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01.12.2019 | Research article | Ausgabe 1/2019 Open Access

BMC Gastroenterology 1/2019

Alcohol relapse and its predictors after liver transplantation for alcoholic liver disease: a systematic review and meta-analysis

Zeitschrift:
BMC Gastroenterology > Ausgabe 1/2019
Autoren:
Lancharat Chuncharunee, Noriyo Yamashiki, Ammarin Thakkinstian, Abhasnee Sobhonslidsuk
Wichtige Hinweise

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Abbreviations
ALD
Alcoholic liver disease
CI
Confidence interval
HRAR
High-Risk Alcohol Relapse
LT
Liver transplantation
OR
Odds ratio

Background

Chronic and excessive alcohol consumption is a major cause of death around the world. Regular alcohol consumption can lead to steatosis, steatohepatitis, liver cirrhosis, and hepatocellular carcinoma [ 13]. Liver transplantation (LT) is an extended treatment for end-stage liver diseases; alcoholic liver cirrhosis is the second most frequent cause for LT in the United States and in Europe [ 4]. Previous studies demonstrated that LT in ALD patients offers an equal survival rate as that in other causes of end-stage liver disease [ 5]. Furthermore, LT for severe alcoholic hepatitis has a favorable outcome and better survival than medical therapy, but non-surgical therapy remains the standard of care for patients with severe alcoholic hepatitis [ 6, 7].
The issues of recidivism and disease recurrence remain a concern in LT for alcoholic liver disease. Alcohol relapse negatively impacts outcomes including graft rejection and graft loss from poor medical compliance, post-transplant malignancy, cardiovascular diseases, alcoholic cirrhosis, and decreased long-term survival [ 811]. An abstinence period of at least 6 months before LT is a mandatory selection criterion in most liver transplant centers, but the benefit of such pre-transplant 6 month abstinence remains unclear [ 8, 12, 13]. Furthermore, there are subsequent reports indicating that an abstinence period of 6 months is not a significant predictive factor for recidivism [ 1416]. Careful evaluation of patients with alcoholic liver disease prior to liver transplantation can identify patients with a high risk of alcohol relapse. Modifying the negative factors before LT can prevent alcohol relapse and improve post-transplant survival.
Most of these studies on alcohol recidivism after LT were done in single centers and were reported as descriptive data [ 1624]. A previously published meta-analysis study of alcohol relapse after liver transplantation by Dew et al. in 2008 only included published reports on this topic up to 2004 [ 25]. Several predictive factors have been reported in the last decade [ 8, 14, 15, 25, 26]. Thus, we performed a systematic review and meta-analysis from the published literature with the following objectives: First, to pool prevalence of alcohol relapse after LT; second, to explore factors associated with alcohol relapse and pool their magnitude of effects in alcoholic liver disease patients with LT.

Methods

This meta-analysis was conducted by following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, and the review protocol was registered at PROSPERO (CRD42017052659).

Search strategy

Two investigators (L.C. and A.S.) independently conducted a search of databases via MEDLINE and SCOPUS via PubMed and Scopus search engines to identify relevant studies published up to 31 March 2018. The search terms were constructed by domains of patients, intervention/exposure, and outcome. The search strategy is outlined in Table  1. The investigators supplemented the manual reviews of article reference lists to identify studies that had not been included from the initial database search and also performed manual reviews of the relevant studies.
Table 1
Search terms and search strategy
Domain
Search term
Search strategy
P-Patient
- “Alcoholic hepatitis”
#1
- “Alcoholic liver disease”
#2
- “Alcoholic cirrhosis”
#3
- “Liver transplantation”
#4
- “Hepatic transplantation”
#5
All P
#6
#1 OR #2 OR #3 AND #4 OR #5
E-Exposure (I-intervention/C-comparator)
- Gender
#7
- Sex
#8
#9
#7 OR #8
- Age
#10
- “Marital status”
#11
- Divorced
#12
#13
#11 OR #12
- “Socioeconomic status”
#14
- Income
#15
- Education
#16
#17
#14 OR #15 OR #16
- “Alcohol dependence”
#18
- Depression
#19
- “Drug use”
#20
- “Substance use”
#21
- “Substance abuse”
#22
- substance
#23
#24
#20 OR #21 OR #22 OR #23
- Family history of alcohol
#25
- Alcohol abstinence
#26
- Alcohol cessation
#27
- Alcohol quit
#28
- Alcohol stop
#29
- Alcohol sobriety
#30
#31
#26 OR #27 OR #28 OR #29 OR #30
- Rehabilitation
#32
- High Risk Alcoholism Relapse
#33
- HRAR
#34
#35
#33 OR #34
All E
#36
#9 OR #10 OR #13 OR #17 OR #18 OR #19 OR #24 OR #25 OR #31 OR #32 OR #35
O-Outcome
- Alcohol relapse
#37
- Alcohol recurrence
#38
- Recidivism
#39
All O
#40
#37 OR #38 OR #39
Overall
 
#6 AND #36 AND #40

Study selection

Two investigators (L.C. and A.S.) determined the eligibility of each article for inclusion by screening for relevance on titles and abstracts in parallel. If an eligibility of the study was indeterminable from abstracts, then the full articles were retrieved. The kappa statistic was used to estimate the agreement between the two reviewers [ 27]. Discordant decisions between the two investigators were advanced to full-text review and resolved by consensus with the third investigator (A.T.).

