Friday, March 14, 2014

Article Review (2010) - Response to the Stangou article

Today's article review will actually cover a letter to the editor that was written in response to the article I reviewed in the February 21, 2014 and February 28, 2014 blog posts, plus a response to that letter from the authors of the original article.

Title: Hereditary fibrinogen A alpha-chain amyloidosis: clinical phenotype and role of liver transplantation. (1)

Authors: JD Gillmore, HJ Lachmann, A Wechalekar, PN Hawkins (National Amyloidosis Centre, London, UK)

Journal: Blood (2010)

You may recall that none of the authors of the original article (the study of 22 patients) were from the National Amyloidosis Centre (NAC) in London. Well, all four authors of this letter to the editor are from the National Amyloidosis Centre, and they clearly state their differences of opinion. At the beginning they refer to the 2009 article they were all coauthors of that followed 71 fibrinogen amyloidosis patients (reviewed in the
January 12, 2014 blog post), and state that 20 of the patients in the 2010 article by Stangou et al were also part of this group of 71. The two main points of contention are whether or not fibrinogen amyloidosis fits the definition of a systemic disease, and the use of organ transplantation in the treatment of fibrinogen amyloidosis.

To make the rest of this review a little easier to read, instead of writing something like "the letter to the editor states that . . ." I will write "Gillmore states that . . ." Similarly, when referring to the authors' response to the letter to the editor, I will write something like "Stangou says . . ." To help you keep things straight, here is a list of the articles and letters that are involved here, and the lead author of each one:

 - Study of 71 AFib patients published in 2009; Gillmore (2)

 - Study of 22 AFib patients published in 2010; Stangou (3)
 - Letter to the editor responding to study of 22 AFib patients; Gillmore
 - Response to letter to the editor; Stangou

Is Fibrinogen Amyloidosis a Systemic or a Renal Disease?

The 2010 Stangou article clearly tries to establish that fibrinogen amyloidosis is a systemic disease, referring to cardiovascular issues as well as autonomic neuropathy. Gillmore, in the letter to the editor, states that in their experience at the NAC, AFib is primarily a renal disease that is not associated with cardiac amyloidosis or autonomic neuropathy in a clinically significant way. He states that few if any AFib patients have the necessary combination of features to fit the international consensus definition of cardiac amyloidosis. Gillmore also states that simply finding amyloid deposits in tissue does not confirm a diagnosis of amyloidosis, since amyloidosis is a clinical disease that results from amyloid deposition. For instance, amyloid deposits are often found in elderly persons who do not have amyloidosis.

Stangou responds by first pointing out that Gillmore’s study of 71 patients showed, via SAP scintigraphy, adrenal amyloid deposits in 21% of patients and splenic deposits in 89%. She also points out that SAP scintigraphy cannot visualize amyloid deposits in the heart or the nerves, and 10 of the 20 patients who were part of both studies had echocardiographic features consistent with cardiac amyloidosis. Stangou then states that the international consensus criteria for distinguishing between localized and systemic amyloidosis supports characterizing AFib as systemic amyloidosis.

Organ Transplantation to Treat Fibrinogen Amyloidosis

Gillmore states that the use of combined liver and kidney transplantation (LKT) to treat fibrinogen amyloidosis is highly contentious due to high early mortality and insufficient follow-up to date that shows a renal or overall survival benefit. He then offers statistics comparing the survival of patients who received just a kidney transplant versus the survival of those receiving a liver and a kidney. Stangou counters with her own statistics which seem to show a benefit of LKT. Stangou also mentions that the side effects of long-term hemodialysis and the advancement of AFib disease in other organs also impacted the early mortality in three of six LKT patients, which highlights the importance of patient selection and timing for transplantation. I am not going to dig into the statistics from either side to try to determine who is right, but just be aware that there are multiple ways of analyzing any set of data. There is often one statistic that seems to show one thing and another statistic that seems to show something contradictory.

So how does Dr. Gillmore feel about Dr. Stangou’s suggestion to consider preemptive isolated liver transplantation in AFib patients? Quoting from the letter to the editor, he considers it “completely unfounded.” First I want to make sure we understand what Stangou means by “preemptive.” Toward the end of the 2010 article, Stangou suggests that isolated liver transplantation be considered “early in the course of amyloid nephropathy,” before end stage renal failure develops, to avoid the need for kidney transplantation. So in that context, “preemptive” is after symptoms develop, but before dialysis or a kidney transplant is needed. It is not before any symptoms develop at all. Gillmore makes it clear that liver transplantation before symptoms develop, which could in theory be considered for someone who has tested positive for an AFib mutation but is asymptomatic, is not advisable because “most carriers never develop any disease.”

