Navigating Your Diagnostic Tests

Confirming a diagnosis of hATTR is a multi-step process that requires specific combinations of tests. Because the symptoms of hATTR can overlap with other types of amyloidosis—most notably AL amyloidosis, which requires hematology-directed plasma cell therapies—your medical team must follow a strict “rule-out” process to ensure you receive the correct treatment ^[1][2].

The Non-Invasive Cardiac Pathway

For many patients whose hATTR affects the heart, a diagnosis can be made without a biopsy. This is known as the non-invasive pathway. It relies on a specific nuclear medicine scan called bone scintigraphy (often referred to as a PYP, DPD, or HMDP scan) ^[1][3].

In this test, a small amount of a radioactive tracer is injected into your blood. In people with ATTR, this tracer “sticks” to the amyloid deposits in the heart ^[4]. Doctors use a grading system (the Perugini Scale) to measure this:

• Grade 0: No tracer in the heart.
• Grade 1: Slight tracer in the heart, but less than in the ribs.
• Grade 2 or 3: Significant tracer in the heart, equal to or more than in the ribs ^[2].

Crucially, a positive scan alone is not enough. A Grade 2 or 3 scan is highly specific when all criteria are met, which means unequivocal myocardial uptake on SPECT or SPECT/CT imaging and a completely negative “monoclonal protein” screen ^[1].

The Role of Monoclonal Protein Testing

Before a doctor can trust a bone scan, they must prove that your body isn’t making the “wrong” kind of protein—the light chains found in AL amyloidosis. This requires three specific blood and urine tests:

1. Serum Immunofixation (sIFE)
2. Urine Immunofixation (uIFE)
3. Serum Free Light Chain (sFLC) assay ^[1][2]

If any of these tests show an abnormal monoclonal result, the bone scintigraphy is rendered non-diagnostic. An abnormal free-light-chain result can be caused by kidney disease or other factors, and a monoclonal protein can coexist with ATTR without proving AL amyloidosis. However, any potentially monoclonal result requires specialist interpretation—often a hematology review and tissue typing—rather than assuming it confirms AL or ignoring it ^[1][5].

When a Biopsy is Required

If your test results are “discordant” (for example, you have a positive bone scan and a monoclonal protein), a tissue biopsy is needed to be sure which disease you have ^[5].

• Congo Red Staining: This is a special laboratory dye. Under a specific type of light, amyloid proteins stained with Congo red will glow a bright “apple-green” ^[6]. This confirms amyloid is present, but it doesn’t say which kind.
• Mass Spectrometry: This is a robust method for typing amyloid. It breaks down the protein to identify its exact molecular fingerprint, confirming whether it is TTR (for hATTR) or light chains (for AL) ^[5][7].

Doctors often start with a “surrogate site” biopsy, like an abdominal fat pad biopsy, because it is less invasive. However, fat-pad sensitivity varies substantially with disease type and burden. A negative fat pad result does not mean a patient should automatically pursue an invasive organ biopsy; rather, it should prompt specialist selection of another affected site ^[8][9].

Genetic Sequencing: Defining the Type

Once ATTR is confirmed, you must have TTR genetic sequencing. This is a blood or saliva test that looks at the TTR gene to see if it is “wild-type” or “hereditary” ^[10][11].

• Wild-type ATTR (ATTRwt): The gene is normal, but the protein becomes unstable due to aging.
• Hereditary ATTR (hATTR/ATTRv): The gene has a pathogenic variant you were born with.

A genetic result alone does not prove that a person has amyloid disease. Distinguishing a pathogenic or likely pathogenic variant from a “variant of uncertain significance” requires genetic counseling ^[11].

Your Diagnosis Completeness Checklist

Use this checklist to ensure your diagnostic workup is thorough:

• [ ] Monoclonal Screen: Were sIFE, uIFE, and sFLC all performed?
• [ ] Bone Scan Results: Was a SPECT or SPECT/CT used to confirm the tracer is in the heart muscle?
• [ ] Congo Red: If a biopsy was done, was this stain used to confirm amyloid?
• [ ] Mass Spectrometry: If amyloid was found or you have a monoclonal protein, was the tissue typed using a validated method?
• [ ] Genetic Test: Was your TTR gene sequenced to check for mutations? ^[1][2][11]