AA Amyloidosis

Complex MONDO:0019439 Pathograph 43 Show in embeddings browser Amyloidosis

Systemic AA amyloidosis results from extracellular deposition of fibrils derived from serum amyloid A (SAA). Most cases complicate chronic inflammatory, autoinflammatory or infectious disease through sustained SAA production; some remain idiopathic, and a rare autosomal dominant SAA1 promoter variant causes hereditary AA amyloidosis without systemic inflammation. Renal disease dominates, with proteinuria, nephrotic syndrome and progressive loss of kidney function. Hepatic, splenic and gastrointestinal involvement also occurs; cardiac failure is less typical. SAA concentration, protein processing, fibril nucleation and extracellular cofactors contribute to deposition, but their sequence in patients is incompletely resolved. Treating the underlying cause and reducing SAA can stabilize disease and permit regression of deposits; established organ damage may persist.

Ask OpenScientist

Ask a research question about AA Amyloidosis. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

🏷

Classifications

Harrison's Part

Mechanistic Nosology

👪

Inheritance

Autosomal dominant in the rare SAA1 promoter-associated form HP:0000006

This inheritance applies to the reported promoter-associated family. Most AA amyloidosis is an acquired complication; inheritance of an upstream autoinflammatory disease must be counseled according to that disease.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:34560138 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"sustained elevation of serum amyloid A levels that segregated in an autosomal dominant pattern in 12 genetically affected and in none of six genetically unaffected relatives"

Documents segregation of elevated SAA in the family, not universal penetrance or dominant inheritance of common AA.

◆

Subtypes

Inflammation-associated AA amyloidosis

The common presentation complicates chronic infectious, inflammatory or autoinflammatory disease with persistent SAA production.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Even though any disorder causing sustained inflammation may increase the risk of AA amyloidosis, chronic infections and inflammatory arthritis are the commonest causes"

Defines the common etiologic presentation.

Idiopathic AA amyloidosis

No overt inflammatory cause is identified after evaluation. This category can include unrecognized genetic or environmental contributors and should not be assumed to be uniformly obesity-driven.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"A substantial proportion of cases (up to 20%) appear to develop AA amyloidosis in the absence of overt inflammation and thus labeled idiopathic"

Describes an etiologic classification, not a distinct fibril precursor.

Hereditary SAA1 promoter-associated AA amyloidosis

A rare autosomal dominant promoter variant produces sustained SAA elevation and systemic AA deposition without the usual inflammatory cause.

Show evidence (1 reference)

PMID:34560138 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Here we describe a family with primary amyloid A amyloidosis due to a chr11:18287683 T>C (human genome version19) mutation in the SAA1 promoter linked to the amyloidogenic SAA1.1 haplotype."

Identifies the rare regulatory hereditary cause.

◈

Mechanistic Hypotheses

Canonical SAA Overproduction Model

canonical_saa_overproduction CANONICAL

Evidence balance 2 support

In the common inflammation-associated pathway, cytokines stimulate hepatic SAA production. Persistent circulating precursor supplies fibril assembly; lower serial SAA concentrations are associated with amyloid regression and better renal and survival outcomes. Adipose production and the rare hereditary SAA1 promoter mechanism provide additional routes to elevated SAA.

Show evidence (2 references)

PMID:25387054 SUPPORT DIRECT REVIEW SYNTHESIS Other

"In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction of serum amyloid A (SAA) by the liver. A chronically high plasma concentration of SAA results in the aggregation of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully understood."

States the cytokine-to-precursor-to-fibril chain that defines the canonical hypothesis group.

PMID:17554117 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Mortality, amyloid burden, and renal prognosis all significantly correlated with the SAA concentration during follow-up."

The 374-patient longitudinal cohort links serial SAA to burden and outcomes; this observational relationship does not establish a universal concentration-duration threshold.

Nucleation-Dependent Seeding Model

nucleation_seeding_model CANONICAL

Evidence balance 2 support

Preformed fibrils can template further amyloid assembly. Experimental cross-seeding accelerates murine AA amyloidosis, but the contribution of environmental heterologous seeds to human disease has not been established.

Show evidence (2 references)

PMID:25387054 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Generation of amyloid fibrils is nucleation dependent, and once formed, fibrils recruit and catalyze the conversion of native molecules."

States the nucleation-and-templating mechanism that distinguishes this model from simple mass-action aggregation.

PMID:15829582 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Our results show that these protein fibrils exert amyloid-accelerating properties in the murine experimental AA amyloidosis, suggesting that such environment factors may be important risk factors in amyloidogenesis."

Direct experimental support for murine cross-seeding; the authors propose, rather than demonstrate, an environmental risk in humans.

Discussions and Knowledge Gaps

Why do only a minority of patients with equivalently sustained, equivalently high SAA concentrations develop AA amyloidosis?

KNOWLEDGE GAP OPEN saa_threshold_vs_deposition_mechanism

Attached to

pathophysiology#SAA Amyloid Fibril Assembly

Persistent SAA elevation, common coding alleles, inflammation and cofactors do not fully predict deposition. The rare promoter variant illustrates a supply mechanism, while cell-free cleavage and fibril assays suggest additional contributors. Their relative effects in patients remain unresolved.

Proposed experiments

Prospective cohort with matched cumulative SAA exposure stratified by SAA1 genotype

exp_aa_matched_saa_exposure_genotype_cohort

Follow inflammatory-disease patients with serial SAA, genotype and prospectively assessed amyloid outcomes. Model cumulative measured exposure and relevant confounders. A genotype association after adjustment would motivate direct functional studies but cannot by itself distinguish processing, tissue exposure, clearance or residual confounding.

Supporting outcome

A reproducible genotype association after measured-SAA adjustment supports additional genotype-linked risk, without locating its molecular mediator.

Refuting outcome

A sufficiently precise null limits the detectable genotype effect in this population, but does not exclude smaller effects or inadequately measured exposure.

Detection of endogenous nucleating seed before clinically apparent deposition

exp_aa_pre_clinical_seed_detection

Apply high-sensitivity amyloid-seeding assays to accessible tissue (fat aspirate, minor salivary gland) from patients with sustained high SAA but no clinical amyloidosis, to test whether a subclinical nucleating seed precedes and predicts overt disease.

Supporting outcome

Prediagnostic seeding activity associated with future disease supports its predictive relevance; it does not by itself establish that seeding is rate-limiting.

Refuting outcome

Absence of detectable seeding activity in patients who subsequently develop amyloidosis would argue against a detectable pre-clinical seed.

Show evidence (1 reference)

PMID:25387054 SUPPORT DIRECT REVIEW SYNTHESIS Other

"A chronically high plasma concentration of SAA results in the aggregation of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully understood."

The authoritative review explicitly states that the mechanism converting high SAA into deposits is incompletely understood, which is the gap recorded here.

Can established AA amyloid deposits be actively cleared, rather than merely allowed to regress by withdrawing the precursor?

KNOWLEDGE GAP OPEN no_deposit_clearing_therapy

Attached to

pathophysiology#Progressive Multi-Organ Amyloid Accumulation

Reducing precursor production can permit regression, but established organ damage may remain. Anti-SAP studies demonstrate amyloid-load reduction in one AA participant without proven functional benefit; later cardiac safety and efficacy limitations arose in other amyloid types. Safe deposit removal with clinical benefit remains an open therapeutic problem.

Show evidence (3 references)

PMID:29298867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Reduction in renal amyloid was observed in 7 of 11 subjects with renal amyloid detected by SAP scintigraphy (five with AFib and one each with AL and AA amyloidosis)"

Only one AA participant had documented renal amyloid-load reduction. Both AA participants received one antibody dose; no AA repeat-dose efficacy is established.

PMID:29298867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Renal function, serum creatinine and urea concentrations, and urinary protein excretion were unchanged in all subjects up to day 42"

Amyloid-load reduction was not accompanied by a demonstrated early functional or proteinuria improvement.

PMID:35152886 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The decision for an early termination of the study was based on the lack of evidence of cardiac amyloid removal or functional benefit, and the reporting of a SAE of vasculitis in a subject in the Phase 2 study."

The later cardiac trial enrolled ATTR and AL, not AA. A suspected large-vessel vasculitis event in the AL participant and absent cardiac benefit prompted termination; neither later study had a death.

Is MICA a modifier locus for amyloidosis risk in familial Mediterranean fever, as sometimes summarized?

INTERPRETATION OPEN mica_not_a_modifier_locus

Attached to

pathophysiology#Sustained Elevation of Circulating Serum Amyloid A

The cited FMF study found no association of the tested MICA exon 5 polymorphism with renal amyloidosis, despite an SAA1 association. This is a cohort-specific null and does not prove absence of every MICA effect. MICA is not entered as an established AA susceptibility locus on this evidence.

Show evidence (2 references)

PMID:15018633 REFUTE DIRECT PRIMARY RESULT Human Clinical

"Moreover, no specific MICA genotype or allele was significantly associated with the development of amyloidosis"

Directly refutes a MICA-amyloidosis association in the cohort that tested it, which is why MICA is not curated as a susceptibility or modifier locus here.

PMID:15018633 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"no association was found between the MICA gene exon 5 polymorphism and the development of renal amyloidosis in FMF patients, whereas the alpha allele and the alpha/alpha genotype of the SAA1 gene were associated with this severe phenotype"

The authors' own conclusion, contrasting the null MICA result with the positive SAA1 result in the same patients - the asymmetry that justifies curating SAA1 but not MICA.

⚙

Pathophysiology

Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus

Persistent inflammation from infections, inflammatory arthritis or monogenic autoinflammatory disease can sustain SAA production. These are heterogeneous causes of the common acquired pathway; overt inflammation is not required in every idiopathic or hereditary case.

inflammatory response GO:0006954 ↑ INCREASED Temporal: CHRONIC

Downstream

IL-6-Driven Hepatic Acute-Phase Response Inflammatory cytokines stimulate hepatocyte SAA production.

Show evidence (2 references)

PMID:25387054 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Therefore, AA amyloidosis can be thought of as a consequence of long-standing inflammatory disease."

Frames chronic inflammatory disease as the upstream trigger of the whole chain.

PMID:17714761 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The amyloidogenic disease was a chronic infection (40.8%), a chronic inflammation (38%), a tumor (9.9%), a hereditary disease (9.9%), or was undetermined in 1.4% of cases."

Quantifies the heterogeneous trigger diseases in a renal AA amyloidosis series, supporting the trigger node as an aetiology-agnostic entry point.

IL-6-Driven Hepatic Acute-Phase Response

IL-6, with other inflammatory cytokines, increases hepatic acute-phase SAA expression and secretion. This node describes the inflammatory liver pathway.

hepatocyte CL:0000182

acute-phase response GO:0006953 ↑ INCREASED

Downstream

Sustained Elevation of Circulating Serum Amyloid A Continued hepatic output supplies circulating SAA.

Show evidence (1 reference)

PMID:25387054 SUPPORT DIRECT REVIEW SYNTHESIS Other

"In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction of serum amyloid A (SAA) by the liver."

Review synthesis of the inflammatory hepatic precursor-production pathway.

Adipose Serum Amyloid A Production

Human adipocytes express SAA1/SAA2 and adipose SAA secretion correlates with adiposity. This offers a plausible additional precursor source in obesity-associated idiopathic AA amyloidosis; the adipocyte study did not test amyloid deposition or establish adipose dominance during severe systemic inflammation.

adipocyte CL:0000136

Experimental models

Human adipose tissue SAA secretion OTHER Directly measures SAA secretion from human adipose explants.

Downstream

Sustained Elevation of Circulating Serum Amyloid A Adipose secretion may contribute to circulating precursor in obesity; the relative contribution in AA patients is unmeasured.

Show evidence (1 reference)

PMID:16737350 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A-SAA mRNA levels and A-SAA secretion from adipose tissue were significantly correlated with body mass index (r = 0.47; p = 0.028 and r = 0.80; p = 0.0002, respectively)."

Human tissue expression and secretion measurements support adipose precursor production; the participants were not an AA amyloidosis cohort.

Hereditary SAA1 Promoter Variant

A rare SAA1 promoter chr11:18287683T>C variant (hg19), linked to SAA1.1, segregated with sustained SAA elevation and hereditary AA amyloidosis in one family.

Downstream

Increased Basal SAA1 Promoter Activity The reported promoter variant increases basal promoter activity.

Show evidence (1 reference)

PMID:34560138 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Here we describe a family with primary amyloid A amyloidosis due to a chr11:18287683 T>C (human genome version19) mutation in the SAA1 promoter linked to the amyloidogenic SAA1.1 haplotype."

Identifies a segregating promoter variant in a rare hereditary form, distinct from common coding susceptibility alleles.

Increased Basal SAA1 Promoter Activity

The hereditary promoter variant approximately doubled basal promoter activity in the reported assay. This regulatory mechanism can elevate SAA without the usual systemic inflammatory driver.

Downstream

Sustained Elevation of Circulating Serum Amyloid A Increased expression provides a plausible link between the promoter assay and sustained SAA elevation in the segregating family.

Show evidence (1 reference)

PMID:34560138 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This condition leads to a doubling of the basal SAA1 promoter activity"

The reported assay supports increased basal promoter activity; the available abstract does not specify the cell system.

Sustained Elevation of Circulating Serum Amyloid A

Persistent precursor availability contributes to amyloid formation. Serial SAA concentrations correlate with clinical outcomes, but no single concentration or exposure duration determines deposition in every individual.

Downstream

SAA Amyloid Fibril Assembly A sustained precursor pool supplies assembly through incompletely resolved processing and conformational steps.

Show evidence (1 reference)

PMID:17554117 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Mortality, amyloid burden, and renal prognosis all significantly correlated with the SAA concentration during follow-up."

Serial measurements in 374 patients associate precursor concentration with burden and outcome; other determinants of conversion remain unresolved.

Heparan Sulfate-Associated HDL-SAA Remodeling

At mildly acidic pH, heparan sulfate remodels HDL-associated SAA into SAA-rich aggregates in vitro. This provides a candidate route from lipid-associated precursor toward aggregation; its timing and anatomical site in human disease remain uncertain.

Experimental models

HDL-SAA remodeling and monocyte amyloid culture OTHER Measures the effect of HS at mildly acidic pH.

Downstream

SAA Amyloid Fibril Assembly HDL remodeling and aggregation can facilitate amyloid formation in the experimental system; additional conversion steps are not resolved.

Show evidence (1 reference)

PMID:19549924 SUPPORT DIRECT PRIMARY RESULT In Vitro

"HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich aggregates."

Biochemical and culture experiments demonstrate pH-dependent HDL-SAA remodeling, without locating or proving this step in patients.

SAA Proteolytic Cleavage

AA deposits contain truncated SAA species, and MMP-1 cleaves SAA isoforms differently in vitro. These observations do not establish that MMP-1 is the relevant human enzyme or that cleavage must precede fibril assembly.

proteolysis GO:0006508

Experimental models

SAA isoform degradation by MMP-1 OTHER Measures isoform-dependent susceptibility to a defined enzyme.

Show evidence (2 references)

PMID:18815155 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found that SAA1.5 is more resistant to degradation by MMP-1 than SAA1.1. This difference is caused by the capacity of MMP-1 to cleave at the site of the polymorphism at position 57."

Immunoblotting and mass spectrometry demonstrate isoform-dependent MMP-1 cleavage in vitro; this does not establish the rate-limiting protease or cleavage sequence in patients.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"The MS analyses showed that SAA is C-terminally trimmed in the amyloid fibrils. Whether precleavage is necessary for recruitment of SAA to the fibril template or it occurs after its association to the amyloid is not known."

Mass spectrometry of extracted mouse AA deposits supports truncation, while the authors explicitly leave the timing of cleavage unresolved. It does not identify MMP-1 as the tissue protease.

Reduced Alpha-Helical Structure of Truncated SAA

Synthetic C-terminal truncation reduces alpha-helical structure in SAA(1–76). This experimentally observed conformational effect is distinct from the unresolved timing of proteolysis in tissue deposits.

protein folding GO:0006457 ⚠ ABNORMAL

Experimental models

Truncated human SAA peptide assembly OTHER Tests the direct structural consequence of a defined C-terminal truncation.

Downstream

SAA Amyloid Fibril Assembly Truncated SAA forms fibrils more readily in the tested heparan sulfate system; the reduced helical structure is a candidate contributor, not an independently rescued causal mediator.

Show evidence (1 reference)

PMID:29288051 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Circular dichroism (CD) measurements demonstrated that the C-terminal truncation induces a reduced α-helical structure of the SAA molecule."

Compares truncated SAA(1–76) with full-length protein; the experiment tests a defined fragment rather than proving when proteolysis occurs in vivo.

SAA-Glycosaminoglycan Binding

Heparan sulfate and heparin interact with SAA and its aggregates. Binding strengthens during oligomerization, and heparin also binds preformed fibrils. Acidic heparin-induced beta-sheet is pH-reversible and distinct from amyloid. Apparent droplets are a proposed intermediate rather than a demonstrated requirement.

glycosaminoglycan binding GO:0005539

Experimental models

Recombinant SAA–glycosaminoglycan assembly assays OTHER Binding increases as soluble oligomers form; heparin also binds previously formed fibrils.

Downstream

SAA Amyloid Fibril Assembly Glycosaminoglycans can accelerate assembly; fibrils also form without them. Their kinetic effect depends on pH and isoform.

Show evidence (1 reference)

PMID:39954777 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the binding affinity increases upon formation of soluble amyloid oligomers."

Recombinant lipid-free SAA assays show stronger glycosaminoglycan binding after oligomer formation. Native human SAA2 did not show detectable binding in these assays.

SAA Amyloid Fibril Assembly

SAA species assemble into cross-beta amyloid fibrils through nucleation and elongation. Truncation and extracellular cofactors can alter kinetics, while preformed fibrils provide seeds. Neither obligatory prior truncation nor indispensable GAG binding is assumed.

amyloid fibril formation GO:1990000 ↑ INCREASED

Experimental models

Recombinant SAA–glycosaminoglycan assembly assays OTHER Heparin addition alters assembly kinetics under defined conditions.

Truncated human SAA peptide assembly OTHER Truncated protein forms fibrils more readily under the tested conditions.

HDL-SAA remodeling and monocyte amyloid culture OTHER Peptides promoted deposition in the monocyte culture model.

Animal models

Heterologous fibril acceleration of murine AA deposition Mus musculus perturbs Heterologous fibrils accelerate splenic AA deposition during an inflammatory challenge, supporting an in vivo seeding contribution to assembly.

Downstream

Progressive Multi-Organ Amyloid Accumulation Persistent fibril production relative to clearance permits extracellular tissue accumulation.

Show evidence (2 references)

PMID:25387054 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Generation of amyloid fibrils is nucleation dependent, and once formed, fibrils recruit and catalyze the conversion of native molecules."

Synthesis of templated fibril assembly.

PMID:39954777 SUPPORT DIRECT PRIMARY RESULT In Vitro

"After incubation, amyloid fibrils were observed by TEM in all samples with and without GAGs"

Glycosaminoglycans modify assembly kinetics but are not required for fibril formation under all tested conditions.

Progressive Multi-Organ Amyloid Accumulation

Extracellular fibrils accumulate in renal, hepatic, splenic and other tissues. The burden can regress after sustained precursor suppression, although regression is not universal and organ injury may remain.

extracellular region GO:0005576

Downstream

Glomerular Filtration Barrier Dysfunction Glomerular deposition is associated with proteinuria and implies impaired filtration selectivity.

Progressive Renal Functional Decline Glomerular, vascular and tubular lesions contribute to renal functional loss.

Gastrointestinal Dysfunction Deposition in enteric tissues may impair motility and absorption.

Hepatomegaly Amyloid accumulation in the affected organ can accompany enlargement. Imaging evidence of deposits alone does not establish symptomatic organ dysfunction.

Splenomegaly Amyloid accumulation in the affected organ can accompany enlargement. Imaging evidence of deposits alone does not establish symptomatic organ dysfunction.

Show evidence (2 references)

PMID:17554117 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Amyloid deposits regressed in 60% of patients who had a median SAA concentration of less than 10 mg per liter, and survival among these patients was superior to survival among those in whom amyloid deposits did not regress (P=0.04)."

Longitudinal scintigraphy documents regression in a subset; the association does not guarantee reversibility of established organ damage.

PMID:28828707 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"AA amyloidosis shows vascular deposits in addition to the glomerular deposits"

Review synthesis of the renal deposition pattern.

Glomerular Filtration Barrier Dysfunction

Glomerular amyloid is associated with heavier proteinuria than vascular-predominant disease. Filtration-barrier injury is the clinical interpretation of this anatomical association; nonselectivity and a specific podocyte lesion were not measured in the cited abstract.

renal glomerulus UBERON:0000074

Downstream

Proteinuria Loss of filtration selectivity produces urinary protein loss.

Show evidence (1 reference)

PMID:17714761 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"The clinical presentation of glomerular and vascular forms was distinct with a clear predominance of proteinuria in glomerular form."

The 68-case renal biopsy series links deposition pattern to proteinuria; a mechanistic filtration-barrier interpretation is indirect.

Progressive Renal Functional Decline

Renal involvement can lead to loss of filtration and end-stage kidney disease. The tempo varies with deposition pattern, baseline injury and control of SAA production; vascular or tubular disease need not pass through nephrotic syndrome.

Downstream

Renal Insufficiency Renal structural injury is associated with reduced kidney function.

End-Stage Kidney Disease Advanced renal injury can progress to kidney failure.

Show evidence (1 reference)

PMID:17714761 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Tubular atrophy, abundance, and distribution pattern of glomerular amyloid deposits at the time of biopsy were independent predictors of renal outcome."

Histological predictors support an association with kidney damage, without proving one obligatory clinical sequence.

Gastrointestinal Dysfunction

Enteric amyloid deposition may impair absorption and motility, causing diarrhea, malabsorption or pseudo-obstruction. The clinical review does not establish one lesion that explains all gastrointestinal manifestations.

Downstream

Intestinal Pseudo-obstruction Myenteric deposition may impair intestinal motility.

Chronic Diarrhea Enteric involvement can produce persistent diarrhea, without one established anatomical lesion accounting for every case.

