Poor Outcomes after Recidivism in Living Donor Liver Transplantation for Alcohol-Related Liver Disease

Abstract

Background

Recidivism in patients who underwent liver transplantation for alcohol-related liver disease (ALD) is shown to be associated with poor survival in some studies.

Methods

Living donor liver transplantation (LDLT) recipients for ALD with at least 2 years of follow-up and history of significant alcohol relapse were included. The recipients underwent LDLT from June 2010 to December 2016, and data were analyzed until June 2019. The cohort had a median follow-up of 54 (33–78 IQR) months. Recidivism (significant alcohol intake) was defined as >21 units per week.

Results

A total of 27 of 463 (5.8%) LDLT recipients (all men), aged 43.5 ± 9.6 years, had significant alcohol intake. A liver biopsy was performed on demand in 14 patients (in the presence of raised levels of liver enzymes or jaundice). The histological diagnoses in these patients were as follows: alcoholic hepatitis in 7 (50%), alcoholic hepatitis and acute cellular rejection or chronic rejection in 4 (28.5%), cirrhosis in 2 (14.2%), and acute cellular rejection and cirrhosis in 1 (7.1%) patient. Four of 5 patients with a biopsy diagnosis of acute or chronic rejection were noncompliant with immunosuppression. Six of these patients died. The mortality after 1 year of transplant was significantly more in patients with recidivism.

Conclusion

Recidivism was associated with significant morbidity and mortality after liver transplantation.

Alcohol-related liver disease (ALD) is a common cause of end-stage liver disease and accounts for a significant proportion of patients undergoing liver transplantation (LT).^1,2 LT for ALD is associated with risk of relapse or recidivism in 10–42% of patients.³ Several studies have shown poor long-term outcomes in patients with a significant amount of alcohol intake after LT,^{3, 4, 5, 6} and these patients may have rapid development of fibrosis.^7,8 There is a scarcity of studies on outcomes of alcohol recidivism after living donor liver transplantation (LDLT). We present the clinical profile and outcomes of patients with significant post-transplant alcohol relapse (recidivism) from a high-volume LDLT center.

Methods

All consecutive patients who underwent LDLT from June 2010 to December 2016 were included, and prospectively collected data until June 2019 were retrospectively analyzed. The institute's ethics board approved the study. The diagnosis of ALD-related cirrhosis before LT was based on history of significant alcohol consumption and exclusion of other causes of cirrhosis. All patients underwent pretransplant evaluation that included psychiatric assessment and clearance. None of the patients had psychiatric contraindication to LT, and all patients had good family support. All patients were counseled regarding abstinence before and after LT. All patients had laboratory investigations at predefined intervals. History of alcohol intake was obtained from the patient and family members during hospital visits and was noted in follow-up data. Significant alcohol intake was defined as more than 21 units per week as defined by Perney et al.⁹ A diagnosis of alcoholic hepatitis was made in the presence of biochemical and histology features as suggested by Crabb et al.¹⁰ The histology diagnosis of alcoholic hepatitis was made in the presence of macrovesicular steatosis with one or more of the following features: ballooning, neutrophil infiltrates, and Mallory bodies.

Statistical Methods

Data are shown as mean (standard deviation), percentage, or median (25–75 interquartile range). The recidivism and nonrecidivism groups were compared using Fisher's exact test or the chi-square test for categorical data and Student's t test for parametric data or the Mann–Whitney test for nonparametric data. Kaplan–Meier survival curves were used to analyze the survival difference between these 2 groups. A 2-tailed P value <0.05 was considered significant.

Results

A total of 463 patients underwent LT for ALD in the study period; the mean age was 47.5 ± 9.0 years, 462 were men, and one patient was a woman. The median follow-up was 54 (33–78) months. Twenty-seven recipients provided a history of significant alcohol intake after LT. The baseline characteristics of these 27 patients and the rest of patients are shown in Table 1. There was no significant difference in the recidivism and nonrecidivism groups other than recipient age at the time of LT and duration of abstinence. The recipients in the recidivism group were younger (mean age = 43.5 ± 9.6 versus 48 ± 8.9 years, respectively, P = 0.011) and had significantly less abstinence (7 [3–11] months versus 10 [5–24] months, respectively) than those in the nonrecidivism group (P = 0.33).

Table 1.

Baseline Characteristics of Patients With or Without Significant Alcohol Intake After LT.

Parameter	Recidivism (n = 27)	Others (n = 436)	P
Age (years) at LT	43.5 ± 9.6	48.0 ± 8.9	0.01
Sex	All males	All males but one	1.0
Child's score	10.0 ± 1.7	10.0 ± 1.8	1.0
Model for End-stage Liver Disease score	20.4 ± 5.8	18.8-±5.8	0.16
Donor's age (years)	33.7 ± 9.8	34.0 ± 10.4	0.88
Genetically related versus unrelated donor	13 (48.1%)	215 (49.3%)	1.0
Combined kidney liver transplantation	0	4 (0.9%)	1.0
Abstinence before transplant (months)a	7 (3–11)	10 (5–24)	0.33

LT = liver transplantation.

