Amyloid fibrils containing fragmented ATTR may be the standard fibril composition in ATTR amyloidosis.

Abstract The clinical phenotype of familial ATTR amyloidosis depends to some extent on the particular mutation, but differences exist also within mutations. We have previously described that two types of amyloid fibril compositions exist among Swedish ATTRV30M amyloidosis patients, one consisting of a mixture of intact and fragmented ATTR (type A) and one consisting of mainly intact ATTR (type B). The fibril types are correlated to phenotypic differences. Patients with ATTR fragments have a late onset and develop cardiomyopathy, while patients without fragments have an early onset and less myocardial involvement. The present study aimed to determine whether this correlation between fibril type and phenotype is valid for familial ATTR amyloidosis in general. Cardiac or adipose tissues from 63 patients carrying 29 different TTR non-V30M mutations as well as 13 Japanese ATTRV30M patients were examined. Fibril type was determined by western blotting and compared to the patients' age of onset and degree of cardiomyopathy. All ATTR non-V30M patients had a fibril composition with ATTR fragments, except two ATTRY114C patients. No clear conclusions could be drawn about a phenotype to fibril type correlation among ATTR non-V30M patients. In contrast, Japanese ATTRV30M patients showed a similar correlation as previously described for Swedish ATTRV30M patients. This study shows that a fibril composition with fragmented ATTR is very common in ATTR amyloidosis, and suggests that fibrils composed of only full-length ATTR is an exception found only in a subset of patients.

Marked cardiomegaly in a patient with familial amyloidotic polyneuropathy after orthotopic liver transplantation: a case study.

Hepatocyte-derived mutant amyloidogenic transthyretin (ATTR) causes familial amyloidotic polyneuropathy (FAP), for which orthotopic liver transplantation is an established curative treatment. However, some patients with FAP have cardiac amyloidosis after transplantation. Here, we describe a man with an autonomic disorder diagnosed as FAP ATTR Val30Met and marked cardiomegaly after liver transplantation. He underwent orthotopic liver transplantation at 49 years of age and was prescribed prednisolone to prevent graft rejection. Two years later, autonomic dysfunction and severe heart failure gradually developed. He died suddenly at 59. The autopsy revealed marked cardiomegaly (heart weight: 1020 g). Histological and ultrastructural examinations demonstrated massive amyloid deposition and unusual myocardial hypertrophic injury associated with nuclear translocation of the glucocorticoid receptor (GR). No other FAP patients without heart failure showed GR nuclear translocation. GR is a nuclear transcription factor that leads to myocardial hypertrophy, and cumulative prednisolone doses may promote marked cardiomegaly and severe cardiac amyloidosis.

Relationship between amyloid deposition and intracellular structural changes in familial amyloidotic polyneuropathy.

Transthyretin-related familial amyloidotic polyneuropathy is a systemic amyloidosis caused by mutations in the transthyretin gene. Extracellular deposition of amyloid is the common pathologic hallmark of amyloidoses including Alzheimer disease, AL amyloidosis, AA amyloidosis, and familial amyloidotic polyneuropathy. However, the exact relationship between amyloid deposition and cell death has not yet been clarified. To elucidate this relationship, we studied the effect of transthyretin amyloid fibrils and prefibrillar aggregates on cells by using autopsy tissues obtained from 8 patients with familial amyloidotic polyneuropathy, as well as cultured cell lines. Ultrastructural studies of amyloid-laden cardiomyocytes showed that intracellular structural changes correlated with the degree of amyloid deposition and may reflect metabolic disturbances caused by physical limitations imposed by the amyloid deposits. Amyloid-laden vascular endothelial cells, mesangial cells, smooth muscle cells, Schwann cells, and cardiomyocytes, however, had well-preserved cell nuclei and showed no apoptotic changes, even when cells were completely surrounded by prefibrillar transthyretin aggregates and amyloid fibrils. Synthesized prefibrillar transthyretin aggregates, transthyretin fibrils, and amyloid fibrils obtained from patients with familial amyloidotic polyneuropathy evidenced no cytotoxicity in cell culture experiments. Our data thus indicate that neither transthyretin amyloid fibrils nor prefibrillar transthyretin aggregates directly induced apoptosis. However, cellular metabolic disturbances caused by cells' being physically confined by amyloid deposits may induce cell degeneration.