Pathophysiology, Classification, and Epidemiology of Amyloidosis

Amyloidosis encompasses a group of disorders caused by tissue deposition, mainly extracellular, of misfolded proteins, so that we may name those heterogenous conditions, more appropriately, as amyloidoses. The current nomenclature uses the letter “A” to identify a form of amyloidosis, followed by a suffix that is an abbreviation of the protein composing the amyloid fibers. For example, AL identifies amyloidosis caused by immunoglobulin light chains, while ATTR amyloidosis is caused by tissue deposition of transthyretin molecules. Amyloidoses can be classified as acquired or hereditary, and systemic or localized forms. At least three factors are believed to convert a protein into an amyloidogenic species: an intrinsic propensity of the protein, changes due to protein processing, or mutations in the amino acid sequence. Amyloid deposits include several molecules (collagen, glycosaminoglycans, serum amyloid P component) that are believed to stabilize amyloid deposits and promote further deposition of amyloidogenic proteins. Once considered a rare disease, it is now well acknowledged that, depending on the amyloid precursors, the prevalence of amyloidosis may be frequent, at least in some specific age ranges or clinical settings. The prognostic impact of the different forms of amyloidosis greatly varies. AL amyloidosis, caused by clonal plasma cells, is usually associated with worse outcomes than ATTR amyloidosis. In the latter, the natural history of the disease largely depends on the specific subtype (wild type or mutant) and location of the amyloid deposits, with the worse outcomes experienced by patients with cardiac involvement.