Recent Advances in the Treatment of Hereditary ATTR Amyloidosis (hATTR) - Episode 5

Diagnosing hATTR Amyloidosis

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Understanding the diagnostic process in making a ATTR amyloidosis diagnosis.

John L. Berk, MD: Let’s get down to brass tacks here. We’ve got 3 very prominent, knowledgeable neurologists pitted against a cardiologist. Cardiologists are making the diagnosis of TTR [transthyretin amyloidosis] every minute of the day. Where are all the neurologists diagnosing polyneuropathy for TTR? Shouldn’t there be more diagnoses and referrals? Why is it so difficult? Dr Polydefkis, can you start us off on that? I know that Dr P. James B. Dyck is going to have an opinion about this.

Michael J. Polydefkis, MD: The biggest reason is what was just mentioned. The echocardiogram often gives a big hint. That’s a routine test; you see a thickened heart wall with some echogenicity, and that prompts you to think of amyloid. At least in the beginning, amyloid neuropathy can be difficult to distinguish from a diabetic neuropathy or other type of neuropathy. Certainly with time, it distinguishes itself by the rate to progression, the presence of weakness, the company it keeps. As others have mentioned, if you look for a family history, look for a history of carpal tunnel syndrome, ask about autonomic dysfunction, which might not be volunteered at first pass; erectile dysfunction, bloating—you’re sensitive to cardiac history. As was mentioned, it could be valvular disease, cardiomyopathy, or thickened heart walls. A patient with peripheral edema might be telling you something about their heart function. All those things can increase your chances of picking up of hATTR [hereditary amyloidosis TTR]. At least at the beginning, it can look quite similar to other forms of neuropathy.

John L. Berk, MD: Thank you. Dr Brannagan, cardiologists obviously have an advantage; they’ve got imaging tools. How are neurologists going to catch up with cardiologists? What’s the imaging strategy? Are there prominent genetic panels? How do neurologists gain ground in making more diagnoses? If you identify someone as having sporadic disease, does that eliminate the possibility of familial amyloid?

Thomas H. Brannagan III, MD: I have to admit that most people I see with hereditary TTR amyloid are sent to me by cardiologists. I certainly would agree that cardiologists identify the disease more commonly, and it is aided by the echocardiogram findings and the PYP [pyrophosphate] findings. I don’t think we have any similar imaging technique. There is some work with MRI identifying nerve damage in amyloid neuropathy, but it’s not clear to me that there’s a distinctive feature on the imaging at this point that leads us toward amyloid as a cause of neuropathy vs other causes of neuropathy.

As Michael said, the history is very important. Often patients will describe years of diarrhea that they never put together with their neuropathy or other autonomic symptoms. If somebody has an autonomic neuropathy early on, many neurologists will think about amyloid very early. One aid that we have, that is increasing the diagnosis, is that next-gen panels are much more easily available. They are available to check not just transthyretin but ALSO other inherited neuropathies, and they’re getting done more frequently. I do see sometimes patients with unexplained neuropathies have next-generation panels that have identified transthyretin as well as other inherited causes of neuropathy.

John L. Berk, MD: And you find that family histories are revealing or deceptive?

Thomas H. Brannagan III, MD: They’re sometimes helpful, but if somebody does not have a family history of neuropathy, we still very frequently find that patients can have hereditary TTR amyloidosis. A very common situation is when you first talk to somebody, they don’t mention a prominent family history, and it’s really not until after the diagnosis is confirmed that people start to know of some relatives that had heart failure or a mild neuropathy that was attributed to diabetes or neuropathic symptoms that were attributed to spinal disease. We always ask about family history; sometimes it’s very helpful. However, the lack of the family history, you certainly would not exclude the disease.

John L. Berk, MD: Dr Witteles, how does penetrance affect the accuracy of your family history?

Ronald Witteles, MD: On the cardiac side, we know that most patients are wild type, so we have to start there. Even on the most common mutation, the hereditary form V122I, has a pretty low penetrance. Of the various mutations, it’s clearly 1 of the lowest. The best evidence from a study that was a longitudinal atherosclerosis study, where they had serial echocardiograms on people, in the ARIC [Atherosclerosis Risk in Communities] study, showed a penetrance of roughly 7% of carriers who ended up having at least overt signs of amyloid cardiomyopathy. It’s probably higher than that if you look for more subtle signs. The point is, it’s still fairly low, so you really can’t use it on the cardiac side.

From my perspective, why do cardiologists diagnose it more? Some of it is clearly that we see the disease a lot more because the wild type and the V122I mutation are the 2 most common types in this country. It passes that threshold, where most cardiologists have some sense at this point that they’re going to see patients with this, whereas on the neurological side it’s clearly more niche. On the other hand, I would say the neurologists have an even easier screening test than we do from an imaging and PYP standpoint, which is the genetic testing that was referred to: In the absence of a pathogenic mutation, it’s not TTR amyloid, and in the presence of it, it probably is. I’m curious what our neurologists think about why that doesn’t get sent more. I wonder how many of those patients with diabetic neuropathy could have a TTR amyloid. In the same way that if we only screened patients with LVH [left ventricular hypertrophy] “without a cause,” we would miss tons of patients because LVH is common from hypertension and aortic valve disease, but we know the 2 often go together.

John L. Berk, MD: Thank you for watching this NeurologyLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box.

Transcript Edited for Clarity