European Nuclear Medicine Guide
[99mTc]Tc-hydroxymethylene-diphosphonate (HMDP)
[99mTc]Tc-2,3-dicarboxypropane-1,1-diphosphonate (DPD)
[99mTc]Tc-pyrophosphate (PYP)
The radiolabelled bisphosphonates HMDP/HDP/DPD and PYP are usually used for bone imaging and are incorporated into the surface of hydroxyapatite crystals in proportion with local bone vascularization and osteoblastic activity. After three/four hours after injection, approximately 60% of the injected amount will be fixed to the skeleton, the unbound fraction (34%) is excreted in the urine, and only 6% remains in circulation.
Cardiac uptake of these tracers in cardiac amyloidosis is well documented in the literature. The positivity of their uptake in the heart appears to be linked to the ability of certain types of amyloids to promote calcium deposition, which seems to serve as the substrate for tracer uptake. However, the exact mechanism behind cardiac uptake remains unknown.
Several hypotheses have been proposed to explain this unusual uptake in an extra-osseous site, such as in the heart: it could be due to higher calcium content or the type of mutation and the result of the proteolysis of myocardial fibres (full-length only vs full-length plus C-terminal ATTR fragments, which could justify the preferential detection in ATTR form – amyloid transthyretin), which could determine uptake of bone radiotracers by amyloid fibrils [32,33].
Recent studies highlight the value of DPD, HMDP, and PYP in diagnosing cardiac ATTR and differentiating it from AL amyloidosis [34], in most cases avoiding the need for an endomyocardial biopsy.
Furthermore, [99mTc]Tc-DPD/HMDP allows the possibility of detecting extra-cardiac (skeletal muscle and lung) amyloid infiltration [35,36].
Patients with suspicion of ATTR-related cardiac amyloidosis based on the diagnosis or clinical suspicion of systemic amyloidosis or on the echocardiographic test of restrictive cardiomyopathy and/or aspects suggestive of infiltrative pathology.
Pregnancy is a relative contraindication. It is not recommended to interrupt breastfeeding [37].
Cardiac involvement has major clinical and prognostic implications in amyloidosis. Acquired monoclonal immunoglobulin light-chain (AL) and transthyretin (TTR)-
related (hereditary form – ATTRh and wild-type form – ATTRwt) disease are the most frequent causes of cardiac amyloidosis [38].
Diagnosis of amyloidosis and differentiation between subtypes is important for prognosis, therapy, and genetic counselling.
Differential diagnosis between TTR-related and AL amyloidosis is often complex and challenging.
In the past, the diagnosis of cardiac amyloidosis required endomyocardial biopsy and typing of the amyloid fibrils in any case. This practice has already changed; it is now rarely used since a non-invasive diagnostic imaging method using bone tracers or 99mTc-pyrophosphate (PYP) [34,39-41] has shown in several studies to have high specificity for the diagnosis of TTR cardiac amyloidosis.
740 MBq (15 to 25 mCi) of 99mTc-labelled diphosphonate or PYP intravenously, with a total-body effective dose for the suggested activities estimated to be in the range of 3.3–4.4 mSv.
Caveat:
It should be noted that the “Effective Dose” quantity does not necessarily reflect the radiation risk associated with this nuclear medicine examination. If the risk associated with the procedure is to be assessed, it is mandatory to adjust the radiation-associated risk factors at least according to the gender and age distribution of the institution’s patient population.
The uptake of the bone tracer in the cardiac region must be localized in the myocardial wall and not referable to persistence of intravascular blood pool. Criteria for assessing the intensity of cardiac uptake have been proposed, using the bone tracer’s (ribs) uptake as a reference.
Perugini score [39] has been assessed and used for semi-quantitative visual scoring of cardiac retention:
score 0, absent cardiac uptake and normal bone uptake
score 1, mild cardiac uptake, lower than bone uptake
score 2, moderate cardiac uptake, equal to or above bone uptake
score 3, strong cardiac uptake, above bone activity and globally reduced bone uptake.
