Keywords
AL - bone scintigraphy - cardiac amyloidosis - transthyretin ATTR
Introduction
Cardiac amyloidosis is a rare cause of rapidly progressive, restrictive cardiomyopathy
and congestive heart failure.[1] It is mostly difficult to diagnose and almost always associated with poor prognosis.
There are two main subtypes of cardiac amyloidosis: transthyretin-related cardiac
amyloidosis (ATTR) and cardiac light-chain (AL) amyloidosis.[2],[3] Differentiating the two is important for both prognosis and management, and this
was only possible through invasive biopsy procedures. Recently, however, a few published
cases have shown that bone scintigraphy is able to reliably distinguish between the
two.[4] In this case, we report findings on the bone scan that supported the diagnosis of
ATTR cardiac amyloidosis.
Case Report
A 76-year-old male who had clinical suspicion for cardiac amyloidosis was referred
to our department for bone scintigraphy to try and differentiate between the two main
clinical subtypes. Planar whole-body images were performed in the anterior and posterior
projections 4 h after intravenous administration of 718 MBq (19.4 mCi) of 99mtechnetium (99mTc) methylene diphosphonate (99mTc MDP).
The bone scan images [Figure 1] demonstrated diffusely increased tracer uptake in the heart and attenuated tracer
uptake throughout the bones. Increased tracer uptake was also seen in the soft tissues
of deltoid, gluteal, and abdominal walls. No other site of abnormal tracer concentration
was seen.
Figure 1 (a and b) shows the planar whole-body bone scan in the anterior projection (a) and
a zoomed image (b) demonstrating moderately intense cardiac uptake with soft tissue
uptake involving the shoulders, chest, abdominal walls, and hips. Skeletal tracer
uptake appears mildly suppressed
[Figure 1a] and [Figure 1b] shows the planar whole-body bone scan in the anterior projection [Figure 1a] and a zoomed image [Figure 1b] demonstrating moderately intense cardiac uptake with soft tissue uptake involving
the shoulders, chest, abdominal walls, and hips. Skeletal tracer uptake appears mildly
suppressed.
Discussion
Cardiac amyloidosis is a rare cause of rapidly progressive, restrictive cardiomyopathy
and congestive heart failure.[1] It is mostly difficult to diagnose and almost always associated with poor prognosis.
There are two main subtypes of cardiac amyloidosis: transthyretin-related cardiac
amyloidosis (ATTR) and cardiac light-chain (AL) amyloidosis.[2],[3] ATTR amyloidosis may be acquired and hereditary that is either associated with variants
in the transthyretin gene or associated with wild-type transthyretin (also called
senile systemic amyloidosis).
Cardiac AL amyloidosis is more rapidly progressive than the ATTR type where the former
is associated with >50% mortality within 6 months after the diagnosis while the ATTR
subtype has a favorable prognosis of 98% 2-year survival.[5],[6] The treatment options for the two subtypes are also different with AL subtype likely
to benefit from cytotoxic chemotherapy,[7] while more novel therapies are used for ATTR including inotersen, which was recently
approved by the FDA for the treatment of hereditary ATTR amyloidosis polyneuropathy.[8] Differentiating the type of cardiac amyloidosis (ATTR or AL) is thus vital in guiding
patient management.
Because cardiac amyloidosis has nonspecific clinical symptoms as well as nonspecific
electrocardiogram and echocardiographic findings,[9] it remains a diagnostic challenge and is often underdiagnosed. The gold standard
for the diagnosis of amyloidosis is through biopsy of a clinically affected organ,
with Congo red histology demonstrating green birefringence. However, when amyloidosis
is clinically suspected, biopsy of the salivary glands, rectum, or subcutaneous fat
usually yields the diagnosis in 60%–80% of patients with AL amyloidosis.[10] Unfortunately, a much lower yield is observed in patients with ATTR amyloidosis
that requires for endomyocardial biopsy (EMB) to confirm the diagnosis.[11] EMB has its own risks including myocardial perforation, tamponade, and fatality.
It also requires expertise and this can introduce diagnostic delays.[12]
Cardiac magnetic resonance imaging (CMR) is a more discriminating method for cardiac
amyloidosis but does not differentiate types of amyloidosis and cannot be performed
in the presence of implanted devices.[13] All of these factors contribute to under diagnosis, which is crucial given the poor
prognosis of AL and ATTR cardiac amyloidosis and the increasing availability of novel
therapies for both subtypes.[14],[15]
Radionuclide bone scans with 99mTc-labeled bisphosphonates have been anecdotally reported to localize cardiac amyloid
deposits, although the molecular basis for this remains unknown.[16] The cardiac uptake on the planar images is visually scored using the Perugini grading
system.[17] Briefly, it is categorized as follows: Grade 0 – no cardiac uptake and normal bone
uptake; Grade 1 – cardiac uptake which is less intense than the bone signal; Grade
2 – cardiac uptake with intensity similar or greater than bone signal; and Grade 3
– cardiac uptake with much attenuated or absent bone signal. An uptake of Grade 2
and above is considered significant.[17] A systematic evaluation of bone scans of 857 patients with histologically proven
amyloid revealed that cardiac ATTR amyloidosis can be reliably diagnosed in the absence
of histology provided that all of the following criteria are met: heart failure with
an echocardiogram or CMR that is consistent with or suggestive of amyloidosis, Grade
2 or 3 cardiac uptake on a radionuclide scan with 99mTc-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD),99mTc-labeled pyrophosphate (99mTc-PYP), or 99mTc-labeled hydroxymethylene diphosphonate, and absence of a detectable monoclonal
protein.[4] More recently, studies[18],[19] have shown that 99mTc-labeled MDP can also preferentially bind to ATTR as similar to 99mTc PYP and 99mTc DPD.
Given that 99mTc-MDP is more readily available than DPD or PYP and already in use for routine bone
scans, it would provide a more feasible option in this diagnostic algorithm. Unfortunately,
cardiac localization of radiotracers also occurs in a small proportion of patients
with AL amyloidosis, and although it is usually low grade, it can confound distinguishing
between cardiac AL and ATTR subtypes.[20] A recent study by Hutt et al.[21] that had a cohort of 321 patients with suspected cardiac amyloidosis that used 99mTc DPD as the radiotracer demonstrated that in addition to the intense cardiac uptake
in patients with ATTR, these patients also demonstrated extensive soft tissue uptake
in the deltoid, abdominal wall, and gluteal muscles that was not seen in the AL amyloidosis
patients. They concluded that the soft tissue uptake in those sites is specific to
ATTR. Our patient demonstrated intense cardiac uptake in addition to soft tissue uptake
in the deltoid, gluteal, and abdominal wall muscles that is relatively specific to
ATTR amyloidosis.
Conclusion
Several studies[4],[20] have concluded that cardiac transthyretin amyloidosis can be reliably diagnosed
in the absence of histology provided that all of the following criteria are met: heart
failure with an echocardiogram or CMR that is consistent with or suggestive of amyloidosis,
intense cardiac uptake on a 99mTc labeled bisphosphonate bone scan, no detectable monoclonal protein in serum with
normal serum-free light chains. AL amyloidosis is unlikely in any patient satisfying
all the above criteria. Invasive EMB can therefore be avoided in elderly patients
who satisfy these criteria. In this regard,99mTc-labeled bisphosphonate bone scans serve an integral role in the workup of patients
with suspected cardiac amyloidosis. Histological confirmation and typing of amyloid
should be sought in all cases of suspected cardiac amyloidosis in whom these criteria
are not met.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