^aData available for 25 patients in the recidivism group and 399 patients in the other group.

An on-demand (in the presence of raised levels of liver enzymes or jaundice) liver biopsy was performed in 14 of 27 patients in the recidivism group (Table 2). The histological diagnoses of these 14 patients were the following: alcoholic hepatitis in 7 (50%), alcoholic hepatitis and acute cellular rejection or chronic rejection in 4 (28.5%), cirrhosis in 2 (14.2%), and acute cellular rejection and cirrhosis in 1 (7.1%) patient. Four of 5 patients with a biopsy diagnosis of acute or chronic rejection were noncompliant to immunosuppression.

Table 2.

Details of Patients With Recidivism Who Underwent a Liver Biopsy.

S.No.	Age at LT (years)	LT to biopsy (months)	Biopsy report	LFTs at biopsy (bilirubin/AST/ALT/GGT/ALP)	Follow-up until June 2019 (months)
1	56	42	Alcoholic hepatitis	18.7/167/25/319/315	Died of graft failure
2	40	35	Alcoholic hepatitis	24.8/163/45/306/133	Died of graft failure
3	32	101	Cirrhosis	6.7/94/32/1334/248	Alive (1)
4	34	61	Chronic rejection, alcoholic hepatitis	2.6/427/273/1918/405	Alive (27)
5	39	19	Alcoholic hepatitis	3.3/172/80/1557/283	Alive (68)
6	42	73	Cirrhosis	5.7/153/107/811/127	Alive (3)
7	28	27	Acute cellular rejection on the background of cirrhosis	0.7/70/87/1383/134	Died owing to graft failure at 28 months of LT
8	35	54	Acute cellular rejection, alcoholic hepatitis	1.7/130/81/187/189	Alive (19)
9	38	41	Acute and chronic rejection, alcoholic hepatitis	0.6/105/102/514/101	Alive (31)
10	37	47	Alcoholic hepatitis	1.4/78/42/1276/165	Alive (23)
11	29	42	Alcoholic hepatitis	1.9/225/112/891/93	Alive (22)
12	51	16	Alcoholic hepatitis	4.8/597/231/4736/787	Alive (40)
13	30	41	Acute and chronic rejection, alcoholic hepatitis	12/65/30/298/142	Died owing to graft failure, sepsis at 53 months of LT
14	32	14	Alcoholic hepatitis	1.4/74/69/1110/264	Alive (36)

Bilirubin is expressed as mg/dl; ALP, ALT, AST, and GGT are expressed as IU/L.

ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; GGT = gamma-glutamyl transpeptidase; LT = liver transplantation; LFT = liver function test.

Mortality

A total of 100 of 436 (22.9%) patients died in the nonrecidivism group, with 79 patients in the first year and 21 after the first year. A total of 6 of 27 (22.2%) recipients died after the first year of LDLT in the recidivism group, whereas 21 of 363 (5.7%) died after the first year of LDLT in the nonrecidivism group. Overall survival was not statistically different (Figure 1). The survival curve was also analyzed after excluding the 1st year of LDLT as patients with early mortality had no chance of recidivism. The survival after the first year of LT was significantly inferior in the recidivism group (Figure 2).

Figure 1.

Survival of liver transplantation recipients for alcoholic liver disease with significant drinking versus no relapse/occasional slips (P = 0.701).

Figure 2.

Survival of liver transplantation recipients for alcoholic liver disease with significant drinking versus no relapse/occasional slips when follow-up started after the first year of transplantation (P = 0.025).

Psychiatric treatment

All patients in the recidivism group received psychiatric counseling and received acamprosate for prevention of relapse. Despite psychiatric intervention and counseling, 4 patients continued to have intermittent alcohol exposure, two of these patients died, and the other 2 showed development of cirrhosis.

Discussion

The current series shows higher morbidity and mortality in patients with significant drinking (recidivism) after LT for ALD than in those who do not relapse. LT for ALD is associated with good survival rates;¹¹ however, the long-term survival is poor in patients with recidivism, likely secondary to graft loss or de novo malignancies.^{1,2,5, 6, 7, 8} While patients with occasional alcohol intake have similar outcomes, recidivism is shown to be associated with poor survival after LT. A meta-analysis of 90 studies showed 22% alcohol relapse (95% confidence interval [CI]: 19–25%) and 14% heavy alcohol relapse (95% CI: 12–16%) at a mean follow-up of 48.4 ± 24.7 months after LT.¹² Several studies have shown poor outcomes in patients with recidivism as compared with those with no or occasional alcohol intake after undergoing LT for ALD. In the study by Pageaux et al,⁴ 10% were occasional drinkers, whereas 21% were heavy drinkers. Although the survival was not different, 3 of 7 deaths in heavy-drinker group were related to alcohol intake. Grąt et al¹³ found that alcohol relapse increased risk of death in the first five years after LT. Cuadrado et al⁵ showed that the survival in the recidivism group was 45.1% at 10 years, compared with 85.5% in the nonrecidivism group. Egawa et al¹⁴ also reported similar findings; the 10-year survival was 21.9% in the relapse group and 73.8% in the no-relapse group. Satapathy et al¹⁵ showed that survival was as 95%, 87%, and 80% in the abstinent group compared with 87%, 49%, and 49% in the recidivism group at 1, 3, and 5 years, respectively (P = 0.001). Pfitzmann et al¹⁶ showed a significantly better survival in recipients with occasional drinking than in patients with significant or abusive drinking. The meta-analysis by Rustad et al⁶ showed that patients with recidivism had higher chances of having steatohepatitis, rejection or graft failure, and mortality.

