diagnosis of amyloidosis€¦ · cardiac amyloidosis – heart failure, arrhythmia, long list of...
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Diagnosis of Amyloidosis
Maria M. Picken MD, PhD Loyola University Medical Center
Chicago [email protected]
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Amyloid: what is it and why it forms Name = misnomer: “amyloid” means starch* but deposits of amyloid contain predominantly protein which became mis-folded Amyloidoses = amyloid diseases
amylum = starch in Latin, ἄμυλον amylon = starch in Greek * the name amyloid comes from the early mistaken identification by Rudolf Virchow (XIX century) of the substance as starch based on crude iodine-staining techniques
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Fibrillogenesis
α helix β pleated sheet
Amyloidoses – protein folding disorders
Conformational shift to β-pleated sheet 20 structure
hydrophobic, insoluble
non-functional
resistant to degradation
sticky (prone to aggregation)
extracellular
affinity to Congo red stain
fibrillar (by electron microscopy)
Congo red positivity with green birefringence
under polarized light
non-branching fibrils by electron microscopy
amyloid binding sites
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Amyloidoses – protein folding disorders
protein quality control systems: intracellular (proteasomes*) extracellular (macrophages)
Increased concentration
mutations Intrinsic instability
Proteolytic cleavage
precursor protein misfolded protein protofibril mature fibrils
Older age
Proteasomes = protein complexes which degrade unneeded or damaged proteins by proteolysis
Proteasomes are part of a major mechanism by which cells degrade misfolded proteins
proteotoxicity
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INCREASED PRODUCTION OF PRECURSOR
NORMAL PRODUCTION OF
MUTANT
Acquired mutations leading to Intrinsic instability
Chronic inflammation Transthyretin (TTR) Mutation increasing instability
Monoclonal plasma cells
Macrophage activation
IL1 & IL6
mTTR…….
Immunoglobulin light chain
increased SAA protein
incomplete proteolysis incomplete proteolysis
aggregation aggregation Aggregation
AL amyloidosis AA amyloidosis ATTR amyloidosis
Pathogenesis of hereditary amyloidosis
Hereditary: ATTR, AFib, AApoAI, AII, C-III…
Amyloidosis derived from transthyretin: ATTR • The most common hereditary amyloidosis in the US • TTR circulates as tetramer, • transport of thyroxin & retinol (vitamin A) • inherited mutation destabilizes tetramer • >95% liver; choroid plexus, eye • >100 mutations
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Hereditary: ATTR Amyloidosis derived from transthyretin: ATTR • polyneuropathies (sensory, autonomic), cardiac gastrointestinal, some kidneys
The most common hereditary amyloidosis in the US
~4% of African Americans (TTR V122I) Variable penetrance Late onset in some Family history often missing Can MIMICK AL – danger of misdiagnosis
Peripheral nerve with amyloid
*
enlarged heart * deposits of amyloid Carpal tunnel bilateral
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ATTRwt (wild type): normal (wild type) transthyretin is prone to fibrillogenesis at older age protein quality control systems are less effective at older age…
- cardiac amyloid at old age “cardiac Alzheimer” Formerly SSA: senile systemic amyloidosis males, under-diagnosed – 25% of octogenarians risk factors? prevention?
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How to diagnose amyloidosis?
1. Detection: - ALL amyloids are Congo red positive 2. Typing of amyloid protein
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DIAGNOSIS: kidney, cardiac, peripheral nerves, other sites laboratory tests to support the diagnosis but not to make it
Routine stain: extracellular “amorphous” deposits, not-specific for amyloid
Diagnosis = Congo* red stain with green birefringence under polarized light [“apple green” birefringence]
Amyloid is fibrillary only by electron microscopy
think – amyloid order Congo red stain
* the name “Congo” was given for marketing purposes but the stain has NO origins in African river
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Differential diagnosis of proteinuria/nephrotic syndrome in adults: 1.Focal and Segmental Glomerular Sclerosis/Minimal change disease 2.Membranous nephropathy 3.Diabetes 4.Amyloidosis!!!
Cardiac amyloidosis – heart failure, arrhythmia, long list of differential Polyneuropathy – sensory and autonomic disturbances, long list of differential Amyloid deposits are unevenly distributed in tissues
think – amyloid order Congo red stain
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Amyloid can be detected in subcutaneous fat Fat biopsy typically from periumbilical abdomen (“surrogate site”)
for diagnosis and screening of patients at risk
“Surrogate” site biopsy
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Amyloid detection in fat:
Sensitivity highly variable 54-93%
Specificity: 93-100%
Affected organ – best yield
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Fine et al, 2014:
ATTR, cardiac versus non-cardiac tissue sampling:
Fat aspiration was the most commonly performed followed by bone marrow
biopsy. Other: rectum, kidney, carpal ligament, liver, small intestine, sural nerve
biopsy all Familial ATTR Wild type senile ATTR
Fat aspirate 225/106+ 47% 141/94+ 67%
84/12+ 14%
Bone marrow 164/60+ 37%
100/41+ 41%
64/19+ 30%
heart 131/131+ 100%
42/42+ 100%
89/89+ 100%
Sural nerve 54/45+ 83%
54/45+ 83%
0
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Pathology of Familial amyloidoses:
1. Detection of amyloid in the index patient
- lack of a family history
- new mutation
2. Screening of family members/known carriers
3. Staging, organ involvement
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Thank you Questions? [email protected]
Increased awareness and education Clinical suspicion… Pathologic suspicion… second opinion Patients’ perspective…
Early diagnosis of amyloidosis = biggest challenge