Amyloidogenic phenotypical variation affects post-transplant outcome of hereditary transthyretin amyloidosis: a retrospective study.

Background: Liver transplantation (LTx) was once the standard of care for hereditary transthyretin amyloidosis (ATTRv), but transthyretin (TTR) stabilising and silencing therapies have supplanted it globally, partly because these therapies work in both hereditary and wild-type ATTR, avoids surgical risks and may improve outcomes across a wider patient population. LTx is now reserved for selected ATTRv cases where drug access or efficacy is limited. The Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) was established in 1993 to analyse the outcome of LTx for ATTRv to support the international transplant society with selection criteria as the indication is rare at most centres. Methods: FAPWTR has, to date, secured data from over 30 years of follow-up. The registry holds data on 2267 patients who had LTx with various TTR variants from 82 centres in 21 countries. All patients studied presented with symptoms of polyneuropathy before LTx. The patient's pre-LTx phenotype was classified according to whether or not the heart and/or the kidney presented symptoms suggestive of amyloidotic involvement as reported by the submitting centre. The present study aims to evaluate the effect of these four different phenotypes on outcome as well as the mortality and morbidity in patients who had LTx with ATTRv. Results: Between 1990 and 2012, before pharmacotherapy became generally available as a treatment option, 1762 patients underwent isolated LTx. Overall, 25-year survival after LTx was 32.4%. Median survival time was 20.4 years. Cardiac and cardiorenal phenotypes were poor prognostic factors, while renal phenotype was not. The cardiac phenotype had statistically significantly worse survival compared with all other phenotypes. Median survival for the cardiac, cardiorenal and polyneuropathy-only phenotype were 15.2, 20.8 and 22.7 years, respectively. Age at transplant, disease duration and modified body mass index had a statistically significant impact on survival. Deterioration of autonomic neuropathy occurred earlier than deterioration of peripheral neuropathy and deterioration of extraneurological symptoms and may be an important marker for additional pharmacological treatment in LTx recipients with disease progression. Conclusion: The FAPWTR provides a useful tool to study late effects of LTx as a disease-modifying therapy for ATTRv and may be important for comparison and evaluation of the long-term effects of the various novel pharmacotherapies used today.