Friday, February 21, 2014

Article Review (2010) - Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation

As promised, today's article review covers one of the more important journal articles dealing with treatment for fibrinogen amyloidosis. It reaches some conclusions and makes some recommendations we have not seen before, which exposes some disagreement among the medical community which continues to this day. I will cover this article and the points of disagreement over the next few posts, so don't worry about having to absorb everything at once.

Title: Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation (1)

Authors: Arie J. Stangou, Nicholas R. Banner, Bruce M. Hendry, Mohamed Rela, Bernard Portmann, Julia Wendon, Mark Monaghan, Philip MacCarthy, Muriel Buxton-Thomas, Christopher J. Mathias, Juris J. Liepnieks, John O'Grady, Nigel D. Heaton, and
Merrill D. Benson (King's College Hospital, London, UK; Royal Brompton and Harefield NHS Trust, London; Imperial College London; King's College London; National Hospital for Neurology and Neurosurgery, London; Indiana University School of Medicine, Indianapolis, IN, USA)

Journal: Blood (2010)

Variants of fibrinogen A α-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome. Twenty-one had E526V and 1, the R554L variant. Coronary atherosclerosis was identified in 68% and systemic atheromatosis in 55%. Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid. Half had autonomic neuropathy. Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up. Serial technetium-99m–labeled dimercaptosuccinic acid (99mTc-DMSA) renal scintigraphy in 2 cases of preemptive LKT demonstrated preserved native kidney residual function at 5 years. Four explanted livers were used successfully for domino transplantation. Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement. LKT is curative; however, cardiovascular amyloidosis may preclude this option. Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation.
Here is a link to the PDF of this article if you would like to follow along:

If you look at the hospital affiliations of the authors of this article you might notice two things. First, out of 14 authors, all but two (Dr. Benson and Dr. Liepnieks) are affiliated with hospitals in London. Second, none of those 12 authors from London are associated with the National Amyloidosis Centre in London. Keep that in mind for later.

As it says in the abstract, this article reports on 22 patients with fibrinogen amyloidosis (AFib) who were assessed for combined liver and kidney transplantation. (I am occasionally going to use the acronym "LKT" for "liver and kidney transplant" in this review to save myself some typing.) The topic of this article may seem familiar to you because there was a previous article review that also covered LKT assessments in a large number of patients (20). That article, reviewed in the November 30, 2013 blog post, was a paper presented at the XIth International Symposium on Amyloidosis in 2006. The older article covered 20 patients evaluated between 1996 and 2006, whereas today's article covers 22 patients evaluated between 1996 and 2007. Although there are only two additional patients in the current article, and six people were listed as authors on both articles, we can expect the current one to be somewhat more thorough with the details since its length is not limited like papers presented at symposia usually are. Plus, it has the benefit of about three more years of clinical experience following these patients.


The introduction of this article lists the types of hereditary renal amyloidosis (fibrinogen, lysozyme, apolipoprotein A1 and apolipoprotein A2), and states that there are a total of 25 different mutations among those types. Fibrinogen amyloidosis (AFib) appears to be the most common type of hereditary renal amyloidosis in Europe and in the US.

Isolated kidney transplantation has been done as a treatment for the renal failure associated with AFib, but the article states it is of limited value because the transplanted kidney (often referred to as an "allograft" or simply "graft") is usually lost within 1 to 7 years due to recurrence of amyloid. Of the 18 reported kidney transplants to date, only one graft (5.5%) has survived at least 10 years. That compares poorly with the 10-year graft survival rate of 64% among all kidney transplants. This poor outcome with isolated kidney transplants led the team at King's College Hospital in London to evaluate combined liver and kidney transplantation for AFib. That would not only restore renal function but also potentially prevent recurrence of amyloid by eliminating the source of the mutant fibrinogen, the liver.


