Friday, May 31, 2013

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

This article review will be a short one since I do not have this article, so we will rely on the abstract. This article reports a case of fibrinogen amyloidosis in a country not previously reported, and the patient has some symptoms not typically associated with this disease.

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.

As stated in the abstract, this article reports on a Portuguese woman who was found to have fibrinogen amyloidosis (Glu526Val mutation). This was the first reported case of fibrinogen amyloidosis in Portugal, and as we will see in a future article it will not be the last.

The really interesting thing about this case is that in addition to the symptoms typically associated with fibrinogen amyloidosis (renal failure and proteinuria) this patient also presented with neuropathy in her feet. Since the lack of neuropathy was a distinguishing characteristic of hereditary renal amyloidosis that differentiated it from the other familial types of amyloidosis, the presence of neuropathy in this case is notable. At this point we do not know if this is an anomaly or if neuropathy will be reported as a symptom in a small percentage of cases.

Since this is such a short blog post I want to focus on one sentence in the abstract which uses a word I have seen in previous articles but have not investigated further until now: "The mutant gene in this patient was associated with the same haplotype as all other reported cases of Glu526Val mutations."

What the heck is a haplotype? To quote from an internet source, a haplotype is a set of DNA variations that tend to be inherited together. In the case of fibrinogen amyloidosis, the Glu526Val mutation is just one DNA variation. But when the researchers have examined the DNA of people with this mutation and looked at other DNA variations on the same chromosome (number 4), they see a number of variations that are common among all the patients (as of this article's publication in 2004). This set of DNA variations is a haplotype. If this same set of DNA variations is common to all patients with the fibrinogen Glu526Val mutation, that is a good indication that these patients all have a common ancestor. That common ancestor can be considered the "founder" of this mutation. We'll be on the lookout in future articles to see whether future cases of the Glu526Val mutation are associated with this same haplotype or with a different one.

Next up: Two articles that summarize what was known about hereditary renal amyloidosis in the mid-2000s.



(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.

Friday, May 24, 2013

Dialysis Five-O

It's hard to believe my last update on Mom was a month ago. I suppose that is a good sign that the issues are getting further and further apart. So what was happening on the April 24 update? Mom had just gotten the results of a biopsy on a lump on her left breast, which turned out to be benign. And the bump on her abdomen, apparently due to a piece of surgical felt that was intentionally left in place after her peritoneal dialysis catheter was removed, appeared to also be benign at this point with no change. So that's good.

This update starts with some good news. On May 1 Mom found out that her hemoglobin was up to 11, which is the highest it has been in about a year. It has been a real struggle to get her hemoglobin up since some time last summer, when it dipped below 8. This is really good news and she will hopefully have more energy as a result. (After all, 11 is one louder than 10.They are still going to give her Epogen during dialysis, which I assume is to make sure it stays above 10. She is obviously in no danger of iron overload at this point.

Mom and Ed went to Hawaii for two weeks in May with several members of Ed's family. She had dialysis a total of six times while in Hawaii, and there were no issues, thank goodness. Well, there were no dialysis issues, anyway . . .

Remember that bump on her abdomen that seemed benign last month? Shortly after they arrived in Hawaii that bump started swelling, eventually to the point where it looked like a pimple with the diameter of a pencil eraser. (That sounds big and gross, doesn't it? Too bad I don't have any pictures.) It ruptured two days before they left Hawaii and it started draining some pus. Mom put a bandage on it which she changed about four times each day. As of today (May 24) they have been back five days and it only has a minor discharge. On the plus side, that bump is pretty much gone and she doesn't feel it any more under her skin. She does have an appointment next week to have it looked at. Hopefully this discharge is just a one-time occurrence and the surgical felt won't cause any more problems.

Naturally, after having two weeks of dialysis in Hawaii with no issues, her very first dialysis session after returning did not go so well. It began fine, but after about two hours she started having intense pain in her arm. She made them stop dialysis at that point because it was hurting so much. One of the techs suggested one of the needles may have been very close to a nerve, and that is what caused the intense pain to begin so suddenly. We don't know if it was that or they infiltrated the fistula. In any case, she only had two hours of dialysis that Monday, but the dialysis sessions on Wednesday and Friday were fine.

