First-Degree Living-Related Donor Liver Transplantation in Autoimmune Liver Diseases

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1 American Journal of Transplantation 2016; 16: Wiley Periodicals Inc. Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /ajt First-Degree Living-Related Donor Liver Transplantation in Autoimmune Liver Diseases A. D. Aravinthan 1,, A. C. Doyle 1,, A. Issachar 1, M. Dib 1, D. Peretz 2, M. S. Cattral 1, A. Ghanekar 1, I. D. McGilvray 1, M. Selzner 1, P. D. Greig 1, D. R. Grant 1, N. Selzner 1, L. B. Lilly 1 and E. L. Renner 1, * 1 Multiorgan Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Canada 2 Manitoba Liver Transplant Program, University of Manitoba, Winnipeg, Canada *Corresponding author: Eberhard L. Renner, eberhard.renner@uhn.ca Co-first authors. Liver transplantation (LT) is the treatment of choice for end-stage autoimmune liver diseases. However, the underlying disease may recur in the graft in some 20% of cases. The aim of this study is to determine whether LT using living donor grafts from first-degree relatives results in higher rates of recurrence than grafts from more distant/unrelated donors. Two hundred sixty-three patients, who underwent a first LT in the Toronto liver transplant program between January 2000 and March 2015 for autoimmune liver diseases, and had at least 6 months of post-lt followup, were included in this study. Of these, 72 (27%) received a graft from a first-degree living-related donor, 56 (21%) from a distant/unrelated living donor, and 135 (51%) from a deceased donor for primary sclerosing cholangitis (PSC) (n = 138, 52%), primary biliary cholangitis (PBC) (n = 69, 26%), autoimmune hepatitis (AIH) (n = 44, 17%), and overlap syndromes (n = 12, 5%). Recurrence occurred in 52 (20%) patients. Recurrence rates for each autoimmune liver disease were not significantly different after first-degree living-related, living-unrelated, or deceased-donor LT. Similarly, time to recurrence, recurrence-related graft failure, graft survival, and patient survival were not significantly different between groups. In conclusion, first-degree living-related donor LT for PSC, PBC, or AIH is not associated with an increased risk of disease recurrence. Abbreviations: AIH, autoimmune hepatitis; BMI, body mass index; CMV, cytomegalovirus; DDLT, deceased donor liver transplantation; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-stage Liver Disease score; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis Received 26 January 2016, revised 07 April 2016 and accepted for publication 08 April 2016 Introduction Autoimmune liver diseases are broadly categorized into three discrete disease entities: primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and autoimmune hepatitis (AIH) (1). Each of these conditions leads to well-defined patterns of injury; PSC and PBC cause progressive biliary destruction leading to chronic cholestatic liver disease, whereas AIH causes chronic parenchymal liver disease through chronic hepatitis (1), all eventually progressing to cirrhosis. The incidence of each of these autoimmune liver diseases is around 1 2 per population per year (2), and together they account for 12 24% of all liver transplantations (LTs) worldwide (3,4). Once cirrhosis is established and decompensation ensues, LT remains the only lifesaving treatment option. Transplant, however, is limited by the availability of deceased donor organs. Due to the ever-increasing gap between donor organ supply and demand, waiting list mortality remains a significant problem even in jurisdictions with relatively high deceased organ donation rates (5 7). Donor access is partially alleviated through living donor liver transplantation (LDLT) (4). LDLT has been reported to be associated with overall recipient outcomes similar to those after deceased donor liver transplantation (DDLT) (8), even in patients with high Model for Endstage Liver Disease (MELD) scores (>25) (9). Recurrence of the underlying liver disease in the grafts post-lt remains a challenge, potentially affecting both deceased and live donor grafts. The recurrence of autoimmune liver diseases is no exception to this despite the use of potent immunosuppression. The incidence of recurrence varies widely and the predisposing factors remain debated. PSC recurs in 5 50% of patients with a median time to diagnosis ranging from 6 months to 5 years post- LT (10 12). Similarly, PBC is reported to recur in up to 50% of patients with a median time to diagnosis of 1 6 years (10,11), and AIH recurrence is diagnosed in approximately 25% following a median time of 1 5 years (10,11). 3512

