Amyloidosis
Amyloidosis is a heterogeneous group of disorders characterized by the extracellular deposition of misfolded protein fibrils, known as amyloid, in various tissues and organs. These amyloid fibrils are formed when normally soluble proteins undergo conformational changes, becoming insoluble and aggregating into beta-pleated sheet-rich structures. The pathogenesis of amyloidosis involves the imbalance between the production and clearance of amyloidogenic proteins, leading to their accumulation and subsequent disruption of normal tissue architecture and function. Depending on the type and extent of organ involvement, amyloidosis can result in a wide spectrum of clinical manifestations, ranging from asymptomatic organ infiltration to life-threatening multi-organ failure. The health impacts are significant, with common complications including restrictive cardiomyopathy, nephrotic syndrome, peripheral neuropathy, hepatic dysfunction, and gastrointestinal disturbances. Early recognition and treatment are crucial, as delayed diagnosis is associated with progressive organ damage and poor prognosis.
AL amyloidosis, also known as primary amyloidosis, is caused by the deposition of immunoglobulin light chains produced by clonal plasma cells, most commonly associated with plasma cell dyscrasias such as multiple myeloma. The amyloid deposits predominantly affect the heart, kidneys, liver, gastrointestinal tract, and peripheral nerves, leading to a range of clinical manifestations including nephrotic syndrome, restrictive cardiomyopathy, hepatomegaly, and autonomic dysfunction. Diagnosis is often challenging due to the protean nature of symptoms and frequent overlap with other conditions.
AA amyloidosis, or secondary amyloidosis, results from the deposition of serum amyloid A protein, an acute-phase reactant produced in response to chronic inflammation. The most common underlying conditions include chronic infections (such as tuberculosis) and inflammatory diseases (such as rheumatoid arthritis and inflammatory bowel disease). The kidneys are most frequently affected, leading to proteinuria and progressive renal dysfunction, but other organs may also be involved.
ATTR amyloidosis arises from the misfolding and aggregation of transthyretin, a plasma transport protein for thyroxine and retinol-binding protein. It is further subdivided into hereditary (variant) ATTR, due to mutations in the TTR gene, and wild-type (senile systemic) ATTR, occurring without genetic mutations and predominantly affecting elderly individuals. Cardiac involvement is prominent, manifesting as restrictive cardiomyopathy and heart failure, while hereditary forms may also cause progressive polyneuropathy and autonomic dysfunction.
Aβ2M amyloidosis primarily affects patients with end-stage renal disease undergoing long-term dialysis. It results from the accumulation and deposition of beta-2 microglobulin, a component of the major histocompatibility complex class I molecules, which is inadequately cleared in renal failure. Amyloid deposits typically occur in osteoarticular tissues, leading to joint pain, carpal tunnel syndrome, and bone cysts.
Several less common forms of amyloidosis exist, including hereditary forms caused by mutations in other proteins (such as apolipoprotein A-I, gelsolin, or fibrinogen alpha-chain), localized amyloidosis affecting single organs (such as the larynx or skin), and iatrogenic amyloidosis related to medical interventions. Each type is defined by the precursor protein involved and demonstrates distinct clinical and pathological features.
The epidemiology of amyloidosis varies significantly by type, geographic region, and underlying risk factors. AL amyloidosis is the most prevalent systemic form in Western countries, with an estimated incidence of 8 to 12 cases per million person-years and a median age at diagnosis of approximately 60 years. AA amyloidosis is more common in regions with a high prevalence of chronic inflammatory diseases and infectious conditions, though its incidence has declined in developed countries due to improved management of these underlying disorders. ATTR amyloidosis exhibits a bimodal distribution: hereditary forms are rare and often underdiagnosed, while wild-type ATTR, also known as senile systemic amyloidosis, is increasingly recognized in the elderly population, with autopsy studies suggesting prevalence rates exceeding 25% in individuals over 80 years of age. Aβ2M amyloidosis primarily affects patients on long-term dialysis, with prevalence rates correlating with duration of dialysis therapy. Overall, amyloidosis remains a rare disease, but its true incidence is likely underestimated due to diagnostic challenges and variable clinical presentations.
The diagnosis of amyloidosis requires a high index of suspicion, particularly in patients presenting with unexplained multi-organ dysfunction. The gold standard for diagnosis is tissue biopsy demonstrating amyloid deposition, typically confirmed by Congo red staining, which reveals apple-green birefringence under polarized light microscopy. Common biopsy sites include the affected organ, abdominal fat pad, minor salivary glands, or rectal mucosa. Once amyloid is identified, further typing is essential to determine the specific precursor protein, utilizing immunohistochemistry, immunofluorescence, or mass spectrometry-based proteomic analysis. Additional laboratory investigations include serum and urine protein electrophoresis with immunofixation to detect monoclonal proteins, serum free light chain assay, and measurement of acute-phase reactants. Cardiac involvement is assessed with echocardiography, cardiac magnetic resonance imaging, and measurement of cardiac biomarkers such as troponin and NT-proBNP. Genetic testing is indicated for suspected hereditary forms. Diagnostic criteria are based on the demonstration of amyloid deposits, clinical evidence of organ involvement, and, where applicable, identification of an underlying plasma cell or inflammatory disorder.
Eplontersen is an agent indicated for the treatment of amyloidosis, specifically acting as an antisense oligonucleotide designed to reduce the production of transthyretin protein, thereby addressing the underlying cause in transthyretin-mediated amyloidosis. Acoramidis is a selective stabilizer of transthyretin, used to prevent the dissociation of the transthyretin tetramer and subsequent amyloid fibril formation, offering therapeutic benefit in patients with transthyretin amyloidosis. Vutrisiran is a small interfering RNA (siRNA) therapeutic that targets hepatic production of transthyretin, resulting in reduced amyloidogenic protein levels and is utilized in the management of hereditary transthyretin-mediated amyloidosis. Daratumumab, available in subcutaneous formulations and in combination with hyaluronidase or vorhyaluronidase alfa, is a monoclonal antibody targeting CD38 on plasma cells, and is employed in the treatment of AL amyloidosis due to its ability to reduce pathogenic light chain production. Inotersen is an antisense oligonucleotide that inhibits hepatic synthesis of transthyretin and is indicated for the management of hereditary transthyretin amyloidosis with polyneuropathy. Patisiran is a lipid nanoparticle-formulated siRNA agent that silences transthyretin gene expression in the liver, thereby lowering circulating transthyretin levels and addressing the polyneuropathy of hereditary transthyretin amyloidosis. Tafamidis, available as both free acid and meglumine salt forms, is a transthyretin stabilizer that binds selectively to the transthyretin tetramer, preventing its dissociation and subsequent amyloid formation, and is indicated for the treatment of transthyretin amyloid cardiomyopathy and polyneuropathy.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
| eplontersen (Rec INN; USAN) | 1637600-16-8 | |||
 | acoramidis (Rec INN; USAN) | 1446711-81-4 | C15 H17 F N2 O3 | 292.305 |
| vutrisiran (Rec INN; USAN) | 1867157-35-4 | |||
| daratumumab SC; daratumumab/hyaluronidase-fihj; daratumumab/vorhyaluronidase alfa | ||||
| inotersen (Rec INN; USAN) | 1492984-65-2 | |||
| patisiran (Rec INN; USAN) | 1420706-45-1 | |||
 | tafamidis; tafamidis meglumine (Prop INNM; USAN) | 594839-88-0 (free acid); 951395-08-7 | C14 H7 Cl2 N O3 . C7 H17 N O5 | 503.33 |
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