Saturday, July 12, 2014

Article Review (2012) - Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses

Today's article under review expands a bit on the topic of organ transplantation that was discussed in a previous article (reviewed in the May 4, 2014 blog post), and it has the first mention of milestone in the treatment of fibrinogen amyloidosis.

Title: Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses (1)

Authors: Arie J. Stangou, Luisa Lobato, Steven Zeldenrust, Mohamed Rela, Bernard Portmann, Reinhold P. Linke, Isabel Conceicao, Gerd Otto, Henryk Wilczek, Ole Suhr, Daniel Azoulay, Gilles Grateau, Maria Picken, John O’Grady, Nigel Heaton, Bo-Goran Ericzon, Merrill D. Benson (UK, Portugal, US, Germany, Sweden, France)

Journal: Amyloid (2012)

Fibrinogen A alpha-chain (AFib) and apolipoprotein AI (AApoAI) amyloidosis due to variants in the AFib and ApoAI genes are the most common types of hereditary amyloidosis in Europe and the United States. Liver is the exclusive source of the aberrant amyloidogenic protein in AFib and responsible for supplying approximately half of the circulating variant ApoAI. Nephrotic syndrome and renal impairment due to renal amyloidosis are common disease manifestations; however, recent research provides evidence to support a more diverse and systemic disease phenotype, which in turn has implications in the management of the hereditary amyloidoses with solid organ transplantation and, in particular, liver transplantation.
Here is a link to the article (not free) if you would like to follow along:

As stated in the abstract, this article discusses the use of organ transplantation (primarily liver) in the treatment of fibrinogen and apolipoprotein amyloidosis. This review will focus on fibrinogen amyloidosis.

The article begins by stating that the use of organ transplantation in the treatment of transthyretin-related amyloidosis (ATTR) has been widely studied, in contrast to the use of organ transplantation in the treatment of non-TTR amyloidosis types, such as fibrinogen, apolipoprotein, lysozyme and gelsolin. That fact becomes obvious when comparing the number of transplants reported to the FAP World Transplant Registry ( for ATTR vs. the non-TTR mutations.

If you think there is a mistake in the first sentence of the abstract, you are correct. The word "renal" is missing. It should state that ". . . amyloidosis due to variants in the AFib and ApoA1 genes are the most common types of hereditary renal amyloidosis in Europe and the United States." The beginning of the section on fibrinogen amyloidosis does state that fibrinogen amyloidosis is the most common form of hereditary renal amyloidosis in the UK, Ireland and the US.

Some of the basic characteristics of fibrinogen amyloidosis (AFib) are presented, specifically:

  • Six different mutations, with the most common being Glu526Val
  • Amyloid deposits consist solely of variant fibrinogen (no wild-type)
  • Patients typically progress to end stage renal failure within 1 to 5 years of presenting with proteinuria and hypertension.
  • In the past, AFib has been regarded as solely nephropathic (affecting the kidneys)

The article then makes the case that fibrinogen amyloidosis is a systemic disease, with reported fibrinogen amyloid deposition in the heart, spleen, vessel walls, abdominal fat, and gastrointestinal tract, in addition to reports of cardiovascular disease and autonomic neuropathy. A series of nine pictures of biopsy slides showing AFib deposits in various organs are shown on this page of the article.

Transplant outcomes are then discussed. Outcomes of isolated kidney transplantation are poor due to rapid recurrence of amyloid in the transplanted kidney. On the other hand, combined liver and kidney transplantation (LKT) is curative but poses significant transplant risks, especially in patients who have been on dialysis for a long time. It is preferred to perform LKT in patients before they begin dialysis. At the time this article was published, twelve cases of combined liver and kidney transplantation for fibrinogen amyloidosis patients had been reported to the FAP World Transplant Registry, with ten of those performed in the UK and two in the US.

