Tissue Biopsies to Confirm hATTR Amyloidosis

John L. Berk, MD: What is the importance of a biopsy showing amyloid, from your perspective? We’re ultimately going to circle back to Akshay regarding the heart, but let’s start with polyneuropathy.

Michael J. Polydefkis, MD: Again, with hereditary disease, you’re born with the trait from day 1, but it’s not a guarantee that you’ll develop the disease. So, as we alluded to, incomplete penetrance. Tissue is helpful, in my mind, to identify that the disease process has begun. And usually, once it’s begun, it’s a ball rolling downhill. It continues. It doesn’t stop. So in the early case where you’re not sure, or an early case where there’s potentially other causes or explanations for neuropathy, having a tissue diagnosis helps seal the deal, and confirms the diagnosis and allows you to start therapy.

John L. Berk, MD: Regarding Jim’s experience with nerve biopsies and detection of amyloid, do you share that enthusiasm for nerve biopsies? Or do you pursue other avenues?

Michael J. Polydefkis, MD: We certainly do use nerve biopsies, but we might start with a skin biopsy. If we see amyloid in the skin and the patient has a mutation, you could do mass spectrometry on the skin, that’s skin amyloid, and you might avoid a nerve biopsy.

John L. Berk, MD: And histologically, if you have the typical axonal changes in a case for which you are suspicious of amyloid, is that sufficient? Or do you really need to see congophilic material?

P. James B. Dyck, MD: I agree with what Michael says. I’m going to step back a bit, but I’ll come back to your question too. The genetic test means that somebody is predisposed to developing amyloidosis. But as we’ve all said, that’s genetic testing. There’s incomplete penetrance and there are many different causes of neuropathy. So for me, at this point, it’s not good enough just to have a positive genetic test and development of some sort of neuropathy. I want to really show that the person has amyloidosis. And to me, as a neurologist, that is a tissue diagnosis. That’s how I feel about it currently, in 2019. I may change over time, but I think the cardiologists have a little bit of a different perspective.

Historically, I would have preferred to show it’s actually in the nerve because then I know that’s the cause of the neuropathy. I think now I’ve changed my position on that. Any sort of tissue confirmation of amyloid, whether that is a salivary gland biopsy, whether that’s a fat pad biopsy, whether that’s a skin biopsy is OK. We have this new technique that we’ve been alluding to, mass spectrometry, where we can actually identify the protein so that you can now show that it’s actually a TTR [transthyretin] amyloidosis based on that amyloid confirmation.

Now back to your specific question about histological findings and nerve biopsy, I don’t think there’s a specific finding on nerve biopsy other than amyloid that’s specific for amyloid. In amyloidosis, you lose fibers. You lose both myelinated and unmyelinated. You may lose unmyelinated fibers at a greater percentage than you would lose large myelinated, but it’s not a specific finding that you can make that diagnosis with. So without actually seeing the congophilic amyloid deposition, I don’t think you can make a diagnosis on nerve biopsy.

John L. Berk, MD: All right, let’s make this a little more provocative then. So we’ve had 2 large phase 3 trials that have led to FDA-approved agents. In one of the trials, a biopsy was required. In the other trial, it was not required. Does that alter the validity of the findings, in your minds?

Michael J. Polydefkis, MD: No. The patients in the trials were not early patients, necessarily. There were patients with a confirmed diagnosis, with a family history. There were many other diagnostic criteria. So I think the diagnosis was quite secure.

P. James B. Dyck, MD: I think it’s quite an interesting question. People want to make direct comparisons between the 2 trials—the APOLLO trial and the inotersen trial. That really shouldn’t be done. The reason I think it shouldn’t be done is that the inclusion criteria for the 2 trials were different. The endpoints were different. The inotersen trial did not take as severe neuropathy as the patisiran trial did. And so, to try to make direct comparisons and say one agent is better than the other is a no-no.

Also, coming back to the fact that the patisiran trial did not require a tissue diagnosis, as Michael was saying, I think there were many other inclusion criteria that confirm very likely that, in fact, they did have hATTR [hereditary transthyretin amyloidosis]. And even though I say I like to have a tissue diagnosis, in most of the patients who have the genetic abnormality and develop a neuropathy, that neuropathy will be due to hATTR; but not all of them will be due to hATTR.