Transthyretin Amyloidosis-From Peculiar Neuropathy to a Treatable Chronic Multisystemic Disease

Transthyretin amyloidosis (ATTR) is a multisystemic disorder associated with extracellular accumulation of misfolded transthyretin (TTR) protein forming insoluble amyloid deposits. Depending on the TTR genotype, ATTR is classified as hereditary ATTR (ATTRv) with pathogenic gene variants and wild-type ATTR (ATTRwt) with a normal TTR genotype. Two cardinal clinical manifestations of ATTR are amyloid cardiomyopathy and peripheral neuropathy, but multisystemic deposition of amyloid may also manifest with ocular and leptomeningeal amyloidosis, various orthopedic complications (carpal tunnel syndrome, spinal stenosis), nephropathy, and gastrointestinal and pulmonary amyloidosis. The natural history of untreated ATTR is characterized by progressive worsening and 25% of patients may die within 24 months from the onset. The first treatment for ATTR was liver transplantation which slows the disease progression, but its use was limited by the scarcity of available liver allografts and complex post-transplant morbidities associated with immunosuppression and various metabolic disturbances. Recent introduction of TTR stabilizers and gene silencing has significantly changed the outcomes and reduced ATTR-related morbidities and mortality, and early diagnosis remains important for improved outcomes. In our narrative expert review, we are discussing epidemiological and clinical features of ATTR, its pathophysiology and available treatments as rapidly progressive fatal disease is being transformed into a treatable chronic disease.