Long-term survival after liver transplantation for alcohol-related liver disease in the Nordic countries

Abstract Objectives Alcohol-related liver disease (ALD) is among the most common indications for liver transplantation (LTX) in Europe and North America, with good five-year survival rates post-LTX. Here we evaluated survival up to and beyond 20 years after LTX for patients with ALD compared to a comparison group. Methods Patients with ALD and a comparison group transplanted in the Nordic countries between 1982 and 2020 were included. Data were analyzed using descriptive statistics, Kaplan–Meier curves and predictors of survival were assessed with Cox-regressions. Results 831 patients with ALD and 2979 patients in the comparison group were included in the study. Patients with ALD were older at the time of LTX (p < .001) and more likely to be male (p < .001). The estimated median follow-up time was 9.1 years for the ALD-group and 11.1 years for the comparison group. 333 (40.1%) patients with ALD and 1010 (33.9%) patients in the comparison group died during follow-up. The overall survival was impaired for patients with ALD compared to the comparison group (p < .001) and was evident for male and female patients, patients transplanted before and after 2005, and observed in all age-groups except patients over 60 years. Age at transplant, waiting time, year of LTX and country of LTX were associated with decreased survival after LTX for patients with ALD. Conclusions Patients with ALD have a decreased long-term survival following LTX. This difference was evident in most sub-groups of patients and warrants close follow-up of liver transplanted patients with ALD with focus on risk reduction.


Introduction
Alcohol-related liver disease (ALD) is one of the most common indications for liver transplantation (LTX) in Europe and North America with increasing numbers in the recent years [1][2][3]. Listing criteria for LTX and access to organs differs between countries, but most countries and LTX programs require a period of abstinence, usually six months, before patients are listed for LTX [4,5]. This period of abstinence might in some cases improve the liver function of the patient and hence in some cases remove the need for LTX [6,7]. Pre-transplant abstinence is seen as a predictor of continuous abstinence after the transplantation [8][9][10] along with other factors, such as psychiatric comorbidities and smoking [8,11].
It is difficult to both predict and measure the degree of alcohol consumption post-LTX and estimates for the percentage of patients that start drinking again range between 20 and 50% [12]. It has been suggested that relapse to moderate alcohol consumption after LTX is not associated with significant graft damage or loss nor reduced survival [13] while excessive alcohol consumption after LTX is known to reduce the long-term survival [14]. Most studies regard all consumption of alcohol post-LTX as relapse, which is stricter than the definition of relapse normally used in the field of addiction medicine [4,15,16] and highlights the importance of distinguishing between minor setbacks and relapse to heavy drinking [12]. Some studies have shown no difference in relapse between ALD-patients and other patients post-LTX [17,18] while a study from Faure et al. showed that patients with a pre-transplant diagnosis of ALD had higher post-transplant consumption of alcohol compared to other patients [19].
No significant differences in one-, three-and five-year survival after LTX have been reported for patients with ALD compared to other cirrhotic patients [13,18,[20][21][22]. Studies evaluating survival beyond the five-year period have inherent difficulties due to patients being lost to follow-up and other potential biases. A small study from Poland reported that LTX recipients with ALD had a negative outcome beyond the fifth-year post-transplant and this was not attributable to recidivism of alcohol abuse [21]. Multiple studies have shown an increased frequency of cardiovascular diseases and de novo malignancies post-transplant among patients with ALD compared to other non-viral and non-malignant etiologies [4,6], which could have a clear negative impact on the survival for patients with ALD.
In this study we aimed to evaluate the long-term survival beyond the fifth-year post-transplant for patients with ALD compared to other cirrhotic patients in a large transplant registry with close to complete follow-up data facilitated by the single-payer Nordic health care systems [23]. This gives us the unique opportunity to evaluate long-term survival also up to and beyond 20 years after transplantation. The practices for organ allocation and temporal changes in the transplant activity in the Nordic countries have previously been reported [23]. Other aims of this study were to analyze differences in retransplantation rate and cause of death between patients with ALD and a comparison group and evaluate differences between the Nordic countries.

