Sunday, January 12, 2014

Article Review (2009) - Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen A alpha-Chain Amyloidosis

Today's article under review is one of the more important articles on fibrinogen amyloidosis. It follows 71 patients who were diagnosed at the National Amyloidosis Centre (NAC) in the UK. Prior to this article, the largest number of patients covered in one article was 20, from the paper presented at the XIth International Symposium on Amyloidosis in 2006. Those patients were also evaluated in the UK, and I reviewed that paper in the November 30, 2013 blog post. It should be very clear by now that fibrinogen amyloidosis is much more prevalent in the UK than in any other country.

Title: Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen A alpha-Chain Amyloidosis (1)

Authors: Julian D. Gillmore, Helen J. Lachmann, Dorota Rowczenio, Janet A. Gilbertson, Cai-Hong Zeng, Zhi-Hong Liu, Lei-She Li, Ashutosh Wechelekar, Philip N. Hawkins (National Amyloidosis Centre, London, UK; Nanjing University School of Medicine, Nanjing, Peoples Republic of China)

Journal: Journal of the American Society of Nephrology (2009)


Mutations in the fibrinogen A -chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen A -chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0 –12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.

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

Note: In this review I will occasionally write "Afib" instead of "fibrinogen amyloidosis."

There is a lot of information packed into that abstract, and even more in the article. Having so much data can seem a little overwhelming, but hopefully by presenting much of the data in a more visually appealing way (bullet points) you can understand what most or all of this data means and decide what matters to you.

Before starting the review I want to define a non-medical term that appears several times in the abstract and will likely appear several times in my review. That term is "median." You may recall studying mean, median and mode in one of your math classes in school. The "mean" of a group of numbers is simply the average. For instance, to find a student's average test score you just add up all of his or her test scores and divide by the number of tests. That number is the average, or mean.

The "median" refers to the value in the middle when the test scores are sorted in order. For example, if a student's scores on five tests were:

85, 95, 68, 100, 90

We first arrange them in order:  68, 85, 90, 95, 100

And we can see that the middle value, the median, is 90. On the other hand, the mean, or average, of those five grades is 87.6. (If the number of test scores were an even number, the median would be the average of the two values in the middle.) If we know the median of a set of numbers, we know half the values are higher than the median and half the values are lower. So the median is the midpoint of a set of numbers when they are sorted in order. Unlike the average (the mean), the median is not impacted by values at one extreme or the other. But if you want to say "average" to yourself when you see the word "median," you will still get the same general idea that is being presented.

That concludes today's math lessons boys and girls. Please put away your calculators and get out your copy of today's article.

The article starts with brief histories of hereditary renal amyloidosis and fibrinogen amyloidosis. It then states that this article reports on 71 fibrinogen amyloidosis patients who were diagnosed and studied at the UK National Amyloidosis Centre between 1992 and 2007. (Later in the article it gives an ending date of February 2008.) The article has one large section in the middle where the majority of the data is presented, so there are no useful section headings to help us navigate. But it looks to me like the data can be grouped into seven categories: symptoms, diagnosis, biopsy results, genetic testing results, progression of the disease, treatment (transplants), and comparison to other diseases. I will use those categories as section headings for this review.

  • 100% of patients had proteinuria.
  • 72% had hypertension
  • 54% had some impairment of renal function. (The article does not say how that was measured, but the typical measurements would include serum creatinine and GFR.)
  • The median age at presentation (first visit with a doctor regarding symptoms) was 58 years old, and it ranged from 38 to 83.
  • The median time from presentation to diagnosis was 8 months, with a range from zero to 164 months. (The zero would be patients who were known to have the mutation before symptoms developed.)
  • Despite the odd number of patients, the male-female distribution was equal according to the article. (35 and 36 is close enough.)

  • 64 patients were diagnosed with amyloidosis based on kidney biopsies. The other 7 patients were known to have Afib in their family and were diagnosed based on genetic testing, renal dysfunction, and SAP scintigraphy.
  • SAP scintigraphy was done on 63 of the 71 patients. It showed amyloid deposits in the kidneys of every patient who had not already reached end stage renal disease.
  • 89% of patients had amyloid deposits in the spleen. (no symptoms)
  • 21% of patients had amyloid deposits in the adrenal glands. (no symptoms)
  • At their initial evaluations, no patients had echocardiograms that indicated cardiac involvement.
  • One patient with a novel Afib mutation (discussed later) had peripheral neuropathy that a biopsy showed was due to amyloid.
  • 12 patients had been incorrectly diagnosed with AL amyloidosis. Five of those patients received chemotherapy and one received a stem cell transplant before receiving the correct diagnosis of fibrinogen amyloidosis. (For more on misdiagnosis of hereditary amyloidosis as AL amyloidosis, see the article reviewed in the blog on May 12, 2013.)
  • 46% of patients had no family history of renal disease or amyloidosis.