Malabsorption Impaired intestinal function may contribute to malabsorption; the review does not resolve the responsible tissue or transport mechanism.

Abdominal Pain Gastrointestinal involvement can manifest as abdominal pain through incompletely resolved pathways.

Gastrointestinal Hemorrhage Enteric disease can be accompanied by upper or lower gastrointestinal bleeding; a specific vascular or mucosal sequence is not established here.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Amyloid deposition in the myenteric plexus can potentially result in intestinal pseudo-obstruction"

The review links enteric neural deposition to dysmotility; other gastrointestinal symptoms can have several contributing lesions.

✶

Histopathology

Congo Red-Positive Amyloid Deposition

Acellular Congo red-positive extracellular deposits showing apple-green birefringence under polarized light. This confirms amyloid but does not identify the precursor; typing is a separate and mandatory step.

Show evidence (1 reference)

PMID:28828707 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Renal amyloidosis is characterized by acellular Congo red positive deposits in the glomeruli, interstitium and/or arteries."

Defines the Congo red-positive histological finding and its renal distribution.

Glomerular-Predominant Deposition Pattern

The 68-case renal series identified mesangial segmental, mesangial nodular, mesangiocapillary and hilar patterns. Glomerular-predominant disease had more proteinuria than the vascular form.

Show evidence (1 reference)

PMID:17714761 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We retrospectively reviewed the clinicopathological features of a series of 68 renal AA amyloidosis observations collected between 1990 and 2005. ... The distribution pattern of glomerular amyloid deposits was mesangial segmental (14.7%), mesangial nodular (26.5%), mesangiocapillary (32.3%), and..."

Names the renal AA amyloidosis cohort, retains its deposition-pattern frequencies and includes the reported proteinuria predominance in the glomerular form.

Amyloid-Associated Giant Cell and Inflammatory Reaction

The renal biopsy series found multinucleated giant cells or a glomerular inflammatory infiltrate in a subset, sometimes with crescents. An immune response contributing to amyloid resolution was proposed; the biopsy observation does not prove the same mechanism as experimental anti-SAP clearance.

Show evidence (1 reference)

PMID:17714761 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"AA amyloidosis-related inflammation was noted in 30 patients (44.1%) and appeared as a multinucleated giant cell reaction (27.9%) or a glomerular inflammatory infiltrate (25%), including glomerular crescents (17.6%)."

Quantifies the amyloid-associated inflammatory reaction and its giant-cell component in the same 68-case series.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 1

Gastrointestinal Hemorrhage HP:0002239

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"episodes of upper and lower gastrointestinal bleeding"

Names episodes of upper and lower gastrointestinal bleeding among the frequently encountered presenting symptoms.

Cardiovascular 2

Splenomegaly HP:0001744

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Hepato- and splenomegaly commonly manifests during disease progression, whereas splenic rupture is exceptionally rare"

Directly documents splenomegaly as a common manifestation of human AA amyloidosis, replacing the model-organism-only support this phenotype previously carried.

Heart Failure Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"While cardiac infiltration is extensively documented in various amyloidosis types, it is a relatively rare cause of heart failure in AA amyloidosis"

The AA clinical review supports this less common manifestation; no numerical frequency is inferred.

Digestive 5

Hepatomegaly HP:0002240

Show evidence (2 references)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Hepato- and splenomegaly commonly manifests during disease progression, whereas splenic rupture is exceptionally rare"

Directly documents hepatomegaly as a common manifestation of human AA amyloidosis during disease progression.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"While splenic and hepatic amyloid deposition is commonly detected in serum amyloid P (SAP) scintigraphy, its clinical relevance is limited"

Records the important caveat that hepatic deposition is frequently imaged but usually not clinically consequential, so this phenotype should not be read as hepatic failure. The limitation is that it qualifies rather than strengthens the association.

Chronic Diarrhea HP:0002014

Temporal: CHRONIC

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Approximately 30% of cases have gastrointestinal involvement. The predominant symptom is diarrhea that is frequently unresponsive to standard treatment"

The review describes diarrhea, while the 30% estimate counts any gastrointestinal involvement and is not used as a diarrhea frequency.

Malabsorption HP:0002024

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Other frequently encountered presenting symptoms include weight loss, abdominal pain, malabsorption, macroglossia, gastroesophageal reflux, esophageal dysmotility, gastric polyps, and episodes of upper and lower gastrointestinal bleeding"

Lists malabsorption among the frequently encountered presenting gastrointestinal symptoms of AA amyloidosis.

Gastroesophageal Reflux HP:0002020

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

The clinical review explicitly lists this manifestation; no individual frequency is assigned.

Intestinal Pseudo-obstruction HP:0004389

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Amyloid deposition in the myenteric plexus can potentially result in intestinal pseudo-obstruction"

The AA clinical review supports this less common manifestation; no numerical frequency is inferred.

Endocrine 1

Nephrogenic Diabetes Insipidus HP:0009806

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Individuals with tubular amyloid accumulation might exhibit bland urinary sediment and minimal proteinuria but can demonstrate symptoms of distal tubular impairment such as nephrogenic diabetes insipidus."

The AA clinical review supports this less common manifestation; no numerical frequency is inferred.

Genitourinary 4

Proteinuria HP:0000093

Show evidence (2 references)

PMID:17714761 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The clinical presentation of glomerular and vascular forms was distinct with a clear predominance of proteinuria in glomerular form."

Proteinuria predominates in glomerular disease. The 80.9% figure counts the histological form, not the proportion with proteinuria.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"the prevailing symptoms frequently involve the emergence of proteinuria and gradual reduction in kidney function, apparent in over 90% of patients upon their initial presentation"

The review reports a combined renal presentation; it does not give a separate proteinuria denominator.

Nephrotic Syndrome FREQUENT HP:0000100

Show evidence (1 reference)

PMID:17714761 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively."

Directly quantifies nephrotic syndrome at 63.1%, which maps to the FREQUENT band (30-79%).

Renal Insufficiency FREQUENT HP:0000083

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:17714761 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively."

Directly quantifies renal insufficiency at 75%, mapping to the FREQUENT band (30-79%).

End-Stage Kidney Disease FREQUENT Stage 5 chronic kidney disease HP:0003774

Show evidence (1 reference)

PMID:17714761 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At the end of follow-up, 26 patients (38.2%) showed end-stage renal disease."

Directly quantifies progression to end-stage renal disease at 38.2%, mapping to the FREQUENT band (30-79%).

Head and Neck 1

Macroglossia HP:0000158

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

The clinical review explicitly lists this manifestation; no individual frequency is assigned.

Metabolism 3

Peripheral Edema HP:0000969

Show evidence (1 reference)

url:https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Classification as nephrotic required a 24-hour urinary excretion of more than 3 g of protein, a serum albumin concentration of less than 3.4 g per deciliter, and either the presence of peripheral edema or the use of diuretics to treat peripheral edema."

The AA trial explicitly defined the nephrotic stratum using low albumin and edema or its treatment. This supports the feature in that clinical context without a whole-disease frequency.

Hypoalbuminemia HP:0003073

Show evidence (1 reference)

url:https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

The AA trial explicitly defined the nephrotic stratum using low albumin and edema or its treatment. This supports the feature in that clinical context without a whole-disease frequency.

Elevated Alkaline Phosphatase OCCASIONAL Elevated circulating alkaline phosphatase concentration HP:0003155

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Elevated serum alkaline phosphatase (ALP) levels are noted in 5% of patients"

Directly quantifies elevated ALP at 5% of patients, mapping to the OCCASIONAL band (5-29%).

Constitutional 1

Abdominal Pain HP:0002027

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

The clinical review explicitly lists this manifestation; no individual frequency is assigned.

Growth 1

Weight Loss HP:0001824

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Lists weight loss among the frequently encountered presenting symptoms of AA amyloidosis.

🧬

Genetic Associations

SAA1

Gene: SAA1 hgnc:10513 gene page relationship_type: SUSCEPTIBILITY

Show evidence (4 references)

PMID:12687559 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the presence of the SAAalpha/alpha genotype (OR 2.99, 95% CI 1.47-6.09)"

Quantifies the independent association of the amyloidogenic SAA1 alpha/alpha genotype with renal amyloidosis in a 277-patient FMF cohort.

PMID:29364741 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for AA amyloidosis irrespective of the type of the disease."

Confirms SAA1 polymorphism as a susceptibility factor across trigger diseases, supporting the SUSCEPTIBILITY relationship type.

PMID:18815155 SUPPORT DIRECT PRIMARY RESULT In Vitro

"These results may explain the higher risk of amyloidosis in patients with a SAA1.1/1.1 genotype vs SAA1.5/1.5 or SAA1.1/1.5 genotype."

The authors propose isoform-dependent MMP-1 cleavage as one explanation for the clinical association; the assay does not establish mediation of human risk.

+ 1 more reference

MEFV

Gene: MEFV hgnc:6998 gene page relationship_type: SUSCEPTIBILITY

Show evidence (3 references)

PMID:12687559 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Logistic regression analysis showed that homozygosity for the M694V allele (odds ratio [OR] 4.27, 95% confidence interval [95% CI] 2.01-9.07)"

The cited 277-patient FMF cohort reports an independent association between M694V homozygosity and renal amyloidosis, with OR 4.27 (95% CI 2.01–9.07).

PMID:12687559 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Overall, disease severity and the development of amyloidosis in FMF are differentially affected by genetic variations within and outside the MEFV gene."

The authors distinguish effects of MEFV and other genetic factors on FMF severity and amyloidosis risk.

PMID:20301405 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"If FMF is untreated, chronic inflammation may lead to AA amyloidosis, the most severe complication of the disease."

GeneReviews describes AA as a complication of untreated FMF.

SAA1 promoter variant

Gene: SAA1 hgnc:10513 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:34560138 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Here we describe a family with primary amyloid A amyloidosis due to a chr11:18287683 T>C (human genome version19) mutation in the SAA1 promoter linked to the amyloidogenic SAA1.1 haplotype."

Identifies a segregating promoter variant in a rare hereditary form, distinct from common coding susceptibility alleles.

💊

Medical Actions

Colchicine (Familial Mediterranean Fever)

Action: Pharmacotherapy NCIT:C15986

Agent: colchicine CHEBI:23359

Platform: Small molecule

Colchicine controls FMF inflammation and reduces the risk of AA amyloidosis. In established FMF-associated renal AA, observational studies report stabilization or proteinuria regression in some patients, with worse outcomes when renal injury is advanced. The historical dose and creatinine associations are not universal modern prescribing thresholds; dosing requires individual assessment of renal function, tolerance and interactions.

Mechanism Target:

INHIBITS Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus — Suppressing FMF inflammatory attacks removes the cytokine drive at the trigger node, preventing the downstream acute-phase SAA surge.

Show evidence (4 references)

PMID:7986228 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Deterioration was related to initial serum creatinine values > or = 1.5 mg/dl (P < 0.01) and to mean colchicine dosage < or = 1.5 mg/day (P < 0.001)."

Associations in a retrospective 1974–1992 cohort of 68 patients with baseline creatinine ≤2.5 mg/dL; this does not establish an absolute response boundary or a dose appropriate for every patient.

PMID:7986228 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At the end of the study period, kidney disease had worsened in 31 patients and remained stable in 22. Proteinuria had regressed in 15 patients."

Documents stabilization or regression of proteinuria in a substantial share of colchicine-treated patients. The limitation is that this is an uncontrolled retrospective series without a comparator arm, and disease still worsened in the largest single group.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In a study examining 960 patients with FMF without evidence of amyloidosis at baseline, the cumulative rate of proteinuria after 11 years was reported as 1.7% in colchicine-compliant patients while 48.9% in the non-compliants"

The review summarizes an observational association between colchicine adherence and less subsequent proteinuria; adherence groups were not randomized.

+ 1 more reference

Anti-TNF-alpha Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: infliximab NCIT:C1789 etanercept NCIT:C2381 adalimumab NCIT:C65216

TNF blockade can control an appropriate underlying inflammatory disease, especially inflammatory arthritis, and may improve AA renal markers. Small observational series show variable outcomes. The retrospective tocilizumab comparison does not establish a universal ranking across AA etiologies. Infliximab and adalimumab are antibodies; etanercept is a soluble receptor fusion protein.

Mechanism Target:

INHIBITS Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus — Neutralizing TNF-alpha suppresses the inflammatory arthropathy at the trigger node, reducing the cytokine drive to hepatic SAA production.

Show evidence (3 references)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In a retrospective series including 15 patients treated with anti-TNF, amyloidosis progressed in seven patients (46.7%), stabilized in five (33.3%), and regression of proteinuria occurred in three (20%) in 10 months"

Quantifies outcomes on anti-TNF therapy. The limitation is that amyloidosis still progressed in the largest single group, so this series does not establish efficacy.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"in a multicenter study in which 36 patients with AA amyloidosis treated with anti-TNF therapy were followed prospectively for 5 years, > 50% decrease in proteinuria was observed in more than half of the patients"

The stronger of the two datasets - prospective, multicentre, 5-year follow-up - showing a substantial proteinuria response in the majority.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"a retrospective analysis including 42 patients with AA amyloidosis demonstrated that tocilizumab was superior to anti-TNFs in terms of obtaining a decrease in SAA, improvement in kidney function, and suppression of the disease activity"

The review reports a 42-patient nonrandomized comparison. Differences in underlying disease and treatment selection limit causal superiority claims.

Interleukin-6 Receptor Blockade (Tocilizumab)

Action: Pharmacotherapy NCIT:C15986

Agent: tocilizumab NCIT:C84217

Platform: Monoclonal antibody

Tocilizumab can suppress SAA in selected refractory inflammatory disorders with AA amyloidosis. A 20-patient uncontrolled series included 14 AA cases and reported rapid SAA reduction with stable or regressing deposits; infections were the predominant adverse effect. A Still disease report also used glucocorticoids, preventing attribution to tocilizumab alone. Choice depends on the cause and clinical context.

Mechanism Target:

INHIBITS IL-6-Driven Hepatic Acute-Phase Response — IL-6 receptor blockade removes the principal signal inducing hepatocyte SAA transcription, collapsing precursor supply at the amplifier node.

Show evidence (3 references)

PMID:26120866 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Whole-cohort median pre-treatment SAA fell from 70 to 4 mg/L within 10 days of the first dose; this response has been maintained over an on-treatment follow-up period of 23 months (p<0.0001). AA amyloid deposits either regressed or remained stable."

The whole-cohort SAA change covers 20 patients, 14 with AA; amyloid findings apply to the affected subset. This is an uncontrolled series.

PMID:26120866 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This small series shows that in patients with treatment-refractory chronic inflammatory conditions TCZ can be effective in suppressing inflammation, and in those with AA amyloidosis, can lead to regression of amyloid deposits."

The authors' own conclusion, recorded with its stated limitation. The limitation is that this is an uncontrolled 20-patient case series, of whom 70% had AA amyloidosis, and the authors call for longer follow-up.

PMID:41670232 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Steroid pulse therapy, followed by tocilizumab, a IL-6 receptor inhibitor, in combination with oral glucocorticoids dramatically improved kidney and cardiac manifestations with reduction in systemic inflammation."

Corroborates organ-level benefit of IL-6 blockade in biopsy-proven AA amyloidosis. The limitation is that it is a single case report with concomitant glucocorticoid therapy.

Interleukin-1 Blockade (Canakinumab, Anakinra)

Action: Pharmacotherapy NCIT:C15986

Agent: canakinumab NCIT:C80971 anakinra NCIT:C38717

Canakinumab (an IL-1beta antibody) and anakinra (an IL-1 receptor antagonist) can control selected autoinflammatory causes of AA. The cited randomized trial demonstrated fewer flares in colchicine-resistant FMF, mevalonate kinase deficiency and TRAPS, not improved AA renal outcomes. Broader GeneReviews guidance supports IL-1 treatment and amyloidosis prevention in the relevant trigger disorders.

Mechanism Target:

INHIBITS Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus — IL-1 pathway inhibition reduces activity of a responsive underlying autoinflammatory disease; canakinumab neutralizes IL-1beta, whereas anakinra blocks its receptor.

Show evidence (2 references)

PMID:29768139 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS."

Randomized trial evidence that canakinumab controls the autoinflammatory trigger diseases. The limitation is that the trial endpoint was control of the trigger disease, not amyloid burden or renal outcome in AA amyloidosis.

PMID:36375008 SUPPORT DIRECT REVIEW SYNTHESIS Other

"IL-1 inhibitors and the TNF inhibitor etanercept control the severity of disease flares and are effective in preventing AA amyloidosis."

TRAPS-specific GeneReviews guidance supports control of this upstream cause, not universal efficacy across AA etiologies.

Kidney Transplantation

Action: Kidney Transplantation NCIT:C15265

Platform: Surgery

Kidney transplantation is an option for suitable individuals with end-stage renal disease. In a contemporary French cohort of 86 recipients, five-year survival was 85.5% and histological recurrence 5.8%. This uncontrolled cohort cannot isolate the effect of biologics; infection requiring hospitalization occurred in 55.8%, and ongoing control of inflammation remains important.

Show evidence (3 references)

PMID:37741608 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5% (77.8-94.0) at 5 years after transplantation."

Provides contemporary patient-survival outcomes after kidney transplantation in 86 patients across 26 French centres.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Kidney transplantation is preferred in patients with kidney failure, and the recurrence of amyloidosis in the allograft has become rare as transplant recipients have started to benefit from the new agents."

States the preference for transplantation and the modern rarity of allograft recurrence.

PMID:37741608 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Histologically proven AA amyloidosis recurrence occurred in 5 transplants (5.8%). An infection requiring hospitalization developed in 55.8% of cases"

Reports recurrence and infection in the selected transplant cohort; neither outcome proves that biologics caused the observed survival.

Dialysis

Action: Dialysis NCIT:C15221

Platform: Device

Hemodialysis or peritoneal dialysis supports patients with established kidney failure. Hypotension and concurrent cardiac or systemic disease can complicate care. Observational differences from transplant recipients are affected by selection and should not be treated as a randomized survival comparison.

Show evidence (2 references)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Dialysis modalities and kidney transplantation are both suitable for patients suffering from AA amyloidosis and kidney failure"

Establishes dialysis as an accepted renal replacement modality in AA amyloidosis.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Still, survival is poor among patients on dialysis, especially when cardiac involvement is prevalent"

The review reports poor dialysis outcomes, especially with cardiac involvement; treatment selection and comorbidity limit comparisons with transplant recipients.

Eprodisate (Investigational)

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

A small molecule intended to interfere with amyloid–glycosaminoglycan interactions. In the initial 183-patient randomized trial, the 24-month worsening proportions were 27% versus 40% (P=.06), while the prespecified time-to-event analysis favored eprodisate (HR 0.58, P=.02). Neither end-stage kidney disease nor mortality improved significantly, and there was no proteinuria or amyloid-load benefit. The 261-patient confirmatory trial failed its different renal composite endpoint (HR 1.0, 95% CI 0.7–1.4; P=.882 in 260 treated participants). These findings do not establish a clinically effective AA therapy.

Mechanism Target:

INHIBITS SAA-Glycosaminoglycan Binding — The intended target is SAA–GAG interaction; recent recombinant-protein assays show only partial binding inhibition, not complete blockade or demonstrated clinical deposit removal.

Show evidence (5 references)

PMID:17554116 SUPPORT DIRECT BACKGROUND Human Clinical

"Eprodisate is a member of a new class of compounds designed to interfere with interactions between amyloidogenic proteins and glycosaminoglycans and thereby inhibit polymerization of amyloid fibrils and deposition of the fibrils in tissues."

States intended pharmacologic action, not a measured demonstration of tissue-deposition inhibition in the clinical trial.

PMID:17554116 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The drug had no significant effect on progression to end-stage renal disease (hazard ratio, 0.54; P=0.20) or risk of death (hazard ratio, 0.95; P=0.94)."

The initial trial did not demonstrate benefit on either individual hard endpoint; the paper does not establish a regulatory reason for nonapproval.

PMID:17554116 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At 24 months, disease was worsened in 24 of 89 patients who received eprodisate (27%) and 38 of 94 patients given placebo (40%, P=0.06); the hazard ratio for worsening disease with eprodisate treatment was 0.58 (95% confidence interval, 0.37 to 0.93; P=0.02)."

Two prespecified analyses gave different significance results; both are retained.

+ 2 more references

Treat the underlying infection

Action: Pharmacotherapy NCIT:C15986

Agent: Anti-Infective Agent NCIT:C254

Use pathogen-appropriate antimicrobial and source-directed treatment for infection-associated AA. Immunomodulation is selected according to the actual cause, not prescribed uniformly for every AA presentation.

Mechanism Target:

INHIBITS Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus — Treating a documented infection reduces its sustained inflammatory stimulus.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"treatment options are tailored accordingly, with infections treated promptly with antimicrobials, and rheumatological and genetic autoinflammatory conditions treated with the appropriate anti-inflammatory therapies."

AA-specific management review supports this intervention; treatment is individualized to renal status and underlying cause.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

AA-specific management review supports this intervention; treatment is individualized to renal status and underlying cause.

Antiproteinuric renin–angiotensin system blockade

Action: Pharmacotherapy NCIT:C15986

Agent: ACE Inhibitor NCIT:C247 Angiotensin II Receptor Antagonist NCIT:C66930

Platform: Small molecule

ACE inhibitors or ARBs can reduce nephrotic-range proteinuria when clinically tolerated, with assessment of kidney function, potassium and perfusion.

Mechanism Target:

INHIBITS Proteinuria — Reduces urinary protein loss without directly removing amyloid deposits.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"In nephrotic syndrome or nephrotic-range proteinuria, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the first choice of drugs with antiproteinuric properties"

AA-specific management review supports this intervention; treatment is individualized to renal status and underlying cause.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"In nephrotic syndrome or nephrotic-range proteinuria, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are the first choice of drugs with antiproteinuric properties"

AA-specific management review supports this intervention; treatment is individualized to renal status and underlying cause.

Edema and volume management

Action: Pharmacotherapy NCIT:C15986

Agent: Loop Diuretic NCIT:C49184

Platform: Small molecule

Dietary sodium reduction and loop diuretics address edema and hypervolemia, with treatment individualized to blood pressure and renal function.