Patients and diagnoses
Data from The Nordic Liver Transplant Registry (NLTR) was used as the basis for this study. NLTR includes all patients undergoing LTX in Denmark, Estonia, Finland, Iceland, Norway and Sweden from the first transplant in 1982. LTX are performed in all these countries except for Icelandic patients that have been transplanted in Denmark or Sweden. The registry includes prospective data on all listed patients from 1990 for patients transplanted in Denmark, Finland, Norway and Sweden and from 2016 for patients from Estonia. Prior to these timepoints all transplanted patients were registered retrospectively.
All adult patients (above 18 years of age) listed with alcoholic cirrhosis as primary diagnosis between 1982 and 2020 in the Nordic countries were included. Adult patients listed with a non-malignant, non-viral and non-acute liver diseases (primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), metabolic disease, cryptogenic cirrhosis, secondary biliary cirrhosis and cirrhosis of unknown cause) were included as a comparison group. To exclude patients with a potential viral etiology that were listed with another primary diagnosis, patients with positive serology for Hepatitis C virus (HCV) antibody, Hepatitis B virus surface (HBs) antigen or Hepatitis B virus core (HBc) antibodies were excluded. Patients listed for highly urgent LTX were excluded in both the ALD and comparison group. Patients who had developed hepatocellular carcinoma (HCC) on the basis of their ALD cirrhosis or the other cirrhotic indications were listed with HCC as the primary diagnosis and thus not included in this study. Complete follow-up data were available until 31 December 2020 or until death for all patients. Information about the causes of death is registered in each country based on clinical information from the local hospital, general practitioners and death certificates and added to NLTR when a patient dies. In this study the information listed in NLTR was used.

Statistical analysis
All statistical analyses were performed using IBM SPSS Statistics for Windows, version 26 (IBM Corp., Armonk, N.Y., USA). Clinical and biochemical variables were compared between groups using the student T-test for continuous variables and the chi-square test for categorical variables. Oneway ANOVA and post hoc tests with Bonferroni correction were used for testing differences in means between three or more groups. Survival analyses were performed with Kaplan-Meier plots and the Log-rank test was used to compare survival distributions. Median follow-up time was estimated using the reverse Kaplan-Meier approach. Actuarial survival was estimated using life tables. Variables predicting patient survival were analyzed using univariate and multivariate Coxregressions. p Values <.05 were considered significant. In the analysis of causes of death, we only evaluated patients that died during the follow-up period and the cause of death was treated as a categorical variable without taking into account the time from LTX to time of death.

