Saturday, April 26, 2014

Article Review (2012) - Renal amyloidosis associated with a novel fibrinogen A alpha chain (Afib) mutation

Today's article under review brings us to the year 2012, and it is the first of two abstracts I will be reviewing from the 2012 XIIIth International Symposium on Amyloidosis. The 2012 symposium was held in May of 2012 in Groningen, The Netherlands, which was also the site of the first International Symposium on Amyloidosis in 1967. These symposia are now held every two years, which means there should be one in 2014. And as some of you know, it is being held April 27 through May 1 in Indianapolis, Indiana, hosted by our very own Dr. Merrill Benson. Here is the link to the web site for this year's symposium:

Wow, I just discovered the symposium book is available to download from that site (go to the Program page), and it seems to have all of the abstracts that will be presented. The word "fibrinogen" is in there at least 14 times, so there might be some interesting abstracts for those of you who want to read ahead. I will likely be reviewing one or more of those articles in the blog in a couple of months. Ok, back to today's abstract . . .

Title: Renal amyloidosis associated with a novel fibrinogen A alpha chain (Afib) mutation

Authors: Yvonne A. Efebera, Dorota Rowczenio, Anjali Satoskar, Don M. Menson, Tobor Nadasdy, Philip N. Hawkins (The Ohio State University; National Amyloidosis Centre, London, UK)

Here is the link to a PDF file with all of the abstracts for the 2012 symposium, if you would like to follow along. This abstract is on pages 413 and 414:

This abstract describes the case of a man diagnosed with mild renal insufficiency in 1998 and mild proteinuria in 2005. In October of 2011, at the age of 80, his kidney problems had worsened to the point where his serum creatinine was 5.95 mg/dl and proteinuria was 6379 mg/day. He had no other significant symptoms, and his past medical history included high blood pressure and high cholesterol, both of which were under control. He had no family history of renal disease. His parents were Russian and died at age 72 and 75.

A kidney biopsy showed amyloid deposits in the glomeruli that stained strongly for fibrinogen, and DNA analysis showed this patient had a previously unreported fibrinogen mutation. This mutation was also at position 526, like the most common fibrinogen amyloidosis mutation, Glu526Val. But instead of substituting Valine for Glutamic acid, this mutation substituted Lysine for Glutamic acid. So this mutation would be written as Glu526Lys (or E526K instead of E526V). (For the uber-curious readers: The GAG for Glutamic Acid was changed to AAG for Lysine in this mutation.)

The abstract states that the clinical presentation for this patient was indistinguishable from that of a patient with the Glu526Val mutation, and the amyloid deposition in the biopsy was similar. One major difference between the two mutations is that this patient is of Russian ancestry, whereas the majority of patients with the Glu526Val mutation are of European ancestry.


This mutation is the first new one reported in the literature since the 2009 article by Gillmore, et al (the study of 71 patients) reported on four new mutations. It is interesting that this mutation occurs at the same point as the Glu526Val mutation. As stated in the article, the symptoms of this patient were the same as what we would expect in a patient with the Glu526Val mutation. The symptoms did appear later in life and progress more slowly than we typically see in patients with the Glu526Val mutation, but we cannot draw any conclusions from a single case.

The article did not state whether or not this patient had any offspring, and it did not mention any other relatives. It will be interesting to see if this mutation appears again in the literature, either in this same kindred or a different one.

Next up for review is another abstract from the 2012 symposium which revisits the topic of organ transplants.

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, fazê-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.

Sunday, April 13, 2014

Article Reviews (2005 and 2008) - AFib in Portugal

Today's blog post will actually cover two more abstracts, both of which describe fibrinogen amyloidosis patients in Portugal

Title: Fibrinogen A-alpha Chain Amyloidosis: Homozygosity for the Glu526Val Mutation

Authors: Carlos M. Matos, Isabel Tavares, Paul Moreira, Elísio Carvalho, Maria J. Saraiva, Luisa Lobato. (Nephrology, Hospital Geral de Santo António, Porto, Portugal; Nephrology, Hospital de São João, Porto, Portugal; Molecular Neurobiology, Instituto de Biologia Molecular e Celular, Porto, Portugal.)