Mechanism Target:

INHIBITS Peripheral Edema — Diuresis and sodium management reduce fluid retention.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Loop diuretics are generally required to manage hypervolemia"

AA-specific management review supports this intervention; treatment is individualized to renal status and underlying cause.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Loop diuretics are generally required to manage hypervolemia"

AA-specific management review supports this intervention; treatment is individualized to renal status and underlying cause.

Renal protection and organ-directed supportive care

Avoid additional hypoperfusion and nephrotoxic injury; assess nutritional, lipid, thrombotic and other organ complications according to their clinical indications.

Mechanism Target:

MODULATES Progressive Renal Functional Decline — Avoiding secondary kidney insults may limit additional loss of function; it does not establish deposit clearance.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"It is imperative to prevent further insults such as hypoperfusion or nephrotoxic drug use."

The review explicitly includes prevention of secondary kidney injury.

Show evidence (1 reference)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"It is imperative to prevent further insults such as hypoperfusion or nephrotoxic drug use."

The review explicitly includes prevention of secondary kidney injury.

Genetic and family counseling for an identified hereditary cause

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Counsel recurrence and offer family evaluation according to the identified cause. The rare SAA1 promoter form segregates dominantly; FMF and TRAPS have their own inheritance and prevention strategies, so a single AA recurrence risk is inappropriate.

Show evidence (2 references)

PMID:34560138 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"sustained elevation of serum amyloid A levels that segregated in an autosomal dominant pattern in 12 genetically affected and in none of six genetically unaffected relatives"

Supports family evaluation for the reported promoter-associated form.

PMID:20301405 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Offer molecular genetic testing for the familial MEFV pathogenic variants to apparently asymptomatic older and younger at-risk sibs of an individual with FMF"

FMF-specific GeneReviews guidance supports identification of relatives who can benefit from early preventive treatment.

Miridesap followed by dezamizumab (Investigational)

SAP depletion followed by anti-SAP antibody was tested in mixed systemic amyloidosis. The 23-person phase 1 extension included two AA participants, each receiving only one dose; one had lower renal amyloid burden on scintigraphy, without demonstrated renal-function or proteinuria improvement through day 42. Neither AA participant had liver deposits. Later cardiac studies enrolled no AA participants and were stopped for lack of efficacy and a serious vasculitis event. These data do not establish routine AA use or an AA-specific contraindication.

Mechanism Target:

INHIBITS Progressive Multi-Organ Amyloid Accumulation — Experimental removal of SAP-bearing amyloid deposits; clinical benefit in AA remains unproven.

Show evidence (3 references)

PMID:29298867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Reduction in renal amyloid was observed in 7 of 11 subjects with renal amyloid detected by SAP scintigraphy (five with AFib and one each with AL and AA amyloidosis)"

Only one AA participant had documented renal amyloid-load reduction. Both AA participants received one antibody dose; no AA repeat-dose efficacy is established.

PMID:29298867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Renal function, serum creatinine and urea concentrations, and urinary protein excretion were unchanged in all subjects up to day 42"

Amyloid-load reduction was not accompanied by a demonstrated early functional or proteinuria improvement.

PMID:35152886 SUPPORT DIRECT PRIMARY RESULT Human Clinical

The later cardiac trial enrolled ATTR and AL, not AA. A suspected large-vessel vasculitis event in the AL participant and absent cardiac benefit prompted termination; neither later study had a death.

🌍

Environmental Factors

Obesity and adipose-derived serum amyloid A

Obesity and older age were associated with idiopathic AA amyloidosis in a retrospective clinical study. Human adipocytes produce SAA, providing a plausible contributing mechanism, but adipose-derived SAA was not traced into deposits and causality was not established.

Show evidence (1 reference)

PMID:29364741 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Obesity, age and the SAA1 polymorphism are susceptibility factors for idiopathic AA amyloidosis."

Directly states obesity as a susceptibility factor for idiopathic AA amyloidosis in a 146-patient study with two control groups.

Mechanism Target:

PREDISPOSES Adipose Serum Amyloid A Production — Higher adiposity is associated with greater adipose SAA expression and secretion; this does not quantify adipose contribution to amyloid deposition.

Show evidence (1 reference)

PMID:16737350 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A-SAA mRNA levels and A-SAA secretion from adipose tissue were significantly correlated with body mass index (r = 0.47; p = 0.028 and r = 0.80; p = 0.0002, respectively)."

Quantifies the correlation between adiposity and adipose SAA output, supporting the route by which obesity feeds the acute-phase precursor node.

🔬

Biochemical Markers

Serum Amyloid A (INCREASED)

Show evidence (2 references)

PMID:17554117 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The effects of renal dysfunction dominate the course of AA amyloidosis, which is associated with a relatively favorable outcome in patients with SAA concentrations that remain in the low-normal range (<4 mg per liter)."

Establishes the prognostic threshold that makes SAA an actionable treat-to-target biomarker.

PMID:26120866 SUPPORT DIRECT BACKGROUND Human Clinical

"The main aim of treatment is to suppress inflammation thereby inhibiting serum amyloid A protein (SAA), which is the precursor of AA amyloid fibrils, to prevent or halt amyloid deposition."

States explicitly that SAA is both the fibril precursor and the treatment target, the dual role this biochemical entry records.

🔬

Diagnosis

Tissue Biopsy with Amyloid Typing

Demonstrate amyloid in tissue and identify the fibril precursor. Congo red staining alone does not distinguish AA from AL or hereditary non-AA amyloidoses. Anti-AA immunohistochemistry is commonly used; laser microdissection/mass spectrometry helps when typing is uncertain. A negative less-invasive fat or salivary-gland sample does not exclude disease when suspicion remains high.

Show evidence (3 references)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Histopathological examination is the gold standard of diagnosis, but magnetic resonance imaging can be used to detect cardiac involvement."

Establishes histopathology as the diagnostic gold standard.

PMID:28828707 SUPPORT DIRECT REVIEW SYNTHESIS Other

"accurate typing of non-AL amyloidosis then requires immunohistochemical or laser microdissection/mass spectrometry studies of the Congo red positive deposits"

States the requirement for immunohistochemical or mass-spectrometric typing beyond Congo red staining.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Other

"If clinical suspicion is significantly high and these approaches render negative results, a sample should be retrieved from the affected organ."

The review cautions against excluding amyloidosis after a negative less-invasive biopsy.

Serum Amyloid A and C-Reactive Protein Monitoring

Serial SAA, renal function and urinary protein measurements follow precursor suppression and organ disease. CRP can assess accompanying inflammation but is not the fibril precursor and can be normal in the hereditary promoter form. SAP scintigraphy, where available, estimates systemic burden and does not replace tissue typing.

Show evidence (1 reference)

PMID:17554117 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The SAA concentration was measured serially, and the amyloid burden was estimated with the use of whole-body serum amyloid P component scintigraphy."

Documents serial SAA and SAP scintigraphy in the longitudinal cohort.

Etiologic investigation and selected SAA1 promoter testing

Investigate chronic infections, inflammatory and autoinflammatory disease. In AA without systemic inflammation, especially with a family history, consider SAA1 promoter analysis and genetic counseling. A standard coding-only panel may not address the reported regulatory variant.

Show evidence (2 references)

PMID:34560138 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Thus, genetic screening of the SAA1 promoter should be pursued in individuals with amyloid A amyloidosis and no systemic inflammation, especially if there is a positive family history."

The family report specifically recommends promoter testing in this setting.

PMID:20301405 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The diagnosis of FMF is established in a proband with suggestive clinical findings and biallelic pathogenic variants in MEFV identified by molecular genetic testing."

GeneReviews informs assessment of FMF as one upstream cause; this is not a diagnostic definition for all AA.

📈

Progression

Subclinical amyloid deposition

Inflammatory AA generally follows sustained precursor production before overt organ disease. Latency varies and cannot be assigned a universal number of years. Renal surveillance is important in at-risk inflammatory diseases; the hereditary promoter form has a distinct upstream cause.

Show evidence (1 reference)

PMID:25387054 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Therefore, AA amyloidosis can be thought of as a consequence of long-standing inflammatory disease."

Supports a prolonged latent phase driven by long-standing inflammation preceding clinical presentation.

Proteinuric and nephrotic phase

In the selected 68-case renal biopsy series, nephrotic syndrome occurred in 63.1% and renal insufficiency in 75%. These overlapping findings do not establish an obligatory sequential course.

Show evidence (1 reference)

PMID:17714761 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of patients, respectively."

Quantifies the proteinuric and nephrotic phase in a renal AA amyloidosis series.

Amyloid storm (rare acute FMF-associated variant)

A minority of FMF patients depart from the indolent course entirely and present with an acute illness: heavy proteinuria, high inflammatory markers, and progression to kidney failure within weeks rather than years, typically precipitated by a superimposed infection. Curated as a distinct trajectory rather than a severity grade, because the timescale (weeks) and the infection trigger are qualitatively different from the usual course.

Show evidence (2 references)

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"While the majority of cases follow an indolent course, a subset of individuals with FMF might undergo acute illness, marked by substantial proteinuria, elevated inflammatory markers, and rapid progression to kidney failure within weeks."

Defines the amyloid storm presentation and contrasts it with the indolent majority course.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"These infrequent instances are named “amyloid storm,” which is thought to be precipitated by superimposed infections or other triggering events"

Names the entity and its precipitating trigger.

Progressive renal decline to end-stage kidney disease

Renal decline varies with underlying disease, baseline injury and treatment. In the initial eprodisate trial, the placebo group lost a mean 15.6 mL/min/1.73 m2 of creatinine clearance per year while receiving physician-managed treatment of underlying inflammation; this is a selected trial comparator, not untreated natural history. A separate 374-patient cohort reported median survival of 133 months after diagnosis.

Show evidence (3 references)

PMID:17554116 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per minute per 1.73 m(2) of body-surface area per year in the eprodisate and the placebo groups, respectively (P=0.02)."

Describes decline in a placebo-controlled trial whose participants also received usual treatment of underlying inflammation. It cannot define the untreated rate for all AA.

PMID:17554117 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Median survival after diagnosis was 133 months"

Provides the median survival benchmark for the progressive phase.

url:https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Treatment of the underlying inflammatory disease was determined by the patient’s physician."

The primary trial Methods establish that usual inflammatory-disease care accompanied both randomized arms, so placebo is not an untreated natural-history cohort.

📊

Prevalence

Patients with rheumatoid arthritis, studies published before 2010

16700.0–25200.0 per 100,000 >1 in 1,000

The systematic review reports a 16.7–25.2% range across heterogeneous rheumatoid arthritis studies published before 2010. This is neither a pooled estimate nor a general-population rate; no midpoint estimate is assigned.

Show evidence (1 reference)

PMID:40516176 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"AAA prevalence rates in rheumatoid arthritis ranged from 16.7 % to 25.2 % before 2010"

Systematic review reporting the historical prevalence range of AA amyloidosis within rheumatoid arthritis cohorts.

Patients with rheumatoid arthritis, studies published after 2010

700.0 per 100,000 >1 in 1,000

The review reports 0.7% in rheumatoid arthritis studies published after 2010. Cohorts and ascertainment differ across eras; the temporal association suggests, but does not establish, an effect of biologic therapy. The review found no clear incidence or mortality trend and calls for population-based data.

Show evidence (1 reference)

PMID:40516176 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"decreased to 0.7 % after 2010, which suggests a potential positive role of biologic therapies"

Reports the later-era estimate and a proposed contribution of biologic therapy, without a causal comparison across equivalent populations.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from AA Amyloidosis:

Systemic AL Amyloidosis MONDO:0017816

Overlapping Features AL amyloid derives from immunoglobulin light chains, whereas AA derives from SAA. Tissue precursor typing is essential because management differs. Renal-predominant presentation and an inflammatory history can suggest AA but do not establish its type.

Distinguishing Features

AA usually has dominant renal involvement; clinically important cardiac involvement is less typical but can occur.
Light-chain restriction supports AL, while negative immunofluorescence suggests a non-AL type; definitive typing remains necessary.

Show evidence (2 references)

PMID:28828707 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The detection of Congo red positive deposits coupled with negative immunofluorescence studies is highly suggestive of non-AL amyloidosis."

Provides the immunofluorescence-based discriminator between AL and non-AL (including AA) renal amyloidosis.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"While cardiac infiltration is extensively documented in various amyloidosis types, it is a relatively rare cause of heart failure in AA amyloidosis"

The review describes cardiac heart failure as relatively rare in AA; this is a contextual clue, not a stand-alone classifier.

🔬

Clinical Trials

NCT00035334 PHASE_III COMPLETED

NCT00035334 randomized 183 patients to eprodisate or placebo for 24 months in addition to physician-directed care of underlying inflammation. Its composite included creatinine doubling, ≥50% creatinine-clearance reduction, end-stage kidney disease or death. The fixed-time worsening comparison had P=.06 while the prespecified time-to-event analysis had P=.02; hard endpoint benefits were not significant.

Target Phenotypes: Renal insufficiency HP:0000083

Show evidence (3 references)

PMID:17554116 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We randomly assigned 183 patients from 27 centers to receive eprodisate or placebo for 24 months."

Describes the trial design and enrolment registered as NCT00035334.

url:https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Treatment of the underlying inflammatory disease was determined by the patient’s physician."

The primary trial Methods establish that usual inflammatory-disease care accompanied both randomized arms, so placebo is not an untreated natural-history cohort.

clinicaltrials:NCT00035334 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The main objective of this study is to evaluate the safety and efficacy of NC-503 compared to placebo in patients with secondary (AA) amyloidosis using a composite assessment of clinical improvement/worsening of both renal and gastrointestinal functions."

Registry summary establishes the study purpose; efficacy and safety conclusions come from the separately cited publication or results record.

NCT01215747 PHASE_III COMPLETED

Confirmatory randomized eprodisate trial: 261 randomized, 260 dosed in the primary time-to-event analysis. Its composite was persistent creatinine-clearance decline ≥40%, serum-creatinine rise ≥80%, or end-stage renal disease, without death as a component. The prespecified superiority analysis was negative (HR 1.0, 95% CI 0.7–1.4; log-rank P=.882).

Show evidence (3 references)

url:https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-022313-25/results SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This primary efficacy endpoint was the time from Baseline to the earliest of a persistent decrease in creatinine clearance (CrCl) of 40% or more, a persistent increase in serum creatinine (SCr) of 80% or more, or progression to end-stage renal disease (ESRD)."

The generated EU results record defines the confirmatory endpoint. Its adjacent prespecified statistical-analysis table reports 260 subjects, HR 1.0, 95% CI 0.7–1.4 and P=.882.

PMID:38568326 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"which was not confirmed in a randomized control trial (NCT01215747)"

The review reports failure of the confirmatory trial; primary EU registry analysis gives HR 1.0, 95% CI 0.7–1.4 and P=.882.

clinicaltrials:NCT01215747 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The primary purpose of this study is to assess the efficacy and safety of treatment with Kiacta in adult patients with AA Amyloidosis."

Registry summary establishes the study purpose; efficacy and safety conclusions come from the separately cited publication or results record.

NCT01777243 PHASE_I COMPLETED

Open-label miridesap/anti-SAP dose-escalation study in systemic amyloidosis. Initial 15 participants were extended to 23, including two AA cases. Both AA participants received a single antibody dose, so the repeated-dose title does not establish repeated-dose AA efficacy.

Show evidence (4 references)

PMID:26176329 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis."

Defines the initial mixed-amyloid study, not an AA-specific efficacy trial.

PMID:29298867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Reduction in renal amyloid was observed in 7 of 11 subjects with renal amyloid detected by SAP scintigraphy (five with AFib and one each with AL and AA amyloidosis)"

Only one AA participant had documented renal amyloid-load reduction. Both AA participants received one antibody dose; no AA repeat-dose efficacy is established.

PMID:29298867 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Renal function, serum creatinine and urea concentrations, and urinary protein excretion were unchanged in all subjects up to day 42"

Amyloid-load reduction was not accompanied by a demonstrated early functional or proteinuria improvement.

+ 1 more reference

🧫

Experimental Models

Recombinant SAA–glycosaminoglycan assembly assays OTHER

Cell-free SAA isoforms were examined with heparin or heparan sulfate using CD/FTIR, thioflavin-T kinetics, TEM, amyloid-reactive antibodies and binding assays. Isoform, pH and aggregation state alter the responses.

Publication

PMID:39954777

Pathograph links

SAA Amyloid Fibril Assembly perturbs fidelity: low Heparin addition alters assembly kinetics under defined conditions.

Limitations: Recombinant lipid-free murine SAA and human SAA1/SAA2 were tested at defined pH; the study does not measure HDL dissociation, patient tissue deposition or organ injury. The early acidic beta-sheet is reversible and distinct from amyloid; apparent droplets are not proven necessary intermediates. GAG-free controls also eventually form fibrils.

Readouts

Amyloid-assembly kinetics

Direction: INCREASED

Interpretation: At pH 7.4 heparin shortened the lag and accelerated growth in the murine protein assay.

Show evidence (1 reference)

PMID:39954777 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Heparin greatly accelerated formation of amyloid-like structure in mSAA at pH 7.4 by eliminating the lag (nucleation) phase and accelerating the growth phase in the ThT kinetic data."

The kinetic effect is measured in recombinant murine SAA at neutral pH; complementary antibody and microscopy assays support amyloid formation.

Show evidence (1 reference)

PMID:39954777 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Heparin greatly accelerated formation of amyloid-like structure in mSAA at pH 7.4 by eliminating the lag (nucleation) phase and accelerating the growth phase in the ThT kinetic data."

The kinetic effect is measured in recombinant murine SAA at neutral pH; complementary antibody and microscopy assays support amyloid formation.

SAA-Glycosaminoglycan Binding measures fidelity: low Binding increases as soluble oligomers form; heparin also binds previously formed fibrils.

Readouts

GAG binding after oligomerization

Direction: INCREASED

Interpretation: The measured increase applies to the protein/aggregate states tested, not a universal native-SAA interaction.

Show evidence (1 reference)

PMID:39954777 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the binding affinity increases upon formation of soluble amyloid oligomers."

Recombinant lipid-free SAA assays show stronger glycosaminoglycan binding after oligomer formation. Native human SAA2 did not show detectable binding in these assays.

Show evidence (1 reference)

PMID:39954777 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the binding affinity increases upon formation of soluble amyloid oligomers."

Recombinant lipid-free SAA assays show stronger glycosaminoglycan binding after oligomer formation. Native human SAA2 did not show detectable binding in these assays.

Truncated human SAA peptide assembly OTHER

Cell-free human SAA(1–76) was compared with full-length SAA in a heparan-sulfate-induced assembly system. CD, FTIR and electron microscopy assess conformation and fibrils.

Publication

PMID:29288051

Pathograph links

Reduced Alpha-Helical Structure of Truncated SAA recapitulates fidelity: low Tests the direct structural consequence of a defined C-terminal truncation.

Limitations: Only the abstract is available after attempted regeneration. It does not establish when cleavage occurs in patients or identify the responsible tissue protease.

Readouts

Alpha-helical structure

Direction: DECREASED

Interpretation: Truncated peptide has less alpha-helical structure than full-length protein.

Show evidence (1 reference)

PMID:29288051 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Circular dichroism (CD) measurements demonstrated that the C-terminal truncation induces a reduced α-helical structure of the SAA molecule."

Compares truncated SAA(1–76) with full-length protein; the experiment tests a defined fragment rather than proving when proteolysis occurs in vivo.

Show evidence (1 reference)

PMID:29288051 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Circular dichroism (CD) measurements demonstrated that the C-terminal truncation induces a reduced α-helical structure of the SAA molecule."

Compares truncated SAA(1–76) with full-length protein; the experiment tests a defined fragment rather than proving when proteolysis occurs in vivo.

SAA Amyloid Fibril Assembly recapitulates fidelity: low Truncated protein forms fibrils more readily under the tested conditions.

Limitations: The comparison does not show that full-length SAA cannot fibrillize under other conditions.

Readouts

Fibrillar aggregates by TEM

Direction: INCREASED

Interpretation: Truncated SAA formed aggregates where full-length SAA scarcely did.

Show evidence (1 reference)

PMID:29288051 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Transmission electron microscopy revealed that short fibrillar aggregates of SAA (1-76) peptides, which became longer with increasing peptide concentrations, were observed under conditions in which full-length SAA scarcely formed fibrillar aggregates."

Truncation accelerates fibril assembly in this experimental system; full-length protein can form fibrils under other conditions.

Show evidence (1 reference)

PMID:29288051 SUPPORT DIRECT PRIMARY RESULT In Vitro

Truncation accelerates fibril assembly in this experimental system; full-length protein can form fibrils under other conditions.

SAA isoform degradation by MMP-1 OTHER

Cell-free SAA isoforms were exposed to MMP-1; immunoblotting and MALDI-TOF identify cleavage differences.

Publication

PMID:18815155

Pathograph links

SAA Proteolytic Cleavage measures fidelity: low Measures isoform-dependent susceptibility to a defined enzyme.

Limitations: Abstract-only evidence. It does not demonstrate the enzyme responsible in human tissue or prove that increased cleavage explains the genotype-associated clinical risk.

Readouts

Isoform cleavage susceptibility

Direction: ALTERED

Interpretation: SAA1.5 was more resistant to MMP-1 than SAA1.1, with a cleavage difference at residue 57.

Show evidence (1 reference)

PMID:18815155 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found that SAA1.5 is more resistant to degradation by MMP-1 than SAA1.1. This difference is caused by the capacity of MMP-1 to cleave at the site of the polymorphism at position 57."

Immunoblotting and mass spectrometry demonstrate isoform-dependent MMP-1 cleavage in vitro; this does not establish the rate-limiting protease or cleavage sequence in patients.

Show evidence (1 reference)

PMID:18815155 SUPPORT DIRECT PRIMARY RESULT In Vitro

"We found that SAA1.5 is more resistant to degradation by MMP-1 than SAA1.1. This difference is caused by the capacity of MMP-1 to cleave at the site of the polymorphism at position 57."

Immunoblotting and mass spectrometry demonstrate isoform-dependent MMP-1 cleavage in vitro; this does not establish the rate-limiting protease or cleavage sequence in patients.

