The pathological and biochemical identification of possible seed-lesions of transmitted transthyretin amyloidosis after domino liver transplantation

摘要

Abstract The most serious issue in domino liver transplantation (DLT) using liver grafts from patients with transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) is the development of iatrogenic transmitted amyloidosis ( de novo amyloidosis) in DLT-recipients. However, little is known regarding the mechanisms of the initial stage of amyloid formation in these recipients. We detected initial lesions (possible seed-lesions) of this iatrogenic amyloidosis in two recipients following liver grafting from FAP patients. Patient 1 underwent DLT at age 65 from an FAP patient with a Val30Met TTR variant and patient 2 received DLT from an FAP patient with a Val30Leu TTR variant at age 32. Patient 2 was started on diflunisal administration from 4 years after DLT. While neither patient had symptoms of FAP, small amyloid deposits were detected on the gastroduodenal mucosae 14 months and 12 years after DLT in patient 1 and patient 2, respectively. The amyloid was analyzed using a laser microdissection system and tandem mass spectrometry. Biochemical analysis indicated that the amyloid was composed mostly of variant TTR produced from the transplanted liver in both patients. In patient 1, wild-type TTR amyloid was detectable in the duodenal mucosa obtained 2 years after DLT. This is the first study to successfully capture the pathological and biochemical features of initial-stage amyloid lesions in DLT recipients. The findings clearly indicate that amyloid deposition can start by deposition of variant TTR followed by deposition of wild-type TTR, and blocking of amyloid seed formation from variant TTR may be a key to prevent or delay the development of DLT-associated amyloidosis.