Here is a link to this abstract if you would like to follow along:

This paper is an abstract presented at the XLII ERA-EDTA Congress in June of 2005. ERA-EDTA is the European Renal Association - European Dialysis and Transplant Association.

The previously reviewed article (in the April 5, 2014 blog post) described the first case of fibrinogen amyloidosis in Portugal. The current abstract, from 2005, presents another case from Portugal with an interesting twist we have not seen before. The patient in this case was a Portuguese woman who presented with hypertension and renal failure (among other things) at the age of 44. A kidney biopsy showed extensive amyloid deposits in the glomeruli. She started hemodialysis at the age of 45 and received a kidney transplant six years later. Nothing unusual about this case so far . . .

Her original kidney biopsy was re-evaluated by immunohistochemistry and found to be positive for fibrinogen. DNA analysis showed she had the Glu526Val mutation, but instead of being heterozygous (one gene is normal, one is mutated) she was homozygous for the mutation. That means she inherited the mutation from her mother and from her father. Both of her parents died in their 80s without any known kidney issues. The only family history of kidney disease she was aware of was an aunt on her father's side who developed end-stage renal disease late in life.

At the time this abstract was written, it was 8 years after her kidney transplant and she had stable kidney function with no proteinuria and a serum creatinine level of 1 mg/dL.


We cannot reach any firm conclusions about the effects of being homozygous vs. heterozygous for the Glu526Val mutation from this one case. It does mean 100% of her fibrinogen was variant instead of 50% for heterozygous patients. On the one hand, she required dialysis at the age of 45, which is toward the low end of the range (36 to 82) presented in the 2009 article by Gillmore, et al. On the other hand, her kidney transplant was showing no clinical sign of amyloid after 8 years. They did find that her fibrinogen levels were low but her blood clotting times were normal.

The fact that this patient inherited the Glu526Val mutation from both parents means the mutation was present in two different family trees that happened to join together when her parents married and had offspring. So the chances are good that some more cases from Portugal will be reported. Sure enough, three years later, at this same conference, another abstract is presented that reports on fibrinogen amyloidosis patients in Portugal.

Title: Fibrinogen Amyloidosis: Report of the Portuguese Cluster

Authors: Isabel Tavares, Luciana Moreira, Joaquim Pinheiro, M. João Rocha, Elíseo Carvalho, Paulo P. Costa, Luísa Lobato. (Unit of Inv. and Research in Nephrology (FCT-725), Portugal, Fac. of Medicine, Porto, Portugal; Centro Estudos Paramiloidose, INSA, Porto, Portugal; Depart. Nephrology, Hospital Militar, D. Pedro, Porto, Portugal; Depart. Nephrology, Hospital Geral Santo António, Porto, Portugal)

Here is a link to this abstract if you would like to follow along:

This paper is an abstract presented at the XLV ERA-EDTA Congress in May of 2008. It states that Portuguese patients with amyloidosis, proteinuria or renal failure since 1985 were evaluated for this study. Biopsies were tested by immunohistochemistry, and if AL, AA, or ATTR amyloidosis could not be identified, then DNA analysis was done to identify mutations in apolipoprotein A1 and A2, fibrinogen and lysozyme. They did not identify any patients with apolipoprotein A1 or A2, or lysozyme, but they did identify 12 patients with the fibrinogen Glu526Val mutation, including the homozygous patient described in the 2005 abstract. (That does explain why her kidney biopsy was re-evaluated, as mentioned in the previous abstract.)

Since all of these patients were from Portugal, a country with a population of about 10 million, that alone seems like a high concentration of fibrinogen amyloidosis patients. But now consider the fact that all of these patients are from the Braga district in northern Portugal, which has a population between 800 and 900 thousand, and it is clear that the word "cluster" to describe this group of AFib patients is appropriate. These kindreds had no known relation to each other, but it is quite likely they have a common ancestor, given the geographical distribution of the families.