The article then mentions that when patients have received a combined liver and kidney transplant before going on dialysis, their residual native kidney function (the remaining function of the patient's original kidneys that are not removed during kidney transplantation) has been salvaged. (That situation was described in greater detail in the 2010 article by Stangou, et al, reviewed in the February 21, 2014 blog post.) This data encourages evaluation of isolated liver transplantation early in the course of the disease to prevent progression to end stage renal failure. Then we have this sentence, informing us that it has, in fact, been done: "The first preemptive isolated liver transplant for AFib was carried out successfully in an AFib patient with moderate renal impairment at the San Francisco Liver Transplant Unit in 2011 (personal communication)."

For those of you who don't know, that patient was our very own Cathy T., who received a liver transplant exactly four years ago today, on July 12, 2010. (Not 2011 as stated in the article.) She was blogging about her experience at the time, so if you want to read about her journey you can start with the first post or jump right to the date of her transplant. She has not blogged in a few years, probably because she is too busy enjoying her bounty of grandchildren which I believe was approaching 20 when Mom and I saw Cathy and her husband at the Familial Support Group meeting in Chicago in October of 2013.

We have seen a few articles suggest an isolated liver transplant may be appropriate for AFib patients who still have a moderate amount of kidney function (GFR above 50 is often given as a recommendation). As you can see from some of Cathy's data near the bottom of the Patient Timelines page, her GFR was considerably lower than that, somewhere between 20 and 30 at the time of her liver transplant. In spite of that, she did receive a liver transplant just before the need for dialysis. (She was also part of a domino transplant, which means her liver was transplanted into another patient.) If she had waited for a liver and kidney transplant, she very likely would have needed dialysis before receiving that transplant.

Cathy's kidney function did improve to some extent after her liver transplant, such that she was no longer eligible for a kidney transplant. My understanding is that even after the source of the amyloid is removed, improvement in kidney function is slow and limited due to the scar tissue that develops. So she is living with the issues that go along with having reduced kidney function, and although her kidney function will likely never get back to "normal," here we are four years post-transplant and she still has not needed dialysis or a kidney transplant. The results of this one case certainly support the suggestion that an isolated liver transplant will halt the progression of fibrinogen amyloidosis. I would expect a patient with more kidney function remaining (higher GFR) at the time of transplant to fare even better.

As far as I know, Cathy is still the only fibrinogen amyloidosis patient to receive just a liver transplant. And I believe this article is the only mention of her transplant in the medical literature to date. Hopefully her case will be published at some point, but until then, if anybody out there is in a similar situation such that an isolated liver transplant is being considered, know that it has been done and it did appear to halt progression of the disease.

This article does give us another way to look at how rare fibrinogen amyloidosis is and how late the diagnosis is, since there had been only 12 combined liver and kidney transplants (and one isolated liver transplant) performed on AFib patients at the time this article was written. That is less than one per year since the first description of a fibrinogen amyloidosis mutation was published in 1993. Going forward, earlier diagnosis in relatives of AFib patients should lead to more cases in which a liver or combined liver and kidney transplant is a viable option. On the other hand, if one or more of the drug treatments under development reduce or eliminate the need for organ transplants in AFib patients, there may be very few additional liver or liver-kidney transplants. Indeed, the times they are a-changin'.


1. Stangou AJ, Lobato L, Zeldenrust S, et al. Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses. Amyloid. 2012;19 Suppl 1:81-84.

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  1. This is Cathy T. David, you are doing a marvelous service with this blog. A couple of updates about my adventure. My creatnine is now 1.8, lower than pre-transplant. I haven't needed any Procrit (for anemia) in two and a half years, and am spilling only a trace of protein. I am so glad I chased after that liver transplant.
    I hope your Mom is doing well. Tell her hi for us.

  2. Good to hear from you Cathy. Thanks for the update. It sounds like the liver transplant went very well for you. Hopefully your experience can be of benefit to others who are considering their transplant options.

    Mom is doing well, in spite of some excitement toward the end of July that I'll be blogging about soon.