Primary biliary cholangitis (PBC) is an autoimmune disorder characterized by immune-mediated chronic progressive inflammatory liver disease resulting in chronic cholestasis, portal inflammation, and fibrosis that can lead to cirrhosis, liver failure, and hepatocellular cancer, ultimately requiring liver transplantation (LT).1-3 PBC predominantly affects middle-aged females, and in the early symptomless stages, the female-to-male ratio can be as high as 12:1.4-6 Although primarily described in white women, the disease course is possibly more severe in Hispanics with suboptimal response to primary drug therapy and higher rates of complications.7 The worldwide prevalence of PBC has been estimated to be between 67 and 940 cases per million population per year, and the incidence is between 0.7 and 49 cases per million population per year.8 The Human Development Index estimated a positive association between the incidence of PBC and socioeconomic status, explaining the lower incidence of PBC in developing countries.9 Recent data suggest that the incidence and prevalence of PBC are increasing in certain populations for yet unknown reasons.10
Pruritus and fatigue are the most common symptoms, affecting up to 85% and 70% of the patients, respectively.11,12 As compared with asymptomatic patients, symptomatic PBC patients are less likely to respond to medical therapy and have approximately 3 times the risk of developing cirrhosis and its complications.13 Ursodeoxycholic acid (UDCA) is the mainstay of medical management for PBC. It can postpone its development, improve long-term clinical outcomes, and is extremely safe and well tolerated.5,6 Some studies have also shown improved survival without LT or reduction in risk of death in patients with UDCA.14,15 The biochemical response after 6 or 12 months of UDCA treatment has been shown to be a powerful predictor of long-term clinical outcomes in patients with PBC.16,17 Unfortunately, about a third of patients fail to respond adequately or tolerate UDCA treatment and remain at risk for progression to advanced liver disease including cirrhosis.18,19 Some novel therapeutic agents, including Farnesoid X receptor agonists like obeticholic acid, fibrates, and various immunosuppressants have shown benefit in nonresponders, but data are limited regarding long-term progression and need for liver transplant.20-22
LT is the ultimate lifesaving treatment for patients with decompensated disease, hepatocellular cancer, and in some cases for severe symptoms of PBC.4 With 1-year graft survival of 88% and 5-year graft survival of 78% with 90% to 95% 1-year patient survival, LT is an excellent choice for PBC.23 Recurrence of PBC after LT is not uncommon and can occur in 21% to 37% of patients at 10 years and around 40% of post-LT patients at 15 years, with a median time to recurrence of 3 to 5.5 years.24 Younger patients with PBC tend to have an aggressive disease course, as suggested by poor response to UDCA, which may require early LT.25 However, data are limited regarding the outcomes of LT in younger patients with PBC. The aim of this study is to assess the characteristics and outcomes of LT in younger patients with PBC in comparison to older adults.
MATERIALS AND METHODS
Using the United Network for Organ Sharing database, all patients who received their first LT during 2000 to 2012 with a primary diagnosis of PBC and a cadaveric donor were identified. Subjects were then divided into 2 groups based on their age at the time of transplant: young patients (≤40 y) and older adults (≥41 y). The term adolescents and young adults characterizes a population of patients beginning at age 15 years with disputable cutoffs at 24, 29, and 39 years of age.26 Within this group, young adults are defined as 20 years and older. This term is widely used by our oncology colleagues who have recognized over the past decade that adolescents and young adults with cancer have different needs and treatment challenges than both younger children and older adults.27 This definition was also recently accepted within the hepatology literature as evident by the publication of articles in high-impact factor journals, such as Hepatology.28 All established or suspected factors associated with LT outcome and/or PBC were assessed, including demographics and clinical characteristics of both donors and recipients, cold ischemia time, cause of death (COD), immunosuppressive regimens (mycophenolate mofetil, rapamycin, cyclosporine/tacrolimus), post-LT length of hospital stay, duration of graft failure, and 5-year morbidity and mortality outcomes. Factors associated with post-LT survivals and retransplantation were also assessed. Given the deidentified nature of the data set, the study was exempt from approval from an ethics’ board.
Data are presented as the mean ± standard deviation or median (25th, 75th percentiles) for continuous variables and frequency (%) for categorical factors. Univariable analysis was performed to assess differences between young patients and older adults. Analysis of variance or the nonparametric Kruskal-Wallis tests were used for continuous variables, and Pearson χ2 tests were used for categorical factors. Kaplan-Meier product limit estimates were used to assess patient and graft survival, and log-rank tests were used to compare the groups. Time of follow-up was defined as months from transplant to event (relisted, retransplanted, or death), and subjects were censored at the time of retransplant or last follow-up. Also, competing risks analysis was used to evaluate relisting and retransplantation rates as death precludes both of these events. Follow-up time for all analyses was truncated at 5 years post-LT for analysis. For multivariable analysis, age group was included in all models, and an automated stepwise variable selection performed on 1000 bootstrap samples was used to choose other variables to include; factors with inclusion rates of at least 50% were included in the final models. SAS version 9.4 (SAS Institute, Cary, NC) was used to perform all analyses, and a P < 0.05 was considered statistically significant.