That's about it for now. Nothing too exciting going on unless Mom has to have surgery to remove the surgical felt from her abdomen.

Saturday, May 18, 2013

Article Review (2003) - Orthotopic liver transplantation for hereditary fibrinogen amyloidosis

This article review will give us some more examples of the use of organ transplantation in the treatment of fibrinogen amyloidosis. I do not have a copy of this article so I will rely primarily on the abstract plus some additional information I have regarding one of the cases presented in this article.

[Update: The following article was reviewed again on 10-12-13.]

Title: Orthotopic liver transplantation for hereditary fibrinogen amyloidosis (1)

Authors: Zeldenrust, S.; Gertz, M.; Uemichi, T.; Björnsson, J.; Wiesner, R.; Schwab, T.; Benson, M.

Journal: Transplantation (2003)

Systemic amyloidosis results from the deposition of insoluble protein fibrils in various organs and tissues. To date, several different proteins have been associated with amyloid fibril formation, including immunoglobulin light chain, serum amyloid A protein, and transthyretin. Recent reports have shown that variant fibrinogen chains can form amyloid in certain kindreds. Hepatic transplantation has previously been reported in the treatment of hereditary amyloidosis associated with variant transthyretin proteins, which are mainly synthesized in the liver. This article reports the first use and long-term follow-up of combined hepatic and renal transplantation in the successful treatment of two patients with hereditary fibrinogen amyloidosis. Both patients experienced sustained improvement in renal function and nutritional status at 6 1/2 years and 28 months of follow-up, respectively. Orthotopic liver transplantation is effective and potentially curative treatment of hereditary fibrinogen amyloidosis.

I want to explain the first word in the title of this article so you don't have to look it up. "Orthotopic" simply means something is occurring in the normal place in the body. In the case of organ transplants, a liver transplant is typically orthotopic because the old liver is removed and the new one is put in its place. Kidney transplants are typically not orthotopic because the old kidneys are left in place and the new kidney is placed below them.

This article reports on two more patients with fibrinogen amyloidosis who underwent liver-kidney transplants. You may recall the first article to document such a case was published in 2000, and I reviewed that article on April 30. So we now have two more documented cases of liver-kidney transplants, with one of these patients doing well 6 1/2 years after the transplant. The abstract of this article also states that liver transplantation is effective and potentially curative for treating fibrinogen amyloidosis.

Since we only have the abstract of this article we do not have the medical history of these patients, describing at what ages they first presented with kidney problems or when they had kidney failure or organ transplants. But I do have some information on one of these patients. The article from 2000 about the English woman who underwent a liver-kidney transplant in October of 1996 mentioned an unpublished report from 1998 about a liver-kidney transplant to treat a fibrinogen amyloidosis patient. It turns out that one of the patients discussed in this 2003 article is the patient that was mentioned in the unpublished report in 1998. Since our current article was published in February of 2003 it is safe to assume it was written late in 2002 (or earlier). If we back up 6 1/2 years from late 2002, that puts us in the first half of 1996, which is the latest date this patient could have received the liver-kidney transplant.

So yes, this patient was the first to receive a liver-kidney transplant for fibrinogen amyloidosis. He initially developed kidney issues before the fibrinogen mutation was discovered. He first had a kidney-only transplant but lost the transplanted kidney due to recurring amyloidosis within 18 months and was back on dialysis. He eventually developed an enlarged spleen and had a liver-kidney transplant at Mayo Clinic.


With this article we now have three reported cases of liver-kidney transplants to treat fibrinogen amyloidosis, through approximately the middle of the year 2000, all with good results and no recurrence of amyloidosis. As stated in the articles, the results seem to indicate that a liver transplant might be considered curative for fibrinogen amyloidosis.

The next article will report on fibrinogen amyloidosis in another country in Europe, and more importantly, a new symptom exhibited by this patient.


(1) Zeldenrust S, Gertz M, Uemichi T, et al. Orthotopic liver transplantation for hereditary fibrinogen amyloidosis. Transplantation 2003; 75: 560-561.

