From Symptoms to Treatment: Understanding Amyloidosis

Summary and Overview

Amyloidosis is a group of disorders caused by extracellular deposition of insoluble misfolded protein fibrils (amyloid) in various organs, leading to progressive dysfunction. The main systemic types are light chain (AL), inflammation-associated (AA), dialysis-related (Aβ2M), and transthyretin (ATTR) amyloidosis. Affected organs include the heart, kidneys, liver, nerves, and blood vessels, resulting in diverse symptoms such as cardiomyopathy, nephrotic syndrome, neuropathy, and macroglossia. Diagnosis requires biopsy confirmation of amyloid deposits, supported by imaging and proteomic subtyping. Treatment advances, especially for AL amyloidosis, include novel antiplasma cell therapies like daratumumab combined with chemotherapy, improving survival. Early diagnosis remains critical, particularly in cardiac AL amyloidosis, to optimize outcomes. Research continues to develop targeted therapies and improve management in specialized centers.

Pathophysiology and Clinical Presentation

Amyloidosis results from misfolded proteins aggregating into beta-sheet fibrils that deposit in tissues, disrupting structure and function. The specific precursor proteins vary by type, with over 60 identified. AL amyloidosis arises from monoclonal light chains, ATTR from mutant or wild-type transthyretin, and AA from serum amyloid A protein linked to chronic inflammation. Deposits cause organ dysfunction: cardiac involvement leads to restrictive cardiomyopathy and heart failure; renal deposition causes proteinuria and nephrotic syndrome; nerve infiltration results in sensory, motor, and autonomic neuropathies. Other manifestations include macroglossia, purpura, and carpal tunnel syndrome. Symptoms vary widely depending on organ involvement.

Diagnosis

Diagnosis combines clinical evaluation, laboratory testing, imaging, and biopsy. Imaging modalities like cardiac MRI and nuclear scans detect organ involvement. Laboratory tests include serum and urine protein electrophoresis, immunofixation, and serum free light chain assays to identify monoclonal proteins, especially in AL amyloidosis. Definitive diagnosis requires tissue biopsy—commonly abdominal fat pad or bone marrow—showing amyloid deposits with Congo red staining. Amyloid typing by immunohistochemistry or mass spectrometry guides treatment. Multidisciplinary approaches improve diagnostic accuracy, especially in cardiac cases.

Disease Progression and Prognosis

Progression depends on amyloid type and organ damage extent. AL amyloidosis has the poorest prognosis, especially with cardiac involvement, where median survival without treatment is about six months. Early diagnosis significantly improves survival. ATTR amyloidosis generally has a better prognosis, with patients often surviving over a decade. AA amyloidosis prognosis depends on controlling the underlying inflammatory disease. Common causes of death include cardiac and hepatic failure and infections.

Treatment and Advances

Treatment has advanced markedly, particularly for AL amyloidosis, where the combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is now frontline therapy, improving response and survival. Autologous stem cell transplantation remains an option for selected patients. Emerging therapies include targeted agents like venetoclax and experimental light chain stabilizers. For ATTR amyloidosis, tafamidis stabilizes transthyretin tetramers, slowing disease progression. Supportive care addressing multisystem symptoms is essential and best delivered through specialized multidisciplinary centers. Participation in clinical trials is encouraged to access novel treatments and advance knowledge.

The content is provided by Jordan Fields, Scopewires