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PubMed This is a summary of 17 peer-reviewed journal articles Updated
Hematology

Diagnosing Amyloidosis: Scans, Biopsies, and Labs

At a Glance

Diagnosing amyloidosis requires a strict step-by-step approach. Doctors first use specific blood and urine tests to rule out AL amyloidosis. If AL is ruled out, specialized bone scans can often diagnose ATTR without a heart biopsy. Mass spectrometry is the most accurate way to type the protein.

The process of diagnosing amyloidosis is like assembling a complex puzzle. Because the treatment for AL amyloidosis is so different from ATTR amyloidosis, doctors use a strict “road map” to ensure they identify the correct type before starting therapy [1][2].

Step 1: The Essential Blood and Urine Screen

The absolute first step for any patient suspected of having amyloidosis is to rule out AL (Light Chain) amyloidosis. This is done through three specific tests that look for “monoclonal proteins” (abnormal proteins produced by plasma cells) [1][2].

  1. Serum Free Light Chain (sFLC) Assay: Measures the levels of “kappa” and “lambda” light chains in your blood.
  2. Serum Protein Electrophoresis (SPEP) with Immunofixation: Looks for a specific abnormal protein “spike” in the blood.
  3. Urine Protein Electrophoresis (UPEP) with Immunofixation: Checks for the same abnormal proteins in a 24-hour urine sample.

Why this matters: If any of these tests are abnormal, you may have AL amyloidosis, which requires immediate attention from a hematologist. You cannot be diagnosed with ATTR using only a bone scan if these tests haven’t been completed first, because AL amyloidosis can sometimes cause a “false positive” on those scans [1][3].

Step 2: The Non-Invasive “Bone Scan” for ATTR

If your blood and urine tests are normal (ruling out AL), doctors can often diagnose ATTR cardiac amyloidosis without a painful heart biopsy [4][5].

  • The Scan: You may receive a PYP (pyrophosphate) or DPD scan. These are nuclear medicine tests where a small amount of tracer is injected into your vein.
  • The Results: Doctors use the Perugini Grading System to see how much tracer the heart muscle absorbs [4].
    • Grade 0: No uptake (Not ATTR).
    • Grade 1: Mild uptake (Inconclusive).
    • Grade 2 or 3: Strong uptake (Confirmed ATTR, provided AL is ruled out) [4][6].
  • SPECT/CT Imaging: This is an extra step during the scan to ensure the tracer is actually inside the heart muscle and not just floating in the blood [7].

Step 3: Understanding Your Lab Biomarkers

Your doctor will monitor two main “biomarkers” in your blood to see how much stress your heart is under [8][9].

  • NT-proBNP: A protein released when the heart walls are stretched or under pressure.
  • Troponin (T or I): A protein released when heart muscle cells are damaged [10][11].
    These numbers help “stage” your disease and allow the care team to track if your treatment is working over time.

The Pathology Checklist (For Biopsies)

If a tissue biopsy is required (for example, from a fat pad, the heart, or a kidney), your pathology report should contain these “gold standard” elements [12][13]:

Must-Have Feature Why It Matters
Congo Red Stain The special dye used to identify amyloid in tissue samples [12].
Apple-Green Birefringence The specific way amyloid glows under a polarized microscope when dyed with Congo Red [14].
Mass Spectrometry (LMD-MS) The most accurate way to “type” the protein. It is far more reliable than older antibody tests [15][16].

If your report uses older methods like “immunohistochemistry” (IHC) and the results are unclear, ask if the sample can be sent for Mass Spectrometry [12][17]. This is the most definitive way to know exactly which protein is causing your illness.

Common questions in this guide

Why do I need blood and urine tests before a bone scan for amyloidosis?
Blood and urine tests are required to rule out AL (light chain) amyloidosis first. This is crucial because AL amyloidosis requires immediate treatment from a hematologist and can sometimes cause a false positive on a bone scan.
What does a Perugini Grade of 2 or 3 mean on my bone scan?
A Perugini Grade of 2 or 3 indicates strong tracer uptake in the heart during a PYP or DPD scan. As long as AL amyloidosis has been ruled out by lab tests, this grade confirms a diagnosis of ATTR cardiac amyloidosis.
What do NT-proBNP and Troponin levels tell my doctor about my heart?
These blood biomarkers measure how much stress and damage your heart muscle is experiencing. Doctors use these numbers to stage your amyloidosis and track how well your treatment is working over time.
What is the most accurate way to type the amyloid protein from a biopsy?
Mass spectrometry (LMD-MS) is the most definitive and accurate method for typing amyloid protein in a tissue sample. It is far more precise than older testing methods like immunohistochemistry (IHC).

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Have I completed all three 'monoclonal protein' tests (Serum Free Light Chains, SPEP with immunofixation, and UPEP with immunofixation)?
  2. 2.What was my Perugini Grade on the bone scintigraphy (PYP/DPD) scan, and did you use a SPECT scan to confirm the location?
  3. 3.Since my NT-proBNP and Troponin levels are on my report, what do these numbers tell us about my current 'stage' of disease?
  4. 4.If my biopsy was inconclusive, can we send the tissue for Mass Spectrometry typing to get a definitive answer?
  5. 5.How often will we re-test my biomarkers to see if my heart is responding to the treatment?

