Friday, December 6, 2013

Article Reviews (2006 and 2013) - How rare is fibrinogen amyloidosis in the US?

Before getting to today's article reviews, I have a quick update on Mom and a note about the monthly blog stats that appear at the end of this post.

I know it has been awhile since I mentioned anything about a kidney transplant for Mom, and that is because there has not been much of anything to report. The two people who did offer to be living donors had both been ruled out as of earlier this year, and there have been no other inquiries since then. In June of this year Mom was notified that she would be removed from the list of transplant candidates within 90 days if she did not have a potential living donor, so we knew where things were likely headed. Her case was presented to the transplant committee in October, and she did receive an official letter dated November 1 that she has been removed from the transplant waiting list. Although it was not really a surprise, it's still a bit depressing, to say the least.

Regarding the monthly blog stats, I have some bad news for you loyal readers who anxiously await the first post each month so you can jump to the end and see what new countries have visited the blog. It is with great sadness that I must report that no new countries viewed the blog in November. After a streak of 13 consecutive months of adding a minimum of two countries to the list, we came up empty in November. Hopefully this will be just a short pause in my quest for world domination. (FYI, the three most populous countries that have not yet visited the blog are Ethiopia, Democratic Republic of the Congo, and Burma.)

The two articles being reviewed today, along with some information I received in 2010, attempt to answer the question posed in the title of this post, which is: How rare is fibrinogen amyloidosis in the US? (It is more common in the UK than in the US, but still rare.) We all know it is rare, and Dr. Skinner's presentation at the 2013 familial amyloidosis meeting listed it as making up less than one percent of the total systemic amyloidosis cases. I have heard the number of amyloidosis cases diagnosed annually in the US is around 3000. That would include types that are not systemic, such as localized, but let's just use 3000 for the approximate number of systemic amyloidosis cases each year. If fibrinogen amyloidosis is less than one percent of that, then all we know is there are fewer than 30 cases of fibrinogen amyloidosis diagnosed in the US each year. By the end of this post it will be obvious that the number of new US cases each year is likely much less than 30.

The first article under review today is the third of three papers I will be reviewing that were presented at the eleventh annual International Symposium on Amyloidosis, which was held in Woods Hole, Massachusetts in November of 2006. The papers presented at this symposium can be found in the book XIth International Symposium on Amyloidosis, edited by Drs. Skinner, Berk, Connors and Seldin, all of the Amyloidosis Center at Boston University.

Title: Recent novel and rare mutations in a clinic population of patients with amyloidosis (1)

Authors: B. Spencer, L. H. Connors, T. Prokaeva, P. Soohoo, C'Hara, and M. Skinner (Boston University, Boston, MA)

Book: XIth International Symposium on Amyloidosis (2007)

Abstract: None

This paper presents some data about the types of familial amyloidosis diagnosed by the team at Boston University between the Xth and XIth International Symposiums on Amyloidosis. The Xth symposium was held in April of 2004, and the XIth symposium was held in November of 2006, so this paper covers a little more than two years. Although there are a number of reasons why you cannot reach any hard conclusions about the general population based on this set of data alone, this paper does give us a good idea of how rare a diagnosis of fibrinogen amyloidosis really is.

The article begins by stating that familial amyloidosis is diagnosed in approximately 10% of the patients evaluated at the Boston University Amyloid Program. It states that the total number of familial patients is 253, which has to be since the program began in 1980. (Currently they see about 200 new patients per year.) Out of those 253 familial amyloidosis patients, 224 (89%) had transthyretin mutations (ATTR). That means through 2006, out of about 2500 patients, Boston had only diagnosed 29 patients with a familial form of amyloidosis other than ATTR.

The paper goes into detail on the mutations that were diagnosed (two for the first time) during this two-year period, but I won't go into all of those here. They did happen to have three cases of fibrinogen amyloidosis, all with the Glu526Val mutation. All three patients had kidney disease, and biopsies showed amyloid deposits predominantly in the glomeruli of the kidneys.

