Etiology
Systemic amyloidosis is characterized by considerable etiological heterogeneity, but clinical manifestations of the different amyloidoses may overlap.[18]
Immunoglobulin light chain (AL) amyloidosis
Etiology is unknown; however, AL amyloidosis is associated with a clonal plasma cell dyscrasia, and is closely related to multiple myeloma. Less than 0.5% of patients diagnosed with AL amyloidosis will progress to overt multiple myeloma.[19]
Patients with AL amyloidosis and coexisting multiple myeloma have a poor prognosis (median overall survival <16 months).[20]
Secondary (AA) amyloidosis (nonfamilial)
Inflammatory polyarthropathies account for 60% of cases; conditions include rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, and ankylosing spondylitis.[16] The risk of developing AA amyloidosis from chronic inflammatory arthritides is decreasing, possibly due to advances in treatment for chronic inflammatory diseases.[15][16][17]
Inflammatory bowel disease (specifically Crohn disease), bronchiectasis, tuberculosis, subcutaneous injection of illicit drugs, decubitus ulcers, chronic urinary tract infections, and osteomyelitis can result in AA amyloidosis.[16] Castleman disease is a noncancerous lymphoproliferative disorder, where the plasma cell variant can cause AA amyloidosis.[21][22]
The likelihood of developing AA amyloidosis in the absence of one of these nonfamilial inflammatory disorders is extremely small.
Familial periodic fever syndromes leading to AA amyloidosis
Familial Mediterranean fever, tumor necrosis factor (TNF) receptor-associated periodic fever syndromes (TRAPS), cryopyrin-associated periodic syndromes (CAPS; e.g., Muckle-Wells syndrome), and mevalonate kinase deficiency (formerly known as hyper-IgD syndrome) have been implicated.[23][24][25][26]
The likelihood of developing AA amyloidosis in the absence of one of these familial inflammatory disorders is extremely small.
Hereditary (familial) amyloidosis
Etiology of hereditary (familial) amyloidosis includes mutations of:[3]
Transthyretin (TTR), leading to progressive cardiomyopathy or progressive neuropathy or both
Fibrinogen A alpha-chain, mainly leading to renal involvement
Apolipoprotein A, mainly leading to renal involvement
Lysozyme, mainly leading to renal involvement
A monoclonal gammopathy may be present in patients with hereditary amyloidosis, which can lead to a misdiagnosis of AL amyloidosis.[27][28] Clinical awareness, a careful family history, and laboratory/pathologic evaluation (including genetic testing) are essential to avoid a misdiagnosis of AL amyloidosis in this setting.[29]
Leukocyte chemotactic factor 2 (LECT2) amyloidosis
LECT2 amyloidosis mainly affects the kidney.[3] It is common among certain ethnicities (e.g., Egyptian, Indian, Pakistani, Hispanic).[30][31][32] Etiology is unknown; genetics may have a role but pathogenic mutations have not been identified.[31][32][33]
Pathophysiology
Amyloidosis comprises a group of disorders that contribute to tissue damage, and organ dysfunction, through the deposition of amyloid proteins.
Immunoglobulin light chain (AL) amyloidosis
AL amyloidosis is caused by clonal plasma cells that produce abnormal immunoglobulin light chains that are inherently prone to misfolding from a native alpha-helical state into an insoluble beta-pleated sheet configuration.[34]
The development of amyloidosis is linked both to the quantity of light chain that is produced, as well as a qualitative thermodynamic tendency for the light chain fragment to misfold into the amyloid configuration.[35][36]
The kidney and the heart are the primary target organs in AL amyloidosis. The liver and nerves can also be targeted.
