Deposition and passage of transthyretin through the blood-nerve barrier in recipients of familial amyloid polyneuropathy livers

Abstract

Familial amyloid polyneuropathy (FAP) is characterized by deposition of mutated transthyretin (TTR) in the peripheral nervous system. Prior to amyloid fibrils, nonfibrillar TTR aggregates are deposited inducing oxidative stress with increased nitration (3-NT). As the major source of TTR is the liver, liver transplantation (LT) is used to halt FAP. Given the shortage of liver donors, domino LT (DLT) using FAP livers is performed. The correlation between TTR deposition in the skin and nerve was tested in biopsies from normal individuals, asymptomatic carriers (FAP 0) and FAP patients; in FAP 0, nonfibrillar TTR was observed both in the skin and nerve in the same individuals; in patients, amyloid was detected in both tissues. The occurrence of amyloidosis in recipients of FAP livers was evaluated 1-7 years after DLT: TTR deposition occurred in the skin 3 years after transplantation either as amyloid or aggregates; in one of the recipients, fibrillar TTR was present in the epineurium 6 years after DLT. Deposits were scarce and 3-NT immunostaining was irrelevant. Nerve biopsies from DLT recipients had no FAP-related neuropathy. Our findings suggest that TTR amyloid formation occurs faster than predicted and that TTR of liver origin can cross the blood-nerve barrier. Recipients of FAP livers should be under surveillance for TTR deposition and tissue damage.

Risk of transmission of systemic transthyretin amyloidosis after domino liver transplantation

“…Previous studies have shown either amyloid or TTR deposits at different gastrointestinal levels as early as 3 years after DLT. 16,17 In our experience, this kind of deposit is quite common (37% of the evaluated patients), and the longer follow-up for our group of patients is likely to have influenced this finding. Asymptomatic FAP patients with the Val30Met mutation have TTR deposits in the form of nonfibrillar aggregates in some organs years before the disease develops.…”

“…16,17 Yamamoto et al 18 showed the development of impaired nerve conduction in DLT recipients but without clinical correlations or biopsy samples. Recently, 3 cases of the transmission of systemic TTR amyloidosis were published.…”

Long-term consequences of domino liver transplantation using familial amyloidotic polyneuropathy grafts

“…There was no evidence of peripheral or autonomic neuropathy 12-40 months after DLT, and gastrointestinal biopsies showed no signs of de novo amyloid deposits 4-24 months after DLT (9). In Portugal, 15 DLT recipients had skin biopsies performed 1-7 years after DLT and TTR depositions were found in a minority of patients 3 years after transplantation (10). A summary of the previous reports is shown in Table 1 (9)(10)(11)(12)(13).…”

“…In Portugal, 15 DLT recipients had skin biopsies performed 1-7 years after DLT and TTR depositions were found in a minority of patients 3 years after transplantation (10). A summary of the previous reports is shown in Table 1 (9)(10)(11)(12)(13). The possibility of de novo amyloidosis as a late complication of DLT is a worrisome issue, and more information is needed to optimize the selection of DLT recipients.…”

Ten Years of Experience with Liver Transplantation for Familial Amyloid Polyneuropathy in Japan: Outcomes of Living Donor Liver Transplantations

“…Development of FAP symptoms has not been reported in any of the domino recipients at up to 7 years follow-up worldwide. However, Sousa et al reported that fibrillar deposits of TTR were observed in the epineurium of the biopsied peripheral nerve in a domino recipient with a 6-year post-operative history (31). Serial and careful follow-up of domino recipients is necessary.…”