For this study, 22 AFib patients were assessed for combined liver and kidney transplantation between 1996 and 2007. One of these patients had the Arg554Leu mutation and the rest had the Glu526Val mutation. The median age at presentation was 55 years, and the median age of assessment for LKT was 57 years. Three of these patients had previously been misdiagnosed as having AL amyloidosis, with one of those receiving chemotherapy. There is a table in the article that gives some demographics and medical information on all 22 patients (age, sex, presenting features, grams per day of proteinuria, etc.) One interesting piece of information is just one patient was known to have the mutation before presenting with symptoms, but only four others had a family history of kidney problems.

The article then goes into great detail on the methods used to evaluate the patients at baseline and during follow-up. Most of that is way beyond my understanding so I am not going to try to discuss it. We are interested in the results anyway.


Other than the obvious evaluation of kidney function, these patients were also evaluated for cardiac function and autonomic neuropathy. The results of those evaluations for each patient are given in a table and discussed in the results section of the article. I will just provide the highlights in bullet form here.

  • 12 patients initially presented with proteinuria.
  • 9 patients initially presented with hypertension or a related condition.
  • 1 patient was diagnosed due to genetic testing after a family member was diagnosed.
  • The median time from initial presentation to diagnosis was 23 months.
  • 2 patients had liver amyloidosis.

  • 15 patients had coronary atherosclerotic disease. Six of those patients had 40% to 80% narrowing of a coronary artery, without any symptoms.
  • 12 patients had severe systemic vascular disease.
  • 11 patients (out of 21) had abnormal echocardiograms, with findings consistent with amyloid.

  • 12 patients had autonomic neuropathy affecting the heart.
  • 15 patients had autonomic neuropathy affecting the GI tract.

  • All kidney biopsies showed extensive amyloid deposits in the glomeruli, with minimal amyloid deposits elsewhere.
  • 4 patients experienced ruptured spleens (three during transplant surgery). The removed spleens had widespread amyloid deposits.
  • 3 out of the 4 heart biopsies showed substantial amyloid deposits which did stain positive for fibrinogen. 

14 of these 22 patients were initially accepted for combined liver and kidney transplant, and nine of those 14 patients had received transplants as of the time this article was written. Four of the remaining patients were removed from the list due to deteriorating health, and one patient was still on the waiting list.

The nine liver and kidney transplants (LKT) occurred between January 1996 and September 2009. At a median follow-up of 67 months, six of those nine patients are alive and well. Five of the six have good kidney function. The sixth patient developed chronic allograft nephropathy, which is the leading cause of kidney transplant failure. (Therefore it was not due to recurrence of amyloid in the transplanted kidney.) Transplant outcomes were better for patients who either had not started dialysis or had been on dialysis less than six months.

Periodic echocardiograms in 8 patients after LKT show no progression of cardiac amyloidosis, up to 12 years post transplant. The autonomic GI issues improved in all patients who received LKT. Two of these patients previously had kidney transplants, and their GI issues had continued after those transplants.

Another indicator of the success of LKT is the results of periodic SAP scintigraphy (an amyloid imaging technique I discussed in the April 30, 2013 blog post). Patients who received liver and kidney transplants showed a reduction in amyloid deposits as soon as one year post-transplant, and the patient with the longest follow-up still did not show any new amyloid deposits with SAP scintigraphy 13 years after transplant. In contrast, two of these patients had previously received kidney only transplants, and SAP scintigraphy showed their amyloid deposits progressing.

Four of the nine patients who received LKT were part of a domino liver transplant, which means their livers were transplanted into patients on the liver transplant waiting list. One of those domino recipients had SAP scans and echocardiograms for five years, with no evidence of amyloid deposits. One had normal liver and kidney function after 2.5 years, and the other two were not followed-up on after they returned to their country of origin.


The discussion section is where things get very interesting. It begins with some background information on fibrinogen and fibrinogen amyloidosis, and then it states that the data in this article suggest that fibrinogen amyloidosis is neither solely nephrotic (affecting the kidneys) nor solely nonneuropathic (not affecting the nervous system). So while it is true that fibrinogen amyloidosis primarily affects the kidneys, the authors of this article are saying that it should be viewed more as a systemic disease, with particular emphasis on potential cardiovascular involvement.