Biopsy Results
  • Every kidney biopsy showed amyloid deposits concentrated almost exclusively in the glomeruli.
  • Immunohistochemical staining for fibrinogen was positive in 93% of the patients with kidney biopsies. (That is surprisingly high based on what I have read in other articles.)
  • In the other 7% of cases, the patients were known to have a fibrinogen amyloidosis mutation and the overall clinical picture was typical for Afib.

Genetic Testing Results
  • 64 patients were heterozygous for the Glu526Val mutation of the fibrinogen A alpha chain. Six of those patients were from a single German family, and the rest were of British Caucasian ancestry.
  • Two British patients were heterozygous for the Arg554Leu mutation. (That was the first Afib mutation discovered, published in 1993.)
  • Four new Afib mutations were discovered at the NAC during this time period:
    • Two German sisters had the Glu540Val mutation. (I previously discussed their case toward the end of the December 30, 2013 blog post.)
    • One Chinese patient had a frameshift mutation caused by a deletion at codon 525.
    • One Chinese patient had a substitution of lysine for threonine at position 538. (Thr538Lys)
    • One Afro-Caribbean patient had a substitution of histidine for proline at position 552. (Pro552His)
  • Other than peripheral neuropathy in the patient with the Thr538Lys mutation, the clinical history and kidney biopsies of patients with these newly discovered mutations was similar to that of patients with the Glu526Val mutation.

Progression of the Disease
  • The patients were followed for a median of 4 years after diagnosis.
  • 17 of the patients died during this study. Median age at death was 67 years, with a range of 57 to 85.
  • Causes of death were:
    • Infection (6)
    • Metastatic malignancy (cancer) (3)
    • Dialysis withdrawal (2)
    • Transplant-related mortality (2)
    • Gastrointestinal blood loss (1)
    • Unknown (3)
  • The estimated median survival from presentation was 15.2 years.
  • The estimated median survival from diagnosis was 10.9 years.
  • 44 patients reached end stage renal disease (ESRD). The median age when dialysis began was 60, with a range of 36 to 82.
  • Median time from presentation with proteinuria to ESRD was 4.6 years (range 0 to 10.2).
  • Median time from diagnosis of amyloidosis to ESRD was 2 years (range 0 to 10.2).
  • Among the 23 patients with an initial estimated GFR of over 20 ml/min, the mean rate of GFR loss was 11.5 ml/min per year.
  • Thirteen of the 44 patients who reached end stage renal disease died during follow-up.
  • The estimated median survival from the start of dialysis was 8.2 years (range 0.2 to 24.8).
  • No patients developed the classic signs of cardiac amyloidosis, although various cardiac and cerebral events were reported.
  • Amyloid deposits in the liver were detected in only two patients, both of whom had presented more than 8 years previously.
  • No patients developed clinically significant autonomic neuropathy.

  • Ten patients received kidney transplants, including two patients who received a second transplanted kidney after the first one failed. (12 transplanted kidneys total.)
  • The median follow-up after kidney transplantation was 5.8 years.
  • Five transplanted kidneys were still functioning and seven had failed. (Three failed immediately up transplantation, so that was obviously not recurrence of amyloid.)
  • The estimated median survival of the transplanted kidneys that did not fail immediately was 6.7 years (range 0.9 to 12.2).
  • Three transplanted kidneys, including two in the same patient, failed due to recurrence of amyloid after 5.8, 6.0 and 7.4 years. The fourth failed transplanted kidney did not have evidence of amyloid.
  • The longest surviving kidney transplant was 12.2 years. Surprisingly, this patient had proteinuria 7.6 years after transplant, and SAP scintigraphy shows amyloid in the transplanted kidney.
  • Seven patients received combined liver and kidney transplants. The longest survivor in this group was healthy and completely free of amyloid 11.5 years after the transplant. One patient died perioperatively (during pre-op, surgery, or recovery) due to acute necrotizing pancreatitis, and the other five patients were doing well with no evidence of recurring amyloid. Median follow-up from combined liver-kidney transplant was 24 months.

Comparison To Other Diseases
  • For these Afib patients, the median time to progress from proteinuria to end stage renal disease was 4.6 years. This is longer than untreated AL amyloidosis (7.5 to 14 months) but shorter than apolipoprotein A1 amyloidosis (8 years).
  • For these Afib patients, the estimated median survival after presentation was 15.2 years, which is significantly less than for AL amyloidosis, both untreated (less than 2 years) and treated (5 years).
  • For these Afib patients, the median survival from the start of dialysis was 8.2 years, which is longer than the median survival among all nondiabetic patients in the UK, aged 55 to 64, who commenced dialysis between 1997 and 2001.

Another interesting finding was regarding family members who were known to have the mutation but were asymptomatic. There were 23 people (not part of the 71) who were in that category, with a median age of 50 years (range 31 to 84). Out of those 23, six of them were older than the oldest family member who did have symptoms and was part of this study. They also did SAP scintigraphy on 12 of these asymptomatic patients, and their SAP scans were normal. I would have expected, especially in the older asymptomatic patients, some evidence of amyloid deposits in the SAP scans. Perhaps some day we will know why some people with the mutation develop amyloid deposits and some do not.

