Friday, February 28, 2014

Article Review (2010) - Fibrinogen amyloidosis: the clot thickens!

Today's post will actually be a continuation of the previous article review plus a review of another article from the same journal issue that discusses the findings and recommendations of the first article. To help you keep things straight, let's refer to the article reviewed in the previous post (February 21, 2014) as Article A. And we will refer to today's article as Article B. First I want to discuss some of the findings in Article A, then I will discuss Article B. (There will be some overlap.)

Article A, the study of 22 patients, gave us some new information in two important areas. First, the initial symptoms these patients presented with (proteinuria and hypertension) was typical of what has been reported in previous cases of fibrinogen amyloidosis. Nothing new there. But the prevalence of other health issues reported in these patients is something we have not seen before. Fifteen of these patients (68%) had some sort of cardiovascular issue. Twenty patients (91%) had some type of autonomic neuropathy affecting the heart only (5), GI tract only (8) or both (7). (I did not mention it in the previous post, but no peripheral neuropathy was found in these patients.) We have only seen occasional reports of cardiovascular or autonomic issues prior to this article, including the study of 71 AFib patients reviewed in the January 12, 2014 blog post. I do find it odd that there were no similar reports in the study of 71 patients, since many of the patients in the study of 22 were also included in the study of 71.

Regarding the cardiovascular issues, it is interesting that significantly more patients had a family history of cardiovascular issues than kidney issues (17 vs. 5). People tend to think of fibrinogen amyloidosis as a kidney issue so they look for a family history of kidney problems. Based on this small sample size, however, it may be just as important, if not more important, to look for a family history of cardiovascular issues.

When talking about cardiovascular issues due to amyloidosis it helps me to separate them into two groups. (Keep in mind that I am not a medical professional so there may be some inaccuracies here. There are certainly some oversimplifications.) The first group of issues is when the heart itself is impacted by amyloids. This is when the walls thicken and get stiff due to amyloid deposits between the cells of the heart. That is the classic cardiac amyloidosis like what was described in a French patient in the article I reviewed on January 6, 2014. The second group of cardiovascular issues, which this article focuses on a bit more, is the buildup of plaque in the blood vessels surrounding the heart. That is a problem that can have many causes, such as high cholesterol, but this article reports that some of these plaque buildups were analyzed and found to be at least partly composed of variant fibrinogen. We know cardiac amyloidosis is underdiagnosed because the symptoms are so similar to "normal" congestive heart failure. So these issues involving a buildup of plaque are even more likely to be underdiagnosed since there is no reason to suspect amyloidosis based solely on plaque buildup in blood vessels.

The second area of significant new information in Article A is the results of combined liver and kidney transplantation (LKT) in nine patients. Based on the follow-up of the LKT patients, all indications are that the amyloid buildup and its effects were either halted or reversed after LKT. The follow-up of patients who had received isolated kidney transplants, on the other hand, clearly indicates that amyloid buildup continues due to the continued presence of variant fibrinogen.

Previous articles have suggested that liver transplant is curative for fibrinogen amyloidosis, but this is the first one that actually recommends just a liver transplant early in the course of the disease and provides some guidelines for when that may be appropriate (GFR above 50). When we inquired about a liver transplant for Mom we were told there was a hard cutoff of 40 for GFR at this particular transplant center (Baylor in Dallas). The medication given after a liver transplant is very hard on the kidneys, so they do not want to give someone a liver transplant and have them end up on dialysis as a result of the medications. One of the 22 patients in this study was initially listed for a liver transplant but then had to be listed for a liver and kidney transplant, so at the time of publication of this article (April of 2010), there had been no isolated liver transplants for fibrinogen amyloidosis. I wonder how long we will have to wait for the first one . . .

Now it's time to move on to Article B, the subject of today's review.

Title: Fibrinogen amyloidosis: the clot thickens! (1)

Author: Maria Picken (Loyola University Medical Center)

Journal: Blood (2010)

Here is a link to the PDF of this article if you would like to follow along:

This short article appears in the same issue of Blood as the previous article that reported on 22 patients. It was written by Dr. Maria Picken, who, as I mentioned in the January 24, 2014 blog post, is a leading pathologist in the field of amyloidosis. She states that the article by Stangou et al expands the current medical literature in two significant ways. These are more or less what I already discussed above, but with some additional analysis.

The first way is the description of the high prevalence of other health issues seemingly related to fibrinogen amyloidosis in these patients, specifically the cardiovascular and neurologic involvement. Dr. Picken notes that the authors of the Stangou article concluded that fibrinogen amyloidosis was a cause of the cardiovascular issues seen in these patients, whereas the authors of the article reporting on a study of 71 patients reached a different conclusion, which was that the incidence of cardiovascular involvement was "comparable to that seen in patients with chronic kidney disease in general, and thus secondary to the process." So the big question is this: Are cardiovascular issues in AFib patients caused by the mutant fibrinogen (among other factors), or are the cardiovascular issues what we would expect to see in patients with any type of chronic kidney disease?

The second significant way the medical literature is expanded is the results of combined liver and kidney transplants. I will not repeat what I already wrote above, but I will quote two sentences from the article that deal with isolated liver transplants for treating AFib. "Because hepatorenal transplantation appears to prevent disease progression and allow reversal of some organ dysfunction, the authors advocate early or even preemptive transplantation of liver alone, that is, before renal failure and significant cardiovascular amyloidosis develop, especially because the latter may preclude transplantation. This is certain to be a contentious isssue, but Stangou et al provide important data to consider in designing the best approach for individual patients."

In the next post we will see just how contentious the issue of isolated liver transplantation is, as well as some questioning of the conclusions reached in the Stangou article.



(1) Picken MM. Fibrinogen amyloidosis: the clot thickens! Blood. 2010;115(15):2985-2986.

(2) Stangou AJ, Banner NR, Hendry BM, et al. Hereditary fibrinogen A alpha-chain amyloidosis: Phenotypic characterization of a systemic disease and the role of liver transplantation. Blood 2010; 115: 2998-3007.

(3) Gillmore JD, Lachmann HJ, Rowczenio D, et al. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis. J Am Soc Nephrol 2009; 20: 444-451.

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