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Secondary, AA, amyloidosis can complicate any long-term inflammatory disorder.
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Extracellular deposition of serum amyloid A (SAA) protein as amyloid primarily affects kidney function, with proteinuria as first clinical manifestation.
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Biopsy is the diagnostic gold standard and serum amyloid P component scintigraphy can help to define amyloid type and distribution.
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Targeted anti-inflammatory treatment promotes normalization of circulating SAA levels, preventing further amyloid deposition and renal
Secondary, AA, Amyloidosis
Section snippets
Key points
Formation of AA Amyloid
Amyloid is an amorphous and insoluble proteolytic resistant material derived from the spontaneous aggregation of fibrils composed of twisted protofilaments.1, 2, 3 Protofilaments derive from misfolded proteins, called amyloid precursors, and share a common X-ray diffraction fingerprint of a β-sheet structure in cross-β conformation.4 At least 30 different proteins can be deposited as amyloid in humans. In addition to the fibrillary protein a number of other proteins are also present in all
Epidemiology
AA amyloidosis has almost certainly been underdiagnosed; the estimated incidence varies from 1 to 2 cases per million person-years, but is now clearly decreasing.49, 50, 51, 52, 53, 54 Prevalence in chronic inflammatory diseases is 5% to 10% or substantially higher if asymptomatic patients are considered.31, 55, 56, 57 A recently reported rise in the median age of diagnosis, from 50 to 70 years, probably reflects changes in the underlying diseases and improved access to effective therapies.58
General Management
Widespread availability of effective agents to control chronic inflammatory conditions, such as antibiotics and biologics, are likely to continue to reduce the incidence of AA amyloidosis in the future (Table 1).98, 99, 100, 101, 102 Once AA amyloid is present, long-term suppression of the circulating SAA level is pivotal to improving patient and renal outcomes,59, 96, 103, 104 and must be achieved by aggressively treating the underlying disease with the aim of persistent normalization of the
Summary
AA amyloidosis can complicate any chronic inflammatory disorders. Despite its rarity, physicians from many specialities may encounter affected patients due to variety of possible underlying causes. Proteinuria is the typical presentation and progression to renal insufficiency occurs if the diagnosis is missed. A routine urine dipstick in patients with inflammatory conditions is an inexpensive screening test. Histology is required for the final diagnosis and positive immunohistochemistry for AA
References (130)
- et al.
Serum amyloid A1: structure, function and gene polymorphism
Gene
(2016) - et al.
Serum amyloid A1 isoforms display different efficacy at Toll-like receptor 2 and formyl peptide receptor 2
Immunobiology
(2014) - et al.
Hepatic serum amyloid A1 aggravates T cell-mediated hepatitis by inducing chemokines via toll-like receptor 2 in mice
J Biol Chem
(2015) - et al.
The cytokine-serum amyloid A-chemokine network
Cytokine Growth Factor Rev
(2016) - et al.
An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses
Cell
(2015) - et al.
Serum amyloid A is an innate immune opsonin for gram-negative bacteria
Blood
(2006) - et al.
Proteolysis of AA amyloid fibril proteins by matrix metalloproteinases-1, -2, and -3
Am J Pathol
(2001) - et al.
Pathogenic serum amyloid A 1.1 shows a long Oligomer-rich fibrillation lag phase contrary to the highly amyloidogenic non-pathogenic SAA2.2
J Biol Chem
(2013) - et al.
Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989
Blood
(1992) - et al.
Primary amyloidosis with spontaneous splenic rupture, cholestasis, and liver failure treated with emergency liver transplantation
Am J Gastroenterol
(1998)
Staging cardiac amyloidosis with CMR
JACC Cardiovasc Imaging
Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens
Blood
Amyloidosis
Annu Rev Med
Cryo-EM reveals the steric zipper structure of a light chain-derived amyloid fibril
Proc Natl Acad Sci U S A
Physical basis of amyloid fibril polymorphism
Nat Commun
Amyloid fibers are water-filled nanotubes
Proc Natl Acad Sci U S A
Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice
J Clin Invest
Levels of the serum amyloid A protein (SAA) in normal persons of different age groups
Clin Exp Immunol
Extracellular matrix-anchored serum amyloid A preferentially induces mast cell adhesion
Am J Physiol
Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway
J Immunol
Regulation of inflammation and angiogenesis in giant cell arteritis by acute-phase serum amyloid A
Arthritis Rheumatol
Naturally occurring antibodies against serum amyloid A reduce IL-6 release from peripheral blood mononuclear cells
PLoS One
Serum amyloid A inhibits dendritic cell differentiation by suppressing GM-CSF receptor expression and signaling
Exp Mol Med
Serum amyloid A is a retinol binding protein that transports retinol during bacterial infection
Elife
Serum Amyloid A proteins take retinol for a ride
Trends Immunol
Serum amyloid A1 (SAA1) protein in human colostrum
FEBS Open Bio
A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4
Oncogene
SAA1 polymorphisms are associated with variation in antiangiogenic and tumor-suppressive activities in nasopharyngeal carcinoma
Oncogene
Acute-phase serum amyloid A regulates tumor necrosis factor α and matrix turnover and predicts disease progression in patients with inflammatory arthritis before and after biologic therapy
Arthritis Rheum
The impairment of macrophage-to-feces reverse cholesterol transport during inflammation does not depend on serum amyloid A
J Lipids
Serum amyloid A3 is required for normal weight and immunometabolic function in mice
PLoS One
Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis
Proc Natl Acad Sci U S A
The inverse relation of HDL anti-oxidative functionality with serum amyloid a is lost in metabolic syndrome subjects
Obesity (Silver Spring)
Historical and current concepts of fibrillogenesis and in vivo amyloidogenesis: implications of amyloid tissue targeting
Front Mol Biosci
Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis
Proc Natl Acad Sci U S A
Amyloidosis is frequently undetected in patients with rheumatoid arthritis
Amyloid
CVID associated with systemic amyloidosis
Case Rep Immunol
Common variable immunodeficiency and pulmonary amyloidosis: a case report
J Clin Immunol
Amyloidosis as a renal complication of chronic granulomatous disease
Iran J Kidney Dis
Infectious and non-infectious complications in primary immunodeficiency disorders: an autopsy study from North India
J Clin Pathol
Obesity is a significant susceptibility factor for idiopathic AA amyloidosis
Amyloid
Susceptibility to AA amyloidosis in rheumatic diseases: a critical overview
Arthritis Rheum
Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis
Rheumatology (Oxford)
SAA1 alleles as risk factors in reactive systemic AA amyloidosis
Amyloid
The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever
Arthritis Rheum
SAA1 α/α alleles in Behçet’s disease related amyloidosis
Clin Rheumatol
Influence of genotypes at SAA1 and SAA2 loci on the development and the length of latent period of secondary AA-amyloidosis in patients with rheumatoid arthritis
Hum Genet
Significance of SAA1.3 allele genotype in Japanese patients with amyloidosis secondary to rheumatoid arthritis
Rheumatology
Relative serum amyloid A (SAA) values: the influence of SAA1 genotypes and corticosteroid treatment in Japanese patients with rheumatoid arthritis
Ann Rheum Dis
A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry
Orphanet J Rare Dis
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