Inclusion criteria

Studies were eligible if they met all of the following criteria

  • The study was an observational design including cohort, cross-sectional, or case-control study published as an original article.
  • The work studied adult patients aged over 18 years with alcoholic liver disease who underwent any type of LT.
  • Reporting any of the following outcomes: alcohol relapse or alcohol recurrence.
  • The study assessed association between alcohol relapse and any risk factor including seven domains as follows: demographic data, psychiatric conditions, socioeconomic status, family support, alcohol abstinence, rehabilitation program, and high-risk alcohol relapse (HRAR) scale [ 28].

Exclusion criteria

Studies were excluded if they met one of the below criteria:
  • Non-English articles that cannot be translated.
  • Studies with multi-organ transplantation.
  • Insufficient data for extraction.

Outcome of interest

The outcome of interest was alcohol relapse and heavy alcohol relapse in patients who underwent LT for alcoholic liver disease. We selected papers on the occurrence of alcohol relapse based on the original authors’ definition of alcohol relapse and heavy relapse and used several methods of relapse assessment such as self-reporting and collateral reporting except for biochemical testing and indirect measures. In general, alcohol relapse was defined as any alcohol consumption post-transplantation, and heavy alcohol relapse was defined as a relapse of alcohol consumption associated with significant medical or social harm [ 29].

Data extraction

Data obtained from each study was independently extracted by two reviewers (L.C. and A.S.) using a standardized extraction form. Study design, details of the publication, the number of subjects, and baseline characteristics of study populations were extracted including patients with alcohol relapse and predictive factors of alcohol relapse after LT.

Quality and risk of bias assessment

All selected studies were independently reviewed by two investigators (L.C. and A.S.). Disagreements between the two reviewers were resolved by consensus with the third investigator (A.T.). Quality was assessed using a Newcastle-Ottawa Scale for eligible studies including selection, exposure, and comparability of studies on the basis of the design or analysis and assessment of the outcomes (Table  2).
Table 2
Newcastle-Ottawa quality assessment scale of each included studies
Author
Year
S1
S2
S3
S4
C
O1
O2
O3
Starzl TE [ 30]
1988
 
   
Bird GLA [ 12]
1990
 
Kumar S [ 31]
1990
✹✹
 
Doffoel M[ 32]
1992
 
   
Knechtle SJ [ 33]
1992
 
Lucey MR [ 34]
1992
✹✹
Berlakovich GA [ 35]
1994
 
Howard L [ 36]
1994
 
Osorio RW [ 37]
1994
✹✹
 
Gerhardt TC [ 38]
1996
✹✹
 
Tringali RA [ 39]
1996
✹✹
 
Tripp LE [ 40]
1996
 
   
Zibari GB [ 41]
1996
 
Anand AC [ 42]
1997
 
Coffman KL [ 43]
1997
 
   
Everson G [ 44]
1997
   
Foster PF [ 24]
1997
Lucey MR [ 45]
1997
Reeck UH [ 46]
1997
 
     
Shakil AO [ 47]
1997
 
   
Stefanini GF [ 48]
1997
 
   
DiMartini A [ 49]
1998
 
     
Fabrega E [ 50]
1998
 
Heinemann A [ 51]
1998
 
Tang H [ 52]
1998
 
✹✹
   
Conjeevaram HS [ 53]
1999
✹✹
 
Gledhill J [ 54]
1999
 
Newton SE [ 55]
1999
 
     
Pageaux GP [ 18]
1999
✹✹
 
Romano DR [ 56]
1999
 
Abosh D [ 57]
2000
 
     
Berlakovich GA [ 58]
2000
Burra P [ 59]
2000
✹✹
 
DiMartini A [ 60]
2000
 
Jain A [ 61]
2000
✹✹
Pereira SP [ 62]
2000
 
Platz KP [ 21]
2000
 
Bellamy CO [ 63]
2001
 
DiMartini A [ 64]
2001
 
Gish RG [ 65]
2001
✹✹
Karman JF [ 66]
2001
 
   
Mackie J [ 15]
2001
✹✹
 
Tome S [ 67]
2002
 
   
Berlakovich GA [ 68]
2004
 
Jauhar S [ 14]
2004
 
✹✹
   
Miguet M [ 69]
2004
 
Björnsson E [ 20]
2005
✹✹
 
Cuadrado A [ 10]
2005
✹✹
DiMartini A [ 70]
2006
 
Hwang S [ 71]
2006
 
Kelly M [ 72]
2006
✹✹
De Gottardi A [ 29]
2007
✹✹
Dumortier J [ 73]
2007
Newton SE [ 74]
2007
 