HDL-SAA remodeling and monocyte amyloid culture OTHER

Biochemical HDL-SAA/HS assays and a monocyte culture system tested pH-sensitive interactions and synthetic peptides containing the H36 region.

Publication

PMID:19549924

Pathograph links

Heparan Sulfate-Associated HDL-SAA Remodeling perturbs fidelity: low Measures the effect of HS at mildly acidic pH.

Limitations: Only abstract evidence is available; precise culture provenance and in-vivo location are not inferred.

Readouts

SAA-rich aggregate production

Direction: INCREASED

Interpretation: HS remodeled HDL-associated SAA in the assay.

Show evidence (1 reference)

PMID:19549924 SUPPORT DIRECT PRIMARY RESULT In Vitro

"HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich aggregates."

Biochemical and culture experiments demonstrate pH-dependent HDL-SAA remodeling, without locating or proving this step in patients.

Show evidence (1 reference)

PMID:19549924 SUPPORT DIRECT PRIMARY RESULT In Vitro

"HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich aggregates."

Biochemical and culture experiments demonstrate pH-dependent HDL-SAA remodeling, without locating or proving this step in patients.

SAA Amyloid Fibril Assembly perturbs fidelity: low Peptides promoted deposition in the monocyte culture model.

Limitations: This does not demonstrate that the same local pH or peptide concentration occurs in patient kidneys.

Show evidence (1 reference)

PMID:19549924 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Synthetic peptides corresponding to this region promoted the deposition of AA amyloid in a monocyte culture model for AA amyloidogenesis. The effects were peptide sequence specific and reliant on the protonation of H36."

The culture experiment supports sequence- and pH-sensitive promotion of assembly; it does not establish a human environmental exposure mechanism.

Human adipose tissue SAA secretion OTHER

Human adipose biopsy explants were cultured with insulin, dexamethasone and/or rosiglitazone; conditioned-medium SAA was measured. Clinical BMI/expression associations were a separate component of the same study.

Publication

PMID:16737350

Pathograph links

Adipose Serum Amyloid A Production measures fidelity: low Directly measures SAA secretion from human adipose explants.

Limitations: These were not amyloid-bearing patient tissues. The study does not trace adipose SAA into AA deposits, establish an AA prevention effect, or support rosiglitazone as AA therapy.

Readouts

SAA accumulation in conditioned medium

Direction: INCREASED

Interpretation: Hormonal stimulation increased secretion; rosiglitazone reduced secretion in this experimental setting.

Show evidence (1 reference)

PMID:16737350 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Incubation of the fat explants for 2 d with insulin or dexamethasone resulted in an SAA accumulation in the medium, and combination of the two hormones was additive in the stimulatory effect."

Human adipose explants directly secrete measurable SAA under defined hormonal conditions; this is ex-vivo tissue culture.

Show evidence (1 reference)

PMID:16737350 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Incubation of the fat explants for 2 d with insulin or dexamethasone resulted in an SAA accumulation in the medium, and combination of the two hormones was additive in the stimulatory effect."

Human adipose explants directly secrete measurable SAA under defined hormonal conditions; this is ex-vivo tissue culture.

🐁

Animal Models

Heterologous fibril acceleration of murine AA deposition Induced (non-transgenic) AA amyloidosis model

Five- to ten-week-old female NMRI mice and age-matched FVB mice of both sexes were studied. Heterologous silk, Sup35 or curli preparations were injected with a silver-nitrate inflammatory challenge; matched vehicle and nonamyloid actin controls also received the challenge. Splenic AA deposition was evaluated after 16 days using blinded Congo-red microscopy and immunohistochemistry. In the FVB Sup35 experiment, 10/12 seeded mice had deposits versus 2/11 controls with minimal deposits; results varied across preparations and strains. This tests experimental cross-seeding, not live bacterial infection, oral transmission or environmental risk in humans.

Species

Mus musculus

Genotype

Non-transgenic NMRI and FVB mice

Pathograph links

SAA Amyloid Fibril Assembly perturbs fidelity: low Heterologous fibrils accelerate splenic AA deposition during an inflammatory challenge, supporting an in vivo seeding contribution to assembly.

Limitations: This induced model does not establish spontaneous clinical latency, human environmental transmission, systemic clinical organ failure or therapeutic rescue. Splenic deposits are an endpoint of assembly and accumulation, not a direct kinetic measurement of molecular nucleation. Separate Sup35-variant results were not significantly different.

Divergences from the human mechanism

proxy quantity

Splenic deposits measured after 16 days reflect assembly and accumulation; they do not directly quantify the kinetics of molecular SAA nucleation.

species mismatch

Injected heterologous fibrils with an inflammatory challenge in NMRI/FVB mice do not establish human environmental transmission or spontaneous clinical organ failure.

Readouts

Splenic AA deposition after Sup35 seeding

Direction: INCREASED

Interpretation: At day 16, deposits were found in 10/12 FVB mice given Sup35 versus minimal deposits in 2/11 vehicle controls; both groups received an inflammatory challenge. The study does not demonstrate clinical renal benefit or rescue.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"Amyloid deposits were detected in the spleens of 10 of the 12 FVB mice treated with Sup35, whereas 2 of 11 mice in a control group treated with 0.9% NaCl developed minimal amyloid deposits"

The comparison quantifies splenic deposition, not human disease penetrance or direct molecular assembly flux.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/ SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Amyloid deposits were detected in the spleens of 10 of the 12 FVB mice treated with Sup35, whereas 2 of 11 mice in a control group treated with 0.9% NaCl developed minimal amyloid deposits"

Mouse deposition is a direct experimental endpoint; its relationship to molecular fibril assembly is inferred from the seeding design.

Show evidence (6 references)

PMID:15829582 SUPPORT DIRECT PRIMARY RESULT Model Organism

"We studied three such naturally occurring protein fibrils: silk from Bombyx mori, Sup35 from Saccharomyces cerevisiae, and curli from Escherichia coli."

Identifies the heterologous seed preparations.

PMID:15829582 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Our results show that these protein fibrils exert amyloid-accelerating properties in the murine experimental AA amyloidosis"

Direct experimental result; environmental human risk is an extrapolation.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/ SUPPORT DIRECT PRIMARY RESULT Model Organism

"Amyloid deposits were detected in the spleens of 10 of the 12 FVB mice treated with Sup35, whereas 2 of 11 mice in a control group treated with 0.9% NaCl developed minimal amyloid deposits"

Direct seeded-versus-vehicle comparison in FVB mice under inflammatory challenge; the control group was not uniformly negative.

