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Management of Cardiac Amyloidosis - Episode 6

Monoclonal Protein Testing and Wild-Type ATTR

John L. Berk, MD: Doctor Witteles, please give us your view of the proper laboratory testing that should occur to interpret a technetium pyrophosphate scan, and the second thing I’d like you to comment on is whether it’s important to identify these unrecognized wild-type TTR [transthyretin] cases if they’re undergoing a TAVR [transcatheter aortic valve replacement] or some other procedure.

Ronald Witteles, MD: On the first point, testing for monoclonal protein can’t be emphasized enough. In 2020 at least, it is the most important issue for people to understand who are doing diagnostic workups of these patients. Technetium pyrophosphate scanning is both the best and the worst thing to ever happen for patients with TTR amyloid, or for patients with amyloid, I should say. It’s the best because it has allowed most patients with TTR amyloidosis [ATTR] to get a correct diagnosis noninvasively and be able to start on treatments that can make a real difference in their disease course. But it’s the worst thing because it has, unfortunately, led to many people either getting misdiagnosed as having a TTR diagnosis when they don’t have amyloidosis at all, or really far more tragically, getting misdiagnosed as having ATTR when they actually have AL [immunoglobulin light chain amyloidosis] amyloidosis.

So it’s important to emphasize, as doctor Desai was getting at before, that positive bone scintigraphy in this country—typically technetium pyrophosphate—is not specific for only ATTR. So, it tends to have the most uptake with ATTR, but you can absolutely get uptake with other forms, including AL. In the landmark study that really led to its widespread use, 22% of the patients who had AL amyloidosis had positive scan results. So, you can absolutely have a positive scan result in a patient with AL amyloidosis, and whereas it’s nice and can make a significant difference for a patient with ATTR to get them on treatment, it is catastrophic to miss a diagnosis of AL amyloidosis and miss the window to be able to get them started on effective light-chain therapy.

So, with that as a preamble, nobody should have a technetium pyrophosphate scan without either concomitantly or beforehand having a monoclonal protein ruled out, and that is with 3 tests. The most important one is the serum-free light-chain assay, which is simply measuring the concentration of serum-free kappa light chains and free lambda light chains. The ratio is typically approximately 1. If it is well off in one direction or the other, it implies there is clonal production of whichever one is off, and that person cannot have a technetium pyrophosphate test to make a diagnosis of ATTR.

The other tests are a serum and a urine protein electrophoresis with immunofixation. It is important to note that it should always be done with immunofixation, which raises the accuracy of the test. There’s no reason to do it without at this point. On the serum test, you’re mainly looking for whole immunoglobulins, and on the urine test, you’re mainly looking for light chains. Why do you need to do that in addition to the free light chain test? Well, for one, regarding those 2 tests, if they show a monoclonal spike, those have proven clonality, whereas with the free light chain test, you have implied clonality by the ratio being off—and if the ratio is off by 10:1 or 100:1, that’s proven clonality. But if the ratio is off by 2:1 or 3:1, it’s tough to say whether you have a true clonal process or not. So, you really want to have all 3 tests, and only when all 3 test results are normal, can you then use a technetium pyrophosphate scan to make a diagnosis of ATTR.

John L. Berk, MD: The second question was about the significance of finding wild-type TTR in certain populations. Is that really important to pursue?

Ronald Witteles, MD: Right, that’s an important question. To some extent, we don’t know the answer to it. We do know that treatment, certainly tafamidis, makes a significant difference in the treatment population who was studied in the phase 3 trial of tafamidis. Now, that was not in a population who was getting screening. So, if you start just screening everybody who is undergoing a TAVR, for example, and make a diagnosis—technically they weren’t included in the ATTR-ACT clinical trial—the phase 3 trial of tafamidis. That being said, the results of ATTR-ACT were quite compelling … in terms of making a significant difference in mortality, making a significant difference in cardiovascular hospitalization, and in progression of the disease based on quality of life and 6-minute walk distance.

So I think probably all of us, if we have a patient who has heart failure and a diagnosis of ATTR, will believe that we’re going to be able to make a significant difference by getting them on tafamidis, and I think screening an appropriate population does make sense.