 
 
Nickels M [ 75]
2007
 
   
Pfitzmann R [ 8]
2007
✹✹
Vieira A [ 76]
2007
 
   
Wells JT [ 77]
2007
Gedaly R [ 23]
2008
 
   
Immordino G [ 17]
2009
 
   
Tandon P [ 26]
2009
Biselli M [ 78]
2010
Chen GH [ 79]
2010
 
DiMartini A [ 80]
2010
 
Karim Z [ 81]
2010
✹✹
 
Hartl J [ 82]
2011
✹✹
 
Mathurin P [ 7]
2011
 
Schmeding M [ 9]
2011
 
Staufer K [ 83]
2011
 
Faure S [ 84]
2012
Addolorato G [ 85]
2013
✹✹
 
Deruytter E [ 86]
2013
✹✹
Kawaguchi Y [ 87]
2013
✹✹
 
Park YH [ 19]
2013
 
✹✹
 
Rice JP [ 88]
2013
 
✹✹
 
Rodrigue JR [ 89]
2013
✹✹
Egawa H [ 16]
2014
✹✹
 
Grąt M [ 90]
2014
 
 
Piano S [ 91]
2014
 
Dumortier J [ 92]
2015
Hasanin M [ 93]
2015
 
 
 
Satapathy SK [ 94]
2015
 
 
Zhou M [ 28]
2015
✹✹
 
Askgaard G [ 95]
2016
✹✹
 
Hajifathalian K [ 96]
2016
 
   
Im GY [ 97]
2016
 
✹✹
   
Kollmann D [ 98]
2016
Lee BP [ 99]
2017
✹✹
 
Onishi Y [ 100]
2017
✹✹
Wigg AJ [ 101]
2017
✹✹

Statistical analysis

The rate of alcohol relapse after LT was estimated along with its 95% confidence interval (CI) for each study. The rate was then pooled across studies using a meta-analysis for pooling proportion [ 102]. The random effect model was applied if there was heterogeneity between studies; otherwise, a fixed-effect model was applied. An odds ratio (OR) along with 95% CI of risk factor associated with alcohol relapse after LT was estimated for each study. Heterogeneity was assessed using the Cochrane Q test and the I 2 statistic. Heterogeneity was present when the Q test was significant ( p < 0.1) or I 2 ≥ 25%. The sources of heterogeneity were then explored using a meta-regression if the data of the co-variables were available. Subgroup analysis by age, region of study, definition of alcohol relapse, and follow-up time was then performed accordingly. Publication bias was assessed by Egger’s test and a funnel plot. If there was asymmetry suggested from either a funnel plot or Egger’s test, then a contour-enhanced funnel plot was used to explore whether the asymmetry was due to publication bias or heterogeneity. All analyses were performed using STATA software version 14.1. P-values < 0.05 and < 0.10 were considered statistically significant for a two-sided test and one-sided test, respectively.

Results

Search result

A total of 291 studies were identified from PubMed and Scopus databases plus 30 additional studies from the reference lists (Fig.  1). The title and abstracts were reviewed for 321 studies; 123 duplicated studies, 1 meta-analysis, and 4 systematic reviews were removed [ 25, 103106]. The remaining 193 studies were reviewed in full text excluding 101 studies. Of the remaining studies, 90 reported the proportion of alcohol relapse, and 37 studies assessed risk factors of alcohol relapse. The kappa index between the two reviewers (L.C. and A.S.) was 0.96 for data extraction, which indicated very good inter-observer agreement.