A total of 2084 patients who received LT for the primary diagnosis of PBC were included in this analysis. Table 1 describes the baseline characteristics of recipients. Briefly, the younger patient group included 158 patients with a median age of 35 years (30–38 y) at the time of transplant as compared to the median age of 57 years (51–63 y) in older adults. Overall, both groups had a low proportion of males, but compared with older adults, young recipients had a relatively higher percentage of males (27.2% versus 15.4%; P < 0.001). The majority of patients in both groups were whites, but the proportion of nonwhites in younger patients was significantly higher (43.7% versus 21.5%; P < 0.001). As compared with the older group, younger recipients had significantly lower body mass index (BMI) (24.6 ± 5.3 versus 26.6 ± 5.5; P < 0.001), obesity (14.1% versus 24.0%; P = 0.005), diabetes (5.8% versus 12.8%; P = 0.011), and hypertension (HTN) (2.2% versus 13.5%; P = 0.002). Although median serum bilirubin at the time of LT in the younger group was higher than adult patients (10.5 versus 6.2; P < 0.001), they had significantly lower serum creatinine (0.8 versus 1.0; P < 0.001). Also, younger patients were less likely to be on life support (1.9% versus 5.8%; P = 0.038). On the other hand, international normalized ratio, albumin level, and Model for End-Stage Liver Disease score showed no significant difference between the 2 age groups. Additionally, patients within the 2 age groups spent similar amounts of time on the waiting list before LT.
The choice of donors was determined by availability at the time of LT. Table 2 summarizes the characteristics of donors in both groups. There were significant differences in the age (34.9 ± 19.1 y in younger versus 41.7 ± 19.1 y in older adults; P < 0.001) and BMI (24.3 ± 5.2 in the younger group versus 25.8 ± 5.6 in adults; P = 0.001) in both donor groups at the time of LT. However, there was no difference in the type of transplant (P = 0.34), geographical allocation of type (P = 0.94), total ischemic time (P = 0.61), male donors (P = 0.99), donation after circulatory death (P = 0.36), and donor risk index (P = 0.42). The COD was different in both groups but did not reach statistical significance (P = 0.006). The noted differences were likely due to the matching algorithm and had a possible meaningful impact on the hazard ratio (HR) of survival for the patients.
As compared with younger recipients, older adults had a prolonged length of stay (LOS) (10 versus 9 days, P = 0.003) after the first LT. Within 5 years of LT, mortality, retransplantation, and relisted for transplantation rates in the younger group compared with older adults were 8.2% versus 15.1%, 14.6% versus 4.7%, and 1.9% versus 1.5% (P < 0.001 for all). Overall, 304 patients (14.5%) died after first LT, with 13 (8.2%) of 158 in the younger group and 291 (15.1%) of 1926 in the older adults group. Multiple organ failure (11.7%) and sepsis (11.3%) were the most common COD in older adults, and graft rejection (15.4%) and hemorrhage (15.4%) were the leading cause of mortality in younger patients. There was no significant difference in the use of immunosuppressive medications (mycophenolate mofetil [P = 0.59], rapamycin [P = 0.63], and cyclosporine/tacrolimus [P = 0.46]) and the patient survival time between younger and older patients (50.1 versus 52.5 mo; P = 0.86) (Table 3).
One-, 3-, and 5-year survival rates were 96.7%, 94.1%, and 88.7% for younger patients and 89.9%, 85.6%, and 82.2%, respectively, for older recipients (Figure 1). A poor post-LT survival was noticed in older adults. On multivariate regression analysis, older age (41 years and older), ventilation use, being on dialysis, and males were found to be associated with higher mortality. After adjusting for albumin, dialysis, ventilation use, and sex of the donor, older recipients had approximately 2 times higher risk of mortality (HR, 1.8, 95% confidence interval [CI], 1.03-3.1; P = 0.039) than younger patients (Table 4).