2 Autoimmune Liver Disease Recurrence After LDLT Genetic predisposition is strongly suspected to be a risk factor for the development of autoimmune liver diseases due to the increased co-incidence of autoimmune liver diseases among monozygotic twins and first-degree relatives (13 17). Furthermore, certain HLA haplotypes in recipients and/or donors have been shown to be associated with recurrence of autoimmune liver diseases after LT (18 20). These findings have led to concerns about an increased risk of disease recurrence in the recipients of live donor grafts taken from first-degree relatives, given the genetic similarity between recipients and donors. Supporting these concerns, two relatively small, retrospective, single-center studies from Japan have demonstrated an increased recurrence of PSC and PBC in first-degree relative LDLT (21,22). Similar studies, however, have not been replicated in other populations, and have not evaluated AIH. This study aimed to determine whether the recipients of LDLT for autoimmune liver diseases are more likely to experience disease recurrence if their donor organ is taken from a first-degree relative, compared to more distant or unrelated donors. Secondary outcomes of patient survival, graft survival, and recurrence-related graft failure were also examined. This analysis was conducted within the Toronto liver transplant program, one of the largest programs in North America, where LDLT accounts for a third of all liver transplant activity. Materials and Methods Patient selection and data collection All patients with PSC, PBC, and AIH who underwent LT since January 2000 and had at least 6 months of follow-up (up to and including March 2015) were included in this study. In patients who underwent more than one LT, only data from the first transplantation were included. Patients who underwent multiorgan transplantation (e.g. combined liver kidney transplantation) and patients with additional etiological cause(s) of liver disease were excluded from this study. The following clinical and demographic data were retrospectively extracted from the prospectively collected electronic transplant database (OTTR: Transplant Care Platform 6, OTTR Chronic Care Solutions, Omaha, NE): date of birth, sex, etiology of liver disease (PSC, PBC, AIH, or overlap syndrome), duration on waiting list, MELD and Sodium-MELD scores at LT, relationship between LDLT recipients and their donors, donor age, donor sex, cold and warm ischemia time, presence of hepatocellular carcinoma (HCC) and/or cholangiocarcinoma (including incidental tumors found on explants), recurrence of primary disease and date of diagnosis, cytomegalovirus (CMV) viremia, biopsy-proven rejection (in the first year of LT and total number of episodes), details of retransplantation, and details of death. In patients with PSC, details of inflammatory bowel disease and colectomy were also collected. All explant pathology reports were reviewed to confirm the etiology of liver disease and to exclude additional cause(s) of liver disease. Patients were divided into three study groups based on donor type those who received grafts from a living first-degree relative (parents, siblings, or offspring; LDLT-related), those who received grafts from a living distant-relative or unrelated donor including anonymous donors (LDLT-other), and those who received graft from deceased donors (DDLT). Comparison was made between these three groups for all autoimmune liver diseases together (PSC, PBC, AIH, and overlap syndrome together) and individually for PSC, PBC, and AIH. Patients with overlap syndrome were not analyzed separately due to their small number. The study was approved by the Toronto University Health Network Research Ethics Board ( BE). Evaluation for disease recurrence Patients presenting with symptoms/signs or laboratory tests suggestive of disease recurrence (i.e. symptoms of cholangitis and/or liver biochemical abnormalities) were investigated further. Routine screening for disease recurrence with protocol liver biopsy or surveillance imaging is not undertaken in the Toronto Liver Transplant Program. Diagnostic criteria of disease recurrence following LT PSC: Diagnosis of recurrence of PSC was made according to the Mayo Clinic criteria, as proposed by Graziadei et al (23), which require (1) confirmed diagnosis of PSC before LT; (2) either cholangiography showing biliary stricturing, beading, and irregularities at least 90 days after LT or histological findings of fibrous cholangitis and/or fibro-obliterative lesions; and (3) absence of hepatic artery thrombosis or stenosis, chronic ductopenic rejection, anastomotic stricture, nonanastomotic strictures before day 90 post-lt and ABO incompatibility between donor and recipient. PBC: Diagnosis of recurrence of PBC was made according to the criteria proposed by Hubscher et al (24), which require (1) confirmed diagnosis of PBC before LT; (2) histological features of lymphoplasmacytic portal infiltrate, lymphoid aggregates, epithelioid granulomas, and evidence of bile duct injury; (3) persistence of antimitochondrial antibody (AMA) or AMA-M2; and (4) absence of acute and/or chronic rejection, graft-versus-host disease, bile flow impairment or cholangitis, vascular complications, and drug-induced hepatitis. AIH: Diagnosis of recurrence of AIH was made according to the criteria summarized by Faisal et al (25) and Duclos-Vallee et al (11), which require (1) confirmed diagnosis of AIH before LT; (2) elevated transaminases, hypergammaglobulinemia (elevated IgG), and presence of autoantibodies (antinuclear antibody, anti-smooth muscle antibody, and/or anti-liver Kidney Microsomal antibody); (3) histological findings of interface hepatitis with portal inflammation and/or lymphoplasmacytic inflammatory infiltrates; (4) response to corticosteroid; and (5) exclusion of differential diagnostic considerations such as acute or late/atypical rejection. Endpoints The primary endpoint of this study was to assess disease recurrence among LT recipients of first-degree living-related and distantly related/ unrelated donors. The secondary endpoints of this study were patient survival, graft survival, and recurrence-related graft failure in the above groups. As describe above, diagnosis of disease recurrence following transplantation was made based on well-established criteria. Patient survival was defined from the time of LT to the date of death from any cause. Patients who were lost to follow-up, or moved to another transplant center for ongoing care, were censored at the time of American Journal of Transplantation 2016; 16:

3 Aravinthan et al their last clinic visit. In the event of more than one LT, cases were censored at the time of the second LT. Graft survival was defined from the time of LT to death from any cause or retransplantation; where this was due to recurrence of primary disease, this was defined as recurrence-related graft failure. Data analysis and statistics Data are shown as median (interquartile range) or number (percentage) unless otherwise stated. A p-value of <0.05 was considered significant. Nonparametric analysis (GraphPad prism 5; GraphPad Software, Inc., San Diego, CA) utilizing the Mann Whitney U test or one-way analysis of variance (ANOVA) (Kruskal Wallis test) was applied where data were not distributed normally. Survival and disease recurrence estimates were calculated using Kaplan Meier analysis (log-rank test). Variables with a p-value of <0.10 on log-rank testing were included in a multivariable Cox proportional hazards model, using a forward stepwise approach. Variables were retained in the multivariable model if they were statistically significant (p < 0.05). Results Patients and study groups During the study period (January 2000 March 2015), 290 patients underwent a first LT in the Toronto Liver Transplant program for autoimmune liver diseases (Figure 1). While 263 of 290 patients met the study inclusion criteria, 27 were excluded for the following reasons: death within 6 months of LT (n = 14), additional etiology for liver disease (alcohol-related liver disease, a-1 anti-trypsin deficiency, chronic inactive hepatitis B infection and Wilson s disease; n = 4), alternative etiology on explant (granulomatous hepatitis; n = 3), multiorgan (combined kidney and liver) transplantation (n = 2), and inadequate follow-up data due to transfer of patient care to another institution (n = 4). Of the 263 patients included in this study, 72 (27%) received a graft from a living first-degree relative (LDLTrelated), 56 (21%) received a graft from a living distantrelative or unrelated donor (LDLT-other), and 135 (51%) received a graft from a deceased donor (DDLT). PSC was the most common etiological indication, accounting for half of the study population (n = 138, 52%), followed by PBC (n = 69, 26%) and AIH (n = 44, 17%). Twelve patients (5%) had histology-confirmed overlap syndrome (AIH and PSC, n = 9 or AIH and PBC, n = 3). Demographics and medical characteristics Demographics of the three study groups (LDLT-related, LDLT-other, and DDLT) are summarized in Table 1. There were no differences in recipient