Study characteristics

Of the 90 studies reporting alcohol relapse, 86 were cohort studies (72 retrospective and 14 prospective cohorts), 2 were cross-sectional studies, and 2 were case-control studies (Table  3). Data for the 86 cohort studies were used for pooling in the incidence of alcohol relapse. Of these, 45 cohorts (40 retrospective and 5 prospective cohorts) were pooled for the proportion of heavy alcohol relapse; 37 studies (43.0%) were from North America, 40 studies (46.5%) were from Europe, 8 studies (9.3%) were from Asia-Pacific, and 1 study (0.1%) was from Brazil.
Table 3
Main characteristics of the studies included in the meta-analysis
Author
Year
Type of study
Region of study
Mean age (years)
Number of population
Number of any relapse
Number of heavy relapse
Follow-up time (months)
Starzl TE [ 30]
1988
Retrospective Cohort
US-Canada
-
35
2
-
24
Bird GL [ 12]
1990
Retrospective Cohort
Europe
-
18
4
-
-
Kumar S [ 31]
1990
Retrospective Cohort
US-Canada
48.2
52
6
2
25
Doffoel M [ 32]
1992
Retrospective Cohort
Europe
-
57
19
-
-
Knechtle SJ [ 33]
1992
Case-control
US-Canada
51
32
4
-
-
Lucey MR [ 34]
1992
Retrospective Cohort
US-Canada
44
45
5
2
15
Berlakovich GA[ 35]
1994
Retrospective Cohort
Europe
47.6
44
14
7
33
Howard L [ 36]
1994
Retrospective Cohort
Europe
50
20
19
16
34
Osorio RW [ 37]
1994
Prospective Cohort
US-Canada
47
37
7
3
21
Gerhardt TC [ 38]
1996
Retrospective Cohort
US-Canada
49
41
20
2
47
Tringali RA [ 39]
1996
Retrospective Cohort
US-Canada
47.4
58
12
10
28
Tripp LE [ 40]
1996
Retrospective Cohort
US-Canada
49
68
9
5
-
Zibari GB [ 41]
1996
Retrospective Cohort
US-Canada
47
29
2
-
-
Anand AC [ 42]
1997
Retrospective Cohort
Europe
47.5
39
5
-
25
Coffman KL [ 43]
1997
Prospective Cohort
US-Canada
-
91
18
-
-
Everson G [ 44]
1997
Retrospective Cohort
US-Canada
53
62
11
6
12
Foster PF [ 24]
1997
Retrospective Cohort
US-Canada
48.6
63
13
-
49.3
Lucey MR [ 45]
1997
Retrospective Cohort
US-Canada
46
50
17
-
63
Reeck UH [ 46]
1997
Retrospective Cohort
Europe
-
52
6
-
-
Shakil AO [ 47]
1997
Retrospective Cohort
US-Canada
41
8
3
-
-
Stefanini GF [ 48]
1997
Retrospective Cohort
Europe
47
11
3
1
48
DiMartini A [ 49]
1998
Retrospective Cohort
US-Canada
49.5
63
15
-
-
Fabrega E [ 50]
1998
Retrospective Cohort
Europe
49
44
8
-
37.8
Heinemann A [ 51]
1998
Retrospective Cohort
Europe
45.6
13
4
-
-
Tang H [ 52]
1998
Retrospective Cohort
Europe
48
56
28
9
24
Conjeevaram HS [ 53]
1999
Retrospective Cohort
US-Canada
47
68
8
8
-
Gledhill J [ 54]
1999
Retrospective Cohort
Europe
48
31
7
-
13.5
Newton SE [ 55]
1999
Retrospective Cohort
US-Canada
47
122
33
-
62
Pageaux GP [ 18]
1999
Retrospective Cohort
Europe
48.8
47
15
5
42.1
Romano DR [ 56]
1999
Case-control
Europe
47.6
152
7
-
-
Abosh D [ 57]
2000
Retrospective Cohort
US-Canada
50
10
5
5
10
Berlakovich GA [ 58]
2000
Retrospective Cohort
Europe
-
118
15
-
53.7
Burra P [ 59]
2000
Prospective Cohort
Asia Pacific
48
34
11
4
40.1
DiMartini A [ 60]
2000
Retrospective Cohort
Europe
50
72
4
1
-
Jain A [ 61]
2000
Retrospective Cohort
US-Canada
50.8
185
37
1
94
Pereira SP [ 62]
2000
Retrospective Cohort
Europe
51
56
28
15
30
Platz KP [ 21]
2000
Retrospective Cohort
Europe
-
117
30
-
-
Bellamy CO [ 63]
2001
Retrospective Cohort
US-Canada
53
123
13
-
84
DiMartini A [ 64]
2001
Prospective Cohort
US-Canada
-
36
8
-
-
Gish RG [ 65]
2001
