In contrast to familial Mediterranean fever, a group of autosomal dominant familial disorders is characterized by deposition of amyloid made up of fibrils derived from mutant transthyretin (TTR). TTR is a transporter of the hormone thyroxine. Remarkably, specific TTR mutant polypeptides tend to form amyloid in different organs; thus, in some families, deposits are seen mainly in peripheral nerves (familial amyloidotic polyneuropathies), whereas in others cardiac deposits predominate. The mutated form of the TTR gene that leads to cardiac amyloidosis is carried by approximately 4% of the black population in the United States, and cardiomyopathy has been identified in both homozygous and heterozygous patients. The precise prevalence of patients with this mutation who develop clinically manifest cardiac disease is not known.
Hemodialysis-Associated Amyloidosis. Patients on long-term hemodialysis for renal failure can develop amyloid deposits derived from β2-microglobulin. This protein is present in high concentrations in the serum of individuals with renal disease, and in the past it was retained in the circulation because it could not be filtered through dialysis membranes. With new dialysis filters, the incidence of this complication has decreased substantially. The classical features of this form of amyloidosis are the triad of scapulohumeral periarthritis, carpal tunnel syndrome, and flexor tenosynovitis of the hand.
Localized Amyloidosis. Sometimes, amyloid deposits are limited to a single organ or tissue without involvement of any other site in the body. The deposits may produce grossly detectable nodular masses or be evident only on microscopic examination. Nodular deposits of amyloid are most often encountered in the lung, larynx, skin, urinary bladder, tongue, and the region about the eye. Frequently, there are infiltrates of lymphocytes and plasma cells associated with these amyloid masses. At least in some cases, the amyloid consists of AL protein and may therefore represent a localized form of plasma cell–derived amyloid.
Endocrine Amyloid. Microscopic deposits of localized amyloid may be found in certain endocrine tumors, such as medullary carcinoma of the thyroid gland, islet tumors of the pancreas, pheochromocytomas, and undifferentiated carcinomas of the stomach, and in the islets of Langerhans in individuals with type 2 diabetes mellitus. In these settings, the amyloidogenic proteins seem to be derived either from polypeptide hormones (e.g., medullary carcinoma) or from unique proteins (e.g., islet amyloid polypeptide).
Amyloid of Aging. Several well-documented forms of amyloid deposition occur with aging. Senile systemic amyloidosis refers to the systemic deposition of amyloid in elderly patients (usually in their seventies and eighties). Because of the dominant involvement and related dysfunction of the heart, this form was previously called senile cardiac amyloidosis. Those who are symptomatic present with a restrictive cardiomyopathy and arrhythmias (Chapter 11). The amyloid in this form, in contrast to familial forms, is derived from normal TTR.