Cardiac Amyloidosis Diagnostic Workup

John L. Berk, MD: Hello and welcome to this NeurologyLive® Peer Exchange titled, “Management of Cardiac Amyloidosis.”

I am Dr John Berk from Boston University School of Medicine.

Joining me today in this virtual discussion are my colleagues:

Dr Akshay Desai, director of the Cardiomyopathy and Heart Failure Program at Brigham and Women’s Hospital in Boston; Dr Mazen Hanna, codirector of the Amyloidosis Center at Cleveland Clinic in Cleveland, Ohio; and Dr Ronald Witteles, codirector, and actually founder of the Amyloid Center at Stanford University in Palo Alto, California.

Today, we’re going to discuss a number of topics pertaining to the diagnosis and treatment of cardiac amyloidosis. Let’s get started on our first topic, which appropriately is: What’s amyloid? Amyloid is a family of diseases resulting from the misassembly and misfolding of particular proteins. There are over 30 proteins that can misfold to form amyloid. Identifying the subunit protein is critical to the management of disease. It not only determines what organs are involved, but ultimately defines what therapies are considerations.

To begin, Ron, can you give us some insights into how you address a referral for a patient with cardiac amyloid with no idea whether we’re talking about AL [light-chain amyloidosis] or a TTR [transthyretin] amyloid?

Ronald Witteles, MD: Sure, thank you. When a referral comes in, most with a suspicion of cardiac amyloidosis, it tends to be for 1 of 2 reasons: either somebody has had cardiac imaging and has the suspicion based on that, that’s been raised as cardiac amyloidosis, or they have a known diagnosis of systemic amyloidosis and there’s a question of cardiac involvement. If we’re talking about the former and it’s really a question of do they have amyloidosis at all, there can be some clues to imaging—I think we’re going to get to that a little bit later, so I won’t address them right now—but often, clues that come off of echocardiography more than anything of being increased wall thickness. That’s what’s often referred to as hypertrophy, although it’s not actually hypertrophy of the muscle but rather deposition of amyloid deposits.

There can be some other clues, things like elevations in cardiac biomarkers, troponin, BNP [brain natriuretic peptide], and more than anything, if you’re talking about systemic amyloidosis, it can be a constellation of abnormalities in other organs or organ systems. Neuropathy, for example, can certainly occur with either of the 2 main types of cardiac amyloidosis, AL, or transthyretin as we’re going to get into. But particularly with AL amyloidosis, other organ dysfunction—renal, hepatic, really just about any organ dysfunction—can occur often, and when people see clustering, it will make them think that.

So, when I’m seeing a new patient with suspected amyloidosis, there’s a couple of things. One is there are basic laboratory screenings that we do for pretty much any patient, which will include, of course, standard labs, including standard biomarkers, but also very importantly ruling out a monoclonal protein—as I think we’ll get to in a little bit—to help guide us whether they could have AL amyloidosis or not. We’ll review basic imaging at least with an echocardiogram and an EKG, and we will go from there. Finally, we’ll look for typical findings on echo that might point us one way or another and typical findings and demographics that point us one way or the other. For example, a particularly extremely thick-looking echo would push us more toward actually thinking about transthyretin than AL, although that’s certainly not an exact science, and demographics. An older male without other signs of organ dysfunction would make me think he has transthyretin. A younger patient, a woman, would push me more toward a diagnosis of AL amyloidosis.

John L. Berk, MD: That’s great. Thanks a lot, Ron. Dr Hanna, you’ve considered the extra cardiac manifestations of disease and actually have conducted a study looking at carpal tunnel involvement. Can you tell us with much the same scenario, meeting a patient for the first time, what are the particular historical features or, more importantly, the physical manifestations that clue you in to TTR versus AL disease?

Mazen Hanna, MD: Yeah, it’s a great question. I will first start with AL. There is 1 physical exam finding that’s essentially pathognomonic for AL, and that’s macroglossia, or an enlarged tongue, from the deposition, although there’s 1 mutation with hereditary TTR that’s been described to have that. I would say 99% of the time, if you see an echo that looks like cardiac amyloid and you see a big thick tongue or macroglossia, that’s essentially pathognomonic for AL. Other physical exam findings which are generally found in patients with heart failure, such as elevated jugular venous pressure and edema, that’s not going to be specific to either one. Typically, if you have significant orthostatic hypotension on exam, then it could either be AL or various mutations that cause hereditary autonomic neuropathy, but wild type doesn’t tend to have that significant of autonomic neuropathy.

As far as historical clues, you brought up carpal tunnel syndrome. Bilateral carpal tunnel syndrome is actually pretty common in patients with ATTR, particularly wild-type ATTR cardiac amyloidosis. Upwards of 40% of patients with this diagnosis will have a preceding history of bilateral carpal tunnel surgery. This can also occur in patients with AL amyloidosis. So, the fact that you have a history of bilateral carpal tunnel syndrome, doesn’t mean you don’t have AL, but it’s more suspicious for ATTR, particularly wild type. Oftentimes, the carpal tunnel manifestations can precede the cardiac manifestations by 5, 10, and even 15 years. So it’s always very important to ask anyone who is presenting with a thickened ventricle or HFpEF [heart failure with preserved ejection fraction] if have they had carpal tunnel surgery.

Another very important historical clue is spinal stenosis, and actually that’s much more commonly seen in patients with ATTR than AL, and in fact, again, almost exclusively in wild type. And finally, biceps tendon rupture. There’s a nice publication, about a third of patients with wild-type ATTR cardiac amyloidosis have a history of biceps tendon rupture. So, these orthopedic or entrapment neuropathy type of manifestations will really heighten the suspicion that a patient can have actual cardiac amyloidosis and more so ATTR than AL in a lot of those manifestations.