Prospective Cohort
US-Canada
47
61
12
-
82.8
Karman JF [ 66]
2001
Retrospective Cohort
US-Canada
49
19
4
-
36
Mackie J [ 15]
2001
Retrospective Cohort
Europe
51
46
21
3
25
Tome S [ 67]
2002
Prospective Cohort
Europe
51
68
7
2
38
Berlakovich GA [ 68]
2004
Case-control
Europe
51.5
44
3
-
43.5
Jauhar S [ 14]
2004
Retrospective Cohort
US-Canada
51
11
17
15
44.1
Miguet M [ 69]
2004
Prospective Cohort
Europe
48.7
51
13
9
35.7
Björnsson E [ 20]
2005
Retrospective Cohort
Europe
53
93
32
7
31
Cuadrado A [ 10]
2005
Retrospective Cohort
Europe
48.9
54
14
14
99.2
DiMartini A [ 70]
2006
Prospective Cohort
US-Canada
49.7
167
70
43
-
Hwang S [ 71]
2006
Retrospective Cohort
US-Canada
50
15
3
-
41
Kelly M [ 72]
2006
Retrospective Cohort
Asia Pacific
50.1
90
28
18
67
De Gottardi A [ 29]
2007
Retrospective Cohort
Europe
51.3
387
46
46
61.2
Dumortier J [ 73]
2007
Retrospective Cohort
Europe
50
305
37
37
63
Newton SE [ 74]
2007
Cross sectional
US-Canada
-
18
4
-
-
Nickels M [ 75]
2007
Retrospective Cohort
US-Canada
48.8
27
8
-
23.4
Pfitzmann R [ 8]
2007
Retrospective Cohort
Europe
51.2
290
56
23
89
Vieira A [ 76]
2007
Retrospective Cohort
Other(Brazil)
47
17
2
-
29.6
Wells JT [ 77]
2007
Retrospective Cohort
Europe
50.3
148
24
20
90.5
Gedaly R [ 23]
2008
Retrospective Cohort
US-Canada
52
142
27
-
41.2
Immordino G [ 17]
2009
Retrospective Cohort
US-Canada
53.2
110
13
-
-
Tandon P [ 26]
2009
Retrospective Cohort
US-Canada
52
171
41
22
64.8
Biselli M [ 78]
2010
Retrospective Cohort
Europe
48
49
13
3
58
Chen GH [ 79]
2010
Retrospective Cohort
Asia Pacific
52.8
16
1
-
32.4
DiMartini A [ 80]
2010
Prospective Cohort
US-Canada
52
208
95
-
-
Karim Z [ 81]
2010
Retrospective Cohort
US-Canada
50.5
80
8
8
-
Hartl J [ 82]
2011
Retrospective Cohort
Europe
52.5
109
17
-
31
Mathurin P [ 7]
2011
Prospective Cohort
Europe
47.4
26
3
2
20
Schmeding M [ 9]
2011
Retrospective Cohort
Europe
48.9
271
73
73
-
Staufer K [ 83]
2011
Prospective Cohort
Europe
53.5
141
28
-
-
Faure S [ 84]
2012
Retrospective Cohort
Europe
51
206
90
50
81.7
Addolorato G [ 85]
2013
Retrospective Cohort
Europe
49.4
92
22
-
-
Deruytter E [ 86]
2013
Retrospective Cohort
Europe
56
108
31
17
55
Kawaguchi Y [ 87]
2013
Retrospective Cohort
Asia Pacific
52
13
1
-
38
Park YH [ 19]
2013
Retrospective Cohort
Asia Pacific
52
18
3
2
57
Rice JP [ 88]
2013
Retrospective Cohort
US-Canada
49.3
300
48
16
82
Rodrigue JR [ 107]
2013
Retrospective Cohort
US-Canada
55
118
40
12
55
Egawa H [ 16]
2014
Retrospective Cohort
Asia Pacific
35
140
32
21
44
Grąt M [ 90]
2014
Retrospective Cohort
Europe
46
66
22
-
88.8
Piano S [ 91]
2014
Prospective Cohort
Europe
60
23
5
-
-
Dumortier J [ 92]
2015
Retrospective Cohort
Europe
47.2
712
128
128
63
Hasanin M [ 93]
2015
Cross-sectional
US-Canada
-
45
8
-
-
Satapathy SK [ 94]
2015
Retrospective Cohort
US-Canada
54
148
16
16
112.8
Zhou M [ 28]
2015
Retrospective Cohort
US-Canada
54.2
35
6
-
-
Askgaard G [ 95]
2016
Retrospective Cohort
Europe
54
156
35
35
-
Hajifathalian K [ 96]
2016
Prospective Cohort
Europe
56
19
4
-
40.8
Im GY [ 97]
2016
Retrospective Cohort
US-Canada
41
9
2
1
24.5
Kollmann D [ 98]
2016
Retrospective Cohort
Europe
-
382
16
-
73
Lee BP [ 99]
2017
Retrospective Cohort
US-Canada
51.4
31
11
7
19.2
Onishi Y [ 100]
2017
Retrospective Cohort
Asia Pacific
46
7
1
-
60
Wigg AJ [ 101]
2017
Retrospective Cohort
Asia Pacific
50
87
18
14
52

