Current Series: Amyloidosis

John L. Berk, MD: We’ve talked about the importance of tissue biopsies, the various sources—salivary gland, abdominal fat pad aspirates. We haven’t discussed any GI [gastrointestinal] biopsies-be they gastric or rectal biopsies. Are those still part of your armamentarium, or have you graduated from those?

P. James B. Dyck, MD: I think one goes to the area where a patient has most of their symptoms. So I think, certainly, if the GI tract is where a patient has a lot of their symptoms, a rectal biopsy is still a good thing to do.

John L. Berk, MD: Michael?

Michael J. Polydefkis, MD: I agree.

John L. Berk, MD: So the implication is then that the GI manifestations of a disease are due to the burden of amyloid in the GI tract. As neurologists, is it your perspective that the dysmotility, the overwhelming diarrhea or profound constipation is due to the burden of amyloid, or is it due to autonomic dysfunction and dysregulation of motility?

P. James B. Dyck, MD: Is there a difference?

John L. Berk, MD: Well, that’s a very good question.

P. James B. Dyck, MD: I don’t think we really actually fundamentally understand what the pathophysiology of amyloid neuropathy is. Earlier, people often thought maybe it was compressive and there was speculation that it was hypoxic. But fundamentally, what is it about amyloid that causes neuropathy? Is it toxic? Is it just a burden? You have to have so much, but what exactly it does and how that damages the nerve I don’t think we really fundamentally understand.

John L. Berk, MD: Michael?

Michael J. Polydefkis, MD: I think that’s correct. I think amyloid infiltrates nerves. It’s associated with damage and dysfunction. How that happens, I’m not sure we fully understand.

John L. Berk, MD: I’m not a card-carrying neurologist, so I can be a little provocative here.

P. James B. Dyck, MD: So do you think it’s fully understood?

John L. Berk, MD: No. If it were, we wouldn’t be here. The diagnosis would be easy. Our experience with nerve biopsies at Boston University is not as encouraging as it is at [The Johns] Hopkins [Hospital] and Mayo Clinic. We often, in the times we do sural nerve biopsies, strike out. And so, our sensitivity is maybe 50%. We may not take a long enough section of nerve. We may not section it exhaustively. So that may be part of our methodology. At the same time, I’m struck by the histology of disease showing rather dramatic axonal and small nerve fiber changes in the absence of any amyloid deposits. And our thinking is that the TTR, in its misfolding, forming oligomers and aggregates, are probably a toxic species that injure nerve without amyloid deposits and, as a consequence, would, in part, explain the relative absence of amyloid deposits. And, in looking back at our GI biopsy history, finding that there are people who have little or no amyloid deposits on multiple biopsies, yet have profound dysfunction, leads us to think that the small nerve fiber control of the GI tract is really the essence of the overwhelming diarrhea, and, potentially, constipation, but certainly the gastroparesis.

P. James B. Dyck, MD: I think it’s very interesting—what it is about amyloid that’s toxic to nerve. Nerve is also this very long, thin organ. And so, you absolutely could have major burden of amyloid upstream. It’s an axonal degeneration causing the generation of the fibers downstream, and so your biopsy may not show it. And that doesn’t mean it’s still not a direct toxic effect upstream or some sort of amyloid burden. But I think fundamentally we don’t know. My father did a paper now probably 50 years ago, which he called, “Associate Sensory Loss in Amyloid.” And what he did was he took 2 case of TTR amyloidosis and did nerve biopsies on both of these cases. And they did in vitro nerve conduction studies and showed that the C fibers, the unmyelinated fibers, were gone electrophysiologically. When he did electron microscopy, there were no unmyelinated fibers. And yet, they still had some large myelinated fibers and some small myelinated fibers.

And this was from a woman who stepped on a nail, felt no pain, but felt blood fill up in her sandal. So what she felt was the wet sensation of the blood touching her skin, but she did not feel pain. So she had dissociated sensory loss. She had small fiber loss but still had some large fiber function. So I do think there is a preferential involvement of unmyelinated fibers in the TTR amyloidosis.

Michael J. Polydefkis, MD: And I think that’s probably variable.

P. James B. Dyck, MD: I think so too.

Michael J. Polydefkis, MD: It’s not true for all patients.

P. James B. Dyck, MD: Yeah, I agree.

Michael J. Polydefkis, MD: Different mutations or even different presentations can have different subsets of fibers differentially involved.

Akshay S. Desai, MD, MPH: Is there an understanding of why it is that certain variants have predilection for certain organs?

P. James B. Dyck, MD: I don’t think so. John may have the answer to that. I think these are things that we continually need to look into. I think it’s very interesting, actually.

John L. Berk, MD: Michael, do you have any insights?

Michael J. Polydefkis, MD: Not yet.

John L. Berk, MD: It’s really unclear. That’s one of the central questions that has evaded answers. There have been speculations of maybe chaperone proteins or gag populations and particular organs that really promote the deposition and act maybe as a nidus, but it remains remarkably unclear. It’s important to understand that as we group these mutations and essentially and simplistically assign some as being more prone to developing cardiomyopathy than a polyneuropathy, indeed, there’s full spectrum disease in the vast majority of people if you look carefully enough. And I think that’s something that we really need to keep in mind.