LDLT in ALD is associated with improved outcomes compared to other etiologies 11,12. With improved outcomes, the focus has shifted to selection, quality of life & preventing relapse. The incidence of relapse and its predisposing factors have not been thoroughly evaluated in the LDLT. In the current study, the incidence rate of post-transplant relapse was 9.85% with a median follow-up of 52 months, and sustained harmful use was seen in 1.97%. Previous studies involving LDLT, have also reported a low relapse rate compared to the DDLT cohorts2,13(Table 4). One study on direct comparison of relapse rate in LDLT versus DDLT cohorts concluded that relapse rate was lower in LDLT (13.9% and 31.7% respectively at 3 years, p = 0.013)14. The alcohol relapse rate of the current study is significantly less than the reported relapse rate in Japan and Korea ( 22.9% and 16.7% respectively)2,15 (Table 4).The reasons for the low relapse rate are multifactorial. Firstly, a major proportion of donors were first-degree relatives or spouse which was protective. Secondly, pre-transplant assessment and selection are based on willingness to abstain and the presence of good socio-family support rather than stringent abstinence criteria. Finally, at our institute, both patients and their family members are interviewed about the nature of alcoholism and the risk associated with pretransplant relapse. When high-risk behavior was found, they were subjected to regular counseling sessions and de-addiction treatment.
Table 4
Review of literature of Relapse rate in LDLT cohorts.
Author and year of Study (LDLT) | Country | No.of patients | Relapse rate | Duration of follow up | Survival | Predictors |
Kawaguchi et al; 201328 | Japan | 102 | 8% | | 91% (5 years) | -Not available |
Egawa et al; 20142 | Japan | 187 | 22.9% | 46 months | 5 yrs. @ 91.9% (abstinent) 83.3% (non-harmful relapse) 74.2% (harmful relapse) | Abstinence period Smoking Non-compliance |
Hwang et al; 200616 | South Korea | 15 | 20% | 18 months | 87.5% (5 years) | Younger age |
Ahn et al; 201417 | South Korea | 126 | 16.7% | 68 months | 85.8% (5 years) | Not available |
Chung et al; 201914 | South Korea | 129 | 25.6% | 40.6 months | | < 6 months abstinence Smoking DDLT |
Saigal et al; 201619 | India | 408 | 9.5% | 34.7 months | 88.5% (3 years) | Age 6 months abstinence |
Present Study | India | 203 | 9.8% | 52 months (median) | 82.8% (5 years) | (1) less than 3 months abstinence period, (2) history of pre-LT recidivism, absence of social support in form of spouse or partner, (3) concurrent smoking/tobacco chewing addiction, and (4) Donor degree of relation. (6) Noncompliance with medications/follow-up. |
LT – Liver transplant DDLT – Deceased donor liver transplant |
The preoperative duration of abstinence has been a highly debatable issue. The validity of the commonly used “six-month rule” in the LDLT scenario has not been thoroughly assessed. Some studies have observed no statistically significant association of post-transplant alcohol relapse with six-month abstinence2,17. On the other hand, few have found longer periods of abstinence to diminish the risk of harmful relapse2,18. In the current study, nearly one third of patients were transplanted with abstinence period of less than 6 months and 5% were transplanted with abstinence period less than 3 months. An ‘abstinence period of less than three months’ predicted relapse. This finding again emphasizes that some duration of sobriety along with other factors is crucial to prevent post LT relapse. LT in alcoholic hepatitis and Acute on chronic liver failure patients has been a contentious issue and a duration of abstinence period may not be realistic in these patients.12 LDLT offers a unique opportunity in this context and selection of patients in this situation is crucial. SAH and ACLF constituted less than 10% of our transplants performed for ALD. The relapse rate in this group of patients was 20% which is comparable to published literature for similar indications. Most of the patients in this cohort were young, which is also an important risk factor for relapse.16,19
In the current study, the incidence of relapse was less when the donation was from spouse and first-degree relatives than from second-degree relatives. One study from Japan in patients with LDLT,18 showed relapse rate was higher from donations other than spouses although the difference was not significant. Another study revealed the rates of harmful relapse were quite high when the donors were the parents or siblings versus spouses (40% and 25% versus 10% respectively)2. Hence, as per our findings and data from previous studies, it can be postulated that the spouse as a donor is a surrogate factor for good family support thereby decreasing the risk of relapse.