+ 3 more references

{ }

Source YAML

click to show

name: AA Amyloidosis
creation_date: '2026-08-08T00:00:00Z'
category: Complex
disease_term:
  preferred_term: AA amyloidosis
  term:
    id: MONDO:0019439
    label: AA amyloidosis
parents:
- Amyloidosis
description: >-
  Systemic AA amyloidosis results from extracellular deposition of fibrils derived from serum amyloid
  A (SAA). Most cases complicate chronic inflammatory, autoinflammatory or infectious disease through
  sustained SAA production; some remain idiopathic, and a rare autosomal dominant SAA1 promoter variant
  causes hereditary AA amyloidosis without systemic inflammation. Renal disease dominates, with proteinuria,
  nephrotic syndrome and progressive loss of kidney function. Hepatic, splenic and gastrointestinal involvement
  also occurs; cardiac failure is less typical. SAA concentration, protein processing, fibril nucleation
  and extracellular cofactors contribute to deposition, but their sequence in patients is incompletely
  resolved. Treating the underlying cause and reducing SAA can stabilize disease and permit regression
  of deposits; established organ damage may persist.
synonyms:
- secondary amyloidosis
- reactive systemic amyloidosis
- inflammatory amyloidosis
- amyloid A amyloidosis
- serum amyloid A amyloidosis
prevalence:
- population: Patients with rheumatoid arthritis, studies published before 2010
  prevalence_class: ABOVE_1_IN_1000
  rate_low: 16700.0
  rate_high: 25200.0
  notes: >-
    The systematic review reports a 16.7–25.2% range across heterogeneous rheumatoid arthritis studies
    published before 2010. This is neither a pooled estimate nor a general-population rate; no midpoint
    estimate is assigned.
  evidence:
  - reference: PMID:40516176
    reference_title: 'AA amyloidosis in inflammatory joint diseases: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AAA prevalence rates in rheumatoid arthritis ranged from 16.7 % to 25.2 %
      before 2010
    explanation: >-
      Systematic review reporting the historical prevalence range of AA amyloidosis within rheumatoid
      arthritis cohorts.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- population: Patients with rheumatoid arthritis, studies published after 2010
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 700.0
  notes: >-
    The review reports 0.7% in rheumatoid arthritis studies published after 2010. Cohorts and ascertainment
    differ across eras; the temporal association suggests, but does not establish, an effect of biologic
    therapy. The review found no clear incidence or mortality trend and calls for population-based data.
  evidence:
  - reference: PMID:40516176
    reference_title: 'AA amyloidosis in inflammatory joint diseases: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      decreased to 0.7 % after 2010, which suggests a potential positive role of
      biologic therapies
    explanation: >-
      Reports the later-era estimate and a proposed contribution of biologic therapy, without a causal
      comparison across equivalent populations.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
mechanistic_hypotheses:
- hypothesis_group_id: canonical_saa_overproduction
  hypothesis_label: Canonical SAA Overproduction Model
  status: CANONICAL
  description: >-
    In the common inflammation-associated pathway, cytokines stimulate hepatic SAA production. Persistent
    circulating precursor supplies fibril assembly; lower serial SAA concentrations are associated with
    amyloid regression and better renal and survival outcomes. Adipose production and the rare hereditary
    SAA1 promoter mechanism provide additional routes to elevated SAA.
  evidence:
  - reference: PMID:25387054
    reference_title: 'AA amyloidosis: pathogenesis and targeted therapy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In AA amyloidosis, the expression of cytokines, particularly interleukin 6,
      leads to overproduction of serum amyloid A (SAA) by the liver. A
      chronically high plasma concentration of SAA results in the aggregation of
      amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully
      understood.
    explanation: >-
      States the cytokine-to-precursor-to-fibril chain that defines the canonical hypothesis group.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:17554117
    reference_title: Natural history and outcome in systemic AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mortality, amyloid burden, and renal prognosis all significantly correlated
      with the SAA concentration during follow-up.
    explanation: >-
      The 374-patient longitudinal cohort links serial SAA to burden and outcomes; this observational
      relationship does not establish a universal concentration-duration threshold.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- hypothesis_group_id: nucleation_seeding_model
  hypothesis_label: Nucleation-Dependent Seeding Model
  status: CANONICAL
  description: >-
    Preformed fibrils can template further amyloid assembly. Experimental cross-seeding accelerates murine
    AA amyloidosis, but the contribution of environmental heterologous seeds to human disease has not
    been established.
  evidence:
  - reference: PMID:25387054
    reference_title: 'AA amyloidosis: pathogenesis and targeted therapy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Generation of amyloid fibrils is nucleation dependent, and once formed,
      fibrils recruit and catalyze the conversion of native molecules.
    explanation: >-
      States the nucleation-and-templating mechanism that distinguishes this model from simple mass-action
      aggregation.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:15829582
    reference_title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results show that these protein fibrils exert amyloid-accelerating
      properties in the murine experimental AA amyloidosis, suggesting that such
      environment factors may be important risk factors in amyloidogenesis.
    explanation: >-
      Direct experimental support for murine cross-seeding; the authors propose, rather than demonstrate,
      an environmental risk in humans.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
pathophysiology:
- name: Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus
  description: >-
    Persistent inflammation from infections, inflammatory arthritis or monogenic autoinflammatory disease
    can sustain SAA production. These are heterogeneous causes of the common acquired pathway; overt inflammation
    is not required in every idiopathic or hereditary case.
  role: trigger
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:25387054
    reference_title: 'AA amyloidosis: pathogenesis and targeted therapy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, AA amyloidosis can be thought of as a consequence of
      long-standing inflammatory disease.
    explanation: >-
      Frames chronic inflammatory disease as the upstream trigger of the whole chain.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:17714761
    reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The amyloidogenic disease was a chronic infection (40.8%), a chronic
      inflammation (38%), a tumor (9.9%), a hereditary disease (9.9%), or was
      undetermined in 1.4% of cases.
    explanation: >-
      Quantifies the heterogeneous trigger diseases in a renal AA amyloidosis series, supporting the trigger
      node as an aetiology-agnostic entry point.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
    temporality: CHRONIC
  downstream:
  - target: IL-6-Driven Hepatic Acute-Phase Response
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Inflammatory cytokines stimulate hepatocyte SAA production.
    evidence:
    - reference: PMID:25387054
      reference_title: 'AA amyloidosis: pathogenesis and targeted therapy.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction
        of serum amyloid A (SAA) by the liver.
      explanation: >-
        Review synthesis of the inflammatory hepatic precursor-production pathway.
- name: IL-6-Driven Hepatic Acute-Phase Response
  description: >-
    IL-6, with other inflammatory cytokines, increases hepatic acute-phase SAA expression and secretion.
    This node describes the inflammatory liver pathway.
  role: amplifier
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:25387054
    reference_title: 'AA amyloidosis: pathogenesis and targeted therapy.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction
      of serum amyloid A (SAA) by the liver.
    explanation: >-
      Review synthesis of the inflammatory hepatic precursor-production pathway.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: acute-phase response
    term:
      id: GO:0006953
      label: acute-phase response
    modifier: INCREASED
  downstream:
  - target: Sustained Elevation of Circulating Serum Amyloid A
    causal_link_type: DIRECT
    description: >-
      Continued hepatic output supplies circulating SAA.
    evidence:
    - reference: PMID:25387054
      reference_title: 'AA amyloidosis: pathogenesis and targeted therapy.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: >-
        In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction
        of serum amyloid A (SAA) by the liver.
      explanation: >-
        Review synthesis of the inflammatory hepatic precursor-production pathway.
- name: Adipose Serum Amyloid A Production
  description: >-
    Human adipocytes express SAA1/SAA2 and adipose SAA secretion correlates with adiposity. This offers
    a plausible additional precursor source in obesity-associated idiopathic AA amyloidosis; the adipocyte
    study did not test amyloid deposition or establish adipose dominance during severe systemic inflammation.
  role: amplifier
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:16737350
    reference_title: 'Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      A-SAA mRNA levels and A-SAA secretion from adipose tissue were significantly correlated with body
      mass index (r = 0.47; p = 0.028 and r = 0.80; p = 0.0002, respectively).
    explanation: >-
      Human tissue expression and secretion measurements support adipose precursor production; the participants
      were not an AA amyloidosis cohort.
  cell_types:
  - preferred_term: adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  downstream:
  - target: Sustained Elevation of Circulating Serum Amyloid A
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Adipose secretion may contribute to circulating precursor in obesity; the relative contribution
      in AA patients is unmeasured.
    evidence:
    - reference: PMID:16737350
      reference_title: 'Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        A-SAA mRNA levels and A-SAA secretion from adipose tissue were significantly correlated with body
        mass index (r = 0.47; p = 0.028 and r = 0.80; p = 0.0002, respectively).
      explanation: >-
        Human tissue expression and secretion measurements support adipose precursor production; the participants
        were not an AA amyloidosis cohort.
- name: Hereditary SAA1 Promoter Variant
  description: >-
    A rare SAA1 promoter chr11:18287683T>C variant (hg19), linked to SAA1.1, segregated with sustained
    SAA elevation and hereditary AA amyloidosis in one family.
  role: trigger
  biological_scale: MOLECULAR
  evidence: &id001
  - reference: PMID:34560138
    reference_title: A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Here we describe a family with primary amyloid A amyloidosis due to a chr11:18287683 T>C (human
      genome version19) mutation in the SAA1 promoter linked to the amyloidogenic SAA1.1 haplotype.
    explanation: >-
      Identifies a segregating promoter variant in a rare hereditary form, distinct from common coding
      susceptibility alleles.
  downstream:
  - target: Increased Basal SAA1 Promoter Activity
    causal_link_type: DIRECT
    description: >-
      The reported promoter variant increases basal promoter activity.
    evidence:
    - reference: PMID:34560138
      reference_title: A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        This condition leads to a doubling of the basal SAA1 promoter activity
      explanation: >-
        The assay directly reports higher basal promoter activity.
- name: Increased Basal SAA1 Promoter Activity
  description: >-
    The hereditary promoter variant approximately doubled basal promoter activity in the reported assay.
    This regulatory mechanism can elevate SAA without the usual systemic inflammatory driver.
  role: amplifier
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:34560138
    reference_title: A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      This condition leads to a doubling of the basal SAA1 promoter activity
    explanation: >-
      The reported assay supports increased basal promoter activity; the available abstract does not specify
      the cell system.
  downstream:
  - target: Sustained Elevation of Circulating Serum Amyloid A
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Increased expression provides a plausible link between the promoter assay and sustained SAA elevation
      in the segregating family.
    evidence:
    - reference: PMID:34560138
      reference_title: A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        sustained elevation of serum amyloid A levels that segregated in an autosomal dominant pattern
        in 12 genetically affected and in none of six genetically unaffected relatives
      explanation: >-
        Family segregation links the regulatory variant to circulating SAA; intermediate expression and
        secretion steps are inferred.
- name: Sustained Elevation of Circulating Serum Amyloid A
  description: >-
    Persistent precursor availability contributes to amyloid formation. Serial SAA concentrations correlate
    with clinical outcomes, but no single concentration or exposure duration determines deposition in
    every individual.
  role: trigger
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:17554117
    reference_title: Natural history and outcome in systemic AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Mortality, amyloid burden, and renal prognosis all significantly correlated with the SAA concentration
      during follow-up.
    explanation: >-
      Serial measurements in 374 patients associate precursor concentration with burden and outcome; other
      determinants of conversion remain unresolved.
  conforms_to: amyloidogenesis#Amyloidogenic Precursor Protein
  downstream:
  - target: SAA Amyloid Fibril Assembly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A sustained precursor pool supplies assembly through incompletely resolved processing and conformational
      steps.
    evidence:
    - reference: PMID:17554117
      reference_title: Natural history and outcome in systemic AA amyloidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Mortality, amyloid burden, and renal prognosis all significantly correlated with the SAA concentration
        during follow-up.
      explanation: >-
        Serial measurements in 374 patients associate precursor concentration with burden and outcome;
        other determinants of conversion remain unresolved.
- name: Heparan Sulfate-Associated HDL-SAA Remodeling
  description: >-
    At mildly acidic pH, heparan sulfate remodels HDL-associated SAA into SAA-rich aggregates in vitro.
    This provides a candidate route from lipid-associated precursor toward aggregation; its timing and
    anatomical site in human disease remain uncertain.
  role: amplifier
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:19549924
    reference_title: 'Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich aggregates.
    explanation: >-
      Biochemical and culture experiments demonstrate pH-dependent HDL-SAA remodeling, without locating
      or proving this step in patients.
  downstream:
  - target: SAA Amyloid Fibril Assembly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      HDL remodeling and aggregation can facilitate amyloid formation in the experimental system; additional
      conversion steps are not resolved.
    evidence:
    - reference: PMID:19549924
      reference_title: 'Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich aggregates.
      explanation: >-
        Biochemical and culture experiments demonstrate pH-dependent HDL-SAA remodeling, without locating
        or proving this step in patients.
- name: SAA Proteolytic Cleavage
  description: >-
    AA deposits contain truncated SAA species, and MMP-1 cleaves SAA isoforms differently in vitro. These
    observations do not establish that MMP-1 is the relevant human enzyme or that cleavage must precede
    fibril assembly.
  role: amplifier
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:18815155
    reference_title: 'Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      We found that SAA1.5 is more resistant to degradation by MMP-1 than SAA1.1. This difference is caused
      by the capacity of MMP-1 to cleave at the site of the polymorphism at position 57.
    explanation: >-
      Immunoblotting and mass spectrometry demonstrate isoform-dependent MMP-1 cleavage in vitro; this
      does not establish the rate-limiting protease or cleavage sequence in patients.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/
    reference_title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism - PMC'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      The MS analyses showed that SAA is C-terminally trimmed in the amyloid fibrils. Whether precleavage is
      necessary for recruitment of SAA to the fibril template or it occurs after its association to the amyloid
      is not known.
    explanation: >-
      Mass spectrometry of extracted mouse AA deposits supports truncation, while the authors explicitly leave
      the timing of cleavage unresolved. It does not identify MMP-1 as the tissue protease.
  biological_processes:
  - preferred_term: proteolysis
    term:
      id: GO:0006508
      label: proteolysis
  notes: >-
    This node is deliberately not joined to the SAA(1–76) conformational assay. MMP-1 cleavage at residue 57 and
    synthetic truncation at residue 76 are different experimental perturbations; neither establishes an
    obligatory cleavage-before-fibril sequence in tissue.
- name: Reduced Alpha-Helical Structure of Truncated SAA
  description: >-
    Synthetic C-terminal truncation reduces alpha-helical structure in SAA(1–76). This experimentally
    observed conformational effect is distinct from the unresolved timing of proteolysis in tissue deposits.
  role: amplifier
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:29288051
    reference_title: Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Circular dichroism (CD) measurements demonstrated that the C-terminal truncation induces a reduced
      α-helical structure of the SAA molecule.
    explanation: >-
      Compares truncated SAA(1–76) with full-length protein; the experiment tests a defined fragment rather
      than proving when proteolysis occurs in vivo.
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  downstream:
  - target: SAA Amyloid Fibril Assembly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Truncated SAA forms fibrils more readily in the tested heparan sulfate system; the reduced helical
      structure is a candidate contributor, not an independently rescued causal mediator.
    evidence:
    - reference: PMID:29288051
      reference_title: Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Transmission electron microscopy revealed that short fibrillar aggregates of SAA (1-76) peptides,
        which became longer with increasing peptide concentrations, were observed under conditions in
        which full-length SAA scarcely formed fibrillar aggregates.
      explanation: >-
        Truncation accelerates fibril assembly in this experimental system; full-length protein can form
        fibrils under other conditions.
- name: SAA-Glycosaminoglycan Binding
  description: >-
    Heparan sulfate and heparin interact with SAA and its aggregates. Binding strengthens during oligomerization,
    and heparin also binds preformed fibrils. Acidic heparin-induced beta-sheet is pH-reversible and distinct
    from amyloid. Apparent droplets are a proposed intermediate rather than a demonstrated requirement.
  role: amplifier
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:39954777
    reference_title: 'Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      the binding affinity increases upon formation of soluble amyloid oligomers.
    explanation: >-
      Recombinant lipid-free SAA assays show stronger glycosaminoglycan binding after oligomer formation.
      Native human SAA2 did not show detectable binding in these assays.
  molecular_functions:
  - preferred_term: glycosaminoglycan binding
    term:
      id: GO:0005539
      label: glycosaminoglycan binding
  downstream:
  - target: SAA Amyloid Fibril Assembly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Glycosaminoglycans can accelerate assembly; fibrils also form without them. Their kinetic effect
      depends on pH and isoform.
    evidence:
    - reference: PMID:39954777
      reference_title: 'Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Heparin greatly accelerated formation of amyloid-like structure in mSAA at pH 7.4 by eliminating
        the lag (nucleation) phase and accelerating the growth phase in the ThT kinetic data.
      explanation: >-
        The kinetic effect is measured in recombinant murine SAA at neutral pH; complementary antibody
        and microscopy assays support amyloid formation.
    - reference: PMID:39954777
      reference_title: 'Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        After incubation, amyloid fibrils were observed by TEM in all samples with and without GAGs
      explanation: >-
        Glycosaminoglycans modify assembly kinetics but are not required for fibril formation under all
        tested conditions.
- name: SAA Amyloid Fibril Assembly
  description: >-
    SAA species assemble into cross-beta amyloid fibrils through nucleation and elongation. Truncation
    and extracellular cofactors can alter kinetics, while preformed fibrils provide seeds. Neither obligatory
    prior truncation nor indispensable GAG binding is assumed.
  role: central_effector
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:25387054
    reference_title: 'AA amyloidosis: pathogenesis and targeted therapy.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Generation of amyloid fibrils is nucleation dependent, and once formed, fibrils recruit and catalyze
      the conversion of native molecules.
    explanation: >-
      Synthesis of templated fibril assembly.
  - reference: PMID:39954777
    reference_title: 'Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      After incubation, amyloid fibrils were observed by TEM in all samples with and without GAGs
    explanation: >-
      Glycosaminoglycans modify assembly kinetics but are not required for fibril formation under all
      tested conditions.
  biological_processes:
  - preferred_term: amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  downstream:
  - target: Progressive Multi-Organ Amyloid Accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Persistent fibril production relative to clearance permits extracellular tissue accumulation.
    evidence:
    - reference: PMID:17554117
      reference_title: Natural history and outcome in systemic AA amyloidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Amyloid deposits regressed in 60% of patients who had a median SAA concentration of less than
        10 mg per liter, and survival among these patients was superior to survival among those in whom
        amyloid deposits did not regress (P=0.04).
      explanation: >-
        Longitudinal scintigraphy documents regression in a subset; the association does not guarantee
        reversibility of established organ damage.
    - reference: PMID:28828707
      reference_title: Pathology and diagnosis of renal non-AL amyloidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        AA amyloidosis shows vascular deposits in addition to the glomerular deposits
      explanation: >-
        Review synthesis of the renal deposition pattern.
- name: Progressive Multi-Organ Amyloid Accumulation
  description: >-
    Extracellular fibrils accumulate in renal, hepatic, splenic and other tissues. The burden can regress
    after sustained precursor suppression, although regression is not universal and organ injury may remain.
  role: effector
  biological_scale: TISSUE
  evidence:
  - reference: PMID:17554117
    reference_title: Natural history and outcome in systemic AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Amyloid deposits regressed in 60% of patients who had a median SAA concentration of less than 10
      mg per liter, and survival among these patients was superior to survival among those in whom amyloid
      deposits did not regress (P=0.04).
    explanation: >-
      Longitudinal scintigraphy documents regression in a subset; the association does not guarantee reversibility
      of established organ damage.
  - reference: PMID:28828707
    reference_title: Pathology and diagnosis of renal non-AL amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      AA amyloidosis shows vascular deposits in addition to the glomerular deposits
    explanation: >-
      Review synthesis of the renal deposition pattern.
  conforms_to: amyloidogenesis#Progressive Tissue Amyloid Accumulation
  cellular_components:
  - preferred_term: extracellular region
    term:
      id: GO:0005576
      label: extracellular region
  downstream:
  - target: Glomerular Filtration Barrier Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Glomerular deposition is associated with proteinuria and implies impaired filtration selectivity.
    evidence:
    - reference: PMID:17714761
      reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        The clinical presentation of glomerular and vascular forms was distinct with a clear predominance
        of proteinuria in glomerular form.
      explanation: >-
        The 68-case renal biopsy series links deposition pattern to proteinuria; a mechanistic filtration-barrier
        interpretation is indirect.
  - target: Progressive Renal Functional Decline
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Glomerular, vascular and tubular lesions contribute to renal functional loss.
    evidence:
    - reference: PMID:17714761
      reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Tubular atrophy, abundance, and distribution pattern of glomerular amyloid deposits at the time
        of biopsy were independent predictors of renal outcome.
      explanation: >-
        Histological predictors support an association with kidney damage, without proving one obligatory
        clinical sequence.
  - target: Gastrointestinal Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Deposition in enteric tissues may impair motility and absorption.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        Amyloid deposition in the myenteric plexus can potentially result in intestinal pseudo-obstruction
      explanation: >-
        The review links enteric neural deposition to dysmotility; other gastrointestinal symptoms can
        have several contributing lesions.
  - target: Hepatomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Amyloid accumulation in the affected organ can accompany enlargement. Imaging evidence of deposits alone
      does not establish symptomatic organ dysfunction.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hepato- and splenomegaly commonly manifests during disease progression,
        whereas splenic rupture is exceptionally rare
      explanation: >-
        Clinical review synthesis links this manifestation to AA organ involvement; the specific lesion and
        intermediate sequence are not demonstrated in individual patients.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  - target: Splenomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Amyloid accumulation in the affected organ can accompany enlargement. Imaging evidence of deposits alone
      does not establish symptomatic organ dysfunction.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hepato- and splenomegaly commonly manifests during disease progression,
        whereas splenic rupture is exceptionally rare
      explanation: >-
        Clinical review synthesis links this manifestation to AA organ involvement; the specific lesion and
        intermediate sequence are not demonstrated in individual patients.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
- name: Glomerular Filtration Barrier Dysfunction
  description: >-
    Glomerular amyloid is associated with heavier proteinuria than vascular-predominant disease. Filtration-barrier
    injury is the clinical interpretation of this anatomical association; nonselectivity and a specific
    podocyte lesion were not measured in the cited abstract.
  role: effector
  biological_scale: TISSUE
  evidence:
  - reference: PMID:17714761
    reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: >-
      The clinical presentation of glomerular and vascular forms was distinct with a clear predominance
      of proteinuria in glomerular form.
    explanation: >-
      The 68-case renal biopsy series links deposition pattern to proteinuria; a mechanistic filtration-barrier
      interpretation is indirect.
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  downstream:
  - target: Proteinuria
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of filtration selectivity produces urinary protein loss.
    evidence:
    - reference: PMID:17714761
      reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        The clinical presentation of glomerular and vascular forms was distinct with a clear predominance
        of proteinuria in glomerular form.
      explanation: >-
        The 68-case renal biopsy series links deposition pattern to proteinuria; a mechanistic filtration-barrier
        interpretation is indirect.
- name: Progressive Renal Functional Decline
  description: >-
    Renal involvement can lead to loss of filtration and end-stage kidney disease. The tempo varies with
    deposition pattern, baseline injury and control of SAA production; vascular or tubular disease need
    not pass through nephrotic syndrome.
  role: consequence
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:17714761
    reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: >-
      Tubular atrophy, abundance, and distribution pattern of glomerular amyloid deposits at the time
      of biopsy were independent predictors of renal outcome.
    explanation: >-
      Histological predictors support an association with kidney damage, without proving one obligatory
      clinical sequence.
  downstream:
  - target: Renal Insufficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Renal structural injury is associated with reduced kidney function.
    evidence:
    - reference: PMID:17714761
      reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Tubular atrophy, abundance, and distribution pattern of glomerular amyloid deposits at the time
        of biopsy were independent predictors of renal outcome.
      explanation: >-
        Histological predictors support an association with kidney damage, without proving one obligatory
        clinical sequence.
  - target: End-Stage Kidney Disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Advanced renal injury can progress to kidney failure.
    evidence:
    - reference: PMID:17714761
      reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Tubular atrophy, abundance, and distribution pattern of glomerular amyloid deposits at the time
        of biopsy were independent predictors of renal outcome.
      explanation: >-
        Histological predictors support an association with kidney damage, without proving one obligatory
        clinical sequence.
- name: Gastrointestinal Dysfunction
  description: >-
    Enteric amyloid deposition may impair absorption and motility, causing diarrhea, malabsorption or
    pseudo-obstruction. The clinical review does not establish one lesion that explains all gastrointestinal
    manifestations.
  role: consequence
  biological_scale: TISSUE
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Amyloid deposition in the myenteric plexus can potentially result in intestinal pseudo-obstruction
    explanation: >-
      The review links enteric neural deposition to dysmotility; other gastrointestinal symptoms can have
      several contributing lesions.
  downstream:
  - target: Intestinal Pseudo-obstruction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Myenteric deposition may impair intestinal motility.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        Amyloid deposition in the myenteric plexus can potentially result in intestinal pseudo-obstruction
      explanation: >-
        The review links enteric neural deposition to dysmotility; other gastrointestinal symptoms can
        have several contributing lesions.
  - target: Chronic Diarrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Enteric involvement can produce persistent diarrhea, without one established anatomical lesion accounting for every case.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Approximately 30% of cases have gastrointestinal involvement. The