The abstract gives some more clinical data on these patients, and it does state that organ involvement in addition to kidneys was frequent with them. I am not going to discuss those details at this point because it is repeated in the next article up for review, which was published three years later in 2011. But I will let you know that the homozygous patient described in the 2005 abstract still had no sign of recurring amyloidosis when this 2008 abstract was written, 11 years after her kidney transplant.

The next article to be reviewed will have more information on these Portuguese patients, plus it will have the benefit of three more years of follow-up. We will take a closer look at the symptoms among this group, and we will also find out about the homozygous patient and her kidney transplant. Stay tuned . . .

Saturday, April 5, 2014

Article Review (2004) - Mutant fibrinogen A alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy

Before getting to today's article review I want to give a quick update on Mom. The previous update on Mom (March 7, 2014) described her reevaluation for getting back on the kidney transplant list. We were feeling good about her chances and expected to hear something in two to three weeks. Well, it seems like there has been very little progress with regard to the pre-transplant group gathering the information they need from Mom's various doctors. I sent an email to Mom's transplant coordinator who then called Mom a few days later, on March 31. She asked Mom several questions about recent doctor visits that Mom knows she answered when we were there at the end of February. Then someone else in the pre-transplant group called me on April 2 and said Mom needs to see her cardiologist so his office can provide a release letter. Gee, thanks for waiting a month before finding out about that.

Although Mom likely would not get a kidney for at least a year even if she were approved today, and her waiting time is still accruing while she is waiting to get back on the list, it is still frustrating to be in this situation after being told we would know something around the middle of March.

Today's article review is another repeat of a previous review that was done when I only had the abstract. This article was first reviewed on May 31, 2013, and it describes a case of fibrinogen amyloidosis that is unique for two reasons. It is the first reported case of fibrinogen amyloidosis from Portugal, and it is the first reported case of peripheral neuropathy in a patient with fibrinogen amyloidosis. The next few articles to be reviewed will also have a Portugal connection, which is why I waited until now to re-review this one.

Title: Mutant fibrinogen A alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy (1)

Authors: Mamede de Carvalho, Reinhold P Linke, Fernando Domingos, Teresinha Evangelista, José Luís Ducla-Soares, Walter BJ Nathrath, Conceição Azevedo-Coutinho, Raquel Lima and Maria João Saraiva (all from Portugal or Germany)

Journal: Amyloid (2004)


A middle age Portuguese woman was investigated for renal amyloidosis. She presented with progressive renal failure, proteinuria, hypertension, and sensory symptoms in the feet. Clinical and neurophysiological evaluation disclosed sensory-autonomic neuropathy. Cardiovascular tests and 123-MIBG investigation showed parasympathetic dysfunction and decrease of myocardial innervation, in accordance with small fiber neuropathy, as usually observed in amyloidosis. Immunohistochemical studies revealed AFib amyloidosis and genetic studies the amino acid exchange Glu526Val of the fibrinogen Aα-chain mutation, which was also present in one of her sons. The mutant gene in this patient was associated with the same haplotype as all other reported cases of Glu526Val mutations. This is the first reported AFib amyloidosis in Portugal, and the first case of AFib in which sensory and autonomic nerve fiber dysfunction is described, indicating that small nerve fiber lesion can occur in the fibrinogen A alpha chain mutation. This can be important for prognosis, in particular when liver transplantation is considered for treatment.

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

This article begins with a brief introduction to the proteins associated with hereditary renal amyloidosis (fibrinogen, lysozyme, and apolipoprotein AI and AII), then it gives some history of fibrinogen amyloidosis and the various mutations that had been discovered up to that point.

The patient in this case was a female who was referred to a nephrologist in 1988 at the age of 55 for proteinuria and moderate renal failure. She was diagnosed with hypertension at the age of 50. There was no history of renal failure in her family and all four of her sons were in good health. Her family originated from northern Portugal.

