TTR vs AL Cardiac Amyloidosis: Don't Rely on Imaging Alone

Omar Abou Ezzeddine, MD, CM, MS; Gayatri Acharya, MD; Martha Grogan, MD

Disclosures

June 05, 2019

Editorial Collaboration

Medscape &

This transcript has been edited for clarity.

Gayatri Acharya, MD: Greetings. I'm Dr Gayatri Acharya, cardiology fellow at Mayo Clinic. During today's roundtable, we'll be discussing cardiac amyloidosis (AL). I am joined by my colleagues, Dr Martha Grogan and Dr Omar Abou-Ezzeddine, who both specialize in this area. Welcome.

Omar Abou-Ezzeddine MD, CM, MS: Thank you.

Acharya: Let's start by talking about AL in general. What clinical characteristics make you suspicious for this when you see a patient?

Cardiac AL—General Characteristics

Martha Grogan, MD: Many times in cardiology, we'll come to the suspicion of AL based on imaging, unexplained heart failure, or unexplained atrial arrhythmias. I would say for many cardiologists, imaging [findings], either from an echo or an MRI, are going to make them suspicious of AL.

Acharya: In addition to imaging findings, what clinical characteristics and physical exam findings would make you concerned?

Abou-Ezzeddine: Physical exam findings are the classic heart failure exam findings, so, typically right-sided symptoms such as jugular venous pressure elevation, lower-extremity edema, abdominal distension, ascites, and hepatomegaly. You can also have findings of pulmonary hypertension—an accentuated second heart sound, for instance, or a right-sided S4. But you obviously also can have left-sided symptoms with elevated left-sided filling pressure, such as pulmonary edema, etc. A physical examination finding that you really need to look for and that we cardiologists sometimes miss is macroglossia.

On history, typically we ask questions that are not classic cardiac clinical questions, such as whether they have a history of carpal tunnel syndrome or spinal stenosis (in our more elderly patients), because these have also been associated with a diagnosis of cardiac AL.

On ECG you could find low voltage; however, that is only present in around 30% of patients or so, more so in hereditary transthyretin (TTR) cardiac AL. You can also have left ventricular hypertrophy signs on the ECG, atrial arrhythmias, or conduction system disease as well. On echocardiography, a classic finding is a restrictive cardiomyopathy-appearing morphology with increased wall thickness (more so in TTR compared with AL, but it can occur in both), biatrial enlargement, diastolic dysfunction, and restricted filling. Those are the main findings that cardiologists may come across clinically in general.

Amyloid Diagnosis: AL vs TTR

Acharya: That raises your initial suspicion of amyloid. Once we reach the thought of amyloid, how do we decide between AL and TTR? Are there differences we can tell?

Grogan: That is a great question because, as I mentioned, many times cardiologists kind of come into the diagnosis because of an imaging abnormality, although all of the things that Dr Abou-Ezzeddine just mentioned are really important clinically. Having said that, once we have the constellation of imaging findings and some clinical findings, we cannot guess at the type of amyloid.

When you look at echo and MRI, it's very dangerous to try to say, "This one is AL, this one is TTR." The TTR patients tend to have even thicker hearts and sometimes are more well compensated, but we really have to get to the specific diagnosis. The key thing for cardiologists to remember is if you're making a diagnosis of AL amyloid, you always have to have tissue. You have to have a tissue biopsy either from the heart or from another organ or the fat, and then we recommend typing with mass spectrometry because that is the most accurate. Not all pathologists are used to looking for amyloid or staining properly, so if you get a negative result, continue to pursue it; send the pathology for review. For AL you always have to have tissue. For TTR amyloid, as Omar is going to tell us, pyrophosphate (PYP) scan can be used if AL amyloid has been excluded when the screen tests for AL are negative.

PYP Scan

Acharya: At what point do you consider the PYP scan?

Abou-Ezzeddine: It depends on the facility and your resources, but here at Mayo we typically get that early on as a diagnostic test when you're working up a patient for amyloid. But as a caution, you really have to draw blood and check for monoclonal protein (free light chains) to make sure that you are not missing that diagnosis; you cannot interpret a PYP scan without having ruled out monoclonal disease.

Grogan: A lot of times people say, "Do I really have to get this test or that test?" Just to make it clear, it's not that hard. [You need] serum free light chains (which are universally available and inexpensive), serum protein electrophoresis with immunofixation, and urine with immunofixation. Do those three things, learn what they are, and get them down. We're seeing that TTR amyloid is really not rare—especially wild-type TTR amyloid—but up to 40% of those patients will have monoclonal gammopathy because that is common as people get older. It is really important for cardiologists to learn these tests. Quit bugging me about whether you need to get them. Yes, you need to get them. Then if the tests are negative, you can use the PYP scan alone. I often use a PYP scan early on because if it's negative, it supports even more if everything else is pointing to AL. Occasionally AL patients can deteriorate very quickly, so we want to get to the diagnosis as fast as possible.