parameters such as age at transplant, gender, and body mass index (BMI) and donor parameters such as donor age, donor BMI, and donor/recipient sex mismatch. The proportion of PSC, PBC, and AIH, and the presence of HCC and cholangiocarcinoma (both known and incidental), were also similar among the three groups. As expected, MELD and Sodium-MELD scores at transplant were significantly lower in LDLT-related and LDLT-other groups compared to the DDLT group. While the duration on the waiting list was numerically shorter in the LDLTrelated group, this did not reach statistical significance (p = 0.07). As expected, cold ischemia time was significantly shorter in the LDLT-related and LDLT-other groups, but the warm ischemia time was similar in all Figure 1: Study design. Two hundred and ninety patients underwent first liver transplantation between January 2000 and March 2015 for autoimmune liver diseases. Twenty-seven were excluded and 263 were included in the study. AIH, autoimmune hepatitis; DDLT, deceased donor liver transplantation; LDLT, living donor liver transplantation; LT, liver transplantation; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis American Journal of Transplantation 2016; 16:

4 Autoimmune Liver Disease Recurrence After LDLT Table 1: Demographics and medical characteristics of patients with autoimmune liver diseases included in the study LDLT-related (n = 72) LDLT-other (n = 56) DDLT (n = 135) Median or number IQR or % Median or number IQR or % Median or number IQR or % p-value Age at LT (years) Female sex 44 61% 31 55% 71 53% 0.50 BMI (kg/m 2 ) Duration on waiting list (months) MELD at LT <0.001 Na-MELD at LT Donor age (years) Donor BMI (kg/m 2 ) Donor/recipient sex mismatch 36 50% 27 48% 50 37% 0.13 Cold ischemia time (min) <0.001 Warm ischemia time (min) Primary indication PSC 36 50% 32 57% 70 52% 0.35 PBC 24 33% 15 27% 30 22% AIH 8 11% 7 12% 29 21% Overlap 4 6% 2 4% 6 4% HCC 3 4% 2 4% 11 8% 0.35 Cholangiocarcinoma 0 0% 2 4% 3 2% 0.32 LT, liver transplantation; BMI, body mass index; MELD, Model for End-stage Liver Disease score; Na-MELD, Sodium Model for Endstage Liver Disease score; PSC, primary sclerosing cholangitis; PBC, primary biliary cholangitis; AIH, autoimmune hepatitis; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; DDLT, deceased donor liver transplantation; IQR, interquartile range. A p-value <0.05 is indicated in bold. three study groups. No ABO incompatible transplantations were undertaken. On analysis of individual diseases separately, the following were significantly different between the three study groups (Table 2): cold ischemia time was significantly lower in LDLT-related and LDLT-other compared to DDLT in PSC, PBC, and AIH; duration on waiting list was significantly lower in LDLT-related compared to LDLT-other and DDLT in PSC alone; and MELD, Sodium-MELD, and donor age were significantly lower in LDLT-related compared to DDLT in PBC alone. In those with PSC, the presence of inflammatory bowel disease and proportion of those who underwent colectomy did not differ among the three study groups. Outcomes Death: Twenty-nine patients (11%) of the total study population died during an overall median follow-up of 6.1 years (interquartile range [IQR] ). Five of the 29 deaths (17% of all deaths) were due to liver-related causes; the rest were due to malignancy (n = 12), sepsis (n = 6), renal failure (n = 5), and cardiovascular disease (n = 1). There was no difference in death from any cause and liver-related deaths between LDLT-related, LDLTother, and DDLT in all autoimmune liver diseases together, and individually in PBC and AIH. In PSC, however, overall mortality was significantly higher in DDLT (Table 3 and Figure 2). Retransplantation and graft survival: Nineteen patients (7%) underwent retransplantation following a median time of 3.6 years (IQR ). The majority (10 of 19, 53%) of the retransplants were performed for either biliary (n = 9) or vascular (n = 1) complications; the rest were due to recurrence of primary disease (n = 8) or chronic rejection (n = 1). Forty-eight grafts (18%) were lost due to deaths from any cause (n = 29) and retransplantation (n = 19) following a median time of 5.3 years (IQR ). Graft survival was not significantly different between the three study groups in all autoimmune liver diseases, regardless of etiology (Table 3 and Figure 2). Disease recurrence: Overall, 52 patients (20%) of the total study population developed recurrence of primary autoimmune liver disease in the graft following a median time of 4.8 years (IQR ). This included 32 of 138 patients (23%) with PSC, 9 of 69 patients (13%) with PBC, 7 of 44 patients (16%) with AIH, and 4 of 12 patients (33%) with overlap syndrome. Recurrence-related graft failure developed in 11 of the 52 patients with recurrence (21%) requiring retransplantation (n = 8) or leading to death (n = 3) following a median time of 7.0 years post-lt (IQR ). The etiology of recurrence-related graft failure was PSC (n = 7; 5.1%), PBC (n = 2; 2.9%), and AIH (n = 2; 4.5%). Neither disease recurrence nor recurrence-related graft failure were American Journal of Transplantation 2016; 16:

