Highlights
- Amyloidosis requires tailored diagnostics and treatments for improved patient outcomes and survival.
- Emerging therapies are transforming amyloidosis management, but access and cost challenges persist.
Summary and Overview
Amyloidosis refers to a group of diseases caused by the extracellular deposition of insoluble amyloid fibrils, which are misfolded protein aggregates that disrupt organ function. Common systemic types include immunoglobulin light chain (AL), serum amyloid A (AA), and transthyretin (ATTR) amyloidosis, each with distinct precursor proteins, organ involvement, and treatments. The disease often affects the heart, kidneys, and nervous system, with cardiac amyloidosis increasingly recognized as a cause of heart failure in older adults. Advances in noninvasive diagnostics and amyloid typing have improved management, while new therapies targeting plasma cells or transthyretin have markedly enhanced outcomes. Challenges remain in cost, accessibility, and early detection, with ongoing research, education, and advocacy efforts focused on improving diagnosis and treatment worldwide.
Causes, Risk Factors, and Pathophysiology
Amyloidosis results from abnormal deposition of amyloid proteins, derived from various precursors depending on the subtype. AL amyloidosis stems from plasma cell clones producing amyloidogenic light chains, mainly affecting the heart and kidneys. AA amyloidosis is linked to chronic inflammation and mainly impacts the kidneys. ATTR amyloidosis includes hereditary (ATTRv) forms caused by TTR gene mutations and wild-type (ATTRwt), an age-related cardiac condition. Dialysis-related amyloidosis (DRA) arises from beta-2 microglobulin accumulation in long-term dialysis patients. These deposits disrupt tissue architecture and organ function through progressive accumulation of beta-sheet–rich fibrils. Genetic mutations play a role in familial forms. Organ tropism varies by amyloid type, affecting cardiac conduction, kidneys, nerves, and other tissues.
Clinical Presentation
Symptoms vary widely based on amyloid type and organs involved, often leading to delayed diagnosis. Common manifestations include cardiomyopathy with heart failure and arrhythmias, peripheral neuropathy causing sensory and autonomic dysfunction, renal impairment with proteinuria, and gastrointestinal disturbances. Cardiac amyloidosis significantly impacts prognosis and is detected by biomarkers like NT-proBNP and troponins. ATTR cardiac amyloidosis is a notable cause of heart failure in the elderly. Peripheral neuropathy and multi-organ involvement complicate clinical recognition, emphasizing the need for heightened awareness.
Diagnosis
Diagnosis relies on detecting amyloid deposits via tissue biopsy with Congo red staining and green birefringence. Abdominal fat and bone marrow biopsies are common initial sites; target organ biopsies are used if needed. Amyloid typing utilizes immunohistochemistry and proteomic methods to guide treatment. Serum and urine immunofixation detect monoclonal light chains in AL amyloidosis. Echocardiography and technetium-labeled bone scintigraphy are key noninvasive tools, especially for ATTR cardiac amyloidosis. Biomarkers such as NT-proBNP aid in assessing cardiac involvement. Despite advances, diagnostic delays remain common, prompting development of streamlined algorithms and novel biomarkers for early and accurate subtype identification.
Treatment and Prognosis
Treatment depends on amyloidosis subtype. AL amyloidosis benefits from plasma cell–directed therapies like daratumumab and bortezomib, improving survival and organ responses. ATTR amyloidosis therapies include transthyretin stabilizers (tafamidis, acoramidis) and gene silencers (vutrisiran), which have transformed management and outcomes. Prognosis varies by subtype and organ involvement, with untreated survival ranging from months to a few years. Early diagnosis and treatment initiation are critical for improving survival, with recent advances increasing 2-year survival rates substantially. Ongoing efforts aim to reduce diagnostic delays and enhance treatment accessibility globally.
Advances in Diagnosis, Treatment, and Accessibility
Recent innovations include noninvasive diagnostic methods such as technetium-labeled bone scintigraphy, advanced echocardiography, and biomarker research. Artificial intelligence and genetic testing support earlier detection, especially of hereditary forms. Therapeutically, multiple FDA-approved agents target transthyretin through stabilization or gene silencing, with more treatments under evaluation. Despite progress, high treatment costs and geographic disparities limit access, especially in low-resource regions. Insurance coverage varies, and patient assistance programs help mitigate barriers. Increasing diagnosis rates have expanded patient populations, underscoring the need for equitable treatment availability and supportive care services.
Patient Management and Support
Management requires a multidisciplinary approach with early diagnosis, monitoring for complications, and integration of new therapies. Clinical trial participation remains important for advancing treatment. Patient support programs provide access to therapies and psychosocial resources. Educational initiatives enhance provider and patient understanding. International organizations promote research, education, and standardized care guidelines to improve quality of life. Innovations such as once-quarterly subcutaneous treatments reduce healthcare burdens and improve patient convenience.
Research Directions and Future Perspectives
Research focuses on understanding amyloid fibril structure and aggregation mechanisms to identify therapeutic targets. Multidisciplinary strategies combining computational and experimental methods aim to accelerate drug discovery. Recent FDA approvals of diverse TTR-targeting agents illustrate treatment diversification. Ongoing trials seek to expand options, including novel small molecules for light chain amyloidosis. Global collaborations and patient networks support research and education. Continuous content updates ensure clinicians access the latest evidence to guide optimal care.
The content is provided by Jordan Fields, Scopewires