The incidence of alcohol relapse

The characteristics of the studies and the data on alcohol relapse rates are detailed in Table  3. A total of 86 cohort studies with 8061 patients reported incidences of alcohol relapse at any time after LT. The mean age of patients ranged from 35 to 60 years, and the mean follow-up time was 10 to 112 months. The alcohol relapse rate varied across studies with a range of 4 to 95% with an I 2 of 90.7%. A random effect model was applied and yielded the pooled alcohol relapse rate of 22% (95% CI: 19–25%) during the mean follow-up time of 48.4 ± 24.7 months. The rate of heavy alcohol relapse varied markedly across studies with an I 2 of 85% and pooled rate of 14% (95%CI: 12–16%).

Pooled risk factors of alcohol relapse

The effects of all of the risk factors on alcohol relapse after LT that were classified by demographic, risk behavior, social, and comorbidity factors; these were pooled in 37 cohort studies (Table  4). The results of pooling these effects are summarized in Table  5. The results showed that psychiatric comorbidities, pre-transplant abstinence less than 6 months, being unmarried, and smoking were significantly associated with alcohol relapse after LT with corresponding pooled ORs of 3.46 (95% CI: 1.87–6.39), 2.76 (95%CI: 2.10–3.61), 1.84 (95%CI: 1.39–2.43), and 1.72 (95%CI: 1.21–2.46), respectively. In addition, the I 2 ranged from 0 to 40.6%, with the highest I 2 in psychiatric comorbidities.
Table 4
Summary of the included studies reported risk factors in the meta-analysis
Author
Year
Demographic factors
Risk behavior factors
Social factors
Comorbidity
Kumar S [ 31]
1990
-
-
Abstinence < 6months
-
Osorio RW [ 37]
1994
Male
Unmarried
Unemployed
Substance use
Abstinence < 6months
Rehabilitation
Psychiatric disease
Gerhardt TC [ 38]
1996
-
-
Abstinence < 6months
-
Tringali RA [ 39]
1996
-
-
Abstinence < 6months
-
Foster PF [ 24]
1997
Family history of alcohol use
Substance use
Abstinence < 6months
Rehabilitation
-
Lucey MR [ 45]
1997
Male
-
Abstinence < 6months
-
Shakil AO [ 47]
1997
Male
-
-
-
Tang H [ 52]
1998
Male
-
-
-
Conjeevaram HS [ 53]
1999
Male
-
-
-
Newton SE [ 55]
1999
-
Substance use
-
-
Pageaux GP [ 18]
1999
Male
Unmarried
Unemployed
-
Abstinence < 6months
-
Burra P [ 59]
2000
Unmarried
Family history of alcohol use
Substance use
Alcohol dependence
Rehabilitation
-
Jain A [ 61]
2000
-
-
Abstinence < 6months
Rehabilitation
-
Mackie J [ 15]
2001
Male
Unmarried
Lack of social support
Low SES
Family history of alcohol use
Smoking
Abstinence < 6months
-
Jauhar S [ 14]
2004
Male
Unmarried
Unemployed
Substance use
Abstinence < 6months
Rehabilitation
Psychiatric disease
Björnsson E [ 20]
2005
-
-
Rehabilitation
-
Cuadrado A [ 10]
2005
Male
-
 