Recurrence and Retransplantation
A detailed summary of the outcomes within 5 years of LT in young patients with PBC is shown in Figure 2A and of the older adults in Figure 2B. Of 27 younger subjects who were relisted, 30% (n = 8) had PBC as the primary diagnosis at the time of listing. The other subjects had cryptogenic cirrhosis (n = 1), primary sclerosing cholangitis (PSC) (n = 2; 1 Crohn disease and 1 no bowel disease), graft versus host disease (n = 1), and other reasons (n = 15). Of the 23 subjects who were retransplanted, 35% (n = 8) had PBC as their primary diagnosis for LT. The other subjects had acute hepatic necrosis (AHN) (n = 1), cryptogenic cirrhosis (n = 1), PSC (n = 2; 1 Crohn disease and 1 no bowel disease), cholestatic liver disease (n = 1), other reasons (n = 9), and 1 for an unknown reason.
Of the 156 older subjects who were relisted, 42% (n = 65) had PBC as the primary diagnosis at the time of listing. The other subjects had AHN (n = 7), cirrhosis (n = 7; 1 type A, 2 type C, 2 cryptogenic, and 2 autoimmune), PSC (n = 3; 2 ulcerative colitis and 1 no bowel disease), metabolic disease (n = 1), graft versus host disease (n = 3), graft failure (n = 1), other reasons (n = 68), and 1 unknown reason. Of the 90 subjects who were retransplanted, 39% (n = 35) had PBC as their primary diagnosis for LT. The other subjects had AHN (n = 12), cirrhosis (n = 3; 2 autoimmune and 1 other reason), PSC (n = 1 ulcerative colitis), cholestatic liver disease (n = 3), metabolic disease (n = 1), primary liver metastasis (n = 1), graft versus host disease (n = 2), graft failure (n = 1), other reasons (n = 27), and 4 were transplanted for unknown reason.
Relisting rates at 1, 3, and 5 years for younger patients were 2.2%, 2.7%, and 3.2% versus 0.6%, 0.6%, and 0.6%, respectively, for the older group (P < 0.001). Similarly, retransplantation rates at 1, 3, and 5 years for younger patients were 2.3%, 2.5%, and 3% compared with 0.4%, 0.4%, and 0.5%, respectively, for the older group (P < 0.001). The exact data on retransplantation indications were unavailable. Although, retransplantation rates after first LT for PBC were different at 5 years (3% in younger versus 0.5% in older group; P < 0.001) (Figure 4), and when results were extrapolated to 10 years, there were still significant differences in retransplantation rates among 2 groups (3.8% in younger versus 0.6% in older group; P < 0.001). Overall, younger patients were at a higher risk for relisting (Figure 3) and retransplantation (Figure 4). After adjusting for sex, ventilator use pre-LT, albumin, time on the waiting list, and donor sex, younger patients had 3 times higher risk of retransplantation than older adults (HR, 3.4; 95% CI, 2.1-5.3; P < 0.001) (Table 5). During a median follow-up period of 8.5 years, 23 (15%) of 158 patients in the younger group were retransplanted and 8 (35%) of 23 had recurrent PBC (rPBC) as an indication for retransplantation. In older patients, during a mean follow-up period of 1.4 years, 90 (5%) of 1926 received re-LT, and 35 (39%) of 90 were transplanted for rPBC.
Despite the recent advances in medical therapies for PBC and a decline in the number of LTs for PBC, LT remains the only definitive treatment for PBC.29,30 Although recurrence of PBC after LT can occur in 21% to 53% of transplanted patients, once end-stage liver disease sets in, LT is the only lifesaving option.24,31 Younger patients with PBC may have a different disease course and distribution, with a more aggressive disease requiring early LT and a higher risk of disease recurrence.31 This study demonstrates that, as compared with older adults with PBC, younger patients had more nonwhites and males affected by PBC, and they had less metabolic comorbidities. Both groups had excellent 1-, 3-, and 5-year outcomes (96.7%, 94.1%, and 88.7% for younger patients and 89.9%, 85.6%, and 82.2%, respectively), but older adults had twice the risk of mortality (HR, 1.8; 95% CI, 1.03-3.1; P = 0.039). After first LT, younger recipients had a higher risk of being listed for retransplantation (P < 0.001) and had 3 times higher risk of retransplantation than older adults (HR, 3.4; 95% CI, 2.1-5.3; P < 0.001). Interestingly, recurrent PBC as an indication for retransplantation was not significantly different in the 2 groups (35% in younger patients versus 39% in older adults).
