Recognizing and Identifying hATTR Amyloidosis

John L. Berk, MD: When we talk about TTR [transthyretin] amyloid cardiomyopathy, do you think we’re really talking about 3000 people in the United States? And how do you break it down between the hereditary and wild-type forms?

Akshay S. Desai, MD, MPH: I think it’s an important distinction, because when we think about heart failure and cardiomyopathy, we’re generally talking about multiple presentations. And often when we’re thinking about amyloid as it relates to heart failure, we’re thinking about patients who have heart failure in the setting of a normal left ventricular ejection fraction [EF]. And I think increasingly it’s clear that if we ask the question, how many of those patients with heart failure and normal ejection fraction or preserved projection fraction have some form of amyloid, and TTR would be the highest on that list, it’s a large fraction of our patients. We think as we look for it increasingly, if we include patients with either the wild-type variant or the familial variant, they’re a large proportion of patients. And within subsets of the population, particularly in the United States—for example, populations of West African descent—there are high prevalence rates for certain familial variants of amyloid, maybe as many as 3% to 4% of the US population, or carriers of the V122I mutation that has been associated with familial amyloid, and those patients tend to have a higher rate of development of cardiomyopathy.

And then there are other mutations that have also been associated—for example, in Irish populations with high rates of cardiomyopathy development. So I think the question about amyloid and heart failure or heart disease is a broad one. Certainly patients with wild-type or nonmutated transthyretin can develop amyloid as a consequence of that later in life, and we’ve called that, perhaps unfortunately, senile systemic amyloidosis. And if we look at elderly populations of patients with heart failure, the prevalence of that disorder is probably very high.

If we’re talking about familial variance in subpopulations as has been mentioned, particularly African Americans, we think the rate might be higher, but it’s still a minority of our heart failure cases, overall.

John L. Berk, MD: When you look at an experience in a heart failure clinic, what percentage of those patients would you anticipate have amyloid cardiomyopathy?

Akshay S. Desai, MD, MPH: So in a heart failure clinic, at large, that’s a tough question because the vast majority of people referred to the attention of a heart failure specialist are patients with low ejection fraction, among whom the prevalence of amyloid heart disease is actually quite low. If we then look at patients with preserved EF heart failure who are referred, it’s again a fraction of patients who actually have amyloid heart disease. We don’t know exactly how many of those patients have underlying amyloid disease because we haven’t screened systematically. But if we look at data from nuclear medicine studies, where we are now able to identify patients more efficiently, for example, with TTR-variant amyloid, it’s probably a large fraction of patients, particularly in subsets that are at high risk, like African Americans.

So as far as percentages go, some have speculated it may be as many as a fifth of the patients with preserved EF heart failure who have some type of amyloid. And how much of that is familial is probably the minority—a very small proportion.

John L. Berk, MD: Jim, I’ve just put Akshay on the hot seat, and now it’s your turn. If we look at a general polyneuropathy population in a place like the Mayo Clinic, which is a large referral center, what percentage of patients are presenting with a sensory motor polyneuropathy? And of those, what percentage do you think have familial amyloid?

P. James B. Dyck, MD: So I am the director of a Peripheral Neuropathy clinic. Most of those patients would have a sensory motor peripheral neuropathy. In the vast majority of them—90%—you have some focal motor neuropathies and some sensory neuropathies. Most, however, are sensory motor polyneuropathies. Of the sensory motor polyneuropathy, less than 1% are going to be hATTR [hereditary transthyretin amyloidosis]. So it’s a very small percentage of the overall neuropathy that we see.

Recently, many of us have been involved in 2 large studies of hATTR amyloidosis. One of the things that has really educated me in early stages of hATTR is how nondescript that neuropathy is and potentially scary it is that many early cases of hATTR are actually getting missed because they’re not that different from other forms of polyneuropathy.

John L. Berk, MD: If there was something that we could do to lessen the number of misdiagnoses, in your opinion, what would that be?

P. James B. Dyck, MD: I don’t think there’s necessarily an easy answer for that. Screening is probably the best idea. Genetic testing as well as fat pad biopsies on a large number of nondescript neuropathies are probably the best ways to pick them up. Because again, early on, those neuropathies are not so easy to distinguish from other forms of neuropathy. As time passes, it becomes easier. So hATTR amyloidosis presents as a motor sensory and autonomic neuropathy. Patients have sensory loss, patients have pain, and patients have large amounts of autonomic disturbance. They can be syncopal, they can have bowel and bladder and GI [gastrointestinal] involvement. They have weight loss, and they develop weakness.

So when you see a patient with all of these 3 systems being involved—motor, sensory, and autonomic—and if they have significant weight loss, I think those are big clues that you are potentially dealing with amyloidosis. But we really don’t want to be discovering these patients later on in their neuropathy course. We want to be discovering them earlier on.

John L. Berk, MD: So when patients have sensory motor and autonomic dysfunction, we’re looking at late expression of disease.

P. James B. Dyck, MD: It’s well into it by the time you have all of that, yeah.

John L. Berk, MD: And in your opinion, what are the earliest manifestations that we should be keying on?

P. James B. Dyck, MD: I think it’s a lot of neuropathies. And again, that’s sort of the point I was trying to make earlier. Some sensory loss, often a length-dependent sensory-predominant neuropathy is how it’s going to present. And so it may not be that dissimilar from a diabetic polyneuropathy early on. A little bit of autonomic, some sensory. Usually at the beginning, there’s not motor involvement.

There are some other things that might go along with it, though. It’s often associated with carpal tunnel syndrome. So if you have a neuropathy that’s also associated with carpal tunnel syndrome, I think that is a clue that you may be dealing with hATTR. That also can happen in diabetes mellitus, though. So there are other conditions that’ll have the same association.