Monday, January 6, 2014

Article Reviews (2008) - Cardiac Amyloidosis with the E526V Mutation of the Fibrinogen A alpha-chain

Today's article review will cover two articles from 2008 that appear to be about the same patient. This is the first reported case of cardiac amyloidosis in a patient with fibrinogen amyloidosis. As if kidney failure is not enough to be concerned with, now we add the possibility of heart involvement. I will talk about that some more at the end of this review, including some correspondence I had with the author of one of these articles and with one of the Boston doctors.

Title: Myocardial involvement in fibrinogen A-alpha chain amyloidosis (1)

Authors: G. Gahide, F. Roubille, J. C. Macia, V. Garrigue, H. Vernhet (Centre Hospitalo-Universitaire de Montpellier, Montpellier, France) 

Journal: European Journal of Internal Medicine (November 2008)

Title: Cardiac Amyloidosis with the E526V Mutation of the Fibrinogen A alpha-chain (2)

Authors: Georges Mourad, Jean-Philippe Delabre, Valerie Garrigue (University of Montpellier Medical School, Montpellier, France)

Journal: New England Journal of Medicine (December 2008)

I will be reviewing these two articles together since they are about the same patient. When I need to refer specifically to one article I will refer to them as the November article and the December article.

The December article is freely available online, and here is a link to the PDF: I found that article in November of 2010, based on the download date on my PDF version. But for some reason I did not find the November article until last month. It is not freely available online, but here is the PubMed link:

The December article begins with these two sentences: "Proteinuria developed in a 48-year-old man in 2003. He mother had died 10 years earlier from renal amyloidosis." That really got my attention the first time I read this article because at the time I was 48 and I knew my mother had fibrinogen amyloidosis.

Here is what I believe is the chronology of this patient, based on information from both of these articles. (I am not positive I have the ages or the sequence of events exactly correct, as it was difficult to reconcile the timelines in both articles.)

Age 48:  Proteinuria (over 7 grams per 24 hours). Creatinine clearance and GFR were normal.

A kidney biopsy showed amyloid deposits in the glomeruli. He was originally diagnosed with AL amyloidosis, but familial amyloidosis was suspected since his mother had died from renal amyloidosis. Genetic testing showed he had the Glu526Val mutation for fibrinogen amyloidosis. (Note: Since his mother died around 1993, she died before the first article on the Glu526Val mutation was published.)

Age 51:  Patient reported dyspnea (shortness of breath), which gradually got worse. He had no family history of heart disease.

Age 53: Patient referred for a myocardial hypertrophy (thickening of the heart muscle). Echocardiogram and MRI showed various heart issues, so multiple heart biopsies were obtained from the affected area(s). Those biopsies showed amyloid, but more importantly, the tissue stained specifically with antifibrinogen antibodies, indicating the amyloid was due to fibrinogen.

Patient received a pacemaker, and then an implanted defibrillator.

Both articles give details on the heart issues found with this patient. I am not going to repeat or summarize those here, since they are way beyond my comprehension. The November article has four images from the cardiac MRI, and it does stress how valuable MRI can be when evaluating cardiac amyloidosis.


These two articles discuss an unusual case of clinically significant heart involvement in a patient with fibrinogen amyloidosis. The articles do not state what his kidney function was after he initially presented with proteinuria at the age of 48, so perhaps we can assume it was less clinically significant than the cardiac issues.

What does all this mean for those of us with a fibrinogen amyloidosis mutation? Do we need to start having periodic echocardiograms or cardiac MRIs now, even if we have no kidney issues? Is it possible to have heart involvement before kidney involvement? Do we just not worry about cardiac amyloidosis until we start having heart issues? These were some of the questions I had after the first time I read the December article. Since the prognosis for cardiac amyloidosis is rather poor if left untreated I have been very interested in this topic for the past three years, so I will give you my current opinion on the subject. Keep in mind that I am not a doctor and all of this is subject to change as more data becomes available, so the best thing to do is discuss it with your doctor.

One thing I did to help answer some of my questions was send an email to the primary author of the December article, Dr. Mourad. Going over my old emails, it looks like I sent that email in February of 2011, the day after I found out I had the Glu526Val mutation. I explained my situation and asked him two questions, and he replied the following day. The first question was about some data from the article, which stated about 40 cases of fibrinogen amyloidosis had been reported since it was first described in 1993. (Remember this article was from 2008.) I asked if that was 40 cases in France, Europe, or globally. He said it was 40 cases reported in the international literature at the time they wrote the article.

In my other question I asked him what he would recommend someone with the mutation who is asymptomatic do proactively before renal symptoms develop, such as getting an echocardiogram. He said he would recommend checking for proteinuria and hematuria annually or every two years, as well as getting an echocardiogram every year or two.