PBC predominantly affects middle-aged white females and usually presents in the fifth or sixth decade of life.4 Besides genetic predisposition and environmental triggers, autoimmunity has been suggested as the underlying mechanism causing cholestasis, fibrosis, and cirrhosis leading to LT.1,6 Up to 55% of patients with PBC have additional autoimmune processes (eg, Sjogren syndrome), further suggesting an underlying immune process as an etiology for PBC.32,33 Along with well-known complications of PBC, like fibrosis and cirrhosis, PBC can also lead to osteopenia/osteoporosis,34 hyperlipidemia,35 and fat-soluble vitamin deficiencies.36 PBC has been linked with metabolic syndrome,37 and the presence of obesity (BMI ≥ 25) has been associated with severe biliary duct damage and fibrosis in patients with PBC.38 The fraction of males and nonwhites affected by PBC in this study was much higher in younger patients as compared with older adults, suggesting that disease distribution could be different in early-onset PBC. Different race and sex distribution in younger patients could contribute to the aggressive disease course and early need for LT. However, long-term follow-up of the young group is required to see if sex and ethnicity trend change with older age. Levy et al7 in a cross-sectional study found that after 1 year of UDCA therapy, patients of Hispanic ethnicity with PBC had reduced biochemical response than non-Hispanic patients (60% versus 88%; P < 0.0001). Hispanics also had higher percentage of ascites (24% versus 12%; P = 0.03) and variceal bleeding (20% versus 7%; P = 0.01). Interestingly, there were no differences in the numbers of deaths or liver transplants. In another cross-sectional study using the United Kingdom-PBC patient cohort, Carbone and colleagues25 found male sex to be an independent predictor of nonresponse to UDCA. In their study, age at diagnosis was also associated strongly and independently with response to UDCA. The response rates ranged from 90% among patients who presented with PBC when they were older than 70 years, to <50% for those younger than 30 years (P < 0.0001), suggesting more rapid progression of the disease and possibly early LT in younger patients. Compared with older adults, higher bilirubin levels in younger patients in our study indicates advanced liver disease from aggressive disease course in younger patients with PBC, leading to early LT.6 Components of metabolic syndrome (BMI, diabetes, obesity, and HTN) were significantly lower in younger patients, which could be due to the early disease presentation, as prevalence of MS increases with age.39 A similar trend between age and MS was noted by Floreani et al.37 They found that the mean age at diagnosis of PBC patients with MS was significantly older than without MS (P < 0.045), and they had a higher incidence of cardiovascular events (P < 0.0001). Response to UDCA was greater in the group without MS, but the difference was not statistically significant (P = 0.452).
In concordance with previous studies, both groups had excellent 1-, 3-, and 5-year post-LT outcomes of more than 80%. Prolonged LOS was noted in older adults, which could be from higher prevalence of obesity and ventilator use in these patients.40,41 Ventilation dependence has also been suggested as a risk factor for prolonged LOS after LT (odds ratio, 1.53; CI, 1.31-1.79).41 Although ventilator use was higher in older adults (4.8% versus 1.9% in younger patients), this difference was not statistically significant (P = 0.095). Increased risks of infections and multiorgan failure from a high prevalence of underlying diabetes,42 older age,43 and age-related comorbidities could be the reasons for higher mortality in older adults.37
Prolonged mean follow-up periods of retransplantation listing (11.4 versus 4.2 y) and for retransplantation (8.4 versus 1.4 y) in younger patients compared with older adults could explain the finding of more young patients being on the waiting list and getting retransplanted. Despite a shorter follow-up period, PBC recurrence was higher in older patients (39% versus 35% in younger), which is contrary to previous studies where risk of recurrence was higher in younger recipients. Donor-recipient mismatches could be a possible reason for this difference, with more male allografts being protective against disease recurrence.31 Additionally, the majority of the differences between the 2 age groups could be due to the response rate to UDCA treatment, but because the United Network for Organ Sharing database does not include the UDCA treatment outcomes, it is difficult to draw any solid conclusions about the patient history of medication use.
In conclusion, our study strongly suggests that compared to older adults with PBC, the disease course and distribution could be significantly different in younger patients with early-onset PBC. Younger patients receiving LT because of PBC in our study were more likely to be male, nonwhite, have a lower BMI and creatinine, higher bilirubin, and were less likely to have diabetes, HTN or be on life support pre-LT. Both groups had an excellent 1-, 3-, and 5-year survival rates, but older adults had prolonged LOS and twice the risk of death after first LT. Although, younger patients were more likely to be relisted and retransplanted, rPBC occurrence was not more common than in older adults. Given the difference in prevalence, disease distribution, and early need for LT, early-onset PBC in younger patients is different from the typical progression of the disease in older adults. Differentiation between the 2 age groups may indicate different pathophysiology for early-onset PBC in younger adults, which warrants further investigation. Future studies should additionally monitor use of UDCA or alternative management medications pre- and post-LT in younger patients with early-onset PBC.
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