Amyloidosis is a localized or systemic disease caused by deposition of proteins in the extracellular space of various organs and tissues. As part of the disease, proteins that were originally soluble misfold and acquire a fibrillar conformation that renders them insoluble and resistant to proteolysis. Systemic amyloidosis is a rare, often underdiagnosed condition. In recent years, the incidence of newly diagnosed cases of amyloidosis has been increasing in association with the aging of the population and greater access to diagnostic tests. From a clinical perspective, systemic amyloidosis is frequently associated with involvement of the kidneys (causing nephrotic syndrome), heart (cardiac failure and arrhythmia), and peripheral nervous system (sensorimotor polyneuropathy and autonomic dysfunction). This condition is important to the rheumatologist for several reasons, such as its systemic involvement that mimics autoimmune rheumatic diseases, its musculoskeletal manifestations, which when recognized can allow the diagnosis of amyloidosis, and also because reactive or secondary AA amyloidosis is a complication of rheumatic inflammatory diseases. The treatment of amyloidosis depends on the type of amyloid protein involved. Early recognition of this rare disease is fundamental for improved clinical outcomes.
Introduction
Amyloidosis is a group of diseases with a diverse presentation that occurs due to excessive buildup of protein aggregates in the extracellular space of different organs and tissues.
The term “amyloid” was coined in 1854 by Rudolph Virchow, who described macroscopic tissue changes identified with iodine-containing dyes. [1] In amyloidosis, proteins that are originally soluble misfold and acquire a fibrillar conformation, becoming insoluble and resistant to proteolysis. [2, 3] The mechanisms behind the misfolding process in amyloidosis have not been fully elucidated, but factors determining its occurrence include hereditary mutations in the variable region of light chains, proliferation of clonal plasma cells producing immunoglobulin fragments, and aging. [2,3,4] More than 40 types of proteins with the potential to become amyloid are currently recognized, some causing systemic amyloidosis and others causing only localized forms of the disease. [5]
On histopathology, amyloid fibrils stain with Congo red and appear birefringent with an apple-green color under polarized light. [2, 3, 5]
Systemic amyloidosis is generally considered rare; its nonspecific clinical manifestations hinder this disease from being recognized and diagnosed early or even during an individual’s entire life. The absence of an early diagnosis prevents adequate treatment, which contributes to an increased mortality in amyloidosis. [2, 4]
In the present review, we will highlight the most common amyloid proteins associated with amyloidosis in clinical practice, i.e., those originating from light chain immunoglobulins, transthyretin, amyloid protein A, and beta2-microglobulin. [2, 3]
The nominal classification of amyloidosis — AA, AL, ATTR, and Abeta2m — is based on the protein deposited in the tissues. The first letter, A, stands for “amyloidosis.” The subsequent letter(s) indicate(s) the type of protein involved. For example, in AA amyloidosis, the second letter A stands for serum amyloid A protein; in AL amyloidosis, the letter L stands for (immunoglobulin) light chain; in ATTR amyloidosis, TTR stands for “transthyretin.” [2, 4].
The incidence of new cases of amyloidosis, especially ATTR and AL amyloidosis, has been increasing in recent years in association with the aging of the population and greater access to diagnostic tests, including research of genetic mutations related to the disease, better cardiac imaging for recognition of cardiac involvement (i.e., magnetic resonance imaging, pyrophosphate myocardial scintigraphy, and echocardiography), and use of mass spectroscopy, immunohistochemistry, and electron microscopy for improved characterization of the type of amyloid protein involved in the disease. [6, 7] Conversely, the prevalence of rheumatologic disorders in AA amyloidosis derived from chronic inflammatory conditions (also known as secondary or reactive amyloidosis) is progressively decreasing, particularly in developed countries, due to the introduction of effective new treatments. [2, 3, 8, 9]
From a clinical perspective, systemic amyloidosis often involves the kidneys (causing nephrotic syndrome), the heart (cardiac failure and arrhythmia), and the peripheral nervous system (sensorimotor polyneuropathy and autonomic dysfunction). Increased organ size from extracellular amyloid deposits, with liver and spleen enlargement, is a frequent finding. Gastrointestinal complications with diarrhea and bleeding also occur. Additionally, musculoskeletal involvement with arthralgias and subchondral cystic bone lesions, as well as carpal tunnel syndrome, may be present. [2, 3]