Her serum creatinine in 1988 was 1.4 mg/dl, and her 24-hour proteinuria was 2 grams. She was slightly anemic with hemoglobin of 10.8 g/dl. A kidney biopsy stained positive for amyloid deposits with Congo red. The amyloid deposits were concentrated in the glomeruli. Remember this was 1988, before the first fibrinogen mutation that caused amyloidosis was discovered.

Ten years later, in 1998, she developed mild neuropathy in her feet. Her serum creatinine was still 1.4 mg/dl but her 24-hour proteinuria had increased to 2.8 grams. An echocardiogram showed some signs of amyloid deposition.

In 1999 her blood pressure became more difficult to control and edema appeared in her legs. Her serum creatinine was still stable but her proteinuria had increased to 3.3 grams/day. A second kidney biopsy was done, and in addition to Congo Red staining, this biopsy also underwent immunohistochemical analysis. (More on that later.)

In 2001 her renal failure progressed to the point that she started hemodialysis, with a serum creatinine was 5.3 mg/dl. Her peripheral neuropathy remained stable compared to her evaluation in 1998.

The Methods section of this article goes into detail on the methods of performing the immunohistochemistry on various tissue samples, the DNA analysis, another type of genetic analysis, and autonomic and cardiovascular evaluations. Most of that is beyond my understanding so we will move to the Results section.

The Results section begins by discussing the immunohistochemistry findings. There was a moderate (not strong) reaction for fibrinogen, with all other types showing a weak or negative reaction. DNA analysis showed she had the fibrinogen Glu526Val mutation. The article says three of her siblings did not have the mutation, then it says the one with the mutation had normal renal function. I am confused by that because at the beginning of the article it says she had three sisters and one brother, but the brother died before the age of two. The abstract says one of her sons had the mutation, so perhaps "the one with the mutation" should be "the one offspring with the mutation."

The results of the haplotype studies are then discussed. A "haplotype," in case you do not remember from the previous review of this article, is a set of DNA variations that tend to be inherited together. This patient's mutation was part of the same haplotype as found in all patients previously described in the medical literature with the Glu526Val mutation, which is a strong indication that all of these patients have a common ancestor with the mutation.

The Discussion section begins by summarizing the case and stating it is the first Portuguese family described with the fibrinogen Glu526Val mutation. The article states that fibrinogen amyloidosis is associated with kidney, liver and spleen involvement, and this case is the first one described with polyneuropathy. Although no amyloid deposits were found on this patient's sural nerve biopsy, this is not unusual and is often the case in ATTR patients because the amyloid does not deposit in a uniform manner along the length of the nerve. There is some additional discussion of this patient's neuropathy that I am unfamiliar with, so I won't try to explain that.


Although this case is the first description of neuropathy in a fibrinogen amyloidosis patient, I find this case very interesting due to the length of time it took the disease to progress from mild renal failure to end stage renal failure. In 1988 this patient had hypertension, proteinuria, and biopsy-proven amyloidosis, yet she did not need dialysis until 2001, 13 years later. In the study of 71 patients published in 2009 (reviewed in the January 12, 2014 blog post),  the median time from presentation with proteinuria to end stage renal disease was 4.6 years, with the longest time at 10.2 years. So this patient from Portugal experienced a much slower progression of the disease than most people do. Her serum creatinine remained stable for at least 11 years (1988 through 1999), so maybe serum creatinine is a better indicator of disease progression then proteinuria.

Next up for review: More patients from Portugal.

==Monthly Blog Status Update===== 

As of March 31, 2014:

Total posts: 132 (4 in March)

Total pageviews: 13,400 (~1200 in February)

Email subscribers: 10 (gained 2 in March)

Total number of countries that have viewed the blog: 88

3 new countries viewed the blog in March:

Puerto Rico


(1) de Carvalho M, Linke RP, Domingos F, Evangelista T, Ducla-Soares JL, Nathrath WB, Azevedo-Coutinho C, Lima R, Saraiva MJ. Mutant fibrinogen A-alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy. Amyloid 2004;11:200–207.