        predominant symptom is diarrhea that is frequently unresponsive to
        standard treatment
      explanation: >-
        Clinical review synthesis links this manifestation to AA organ involvement; the specific lesion and
        intermediate sequence are not demonstrated in individual patients.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  - target: Malabsorption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired intestinal function may contribute to malabsorption; the review does not resolve the responsible
      tissue or transport mechanism.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Other frequently encountered presenting symptoms include weight loss,
        abdominal pain, malabsorption, macroglossia, gastroesophageal reflux,
        esophageal dysmotility, gastric polyps, and episodes of upper and lower
        gastrointestinal bleeding
      explanation: >-
        Clinical review synthesis links this manifestation to AA organ involvement; the specific lesion and
        intermediate sequence are not demonstrated in individual patients.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
  - target: Abdominal Pain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Gastrointestinal involvement can manifest as abdominal pain through incompletely resolved pathways.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        Other frequently encountered presenting symptoms include weight loss, abdominal pain, malabsorption,
        macroglossia, gastroesophageal reflux, esophageal dysmotility, gastric polyps, and episodes of upper
        and lower gastrointestinal bleeding
      explanation: >-
        Clinical review synthesis links this manifestation to AA organ involvement; the specific lesion and
        intermediate sequence are not demonstrated in individual patients.
  - target: Gastrointestinal Hemorrhage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Enteric disease can be accompanied by upper or lower gastrointestinal bleeding; a specific vascular or
      mucosal sequence is not established here.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Other frequently encountered presenting symptoms include weight loss,
        abdominal pain, malabsorption, macroglossia, gastroesophageal reflux,
        esophageal dysmotility, gastric polyps, and episodes of upper and lower
        gastrointestinal bleeding
      explanation: >-
        Clinical review synthesis links this manifestation to AA organ involvement; the specific lesion and
        intermediate sequence are not demonstrated in individual patients.
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
phenotypes:
- category: Renal
  name: Proteinuria
  description: >-
    Proteinuria is a major renal presentation, especially with glomerular deposition. The review groups
    proteinuria with declining kidney function in its >90% estimate, so that percentage is not assigned
    to proteinuria alone.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:17714761
    reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical presentation of glomerular and vascular forms was distinct
      with a clear predominance of proteinuria in glomerular form.
    explanation: >-
      Proteinuria predominates in glomerular disease. The 80.9% figure counts the histological form, not
      the proportion with proteinuria.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the prevailing symptoms frequently involve the emergence of proteinuria and
      gradual reduction in kidney function, apparent in over 90% of patients upon
      their initial presentation
    explanation: >-
      The review reports a combined renal presentation; it does not give a separate proteinuria denominator.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- category: Renal
  name: Nephrotic Syndrome
  description: >-
    Nephrotic syndrome occurred in 63.1% of a selected 68-case renal AA biopsy series. This cohort frequency
    is not a population estimate for all systemic AA amyloidosis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: PMID:17714761
    reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of
      patients, respectively.
    explanation: >-
      Directly quantifies nephrotic syndrome at 63.1%, which maps to the FREQUENT band (30-79%).
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Renal
  name: Renal Insufficiency
  description: >-
    Renal insufficiency occurred in 75% of the 68-case renal biopsy series; renal selection limits generalization.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:17714761
    reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of
      patients, respectively.
    explanation: >-
      Directly quantifies renal insufficiency at 75%, mapping to the FREQUENT band (30-79%).
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Renal
  name: End-Stage Kidney Disease
  description: >-
    At the end of follow-up, 26/68 patients in the selected renal series had end-stage kidney disease.
    This cumulative follow-up observation is not an initial-presentation prevalence.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:17714761
    reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the end of follow-up, 26 patients (38.2%) showed end-stage renal disease.
    explanation: >-
      Directly quantifies progression to end-stage renal disease at 38.2%, mapping to the FREQUENT band
      (30-79%).
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Constitutional
  name: Peripheral Edema
  description: >-
    Edema can accompany nephrotic protein loss and hypervolemia.
  phenotype_term:
    preferred_term: Edema
    term:
      id: HP:0000969
      label: Edema
  evidence:
  - reference: url:https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf
    reference_title: https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Classification as nephrotic required a 24-hour urinary excretion of more than 3 g of protein, a
      serum albumin concentration of less than 3.4 g per deciliter, and either the presence of peripheral
      edema or the use of diuretics to treat peripheral edema.
    explanation: >-
      The AA trial explicitly defined the nephrotic stratum using low albumin and edema or its treatment.
      This supports the feature in that clinical context without a whole-disease frequency.
- category: Laboratory
  name: Hypoalbuminemia
  description: >-
    Reduced serum albumin resulting from urinary protein loss; a component of the nephrotic syndrome and
    a marker of its severity.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: url:https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf
    reference_title: https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Classification as nephrotic required a 24-hour urinary excretion of more than 3 g of protein, a
      serum albumin concentration of less than 3.4 g per deciliter, and either the presence of peripheral
      edema or the use of diuretics to treat peripheral edema.
    explanation: >-
      The AA trial explicitly defined the nephrotic stratum using low albumin and edema or its treatment.
      This supports the feature in that clinical context without a whole-disease frequency.
- category: Hepatosplenic
  name: Hepatomegaly
  description: >-
    Hepatomegaly can develop with hepatic deposition. Imaging evidence of deposition does not necessarily
    imply functional liver disease.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepato- and splenomegaly commonly manifests during disease progression,
      whereas splenic rupture is exceptionally rare
    explanation: >-
      Directly documents hepatomegaly as a common manifestation of human AA amyloidosis during disease
      progression.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While splenic and hepatic amyloid deposition is commonly detected in serum
      amyloid P (SAP) scintigraphy, its clinical relevance is limited
    explanation: >-
      Records the important caveat that hepatic deposition is frequently imaged but usually not clinically
      consequential, so this phenotype should not be read as hepatic failure. The limitation is that it
      qualifies rather than strengthens the association.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- category: Hepatosplenic
  name: Splenomegaly
  description: >-
    Splenomegaly can occur during progression. Splenic deposits can be imaged even when clinically silent;
    rupture is exceptionally rare.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepato- and splenomegaly commonly manifests during disease progression,
      whereas splenic rupture is exceptionally rare
    explanation: >-
      Directly documents splenomegaly as a common manifestation of human AA amyloidosis, replacing the
      model-organism-only support this phenotype previously carried.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- category: Gastrointestinal
  name: Chronic Diarrhea
  description: >-
    Diarrhea is the predominant symptom of gastrointestinal involvement and can be refractory to usual
    symptomatic treatment. The reported approximately 30% frequency applies to gastrointestinal involvement
    overall, not specifically to diarrhea.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 30% of cases have gastrointestinal involvement. The
      predominant symptom is diarrhea that is frequently unresponsive to
      standard treatment
    explanation: >-
      The review describes diarrhea, while the 30% estimate counts any gastrointestinal involvement and
      is not used as a diarrhea frequency.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- category: Gastrointestinal
  name: Malabsorption
  description: >-
    Amyloid infiltration of the bowel wall impairs absorption, contributing with chronic diarrhoea to
    the weight loss seen in advanced disease.
  phenotype_term:
    preferred_term: Malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequently encountered presenting symptoms include weight loss,
      abdominal pain, malabsorption, macroglossia, gastroesophageal reflux,
      esophageal dysmotility, gastric polyps, and episodes of upper and lower
      gastrointestinal bleeding
    explanation: >-
      Lists malabsorption among the frequently encountered presenting gastrointestinal symptoms of AA
      amyloidosis.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- category: Gastrointestinal
  name: Gastrointestinal Hemorrhage
  description: >-
    Upper or lower gastrointestinal bleeding is reported with gastrointestinal AA involvement.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      episodes of upper and lower gastrointestinal bleeding
    explanation: >-
      Names episodes of upper and lower gastrointestinal bleeding among the frequently encountered presenting
      symptoms.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- category: Constitutional
  name: Weight Loss
  description: >-
    Weight loss is reported among gastrointestinal presentations; the relative contributions of malabsorption
    and systemic illness vary.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequently encountered presenting symptoms include weight loss,
      abdominal pain, malabsorption, macroglossia, gastroesophageal reflux,
      esophageal dysmotility, gastric polyps, and episodes of upper and lower
      gastrointestinal bleeding
    explanation: >-
      Lists weight loss among the frequently encountered presenting symptoms of AA amyloidosis.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- category: Laboratory
  name: Elevated Alkaline Phosphatase
  description: >-
    The review reports elevated alkaline phosphatase in approximately 5% of patients. This nonspecific
    finding does not by itself establish hepatic amyloid injury.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase concentration
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevated serum alkaline phosphatase (ALP) levels are noted in 5% of
      patients
    explanation: >-
      Directly quantifies elevated ALP at 5% of patients, mapping to the OCCASIONAL band (5-29%).
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- name: Abdominal Pain
  category: Gastrointestinal
  description: >-
    Abdominal pain is reported with gastrointestinal involvement.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Other frequently encountered presenting symptoms include weight loss, abdominal pain, malabsorption,
      macroglossia, gastroesophageal reflux, esophageal dysmotility, gastric polyps, and episodes of upper
      and lower gastrointestinal bleeding
    explanation: >-
      The clinical review explicitly lists this manifestation; no individual frequency is assigned.
- name: Macroglossia
  category: Gastrointestinal
  description: >-
    Macroglossia can occur; its relative rarity in AA does not make it an exclusionary finding.
  phenotype_term:
    preferred_term: Macroglossia
    term:
      id: HP:0000158
      label: Macroglossia
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Other frequently encountered presenting symptoms include weight loss, abdominal pain, malabsorption,
      macroglossia, gastroesophageal reflux, esophageal dysmotility, gastric polyps, and episodes of upper
      and lower gastrointestinal bleeding
    explanation: >-
      The clinical review explicitly lists this manifestation; no individual frequency is assigned.
- name: Gastroesophageal Reflux
  category: Gastrointestinal
  description: >-
    Gastroesophageal reflux is reported among gastrointestinal manifestations.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Other frequently encountered presenting symptoms include weight loss, abdominal pain, malabsorption,
      macroglossia, gastroesophageal reflux, esophageal dysmotility, gastric polyps, and episodes of upper
      and lower gastrointestinal bleeding
    explanation: >-
      The clinical review explicitly lists this manifestation; no individual frequency is assigned.
- name: Intestinal Pseudo-obstruction
  category: Gastrointestinal
  description: >-
    Enteric plexus deposition can impair motility and produce pseudo-obstruction.
  phenotype_term:
    preferred_term: Intestinal pseudo-obstruction
    term:
      id: HP:0004389
      label: Intestinal pseudo-obstruction
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Amyloid deposition in the myenteric plexus can potentially result in intestinal pseudo-obstruction
    explanation: >-
      The AA clinical review supports this less common manifestation; no numerical frequency is inferred.
- name: Nephrogenic Diabetes Insipidus
  category: Renal
  description: >-
    Tubular amyloid can impair urine concentration even when proteinuria is limited.
  phenotype_term:
    preferred_term: Nephrogenic diabetes insipidus
    term:
      id: HP:0009806
      label: Nephrogenic diabetes insipidus
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Individuals with tubular amyloid accumulation might exhibit bland urinary sediment and minimal proteinuria
      but can demonstrate symptoms of distal tubular impairment such as nephrogenic diabetes insipidus.
    explanation: >-
      The AA clinical review supports this less common manifestation; no numerical frequency is inferred.
- name: Heart Failure
  category: Cardiovascular
  description: >-
    Cardiac infiltration can cause heart failure, although clinically important cardiac disease is relatively
    rare in AA.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      While cardiac infiltration is extensively documented in various amyloidosis types, it is a relatively
      rare cause of heart failure in AA amyloidosis
    explanation: >-
      The AA clinical review supports this less common manifestation; no numerical frequency is inferred.
genetic:
- name: SAA1
  notes: >-
    Common SAA1 coding haplotypes modify AA risk in selected inflammatory-disease cohorts. SAAalpha/alpha
    was associated with renal amyloidosis in a 277-patient FMF cohort (OR 2.99, 95% CI 1.47–6.09). Isoform-dependent
    MMP-1 cleavage is a candidate biochemical explanation, not proof of the human causal pathway. A separate
    rare promoter variant is causal in hereditary AA amyloidosis and is recorded independently below.
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: SAA1
    term:
      id: hgnc:10513
      label: SAA1
  evidence:
  - reference: PMID:12687559
    reference_title: The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the presence of the SAAalpha/alpha genotype (OR 2.99, 95% CI 1.47-6.09)
    explanation: >-
      Quantifies the independent association of the amyloidogenic SAA1 alpha/alpha genotype with renal
      amyloidosis in a 277-patient FMF cohort.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:29364741
    reference_title: Obesity is a significant susceptibility factor for idiopathic AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for
      AA amyloidosis irrespective of the type of the disease.
    explanation: >-
      Confirms SAA1 polymorphism as a susceptibility factor across trigger diseases, supporting the SUSCEPTIBILITY
      relationship type.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:18815155
    reference_title: 'Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results may explain the higher risk of amyloidosis in patients with a
      SAA1.1/1.1 genotype vs SAA1.5/1.5 or SAA1.1/1.5 genotype.
    explanation: >-
      The authors propose isoform-dependent MMP-1 cleavage as one explanation for the clinical association;
      the assay does not establish mediation of human risk.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:15018633
    reference_title: 'Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      no association was found between the MICA gene exon 5 polymorphism and the development of renal
      amyloidosis in FMF patients, whereas the alpha allele and the alpha/alpha genotype of the SAA1 gene
      were associated with this severe phenotype
    explanation: >-
      This independent FMF study supports the SAA1 association and reports a cohort-specific MICA null.
      It does not prove a universal absence of MICA effects.
- name: MEFV
  notes: >-
    MEFV causes familial Mediterranean fever, an upstream inflammatory cause of AA amyloidosis. M694V
    homozygosity was associated with renal amyloidosis in the cited FMF cohort (OR 4.27, 95% CI 2.01–9.07);
    treatment and other genetic and environmental factors influence risk.
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: MEFV
    term:
      id: hgnc:6998
      label: MEFV
  evidence:
  - reference: PMID:12687559
    reference_title: The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Logistic regression analysis showed that homozygosity for the M694V allele (odds ratio [OR] 4.27,
      95% confidence interval [95% CI] 2.01-9.07)
    explanation: >-
      The cited 277-patient FMF cohort reports an independent association between M694V homozygosity and
      renal amyloidosis, with OR 4.27 (95% CI 2.01–9.07).
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:12687559
    reference_title: The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, disease severity and the development of amyloidosis in FMF are
      differentially affected by genetic variations within and outside the MEFV
      gene.
    explanation: >-
      The authors distinguish effects of MEFV and other genetic factors on FMF severity and amyloidosis
      risk.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:20301405
    reference_title: Familial Mediterranean Fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      If FMF is untreated, chronic inflammation may lead to AA amyloidosis, the most severe complication
      of the disease.
    explanation: >-
      GeneReviews describes AA as a complication of untreated FMF.
- name: SAA1 promoter variant
  gene_term:
    preferred_term: SAA1
    term:
      id: hgnc:10513
      label: SAA1
  relationship_type: CAUSATIVE
  notes: >-
    The chr11:18287683T>C promoter variant (hg19) linked to SAA1.1 was reported in a family with autosomal
    dominant sustained SAA elevation and AA deposition. This rare regulatory cause does not imply Mendelian
    inheritance for common inflammation-associated AA.
  evidence: *id001
environmental:
- name: Obesity and adipose-derived serum amyloid A
  description: >-
    Obesity and older age were associated with idiopathic AA amyloidosis in a retrospective clinical study.
    Human adipocytes produce SAA, providing a plausible contributing mechanism, but adipose-derived SAA
    was not traced into deposits and causality was not established.
  effect: Increases risk of idiopathic AA amyloidosis
  evidence:
  - reference: PMID:29364741
    reference_title: Obesity is a significant susceptibility factor for idiopathic AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Obesity, age and the SAA1 polymorphism are susceptibility factors for
      idiopathic AA amyloidosis.
    explanation: >-
      Directly states obesity as a susceptibility factor for idiopathic AA amyloidosis in a 146-patient
      study with two control groups.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  influences_mechanisms:
  - target: Adipose Serum Amyloid A Production
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Higher adiposity is associated with greater adipose SAA expression and secretion; this does not
      quantify adipose contribution to amyloid deposition.
    evidence:
    - reference: PMID:16737350
      reference_title: 'Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A-SAA mRNA levels and A-SAA secretion from adipose tissue were
        significantly correlated with body mass index (r = 0.47; p = 0.028 and r
        = 0.80; p = 0.0002, respectively).
      explanation: >-
        Quantifies the correlation between adiposity and adipose SAA output, supporting the route by which
        obesity feeds the acute-phase precursor node.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
biochemical:
- name: Serum Amyloid A
  notes: >-
    SAA is the circulating fibril precursor and an important serial biomarker. In the 374-patient cohort,
    median SAA below 10 mg/L was associated with deposit regression in 60%, and persistent low-normal
    levels below 4 mg/L with favorable outcomes. These observational thresholds inform monitoring but
    are not a guarantee of individual response.
  presence: INCREASED
  evidence:
  - reference: PMID:17554117
    reference_title: Natural history and outcome in systemic AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The effects of renal dysfunction dominate the course of AA amyloidosis,
      which is associated with a relatively favorable outcome in patients with
      SAA concentrations that remain in the low-normal range (<4 mg per liter).
    explanation: >-
      Establishes the prognostic threshold that makes SAA an actionable treat-to-target biomarker.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:26120866
    reference_title: 'Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main aim of treatment is to suppress inflammation thereby inhibiting
      serum amyloid A protein (SAA), which is the precursor of AA amyloid
      fibrils, to prevent or halt amyloid deposition.
    explanation: >-
      States explicitly that SAA is both the fibril precursor and the treatment target, the dual role
      this biochemical entry records.
    directness: DIRECT
    quote_role: BACKGROUND
histopathology:
- name: Congo Red-Positive Amyloid Deposition
  description: >-
    Acellular Congo red-positive extracellular deposits showing apple-green birefringence under polarized
    light. This confirms amyloid but does not identify the precursor; typing is a separate and mandatory
    step.
  diagnostic: true
  finding_term:
    preferred_term: amyloid deposition
    term:
      id: NCIT:C54018
      label: Amyloid Deposition
  evidence:
  - reference: PMID:28828707
    reference_title: Pathology and diagnosis of renal non-AL amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Renal amyloidosis is characterized by acellular Congo red positive deposits
      in the glomeruli, interstitium and/or arteries.
    explanation: >-
      Defines the Congo red-positive histological finding and its renal distribution.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- name: Glomerular-Predominant Deposition Pattern
  description: >-
    The 68-case renal series identified mesangial segmental, mesangial nodular, mesangiocapillary and
    hilar patterns. Glomerular-predominant disease had more proteinuria than the vascular form.
  finding_term:
    preferred_term: amyloid deposition
    term:
      id: NCIT:C54018
      label: Amyloid Deposition
  evidence:
  - reference: PMID:17714761
    reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We retrospectively reviewed the clinicopathological features of a series of 68 renal AA
      amyloidosis observations collected between 1990 and 2005. ... The distribution pattern of
      glomerular amyloid deposits was mesangial segmental (14.7%), mesangial nodular (26.5%),
      mesangiocapillary (32.3%), and hilar (26.5%). Glomerular form was observed in 80.9% of cases
      and vascular form in 19.1%. ... The clinical presentation of glomerular and vascular forms was
      distinct with a clear predominance of proteinuria in glomerular form.
    explanation: >-
      Names the renal AA amyloidosis cohort, retains its deposition-pattern frequencies and includes
      the reported proteinuria predominance in the glomerular form.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Amyloid-Associated Giant Cell and Inflammatory Reaction
  description: >-
    The renal biopsy series found multinucleated giant cells or a glomerular inflammatory infiltrate in
    a subset, sometimes with crescents. An immune response contributing to amyloid resolution was proposed;
    the biopsy observation does not prove the same mechanism as experimental anti-SAP clearance.
  finding_term:
    preferred_term: amyloid deposition
    term:
      id: NCIT:C54018
      label: Amyloid Deposition
  evidence:
  - reference: PMID:17714761
    reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AA amyloidosis-related inflammation was noted in 30 patients (44.1%) and
      appeared as a multinucleated giant cell reaction (27.9%) or a glomerular
      inflammatory infiltrate (25%), including glomerular crescents (17.6%).
    explanation: >-
      Quantifies the amyloid-associated inflammatory reaction and its giant-cell component in the same
      68-case series.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
diagnosis:
- name: Tissue Biopsy with Amyloid Typing
  description: >-
    Demonstrate amyloid in tissue and identify the fibril precursor. Congo red staining alone does not
    distinguish AA from AL or hereditary non-AA amyloidoses. Anti-AA immunohistochemistry is commonly
    used; laser microdissection/mass spectrometry helps when typing is uncertain. A negative less-invasive
    fat or salivary-gland sample does not exclude disease when suspicion remains high.
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Histopathological examination is the gold standard of diagnosis, but
      magnetic resonance imaging can be used to detect cardiac involvement.
    explanation: >-
      Establishes histopathology as the diagnostic gold standard.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:28828707
    reference_title: Pathology and diagnosis of renal non-AL amyloidosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      accurate typing of non-AL amyloidosis then requires immunohistochemical or
      laser microdissection/mass spectrometry studies of the Congo red positive
      deposits
    explanation: >-
      States the requirement for immunohistochemical or mass-spectrometric typing beyond Congo red staining.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      If clinical suspicion is significantly high and these approaches render negative results, a sample
      should be retrieved from the affected organ.
    explanation: >-
      The review cautions against excluding amyloidosis after a negative less-invasive biopsy.
- name: Serum Amyloid A and C-Reactive Protein Monitoring
  description: >-
    Serial SAA, renal function and urinary protein measurements follow precursor suppression and organ
    disease. CRP can assess accompanying inflammation but is not the fibril precursor and can be normal
    in the hereditary promoter form. SAP scintigraphy, where available, estimates systemic burden and
    does not replace tissue typing.
  evidence:
  - reference: PMID:17554117
    reference_title: Natural history and outcome in systemic AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The SAA concentration was measured serially, and the amyloid burden was
      estimated with the use of whole-body serum amyloid P component
      scintigraphy.
    explanation: >-
      Documents serial SAA and SAP scintigraphy in the longitudinal cohort.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Etiologic investigation and selected SAA1 promoter testing
  description: >-
    Investigate chronic infections, inflammatory and autoinflammatory disease. In AA without systemic
    inflammation, especially with a family history, consider SAA1 promoter analysis and genetic counseling.
    A standard coding-only panel may not address the reported regulatory variant.
  evidence:
  - reference: PMID:34560138
    reference_title: A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Thus, genetic screening of the SAA1 promoter should be pursued in individuals with amyloid A amyloidosis
      and no systemic inflammation, especially if there is a positive family history.
    explanation: >-
      The family report specifically recommends promoter testing in this setting.
  - reference: PMID:20301405
    reference_title: Familial Mediterranean Fever.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      The diagnosis of FMF is established in a proband with suggestive clinical findings and biallelic
      pathogenic variants in MEFV identified by molecular genetic testing.
    explanation: >-
      GeneReviews informs assessment of FMF as one upstream cause; this is not a diagnostic definition
      for all AA.
differential_diagnoses:
- name: Systemic AL Amyloidosis
  description: >-
    AL amyloid derives from immunoglobulin light chains, whereas AA derives from SAA. Tissue precursor
    typing is essential because management differs. Renal-predominant presentation and an inflammatory
    history can suggest AA but do not establish its type.
  disease_term:
    preferred_term: primary systemic amyloidosis
    term:
      id: MONDO:0017816
      label: primary systemic amyloidosis
  distinguishing_features:
  - AA usually has dominant renal involvement; clinically important cardiac involvement is less typical but can occur.
  - Light-chain restriction supports AL, while negative immunofluorescence suggests a non-AL type; definitive typing remains necessary.
  evidence:
  - reference: PMID:28828707
    reference_title: Pathology and diagnosis of renal non-AL amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The detection of Congo red positive deposits coupled with negative
      immunofluorescence studies is highly suggestive of non-AL amyloidosis.
    explanation: >-
      Provides the immunofluorescence-based discriminator between AL and non-AL (including AA) renal amyloidosis.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While cardiac infiltration is extensively documented in various amyloidosis
      types, it is a relatively rare cause of heart failure in AA amyloidosis
    explanation: >-
      The review describes cardiac heart failure as relatively rare in AA; this is a contextual clue,
      not a stand-alone classifier.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
progression:
- phase: Subclinical amyloid deposition
  notes: >-
    Inflammatory AA generally follows sustained precursor production before overt organ disease. Latency
    varies and cannot be assigned a universal number of years. Renal surveillance is important in at-risk
    inflammatory diseases; the hereditary promoter form has a distinct upstream cause.
  evidence:
  - reference: PMID:25387054
    reference_title: 'AA amyloidosis: pathogenesis and targeted therapy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, AA amyloidosis can be thought of as a consequence of
      long-standing inflammatory disease.
    explanation: >-
      Supports a prolonged latent phase driven by long-standing inflammation preceding clinical presentation.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- phase: Proteinuric and nephrotic phase
  notes: >-
    In the selected 68-case renal biopsy series, nephrotic syndrome occurred in 63.1% and renal insufficiency
    in 75%. These overlapping findings do not establish an obligatory sequential course.
  evidence:
  - reference: PMID:17714761
    reference_title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nephrotic syndrome and renal insufficiency were noted in 63.1% and 75% of
      patients, respectively.
    explanation: >-
      Quantifies the proteinuric and nephrotic phase in a renal AA amyloidosis series.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- phase: Amyloid storm (rare acute FMF-associated variant)
  notes: >-
    A minority of FMF patients depart from the indolent course entirely and present with an acute illness:
    heavy proteinuria, high inflammatory markers, and progression to kidney failure within weeks rather
    than years, typically precipitated by a superimposed infection. Curated as a distinct trajectory rather
    than a severity grade, because the timescale (weeks) and the infection trigger are qualitatively different
    from the usual course.
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the majority of cases follow an indolent course, a subset of
      individuals with FMF might undergo acute illness, marked by substantial
      proteinuria, elevated inflammatory markers, and rapid progression to kidney
      failure within weeks.
    explanation: >-
      Defines the amyloid storm presentation and contrasts it with the indolent majority course.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These infrequent instances are named “amyloid storm,” which is thought to
      be precipitated by superimposed infections or other triggering events
    explanation: >-
      Names the entity and its precipitating trigger.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- phase: Progressive renal decline to end-stage kidney disease
  notes: >-
    Renal decline varies with underlying disease, baseline injury and treatment. In the initial eprodisate
    trial, the placebo group lost a mean 15.6 mL/min/1.73 m2 of creatinine clearance per year while receiving
    physician-managed treatment of underlying inflammation; this is a selected trial comparator, not untreated
    natural history. A separate 374-patient cohort reported median survival of 133 months after diagnosis.
  evidence:
  - reference: PMID:17554116
    reference_title: Eprodisate for the treatment of renal disease in AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mean rates of decline in creatinine clearance were 10.9 and 15.6 ml per
      minute per 1.73 m(2) of body-surface area per year in the eprodisate and
      the placebo groups, respectively (P=0.02).
    explanation: >-
      Describes decline in a placebo-controlled trial whose participants also received usual treatment
      of underlying inflammation. It cannot define the untreated rate for all AA.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:17554117
    reference_title: Natural history and outcome in systemic AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Median survival after diagnosis was 133 months
    explanation: >-
      Provides the median survival benchmark for the progressive phase.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf
    reference_title: https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Treatment of the underlying inflammatory disease was determined by the patient’s physician.
    explanation: >-
      The primary trial Methods establish that usual inflammatory-disease care accompanied both randomized
      arms, so placebo is not an untreated natural-history cohort.
treatments:
- name: Colchicine (Familial Mediterranean Fever)
  description: >-
    Colchicine controls FMF inflammation and reduces the risk of AA amyloidosis. In established FMF-associated
    renal AA, observational studies report stabilization or proteinuria regression in some patients, with
    worse outcomes when renal injury is advanced. The historical dose and creatinine associations are
    not universal modern prescribing thresholds; dosing requires individual assessment of renal function,
    tolerance and interactions.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: colchicine
      term:
        id: CHEBI:23359
        label: colchicine
  target_mechanisms:
  - target: Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus
    treatment_effect: INHIBITS
    description: >-
      Suppressing FMF inflammatory attacks removes the cytokine drive at the trigger node, preventing
      the downstream acute-phase SAA surge.
  evidence:
  - reference: PMID:7986228
    reference_title: Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Deterioration was related to initial serum creatinine values > or = 1.5 mg/dl (P < 0.01) and to
      mean colchicine dosage < or = 1.5 mg/day (P < 0.001).
    explanation: >-
      Associations in a retrospective 1974–1992 cohort of 68 patients with baseline creatinine ≤2.5 mg/dL;
      this does not establish an absolute response boundary or a dose appropriate for every patient.
  - reference: PMID:7986228
    reference_title: Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the end of the study period, kidney disease had worsened in 31 patients
      and remained stable in 22. Proteinuria had regressed in 15 patients.
    explanation: >-
      Documents stabilization or regression of proteinuria in a substantial share of colchicine-treated
      patients. The limitation is that this is an uncontrolled retrospective series without a comparator
      arm, and disease still worsened in the largest single group.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a study examining 960 patients with FMF without evidence of amyloidosis
      at baseline, the cumulative rate of proteinuria after 11 years was reported
      as 1.7% in colchicine-compliant patients while 48.9% in the non-compliants
    explanation: >-
      The review summarizes an observational association between colchicine adherence and less subsequent
      proteinuria; adherence groups were not randomized.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, evidence for its efficacy in AA amyloidosis due to causes other
      than FMF is still quite limited
    explanation: >-
      Records the scope limit deliberately encoded in this treatment's name: colchicine's evidence base
      is FMF-specific and should not be generalized to AA amyloidosis from other triggers.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- name: Anti-TNF-alpha Therapy
  description: >-
    TNF blockade can control an appropriate underlying inflammatory disease, especially inflammatory arthritis,
    and may improve AA renal markers. Small observational series show variable outcomes. The retrospective
    tocilizumab comparison does not establish a universal ranking across AA etiologies. Infliximab and
    adalimumab are antibodies; etanercept is a soluble receptor fusion protein.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: infliximab
      term:
        id: NCIT:C1789
        label: Infliximab
    - preferred_term: etanercept
      term:
        id: NCIT:C2381
        label: Etanercept
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
  target_mechanisms:
  - target: Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus
    treatment_effect: INHIBITS
    description: >-
      Neutralizing TNF-alpha suppresses the inflammatory arthropathy at the trigger node, reducing the
      cytokine drive to hepatic SAA production.
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a retrospective series including 15 patients treated with anti-TNF,
      amyloidosis progressed in seven patients (46.7%), stabilized in five
      (33.3%), and regression of proteinuria occurred in three (20%) in 10
      months
    explanation: >-
      Quantifies outcomes on anti-TNF therapy. The limitation is that amyloidosis still progressed in
      the largest single group, so this series does not establish efficacy.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in a multicenter study in which 36 patients with AA amyloidosis treated
      with anti-TNF therapy were followed prospectively for 5 years, > 50%
      decrease in proteinuria was observed in more than half of the patients
    explanation: >-
      The stronger of the two datasets - prospective, multicentre, 5-year follow-up - showing a substantial
      proteinuria response in the majority.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a retrospective analysis including 42 patients with AA amyloidosis
      demonstrated that tocilizumab was superior to anti-TNFs in terms of
      obtaining a decrease in SAA, improvement in kidney function, and
      suppression of the disease activity
    explanation: >-
      The review reports a 42-patient nonrandomized comparison. Differences in underlying disease and
      treatment selection limit causal superiority claims.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- name: Interleukin-6 Receptor Blockade (Tocilizumab)
  description: >-
    Tocilizumab can suppress SAA in selected refractory inflammatory disorders with AA amyloidosis. A
    20-patient uncontrolled series included 14 AA cases and reported rapid SAA reduction with stable or
    regressing deposits; infections were the predominant adverse effect. A Still disease report also used
    glucocorticoids, preventing attribution to tocilizumab alone. Choice depends on the cause and clinical
    context.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tocilizumab
      term:
        id: NCIT:C84217
        label: Tocilizumab
  target_mechanisms:
  - target: IL-6-Driven Hepatic Acute-Phase Response
    treatment_effect: INHIBITS
    description: >-
      IL-6 receptor blockade removes the principal signal inducing hepatocyte SAA transcription, collapsing
      precursor supply at the amplifier node.
  evidence:
  - reference: PMID:26120866
    reference_title: 'Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-cohort median pre-treatment SAA fell from 70 to 4 mg/L within 10 days
      of the first dose; this response has been maintained over an on-treatment
      follow-up period of 23 months (p<0.0001). AA amyloid deposits either
      regressed or remained stable.
    explanation: >-
      The whole-cohort SAA change covers 20 patients, 14 with AA; amyloid findings apply to the affected
      subset. This is an uncontrolled series.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:26120866
    reference_title: 'Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This small series shows that in patients with treatment-refractory chronic
      inflammatory conditions TCZ can be effective in suppressing inflammation,
      and in those with AA amyloidosis, can lead to regression of amyloid
      deposits.
    explanation: >-
      The authors' own conclusion, recorded with its stated limitation. The limitation is that this is
      an uncontrolled 20-patient case series, of whom 70% had AA amyloidosis, and the authors call for
      longer follow-up.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:41670232
    reference_title: Tocilizumab prevented the progression of AA amyloidosis derived from adult-onset Still's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Steroid pulse therapy, followed by tocilizumab, a IL-6 receptor inhibitor,
      in combination with oral glucocorticoids dramatically improved kidney and
      cardiac manifestations with reduction in systemic inflammation.
    explanation: >-
      Corroborates organ-level benefit of IL-6 blockade in biopsy-proven AA amyloidosis. The limitation
      is that it is a single case report with concomitant glucocorticoid therapy.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- name: Interleukin-1 Blockade (Canakinumab, Anakinra)
  description: >-
    Canakinumab (an IL-1beta antibody) and anakinra (an IL-1 receptor antagonist) can control selected
    autoinflammatory causes of AA. The cited randomized trial demonstrated fewer flares in colchicine-resistant
    FMF, mevalonate kinase deficiency and TRAPS, not improved AA renal outcomes. Broader GeneReviews guidance
    supports IL-1 treatment and amyloidosis prevention in the relevant trigger disorders.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: canakinumab
      term:
        id: NCIT:C80971
        label: Canakinumab
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  target_mechanisms:
  - target: Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus
    treatment_effect: INHIBITS
    description: >-
      IL-1 pathway inhibition reduces activity of a responsive underlying autoinflammatory disease; canakinumab
      neutralizes IL-1beta, whereas anakinra blocks its receptor.
  evidence:
  - reference: PMID:29768139
    reference_title: Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this trial, canakinumab was effective in controlling and preventing
      flares in patients with colchicine-resistant familial Mediterranean fever,
      mevalonate kinase deficiency, and TRAPS.
    explanation: >-
      Randomized trial evidence that canakinumab controls the autoinflammatory trigger diseases. The limitation
      is that the trial endpoint was control of the trigger disease, not amyloid burden or renal outcome
      in AA amyloidosis.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:36375008
    reference_title: TNF Receptor-Associated Periodic Fever Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      IL-1 inhibitors and the TNF inhibitor etanercept control the severity of disease flares and are
      effective in preventing AA amyloidosis.
    explanation: >-
      TRAPS-specific GeneReviews guidance supports control of this upstream cause, not universal efficacy
      across AA etiologies.
- name: Kidney Transplantation
  description: >-
    Kidney transplantation is an option for suitable individuals with end-stage renal disease. In a contemporary
    French cohort of 86 recipients, five-year survival was 85.5% and histological recurrence 5.8%. This
    uncontrolled cohort cannot isolate the effect of biologics; infection requiring hospitalization occurred
    in 55.8%, and ongoing control of inflammation remains important.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Kidney Transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  evidence:
  - reference: PMID:37741608
    reference_title: 'Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5%
      (77.8-94.0) at 5 years after transplantation.
    explanation: >-
      Provides contemporary patient-survival outcomes after kidney transplantation in 86 patients across
      26 French centres.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Kidney transplantation is preferred in patients with kidney failure, and
      the recurrence of amyloidosis in the allograft has become rare as
      transplant recipients have started to benefit from the new agents.
    explanation: >-
      States the preference for transplantation and the modern rarity of allograft recurrence.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:37741608
    reference_title: 'Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Histologically proven AA amyloidosis recurrence occurred in 5 transplants (5.8%). An infection requiring
      hospitalization developed in 55.8% of cases
    explanation: >-
      Reports recurrence and infection in the selected transplant cohort; neither outcome proves that
      biologics caused the observed survival.
- name: Dialysis
  description: >-
    Hemodialysis or peritoneal dialysis supports patients with established kidney failure. Hypotension
    and concurrent cardiac or systemic disease can complicate care. Observational differences from transplant
    recipients are affected by selection and should not be treated as a randomized survival comparison.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Dialysis
    term:
      id: NCIT:C15221
      label: Dialysis
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dialysis modalities and kidney transplantation are both suitable for
      patients suffering from AA amyloidosis and kidney failure
    explanation: >-
      Establishes dialysis as an accepted renal replacement modality in AA amyloidosis.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Still, survival is poor among patients on dialysis, especially when cardiac
      involvement is prevalent
    explanation: >-
      The review reports poor dialysis outcomes, especially with cardiac involvement; treatment selection
      and comorbidity limit comparisons with transplant recipients.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- name: Eprodisate (Investigational)
  description: >-
    A small molecule intended to interfere with amyloid–glycosaminoglycan interactions. In the initial
    183-patient randomized trial, the 24-month worsening proportions were 27% versus 40% (P=.06), while
    the prespecified time-to-event analysis favored eprodisate (HR 0.58, P=.02). Neither end-stage kidney
    disease nor mortality improved significantly, and there was no proteinuria or amyloid-load benefit.
    The 261-patient confirmatory trial failed its different renal composite endpoint (HR 1.0, 95% CI 0.7–1.4;
    P=.882 in 260 treated participants). These findings do not establish a clinically effective AA therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: SAA-Glycosaminoglycan Binding
    treatment_effect: INHIBITS
    description: >-
      The intended target is SAA–GAG interaction; recent recombinant-protein assays show only partial
      binding inhibition, not complete blockade or demonstrated clinical deposit removal.
  evidence:
  - reference: PMID:17554116
    reference_title: Eprodisate for the treatment of renal disease in AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eprodisate is a member of a new class of compounds designed to interfere
      with interactions between amyloidogenic proteins and glycosaminoglycans and
      thereby inhibit polymerization of amyloid fibrils and deposition of the
      fibrils in tissues.
    explanation: >-
      States intended pharmacologic action, not a measured demonstration of tissue-deposition inhibition
      in the clinical trial.
    quote_role: BACKGROUND
    directness: DIRECT
  - reference: PMID:17554116
    reference_title: Eprodisate for the treatment of renal disease in AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The drug had no significant effect on progression to end-stage renal
      disease (hazard ratio, 0.54; P=0.20) or risk of death (hazard ratio, 0.95;
      P=0.94).
    explanation: >-
      The initial trial did not demonstrate benefit on either individual hard endpoint; the paper does
      not establish a regulatory reason for nonapproval.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:17554116
    reference_title: Eprodisate for the treatment of renal disease in AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      At 24 months, disease was worsened in 24 of 89 patients who received eprodisate (27%) and 38 of
      94 patients given placebo (40%, P=0.06); the hazard ratio for worsening disease with eprodisate
      treatment was 0.58 (95% confidence interval, 0.37 to 0.93; P=0.02).
    explanation: >-
      Two prespecified analyses gave different significance results; both are retained.
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      which was not confirmed in a randomized control trial (NCT01215747)
    explanation: >-
      The review reports failure of the confirmatory trial; primary EU registry analysis gives HR 1.0,
      95% CI 0.7–1.4 and P=.882.
  - reference: PMID:39954777
    reference_title: 'Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      eprodisate only partially blocked heparin binding.
    explanation: >-
      Direct cell-free binding result qualifies the proposed mechanism.
- name: Treat the underlying infection
  description: >-
    Use pathogen-appropriate antimicrobial and source-directed treatment for infection-associated AA.
    Immunomodulation is selected according to the actual cause, not prescribed uniformly for every AA
    presentation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Anti-Infective Agent
      term:
        id: NCIT:C254
        label: Anti-Infective Agent
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      treatment options are tailored accordingly, with infections treated promptly with antimicrobials,
      and rheumatological and genetic autoinflammatory conditions treated with the appropriate anti-inflammatory
      therapies.
    explanation: >-
      AA-specific management review supports this intervention; treatment is individualized to renal status
      and underlying cause.
  target_mechanisms:
  - target: Chronic Inflammatory, Autoinflammatory, or Infectious Stimulus
    treatment_effect: INHIBITS
    description: >-
      Treating a documented infection reduces its sustained inflammatory stimulus.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: >-
        treatment options are tailored accordingly, with infections treated promptly with antimicrobials,
        and rheumatological and genetic autoinflammatory conditions treated with the appropriate anti-inflammatory
        therapies.
      explanation: >-
        AA-specific management review supports this intervention; treatment is individualized to renal
        status and underlying cause.
- name: Antiproteinuric renin–angiotensin system blockade
  description: >-
    ACE inhibitors or ARBs can reduce nephrotic-range proteinuria when clinically tolerated, with assessment
    of kidney function, potassium and perfusion.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE Inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: Angiotensin II Receptor Antagonist
      term:
        id: NCIT:C66930
        label: Angiotensin II Receptor Antagonist
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      In nephrotic syndrome or nephrotic-range proteinuria, angiotensin-converting enzyme inhibitors or
      angiotensin receptor blockers are the first choice of drugs with antiproteinuric properties
    explanation: >-
      AA-specific management review supports this intervention; treatment is individualized to renal status
      and underlying cause.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Proteinuria
    treatment_effect: INHIBITS
    description: >-
      Reduces urinary protein loss without directly removing amyloid deposits.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: >-
        In nephrotic syndrome or nephrotic-range proteinuria, angiotensin-converting enzyme inhibitors
        or
        angiotensin receptor blockers are the first choice of drugs with antiproteinuric properties
      explanation: >-
        AA-specific management review supports this intervention; treatment is individualized to renal
        status and underlying cause.
- name: Edema and volume management
  description: >-
    Dietary sodium reduction and loop diuretics address edema and hypervolemia, with treatment individualized
    to blood pressure and renal function.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Loop Diuretic
      term:
        id: NCIT:C49184
        label: Loop Diuretic
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Loop diuretics are generally required to manage hypervolemia
    explanation: >-
      AA-specific management review supports this intervention; treatment is individualized to renal status
      and underlying cause.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Peripheral Edema
    treatment_effect: INHIBITS
    description: >-
      Diuresis and sodium management reduce fluid retention.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: >-
        Loop diuretics are generally required to manage hypervolemia
      explanation: >-
        AA-specific management review supports this intervention; treatment is individualized to renal
        status and underlying cause.
- name: Renal protection and organ-directed supportive care
  description: >-
    Avoid additional hypoperfusion and nephrotoxic injury; assess nutritional, lipid, thrombotic and other
    organ complications according to their clinical indications.
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      It is imperative to prevent further insults such as hypoperfusion or nephrotoxic drug use.
    explanation: >-
      The review explicitly includes prevention of secondary kidney injury.
  target_mechanisms:
  - target: Progressive Renal Functional Decline
    treatment_effect: MODULATES
    description: >-
      Avoiding secondary kidney insults may limit additional loss of function; it does not establish deposit
      clearance.
    evidence:
    - reference: PMID:38568326
      reference_title: 'AA Amyloidosis: A Contemporary View.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: >-
        It is imperative to prevent further insults such as hypoperfusion or nephrotoxic drug use.
      explanation: >-
        The review explicitly includes prevention of secondary kidney injury.
- name: Genetic and family counseling for an identified hereditary cause
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  description: >-
    Counsel recurrence and offer family evaluation according to the identified cause. The rare SAA1 promoter
    form segregates dominantly; FMF and TRAPS have their own inheritance and prevention strategies, so
    a single AA recurrence risk is inappropriate.
  evidence:
  - reference: PMID:34560138
    reference_title: A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      sustained elevation of serum amyloid A levels that segregated in an autosomal dominant pattern in
      12 genetically affected and in none of six genetically unaffected relatives
    explanation: >-
      Supports family evaluation for the reported promoter-associated form.
  - reference: PMID:20301405
    reference_title: Familial Mediterranean Fever.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Offer molecular genetic testing for the familial MEFV pathogenic variants to apparently asymptomatic
      older and younger at-risk sibs of an individual with FMF
    explanation: >-
      FMF-specific GeneReviews guidance supports identification of relatives who can benefit from early
      preventive treatment.
- name: Miridesap followed by dezamizumab (Investigational)
  description: >-
    SAP depletion followed by anti-SAP antibody was tested in mixed systemic amyloidosis. The 23-person
    phase 1 extension included two AA participants, each receiving only one dose; one had lower renal
    amyloid burden on scintigraphy, without demonstrated renal-function or proteinuria improvement through
    day 42. Neither AA participant had liver deposits. Later cardiac studies enrolled no AA participants
    and were stopped for lack of efficacy and a serious vasculitis event. These data do not establish
    routine AA use or an AA-specific contraindication.
  target_mechanisms:
  - target: Progressive Multi-Organ Amyloid Accumulation
    treatment_effect: INHIBITS
    description: >-
      Experimental removal of SAP-bearing amyloid deposits; clinical benefit in AA remains unproven.
  evidence:
  - &id002
    reference: PMID:29298867
    reference_title: Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Reduction in renal amyloid was observed in 7 of 11 subjects with renal amyloid detected by SAP scintigraphy
      (five with AFib and one each with AL and AA amyloidosis)
    explanation: >-
      Only one AA participant had documented renal amyloid-load reduction. Both AA participants received
      one antibody dose; no AA repeat-dose efficacy is established.
  - &id003
    reference: PMID:29298867
    reference_title: Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Renal function, serum creatinine and urea concentrations, and urinary protein excretion were unchanged
      in all subjects up to day 42
    explanation: >-
      Amyloid-load reduction was not accompanied by a demonstrated early functional or proteinuria improvement.
  - &id004
    reference: PMID:35152886
    reference_title: 'Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      The decision for an early termination of the study was based on the lack of evidence of cardiac
      amyloid removal or functional benefit, and the reporting of a SAE of vasculitis in a subject in
      the Phase 2 study.
    explanation: >-
      The later cardiac trial enrolled ATTR and AL, not AA. A suspected large-vessel vasculitis event
      in the AL participant and absent cardiac benefit prompted termination; neither later study had a
      death.
clinical_trials:
- name: NCT00035334
  phase: PHASE_III
  status: COMPLETED
  description: >-
    NCT00035334 randomized 183 patients to eprodisate or placebo for 24 months in addition to physician-directed
    care of underlying inflammation. Its composite included creatinine doubling, ≥50% creatinine-clearance
    reduction, end-stage kidney disease or death. The fixed-time worsening comparison had P=.06 while
    the prespecified time-to-event analysis had P=.02; hard endpoint benefits were not significant.
  target_phenotypes:
  - preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: PMID:17554116
    reference_title: Eprodisate for the treatment of renal disease in AA amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We randomly assigned 183 patients from 27 centers to receive eprodisate or
      placebo for 24 months.
    explanation: >-
      Describes the trial design and enrolment registered as NCT00035334.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: url:https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf
    reference_title: https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Treatment of the underlying inflammatory disease was determined by the patient’s physician.
    explanation: >-
      The primary trial Methods establish that usual inflammatory-disease care accompanied both randomized
      arms, so placebo is not an untreated natural-history cohort.
  - reference: clinicaltrials:NCT00035334
    reference_title: A Phase II/III Study of the Safety and Efficacy of NC-503 in Patients Suffering From Secondary (AA) Amyloidosis
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main objective of this study is to evaluate the safety and efficacy of NC-503 compared to placebo
      in patients with secondary (AA) amyloidosis using a composite assessment of clinical improvement/worsening
      of both renal and gastrointestinal functions.
    explanation: >-
      Registry summary establishes the study purpose; efficacy and safety conclusions come from the separately
      cited publication or results record.
- name: NCT01215747
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Confirmatory randomized eprodisate trial: 261 randomized, 260 dosed in the primary time-to-event analysis.
    Its composite was persistent creatinine-clearance decline ≥40%, serum-creatinine rise ≥80%, or end-stage
    renal disease, without death as a component. The prespecified superiority analysis was negative (HR
    1.0, 95% CI 0.7–1.4; log-rank P=.882).
  evidence:
  - reference: url:https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-022313-25/results
    reference_title: EudraCT Number 2010-022313-25 - Clinical trial results - EU Clinical Trials Register
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      This primary efficacy endpoint was the time from Baseline to the earliest of a persistent decrease
      in creatinine clearance (CrCl) of 40% or more, a persistent increase in serum creatinine (SCr) of
      80% or more, or progression to end-stage renal disease (ESRD).
    explanation: >-
      The generated EU results record defines the confirmatory endpoint. Its adjacent prespecified statistical-analysis
      table reports 260 subjects, HR 1.0, 95% CI 0.7–1.4 and P=.882.
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      which was not confirmed in a randomized control trial (NCT01215747)
    explanation: >-
      The review reports failure of the confirmatory trial; primary EU registry analysis gives HR 1.0,
      95% CI 0.7–1.4 and P=.882.
  - reference: clinicaltrials:NCT01215747
    reference_title: International Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of the Efficacy and Safety of KIACTA in Preventing Renal Function Decline in Patients With AA Amyloidosis
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The primary purpose of this study is to assess the efficacy and safety of treatment with Kiacta
      in adult patients with AA Amyloidosis.
    explanation: >-
      Registry summary establishes the study purpose; efficacy and safety conclusions come from the separately
      cited publication or results record.
- name: NCT01777243
  phase: PHASE_I
  status: COMPLETED
  description: >-
    Open-label miridesap/anti-SAP dose-escalation study in systemic amyloidosis. Initial 15 participants
    were extended to 23, including two AA cases. Both AA participants received a single antibody dose,
    so the repeated-dose title does not establish repeated-dose AA efficacy.
  evidence:
  - reference: PMID:26176329
    reference_title: Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic
      amyloidosis.
    explanation: >-
      Defines the initial mixed-amyloid study, not an AA-specific efficacy trial.
  - *id002
  - *id003
  - reference: clinicaltrials:NCT01777243
    reference_title: A Single Dose First in Human Study of GSK2398852 Co-Administered With GSK2315698 in Patients With Systemic Amyloidosis
    supports: SUPPORT
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first (Part A) will be an open label single dose escalation part beginning with the proposed
      starting dose level of GSK2398852 as 5 milligram (mg)
    explanation: >-
      Registry summary establishes the study purpose; efficacy and safety conclusions come from the separately
      cited publication or results record.
discussions:
- discussion_id: saa_threshold_vs_deposition_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why do only a minority of patients with equivalently sustained, equivalently
    high SAA concentrations develop AA amyloidosis?
  rationale: >-
    Persistent SAA elevation, common coding alleles, inflammation and cofactors do not fully predict deposition.
