Imaging Systemic Diseases
Brett W. Sperry
Wael A. Jaber
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1. A 69-year-old male presents with dyspnea on exertion. His medical history is notable for paroxysmal atrial fibrillation, hypertension, and hyper-lipidemia. On exam, he has jugular venous distention and mild peripheral edema. His electrocardiogram shows normal sinus rhythm with normal voltage. Echocardiogram demonstrates severely increased wall thickness of both ventricles, biatrial enlargement, a trace pericardial effusion, and a restrictive filling pattern. The clinical concern is for cardiac amyloidosis. What is the next best test?
A. No further testing. The diagnosis is secure.
B. Serum free light chains to assess for light chain amyloidosis (AL).
C. SPECT study for transthyretin amyloidosis (ATTR).
D. Cardiac MRI for transthyretin amyloidosis (ATTR).
1. ANSWER: B. Amyloidosis is characterized by the deposition of misfolded proteins that aggregate into β-sheet fibrils. In the heart, amyloidosis can result from a plasma cell dyscrasia related to immunoglobulin light chains (AL) or from transthyretin (ATTR), which is further subdivided into wild-type and mutant forms. Wild-type ATTR, also referred to as senile systemic amyloidosis, typically affects white males with a median age of 70 and is often accompanied by bilateral carpal tunnel syndrome. In patients with mutant ATTR, heart failure typically develops at a similar age to wild-type ATTR. Even though the end result of cardiac amyloid deposits is a restrictive diastolic profile and heart failure, AL and ATTR are distinctly different in their initial presentation, diagnosis, and treatment. Therefore, in a patient with suspected cardiac amyloid, the investigation should begin with biochemical testing to identify a monoclonal protein in the blood or urine.
Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005;112:2047-2060.
Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Contemporary reviews in cardiovascular medicine. Circulation. 2012;126:1286-1300.
2. The above patient is eventually referred for SPECT testing. Which radiotracers can be used to diagnose cardiac amyloidosis?
D. 99mTc-phosphate derivatives
2. ANSWER: D. Developed initially for bone imaging, 99mTc-phosphate derivatives also accumulate in the heart after an acute myocardial infarction. The radiotracer typically accumulates several days after an infarct, possibly related to calcium overloading of the mitochondria. Subsequently, 99mTc-DPD (technetium-3,3-diphosphono-1,2-propanodicarboxylic acid) and 99mTc-PYP (technetium pyrophosphate) have both been shown to accumulate in patients with cardiac amyloidosis. More recently, 99mTc-HDP (technetium-hydroxymethylene diphosphonate) has been similarly detected in patients with ATTR. In Europe, 99mTc-DPD is the predominant agent, but is not approved by the Federal Drug Administration. 99mTc-PYP is therefore most often used in the United States, and unfortunately, there are no studies that directly compare 99mTc-phosphate derivatives.
Glaudemans AWJM, van Rheenen RWJ, van den Berg MP, et al. Bone scintigraphy with 99mtech-netium-hydroxymethylene diphosphonate allows early diagnosis of cardiac involvement in patients with transthyretin-derived systemic amyloidosis. Amyloid. 2013;21:35-44.
Sobol SM, Brown JM, Bunker SR, et al. Noninvasive diagnosis of cardiac amyloidosis by technetium-99m-pyrophosphate myocardial scintigraphy. Am Heart J. 1982;103(4 Pt 1):563-565.
3. What is the primary reason for the early poor diagnostic performance of nuclear studies for cardiac amyloidosis?
A. 99mTc-phosphate derivatives were not available.
B. Diagnostic testing was performed only in patients with abnormal echocardiograms.
C. Early nuclear testing predated the era of routine typing of AL versus ATTR amyloidosis.
D. None of the above. Nuclear studies have always had an excellent performance for the diagnosis of cardiac amyloidosis.
3. ANSWER: C. Early studies using 99mTc-phosphate derivatives to diagnose cardiac amyloidosis were underwhelming, primarily because they were performed in an era before routine typing of AL versus ATTR amyloid. The predilection of 99mTc-DPD for ATTR was subsequently demonstrated, though the underlying mechanism remains poorly understood. Presumably, 99mTc-phosphate derivatives have a calcium-binding affinity for amyloid fibrils. Given the indolent course of ATTR compared to AL, the slower accumulation of fibrils in ATTR may be associated with increased calcium deposition.
As discussed, 99mTc-phosphate derivative have been available for decades (choice A). In addition, diagnostic testing for cardiac amyloidosis is usually performed in patients with abnormal echocardiograms (choice B), and it is unclear if the diagnostic performance would be as good in patients with normal echocardiograms who are presumably at an earlier stage of disease.
Falk RH, Lee VW, Rubinow A, et al. Sensitivity of technetium-99m-pyrophosphate scintigraphy in diagnosing cardiac amyloidosis. Am J Cardiol. 1983;51(5):826-830.
Kula RW, Engel WK, Line BR. Scanning for soft-tissue amyloid. Lancet. 1977;1(8002):92-93.
4. The above patient’s whole-body planar imaging with 99mTc-PYP is shown. Which of the following is the most correct interpretation? (Fig. 7.1)
A. Moderate cardiac uptake, approximately equal to bone, consistent with ATTR amyloidosis
B. No cardiac uptake, consistent with ATTR amyloidosis
C. Metastatic prostate cancer
D. Diffuse soft tissue uptake, consistent with ATTR amyloidosis
E. Normal study
4. ANSWER: A. For an assessment of ATTR amyloidosis, whole-body planar imaging is often initially performed, followed by chest SPECT if myocardial uptake is noted. In this patient, planar imaging with 99mTc-PYP demonstrates moderate cardiac uptake, approximately equal to bone, consistent with ATTR amyloidosis. For visual scoring, cardiac and bone uptake are compared as follows:
0 = absent cardiac uptake and intense bone uptake
1= mild cardiac uptake, less than bone uptake
2 = moderated cardiac uptake, equal to bone uptake
3 = high cardiac uptake, greater than bone uptake
In general, visual scoring has a high positive and negative predictive value for ATTR in patients with suspected cardiac amyloidosis. Interestingly, the relative decrease in bone uptake on planar imaging in ATTR may not be entirely explained by competitive reduction in bone, but may also be attributed to extensive overlying soft tissue uptake, though this finding is typically better appreciated on SPECT-CT imaging.
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 Cardiovas Imaging. 2014;15(11):1289-1298.
Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol. 2005;46:1076-1084.
5. For this patient, a quantitative assessment is also performed by comparing counts over the heart to the contralateral chest (Fig. 7.2). The ratio of counts over the heart compared to the contralateral chest is 1.8. What is the diagnostic utility of this ratio?
A. A ratio < 1.5 is highly sensitive and specific for distinguishing ATTR from AL cardiac amyloid.
B. A ratio > 1.5 is highly sensitive and specific for distinguishing ATTR from AL cardiac amyloid.
C. A ratio > 1 has a high negative predictive value for AL cardiac amyloid.
D. A ratio > 1 has a high positive predictive value for AL cardiac amyloid.
5. ANSWER: B. Compatible with the hypothesis that AL fibrils may have less calcium, about a third to one-half of AL patients will have a positive 99mTc-phosphate scan, typically with a milder degree of tracer uptake. Given this overlap, in certain situations, a quantitative evaluation of uptake may improve the diagnostic yield for ATTR versus AL. In fact, by comparing counts over the heart to the contralateral chest, a ratio of >1.5 had nearly perfect sensitivity and specificity in distinguishing ATTR from AL. More recently, this ratio has also been shown to have prognosis significance.
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