The results section of the article concludes by stating that combined liver and kidney transplantation typically provides a better outcome than kidney transplant alone, but it comes with additional risks associated with the surgery and recovery. Since it takes several years to realize the benefits of liver-kidney transplantation over an isolated kidney transplant, the authors state that their practice is to recommend liver-kidney transplants only in their younger, healthier patients.

The last section of the article just goes into some of the details on some of the analyses that were done as part of this study.


With this article we have by far the largest number of fibrinogen amyloidosis patients described in one article. In terms of study size, 71 is still a small number compared to typical study sizes in most medical studies. But with a rare disease like this one you just are not going to find studies that include hundreds or thousands of patients.

Other than the four new Afib mutations that were discovered, there was not much unusual, or out of the norm, about these patients. One patient had peripheral neuropathy due to amyloid, and 21% of the patients had adrenal amyloid deposits (but no symptoms).

Let's look at the symptoms first. Every patient had proteinuria, with hypertension being the second most common symptom and renal impairment being third. Those are the three symptoms that have typically been mentioned in the previously published articles, so no real surprise there. But it is good to know that the first sign of amyloids affecting the kidneys may not be renal impairment. The median age at presentation was 58, which is comparable to the presentation ages previously reported.

In the diagnosis section we learn that 89% of these patients had amyloid deposits in the spleen, but no symptoms associated with that. Although previous articles had reported some spleen involvement (such as splenic rupture), this finding tells us that fibrinogen amyloid deposits are almost as likely to build up in the spleen as they are in the kidneys. Based on previous articles it seems like significant symptoms with the spleen only occur many years after kidney issues develop, although anemia among Afib patients seems to be rather common. There was no mention of anemia in this article.

The biopsy results of these patients all exhibited the classic Afib pattern of amyloid deposits almost exclusively in the glomeruli. As previously noted, there was a very high success rate (93%) of typing the amyloid in these biopsies using immunohistochemical staining.

There was no surprise with the genetic testing results, as 64 out of 71 patients (90%) had the Glu526Val mutation, which had already been presumed to be the most common Afib mutation. The four new mutations brings the total number of published Afib mutations up to nine according to the article.

The section on Progression of the Disease is what I suspect most people are really interested in. If you know you have the mutation, you want to know the answer to this question: "Once I develop symptoms, how long will it be before X happens?" There is no need to repeat the data here in paragraph form, but before you draw any firm conclusions from the data in this article, keep in mind the following points:

  • This study included only 71 patients, and the median length of the follow-up period was only four years. That means only about 35 of these patients had been followed for over four years.
  • If you look at the range given for each piece of data, you can see that the progression of this disease varies tremendously from patient. The median time from presentation to end stage renal disease was 4.6 years, but that varied from a low of 0 years to a high of 10.2. That means that from the time a patient presents with proteinuria, there is a 50% chance that patient will reach end stage renal disease within about four and a half years. But it could happen in less than a year, or it could take 10 years to happen.
  • The decline of GFR is an important piece of information we have not seen in previous articles. GFR (estimated glomerular filtration rate) can be thought of as a rough approximation of the amount of remaining kidney function. For example, a GFR of 35 means the kidneys are functioning at approximately 35%. Previous articles have stated that fibrinogen amyloidosis is inexorably progressive, meaning it just steadily marches on and on if left untreated. It does not go into remission like some types of cancer do. This annual decline of GFR is a measure of that progression of the disease.

In the section on transplants we learn that ten of these patients received kidney transplants and seven received combined liver-kidney transplants. Previous articles have reported the failure of kidney transplants due to recurring amyloid, and this article mentions three that failed for that reason between 5 and 8 years after the kidney transplant. This article clearly shows the benefit of liver-kidney transplant over kidney transplant, while acknowledging the increased risk of the combined transplant. As with most significant medical decisions, each patient's case will be slightly different, and what is best for one patient may not be the best for another patient. This whole subject of organ transplants is one reason I think it is so important for family members to be tested for the mutation. I would much prefer having plenty of time to learn about treatment options and the pros and cons of each, rather than being faced with a transplant decision relatively soon after being diagnosed.

In the section on comparison to other disease, the article provides some data that show fibrinogen amyloidosis compares favorably to AL amyloidosis in terms of both progression to end stage kidney disease and length of survival after presentation.

In summary, there is a lot of data presented in this article that gives us an idea of what typically happens with a patient with fibrinogen amyloidosis. But the main thing to realize is that there is a very wide range of possibilities for any category of data presented here, with no way to predict what will happen with any individual patient. We already know that some people with the mutation will never develop symptoms, and among the patients in this article, all of whom did develop symptoms, the age at which symptoms were noted ranged from 38 to 83. Once symptoms do develop we know they will progress to end stage renal disease if left untreated, but we do not know how quickly that will occur. The fact that you have a fibrinogen mutation in the first place means you are not "average," so the progression of your disease may not turn out to be "average" either.

Next up: Another report on a "large" group of patients, from another European country.



(1) Gillmore JD, Lachmann HJ, Rowczenio D, et al. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis. J Am Soc Nephrol 2009; 20: 444-451.

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