Saturday, November 30, 2013

Article Review (2006) - Hereditary fibrinogen A alpha-chain amyloidosis: Clinical features and the curative role of liver transplantation

Today's article under review is the second of three papers I will be reviewing that were presented at the eleventh annual International Symposium on Amyloidosis, which was held in Woods Hole, Massachusetts in November of 2006. The papers presented at this symposium can be found in the book XIth International Symposium on Amyloidosis, edited by Drs. Skinner, Berk, Connors and Seldin, all of the Amyloidosis Center at Boston University.

This paper gives us some statistics on twenty patients with fibrinogen amyloidosis who were evaluated in the UK over the course of 10 years. There are some interesting findings regarding additional organ involvement and how that impacts the actual transplant surgery, as well as some promising post-transplant assessments. (In other words, this one is worth a careful read.)

Title: Hereditary Fibrinogen A alpha-chain amyloidosis: Clinical features and the curative role of liver transplantation (1)

Authors: N. D. Heaton, J. O. Grady, M. Rela, P. Muiesan, J. A. Wendon, L. Sizer, J. Sedgwick, M. Thomas, F. Murgatroyd, C. J. Mathias, H. J. Goodman, D. Rowczenio, A. Bybee, G. Tennent, P. N. Hawkins, and A. J. Stangou (King's College Hospital, London, UK; National Hospital for Neurology and Neurosurgery, London, UK; Centre for Amyloidosis and Acute Phase Proteins, Royal Free and University College Medical School, London, UK)

BookXIth International Symposium on Amyloidosis (2007)

Abstract: None

I do not know if the first sentence of this article was true in 2006, but it is definitely not true (or is at least misleading) today. Here it is: "Hereditary fibrinogen A alpha-chain Glu526Val amyloidosis (AFib) is the most frequently diagnosed form of hereditary amyloid in the U. K." Although fibrinogen amyloidosis is much more common in the UK than it is in the US, everything I have seen, such as the UK Amyloidosis Patient Information Site, indicates that ATTR is the most common form of hereditary amyloidosis in the UK. However, since there are over 100 mutations known to cause ATTR amyloidosis, I suppose the rankings may be different if each mutation is considered separately. Anyway, the first paragraph of the article then states that end stage renal failure typically occurs in patients with fibrinogen amyloidosis within one to five years of presenting with proteinuria and hypertension. In patients who receive just a kidney transplant, amyloid almost always recurs in the transplanted kidney within 7 years.

The twenty patients in this paper were evaluated for combined liver and kidney transplants at King's College Hospital in the UK between 1996 and 2006. Their ages when they first presented with symptoms ranged from 36 to 69, and they were assessed between the ages of 57 and 69. The median time from diagnosis to end stage renal failure was 29 months.

Part of the assessment of these patients was SAP scintigraphy, which provides a visual indication of where amyloid deposits are in the body. SAP scintigraphy was very accurate in identifying amyloid deposits in the kidneys as well as other organs. One interesting finding was that SAP scintigraphy would show amyloid deposits in the spleen even though conventional methods of analyzing the spleen did not detect any issues. The paper states that splenic involvement is usually clinically significant in AFib patients due to increased erythropoetin requirements. (Translation: A need for something like Epogen or Procrit due to anemia.) In fact, rupture of the spleen is such a concern that they have altered their surgical technique during transplants in these patients to reduce the risk of rupturing the spleen, as well as increased the vaccination regimen of patients who are on the waiting list.

Another part of the initial evaluation of these patients was a thorough assessment of their peripheral and autonomic neurological function. As we learned from Dr. Gertz' opening presentation at the familial amyloidosis meeting in October, the peripheral nervous system gives us feeling in our extremities and allows us to control the muscles in those extremities, whereas the autonomic nervous system is mostly out of our control and affects things like perspiration, heart rate, and the digestive system. The article states that about half of these transplant candidates showed some level of autonomic neuropathy affecting either the heart or the gastrointestinal tract. But the good news is that the autonomic neuropathy was resolved in the patients who received a liver and kidney transplant.

The article then gives some details on the outcomes of the transplants. Of the twenty patients evaluated, seven underwent combined liver and kidney transplant (LKT). Three of those patients either had not started dialysis or had been on dialysis less than six months at the time of transplant. The other four patients had been on hemodialysis at least two years at the time of transplant. The only complications during surgery were two cases where the spleen ruptured during surgery.