The presence of pre-LT relapse history demonstrates addiction psychopathology in which they have prior failed attempts at rehabilitation and thus have high chances of relapse. As a result, these patients need proper psychosocial evaluation and intervention to treat addiction at an early period. In addition, the presence of psychiatric comorbidities such as personality disorders, violent behavior & depression were one of the risk factors in this study which was initially identified in the study by DiMartini et al and later in a meta-analysis published in 200820,21. Concurrent smoking/tobacco chewing is also a risk factor for relapse as shown in this study. Similarly, in a study by Egawa et al, the relapse rate was higher for concurrent smokers compared with that of ex-smokers/nonsmokers. (22.4% v/s 5.8% at 3 years, p = 0.05)2. Co-use of smoking & alcohol is quite common as it enhances the pleasure for the user. This makes it difficult to rehabilitate these patients in view of the high alcohol relapse rate among concurrent smokers due to mutual craving22.
In the current study, half of the recipients with post-transplant relapse experienced at least one episode of allograft rejection during follow-up beyond the perioperative period (table no.3). However, tacrolimus coefficient of variation (Tac COV) was similar in both groups, suggesting that medication non-adherence was present in both the groups but patients with relapse had more tendency towards rejection due to effects of alcohol intake on graft along with inadequate serum tacrolimus levels. Previous studies have found that a COV > 0.40 is associated with an increased risk of graft rejection23. At our institute, we maintain relatively lower tacrolimus trough levels as compared to other major centers because the overall general condition of Indian patients has a higher incidence of sarcopenia and higher pre-transplant MELD score.24
We found that relapse was reported mostly after six months of liver transplant and within 12 months of LT. Studies of alcohol relapse in the post-transplant period on long-term survival show conflicting results; one study attributed alcohol relapse to poor survival, while another study did not.1,2,25Although alcohol relapse was not significantly associated with mortality in our study, this might be due to overall low incidence of relapse and only two mortalities in the relapse group to have any meaningful statistical evaluation. Furthermore, most of the recipients had a history of occasional intake rather than sustained harmful use. Our study showed good long-term outcomes with 5 years survival rate of 81.2% in patients with alcohol relapse versus the non-relapse group of 82%. It could be attributed to early intervention in the form of regular counseling & anti-craving measures which prevented further episodes of relapse and associated complications.
The constraints of this study were assessment of relapse was based on self-reporting by patients which could underestimate the incidence of alcoholic relapse. The exact timing of alcohol relapse was difficult to detect, so the time to relapse was based on patients' confessions or details obtained from close relatives. We tried to detect relapse objectively by using blood ethyl glucuronide testing which can detect up to 48–72 hours of alcohol binge. However, in view of most of the relapse was of occasional intake type rather than harmful relapse, this objective testing could grossly underestimate the true incidence of relapse and hence was abandoned. While studies have shown that testing other alcohol biomarkers such as hair ethyl glucuronide can detect early alcohol relapse in pre-and post-LT patients, it is not yet a standardized guideline, and this could be considered in the future26.
Despite these limitations, this study has several advantages to enumerate. It includes a large number of ALD recipients and identifies the timeline of alcoholic relapse after LDLT. Various predictors for relapse have been analyzed thoroughly including pre-transplant alcohol abuse behavior and in particular the period of abstinence, which provides us insight into the timing of LT in ALD patients. In addition, the impact on allograft and evaluation of QOL gives future direction for management of alcohol relapse after LT. Finally, stringent follow-up and psycho-behavioral therapy could help achieve good QOL and long-term survival in these patients.
In conclusion, LDLT offers a unique opportunity for liver transplantation in patients with alcoholic liver disease with an excellent five-year survival rate. The incidence rate of relapse after LDLT in our cohort was low compared to published literature. Donation from spouse and first-degree relative seems to have a protective effect on relapse. History of pre-LT relapse, daily intake of alcohol, absence of social support in form of spouse or partner, concurrent smoking and tobacco addiction, second-degree relation of the donor, and noncompliance with medications/follow-up are significant predictors for relapse. Pre-transplant abstinence of less than three-month duration was found to be a significant predictor for relapse whereas, the commonly cited predictor “six months-abstinence” did not predict relapse. Post-transplant alcohol relapse was associated with an increased risk of allograft rejection.