Patients and diagnosis
In total 1028 patients were listed for LTX with ALD as the primary diagnosis. Sixty-five of these patients were excluded due to positive serology for Hepatitis B virus (HBV) or HCV, three patients due to listing for an urgent LTX and 129 patients because they did not end up undergoing transplant. Eight-hundred and thirty-one patients with ALD were thus included in the final study group (Figure 1). The number of patients listed with ALD as their primary diagnosis was steadily increasing through the study period (Supplementary Figure 1A). The highest number of transplanted patients were transplanted in Sweden (n ¼ 298) while the fewest were transplanted in Estonia (n ¼ 13) (Table 1). When evaluated in relation to the population size, Estonia clearly had the lowest number of transplants due to ALD per million population while for the remaining countries it was on the same level with the highest number in Finland ( Table 1). The mean age of the patients with ALD at the time of the first LTX was 55.7 years and the median age was 56.2 years ( Table 2). The mean age at LTX increased from 49.0 years in the period from 1982 to 1990 (n ¼ 5) to 57.7 years during the last five-year period from 2016 to 2020 (n ¼ 238) (p ¼ .017). After exclusion of the small number of Estonian patients (n ¼ 13) the difference in mean age at LTX between the four other countries was statistically significant (p < .001). Norway had the highest mean age with 57.7 years (95% CI 56.6-58.9 years) and Denmark the lowest with 53.6 years (95% CI 52.6-54.6 years). The difference in mean age was statistically significant between Denmark and Sweden (p < .001), Denmark and Norway (p < .001) and Finland and Norway (p ¼ .037).
Among all patients who received a LTX in the Nordic countries during the study period ALD was the third most common indication (11.5%). PSC (16.1%) and HCC (11.7%) Figure 1. Selection of patients with alcohol-related liver disease (ALD) in the study group and patients with another non-viral, non-malignant and non-acute liver disease in the comparison group from the Nordic Liver Transplant Registry (NLTR). Patients under 18 years of age, patients with other primary diagnoses, positive serology for Hepatitis B virus (HBV) or Hepatitis C virus (HCV), patients with urgent liver transplantation (LTX) and patients who did not receive a LTX were excluded from the primary analysis. Patients not receiving a LTX were included in the intention-to-treat analysis. Note: The number of patients with ALD and patients in the comparison group who received a LTX in the different countries are given as both absolute numbers and relative to population size.
were the two most frequent diagnoses. The proportion of patients transplanted with ALD increased from 1.8% in the period from 1982 to 1990 (n ¼ 5) to 13.9% in the period from 2016 to 2020 (n ¼ 255) (p < .001). Two thousand nine hundred and seventy-nine patients were included in the comparison group ( Figure 1). The most common diagnoses in this group were PSC (n ¼ 1208), PBC (n ¼ 590) and metabolic disease (n ¼ 432). The mean age of the patients in the comparison group was 49.1 years and the median age was 50.4 years at the time of transplant ( Table  2). The mean age at LTX increased from 46.2 years in the period from 1982 to 1990 (n ¼ 124) to 50.1 years in the period 2016-2020 (n ¼ 679) within the comparison group (p ¼ .002).
Differences in clinical baseline variables in the ALD-group compared to the comparison group at the time of listing are shown in Table 2. Notably, the group transplanted for ALD were older at the time of first LTX (55.7 vs. 49.1, p < .001), more likely to be male (76.4% vs. 52.6%, p < .001) and had a higher body mass index (BMI) (26.2 vs. 24.7, p < .001). A higher percentage of the transplants in the ALD-group occurred in 2005 or later compared to the comparison group (71.2 vs. 63.8, p < .001) (Supplementary Figure 1B).

Donor characteristics and transplant
The mean donor age for the patients with ALD was 53.0 years compared to 47.8 years for the comparison group (p < .001). The donors were more frequently male (60.0% vs. 51.7%, p < .001) and had a higher mean BMI (25.3 vs. 24.6, p ¼ .002) in the ALD-group compared to the comparison group.