The patients who had not been on long term dialysis had fewer complications after their transplants than the ones who had been on dialysis at least two years. At the time this paper was written, six of the seven patients were still alive and their transplanted organs were functioning in the normal range. The authors of the paper did confirm there was no variant (mutant) fibrinogen circulating in the blood of these patients after their transplants. (More on that subject in a 2007 article.) Using SAP scintigraphy they could also determine that no new amyloid deposits appeared in the transplant patients, and the existing deposits regressed quite rapidly.

The conclusion of the paper states that the outcomes of combined liver and kidney transplants endorse it as a curative treatment for fibrinogen amyloidosis.


Before this paper was published there were a few isolated cases reported of combined liver and kidney transplant being used to treat fibrinogen amyloidosis, so now we have one paper reporting the outcomes of seven cases. All indications are that a combined liver and kidney transplant is curative, since a) the liver is the source of the variant fibrinogen, and b) the body appears to be able to eliminate the fibrinogen amyloid deposits once the source is removed and they stop accumulating. That differentiates AFib from ATTR (transthyretin amyloidosis) in two important ways. First, the liver is not the sole source of variant transthyretin, so patients with ATTR who undergo a liver transplant are still producing variant ATTR but at a slower rate. The second difference is that once amyloid deposits due to variant ATTR are formed, the wild-type (normal) transthyretin will continue to accumulate and build up those deposits. That makes ATTR much more difficult to manage, even after a liver transplant.

I was surprised by the reports of autonomic neuropathy in 50% of these transplant candidates. There was a case of peripheral neuropathy previously reported in a fibrinogen amyloidosis patient, but I do not recall any reports of autonomic neuropathy. It may be that this neuropathy is typically not clinically significant, so a thorough evaluation is not typically done and it is never discovered. In any case, it is good to know that it does improve after a liver transplant.

Before reading this paper I was aware that fibrinogen amyloidosis could eventually affect the spleen, and amyloid deposits are often found in the spleen on autopsy, but I had not really considered it to be clinically significant unless and until the spleen becomes enlarged or ruptures. However, this paper states that anemia is a sign of splenic involvement. Since Mom has anemia, and I know of some other AFib patients (AFibbers?) where anemia is or was an issue, perhaps it is reasonable to state that the spleen is involved once a person with fibrinogen amyloidosis becomes anemic. I don't know if that changes anything in terms of the treatment for the anemia, but it might be worth mentioning to your doctor if that is your situation. I would also recommend (not sure if I have mentioned this before) that anyone with fibrinogen amyloidosis who is on dialysis tell your doctor to be on the lookout for an enlarged spleen, and be aware of the signs of a ruptured spleen (severe pain in upper left abdomen), since that is an emergency medical condition that can be life threatening.

Speaking of spleens, I found the discussion of ruptured spleens in this paper interesting. They state that three of these patients had ruptured spleens, with two of those occurring during the transplant surgery. So if and when you are approved for a liver or liver-kidney transplant, that might be something worth mentioning to the transplant team before you get that phone call to rush to the hospital. You don't want to wait until you are about to be anesthetized to ask the surgeon, "Hey doc, are you going to use mesenteric bypass to avoid a sudden increase in splenic pulp pressure and splenic rupture?"

In summary, this paper definitely provides some more data pointing to a combined liver and kidney transplant being a cure for fibrinogen amyloidosis. I do not know if any of the other types of amyloidosis (hereditary or otherwise) can really be considered "cured" with any treatment. With AL amyloidosis, for instance, the doctors speak in terms of a patient's response to treatment (no response, partial response, very good partial response, and complete response), and even if a patient has a complete response there is no guarantee that the amyloidosis will not come back. So although an organ transplant is a major medical procedure with significant risk, at least it can be considered curative for fibrinogen amyloidosis based on the data in this paper from 2006. We will have to wait until 2009 and 2010 for some more published articles covering larger groups of patients. (But feel free to read ahead. You know where to find them.)

The next article review will give us some idea of how rare fibrinogen amyloidosis is compared to other types of familial amyloidosis.



(1) Skinner M, Berk JL, Connors LH, Seldin DC. XIth International Symposium on Amyloidosis: Taylor & Francis; 2010.

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