Sunday, May 12, 2013

Article Review (2002) - Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis

This article review covers another article from many of the same doctors who authored the previously reviewed article from 2000. This article gives us some idea of how common the fibrinogen Glu526Val mutation really is.

TitleMisdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis (1)

Authors:  Helen J. Lachmann, M.B., B.Chir., David R. Booth, Ph.D., Susanne E. Booth, Alison Bybee, Ph.D., Janet A. Gilbertson, Julian D. Gillmore, M.B., B.S., M.D., Mark B. Pepys, M.D., Ph.D., and Philip N. Hawkins, M.B., B.S., Ph.D. (All from the National Amyloidosis Centre, London, UK)

Journal: New England Journal of Medicine (2002)

Background: Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes encoding transthyretin, fibrinogen A α-chain, lysozyme, or apolipoprotein A-I, is thought to be extremely rare and is not routinely included in the differential diagnosis of systemic amyloidosis unless there is a family history.
Methods: We studied 350 patients with systemic amyloidosis, in whom a diagnosis of the light-chain (AL) type of the disorder had been suggested by clinical and laboratory findings and by the absence of a family history, to assess whether they had amyloidogenic mutations.
Results: Amyloidogenic mutations were present in 34 of the 350 patients (9.7 percent), most often in the genes encoding fibrinogen A α-chain (18 patients) and transthyretin (13 patients). In all 34 of these patients, the diagnosis of hereditary amyloidosis was confirmed by additional investigations. A low-grade monoclonal gammopathy was detected in 8 of the 34 patients (24 percent).
Conclusions: A genetic cause should be sought in all patients with amyloidosis that is not the reactive systemic amyloid A type and in whom confirmation of the AL type cannot be obtained.

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

This article starts with a discussion about differential diagnosis with amyloidosis, which is typically trying to determine whether a patient has AL or AA amyloidosis. Since familial types of amyloidosis are thought to be so rare, they are usually not considered in the differential diagnosis unless a patient has a family history that would indicate they may have a familial type. However, recent studies have indicated that two specific mutations associated with familial amyloidosis (the transthyretin Val30Met and the fibrinogen Glu526Val mutations) may not be as rare as previously thought.

The Methods section of the article describes the population of patients included in this study and the types of testing they did across the population. They studied 350 patients who had been referred to the National Amyloidosis Centre in the UK between 1997 and 2000 with a diagnosis of AL amyloidosis. AA amyloidosis had been ruled out for each patient, and none of the patients were aware of any family history that would indicate hereditary amyloidosis. They also studied the DNA of 50 anonymous healthy people from the general British population, and 22 additional healthy people who were first-degree relatives of patients with the fibrinogen Glu526Val mutation.

The tests performed on each of the 350 AL amyloidosis patients were:

  • DNA analysis, looking for known genetic mutations in transthyretin, apolipoprotein A1, fibrinogen A alpha-chain, and lysozyme.
  • Whole body SAP scintigraphy (graphical representation of amyloid load, previously discussed in this article review from 2000).
  • Staining of tissue samples, specifically looking for the types of amyloid fibrils associated with the various hereditary types of amyloidosis.

The Results section of the article describes how many patients (out of 350 diagnosed with AL amyloidosis) were found to have various types of familial amyloidosis.

  • 18 patients (5.1 percent) had the fibrinogen Glu526Val mutation.
  • 13 patients (3.7 percent) had one of the transthyretin mutations, including three new mutations that had previously not been described.
  • One patient had a known lysozyme mutation.
  • One patient had a known apolipoprotein A1 mutation.
  • One patient had a previously unknown apolipoprotein A1 mutation.

Adding up those numbers, that is 34 out of 350 patients who were misdiagnosed as having AL amyloidosis. So just under 10 percent of these 350 patients had a rare disease but were misdiagnosed with the wrong type of that rare disease.

