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Canepa et al. Vessel Plus 2022;6:30 https://dx.doi.org/10.20517/2574-1209.2021.106 Page 7 of 13

microcalcifications within the amyloid tissue. Nonetheless, it is important to underline that a proper AL-CA
workup should always precede the execution of bone scintigraphy in patients with suspected CA. This
workup must screen for the presence of a monoclonal protein and should always include serum free light-
chain levels and serum and urine protein electrophoresis with immunofixation. The combination of normal
serum protein electrophoresis with immunofixation, normal urine protein electrophoresis with
immunofixation, and a normal serum free light-chain ratio nearly always rules out systemic AL
amyloidosis . Unfortunately, the prescription of these tests is frequently incomplete. A recent work from a
[3]
tertiary institution found that, among 550 patients screened for suspected CA, 174 (32%) did not undergo
both serum immunofixation and serum free light-chain analysis tests, and only 219 (40%) did undergo
[61]
complete testing . It is important to remark that, regardless of whether the light chain is produced in large
quantities or if the plasma cell clone itself is particularly aggressive, as long as it produces a monoclonal light
chain, it is capable of causing AL amyloidosis . This is why even an isolated alteration in the free light-
[3]
chain ratio should warrant an extended hematological workup in patients with suspected CA. If any
monoclonal protein is present, a biopsy of the affected organ, instead of bone scintigraphy, should be
pursued to confirm or rule out a diagnosis of AL amyloidosis .
[59]
Issues with visual grading and need to systematically perform single photon emission computed
tomography imaging
Grading systems for the degree of cardiac uptake on planar imaging at bone scintigraphy are both
qualitative and semiquantitative. The qualitative score relates cardiac uptake as compared with rib bone
uptake: grade 0, no uptake; grade 1, mild uptake, less than ribs; grade 2, moderate uptake, equal to ribs;
grade 3, severe uptake, greater than ribs . This visual grading scale has been validated for three bone
[64]
tracers [99mTc-pyrophosphate (99mTc-PYP), 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid
(99mTc-DPD), and 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP)], and a grade 2 or 3 cardiac
uptake, in the absence of a plasma cell dyscrasia, is today considered diagnostic of ATTR-CA without the
[2,7]
need of performing a confirmatory endomyocardial biopsy . Although visual grading appears adequate for
diagnosis in properly selected patients, it has proved insufficient for the differential diagnosis with AL-CA
in cases with an associated monoclonal gammopathy and for risk stratification in cases of confirmed
[65]
[7]
ATTR-CA. Similar limitations apply to semiquantitative scores, which include the heart/contralateral
thorax and the heart/whole body ratio. Although these parameters have been shown to provide some
additional diagnostic and prognostic value [65-67] , they are still based on planar imaging and rely on
extracardiac sites as uptake reference. This can be a problem in the presence of significant abnormal
extracardiac uptake (reported in up to 60% of patients with ATTR-CA [65,68] ) and is one of the reasons the
systematic use of single photon emission computed tomography (SPECT) is recommended [60,69] . SPECT
acquisitions also have the advantage of better differentiating myocardial activity from blood pooling, which
(beyond myocardial uptake in AL-CA) is the primary cause of false-positive results with planar images .
[2]
Two recent studies that together included about 1000 patients noted that nearly two-thirds of grade 2 scans
were either entirely negative or equivocal with blood pooling when evaluated by SPECT [61,70] . The
consequences of these errors might be detrimental, and cases have recently been presented of patients
[71]
inappropriately prescribed with tafamidis after false-positive bone scans .

False-negative results may also occur , for example in patients with a previous myocardial infarction , or
[72]
[2]
when myocardial infiltration is minimal, as in early stage disease, thus causing uptake to be below the
current diagnostic detection threshold. The role of SPECT imaging in these contexts appears fundamental,
but it has not been systematically investigated yet. Finally, we and others also noted that patients with
typical cardiac involvement by echocardiography but certain pathogenic TTR mutations, including
Phe64Leu and Val30Met, may have negative or mildly positive cardiac scintigraphy results [2,73] . In the case of
great clinical suspicion of ATTRv-CA but negative bone scintigraphy results, the use of additional testing