Amyloidosis

Pathologic extracellular deposition of insoluble misfolded protein fibrils (β-pleated sheets) in tissues, leading to progressive organ dysfunction.

• Multi-organ, potentially fatal disease; hallmark Congo red stain (apple-green birefringence) and the need to identify the amyloid type (AL vs AA vs ATTR) make it a frequently tested diagnosis.

• Standardized nomenclature convention: A X (A = amyloidosis; X = fibril protein). Examples: AL (amyloid light chain), AA (amyloid A protein), ATTR (amyloid transthyretin).
• AL (primary) amyloidosis: monoclonal immunoglobulin light chains (from a plasma cell dyscrasia like multiple myeloma) deposit as AL amyloid. Typically causes nephrotic syndrome, restrictive cardiomyopathy, peripheral neuropathy; classic features include macroglossia and periorbital purpura.
• AA (secondary) amyloidosis: chronic inflammation/infection (e.g., rheumatoid arthritis, TB) → high serum amyloid A → AA amyloid deposits. Classically presents with renal involvement (e.g., nephrotic syndrome); may also cause hepatosplenomegaly.
• ATTR (wild-type, senile) amyloidosis: deposition of normal transthyretin (TTR) in older adults (median age ~75; ~90% men). Predominantly cardiac involvement (restrictive cardiomyopathy, arrhythmias) and often carpal tunnel syndrome; progression is slower than AL amyloidosis.
• ATTR (hereditary) amyloidosis: autosomal dominant mutations in transthyretin. Presents as familial amyloid polyneuropathy (peripheral/autonomic neuropathy, onset in 20–40s) or familial amyloid cardiomyopathy (heart failure in middle-age or later).
• Aβ₂M (dialysis-related) amyloidosis: β₂-microglobulin accumulates in patients with end-stage renal disease on long-term dialysis. Deposits in joints and tendons (e.g., shoulder pain, carpal tunnel syndrome, bone cysts), typically after >10 years on dialysis.

1. Confirm amyloid: biopsy (abdominal fat pad aspirate or involved organ) with Congo red staining (shows apple-green birefringence). Then perform fibril typing via immunohistochemistry or mass spectrometry to determine the amyloid protein.
2. Identify underlying cause: if AL suspected, check for monoclonal proteins (SPEP/UPEP, serum free light chains) and do bone marrow biopsy for plasma cell dyscrasia; if AA, search for chronic infection/inflammation (e.g., culture, inflammatory markers); if ATTR, consider genetic testing for transthyretin mutations.
3. Cardiac evaluation: if heart involvement is suspected, obtain ECG (classically low voltage with amyloid cardiomyopathy) and echocardiogram. A nuclear 99m Tc-PYP scan can noninvasively detect ATTR cardiac amyloid and help distinguish it from AL.

1. Treat the underlying cause of the amyloid protein when possible (specialist-guided by type).
2. AL amyloidosis: systemic chemotherapy (e.g., melphalan plus corticosteroids, or newer regimens like bortezomib-based therapy) ± autologous stem cell transplant for eligible patients.
3. AA amyloidosis: aggressive management of the chronic inflammatory disease (e.g., immunosuppressants for rheumatoid arthritis, colchicine for familial Mediterranean fever) to reduce serum amyloid A production.
4. ATTR amyloidosis: newer disease-modifying agents (e.g., tafamidis to stabilize transthyretin) or, for hereditary cases, liver transplant to remove the source of mutant TTR. Advanced cardiac amyloidosis may require heart transplant; provide supportive care for heart failure and other complications.

• Think Congo red → apple-green birefringence under polarized light: classic pathologic finding for amyloid deposits.
• Clues for AL amyloidosis: macroglossia or periorbital purpura (raccoon eyes) are highly specific and rarely seen in other types.
• Amyloid cardiomyopathy often shows low-voltage ECG despite thickened ventricular walls (due to insulating amyloid in myocardium).

• Suspected AL amyloidosis with cardiac involvement is a medical emergency – without prompt therapy, median survival can be under 1 year. Rapidly worsening heart failure or arrhythmias in AL amyloid warrants urgent specialist intervention.
• Amyloidosis can lead to sudden cardiac death (due to arrhythmias/conduction block) or irreversible renal failure. Monitor cardiac rhythm and renal function closely; consider defibrillator placement for high-risk cardiac amyloid patients and timely dialysis/transplant referral for progressing renal impairment.

1. Unexplained multi-organ dysfunction (e.g., cardiomyopathy + nephrotic syndrome + neuropathy) → suspect amyloidosis.
2. Initial evaluation: screen for monoclonal proteins (SPEP/UPEP, light chains) and inflammatory markers; perform relevant imaging (e.g., echo, MRI, PYP scan if ATTR suspected).
3. Obtain a tissue biopsy (fat pad or involved organ) → if Congo red positive (amyloid), proceed to amyloid typing (via IHC or mass spec) to determine AL vs AA vs ATTR.
4. Direct treatment according to type: plasma cell–directed therapy for AL, treat underlying disease for AA, or specific measures (tafamidis, transplant) for ATTR; provide supportive care for organ dysfunction.

• Older adult with unexplained restrictive cardiomyopathy (heart failure with preserved ejection fraction), heavy proteinuria (nephrotic-range), and enlarged tongue on exam → AL (primary) amyloidosis (confirm with Congo red stain).
• Patient with long-standing rheumatoid arthritis who develops nephrotic syndrome and hepatomegaly → AA (reactive) amyloidosis from chronic inflammation.
• Elderly man (~75) with congestive heart failure symptoms and history of bilateral carpal tunnel syndrome → senile ATTR amyloidosis (wild-type transthyretin deposits in heart/tendons).