Highlighting Misdiagnosis: Technetium-Pyrophosphate Cardiac Scintigraphy Shows Limits of Transthyretin Amyloid Imaging

The majority of cardiac amyloidosis (CA) cases are attributed to immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis. The latest advances in noninvasive diagnostic technology and techniques have precipitated a paradigm shift through cardiac imaging improvements that have enabled a reduction in the need for tissue diagnosis for ATTR-CA. Clinicians need to be aware that other amyloid proteins may potentially infiltrate the myocardium and may cause misdiagnosis based on uptake of myocardial pyrophosphate (PYP) radiotracer during 99mtechnetium (99mTc)-PYP cardiac scintigraphy.

A case study presented by Korosh Sharain, MD, of the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, noted that caution is warranted when using myocardial PYP radiotracer to make diagnoses.

A 78-year-old male presented to the Mayo Clinic for a second opinion, with early satiety, reduced appetite, exercise intolerance, and unintentional weight loss.

Pertinent medical history included a history of paroxysmal atrial fibrillation, idiopathic peripheral neuropathy, spinal stenosis, and renal insufficiency (glomerular filtration rate 35 mL/min/body surface area).

A left ventricular ejection fraction of 47% was revealed through echocardiogram that also showed an increased septal wall thickness (15 mm), diastolic dysfunction, severely elevated filling pressures (E/e’20) and reduced global longitudinal strain of –13% with a pattern of apical sparing. To differentiate between normal and reduced left ventricular systolic function, N-terminal-pro hormone B-type natriuretic peptide was assessed as 17,000 pg/mL.

Biopsy of the small bowel revealed congophilic deposits. Apple-green birefringence was seen under polarized light, that is generally regarded as a specific sign for amyloid material.1

At this point, the amyloid protein was not further subtyped. The serum free light chains were assessed as normal (κ 2.1, λ 2.1 mg/dL) with no monoclonal protein present. Bone marrow biopsy was considered unremarkable.

However, results of the myocardium 99mTc-PYP cardiac scintigraphy revealed an uptake Perugini grade 3 level at 1 and 3 hours. Therefore, a presumptive diagnosis of ATTR-CA was made, and tafamidis was prescribed.

Further evaluation was conducted. From a prior small bowel biopsy, the patient’s amyloid protein was analyzed, revealing apolipoprotein A-IV (apoA-IV). Amyloid was also shown through a nerve biopsy from the epidermal region. Based on these findings, the patient was diagnosed with apoA-IV amyloidosis with cardiac, renal, and gastrointestinal involvement. The decision was made to discontinue treatment with tafamidis.

This case study underscores that in the absence of monoclonal protein, while the specificity and positive predictive value of Perugini grade 2-3 uptake on PYP for ATTR-CA has been reported to approach 100%, other amyloid subtypes, including apoA-IV, can also cause myocardial PYP radiotracer uptake. Clinicians should be acutely aware that despite the absence of elevated light chains, increased myocardial PYP uptake does not always rule in ATTR-CA.

As demonstrated in this case, on tissue biopsy, if amyloid protein is identified with suspicion of amyloidosis, mass spectrometry must be used to appropriately and accurately subtype diagnosis. The therapeutic ramifications are significant. While treatment for apoA-IV CA is supportive, and there are currently no targeted therapies available, treatment with transthyretin stabilizers indicated for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis was inappropriate based on the revised diagnosis.

Source: Sharain K, Jain CC, Davies DR, et al. 99mTechnetium-pyrophosphate cardiac scintigraphy: not all that glitters is transthyretin amyloid. Presented at: American College of Cardiology 69th Annual Scientific Session & Expo. March 20-30, 2020. Moderated Poster Session 1010.

Reference

  1. El-Meanawy A, Mueller C, Iczkowski KA. Improving sensitivity of amyloid detection by Congo red stain by using polarizing microscope and avoiding pitfalls. Diagn Pathol. 2019;1:57.

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