Saturday, April 19, 2014

Article Review (2011) - Long-term follow-up of patients with hereditary fibrinogen A alpha-chain amyloidosis

Today's article review concludes the Portugal series, which started with the April 5, 2014 blog post on a 2004 article describing the first fibrinogen amyloidosis case in Portugal. Then the April 12 blog post covered two abstracts about Portuguese patients (2005 and 2008), and we learned about a cluster of patients concentrated in northern Portugal. Today's article from 2011 reports on this same cluster of patients.

Title: Long-term follow-up of patients with hereditary fibrinogen A alpha-chain amyloidosis (1)

Authors: I. Tavares, L. Lobato, L. Moreira, J. Santos, P. Lacerda, J. Pinheiro, P. Costa (Various institutions in Portugal)

Journal: Amyloid (2011)

Fibrinogen A alpha-chain amyloidosis (AFib) is an autosomal dominant condition with variable penetrance, usually of late onset. Progression to stage V chronic kidney disease is a consistent feature. There is a cluster of AFib in the district of Braga, Portugal, characterized as a systemic disease with a high penetrance.

Here is a link to the article (not free) if you would like to follow along:

The introduction of this article gives some background on fibrinogen amyloidosis and refers to the 2009 article by Gillmore, et al (reviewed January 12, 2014) and the 2010 article by Stangou, et al (reviewed February 21, 2014). It then states that this article reports on a systematic study of 25 Portuguese patients with AFib who were followed for a median time of eight years.

The Methods section of the article states that 12 of these patients were identified in a biopsy study, and 13 were identified in a screening study after that. The screening study involved 190 patients from the same geographical area (Braga district of northern Portugal) who were either relatives of the initial 12 patients, or had some reason to suspect amyloidosis, such as kidney failure or proteinuria.

The Results section of the article states that they identified 25 patients with AFib, 14 asymptomatic carriers, and 8 carriers with hypertension. That is a total of 47 patients with the Glu526Val mutation, including the one patient who was homozygous (reported in the 2005 abstract.) The kidney biopsies all showed massive glomerular deposits, but there were some deposits elsewhere. Amyloid deposits were also found in the abdominal subcutaneous fat of one patient. (Fat pad biopsies on AFib patients are usually negative.) Another unusual finding was a family history of renal disease in 80% of the patients, which is much higher than in previously published reports.

The median age at presentation for these patients was 62 years, and the median time from presentation to dialysis was 50 months. Clinically significant medical issues other than renal disease included:
  • Eight patients had strokes.
  • Two patients had severe coronary disease.
  • One patient had echocardiogram findings consistent with cardiac amyloid.
  • One patient had a pacemaker.
  • One patient had resections of the small intestine and the colon. Biopsies of both of the removed sections showed amyloid deposits.
  • Seven patients had peptic ulcer disease.
  • One patient had a spontaneous spleen rupture. Amyloid deposits were found in the ruptured spleen.
  • Four patients had peripheral neuropathy

Only one of these patients had an organ transplant, and that was the patient who was homozygous for the mutation. She had a kidney transplant in 1996, and fourteen years later there was still no clinical evidence of amyloid recurring.

Of the 25 AFib patients, 17 had died as of when this article was written. Their median age at death was 75 years (range 46 to 84), and stroke was the leading cause of death (6 patients).

The article concludes by stating that fibrinogen amyloidosis in this cluster of patients is a systemic disease with high penetrance. It also states that vascular disease was a frequent cause of morbidity and mortality.


The first thing that stands out about this group of patients is their geographical concentration in one area of Portugal. The Braga district has an area of just over 1000 square miles and a population slightly under one million people. To give you some perspective of how prevalent fibrinogen amyloidosis is in this area compared to the rest of the world, if this same mutation rate of 47 per million people were applied to England and the US, there would be over 2400 AFib cases in England and over 14,000 in the US.

The symptoms beyond kidney disease (extra-renal symptoms) among this group of patients are somewhat similar to the symptoms reported previously in other populations. Even though amyloid deposits are found in other organs, I think it is difficult to determine how much the variant fibrinogen contributed to those other symptoms, and it is almost certainly impossible to predict what organs may be affected in a newly diagnosed patient or one who is just beginning to develop symptoms. The important thing to learn from these various reports of extra-renal symptoms is that fibrinogen amyloidosis is clearly a systemic disease, and one or more organs other than the kidneys will likely become affected to some extent after reaching end stage renal disease.

It is interesting that only one of these patients has received a kidney transplant, and that occurred in 1996. I did a bit of Googling on transplant rates worldwide, and although Portugal is not in the top group in terms of transplants per million people, it seems to be in the second group (out of five.) In fact, all residents of Portugal are presumed to be organ donors unless they opt out, so there should not be a shortage of donors. There are likely many things that factor into the reason for so few organ transplants for these AFib patients, such as the number of experienced transplant centers in that part of the country, but it is odd when compared to the reports from the US and UK. If any of our Portuguese readers would like to comment, please do so, or send me an email. (Se algum dos nossos leitores portugueses gostaria de comentar, por favor, fazĂȘ-lo, ou me envie um e-mail. Obrigado.)

In conclusion, this article informs us about a highly concentrated group of AFib patients with presumably close genetic ties who still have the typical variations in age of onset and extra-renal symptoms. If you combine that data with the variations among individuals within a kindred, then in my opinion this seems to indicate that genetics may play only a small role, or perhaps none at all, in determining how or when a person with the Glu526Val will be affected by the variant fibrinogen. The only thing that is remotely predictable is the progression to kidney failure once symptoms develop, but even that has significant variation.

The next article up for review takes us back to the subject of analyzing kidney biopsies.



(1) Tavares I, Lobato L, Moreira L, et al. Long-term follow-up of patients with hereditary fibrinogen A alpha-chain amyloidosis. Amyloid. 2011;18 Suppl 1:221-222.

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