Although this paper does not give us any new information in terms of the diagnosis or treatment of fibrinogen amyloidosis, it does give us some idea of how rare the diagnosis really is. Over the course of two years, Boston diagnosed three patients (out of about 400) with fibrinogen amyloidosis. Adding some more data to the Boston numbers, when I was corresponding with Dr. Skinner shortly after Mom's diagnose in 2010, she said Boston had only seen a total of 10 to 15 patients with fibrinogen amyloidosis. So that means since the discovery of fibrinogen amyloidosis in the early 1990s, Boston has averaged just under one case per year out of the 200 new patients they see annually.

So that is the picture from Boston. How about Mayo Clinic? It just so happens there was an article published this year that gives us some data from the Mayo Clinic.

Title: Renal Amyloidosis: Origin and Clinicopathologic Correlations of 474 Recent Cases (2)

Authors: S. M. Said, S. Sethi, A. M. Valeri, N. Leung, L. D. Cornell, M. E. Fidler, L. H. Hernandez, J. A. Vrana, J. D. Theis, P. S. Quint, A. Dogan, S. H. Nasr (Mayo Clinic, Rochester, MN; Columbia University, New York, NY)

Journal: Clinical Journal of the American Society of Nephrology (2013)

BACKGROUND AND OBJECTIVES:  The kidney is the organ most commonly involved in systemic amyloidosis. This study reports the largest clinicopathologic series of renal amyloidosis.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:  This study provides characteristics of 474 renal amyloidosis cases evaluated at the Mayo Clinic Renal Pathology Laboratory from 2007 to 2011, including age, sex, serum creatinine, proteinuria, type of amyloid, and tissue distribution according to type.
RESULTS:  The type of amyloid was Ig amyloidosis in 407 patients (85.9%), AA amyloidosis in 33 (7.0%), leukocyte chemotactic factor 2 amyloidosis in 13 (2.7%), fibrinogen A α chain amyloidosis in 6 (1.3%), Apo AI, Apo AII, or Apo AIV amyloidosis in 3 (0.6%), combined AA amyloidosis/Ig heavy and light chain amyloidosis in 1 (0.2%), and unclassified in 11 (2.3%). Laser microdissection/mass spectrometry, performed in 147 cases, was needed to determine the origin of amyloid in 74 of the 474 cases (16%), whereas immunofluorescence failed to diagnose 28 of 384 light chain amyloidosis cases (7.3%). Leukocyte chemotactic factor 2 amyloidosis and Apo AI, Apo AII, or Apo AIV amyloidosis were characterized by diffuse interstitial deposition, whereas fibrinogen A α chain amyloidosis showed obliterative glomerular involvement. Compared with other types, Ig amyloidosis was associated with lower serum creatinine, higher degree of proteinuria, and amyloid spicules.
CONCLUSIONS:  In the authors' experience, the vast majority of renal amyloidosis cases are Ig derived. The newly identified leukocyte chemotactic factor 2 amyloidosis form was the most common of the rarer causes of renal amyloidosis. With the advent of laser microdissection/mass spectrometry for amyloid typing, the origin of renal amyloidosis can be determined in >97% of cases.
Here is a link to the article (not freely available):

I do not have this article, so I will just be discussing the abstract. This article describes the types of amyloidosis that were diagnosed in 474 renal amyloidosis cases evaluated at the Mayo Clinic Renal Pathology Laboratory from 2007 to 2011. So these were instances where a diagnosis was made from a kidney biopsy. Out of these 474 cases over five years, only six were diagnosed with fibrinogen amyloidosis. Keep in mind that this may not be the total number of fibrinogen cases diagnosed at Mayo during this time period, since sometimes a diagnosis cannot be determined from a kidney biopsy and genetic testing is required. (That was the case with Mom's diagnosis from Boston.) The abstract does state that there were 11 cases where the type of amyloidosis could not be determined from the biopsy, so it is possible some of those cases were eventually diagnosed with fibrinogen amyloidosis.