5 Aravinthan et al Table 2: Demographics and medical characteristics of patients with primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis Median or number IQR or % Median or number IQR or % Median or number IQR or % Primary sclerosing cholangitis LDLT-related (n = 36) LDLT-other (n = 32) DDLT (n = 70) p-value Age at LT (years) Female sex 12 33% 13 41% 21 30% 0.57 BMI (kg/m 2 ) Duration on waiting list (months) MELD at LT Na-MELD at LT Donor age (years) Donor BMI (kg/m 2 ) Donor/recipient sex mismatch 19 53% 13 41% 27 39% 0.36 Cold ischemia time (min) <0.001 Warm ischemia time (min) Inflammatory bowel disease (UC/CD) 29 (24/5) 81% (67/14) 27 (21/6) 84% (66/18) 55 (49/6) 79% (70/9) 0.79 Colectomy 5 14% 8 25% 13 19% 0.50 HCC 1 3% 2 6% 5 7% 0.66 Cholangiocarcinoma 0 0% 1 3% 3 4% 0.46 Primary biliary cholangitis LDLT-related (n = 24) LDLT-other (n = 15) DDLT (n = 30) p-value Age at LT (years) Female sex 22 92% 13 87% 24 80% 0.48 BMI (kg/m 2 ) Duration on waiting list (months) MELD at LT Na-MELD at LT Donor age (years) Donor BMI (kg/m 2 ) Donor/recipient sex mismatch 14 58% 8 53% 10 33% 0.16 Cold ischemia time (min) <0.001 Warm ischemia time (min) HCC 2 8% 0 0% 3 10% 0.46 Cholangiocarcinoma 0 0% 0 0% 0 0% NA Autoimmune hepatitis LDLT-related (n = 8) LDLT-other (n = 7) DDLT (n = 29) p-value Age at LT (years) Female sex 7 88% 3 43% 22 76% 0.12 BMI (kg/m 2 ) Duration on waiting list (months) MELD at LT Na-MELD at LT Donor age (years) Donor BMI (kg/m 2 ) (Continued) 3516 American Journal of Transplantation 2016; 16:

6 Autoimmune Liver Disease Recurrence After LDLT Table 2. Continued Autoimmune hepatitis LDLT-related (n = 8) LDLT-other (n = 7) DDLT (n = 29) p-value Donor/recipient sex mismatch 2 25% 6 86% 13 45% Cold ischemia time (min) <0.001 Warm ischemia time (min) HCC 0 0% 0 0% 2 7% 0.58 Cholangiocarcinoma 0 0% 1 14% 0 0% 0.07 IQR, interquartile range; LT, liver transplantation; BMI, body mass index; UC/CD, ulcerative colitis/crohn s disease; MELD, Model for End-stage Liver Disease score; Na-MELD, Sodium Model for End-stage Liver Disease score; PSC, primary sclerosing cholangitis; PBC, primary biliary cholangitis; AIH, autoimmune hepatitis; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; DDLT, deceased donor liver transplantation. A p-value <0.05 is indicated in bold. significantly different between the three study groups when all autoimmune liver diseases were analyzed either together or separately (Table 3 and Figure 3). Other secondary outcomes: The number of patients with biopsy-proven acute cellular rejection and those with episodes of CMV viremia did not differ between LDLT-related, LDLT-other, and DDLT in all autoimmune liver diseases together or separately, except in AIH where biopsy-proven rejection was significantly higher in the LDLT-other group (Table 3). Multivariate analysis In order to minimize the risk of confounding factors potentially causing false negative results, an analysis using a multivariable Cox proportional hazards model was performed for the primary outcomes of time to disease recurrence, for each autoimmune etiology, between the groups of LDLT-related, LDLT-other, and DDLT. Covariates incorporated into these models included baseline factors that differed between groups with a p-value of <0.1 on univariate analysis (Table 2). These factors included the following: duration on waiting list, MELD, donor age, and cold ischemia time for PSC; MELD, donor age, and cold ischemia time for PBC; and cold ischemia time alone for AIH. No statistically significant associations with outcomes were maintained on multivariable analysis for any of the included covariates in a forward stepwise model (p > 0.05), and therefore, no confounding factors influencing disease recurrence were identified. Discussion This single-center cohort study is the first of its kind to be undertaken in a Western patient population to evaluate the impact of first-degree LDLT on recurrence of autoimmune liver disease. This study supports the practice of first-degree related