Once symptoms do appear, though, Gillmore still is not in favor of isolated liver transplantation because of the substantial kidney damage that is usually present at the time of clinical presentation. He states that significant kidney damage occurs in approximately 35% of liver transplant recipients anyway, so the stress of a liver transplant followed by long-term anti-rejection medication would place kidneys already damaged by AFib at even greater risk. Stangou had already addressed those concerns in the original article (suggesting GFR > 50 as a requirement for isolated liver transplantation), and in her response to Gillmore she mentioned the fact that in both of the patients who received liver and kidney transplants before reaching end stage renal failure, they determined that the patients’ original kidneys maintained their function post‑transplant. Then she simply states again that isolated liver transplantation is a feasible and rational approach that should be considered for patients in the early stages of the disease, with the results evaluated regularly.

My Two Cents

Regarding the question of whether fibrinogen amyloidosis is a systemic or a renal disease, it certainly appears to be a renal disease when patients first present. But we have seen many documented cases of other organs involved such as the spleen, liver, and heart, not only in these recent articles but in many of the previously published articles. The involvement of other organs definitely does not occur as frequently as kidney involvement, but much like the penetration of AFib in general, which is less than 100% (less than 100% of patients with the mutation will develop symptoms), the penetration into other organs appears to be lower still. If we can call AFib a renal disease with less than 100% penetration into the kidneys, we should be able to call it a systemic disease with less than 100% penetration into other organs. I suspect as more AFib patients are followed and live longer, more cases of other organ involvement will be documented.

Regardless of any official classification, treatment options are still what really matters to the patients. Setting aside potential drug treatments for now, the options for organ transplants to treat AFib are kidney only, liver plus kidney, and liver only. With isolated kidney transplantation, the patient’s kidney function is restored but the transplanted kidney tends to become affected by amyloid deposits at some point. The time required for that to take place varies over a wide range, so it is difficult if not impossible to predict how long a transplanted kidney will last. Combined liver and kidney transplantation (LKT) satisfies the need to restore kidney function and also eliminates the source of the variant fibrinogen. The best reported outcomes have been after combined liver and kidney transplants, since the data clearly shows amyloid deposits regress after LKT, and no additional amyloid deposits develop.

Based on outcomes alone, it would seem like a combined liver and kidney transplant is a better option than kidney transplant alone. But there is a lot to consider in addition to the potential outcome. One has to also weigh the risks of any medical procedure, which are significant in the case of organ transplants and very dependent on the patient’s current health status. My understanding is that a liver transplant is much more complicated (riskier) than a kidney transplant, and that was the point Gillmore was making in response to the Stangou article. So when deciding between a kidney only vs. a liver and kidney transplant, the patient’s current health and life expectancy are important factors to consider.

Regarding liver only transplants for AFib, there is no published data to refer to since the first one was done in July of 2010, a few months after these articles were published. That patient, our very own Cathy T., underwent a liver transplant with a GFR well under 30, which is considerably lower than the minimum of 50 that was recommended in the Stangou article. As of three years post-transplant she was doing very well, and she did recover enough kidney function such that she is no longer eligible for a kidney transplant. I am not aware of any other liver-only transplants for AFib patients, so we only have this one example from which to draw any conclusions. Based on that one data point, though, it seems reasonable to consider an isolated liver transplant early in the course of the disease.

In conclusion, when treating fibrinogen amyloidosis, the decision on which type of organ transplant to pursue, if any, must take a lot of factors into consideration. There are no easy answers and there are differences of opinion even among the experts within the medical community. If you add in the possibility of drug treatments that are currently in clinical trials, there is even more to consider. That is one reason it is so important to consult with doctors at a center of experience if at all possible, since they will have access to the latest information regarding treatment options.

The question of which type of organ transplant is definitely a situation where the patient needs to be informed enough to participate in the decision-making process. There is a lot to consider and it takes time to process it all, which is another reason possibly affected family members should consider genetic testing sooner rather than later. A person who waits until symptoms develop before learning about treatment options is at a big disadvantage compared to a person who starts learning about treatment options before symptoms develop. 



(1) Gillmore JD, Lachmann HJ, Wechalekar A, Hawkins PN. Hereditary fibrinogen A alpha-chain amyloidosis: clinical phenotype and role of liver transplantation. Blood. 2010;115(21):4313; author reply 4314-43

(2) 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.

(3) 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.

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