The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort

Abstract

Background & aims: Liver transplantation improves survival in end-stage primary biliary cirrhosis (PBC), but the benefit for systemic symptoms including fatigue is less clear. The aim of this study was to utilise the comprehensive UK-PBC Research Cohort, including 380 post-transplant patients and 2300 non-transplanted patients, to answer key questions regarding transplantation for PBC.

Methods: Cross-sectional study of post-transplant PBC patients and case-matched non-transplanted patients. Detailed clinical information was collected, together with patient systemic symptom impact data using validated assessment tools.

Results: Over 25% of patients in the transplant cohort were grafted within 2 years of PBC diagnosis suggesting advanced disease at presentation. Transplanted patients were significantly younger at presentation than non-transplanted (mean 7 years) and >35% of all patients in the UK-PBC cohort who presented under 50 years had already undergone liver transplantation at the study censor point (>50% were treatment failures (post-transplant or unresponsive to UDCA)). Systemic symptom severity (fatigue and cognitive symptoms) was identical in female post-transplant patients and matched non-transplanted controls and unrelated to disease recurrence or immunosuppression type. In males, symptoms were worse in transplanted than in non-transplanted patients.

Conclusions: Age at presentation is a major risk factor for progression to transplant (as well as UDCA non-response) in PBC. Although both confirmatory longitudinal studies, and studies utilising objective as well as subjective measures of function, are needed if we are to address the question definitively, we found no evidence of improved systemic symptoms after liver transplantation in PBC and patients should be advised accordingly. Consideration needs to be given to enhancing rehabilitation approaches to improve function and life quality after liver transplant for PBC.

Fig. 1. Transplantation parameters in PBC.

(A) Timing of LT in relation to timing of diagnosis with PBC for the post-transplant UK-PBC patient cohort. 50% of patients undergoing transplantation had done so by six years following diagnosis. The kinetics of reaching transplantation suggests that a significant proportion of patients presenting with PBC, and who will require transplantation, have advanced disease at the point of presentation. Improved therapy to reduce the need for transplantation will require improved diagnosis and case finding as well as application of effective therapies. (B) Age of diagnosis of PBC in the transplanted (trans) and non-transplanted patient groups in the UK-PBC patient cohort. Patients who had undergone transplantation presented at a significantly younger age. The effect of age of presentation in all age groups on (C) likelihood of the patient within the cohort being transplanted and (D) being in treatment failure (defined as either having had a transplant or having serum biochemistry compatible with non-response to UDCA at the study point). (E) The impact of age of presentation (dichotomised around age 45 on the likelihood of patients being in treatment failure) throughout the disease natural history. Younger age at presentation is associated with significantly increased risk of treatment failure at all points through the disease course. n.a., not available.

Fig. 2. Fatigue severity assessed using the PBC-40 fatigue domain.

(A) Transplanted (trans) male and female PBC patients and case-matched nontransplanted patients (matched for age at diagnosis and disease duration). (B) Post-transplant PBC patients treated with cyclosporine A and tacrolimus immunosuppression (data for 3 of the 7 UK transplant centres). (C) Post-transplant PBC patients with and without histologically confirmed recurrent PBC (data for 3 of the 7 UK transplant centres). (D) Post-transplant PBC patients according to the centre in which they were transplanted within the UK. No differences of significance were observed. n.s., not significant.

Fig. 3. Comparison between non-transplanted and transplanted female and male patients for the PBC fatigue-associated symptoms.

(A) Daytime somnolence as assessed using ESS, (B) depression as assessed using HADS-D, and (C) autonomic dysfunction as assessed using OGS.

Fig. 4. Differences between transplanted and case-matched non-transplanted PBC patients that would directly implicate autonomic dysfunction in the pathogenesis of cognition abnormality and, as previously suggested, fatigue in PBC.

(A) Differences in OGS score between transplanted and case-matched non-transplanted male PBC patients and PBC-40 fatigue domain score. (B) Cognitive symptoms assessed using the PBC-40 cognitive domain in transplanted (trans) and case-matched non-transplanted male and female PBC patients. (C) Association between the differences in OGS score between transplanted and case-matched non-transplanted male PBC patients and PBC-40 cognitive domain score. In male PBC patients, the difference in severity of autonomic symptoms seen between case-matched transplanted and non-transplanted patients is directly proportional to the difference in cognitive and fatigue symptoms. n.s., not significant.