Acharya: Can you explain for us what a PYP scan is and what the strengths and limitations of that test are?

Abou-Ezzeddine: PYP is a bone tracer we use in North America that is US Food and Drug Administration (FDA) approved for bone scans. Actually, it was previously described in the 1980s as a potential screening tool for cardiac AL because patients with amyloid were noted to have myocardial uptake with this bone tracer. However, that technology was not pursued because it was noted that some patients with amyloid didn't have positive scans; we think that is probably because those were light chain AL patients rather than TTR cardiac amyloid patients. In the early 2000s, Dr Rapezzi's group in Italy did a landmark study[1] looking at patients with TTR cardiac amyloid, AL, and controls, and they found that there was indeed myocardial uptake in TTR much more significantly compared with ALs and controls. They used a bone tracer called 99mTc-DPD, which is not FDA-approved for use in the United States.

There are some limitations of planar imaging with PYP scans. Essentially, a planar image is a 2D x-ray-like image of the chest cavity. We look at myocardial uptake either in a semi-quantitative fashion compared with bone uptake or in a quantitative fashion as described initially by Dr Maurer and colleagues at Columbia,[2] where we look at myocardial uptake in the heart over the contralateral (H/CL) chest ratio of uptake, and that is thought to normalize for bone and soft tissue uptake. If that H/CL ratio is over a certain threshold, then it's believed to be diagnostic for cardiac AL with a specificity that approaches 100%. (The caveat once again is that you have ruled out light chain AL.) Essentially, that gets rid of the need for a cardiac biopsy, which is quite practice-changing.

It's very important that the limitations of the PYP scan be considered. After ruling out light chain AL, once you are doing this scan, make sure you're not facing a case of falsely elevated H/CL ratio. Since it's a bone tracer, anything in the chest cavity on that side, such as bone fractures, mitral annular calcification, aortic stenosis that is severely calcified, calcified lung nodules, and even breast tissue, can falsely elevate that ratio. You have to be very rigorous in interpreting a PYP scan.

Equivocal PYP Scan Results

Acharya: Do we have standardized cutoffs for these ratios that we should be using, and what do you do with equivocal results?

Grogan: These are great questions. The cutoff will depend on what your institution has set as your cutoff. Many centers use imaging at 1 hour, but our center and some others use 3-hour imaging. Ours will be 1.3 for the H/CL ratio. This is very important. People will sometimes call us up and say, "I have a person who had this positive PYP scan and here is the ratio." And when we ask the practitioner when the patient was imaged, they don't know. So the protocol is really important.

As far as false positives, we saw one patient with Plaquenil (hydroxychloroquine) cardiotoxicity who had a positive PYP and then went on to have a biopsy. A couple others were suspicious too, but we've had one very definite one. We have to remember that the original papers[3] or all of the data so far have been in patients who had a high pretest likelihood of having AL, mostly a high pretest likelihood of TTR amyloid, but also of AL. Could there be other cardiac conditions? It's possible. It's a new test; we all have to take that with a grain of salt. Having said that, the consensus guidelines[4] say that if your screening for AL is negative and if you have a typical echo (ie, thickened walls, abnormal strain, restrictive filling, etc) and/or MRI findings, [the PYP scan] is a very good test. Some people will say, " You're still going to have those patients with monoclonal protein, and I'm still going to have to get tissue." That is maybe 40%. You still have at least 40%-60% where you won't need a heart biopsy, whereas previously 85% of these patients needed a heart biopsy. It really has revolutionized our ability to make this diagnosis.

Acharya: Making things as noninvasive as possible is always going to be the safer option for our patients.

Grogan: One crucial thing: It is well known that AL can have uptake on PYP. We've recently even seen patients with pretty strong grade 3 uptake or more, so make sure that you get tissue if those AL screening tests are abnormal, because you do not want to make the mistake of thinking the patient has TTR amyloid when they have AL. The treatment will be completely different, and you don't want to delay chemotherapy because you have made that mistake.