Regarding the patients with the fibrinogen mutation, all 18 were of northern European ancestry and none were initially aware of any family history of amyloidosis, although one patient later discovered that her twin had died of renal failure at the age of 76. Two patients were found to be related. All 18 of these patients presented with renal dysfunction and proteinuria, and most of them had hypertension. The youngest patient initially presented while in her 30s, and the oldest presented at the age of 78.

SAP scintigraphy showed renal deposits in all 18 patients, and deposits in the spleen in all but one patient. Electrocardiogram and echocardiogram results did not suggest the presence of cardiac amyloidosis in any of the patients, and none were showing signs of neuropathy. As reported in previous articles on the Glu526Val mutation, all measurements associated with blood clotting times were normal in all of these patients.

They were able to study renal biopsy tissues from 17 of the 18 patients with the fibrinogen mutation. Apparently there are specific staining techniques that will only stain amyloid fibrils from fibrinogen. Each of these biopsy specimens did stain for fibrinogen, but the intensity of the staining varied significantly.

One piece of data that actually supported the misdiagnosis of AL amyloidosis in four of these 18 patients was a low-grade paraproteinemia, also known as monoclonal gammopathy. This condition refers to excessive amounts of paraproteins in the blood, and it is often associated with AL amyloidosis. (I have now told you more than I know about AL amyloidosis and paraprotein, so I won't go into that any further.) Three of these four patients had in fact received chemotherapy in an effort to treat what was believed to be AL amyloidosis, and not surprisingly there was no clinical response.

Regarding the 22 first-degree relatives of patients with the Glu526Val mutation, 12 of them were found to have the same mutation. All were over the age of 50 and none had proteinuria or evidence of amyloidosis on SAP scintigraphy.

The Results section (and the Discussion section) also discussed the 16 patients with mutations other than fibrinogen, but I won't go into those here.

The  Discussion section of the article begins with a statement about the current clinical practices at the National Amyloidosis Centre, presumably as a result of this study. Given the variable penetrance of hereditary amyloidosis and the fact that most patients with the fibrinogen Glu526Val mutation do not have a relevant family history, they now routinely do a DNA analysis in all patients with systemic amyloidosis. This practice has already shown benefits to patients initially diagnosed with AL amyloidosis.

The article then discusses the similarities among the patients in this study with this fibrinogen mutation. They all presented with isolated renal issues, meaning they were not caused by some other disease or condition. The progress of renal dysfunction in patients with fibrinogen amyloidosis is slower than in patients with AL amyloidosis, although end stage renal failure is always reached within five years of the onset of renal issues. In two of their patients, transplanted kidneys failed within six years due to recurring amyloidosis. Two patients also exhibited some type of liver involvement long after the initial presentation with renal issues.

The article then mentions that liver transplantation is an effective treatment in types of hereditary amyloidosis in which the amyloidogenic protein is synthesized by the liver.


My initial reaction to this article is that it reinforces the need for genetic testing if you are related to someone with fibrinogen amyloidosis. Although this article showing a misdiagnosis rate of approximately 10% is from 2002, and I would hope that number has improved in the past 11 years, I am sure there is still a significant misdiagnosis rate, at least in the US. I know they still see it frequently at Mayo Clinic, and it very nearly happened to my mother since her initial kidney biopsy report did not detect fibrinogen amyloidosis although that was one of the types they looked for when staining her biopsy slides.

This article definitely indicates that fibrinogen amyloidosis affects people of northern European ancestry and is much more prevalent than previously known. In fact, before this article was published the Glu526Val mutation had been described in only five kindreds. That number more than quadruples just with the patients in this study, since it was diagnosed in 18 individuals and only two of them were related.

The clinical picture of fibrinogen amyloidosis is getting sharper with each article. Patients typically present in middle age or later with renal dysfunction with no detectable underlying cause, progressing to end stage renal failure within five years. Biopsy results show the amyloid fibrils deposited in the glomeruli of the kidney. Spleen and liver deposits may show up much later.

Regarding treatment, once again we have an article that mentions liver transplant as potentially curative. That was first mentioned in a 1996 article, reviewed here, and the first reported case of a liver-kidney transplant for fibrinogen amyloidosis was performed in 1996 and published in 2000 (reviewed here). I wonder how long we will have to wait for a liver-only transplant to occur?

