What You Need to Know About Amyloidosis This Year

Summary and Overview

Amyloidosis comprises rare disorders caused by extracellular deposition of insoluble amyloid fibrils from misfolded proteins, leading to progressive organ dysfunction. Key subtypes include light-chain (AL) amyloidosis, arising from abnormal plasma cell production of immunoglobulin light chains, and transthyretin (ATTR) amyloidosis, caused by misfolded transthyretin protein in hereditary (ATTRv) or wild-type (ATTRwt) forms. Cardiac amyloidosis, involving heart infiltration, is increasingly diagnosed due to improved imaging. Both AL and ATTR amyloidosis cause significant morbidity and mortality, with prognosis depending on early diagnosis and organ involvement.

Amyloidosis affects multiple organs, especially kidneys, heart, and nervous system. AL amyloidosis is linked to plasma cell disorders, while ATTR amyloidosis involves transthyretin gene mutations or wild-type protein accumulation, predominantly in older men. Diagnosis is challenging due to nonspecific symptoms, relying on tissue biopsy with Congo red staining and biomarkers. Advances in targeted therapies for AL and ATTR amyloidosis have improved outcomes, but underdiagnosis remains a problem.

Causes, Pathophysiology, and Risk Factors

Amyloidosis results from protein misfolding and aggregation into insoluble fibrils that deposit in tissues, disrupting function. AL amyloidosis stems from abnormal plasma cells producing amyloidogenic light chains, often associated with multiple myeloma. Hereditary ATTR amyloidosis involves transthyretin gene mutations, while secondary amyloidosis (AA) is linked to chronic inflammation, and dialysis-related amyloidosis arises from beta-2 microglobulin accumulation. Genetic mutations and factors affecting protein stability contribute to disease risk.

At the molecular level, misfolded proteins form β-sheet rich amyloid fibrils via nucleation and polymerization, with small oligomers being cytotoxic. Amyloid deposits include modified protein variants and chaperones, causing tissue damage. Diagnostic dyes like Congo red aid detection. Understanding these mechanisms guides development of targeted therapies.

Clinical Presentation

Amyloidosis presents variably depending on subtype and organ involvement, often delaying diagnosis. Common manifestations include:

• Renal: Heavy proteinuria and nephrotic syndrome, mainly in AL and AA types.
• Cardiac: Heart failure, arrhythmias, and conduction abnormalities, increasingly recognized especially in older patients.
• Neurologic: Peripheral and autonomic neuropathy, particularly in hereditary ATTR.
• Hepatic/Gastrointestinal: Rare isolated liver involvement; GI symptoms from motility impairment.
• Dermatologic: Signs like periorbital purpura and macroglossia in AL amyloidosis.

Constitutional symptoms such as fatigue and weight changes are common. Diagnostic delays are frequent due to nonspecific symptoms and variable presentations.

Diagnosis

Diagnosis relies on tissue biopsy with Congo red staining showing amyloid deposits under polarized light. Non-invasive biopsy sites such as abdominal fat pad are preferred, with biopsy of affected organs reserved for inconclusive cases. Laboratory tests detect monoclonal light chains by serum and urine immunofixation and free light chain assays, critical for AL amyloidosis diagnosis. Bone marrow studies assist in plasma cell characterization. Biomarker-based staging using cardiac and hematologic markers guides prognosis and treatment. Improved imaging techniques enhance detection, especially of cardiac involvement.

Epidemiology

AL amyloidosis incidence is about 10 cases per million annually, with a 20-year prevalence near 51 per million. Hospitalizations for cardiac amyloidosis have risen, particularly in certain US regions. Epidemiologic data aid awareness and resource allocation.

Treatment

Treatment differs by subtype:

• AL amyloidosis: Targeting clonal plasma cells with regimens like cyclophosphamide, bortezomib, dexamethasone (CyBorD) combined with anti-CD38 antibody daratumumab (Dara-CyBorD) is standard. Research into therapies degrading amyloid fibrils and targeting toxicity is ongoing.
• ATTR amyloidosis: Transthyretin stabilizers such as tafamidis are mainstays. RNA interference agents like patisiran and vutrisiran reduce transthyretin production. Experimental therapies targeting amyloid fibrils are in development. Early diagnosis facilitates timely treatment initiation.

Prognosis

Prognosis depends on amyloidosis type, organ involvement, and diagnostic timing. Early diagnosis improves survival, especially in AL amyloidosis where delayed diagnosis increases mortality. Organ responses lag behind hematologic responses, requiring ongoing monitoring. Advances in therapies have improved outcomes, though patients with advanced cardiac or hepatic involvement face poorer prognosis.

Research and Future Directions

Research focuses on understanding amyloid fibril structure and aggregation mechanisms to develop targeted treatments. Novel biomarkers stratified by disease stage aim to improve early detection and monitoring. Therapeutic advances include anti-CD38 therapies for AL and multiple FDA-approved agents for ATTR cardiac amyloidosis. Efforts continue to refine diagnostics, expand treatment options, and integrate multidisciplinary care, transforming amyloidosis into a more manageable condition.

The content is provided by Harper Eastwood, Scopewires