So now we have rough estimates from Boston (just under one) and from Mayo Clinic (a little over one) on the number of new fibrinogen amyloidosis cases diagnosed per year. Those two centers certainly see the vast majority of new amyloidosis patients each year in the US, and the only other location that might diagnosis nearly as many (or perhaps more) fibrinogen amyloidosis cases would be Dr. Benson in Indianapolis. But even if we estimate one from Boston, two from Mayo Clinic, and two from Dr. Benson annually, that's only five new cases per year in the US. Keep in mind that these are new cases where a patient has symptoms and gets a diagnosis, so there will be additional cases where people test positive for the mutation but are asymptomatic. So let's double the number to account for the asymptomatic patients, and now we're up to ten per year, which is probably on the high side.

So whenever someone in the US learns they have a genetic mutation for fibrinogen amyloidosis, I think it is safe to say they can use their fingers to count all the other people in the US who learned the same thing that year, and they may not even need both hands.

Aren't we special?

[The following update, regarding an abstract presented at the 2013 Annual Meeting of the American Society of Hematology, was added December 7, 2013.]

As luck would have it, I found some more data the day after I published this blog post. This additional info is from an abstract presented December 7, 2013, at the 2013 Meeting of the American Society of Hematology. Here is the title and a link to the abstract:

Title: Proteome of Amyloidosis: Mayo Clinic Experience In 4139 Cases


First of all, what is a proteome? The dictionary definition is that a proteome is the entire complement of proteins found within a cell, tissue or organism. In this context, the proteome of amyloidosis is the complete list of proteins that are known to cause amyloidosis. (These are often referred to as precursor proteins.) This paper gives the breakdown of amyloid subtypes found in 4139 cases where a tissue biopsy was evaluated at Mayo Clinic since 2008, when they started using a newly developed method for subtyping amyloid deposits. (It's called liquid chromatography electrospray tandem mass spectrometry, or LC-MS/MS. This is probably the technique people refer to as mass spec.) I assume there will be some overlap with the previous article that covered the years 2007 to 2011 in the Renal Pathology Lab at Mayo Rochester.

Here is the table showing the distribution of amyloid subtypes in these 4139 cases.

Frequency of amyloid subtypes observed in the Mayo Clinic Amyloid Cohort (n=4139).
Asterisk denotes non-canonical subtypes.

As shown in the table, there were 26 fibrinogen amyloidosis (AFib) diagnoses among these 4139 cases (0.63%), over a period of five to six years (2008 to 2013 inclusive). So that is still only 4 or 5 per year diagnosed at Mayo Clinic. But what if we compare the data in this article to the previous one, which had data from the Mayo Clinic Renal Pathology Laboratory from 2007 to 2011? The earlier article reported six cases of Afib, whereas this more recent article reported 26 cases. Does that mean there have been at least 20 cases diagnosed at Mayo Clinic since the data was gathered for the earlier paper? It looks that way based solely on the data we have, but we cannot say for certain without more information, such as the date of each fibrinogen amyloidosis diagnosis at Mayo Clinic since 2007.

Whatever the true numbers may be, the data clearly shows that fibrinogen amyloidosis is among the rare types of familial amyloidosis, and familial amyloidosis only accounts for about 20% of the total amyloidosis cases, and amyloidosis itself is a rare disease.

=====Monthly Blog Status Update=====

Total posts: 113 (7 in November)

Total pageviews: 9700 (~1000 in November)

Email subscribers: 6

Total number of countries that have viewed the blog: 79

No new countries viewed the blog in November: :-(


(1) Skinner M, Berk JL, Connors LH, Seldin DC. XIth International Symposium on Amyloidosis: Taylor & Francis; 2010.

(2) Said SM, Sethi S, Valeri AM, et al. Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases. Clin J Am Soc Nephrol. 2013;8(9):1515-1523.

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