HaematologyTier 2Disease (DEADMAN)

Amyloidosis

Description

Amyloidosis - extracellular deposition of misfolded protein in a characteristic beta-pleated sheet structure, resistant to normal proteolytic degradation - causes progressive organ dysfunction wherever it accumulates; the haematological perspective centres on AL (light chain) amyloidosis, arising from a clonal plasma cell disorder

AL amyloidosis is the most common systemic amyloidosis in developed countries; arises from an underlying clonal plasma cell (or, less commonly, B cell) population producing free light chains that misfold and deposit as amyloid - related to, but distinct from, multiple myeloma (most AL amyloidosis patients do not meet full myeloma diagnostic criteria)

Misfolded immunoglobulin free light chains (kappa or lambda) form amyloid fibrils that deposit in tissue, disrupting normal organ architecture and function - the heart and kidneys are most commonly and critically affected, and cardiac involvement is the dominant driver of mortality

Cardiac involvement: restrictive cardiomyopathy, raised NT-proBNP/troponin (even without acute coronary syndrome, reflecting amyloid infiltration), characteristic echocardiographic findings (increased wall thickness with normal/reduced voltage on ECG - a discordance pointing toward infiltrative disease rather than true hypertrophy)
Renal involvement: nephrotic-range proteinuria
Tissue biopsy with Congo red staining (apple-green birefringence under polarised light) confirms amyloid; typing (mass spectrometry or immunohistochemistry) distinguishes AL from other amyloid types (e.g. ATTR - transthyretin-related, a different disease requiring entirely different treatment) - correct typing is essential before treatment, since AL and ATTR amyloidosis are managed completely differently
Serum free light chain assay and serum/urine electrophoresis identify and quantify the underlying clonal plasma cell disorder

Chemotherapy targeting the underlying clonal plasma cell population (bortezomib-based regimens are standard, analogous to myeloma treatment) to reduce production of the amyloidogenic light chain - the disease-modifying approach, since established amyloid deposits themselves cannot be directly removed
Autologous stem cell transplant considered in eligible (cardiac function permitting) patients
Supportive management of affected organs (heart failure management adapted for the restrictive physiology, renal support) alongside disease-directed therapy

Multiple myeloma (related but distinct clonal plasma cell disorder), restrictive cardiomyopathy, nephrotic syndrome, ATTR amyloidosis (the key differential requiring different treatment)

Correctly distinguishing AL from ATTR amyloidosis is critical and easily missed if typing is not performed - AL amyloidosis requires urgent chemotherapy targeting the underlying clonal disorder, while ATTR amyloidosis requires an entirely different treatment approach (transthyretin stabilisers/gene-silencing therapy) with no role for chemotherapy

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