Abou-Ezzeddine: I want to tag on to Dr Grogan's response as far as when you have equivocal planar imaging. Here at Mayo, we have been doing concomitant SPECT/CT imaging to specifically look at the myocardium, the morphology of the myocardium, and where that uptake is. Is it indeed in the myocardium? Is it in the blood pool? We are increasingly seeing cases that are positive on the planar imaging (on the H/CL ratio), but when you actually look at the SPECT/CT and at the myocardium itself, the uptake is all blood pool or you're capturing calcified valves or a rib fracture, for example. We see those quite commonly in the nuclear lab as well. It's an important addition to the approach that has been initially described with planar imaging.

Grogan: Another thing that we sometimes forget to talk about is that PYP previously was used to grade the size of myocardial infarction (MI). So if a patient has had a recent MI, then PYP is going to light up in that area. It's quite easy even for those who do not interpret PYP scans to learn to read them, and it's pretty simple to look at those SPECT images to see if it is lighting up and whether it is lighting up diffusely. Also, if you're really unsure, then get a heart biopsy.

Abou-Ezzeddine: We typically wait around 4 weeks after an MI to image the patient. It's thought that the activity sort of abates after the 4-week cut point.

Unequivocal PYP Scan

Acharya: When you have an unequivocal positive PYP scan, what's the next step for our patients?

Abou-Ezzeddine: In the cardiac amyloid clinic, our next step after they have this diagnosis—again, once you've ruled out light chain because of prognostic and therapeutic consequences—is to proceed with genetic testing. Yes, the patient may be elderly or what we think is elderly, but they do have children that are not, and if this is a hereditary process that we're missing, then we're not doing our due diligence as providers. Our typical approach is to sequence the TTR gene and look for any mutations that would explain that diagnosis.

Grogan: That cost has come down considerably. Whenever you ask about cost, you'll get different numbers, but it's not as expensive as it would have been in the past. There are complimentary programs through some of the various industry sponsors if a person can't afford the testing. We just need to get it in everyone. We've seen patients who are 85 years old and have a pathogenic mutation. One could argue how much of a role it played in that patient, but now that we know they have that, their children are at increased risk for amyloid and need to at least consider genetic testing.

PYP Scan Procedure

Acharya: What is required to perform a PYP scan, and what would the time commitment be for a patient? If you're referring someone and they ask you, how do you best answer that?

Abou-Ezzeddine: Any nuclear lab that's performing stress testing or has access to a technetium generator is all you need from a radiotracer standpoint. We have a SPECT/CT camera here at Mayo. Our protocol is a bit different from other places' in that we do imaging not only at baseline or at 15 minutes (that is typically a 5-minute scan after injecting the PYP) but also at 3 hours. So that is typically a longer SPECT/CT scan, around 40-45 minutes long. However, if you are just doing planar imaging, it's much shorter than that. We typically have patients present, get the isotope, image at 15 minutes, and then they come back at the 3-hour time point for their 3-hour imaging. We really use the 3-hour imaging to confirm or rule out myocardial uptake of PYP.

Acharya: Is it useful to receive scans from an outside institution? Are those able to be interpreted easily for continuing tertiary care?

Abou-Ezzeddine: It's an excellent question, and in the ideal world, the answer would be yes. But many times when the imaging comes, we don't know what protocol was used and we don't know how much radioisotope was used. It may be [useful], but there are countless times where I've needed to repeat imaging here because of the image quality or whatnot. Because we don't have full access to data that are provided, we cannot actually reinterpret it using our software, per se. Potentially down the line, yes.

Grogan: It's fairly easy to assess that. People are starting up this imaging and are at different points in their own laboratories of how comfortable they are, and how much they have set up their protocols. We're starting to see more where you will get the images, have the report, and know the sequence, and if it's all positive, you don't necessarily need to repeat it. I think we'll start to see a little more standardization.

TTR AL

Acharya: What is next for our patients with TTR AL? What options do we have in the future?

Grogan: It's a really exciting time. We'll have to have another video to talk about treatment. As many people may know, for years, wild-type TTR particularly was considered an "academic" disease. Why are you even looking for it? We used to call it senile systemic AL. But now our youngest patient here at Mayo was 47 years old, so we got rid of that [name]. We know that it can occur in younger patients.

We have a variety of options that are just emerging both for wild-type and hereditary patients with cardiac involvement. Tafamidis is a TTR stabilizer and has been shown to reduce mortality and cardiovascular hospitalization in patients with TTR and cardiac involvement. RNA-interfering drugs that knock down TTR, which have been studied primarily for neuropathy, [are being evaluated]. There are ongoing and new trials. It's really an exciting time where we've taken it out from the academic to the real world. We need to know what this is.

Acharya: Dr Grogan and Dr Abou-Ezzeddine, thank you so much for your important insights on this topic, and thank you, the audience, for joining us on theheart.org on Medscape Cardiology.

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