    The rare promoter variant illustrates a supply mechanism, while cell-free cleavage and fibril assays
    suggest additional contributors. Their relative effects in patients remain unresolved.
  attaches_to:
  - pathophysiology#SAA Amyloid Fibril Assembly
  status: OPEN
  proposed_experiments:
  - experiment_id: exp_aa_matched_saa_exposure_genotype_cohort
    name: Prospective cohort with matched cumulative SAA exposure stratified by SAA1 genotype
    description: >-
      Follow inflammatory-disease patients with serial SAA, genotype and prospectively assessed amyloid
      outcomes. Model cumulative measured exposure and relevant confounders. A genotype association after
      adjustment would motivate direct functional studies but cannot by itself distinguish processing,
      tissue exposure, clearance or residual confounding.
    supporting_outcome:
    - A reproducible genotype association after measured-SAA adjustment supports additional genotype-linked risk, without locating its molecular mediator.
    refuting_outcome:
    - A sufficiently precise null limits the detectable genotype effect in this population, but does not exclude smaller effects or inadequately measured exposure.
  - experiment_id: exp_aa_pre_clinical_seed_detection
    name: Detection of endogenous nucleating seed before clinically apparent deposition
    description: >-
      Apply high-sensitivity amyloid-seeding assays to accessible tissue (fat aspirate, minor salivary
      gland) from patients with sustained high SAA but no clinical amyloidosis, to test whether a subclinical
      nucleating seed precedes and predicts overt disease.
    supporting_outcome:
    - Prediagnostic seeding activity associated with future disease supports its predictive relevance; it does not by itself establish that seeding is rate-limiting.
    refuting_outcome:
    - Absence of detectable seeding activity in patients who subsequently develop amyloidosis would argue against a detectable pre-clinical seed.
  evidence:
  - reference: PMID:25387054
    reference_title: 'AA amyloidosis: pathogenesis and targeted therapy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A chronically high plasma concentration of SAA results in the aggregation
      of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully
      understood.
    explanation: >-
      The authoritative review explicitly states that the mechanism converting high SAA into deposits
      is incompletely understood, which is the gap recorded here.
    directness: DIRECT
    quote_role: REVIEW_SYNTHESIS
- discussion_id: no_deposit_clearing_therapy
  kind: KNOWLEDGE_GAP
  prompt: >-
    Can established AA amyloid deposits be actively cleared, rather than merely
    allowed to regress by withdrawing the precursor?
  rationale: >-
    Reducing precursor production can permit regression, but established organ damage may remain. Anti-SAP
    studies demonstrate amyloid-load reduction in one AA participant without proven functional benefit;
    later cardiac safety and efficacy limitations arose in other amyloid types. Safe deposit removal with
    clinical benefit remains an open therapeutic problem.
  attaches_to:
  - pathophysiology#Progressive Multi-Organ Amyloid Accumulation
  status: OPEN
  evidence:
  - *id002
  - *id003
  - *id004
- discussion_id: mica_not_a_modifier_locus
  kind: INTERPRETATION
  prompt: >-
    Is MICA a modifier locus for amyloidosis risk in familial Mediterranean
    fever, as sometimes summarized?
  rationale: >-
    The cited FMF study found no association of the tested MICA exon 5 polymorphism with renal amyloidosis,
    despite an SAA1 association. This is a cohort-specific null and does not prove absence of every MICA
    effect. MICA is not entered as an established AA susceptibility locus on this evidence.
  attaches_to:
  - pathophysiology#Sustained Elevation of Circulating Serum Amyloid A
  status: OPEN
  evidence:
  - reference: PMID:15018633
    reference_title: 'Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, no specific MICA genotype or allele was significantly associated
      with the development of amyloidosis
    explanation: >-
      Directly refutes a MICA-amyloidosis association in the cohort that tested it, which is why MICA
      is not curated as a susceptibility or modifier locus here.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:15018633
    reference_title: 'Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      no association was found between the MICA gene exon 5 polymorphism and the
      development of renal amyloidosis in FMF patients, whereas the alpha allele
      and the alpha/alpha genotype of the SAA1 gene were associated with this
      severe phenotype
    explanation: >-
      The authors' own conclusion, contrasting the null MICA result with the positive SAA1 result in the
      same patients - the asymmetry that justifies curating SAA1 but not MICA.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
animal_models:
- name: Heterologous fibril acceleration of murine AA deposition
  species: Mus musculus
  genotype: Non-transgenic NMRI and FVB mice
  category: Induced (non-transgenic) AA amyloidosis model
  description: >-
    Five- to ten-week-old female NMRI mice and age-matched FVB mice of both sexes were studied. Heterologous
    silk, Sup35 or curli preparations were injected with a silver-nitrate inflammatory challenge; matched
    vehicle and nonamyloid actin controls also received the challenge. Splenic AA deposition was evaluated after
    16 days using blinded Congo-red microscopy and immunohistochemistry. In the FVB Sup35 experiment, 10/12
    seeded mice had deposits versus 2/11 controls with minimal deposits; results varied across preparations and
    strains. This tests experimental cross-seeding, not live bacterial infection, oral transmission or
    environmental risk in humans.
  evidence:
  - reference: PMID:15829582
    reference_title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      We studied three such naturally occurring protein fibrils: silk from Bombyx mori, Sup35 from Saccharomyces
      cerevisiae, and curli from Escherichia coli.
    explanation: >-
      Identifies the heterologous seed preparations.
  - reference: PMID:15829582
    reference_title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Our results show that these protein fibrils exert amyloid-accelerating properties in the murine
      experimental AA amyloidosis
    explanation: >-
      Direct experimental result; environmental human risk is an extrapolation.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/
    reference_title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism - PMC'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Amyloid deposits were detected in the spleens of 10 of the 12 FVB mice treated with Sup35, whereas 2 of 11
      mice in a control group treated with 0.9% NaCl developed minimal amyloid deposits
    explanation: >-
      Direct seeded-versus-vehicle comparison in FVB mice under inflammatory challenge; the control group was not uniformly negative.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/
    reference_title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism - PMC'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      No amyloid was detected in 13 (9 NMRI and 4 FVB) mice treated with actin fibrils or in 14 (9 NMRI and 5
      FVB) mice treated with G-buffer.
    explanation: >-
      Actin and buffer groups provide a nonamyloid-fibril comparison under the same induction framework.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/
    reference_title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism - PMC'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      The slides were examined blindly in a polarization microscope (BX51, Olympus, Melville, NY) for bright
      green birefringence, typical of amyloid.
    explanation: >-
      Blinded histological detection supports the splenic amyloid readout. This is not a renal-function or survival endpoint.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/
    reference_title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism - PMC'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      No significant differences were found (amyloid occurred in three of nine mice treated with wild-type NM
      and one of eight mice treated with R2E2 NM).
    explanation: >-
      The NMRI Sup35-variant experiment did not demonstrate a significant difference; seeding results should not
      be generalized across all preparations.
  modeled_mechanisms:
  - target: SAA Amyloid Fibril Assembly
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Heterologous fibrils accelerate splenic AA deposition during an inflammatory challenge, supporting an in
      vivo seeding contribution to assembly.
    limitations: >-
      This induced model does not establish spontaneous clinical latency, human environmental transmission,
      systemic clinical organ failure or therapeutic rescue. Splenic deposits are an endpoint of assembly and
      accumulation, not a direct kinetic measurement of molecular nucleation. Separate Sup35-variant results
      were not significantly different.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/
      reference_title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism - PMC'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: >-
        Amyloid deposits were detected in the spleens of 10 of the 12 FVB mice treated with Sup35, whereas 2 of
        11 mice in a control group treated with 0.9% NaCl developed minimal amyloid deposits
      explanation: >-
        Mouse deposition is a direct experimental endpoint; its relationship to molecular fibril assembly is
        inferred from the seeding design.
    readouts:
    - name: Splenic AA deposition after Sup35 seeding
      target: SAA Amyloid Fibril Assembly
      direction: INCREASED
      interpretation: >-
        At day 16, deposits were found in 10/12 FVB mice given Sup35 versus minimal deposits in 2/11 vehicle
        controls; both groups received an inflammatory challenge. The study does not demonstrate clinical renal
        benefit or rescue.
      evidence:
      - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/
        reference_title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism - PMC'
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          Amyloid deposits were detected in the spleens of 10 of the 12 FVB mice treated with Sup35, whereas 2
          of 11 mice in a control group treated with 0.9% NaCl developed minimal amyloid deposits
        explanation: >-
          The comparison quantifies splenic deposition, not human disease penetrance or direct molecular assembly flux.
    divergences:
    - divergence_type: PROXY_QUANTITY
      description: >-
        Splenic deposits measured after 16 days reflect assembly and accumulation; they do not directly
        quantify the kinetics of molecular SAA nucleation.
    - divergence_type: SPECIES_MISMATCH
      description: >-
        Injected heterologous fibrils with an inflammatory challenge in NMRI/FVB mice do not establish
        human environmental transmission or spontaneous clinical organ failure.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
  - classification_value: KIDNEY_URINARY_TRACT
  mechanistic_category:
  - classification_value: amyloidopathy
notes: >-
  AA amyloidosis has no disease-wide GeneReviews chapter. GeneReviews chapters for FMF and TRAPS address
  specific upstream causes and do not replace AA-specific diagnosis and management sources. The rare hereditary
  SAA1 promoter form is included separately from common coding susceptibility variants. Renal cohort percentages
  retain their selected population and follow-up context; gastrointestinal involvement is not used as
  a diarrhea denominator. The obesity report lists 146 patients but its reported subgroups sum to 148;
  no pooled proportion is computed. Thyroid/adrenal deposition alone does not establish endocrine failure.
  Full-text review distinguishes optional GAG amplification from indispensable nucleation, and deposit
  fragment composition from an obligatory cleavage-before-assembly sequence. The 2024 review inaccurately
  summarizes the anti-SAP stopping history; the primary 2018 and 2022 reports show no fatal arrhythmia
  and distinguish two single-dose AA participants from later ATTR/AL cardiac studies. The confirmatory
  eprodisate registry contains irregular event-time table cells; only its explicit endpoint and prespecified
  HR/log-rank analysis are used. No exact HPO term was selected for nonspecific gastric polyps or esophageal
  dysmotility; narrower polyposis or structural terms would overstate the source.
references:
- reference: PMID:7986228
  title: Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome.
- reference: PMID:12687559
  title: The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever.
- reference: PMID:15018633
  title: 'Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects.'
- reference: PMID:15829582
  title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism.'
- reference: PMID:16737350
  title: 'Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.'
- reference: PMID:17554116
  title: Eprodisate for the treatment of renal disease in AA amyloidosis.
- reference: PMID:17554117
  title: Natural history and outcome in systemic AA amyloidosis.
- reference: PMID:17714761
  title: 'Clinical and histological characteristics of renal AA amyloidosis: a retrospective study of 68 cases with a special interest to amyloid-associated inflammatory response.'
- reference: PMID:18815155
  title: 'Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis.'
- reference: PMID:19549924
  title: 'Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch.'
- reference: PMID:25387054
  title: 'AA amyloidosis: pathogenesis and targeted therapy.'
- reference: PMID:26120866
  title: 'Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature.'
- reference: PMID:26176329
  title: Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component.
- reference: PMID:28828707
  title: Pathology and diagnosis of renal non-AL amyloidosis.
- reference: PMID:29288051
  title: Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A.
- reference: PMID:29364741
  title: Obesity is a significant susceptibility factor for idiopathic AA amyloidosis.
- reference: PMID:29768139
  title: Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes.
- reference: PMID:37741608
  title: 'Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort.'
- reference: PMID:38568326
  title: 'AA Amyloidosis: A Contemporary View.'
- reference: PMID:39954777
  title: 'Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.'
- reference: PMID:40516176
  title: 'AA amyloidosis in inflammatory joint diseases: A systematic review.'
- reference: PMID:41670232
  title: Tocilizumab prevented the progression of AA amyloidosis derived from adult-onset Still's disease.
- reference: PMID:34560138
  title: A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis.
- reference: PMID:20301405
  title: Familial Mediterranean Fever.
  tags:
  - GeneReviews
- reference: PMID:36375008
  title: TNF Receptor-Associated Periodic Fever Syndrome.
  tags:
  - GeneReviews
- reference: PMID:29298867
  title: Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis.
- reference: PMID:35152886
  title: 'Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.'
- reference: url:https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-022313-25/results
  title: EudraCT Number 2010-022313-25 - Clinical trial results - EU Clinical Trials Register
- reference: url:https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf
  title: https://amyloid.nl/Files/Dember%20Eprodisate%20New%20England.pdf
- reference: clinicaltrials:NCT00035334
  title: A Phase II/III Study of the Safety and Efficacy of NC-503 in Patients Suffering From Secondary (AA) Amyloidosis
- reference: clinicaltrials:NCT01215747
  title: International Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of the Efficacy and Safety of KIACTA in Preventing Renal Function Decline in Patients With AA Amyloidosis
- reference: clinicaltrials:NCT01777243
  title: A Single Dose First in Human Study of GSK2398852 Co-Administered With GSK2315698 in Patients With Systemic Amyloidosis
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC1087940/
  title: 'Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism - PMC'
has_subtypes:
- name: Inflammation-associated AA amyloidosis
  description: >-
    The common presentation complicates chronic infectious, inflammatory or autoinflammatory disease with
    persistent SAA production.
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      Even though any disorder causing sustained inflammation may increase the risk of AA amyloidosis,
      chronic infections and inflammatory arthritis are the commonest causes
    explanation: >-
      Defines the common etiologic presentation.
- name: Idiopathic AA amyloidosis
  description: >-
    No overt inflammatory cause is identified after evaluation. This category can include unrecognized
    genetic or environmental contributors and should not be assumed to be uniformly obesity-driven.
  evidence:
  - reference: PMID:38568326
    reference_title: 'AA Amyloidosis: A Contemporary View.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: >-
      A substantial proportion of cases (up to 20%) appear to develop AA amyloidosis in the absence of
      overt inflammation and thus labeled idiopathic
    explanation: >-
      Describes an etiologic classification, not a distinct fibril precursor.
- name: Hereditary SAA1 promoter-associated AA amyloidosis
  description: >-
    A rare autosomal dominant promoter variant produces sustained SAA elevation and systemic AA deposition
    without the usual inflammatory cause.
  evidence:
  - reference: PMID:34560138
    reference_title: A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      Here we describe a family with primary amyloid A amyloidosis due to a chr11:18287683 T>C (human
      genome version19) mutation in the SAA1 promoter linked to the amyloidogenic SAA1.1 haplotype.
    explanation: >-
      Identifies the rare regulatory hereditary cause.
inheritance:
- name: Autosomal dominant in the rare SAA1 promoter-associated form
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    This inheritance applies to the reported promoter-associated family. Most AA amyloidosis is an acquired
    complication; inheritance of an upstream autoinflammatory disease must be counseled according to that
    disease.
  evidence:
  - reference: PMID:34560138
    reference_title: A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: >-
      sustained elevation of serum amyloid A levels that segregated in an autosomal dominant pattern in
      12 genetically affected and in none of six genetically unaffected relatives
    explanation: >-
      Documents segregation of elevated SAA in the family, not universal penetrance or dominant inheritance
      of common AA.
experimental_models:
- name: Recombinant SAA–glycosaminoglycan assembly assays
  experimental_model_type: OTHER
  description: >-
    Cell-free SAA isoforms were examined with heparin or heparan sulfate using CD/FTIR, thioflavin-T kinetics,
    TEM, amyloid-reactive antibodies and binding assays. Isoform, pH and aggregation state alter the responses.
  publication: PMID:39954777
  modeled_mechanisms:
  - target: SAA Amyloid Fibril Assembly
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Heparin addition alters assembly kinetics under defined conditions.
    limitations: >-
      Recombinant lipid-free murine SAA and human SAA1/SAA2 were tested at defined pH; the study does
      not measure HDL dissociation, patient tissue deposition or organ injury. The early acidic beta-sheet
      is reversible and distinct from amyloid; apparent droplets are not proven necessary intermediates.
      GAG-free controls also eventually form fibrils.
    evidence:
    - reference: PMID:39954777
      reference_title: 'Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Heparin greatly accelerated formation of amyloid-like structure in mSAA at pH 7.4 by eliminating
        the lag (nucleation) phase and accelerating the growth phase in the ThT kinetic data.
      explanation: >-
        The kinetic effect is measured in recombinant murine SAA at neutral pH; complementary antibody
        and microscopy assays support amyloid formation.
    readouts:
    - name: Amyloid-assembly kinetics
      target: SAA Amyloid Fibril Assembly
      direction: INCREASED
      interpretation: >-
        At pH 7.4 heparin shortened the lag and accelerated growth in the murine protein assay.
      evidence:
      - reference: PMID:39954777
        reference_title: 'Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.'
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          Heparin greatly accelerated formation of amyloid-like structure in mSAA at pH 7.4 by eliminating
          the lag (nucleation) phase and accelerating the growth phase in the ThT kinetic data.
        explanation: >-
          The kinetic effect is measured in recombinant murine SAA at neutral pH; complementary antibody
          and microscopy assays support amyloid formation.
  - target: SAA-Glycosaminoglycan Binding
    relationship: MEASURES
    fidelity: LOW
    description: >-
      Binding increases as soluble oligomers form; heparin also binds previously formed fibrils.
    limitations: >-
      Recombinant lipid-free murine SAA and human SAA1/SAA2 were tested at defined pH; the study does
      not measure HDL dissociation, patient tissue deposition or organ injury. The early acidic beta-sheet
      is reversible and distinct from amyloid; apparent droplets are not proven necessary intermediates.
      GAG-free controls also eventually form fibrils.
    evidence:
    - reference: PMID:39954777
      reference_title: 'Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        the binding affinity increases upon formation of soluble amyloid oligomers.
      explanation: >-
        Recombinant lipid-free SAA assays show stronger glycosaminoglycan binding after oligomer formation.
        Native human SAA2 did not show detectable binding in these assays.
    readouts:
    - name: GAG binding after oligomerization
      target: SAA-Glycosaminoglycan Binding
      direction: INCREASED
      interpretation: >-
        The measured increase applies to the protein/aggregate states tested, not a universal native-SAA
        interaction.
      evidence:
      - reference: PMID:39954777
        reference_title: 'Serum Amyloid A Binding to Glycosaminoglycans is Synergistic with Amyloid Formation: Therapeutic Targeting in the Inflammation-linked Amyloidosis.'
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          the binding affinity increases upon formation of soluble amyloid oligomers.
        explanation: >-
          Recombinant lipid-free SAA assays show stronger glycosaminoglycan binding after oligomer formation.
          Native human SAA2 did not show detectable binding in these assays.
- name: Truncated human SAA peptide assembly
  experimental_model_type: OTHER
  description: >-
    Cell-free human SAA(1–76) was compared with full-length SAA in a heparan-sulfate-induced assembly
    system. CD, FTIR and electron microscopy assess conformation and fibrils.
  publication: PMID:29288051
  modeled_mechanisms:
  - target: Reduced Alpha-Helical Structure of Truncated SAA
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      Tests the direct structural consequence of a defined C-terminal truncation.
    limitations: >-
      Only the abstract is available after attempted regeneration. It does not establish when cleavage
      occurs in patients or identify the responsible tissue protease.
    evidence:
    - reference: PMID:29288051
      reference_title: Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Circular dichroism (CD) measurements demonstrated that the C-terminal truncation induces a reduced
        α-helical structure of the SAA molecule.
      explanation: >-
        Compares truncated SAA(1–76) with full-length protein; the experiment tests a defined fragment
        rather than proving when proteolysis occurs in vivo.
    readouts:
    - name: Alpha-helical structure
      target: Reduced Alpha-Helical Structure of Truncated SAA
      direction: DECREASED
      interpretation: >-
        Truncated peptide has less alpha-helical structure than full-length protein.
      evidence:
      - reference: PMID:29288051
        reference_title: Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          Circular dichroism (CD) measurements demonstrated that the C-terminal truncation induces a reduced
          α-helical structure of the SAA molecule.
        explanation: >-
          Compares truncated SAA(1–76) with full-length protein; the experiment tests a defined fragment
          rather than proving when proteolysis occurs in vivo.
  - target: SAA Amyloid Fibril Assembly
    relationship: RECAPITULATES
    fidelity: LOW
    description: >-
      Truncated protein forms fibrils more readily under the tested conditions.
    limitations: >-
      The comparison does not show that full-length SAA cannot fibrillize under other conditions.
    evidence:
    - reference: PMID:29288051
      reference_title: Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Transmission electron microscopy revealed that short fibrillar aggregates of SAA (1-76) peptides,
        which became longer with increasing peptide concentrations, were observed under conditions in
        which full-length SAA scarcely formed fibrillar aggregates.
      explanation: >-
        Truncation accelerates fibril assembly in this experimental system; full-length protein can form
        fibrils under other conditions.
    readouts:
    - name: Fibrillar aggregates by TEM
      target: SAA Amyloid Fibril Assembly
      direction: INCREASED
      interpretation: >-
        Truncated SAA formed aggregates where full-length SAA scarcely did.
      evidence:
      - reference: PMID:29288051
        reference_title: Acceleration of amyloid fibril formation by carboxyl-terminal truncation of human serum amyloid A.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          Transmission electron microscopy revealed that short fibrillar aggregates of SAA (1-76) peptides,
          which became longer with increasing peptide concentrations, were observed under conditions in
          which full-length SAA scarcely formed fibrillar aggregates.
        explanation: >-
          Truncation accelerates fibril assembly in this experimental system; full-length protein can
          form fibrils under other conditions.
- name: SAA isoform degradation by MMP-1
  experimental_model_type: OTHER
  description: >-
    Cell-free SAA isoforms were exposed to MMP-1; immunoblotting and MALDI-TOF identify cleavage differences.
  publication: PMID:18815155
  modeled_mechanisms:
  - target: SAA Proteolytic Cleavage
    relationship: MEASURES
    fidelity: LOW
    description: >-
      Measures isoform-dependent susceptibility to a defined enzyme.
    limitations: >-
      Abstract-only evidence. It does not demonstrate the enzyme responsible in human tissue or prove
      that increased cleavage explains the genotype-associated clinical risk.
    evidence:
    - reference: PMID:18815155
      reference_title: 'Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        We found that SAA1.5 is more resistant to degradation by MMP-1 than SAA1.1. This difference is
        caused
        by the capacity of MMP-1 to cleave at the site of the polymorphism at position 57.
      explanation: >-
        Immunoblotting and mass spectrometry demonstrate isoform-dependent MMP-1 cleavage in vitro; this
        does not establish the rate-limiting protease or cleavage sequence in patients.
    readouts:
    - name: Isoform cleavage susceptibility
      target: SAA Proteolytic Cleavage
      direction: ALTERED
      interpretation: >-
        SAA1.5 was more resistant to MMP-1 than SAA1.1, with a cleavage difference at residue 57.
      evidence:
      - reference: PMID:18815155
        reference_title: 'Increased susceptibility of serum amyloid A 1.1 to degradation by MMP-1: potential explanation for higher risk of type AA amyloidosis.'
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          We found that SAA1.5 is more resistant to degradation by MMP-1 than SAA1.1. This difference
          is caused
          by the capacity of MMP-1 to cleave at the site of the polymorphism at position 57.
        explanation: >-
          Immunoblotting and mass spectrometry demonstrate isoform-dependent MMP-1 cleavage in vitro;
          this does not establish the rate-limiting protease or cleavage sequence in patients.
- name: HDL-SAA remodeling and monocyte amyloid culture
  experimental_model_type: OTHER
  description: >-
    Biochemical HDL-SAA/HS assays and a monocyte culture system tested pH-sensitive interactions and synthetic
    peptides containing the H36 region.
  publication: PMID:19549924
  modeled_mechanisms:
  - target: Heparan Sulfate-Associated HDL-SAA Remodeling
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Measures the effect of HS at mildly acidic pH.
    limitations: >-
      Only abstract evidence is available; precise culture provenance and in-vivo location are not inferred.
    evidence:
    - reference: PMID:19549924
      reference_title: 'Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich aggregates.
      explanation: >-
        Biochemical and culture experiments demonstrate pH-dependent HDL-SAA remodeling, without locating
        or proving this step in patients.
    readouts:
    - name: SAA-rich aggregate production
      target: Heparan Sulfate-Associated HDL-SAA Remodeling
      direction: INCREASED
      interpretation: >-
        HS remodeled HDL-associated SAA in the assay.
      evidence:
      - reference: PMID:19549924
        reference_title: 'Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch.'
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich aggregates.
        explanation: >-
          Biochemical and culture experiments demonstrate pH-dependent HDL-SAA remodeling, without locating
          or proving this step in patients.
  - target: SAA Amyloid Fibril Assembly
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Peptides promoted deposition in the monocyte culture model.
    limitations: >-
      This does not demonstrate that the same local pH or peptide concentration occurs in patient kidneys.
    evidence:
    - reference: PMID:19549924
      reference_title: 'Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Synthetic peptides corresponding to this region promoted the deposition of AA amyloid in a monocyte
        culture model for AA amyloidogenesis. The effects were peptide sequence specific and reliant on
        the protonation of H36.
      explanation: >-
        The culture experiment supports sequence- and pH-sensitive promotion of assembly; it does not
        establish a human environmental exposure mechanism.
- name: Human adipose tissue SAA secretion
  experimental_model_type: OTHER
  description: >-
    Human adipose biopsy explants were cultured with insulin, dexamethasone and/or rosiglitazone; conditioned-medium
    SAA was measured. Clinical BMI/expression associations were a separate component of the same study.
  publication: PMID:16737350
  modeled_mechanisms:
  - target: Adipose Serum Amyloid A Production
    relationship: MEASURES
    fidelity: LOW
    description: >-
      Directly measures SAA secretion from human adipose explants.
    limitations: >-
      These were not amyloid-bearing patient tissues. The study does not trace adipose SAA into AA deposits,
      establish an AA prevention effect, or support rosiglitazone as AA therapy.
    evidence:
    - reference: PMID:16737350
      reference_title: 'Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: >-
        Incubation of the fat explants for 2 d with insulin or dexamethasone resulted in an SAA accumulation
        in the medium, and combination of the two hormones was additive in the stimulatory effect.
      explanation: >-
        Human adipose explants directly secrete measurable SAA under defined hormonal conditions; this
        is ex-vivo tissue culture.
    readouts:
    - name: SAA accumulation in conditioned medium
      target: Adipose Serum Amyloid A Production
      direction: INCREASED
      interpretation: >-
        Hormonal stimulation increased secretion; rosiglitazone reduced secretion in this experimental
        setting.
      evidence:
      - reference: PMID:16737350
        reference_title: 'Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications.'
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: >-
          Incubation of the fat explants for 2 d with insulin or dexamethasone resulted in an SAA accumulation
          in the medium, and combination of the two hormones was additive in the stimulatory effect.
        explanation: >-
          Human adipose explants directly secrete measurable SAA under defined hormonal conditions; this
          is ex-vivo tissue culture.

📚

References & Deep Research

References

PMID:7986228

Colchicine treatment of AA amyloidosis of familial Mediterranean fever. An analysis of factors affecting outcome.