-
Hwang S [ 71]
2006
-
-
Abstinence < 6months
-
Kelly M [ 72]
2006
Unmarried
Lack of social support
Unemployed
Substance use
Abstinence < 6months
Psychiatric disease
Depression
De Gottardi A [ 29]
2007
Age < 50 years
Male
Unmarried
Low SES
Unemployed
High HRAR
Abstinence < 6months
Psychiatric disease
Nickels M [ 75]
2007
Age < 50 years
Male
Alcohol dependence
-
Depression
Pfitzmann R [ 8]
2007
Age < 50 years
Male
Unmarried
-
Abstinence < 6months
-
Karim Z [ 81]
2010
Age < 50 years
Male
Unmarried
Low SES
Unemployed
Smoking
Substance use
Abstinence < 6months
Rehabilitation
Psychiatric disease
Hartl J [ 82]
2011
-
Smoking
Abstinence < 6months
Rehabilitation
-
Addolorato G [ 85]
2013
-
-
Rehabilitation
-
Deruytter E [ 86]
2013
Age < 50 years
Male
Unmarried
Unemployed
Family history of alcohol use
Smoking
Alcohol dependence
-
Psychiatric disease
Kawaguchi Y [ 87]
2013
Male
High HRAR
-
-
Park YH [ 19]
2013
Male
-
Abstinence < 6months
-
Rice JP [ 88]
2013
Male
-
-
-
Rodrigue JR [ 89]
2013
Lack of social support
Smoking
Abstinence < 6months
Rehabilitation
-
Egawa H [ 16]
2014
Male
Unmarried
Lack of social support
Unemployed
Smoking
High HRAR
Abstinence < 6months
Psychiatric disease
Zhou M [ 28]
2015
-
High HRAR
-
-
Askgaard G [ 95]
2016
Male
Unmarried
Unemployed
Family history of alcohol use
Smoking
Alcohol dependence
Abstinence < 6 months
Depression
Im GY [ 97]
2016
Male
Unmarried
Family history of alcohol use
Smoking
-
Psychiatric disease
Lee BP [ 99]
2017
Male
-
-
-
Onishi Y [ 100]
2017
Age < 50 years
Male
-
-
-
Wigg AJ [ 101]
2017
Male
Unmarried
Lack of social support
Unemployed
Family history of alcohol use
Smoking
Substance use
Rehabilitation
Psychiatric disease
Table 5
Pooled risk factors of alcohol relapse
Factors
N
OR
95%CI
Pooling method
I 2
Egger test (P-value)
Demographic factors
 Age < 50 years
6
1.16
0.43 - 3.15
Random effect
75.2
0.55
 Sex (male)
23
0.89
0.69 - 1.11
Fixed effect
21.7
0.43
 Unmarried
14
1.84
1.39 - 2.43
Fixed effect
14.6
0.57
 Lack of social support
5
1.78
0.72 - 4.38
Random effect
49.5
0.18
 Low SES
3
0.99
0.15 - 6.50
Random effect
86.3
0.28
 Unemployed
10
1.33
0.93 - 1.89
Fixed effect
7.7
0.74
 Family history of alcohol use
7
1.49
0.94 - 2.36
Fixed effect
23.0
0.50
Risk behavior factors
 Smoking
9
1.72
1.21 - 2.46
Fixed effect
0
0.69
 Substance use
8
1.06
0.48 - 2.34
Random effect
58.5
0.71
 Alcohol dependence
4
1.22
0.43 - 3.40
Random effect
61.8
0.15
 High HRAR
4
2.93
0.30 - 28.64
Random effect
79.6
0.18
Social factors
 Abstinence < 6 months
20
2.76
2.10 - 3.61
Fixed effect
18.1
0.02
 Rehabilitation program
11
1.10
0.59 - 2.04
Random effect
67
0.71
Comorbidity
 Psychiatric disease
9
3.46
1.87 - 6.39
Random effect
40.6
0.02
 Depression
3
2.13
0.49 - 9.25
Random effect
54.4
0.60
N Number, OR Odds ratio, CI Confidence interval, I 2 I 2statistics, SES Socioeconomic status, HRAR High-risk alcohol relapse scale

Subgroup analysis

Subgroup analysis by age (≤ 50 years or > 50 years), regions of studies (Europe, North America, Asia Pacific and Brazil), definition of alcohol relapse (only report or report combining with biochemical testing), and follow-up time (≤ 4 years or > 4 years) was performed to explore the potential cause of heterogeneity of pooled rates of alcohol relapse and heavy alcohol relapse. Likewise, the subgroup analysis was performed with psychiatric comorbidities to identify the factor associated with alcohol relapse with the highest risk and heterogeneity. Subgroup analyses showed no significant difference in all analyses of alcohol relapse and heavy alcohol relapse rates except for one analysis of psychiatric comorbidities. Patients with psychiatric comorbidities who had longer follow-up time (> 4 years) had an increased risk of alcohol relapse versus those with a shorter follow-up time (≤ 4 years) (Fig.  2).

Publication bias

The Egger test showed no evidence of publication bias among the studies, and the shape of the funnel plots was symmetrical in all analyses except for psychiatric comorbidities (Fig.  3) and abstinence less than 6 months (Fig.  4). The studies that reported less than 6 months of abstinence were both non-significant and significant leading to a contour-enhanced funnel plot; thus, asymmetry may not be due to either publication bias or heterogeneity. The studies with negative effect of psychiatric co-morbidities and abstinence less than 6 months were not reported.