In October of 2012 I became curious about this subject again for some reason, so I sent Dr. Berk in Boston an email with the same general question regarding periodic echocardiograms for someone who has the mutation but is asymptomatic, vs. someone who does have kidney involvement. He said there are no consensus guidelines, but the focus of periodic checkups should be on renal function. He did say periodic echocardiograms or measurements of cardiac biomarkers should suffice, with additional studies as appropriate.

I also asked Dr. Berk about having an echocardiogram done outside of a Center of Experience such as Boston or Mayo Clinic, because I had heard or read that detecting amyloid on an echocardiogram can be easily missed by someone with very little training or experience with cardiac amyloidosis. He said echocardiogram reports tend to reflect the familiarity of the person reading the echocardiogram with amyloidosis, and he would recommend having echo images reviewed by a cardiologist well versed in amyloid.

One thing I have learned over the years is that cardiac amyloidosis can be difficult to diagnose and often goes undiagnosed because the symptoms are so similar to those caused by other more common heart ailments. Unlike declining kidney function, which has early warning biomarkers such as proteinuria, GFR, and serum creatinine level, there are no biomarkers that are considered clear early warning signs of cardiac amyloidosis. It requires more of an overall assessment, including tests like echocardiogram or MRI.

Based on all that, I do not think a person with fibrinogen amyloidosis needs to be overly concerned about possible cardiac involvement. Keep in mind that these articles from 2008 are the only published account of cardiac amyloidosis in a patient with fibrinogen amyloidosis. (There are some later articles that indicate some degree of cardiac involvement may be more common than previously thought, but it generally does not become clinically significant.) Another important fact from this 2008 case is that this patient had proteinuria for three years before he had any signs of heart trouble. As long as you are getting an annual physical exam and there are no kidney or heart issues, I do not think there is a need to go looking for cardiac involvement.

The situation changes once kidney issues appear, however. At that point it may make sense to talk to your doctor about getting an echocardiogram to serve as a baseline measurement if nothing else. I do not think it is urgent by any means, and if you start investigating a liver or combined liver and kidney transplant, you may have an echocardiogram as part of that evaluation anyway. If you are evaluated at Mayo Clinic or Boston you will almost certainly have an echocardiogram done there.

The situation definitely changes if heart issues develop to the point where you are referred to a cardiologist. That is where the patient really needs to be their own advocate and talk to their cardiologist about amyloidosis. You do not necessarily have to become well-versed in the medical terminology such that you are comfortable talking about ejection fraction, wall-thickening, and the classic sparkly appearance of amyloid on echocardiograms. At a minimum, you need to make sure your cardiologist understands that cardiac amyloidosis can mimic other more common heart ailments, and suggest that he or she consult with an experienced cardiologist at either Boston or Mayo Clinic (or perhaps another Center of Experience if not in the US.)

When I went to Mom's cardiologist appointments with her earlier this year, I had a good discussion with him and felt like he was aware of what to look for. I did bring a copy of the December article for him to keep and review at his leisure if he wanted to. (No need to make him scan it over quickly during the appointment, just to hand it back and say he does not need a copy.)

Given the rarity of the diagnosis in this case (fibrinogen amyloidosis with cardiac involvement), there simply is not a lot of experience to generate any firm guidelines on how to proceed. Each patient's case will be different, and based on the data we have it will not be an issue at all for most patients. My goal here is to make people aware of the possibility so they can decide for themselves what they are comfortable doing. Some people may decide not to do anything until they have heart issues, whereas others may want to get a baseline echocardiogram before reaching the age of 40 while they are asymptomatic. Either approach can be considered reasonable.

In summary, my opinion is that there is no need to panic about possibly having cardiac involvement if you have a fibrinogen amyloidosis mutation. You do need to be aware of the possibility, especially if and when you develop kidney issues, since kidney issues will very likely occur first. At that point it may make sense to be proactive and get an echocardiogram before heart issues develop. That is certainly something to discuss with your doctor at that point. If you do develop heart issues, you want to make sure you are under the care of a cardiologist who either has some familiarity with amyloidosis, or will consult with a cardiologist who does.

The next article up for review is one of the more important ones published to date regarding fibrinogen amyloidosis, as it reports on 71 patients. Yes, 71. I have not looked at this article in a year or two, but you can probably expect a lengthy post (maybe even a two-parter) with lots of data.



(1) Gahide G, Roubille F, Macia JC, Garrigue V, Vernhet H. Myocardial involvement in fibrinogen A-alpha chain amyloidosis. Eur J Intern Med. 2008;19(7):e54-56.

(2) Mourad G, Delabre JP, Garrigue V. Cardiac amyloidosis with the E526V mutation of the fibrinogen A alpha-chain. N Engl J Med. 2008;359(26):2847-2848.

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