DIAGNOSIS

Establish a diagnosis in 3 steps*:

Rule out AL amyloidosis with monoclonal protein screens
Detect amyloid deposition in myocardial tissue with nuclear scintigraphy (e.g., 99mTc-PYP) or cardiac biopsy
Once ATTR-CM is confirmed, use genetic testing to determine if it is hereditary

Follow the diagnostic algorithm†

A chart showing a diagnostic algorithm for ATTR-CM amyloidosis A chart showing a diagnostic algorithm for ATTR-CM amyloidosis

Establish a diagnosis in 3 steps*:

Rule out AL amyloidosis with monoclonal protein screens
If family history of hATTR, conduct genetic testing and follow with tissue biopsy if negative.
If no family history of hATTR, conduct tissue biopsy and follow with genetic testing if positive.

Follow the diagnostic algorithm†

A chart showing a diagnostic algorithm for hATTR-PN A chart showing a diagnostic algorithm for hATTR-PN
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Nuclear scintigraphy can be used to confirm an ATTR‑CM diagnosis

Once AL amyloidosis is ruled out with simple monoclonal protein screens, nuclear scintigraphy, tissue biopsy, and genetic testing can be used to confirm and identify the type of ATTR.

Nuclear scintigraphy3,6-9

Planar imaging: 99mTc-PYP planar scan in a patient with wtATTR-CM: Grade 3 cardiac uptake
SPECT/CT: Confirmation of myocardial uptake in the same patient
Planar imaging: Negative scan, no myocardial uptake
SPECT/CT: Negative scan, no myocardial uptake

Noninvasive Technique

  • Scintigraphy identifies amyloid buildup in the heart using radioactive tracers that bind to amyloid deposits
  • Radiotracers 99mTc-PYP and HMDP have high diagnostic accuracy for ATTR-CM

SPECT or SPECT/CT Improves Diagnostic Confidence

  • In addition to planar imaging, SPECT or SPECT/CT imaging is recommended to confirm that uptake is in the myocardium and not the result of blood pool radio tracer uptake

Grading and Confirmation

  • Scintigraphy with Grade 2/3 uptake confirms an ATTR-CM diagnosis
  • If tracer uptake is Grade 0/1 but high suspicion of ATTR-CM remains, a tissue biopsy and/or cMRI should be performed

TISSUE BIOPSY2,5,10-12

Biopsy of affected tissues can detect ttr amyloid deposition

Tissue biopsy can help confirm a diagnosis of ATTR when noninvasive screenings are unavailable or inconclusive.
Standard Technique
  • Biopsy of affected tissue with Congo red staining can detect TTR amyloid deposition.
Use in Cardiology
  • Cardiac tissue biopsy is used when nuclear scintigraphy is negative/equivocal despite a high clinical suspicion of ATTR-CM, or if scintigraphy is unavailable.
Use in Neurology
  • Tissue biopsy is used in the absence of a family history of ATTR, or when genetic testing is inconclusive despite family history, and a high clinical suspicion of hATTR-PN remains.

GENETIC TESTING

genetic testing can detect TTR Variants and identify hereditary disease1,2,13

Following an ATTR diagnosis, genetic testing can distinguish hereditary from wild type. Current techniques detect over 99% of TTR variants.
Alnylam Act® US Genetic Testing and Counseling Program
  • Alnylam Act® offers third-party genetic screening and counseling programs for patients who may have hATTR amyloidosis at no charge to patients, physicians, and payers.
  • Alnylam Act® is available for patients 18 years and older who may be at risk for carrying a genetic variant known to be associated with hATTR amyloidosis.
  • The Alnylam Act® program was created to provide access to genetic testing and counseling to patients as a way to help people make more informed decisions about their health.
  • While Alnylam provides financial support for this program, tests and services are performed by independent third parties. Healthcare professionals must confirm that patients meet certain criteria to use the program.
  • No patients, healthcare professionals, or payers, including government payers, are billed for this program.
Order a genetic test for hATTR
Alnylam receives de-identified patient data from this program, but at no time does Alnylam receive patient-identifiable information. Alnylam uses healthcare professional contact information for research and commercial purposes.
Healthcare professionals or patients who use this program have no obligation to recommend, purchase, order, prescribe, promote, administer, use, or support any Alnylam product.
Not a comprehensive list of all diagnostic tools.
*
Refer to American Heart Association diagnosis guidelines on amyloidosis and heart failure for further details.
†This algorithm has been developed based on the references cited as well as the collective expert consensus of key opinion leaders.1-3
‡Some variants of hATTR are associated with Grade 0 99mTc-PYP uptake in patients.1-3
§This step is relevant if not already conducted earlier in patient diagnostic journey to raise clinical suspicion.1-3
||Based on signs, symptoms, and initial findings consistent with hATTR amyloidosis.
The 2023 ACC Expert Consensus recommends a urine immunofixation electrophoresis and serum free light-chain assay to exclude AL amyloidosis in the initial diagnostic workup.
#Possible biopsy sites include labial salivary gland, subcutaneous fatty tissue of abdominal wall, skin, kidney, nerve, and gastrointestinal tract, including submucosa.
**
Sensitivity of a non-endomyocardial biopsy varies by site; negative fat-pad biopsy is not sufficient to exclude ATTR amyloidosis.
99mTc-DPD=technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid; 99mTc-HMDP=technetium-99m-hydroxymethylene diphosphonate; 99mTc-PYP=technetium-99m-pyrophosphate; ACC=American College of Cardiology; AL=amyloid light chain; AL-CM=amyloid light chain cardiomyopathy; ASNC=American Society of Nuclear Cardiology; ATTR=transthyretin-mediated amyloidosis; ATTR‑CM=cardiomyopathy of transthyretin-mediated amyloidosis; cMRI=cardiac magnetic resonance imaging; CT=computed tomography; FLC=free light chains; hATTR=hereditary transthyretin-mediated amyloidosis; hATTR-PN=polyneuropathy of hereditary transthyretin-mediated amyloidosis; H/CL=heart-to-contralateral lung; HMDP=hydroxymethylene diphosphonate; LGE=late gadolinium enhancement; MGUS=monoclonal gammopathy of undetermined significance; SPECT=single-photon emission computed tomography; TTR=transthyretin; wtATTR=wild-type transthyretin-mediated amyloidosis.
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References:

  1. Kittleson MM et al. Circulation. 2020;142(1):e7-e22.
  2. Kittleson MM et al. J Am Coll Cardiol. 2023;81(11):1076-1126.
  3. Dorbala S et al. Circ Cardiovasc Imaging. 2021;14(7):e000029.
  4. Carroll A et al. J Neurol Neurosurg Psychiatry. 2022;93(6):668-678.
  5. Adams D et al. J Neurol. 2021;268(6):2109-2122.
  6. Gillmore JD et al. Circulation. 2016;133(24):2404-2412.
  7. Ruberg FL et al. Circulation. 2012;126(10):1286-1300.
  8. Dharmarajan K et al. J Am Geriatr Soc. 2012;60(4):765-774.
  9. Gertz MA et al. J Am Coll Cardiol. 2015;66(21):2451-2466.
  10. Maurer MS et al. Circ Heart Fail. 2019;12(9):e006075.
  11. Witteles RM et al. JACC Heart Fail. 2019 Aug;7(8):709-716.
  12. Gonzalez-Lopez E et al. J Am Coll Cardiol. 2024;83(11):1085-1099.
  13. Ando Y et al. Orphanet J Rare Dis. 2013;8:31.
  14. Cardiac Amyloidosis. ASNC Practice Points Update. 2022;1-13.