Amyloidosis: Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Amyloidosis refers to a group of disorders in which misfolded proteins deposit as insoluble amyloid fibrils in organs and tissues, causing progressive organ dysfunction. The most clinically important types: AL amyloidosis (immunoglobulin light chain, plasma cell dyscrasia-related), ATTR amyloidosis (transthyretin: wild-type or hereditary), and AA amyloidosis (serum amyloid A, inflammation-related). Any organ may be affected.

AL amyloidosis: clonal plasma cells produce abnormal immunoglobulin light chains (lambda more common than kappa) that misfold and aggregate. ATTR amyloidosis: either age-related wild-type ATTR (ATTRwt, formerly senile cardiac amyloidosis) or hereditary ATTR (ATTRv) from transthyretin gene mutations — Val122Ile (common in African Americans, cardiac predominant), Val30Met (familial amyloid polyneuropathy, endemic in Portugal, Japan, Sweden). AA amyloidosis: chronic inflammatory diseases (RA, IBD, FMF, recurrent infections, Castleman disease).

AL amyloidosis: nephrotic syndrome (heavy proteinuria, edema), restrictive cardiomyopathy with preserved EF (dyspnea, heart failure), autonomic neuropathy (orthostatic hypotension, diarrhea/constipation), macroglossia (pathognomonic), bilateral periorbital purpura ('raccoon eyes'), carpal tunnel syndrome, and hepatomegaly. ATTR: predominantly restrictive cardiomyopathy, bilateral carpal tunnel, and peripheral neuropathy in hereditary form. AA: nephrotic syndrome predominantly.

Abdominal fat pad or rectal biopsy with Congo red staining (apple-green birefringence under polarized light microscopy) screens for amyloid. Mass spectrometry proteomics on biopsy is the gold standard for amyloid typing (essential to distinguish AL from ATTR and AA before treatment). Serum free light chains and SPEP/UPEP for AL. Bone marrow biopsy for clonal plasma cells. 99mTc-pyrophosphate (PYP) or DPD scintigraphy for ATTR cardiac amyloidosis (>95% sensitivity/specificity).

AL amyloidosis: treat the underlying plasma cell clone — daratumumab-VCd (bortezomib, cyclophosphamide, dexamethasone) is the current first-line standard, achieving hematologic complete response in approximately 53% and significant organ improvement. Autologous SCT for eligible patients with limited organ involvement. ATTR amyloidosis: tafamidis (kinetic stabilizer) for ATTRwt and ATTRv cardiac amyloidosis — reduced CV mortality and hospitalizations (ATTR-ACT trial). RNA silencer therapies: patisiran or vutrisiran for ATTRv polyneuropathy. AA amyloidosis: control the underlying inflammatory disease (biologics for RA/IBD, colchicine for FMF).

AL amyloidosis: untreated with cardiac involvement median OS less than 6 months; with daratumumab-VCd and achievement of hematologic CR, significant cardiac and renal organ improvement and prolonged survival. ATTR cardiac amyloidosis: tafamidis significantly reduces mortality (ATTR-ACT: 29.5% vs 42.9% mortality at 30 months vs placebo). ATTRv polyneuropathy with RNA silencer: significant improvement in neuropathy scores. AA amyloidosis: renal survival excellent if underlying disease controlled.