Survival
The overall survival was impaired for patients with ALD compared to the comparison group (p < .001) (Figure 2). The patient survival rates at 1, 5, 10, 15 and 20 years post liver transplantation in the ALD-group were 90%, 81%, 63%, 41% and 27%, respectively. In the comparison group the survival rates at 1, 5, 10, 15 and 20 years after LTX were 90%, 83%, 73%, 62% and 49%, and it was evident that the survival for ALD was similar to the comparison group in the first five years post transplantation (p ¼ .18). The inferior survival in patients with ALD compared to the comparison group was still evident if PSC and PBC patients were removed from the comparison group (p < .001).
To rule out that this effect on survival was due differences in baseline characteristics in the two groups stratified analyses were performed. The observed difference in the survival between ALD-patients and the comparison group was present both for patients transplanted before 2005 and after 2005 (Supplementary Figure 3). Interestingly the survival differences were evident in even the youngest age group with patients under 40 years (n ALD ¼ 22 n comp ¼ 752, p < .001) as well as in patients between 40 and 50 years (n ALD ¼ 158 n comp ¼ 705, p ¼ .004) and patients between 50 and 60 years (n ALD ¼ 397 n comp ¼ 834, p ¼ .002) (Supplementary Figure 4). There was no difference in survival (n ALD ¼ 254 n comp ¼ 688, p ¼ .78) for the ALD-patients over 60 years compared to the comparison group (Supplementary Figure 4). There were statistically significant differences in survival between ALDpatients and the comparison group in Sweden (n ALD ¼ 298 n comp ¼ 1363, p < .001), Denmark (n ALD ¼ 188 n comp ¼ 461, p < .001) and Norway (n ALD ¼ 146 n comp ¼ 614, p ¼ .003), while there was lacking clear evidence for a difference in survival between the two groups in Finland (n ALD ¼ 186 figure 5). No difference in survival was detected for Estonian patients (n ALD ¼ 13 n comp ¼ 23, p ¼ .67) which is most likely due to the low number of patients in this sub-cohort (Supplementary figure 5). There was a significant difference in survival between the patients transplanted for ALD and the comparison group both for women (n ALD ¼ 196 n comp ¼ 1413, p ¼ .008) and men (n ALD ¼ 635 n comp ¼ 1566, p < .001) (Supplementary Figure 6). The difference in long-term survival was still evident after adjusting for other variables in a multivariate Cox-regression analysis (p ¼ .001) ( Table 3). Comparison of graft survival between the two groups displayed a similar pattern as the patient survival for the respective groups (p < .001) (Supplementary Figure 2).

Retransplantation
Among the patients with ALD 5.3% (n ¼ 44) were retransplanted during the study period compared to 10.4% (n ¼ 310) in the comparison group (p < .001). This difference could not explain the impaired patient survival between patients with ALD and the comparison group as the impaired survival Table 2. Clinical characteristics of patients with alcohol-related liver disease (ALD) and patients in the comparison group. .002 Notes: Recipient and donor age are shown as mean age with the 95% confidence intervals. Differences in distributions were analyzed with the chi-square test for recipient sex, liver transplantation (LTX) year and donor sex and with Student's t-test for all other variables. The difference in waiting time between the two groups are compared on the constructed variable ln(waiting time in days þ 1) to gain normal distribution of the test statistics.
between the two groups was evident for the graft survival as well (Supplementary Figure 2). The retransplantation rate within the first three months after LTX were similar within the two groups at respectively 2.3% (n ¼ 19) for patients with ALD and 3.0% (n ¼ 88) for the comparison group (p ¼ .30). There was no difference in three-month patient survival after first LTX between the two groups (p ¼ .69).

Causes of death
By the end of the study period 333 patients with ALD who had received a LTX had died. Cardiovascular or cerebrovascular conditions accounted for 14.7% (n ¼ 49), liver complications for 13.5% (n ¼ 45), de novo or recurrence of tumor for 19.2% (n ¼ 64) and infections for 12.3% (n ¼ 41) of the deaths while 14.1% had an unknown cause of death (n ¼ 47) and 26.1% had other causes of death (n ¼ 87). Causes of death for the patients with ALD did not differ significantly from the comparison group (Table 4). There were no differences in causes of deaths during the first five years following transplant when the two groups were compared (data not shown).

Predictors of patient survival
A univariate Cox-regression analyzing potential predictors for survival after LTX for patients with ALD can be found in   Table 5. In this analysis waiting time, LTX-period and country were significantly associated with survival. The same variables, except Model for End-stage Liver Disease (MELD) score due to a high number of missing values, were included in a multivariate Cox-regression (Table 6). In this multivariate analysis recipient age, waiting time, LTX-period and country were significant predictors of survival.

Intention-to-treat analysis
In an intention-to-treat analysis survival from entry on waiting list for patients listed with ALD (n ¼ 960) was compared to survival for patients listed to the comparison group (n ¼ 3313) after excluding patients under 18 years of age, patients with positive serology for HBV or HCV and patients with urgent LTX (Figure 1). The difference between long term survival between the two groups was also evident in the intention-to-treat analysis. The patient survival 1, 5, 10 and 15 years after listing for the patients with ALD was 82%, 72%, 56% and 37% compared to 87%, 79%, 68% and 58% for the comparison group (p < .001).

