amyloidoses

Amyloidoses are a group of disorders characterized by extracellular deposition of insoluble amyloid fibrils in tissues and organs, caused by misfolded precursor proteins that adopt a beta-pleated sheet configuration. The main clinical types are AL (light-chain) amyloidosis, AA (secondary) amyloidosis, transthyretin-related (ATTR) amyloidosis, and less common forms such as dialysis-related beta-2 microglobulin (Aβ2M) and hereditary amyloidoses.

Pathophysiology and diagnosis begin with misfolded precursor proteins that aggregate into amyloid fibrils, disrupting tissue architecture and function. Tissue confirmation traditionally relies on Congo red staining, which shows apple-green birefringence under polarized light. Subtyping the fibrils by immunohistochemistry or, more accurately, mass spectrometry, is essential to guide treatment. Noninvasive screening and monitoring include serum free light chains and protein electrophoresis to detect abnormal immunoglobulin components, while imaging evaluates organ involvement.

Clinical features depend on the organs affected. The kidneys commonly show proteinuria and nephrotic syndrome; the heart may develop restrictive cardiomyopathy and arrhythmias; the liver and spleen can be enlarged; peripheral and autonomic neuropathies occur, along with gastrointestinal symptoms. Skin involvement can occur in some hereditary forms.

Treatment is type-specific. AL amyloidosis is managed with chemotherapy regimens (often bortezomib-based) and, in select patients, autologous stem cell transplantation. AA amyloidosis targets the underlying inflammatory disease. ATTR amyloidosis uses TTR stabilizers (such as tafamidis) and, for hereditary forms, gene-silencing therapies (patisiran, inotersen); liver transplantation may be considered in select hereditary cases. Dialysis-related amyloidosis due to beta-2 microglobulin has become less common with improved dialysis but remains a management consideration.

Prognosis varies with type and organ involvement; earlier diagnosis and disease-specific therapies improve outcomes.