Significant differences in gene usage are found in AL amyloidosis.[37] Patients with AL clones derived from 6aV lambda VI germline gene usage are more likely to present with dominant renal involvement. Those with clones derived from 1c, 2a2, and 3r V lambda genes are more likely to present with cardiac and multisystem disease.[38]
Renal involvement is reported in approximately 55% of patients with AL amyloidosis.[39] The light chains interact with mesangial cells, which catabolize them into fragments that form amyloid fibrils.[40] Amyloid fibrils deposit extracellularly in the mesangium and capillary loops, resulting in disruption of the glomerular basement membrane.[40]
Cardiac involvement is reported in 55% to 76% of patients with AL amyloidosis, and is the main cause of death in these patients.[41][42][43] Amyloid fibrils deposit extracellularly within the myocardium, which disrupts myocardial contractility and relaxation, and electrical conductance.[44][45] Cardiac amyloidosis resembles idiopathic restrictive cardiomyopathy, but ventricular long axis function is depressed in all patients with cardiac amyloidosis compared with only 36% of patients with idiopathic restrictive cardiomyopathy.[46]
Liver involvement is reported in approximately 15% of patients with AL amyloidosis.[47] Approximately 10% of patients have palpable hepatomegaly (>5 cm below the right costal margin).[16][48]
Nerve involvement is reported in 10% of patients with AL amyloidosis.[47] Amyloid deposits in the vasa nervorum result in clinical findings similar to ischemic neuropathy and lead to a mixed axonal demyelinating picture. Carpal tunnel syndrome occurs in approximately 50% of patients.[49] The presence of autonomic neuropathy (e.g., signs of erectile dysfunction, orthostatic hypotension, gastrointestinal dysfunction, or urinary dysfunction) is an important clue.[50]
Secondary (AA) amyloidosis (nonfamilial) and familial periodic fever syndromes
AA amyloidosis results from impaired proteolysis of the acute phase reactant, serum amyloid A protein (SAA). N-terminal fragments of SAA, termed amyloid A, are deposited as fibrils in tissue and organs, causing organ damage. Amyloid A is common to AA amyloidosis (nonfamilial) and familial periodic fever syndromes.
AA amyloidosis most commonly affects the kidney and less commonly the gastrointestinal tract and thyroid.[51][52] The most common late sequela of sustained production of AA amyloid is dialysis-dependent renal failure.
Long-term survivors of AA amyloidosis (nonfamilial) can develop cardiac amyloidosis, but with a frequency much lower than that seen in AL amyloidosis and familial periodic fever syndromes.
Hereditary (familial) amyloidosis
Most forms of hereditary amyloidosis are a consequence of misfolding of an inherited mutant transthyretin (TTR) molecule.
Rarer forms of hereditary amyloidosis are due to mutations of apolipoprotein A1, apolipoprotein A2, fibrinogen, gelsolin, and lysozyme.
Hereditary TTR amyloidosis usually presents as cardiomyopathy and/or neuropathy (peripheral and autonomic).[53][54]
Wild-type transthyretin (ATTRwt) amyloidosis
Occurs in the elderly and is sometimes referred to as senile systemic amyloidosis or senile cardiac amyloidosis.[53]
Amyloid deposition occurs predominantly in the heart. Up to 20% of patients may have mild peripheral neuropathy.[55]
Leukocyte chemotactic factor 2 (LECT2) amyloidosis
Classification
Types of amyloidosis[3]
Localized
Systemic
Derived from immunoglobulin light chains (referred to as AL amyloidosis or primary systemic amyloidosis)
Derived from amyloid A protein (referred to as AA amyloidosis or secondary amyloidosis)
Derived from other proteins (e.g., leukocyte chemotactic factor 2 [LECT2])
Familial periodic fever syndromes causing AA amyloidosis
Familial Mediterranean fever
Tumor necrosis factor (TNF) receptor-associated periodic fever syndromes (TRAPS)
Cryopyrin-associated periodic syndromes (CAPS; e.g., Muckle-Wells syndrome)
Mevalonate kinase deficiency (formerly known as hyper-IgD syndrome)
Hereditary (familial) amyloidosis
Hereditary transthyretin (TTR) amyloidosis (referred to as variant or ATTRv amyloidosis)
Neuropathy
Cardiomyopathy
Fibrinogen amyloidosis
Apolipoprotein amyloidosis
Gelsolin amyloidosis
Lysozyme amyloidosis
Wild-type TTR amyloidosis (referred to as ATTRwt amyloidosis)
Dialysis-related amyloidosis (beta-2 microglobulin amyloidosis)
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