LDLT, with no difference in disease recurrence compared to distant-related/unrelated LDLT, and DDLT in autoimmune liver diseases (PSC, PBC, and AIH). This study also found no difference in patient survival, graft survival, and recurrence-related graft failure between first-degree related LDLT and distant/unrelated LDLT or DDLT in autoimmune liver diseases. These findings differ from those of two previous, much smaller, retrospective single-center studies from Japan, which found increased rates of PBC and PSC recurrence, and increased graft failure with PSC recurrence, in those who received grafts from first-degree relatives (21,22). While the reason(s) for this discrepancy remains unclear, it is tempting to speculate that the difference in findings may be attributed to this study having a significantly larger American Journal of Transplantation 2016; 16:

7 Aravinthan et al Table 3: Outcomes of patients with primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis Number % Number % Number % All autoimmune diseases LDLT-related (n = 72) LDLT-other (n = 56) DDLT (n = 135) p-value Disease recurrence 13 18% 11 20% 28 21% 0.90 CMV viremia 6 8% 3 5% 16 12% 0.35 Biopsy-proven rejection 23 32% 19 34% 52 39% 0.61 Biopsy-proven rejection in first year 19 26% 14 25% 35 26% 0.98 Recurrence-related graft failure 2 3% 3 5% 5 4% 0.67 Retransplantation 7 10% 4 7% 8 6% 0.60 Death (any cause) during follow-up 5 7% 6 11% 18 13% 0.38 Death (liver-related) during follow-up 0 0% 2 4% 3 2% 0.32 Primary sclerosing cholangitis LDLT-related (n = 36) LDLT-other (n = 32) DDLT (n = 70) p-value Disease recurrence 7 19% 5 16% 20 29% 0.29 CMV viremia 1 3% 0 0% 8 11% Biopsy-proven rejection 13 36% 7 22% 28 40% 0.20 Biopsy-proven rejection in first year 11 31% 4 13% 19 27% 0.18 Recurrence-related graft failure 1 3% 2 6% 4 6% 0.94 Retransplantation 3 8% 2 6% 5 7% 0.95 Death (any cause) during follow-up 0 0% 3 9% 12 17% 0.03 Death (liver-related) during follow-up 0 0% 1 3% 2 3% 0.58 Primary biliary cholangitis LDLT-related (n = 24) LDLT-other (n = 15) DDLT (n = 30) p-value Disease recurrence 4 17% 2 13% 3 10% 0.77 CMV viremia 3 13% 2 13% 5 17% 0.90 Biopsy-proven rejection 10 42% 7 47% 13 43% 0.95 Biopsy-proven rejection in first year 8 33% 6 40% 10 33% 0.89 Recurrence-related graft failure 0 0% 1 7% 1 3% 0.47 Retransplantation 3 13% 2 13% 2 7% 0.70 Death (any cause) during follow-up 4 17% 3 20% 3 10% 0.62 Death (liver-related) during follow-up 0 0% 0 0% 1 3% 0.52 Autoimmune hepatitis LDLT-related (n = 8) LDLT-other (n = 7) DDLT (n = 29) p-value Disease recurrence 1 13% 3 43% 3 10% 0.10 CMV viremia 2 25% 1 14% 3 10% 0.56 Biopsy-proven rejection 0 0% 4 57% 8 28% Biopsy-proven rejection in first year 0 0% 3 43% 5 17% 0.10 Recurrence-related graft failure 1 13% 0 0% 1 3% 0.17 Retransplantation 1 13% 0 0% 1 3% 0.45 Death (any cause) during follow-up 1 13% 0 0% 3 10% 0.65 Death (liver-related) during follow-up 0 0% 1 14% 0 0% 0.07 CMV, cytomegalovirus; LDLT, living donor liver transplantation; DDLT, deceased donor liver transplantation. A p-value <0.05 is indicated in bold. sample size, as well as difference in ethnic distributions (Western vs. Japanese). It is well established that different ethnic groups may have differing underlying risk for the development of autoimmune liver disease (26 28). Given the heterogeneous population serviced by the Toronto Liver Transplant program, this may have led to bias in the risk of disease recurrence when compared to monoethnic populations as reported in the prior studies. Overall 5-, 10-, and 15-year recurrence rates were 17%, 34%, and 45% for PSC, 15%, 19%, and 19% for PBC, and 5%, 20%, and 30% for AIH. These results are in line with other current estimates (25,29), and suggest an increasing risk of disease recurrence over time for all three autoimmune liver diseases, especially in the first 10 years after transplantation. Therefore, if routine surveillance for disease recurrence is to be undertaken, whether in the 3518 American Journal of Transplantation 2016; 16:

8 Autoimmune Liver Disease Recurrence After LDLT Figure 2: Patient survival and graft survival. Kaplan Meier estimates of patient survival time and graft survival time following living first-degree relative (green, interrupted line), living distant-relative or unrelated donor (blue, interrupted line) and deceased donor (red, interrupted line) liver transplantation in all autoimmune liver diseases together, as well as separately for primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis. The overall survival is shown by the black continuous line. AIH, autoimmune hepatitis; DDLT, deceased donor liver transplantation; LDLT, living donor liver transplantation; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis. American Journal of Transplantation 2016; 16:

