.63 – 0.81).

OR, odds ratio; 95% CI, 95% confidence interval; AUROC, area under the receiving operator characteristics

curve.

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254x190mm (300 x 300 DPI)

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254x190mm (300 x 300 DPI)

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