Questions For You

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References

References (17)
  1. 1

    Updates in Cardiac Amyloidosis Diagnosis and Treatment.

    Stern LK, Kittleson MM

    Current oncology reports 2021; (23(4)):47 doi:10.1007/s11912-021-01028-8.

    PMID: 33725199
  2. 2

    Diagnosing Transthyretin Cardiac Amyloidosis by Technetium Tc 99m Pyrophosphate: A Test in Evolution.

    Poterucha TJ, Elias P, Bokhari S, et al.

    JACC. Cardiovascular imaging 2021; (14(6)):1221-1231 doi:10.1016/j.jcmg.2020.08.027.

    PMID: 33221204
  3. 3

    Myocardial Amyloidosis: The Exemplar Interstitial Disease.

    Fontana M, Ćorović A, Scully P, Moon JC

    JACC. Cardiovascular imaging 2019; (12(11 Pt 2)):2345-2356 doi:10.1016/j.jcmg.2019.06.023.

    PMID: 31422120
  4. 4

    Case report regarding the evolution of electrocardiographic and echocardiographic features in cardiac amyloidosis.

    Vervaat FE, Bouwmeester S, Vlaar PJ

    European heart journal. Case reports 2021; (5(1)):ytaa426 doi:10.1093/ehjcr/ytaa426.

    PMID: 33644637
  5. 5

    Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis.

    Gillmore JD, Maurer MS, Falk RH, et al.

    Circulation 2016; (133(24)):2404-12 doi:10.1161/CIRCULATIONAHA.116.021612.

    PMID: 27143678
  6. 6

    Diagnostic Work-Up of Cardiac Amyloidosis Using Cardiovascular Imaging: Current Standards and Practical Algorithms.

    Korosoglou G, Giusca S, André F, et al.

    Vascular health and risk management 2021; (17()):661-673 doi:10.2147/VHRM.S295376.

    PMID: 34720583
  7. 7

    The Rise of Cardiac Amyloidosis Imaging.

    Satyavolu B, Deitz J, Soman P

    Journal of nuclear medicine technology 2023; (51(2)):129-132 doi:10.2967/jnmt.123.265635.

    PMID: 37268321
  8. 8

    Cardiac Troponin in Patients With Light Chain and Transthyretin Cardiac Amyloidosis: JACC: CardioOncology State-of-the-Art Review.

    De Michieli L, Cipriani A, Iliceto S, et al.

    JACC. CardioOncology 2024; (6(1)):1-15 doi:10.1016/j.jaccao.2023.12.006.

    PMID: 38510286
  9. 9

    Diagnosing AL and ATTR Amyloid Cardiomyopathy: A Multidisciplinary Approach.

    Aus dem Siepen F, Hansen T

    Journal of clinical medicine 2024; (13(19)) doi:10.3390/jcm13195873.

    PMID: 39407933
  10. 10

    High-Sensitivity Cardiac Troponin I for Risk Stratification in Wild-Type Transthyretin Amyloid Cardiomyopathy.

    De Michieli L, Sinigiani G, Guida G, et al.

    Circulation. Heart failure 2025; (18(8)):e012816 doi:10.1161/CIRCHEARTFAILURE.125.012816.

    PMID: 40371473
  11. 11

    Bio-Adrenomedullin Predicts Death and Major Adverse Cardiovascular Events in Cardiac Amyloidosis: A Cross-Continental Multicenter Study.

    Müller ML, Knebel F, Hahn K, et al.

    Journal of the American Heart Association 2026; (15(1)):e043736 doi:10.1161/JAHA.125.043736.

    PMID: 41432138
  12. 12

    A comprehensive panel of testing for amyloidosis.

    Tang H, Zhao F, Zhu Y, et al.

    Journal of histotechnology 2025; (48(4)):191-199 doi:10.1080/01478885.2025.2553926.

    PMID: 40927889
  13. 13

    Confirming the Diagnosis of Amyloidosis.

    Wisniowski B, Wechalekar A

    Acta haematologica 2020; (143(4)):312-321 doi:10.1159/000508022.

    PMID: 32544917
  14. 14

    Immunoglobulin light chain amyloidosis: 2022 update on diagnosis, prognosis, and treatment.

    Gertz MA

    American journal of hematology 2022; (97(6)):818-829 doi:10.1002/ajh.26569.

    PMID: 35429180
  15. 15

    A Spatial Proteomics Approach to Isolate and Analyze Amyloid Proteins Using Laser Capture Microdissection and Mass Spectrometry.

    Aguilan J, Horton M, Pessin JE, Sidoli S

    Methods in molecular biology (Clifton, N.J.) 2026; (3015()):121-134 doi:10.1007/978-1-0716-5154-4_10.

    PMID: 41629715
  16. 16

    Mass Spectrometry Amyloid Typing Is Reproducible across Multiple Organ Sites.

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    BioMed research international 2019; (2019()):3689091 doi:10.1155/2019/3689091.

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    Implementation and evaluation of amyloidosis subtyping by laser-capture microdissection and tandem mass spectrometry.

    Mollee P, Boros S, Loo D, et al.

    Clinical proteomics 2016; (13()):30 doi:10.1186/s12014-016-9133-x.

    PMID: 27795698

This page provides educational information about amyloidosis diagnostic tests and pathology. It does not replace professional medical advice. Always consult your hematologist or cardiologist to interpret your specific scan and lab results.

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