Based on previously published results, visual scores of greater than or equal to 2 on planar [39,40] or SPECT images at 3 hours [10] are classified as strongly suggestive of TTR cardiac amyloidosis after exclusion of AL with serum and urine immunofixation and serum-free light chain assay, while a score of 1 is considered doubtful for TTR cardiac amyloidosis and a score of 0 unlikely for cardiac TTR amyloidosis.
While grades 2 or 3 are strongly suggestive of ATTR amyloidosis, any degree (Perugini score from 0 to 3) of 99mTc-DPD or HMDP or PYP myocardial uptake can occasionally be seen in AL amyloidosis. Indeed, substantial cardiac uptake has been reported in more than 20% of patients with AL cardiac amyloidosis [34].
Therefore, DPD, HMDP and PYP should always be interpreted in conjunction with the results of serum and urine immunofixation and serum-free light chain assay studies to exclude AL amyloidosis.
An overall interpretation of the findings into categories for ATTR cardiac amyloidosis includes:
A semi-quantitative visual score of 0=Not suggestive of ATTR amyloidosis.
In these cases, AL amyloid should be excluded. If AL amyloid has been excluded and suspicion persists, consider CMR followed by cardiac or extracardiac biopsy, as bone scintigraphy could be negative in some ATTRh mutations (tracer uptake depends on TTR fibril composition) in rare subtypes of cardiac amyloidosis or early stages of the disease.
A visual score of 1= Result equivocal. In the presence of low-grade uptake on a 99mTc-PYP/DPD/HMDP scan a histological diagnosis is still required, even if AL amyloidosis has been excluded.
A visual score of at least 2 (2 or 3) = Strongly suggestive of ATTR amyloidosis. In these cases, if no evidence of monoclonal proteins is found in blood or urine (to rule out plasma cell dyscrasia all 3 of these tests must be performed: serum and urine immunofixation and serum-free light chain assay), a diagnosis of ATTR cardiac amyloidosis can be made without a biopsy, with a specificity and positive predictive value of over 98% [34].
No specific test preparation is required.
A dual-head camera equipped with low-energy, high-resolution collimators is recommended. If 99mTc-labelled diphosphonate ia used, whole-body scans are performed three hours after injection [39].
If PYP is used, a series of planar images of anterior thorax (and optionally lateral and left anterior oblique planar views) with the heart centred in the field of view have to be obtained at 1 hour post-injection (over 8 minutes duration) to calculate a semi-quantitative analysis of heart retention by drawing a region of interest (ROI) over the heart and on the contralateral chest. The fraction of mean counts in the heart ROI to contralateral chest ROI is calculated as the heart-to-contralateral (H/CL) ratio [59].
A semi-quantitative visual scoring of cardiac retention must be undertaken in the late images at three hours after injection.
Planar whole-body late imaging is useful for visual interpretation, especially when negative, and when positive for quantification of the degree of myocardial uptake by visual comparison to bone uptake, using both 99mTc-labelled diphosphonate and PYP.
Identifying the uptake of 99mTc-DPD or 99mTc-HMDP in the shoulder and hip girdles may be helpful as a striking finding of systemic ATTR amyloidosis [41] and to identify a low bone soft-tissue uptake in the extremities, which could be a sign of systemic ATTR amyloidosis.
Nevertheless, it is important to remember that no specific scintigraphic pattern alone can diagnose the type of cardiac amyloidosis.
Single-photon emission computed tomography (SPECT) imaging should be performed if there is cardiac uptake of these tracers on planar images. Acquisition parameters for the SPECT imaging are low-energy, high-resolution collimators, matrix 64×64 with 1.46 zoom. The Butterworth filter is used with a cut-off of 0.50 and order of 5.00.
SPECT imaging is necessary in all cases with myocardial uptake planar scintigraphy to:
Avoid overlap of bone uptake
Distinguish blood-pool activity from myocardial activity [40]
Assess the regional distribution of myocardial 99mTc-DPD or 99mTc-HMDP uptake
Identify 99mTc-DPD, PYP or HMDP uptake in the interventricular septum (commonly involved in amyloidosis)
Quantify the degree of myocardial uptake by comparison to bone uptake or by calculating standardized uptake values with appropriate software.