Three patients in the present study had recurrence of cirrhosis after 27, 73, and 101 months of alcohol intake, which is in contrast to development of alcoholic cirrhosis in normal persons, which requires many years of alcohol intake. Other studies have also suggested risk of significant fibrosis development even after short-term alcohol intake in patients with recidivism. Rice et al¹⁷ showed that heavy drinking was associated with significant fibrosis and allograft loss (hazard ratio = 2.57). Burra et al⁸ showed that pericellular fibrosis and fatty change on biopsy were significantly more common in patients with recidivism. A French long-term study (follow-up = 3–18 years, median = 11 years) showed severe alcohol relapse in 20% (73 of 369) of LT recipients; 18 patients had recurrence of alcoholic cirrhosis at 6 years (3–10 years after LT) and 4.5 years (2–8 years) after severe alcohol relapse. The cumulative risk of F4 fibrosis after severe relapse was 54% at 10 years.⁷ The predictors of alcohol relapse after transplantation can be divided into the following categories: less duration of pretransplant abstinence, psychiatric comorbidities (substance addiction, depression, prior rehabilitation, lack of insight that alcohol is a problem, and so on), lack of social support, and other factors (younger age, female sex, smoking, alcohol abuse in first-degree relatives, presence of young children, noncompliance with clinic visits, absence of hepatocellular carcinoma, continued engagement in social activities with alcohol present, and so on).^3,18 Patients with multiple factors remain at higher risk of alcohol relapse, as shown by risk scores.¹⁹ An active involvement by a psychiatrist may help in decreasing risk of alcohol relapse.^{20, 21, 22, 23} Rodrigue et al²⁰ showed that patients with history of substance abuse treatment before and after LT had lower alcohol relapse (16%) than patients without treatment (41%) or pretransplant treatment only (45%). Attilia et al²¹ showed that adoption of a multidisciplinary support program decreased alcohol relapse. Sixty-nine patients underwent support program, and 8.7% presented with alcohol relapse. A shorter time on multidisciplinary support, alcohol withdrawal syndrome, and female gender were risk factors for relapse. The rate of relapse was significantly higher in a historical group without multidisciplinary support (subdistributional hazards = 0.21).²¹ Egawa et al¹⁴ found that noncompliance to clinical visits was associated with alcohol relapse; thus, multidisciplinary support and frequent visits to the transplant team may help in decreasing relapse.

This is the first Indian study describing post-transplant outcomes of patients with ALD who have significant alcohol relapse, in a predominantly LDLT series. The strength of the study is a large sample size with a long follow-up after LT. The limitations include the study being retrospective in nature and significant alcohol intake defined by patients/relatives; thus, it is possible that some patients with recidivism may have been missed. In addition, occasional slips were not accounted for in this study. Other limitations include the definition of significant alcohol intake as there is no universally accepted definition and various studies have considered different values as significant,²⁴ and there are no data on nicotine use before or after LT. In addition, diagnosis of recidivism was based on history and not by biochemical tests; thus, it is possible that we have missed some patients with significant alcohol intake who had normal graft functions. Although performing a liver biopsy in all recipients with recidivism to evaluate steatohepatitis and fibrosis would have led to better understanding, it cannot be recommended owing to the invasive nature and risk of complications. It is to be investigated if FibroScan is useful in such patients.

To conclude, 27 of 463 patients had history of significant alcohol intake after LT, half of these had graft dysfunction, 6 (22.2%) died, and 3 developed cirrhosis. Every effort should be made to prevent recidivism in patients who underwent transplantation for ALD. The role of proactive psychiatric intervention (before relapse) in this group should be investigated further.

CREDIT AUTHORSHIP CONTRIBUTION STATEMENT

N.S. and N.S.C. contributed to conception and helped in drafting. N.S.C. and S.W. prepared the first draft. D.G., A.R., P.B., and S.T. contributed to data and helped in draft writing. V.R. and S.M. helped in patient management and prepared the first draft. N.S., S.S., and A.S. contributed to critical revision.

Conflicts of interest

The authors have none to declare.

Acknowledgments

The authors thank Ms. Shivani Sharma (research coordinator).

Funding

None.