Remember when I mentioned that only five patients out of this series of 22 had a family history of kidney problems? Another bit of data on each patient that can be found in the same table is whether or not there was a family history of cardiovascular problems, and the table indicates that 17 of these patients did have such a family history. Of course the question that needs to be asked is whether or not the family members with cardiovascular problems also had the mutation for fibrinogen amyloidosis, and the article states that DNA testing of family members either confirmed they did have the mutation or they were obligatory carriers due to their relationship to other family members who were confirmed to have the mutation. So for this small group of 22 AFib patients, only 5 (23%) had a family history of kidney problems but 17 (77%) had a family history of cardiovascular problems.

The type of cardiovascular disease prominent among these AFib patients and their family members is described as cardiovascular atheromatous disease, which is essentially a buildup of plaque on the inner walls of the blood vessels. A reasonable question to ask is whether this buildup is due to the variant fibrinogen that is present in the bloodstream, the effects of kidney failure, or one of the other known causes of plaque buildup. Well, in the few cases where they could analyze this material that was removed from patients, biochemical analysis showed that it was indeed composed of variant fibrinogen. The article proposes that it is a combination of factors such as hypertension, hyperlipidemia (high cholesterol), and declining kidney function that may accelerate the formation of plaque deposits composed of variant fibrinogen on the inner walls of the blood vessels. Since the glomeruli in the kidneys are essentially blood vessels, that is exactly what appears to be happening the kidneys.

The article then presents three facts that point to liver transplant being curative for fibrinogen amyloidosis. They are:
  • The amyloid deposits in AFib patients have been shown to be made exclusively of variant fibrinogen, unlike in ATTR amyloidosis, where the amyloid deposits consist of both mutant and wild-type (normal) transthyretin.
  • Variant fibrinogen is eliminated after a liver transplant. (We learned that in the article reviewed in the December 18, 2013 blog post.)
  • AFib patients who are long-term recipients of liver and kidney transplants have shown no amyloid progression at up to 12 years of follow-up.
Another related piece of data supporting the suggestion that liver transplant is curative is in the post-transplant analysis of kidney function in two transplant recipients. These patients received LKT before starting dialysis, so they had some remaining kidney function at the time of transplant. Since the native kidneys are typically left in place with a kidney transplant, the function of these native kidneys could be evaluated after transplant. They found that the native kidney function had stabilized, such that they were still providing 15% to 20% of total renal function up to five years post-transplant.
The discussion section closes with a few recommendations regarding organ transplants to treat fibrinogen amyloidosis. The third one is something we have not seen before.
  • Patients with low cardiovascular risk should be considered for combined liver and kidney transplant.
  • Patients with higher cardiovascular risk for liver transplant, or who have been on dialysis for a long time, should be considered for a kidney transplant.
  • Patients who are in the early stages of kidney involvement due to AFib should be considered for isolated liver transplantation, to prevent progression to end stage renal failure and the progression of other systemic issues as described in this article.

Regarding the isolated liver transplantation, the article recommends that a patient listed for a liver transplant be monitored monthly to ensure the GFR remains above 50 ml/min. (Units for GFR are actually ml/min/1.73 m^2, which is not only clunky to write but is difficult to grasp intuitively. Just think of it as percentage of kidney function.) If it falls below 50 the patient should be listed for combined liver and kidney transplant. I did not realize it until I read the article again for this review, but one of the patients in this study was initially listed for an isolated liver transplant but had to be listed instead for LKT when his GFR dropped too low. He is the patient still waiting for a liver and kidney transplant at the time this article was written.


Ok, there is a lot to talk about in that article. But since this post is long enough already I am going to save the discussion for the next article review, which is actually a short article about this article, from the same issue of the same journal.



(1) Stangou AJ, Banner NR, Hendry BM, et al. Hereditary fibrinogen A alpha-chain amyloidosis: Phenotypic characterization of a systemic disease and the role of liver transplantation. Blood 2010; 115: 2998-3007. 

[Edit 2-24-14: Minor typo.]

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