Discussion

Alcohol relapse after LT remains an ethical issue in LT for alcoholic liver disease due to its harmful and negative impacts on liver grafts. One meta-analysis and four systemic reviews of alcoholic liver disease in LT patient were published earlier [ 25, 103106]. The well-designed meta-analysis of rate and risk factors of alcohol relapse by Dew et al. in 2008 included 54 studies published between 1983 and 2005 [ 25]. A systematic review by Rustard et al. in 2015 selected only articles of the risk factors of alcohol relapse [ 103]. A systematic review by McCallum et al. in 2006 included only studies that were associated with psychosocial criteria [ 106]. Bravata et al. performed a systematic review of alcohol relapse and evaluated only the association between employment aspect and alcohol relapse [ 105]. One systematic review focused on neither alcohol relapse rate nor risk factor [ 104]. Our study is a systematic review and meta-analysis of all published studies up to 2018, which aimed to estimate post-LT alcohol relapse rate and its predictive factors. To date, the current study is the most extensive meta-analysis of alcohol relapse in LT patients.
Our study demonstrated that any alcohol relapse and heavy alcohol relapse rates were as high as 22 and 14% during the mean follow-up time of 48.4 ± 24.7 months, respectively. The literature on alcohol relapse post-transplantation has reported a wide range of alcohol relapse rates, which might be due to different definitions of alcohol relapse. Dew et al. reported that the average rate for alcohol relapse after LT was 5.6 cases per 100 patients per year for any alcohol relapse and 2.5 cases per 100 patients per year for heavy alcohol relapse [ 25]. The authors suggested that a significant proportion of patients who returned to any alcohol drinking then became heavy drinkers, which led to a significant harm to LT recipients [ 25].
In our study, the most significant risk factors of relapse were psychiatric comorbidities followed by pre-transplant alcohol abstinence less than 6 months, being unmarried, and smoking. Four of the nine studies reported that psychiatric conditions had a link with alcohol relapse [ 16, 29, 72, 81]. The finding was consistent with the previous meta-analysis [ 25]. The study identified 3 of the 12 psychosocial variables associated with any alcohol relapse: < 6 months abstinence prior to transplant, poor social support, and a family history of alcohol abuse or dependence [ 25]. We found that 9 of the 20 studies revealed that alcohol abstinence less than 6 months was associated with alcohol relapse [ 8, 18, 29, 37, 81, 82, 95, 107, 108]. Our study confirms the validity of using the 6-month rule of alcohol abstinence as a criterion for pre-transplant selection in patients with ALD; this is consistent with the previous meta-analysis study [ 25].
A systematic review of large prospective studies focusing on risk factors for alcohol relapse following LT has also suggested that a shorter length of pre-transplant sobriety was a significant predictor of alcohol relapse [ 103]. However, the 6-month rule cannot be applied in LT for patients with severe acute alcoholic hepatitis whose condition is not allowed to wait until 6 months. LT in this group of patients remains a controversial issue in many transplant centers. The current data do not suggest that LT in patients with severe alcoholic hepatitis leads to more alcohol relapse [ 109]. Therefore, 6 months of alcohol abstinence may not reliably predict post-LT alcohol relapse. Other risk factors were psychiatric comorbidities, a high score on the HRAR scale, and a diagnosis of alcohol dependence [ 103]. Scoring systems to predict alcohol relapse after LT such as HRAR and the ARRA were proposed for use, but they have never been validated by well-designed studies.
In this study, psychiatric co-morbidities and pre-transplant abstinence less than 6 months were strong predictive factors of alcohol relapse with some publication bias against negative studies. Psychiatric comorbidities were the strongest risk factor in this study but with high heterogeneity. Interestingly, subsequent subgroup analysis showed that longer follow-up times led to an increased impact of psychiatric comorbidities on any alcohol relapse. The psychiatric comorbidities defined in enrolled studies included all psychiatric conditions that could cause impaired daily functioning, i.e. anxiety, schizophrenia, and personality disorders. In this study, we analyzed three cohort studies that reported depression separately because depression is a known risk factor associated with alcoholic drinking. We found that depression was not a significant factor in alcohol relapse (OR = 3; 95%CI 0.49–9.25).
Clinical practice has changed considerably since the first studies that recruited in 1988. The differences in the definition of alcohol relapse and heavy relapse as well as a lack of objective means of documenting alcohol use in these studies are limitations. Furthermore, heavy alcohol relapse was defined only in some studies (Table  2). Including unpublished studies may solve this problem. The absence of negative studies of psychiatric co-morbidities and abstinence less than 6 months likely caused publication bias. However, this attempt cannot guarantee a reasonably low heterogeneity after including unpublished studies.

Conclusions

We demonstrated the pooled rates of any alcohol relapse and heavy alcohol relapse post-LT. Furthermore, we identified predictive factors of alcohol relapse after LT to be used during the selection process of LT candidates. With respect to the prevention of alcohol relapse post-LT, alcohol abstinence of at least 6 months, appropriate screening and care of psychiatric co-morbidities, and smoking cessation should be incorporated in pre-transplant selection and management periods. Careful selection of LT candidates and modifying pre-transplant risk factors of alcohol relapse has the potential to reduce alcohol relapse after LT.

Acknowledgments

We would like to thank the statistical team of Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital for statistical analysis assistance.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

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