Hereditary ATTR Amyloidosis Testing & Diagnosis

Generalized hATTR amyloidosis diagnostic workup

Cardiac Amyloid
Suspicion of hATTR amyloidosis based on cardiac manifestations, echocardiography, and/or CMR1
Hereditary ATTR
Suspicion of hATTR amyloidosis based on neurologic manifestations and/or paraclinical tests2
Cardiovascular Manifestations
Suspicion of hATTR amyloidosis based on cardiac manifestations, echocardiography, and/or CMR1
Peripheral Sensory Motor Neuropathy
Suspicion of hATTR amyloidosis based on neurologic manifestations and/or paraclinical tests2

For a more detailed diagnostic algorithm, refer to the hATTR amyloidosis diagnostic card.

Download Diagnostic Card


Scintigraphy (technetium-99m stannous pyrophosphate [PYP] scanning) is widely available and can be used to noninvasively diagnose hATTR amyloidosis with cardiomyopathy.1,3

PYP scanning shows 97% sensitivity and 100% specificity for identifying TTR in the heart.4

PYP scanning visualizes cardiac transthyretin amyloid deposits

Cardiac amyloidosis is almost always due to either ATTR or immunoglobulin light chain (AL) amyloidosis. Understanding the source of amyloid deposits determines appropriate patient treatment.5

Patient without cardiac TTR amyloid
Patient without cardiac TTR amyloid
No cardiac uptake of tracer (grade 0)
Patient with cardiac TTR amyloid
Patient with cardiac TTR amyloid
Positive cardiac uptake of tracer (grade 2)
Figure reproduced from Hutt DF et al, by permission of the European Society of Cardiology and Oxford University Press.6

Cardiac uptake of tracer (99mTc-PYP/DPD/HMDP) is typically stronger in patients with ATTR amyloidosis than AL amyloidosis (median grade 2 for ATTR; median grade 1 for AL).1,6

When scintigraphy tracer uptake is positive, differentiating between ATTR and AL amyloidosis may require testing for the presence of serum monoclonal protein and/or biopsy, with amyloid typing by immunohistochemistry or mass spectrometry.1

Genetic Testing

Genetic testing is a crucial component of the diagnostic process in determining a hATTR amyloidosis diagnosis, because it identifies the specific TTR mutation present.3

In a patient with confirmed TTR amyloid, genetic testing differentiates between hereditary and wild-type ATTR amyloidosis.3

Mutation in TTR gene sequence?

YES: hereditary ATTR (hATTR) amyloidosis
YES: hereditary ATTR (hATTR) amyloidosis
The most common TTR mutations include V30M and V122I worldwide, but V122I and T60A are the common mutations in the United States. More than 120 causative mutations have been identified.3,7,8
NO: wild-type ATTR (wtATTR amyloidosis)
NO: wild-type ATTR (wtATTR amyloidosis)
Wild-type ATTR amyloidosis is acquired and is most commonly diagnosed in men >60 years of age.9,10

Manifestations of hATTR and wtATTR amyloidosis can overlap significantly, but differentiation is important because5:

  • The natural histories of hATTR and wtATTR amyloidosis differ; understanding etiology can raise suspicion of commonly co-occurring ATTR manifestations. Many patients with hATTR have cardiac, gastrointestinal, and neurologic involvement5,8,11
  • Identifying a TTR gene mutation in a patient has important implications for their family members

Considering genetic testing for hATTR amyloidosis?

Akcea Therapeutics and Ambry Genetics are partnering to offer confidential, no-cost genetic testing and confidential counseling to patients suspected of having or clinically diagnosed with hATTR amyloidosis through the hATTR Compass program.

Learn More


A tissue biopsy with Congo red staining, which gives a characteristic apple-green color when viewed under polarizing microscopy, can confirm the presence of amyloid. A variety of tissues can be used for biopsy, including skin, fat pad, nerve tissue, and gastric mucosa.1,3,8

Once amyloidosis has been identified, the use of immunohistochemistry or mass spectroscopy is required to differentiate ATTR amyloidosis from amyloid light-chain (AL) amyloidosis.1,3,8

Biopsy and histopathology confirm the presence of amyloid deposits. Amyloid typing by immunohistochemistry or mass spectrometry identifies the protein source of amyloid.2

Histopathology of sural nerve biopsy from a patient with hATTR amyloidosis

Congo Red Staining
bright light
polarized light
fluorescence microscopy
Amyloid Typing
TTR immunohistochemistry
Figure adapted from Kollmer J et al, with permission from Oxford University Press.12

Understanding the source of amyloid deposits determines appropriate patient treatment.

Possible biopsy sites include2:

  • Salivary gland
  • Subcutaneous fatty tissue of abdominal wall
  • Rectal mucosa
  • Gastric
  • Kidney
  • Sural nerve
  • Tenosynovial tissue (eg, at time of carpal tunnel release surgery)13

Amyloid stained with Congo red shows characteristic apple-green birefringence under polarized light.2

In Life-Threatening hATTR Amyloidosis, Hope Starts With Diagnosis.14

For a more detailed diagnostic algorithm, refer to the hATTR amyloidosis diagnostic card.

Download Diagnostic Card
References: 1. Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404-2412. 2. Carvalho A, Rocha A, Lobato L. Liver transplantation in transthyretin amyloidosis: issues and challenges. Liver Transpl. 2015;21(3):282-292. 3. Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(suppl 7):S107-S112. 4. Bokhari S, Shahzad R, Castaño A, Maurer MS. Nuclear imaging modalities for cardiac amyloidosis. J Nucl Cardiol. 2014;21(1):175-184. doi:10.1007/s12350-013-9803-2. 5. Maurer MS, Hanna M, Grogan M, et al; THAOS Investigators. Genotype and phenotype of transthyretin cardiac amyloidosis. THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161-172. 6. Hutt DF, Quigley AM, Page J, et al. Utility and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in systemic amyloidosis. Eur Heart J Cardiovasc Imaging. 2014;15(11):1289-1298. 7. Rowczenio DM, Noor I, Gillmore JD, et al. Online registry for mutations in hereditary amyloidosis including nomenclature recommendations. Hum Mutat. 2014;35(9):E2403-E2412. doi:10.1002/humu.22619. 8. Coelho T, Maurer MS, Suhr OB. THAOS—the Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63-76. 9. Grogan M, Scott CG, Kyle RA, et al. Natural history of wild-type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol. 2016;68(10):1014-1020. 10. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377. 11. Wixner J, Mundayat R, Karayal ON, Anan I, Karling P, Suhr OB; THAOS investigators. THAOS: gastrointestinal manifestations of transthyretin amyloidosis—common complications of a rare disease. Orphanet J Rare Dis. 2014;9:61. 12. Kollmer J, Hund E, Hornung B, et al. In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography. Brain. 2015;138(Pt 3):549-562. doi:10.1093/brain/awu344. 13. Ikram A, Sperry B, Reyes B, Seitz W, Hanna M. Carpal tunnel syndrome and amyloid cardiomyopathy. J Card Fail. 2017;23(8)(suppl):S11-S12. 14. Conceição I, González-Duarte A, Obici L, et al. “Red-flag” symptom clusters in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. 2016;21(1):5-9.