Discussion
The main finding of this study is that patients with ALD have a decreased long-term survival compared to patients with other non-malignant, non-viral and non-acute end-stage liver diseases. This difference was present after adjusting for other covariates such as gender, year of transplantation and recipient age. There was no difference in the rates of acute death or retransplantation during the first three months post-transplant. Importantly, the two groups had similar survival rates during the first five years after LTX. Beyond this point the ALD-group shows a steeper decline in survival. The difference in long-term survival was not due to the lower retransplantation rate in the ALD-patients as the graft survival was similarly impaired.
Among the patients with ALD we observed that the age of the recipient, waiting time from acceptance to the waiting list to transplant, year of LTX and country of LTX were factors associated with a decreased survival time after LTX. Constant improvements in surgical techniques and immunosuppressive treatment post-LTX have been attributed to patients transplanted in recent years having a survival benefit following LTX [24,25] and this effect is also evident for patients with ALD [13]. Since shorter waiting time is a significant contributor to survival indicates that all LTX programs should strive to keep the waiting time as low as possible.
In the four countries with a high number of transplantations (i.e., excluding Estonia) performed, Finland stands out as the only country where we did not observe a difference in the long-term survival between the ALD-patients and the comparison group. Finland also had higher median survival time after LTX compared to Sweden, Denmark and Norway for both the ALD-patients and the comparison group. These differences were also present after adjusting for other  variables using multivariate Cox-regression. Given the data presently available in NLTR we were not able to evaluate potential explanatory factors regarding details on clinical status of the patients, surgical methods and differences in the medical follow up programs between the countries. The differences between the countries underline the importance of exchanging knowledge between the different transplant centers and exploring such differences in an effort to improve clinical practice.
ALD accounts for the majority of liver deaths in Europe [26,27] and for patients with end-stage ALD there are no medical treatment alternatives rendering liver transplantation the only curative treatment option available [5]. Within the Scandiatransplant-area the access to liver-grafts has been adequate, thus there is less need to prioritize between different patient-groups. This situation might change in the future with a larger group of patients with end-stage liver disease being eligible for transplantation. Most transplant programs, including the programs in the Nordic countries, lack a systematic follow up and approach to relapse of alcohol consumption [5,28]. Potential differences in alcohol consumption-patterns between the patients with ALD and the comparison group in our study might to some extent explain the impaired survival we have shown. This warrants the importance of optimal selection of graft recipients and proper follow-up care after transplantation.
This study has some limitations regarding selection bias in the comparison group and confounders. The registration of clinical characteristics in NLTR such as pre-transplant comorbidities and smoking are limited. Previous studies have shown that a significantly higher proportion of patients with ALD are smoking both before and after LTX compared to patients transplanted for other liver diseases [29,30]. Continued smoking after LTX is associated with increased risk of death due to cardiovascular diseases and smokingrelated malignancies and the incidence of cardiovascular events and de novo tumors are higher among patients with ALD than patients with other liver diseases after LTX [13,29,[31][32][33]. We did not find differences in cause of death in our study, but still believe that closer follow up of risk behavior and comorbidities among patients with ALD could reduce the gap in long-term survival. Standardization of reporting of clinical features pre-and post-transplant in recent years will allow more thoroughly investigation of the impact these factors have on the long-term survival post liver transplantation.
In conclusion, we have consistently demonstrated that the survival following LTX for ALD is just as good as for other cirrhotic indications in the first five years following transplant and is then followed by a steep decline which was present across different age-groups, gender and transplant centers. This finding strongly encourages close long-term medical follow-up of patients with ALD undergoing LTX with a focus on risk reduction. The same potential predictors of patient survival as in the univariate Cox-regression were included in the multivariate Cox-regression. Model for End-stage Liver Disease (MELD) score was only available for 411 patients and therefore not included.