The next four articles up for review include one on transplants, one case with a unique clinical presentation, and two others that provide a general overview of the current state of medical knowledge on hereditary renal amyloidosis. Unfortunately I do not have any of these four articles, so you can expect shorter reviews since all I have to go on is the abstracts and what I have learned about the specific articles elsewhere.



(1) Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis. N Engl J Med 2002; 346: 1786-1791.

Monday, May 6, 2013

Solidifying Moose Brain

Today's post will cover a few random things about the blog, including some new pages I recently added. Toward the end I'll explain where the title of this post came from, and then I'll finish with the monthly blog stats where I learn about a country I've never heard of before.

First, if you subscribe by email then the two pictures in the last post (April 30) may not have appeared correctly or at all. They did not look right in my email, but that post and the pictures do look fine on the blog, though, in case something seemed to be missing from your email. I think it has to do with how I added those pictures to that post. If it happens again I will issue a full refund to all subscribers.

New Pages

I recently added some new pages to the blog, listed on the right side near the top. One page that has been there a couple of months but I may not have mentioned before is a page titled "Welcome New Visitors!" It is just what it says, a page for new visitors to find out what is available on the blog.

Next is a page titled "What should I do now?" This page has my recommendations on what people should do when they or someone in their family is diagnosed with fibrinogen amyloidosis. These recommendations depend on whether or not a person has been genetically tested for the mutation, whether or not they have symptoms of kidney problems, and whether or not amyloidosis has been confirmed by a kidney biopsy. I came up with six different scenarios a person could be in based on the status of those three things and I created a list of recommendations for each scenario. (You nerdy types in the audience will be happy to know that I created a truth table with these three variables to make sure I covered all possible scenarios. Two scenarios were considered invalid, which is why there are only six instead of eight.) Feedback is certainly welcome on that page. I tweak it a little almost every time I read through it.

Then the most recently added page, which is definitely in its infancy, is a glossary. I named this page Simple Glossary because it is my attempt at providing definitions of some of the medical terminology used in the journal articles and in the blog. I'm not duplicating the definitions that can already be found elsewhere on the internet, because those tend to be quite detailed and cover a lot that does not really matter in this context. What I am trying to provide is very simple definitions to help people understand the articles in medical journals and also to help people explain things to friends and family without giving them a medical lesson first.

I have wanted to do this glossary page ever since I wrote the first article review in February of this year, but I never took the time to work on it for very long. Now that it is public I guess I'll have to keep adding to it.

Spam Comments

With the increase in traffic to the blog there has been a corresponding increase in the number of spam comments submitted. Fortunately, Blogger does a great job at putting those in a spam folder such that I don't have to do anything and they never appear on the blog. So far I think every comment flagged as spam has included a link to a web site, and most of them tell me what a wonderful job I am doing and how much they like the blog. (Awwww, thanks, spammers!) Anyway, if you submit a comment and don't see it posted within 24 hours, ask me if it landed in the spam folder.

Here is my favorite sentence from the April spam comments:

"This is both welcome and long overdue, since more progress needs to be made against the Libyan leader, one of the darkest acts that exist in the wild flowers growing near the pond."

Solidifying Moose Brain

What the heck does a solidifying moose brain have to do with fibrinogen amyloidosis? Nothing really, but if you rearrange the letters in "fibrinogen amyloidosis" you can spell "solidifying moose brain." (I'll take anagrams for $200, Alex.) Yes, sometimes I just have too much time on my hands . . .

And finally, the eagerly anticipated monthly blog stats. April was a record month for total pageviews as well as for the number of new countries visiting the blog (10), including one in Eastern Europe that I had never heard of. (Quick: What country is between Romania and Ukraine?)

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

Total posts: 75 (5 in April)

Total pageviews: 1932 (620 in April)

Email subscribers: 4

RSS subscribers: 2 (Hooray! Somebody besides me subscribes via RSS.)

Total number of countries that have viewed the blog: 44

10 new countries viewed the blog in April:

Mexico (Why did it take our neighbors to the south so long to find us?)