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PubMed This is a summary of 26 peer-reviewed journal articles Updated
Cardiology · Wild-Type Transthyretin Amyloidosis

Getting the Right Answer: Diagnosis and Avoiding Misdiagnosis

At a Glance

To accurately diagnose wild-type ATTR amyloidosis (wtATTR), doctors must use a combination of tests. A positive bone scan is not enough on its own. You must also undergo three specific blood and urine tests to rule out AL amyloidosis, followed by genetic testing to confirm it is the wild-type form.

Getting an accurate diagnosis of wild-type transthyretin amyloidosis (wtATTR) has changed significantly in recent years. While it used to require a surgical biopsy of the heart, most patients can now be diagnosed using a “non-invasive” pathway [1][2]. However, this pathway is only safe and accurate if very specific steps are followed to avoid a dangerous misdiagnosis [3][4].

The Non-Invasive Diagnostic “Gold Standard”

The current standard for diagnosing wtATTR-CM without a biopsy involves a specialized bone scan called scintigraphy (using tracers like 99mTc-PYP, DPD, or HMDP) [1][5].

Doctors use the Perugini Grading Scale to interpret these scans based on how much “glow” or tracer uptake is visible in the heart compared to the ribs [6]:

  • Grade 0: No uptake (rules out ATTR) [5].
  • Grade 1: Some uptake, but less than the ribs (inconclusive) [7].
  • Grade 2 or 3: Uptake equal to or greater than the ribs. This is considered a “positive” result for ATTR-CM, but only if blood and urine tests are clear [5][3].

A Critical Warning: Ruling Out “AL” Amyloidosis

A positive bone scan is not enough on its own to diagnose wtATTR [4]. There is another form of the disease called AL amyloidosis (light-chain amyloidosis), which is caused by a plasma cell disorder or bone marrow cancer [3][4].

Why this matters:

  • Misdiagnosis Risk: About 10–17% of patients with AL amyloidosis will actually show a “positive” (Grade 2 or 3) result on a bone scan [8].
  • Treatment Difference: wtATTR is treated with protein-stabilizing medications, while AL amyloidosis is a medical emergency that requires chemotherapy [9][10].
  • The Required “Trio”: To safely diagnose wtATTR, your doctor must run three specific tests to rule out AL [4]:
    1. sFLC (Serum Free Light Chain assay): A blood test.
    2. sIFE (Serum Immunofixation Electrophoresis): A blood test.
    3. uIFE (Urine Immunofixation Electrophoresis): A 24-hour or “spot” urine test.

If any of these three tests are abnormal, you cannot be diagnosed with wtATTR by a bone scan alone. You must proceed to a biopsy to be certain of the disease type [11][12].

The Mandatory Final Step: Genetic Testing

Even if your bone scan is positive (Grade 2/3) and your AL tests (the “Trio”) are totally clear, your diagnosis is still not complete.

These tests only confirm you have ATTR-CM (Transthyretin Amyloid Cardiomyopathy). To prove it is the age-related wild-type (wtATTR) and not the genetic, inherited form (hATTR), you must undergo a genetic test (often a simple blood or saliva sample) [13][14].

This genetic test will sequence the TTR gene. This is absolutely crucial because if a genetic mutation is found, it changes the treatment options available to you and means your biological children and family members may be at risk and should be offered screening [13][15].

When is a Heart Biopsy Necessary?

An endomyocardial biopsy (taking a small tissue sample from the heart) remains the absolute “gold standard” for diagnosis [16][17]. It is required if:

  • Your blood or urine tests (the “Trio” above) show signs of monoclonal proteins [18][19].
  • Your bone scan is inconclusive (Grade 1) [20].
  • Your doctors suspect you may have a rare combination of both types of amyloidosis [21].

Why an Echocardiogram is Not Enough

In the past, doctors relied heavily on an echocardiogram (heart ultrasound) to look for “wall thickness” [22]. While an ultrasound can show that the heart walls are thick, it cannot tell why they are thick. Many things, such as long-term high blood pressure, can cause thick heart walls [23][24].

Relying only on wall thickness often leads to years of delay. Modern diagnosis requires looking for specific patterns (like apical sparing on a strain-imaging echocardiogram) and confirming with the scintigraphy, blood test pathway, and genetic testing described above [25][26].

Previous: Symptoms and Warning Signs | Next: Understanding Your Stage and Outlook

Common questions in this guide

Can an echocardiogram diagnose wild-type ATTR amyloidosis?
No. While an echocardiogram can show that your heart walls are abnormally thick, it cannot determine the underlying cause. A proper diagnosis requires specialized blood and urine tests, a bone scan, and genetic testing to confirm amyloidosis.
What does a Perugini Grade of 2 or 3 mean on my bone scan?
The Perugini Grading Scale measures how much radioactive tracer 'glows' in your heart during a specialized bone scan. A Grade 2 or 3 suggests ATTR amyloidosis, but this result is only considered positive if specific blood and urine tests also come back completely clear.
Why do I need blood and urine tests if my bone scan already shows amyloidosis?
A positive bone scan can also occur with a more dangerous cancer-related form of the disease called AL amyloidosis. Doctors must run three specific tests (sFLC, sIFE, and uIFE) to rule out AL amyloidosis before they can safely confirm you have the ATTR type.
Why is genetic testing required for a wild-type ATTR diagnosis?
Even if tests confirm you have ATTR amyloidosis in your heart, genetic testing is the only way to prove you have the age-related 'wild-type' form and not the inherited form. Finding a genetic mutation changes your treatment options and indicates your family members may need screening.
When is a heart biopsy needed to diagnose amyloidosis?
A biopsy is required if your blood or urine tests show signs of abnormal proteins, if your bone scan results are inconclusive, or if doctors suspect you might have a combination of different types of amyloidosis.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Have all three screening tests (sFLC, sIFE, and uIFE) been performed to rule out AL amyloidosis?
  2. 2.What was my 'Perugini Grade' on the bone scintigraphy scan, and did you use a SPECT/CT to confirm the tracer is actually in the heart muscle?
  3. 3.Has my genetic testing (TTR gene sequencing) been ordered to confirm this is definitively the 'wild-type' form?
  4. 4.If my monoclonal protein tests were positive or inconclusive, when will we schedule an endomyocardial biopsy?
  5. 5.Does my echocardiogram show 'apical sparing,' and how does that fit into my overall diagnosis?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

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This page explains the diagnostic pathway for wtATTR amyloidosis for educational purposes only. Always consult your cardiologist or amyloidosis specialist to interpret your specific scan results and blood tests.

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