9 Aravinthan et al Figure 3: Disease recurrence. Kaplan Meier estimates of disease recurrence following living first-degree relative (green, interrupted line), living distant-relative or unrelated donor (blue, interrupted line), and deceased donor (red, interrupted line) liver transplantation in primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and autoimmune hepatitis (AIH). The overall recurrence of PSC, PBC, and AIH is shown by a black continuous line. DDLT, deceased donor liver transplantation; LDLT, living donor liver transplantation. form of regular imaging or protocol biopsy, targeting the first 10 years posttransplantation may be most important. This study has its own strengths and limitations. LDLT accounts for a third of all LT activity in the Toronto Liver Transplant Program with overall recipient outcomes comparable to that of DDLT (30), even in those with MELD scores above 25 (9). This makes it an ideal cohort for outcome studies comparing LDLT to DDLT. In addition, LDLT is systematically recommended to all patients accepted for LT and thus mitigates selection bias. This study cohort is much larger than prior studies, especially for PSC, for which it is over 90% powered to detect a 20% difference in recurrence rates between groups on ANOVA testing. Smaller numbers for PBC and AIH, however, led to a reduction in power, and is an acknowledged limitation of this study. This may have led to masking of a small but significant difference in the study groups. The current practice, which leads to the diagnosis of disease recurrence of autoimmune liver disease, only captures clinically significant disease. The lack of protocol screening therefore underestimates the true rate of recurrence and is an important limitation of this study. Furthermore, this study describes a 15-year study period, during which there has been a shift toward the transplantation of sicker patients using live donors, which may have the potential to impact results. The use of multivariate analysis, however, has not shown any association between outcomes and multiple cofactors, including severity of disease at transplantation (i.e. MELD score). In conclusion, this study indicates that recipients with autoimmune liver diseases who receive grafts from first-degree relatives are not disadvantaged by increased disease recurrence, reduced graft survival, or reduced patient survival compared to those who receive grafts from distant/unrelated donors and deceased donors. Living-related LDLT therefore remains a safe option for all patients requiring a LT for autoimmune liver diseases. Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. References 1. Washington MK. Autoimmune liver disease: Overlap and outliers. Mod Pathol 2007; 20(Suppl 1): S15 S Jepsen P, Gronbaek L, Vilstrup H. Worldwide incidence of autoimmune liver disease. Dig Dis 2015; 33(Suppl 2): Ilyas JA, O Mahony CA, Vierling JM. Liver transplantation in autoimmune liver diseases. Best Pract Res Clin Gastroenterol 2011; 25: Adam R, Karam V, Delvart V, et al. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol 2012; 57: Schuetz C, Dong N, Smoot E, et al. HCC patients suffer less from geographic differences in organ availability. Am J Transplant 2013; 13: Johnson RJ, Bradbury LL, Martin K, Neuberger J, Registry UKT. Organ donation and transplantation in the UK the last decade: A report from the UK national transplant registry. Transplantation 2014; 97(Suppl 1): S1 S Northup PG, Intagliata NM, Shah NL, Pelletier SJ, Berg CL, Argo CK. Excess mortality on the liver transplant waiting list: Unintended policy consequences and Model for End-Stage Liver Disease (MELD) inflation. Hepatology 2015; 61: Olthoff KM, Smith AR, Abecassis M, et al. Defining long-term outcomes with living donor liver transplantation in North America. Ann Surg 2015; 262: ; discussion Selzner M, Kashfi A, Cattral MS, et al. Live donor liver transplantation in high MELD score recipients. Ann Surg 2010; 251: Gautam M, Cheruvattath R, Balan V. Recurrence of autoimmune liver disease after liver transplantation: A systematic review. Liver Transpl 2006; 12: Duclos-Vallee JC, Sebagh M. Recurrence of autoimmune disease, primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis after liver transplantation. Liver Transpl 2009; 15(Suppl 2): S25 S American Journal of Transplantation 2016; 16:

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