Friday, October 18, 2013

Article Review (2006) - Successful Hepatorenal Transplantation in Hereditary Amyloidosis Caused by a Frame-Shift Mutation in Fibrinogen A alpha-chain Gene

The article under review in this post is sort of a follow-up to an article that was published earlier, since it follows the progress of the same two patients. The original article, published in 1997, was Renal Amyloidosis With a Frame Shift Mutation in a Fibrinogen A Alpha Chain Gene Producing a Novel Amyloid Protein (1), and I reviewed that article on April 18, 2013. That article described a father and son who were found to have a new mutation causing fibrinogen amyloidosis. This mutation not only seemed to have an earlier age of onset than the Glu526Val mutation but it also caused amyloidosis to quickly recur in kidney transplants of both patients. So what do you do after a kidney transplant fails? Let's find out . . .

Title: Successful Hepatorenal Transplantation in Hereditary Amyloidosis Caused by a Frame-Shift Mutation in Fibrinogen A alpha-Chain Gene (2)

Authors: C. Mousson, B. Heyd, E. Justrabo, J.-M. Rebibou, Y. Tanter, J.-P. Miguet and G. Rifle (University Hospital, Dijon, France; University Hospital, Besancon, France)

Journal: American Journal of Transplantation (2006)

Hereditary systemic amyloidosis comprises several autosomal dominant diseases caused by mutations in a number of plasma proteins, including the fibrinogen A alpha-chain. Four mutations in the fibrinogen A alpha-chain that are able to induce amyloidosis have been identified so far, the most common being the Glu526Val mutation. We have observed a family in which the father and his son reached end-stage renal failure because of renal amyloidosis induced by a frame-shift mutation in the fibrinogen A alpha-chain gene producing a novel amyloid protein. Two kidney transplantations in the father and one in the son resulted in fast graft loss caused by recurrence of amyloid deposition. We then performed hepatorenal transplantation in the son. Three years later, liver and kidney functions are normal without recurrence of amyloid deposition. This case, together with three others with the Glu526Val mutation in the extensive literature, suggests that liver transplantation can cure hereditary fibrinogen amyloidosis, whatever the mutation may be.

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

The first patient described is the father, who developed kidney issues in 1984 at the age of 31. A kidney biopsy showed amyloid deposits in the glomeruli, but liver, bone marrow and rectal biopsies were all negative for amyloids. He was believed to have AL amyloidosis so he was treated with chemotherapy, which offered no improvement so his kidney function continued to decline to the point where he needed hemodialysis. He received a kidney transplant in 1988 at the age of 35. A biopsy two years later showed the presence of amyloid in the transplanted kidney, and he started hemodialysis again in 1994. The transplanted kidney was removed in 1995 and he received another kidney transplant in 1996. That kidney was also quickly affected by amyloid deposits and he was back on hemodialysis in 2001.

Analysis of the first transplanted kidney after it was removed showed that he had a frame-shift mutation in the fibrinogen A alpha-chain gene, as described in the 1997 article.

The son of this patient developed kidney issues in 1992 at the age of 12. A kidney biopsy showed amyloid deposits in the glomeruli, and he started peritoneal dialysis in 1993. DNA analysis showed he had the same fibrinogen mutation as his father. He received a kidney transplant in 1995 at the age of 15. He developed proteinuria and hypertension one year later, and a kidney biopsy showed amyloid deposits in the transplanted kidney. He started peritoneal dialysis again in February of 1998, then went on hemodialysis in 2000.

So at this point there were three failed kidney transplants, two in the father and one in the son. It was obvious that this particular form of fibrinogen amyloidosis would affect a transplanted kidney very quickly, so it was unreasonable to have the son undergo another kidney transplant. Since they knew fibrinogen was produced in the liver, and liver transplants had been used to treat other forms of familial amyloidosis, they decided to do a liver and kidney transplant on the son. That transplant occurred in May of 2002, and his kidney and liver functions rapidly recovered. Three years later, when this article was written, he was doing well with perfectly normal kidney and liver function. The father was waiting on a combined liver and kidney transplant at the time this article was written.

The article then discusses the use of liver transplants to treat other forms of hereditary amyloidosis, primarily those due to transthyretin mutations. Although the progression of the disease is slowed, liver transplants do not appear to be a "cure" for other types of amyloidosis because transthyretin, for instance, is produced in a few areas of the body in addition to the liver. "On the other hand, fibrinogen is only synthesized by the liver. Therefore, it can be postulated that liver replacement can really cure mutant fibrinogen-induced amyloidosis." The article then briefly describes the three cases of combined liver-kidney transplants for fibrinogen amyloidosis that have been previously published. Those results indicate that a liver transplant can cure fibrinogen amyloidosis.

The article closes with a discussion of domino liver transplants, where a cadaver liver is transplanted into patient A, and patient A's liver is transplanted into patient B. Domino liver transplants have been done with familial amyloidosis patients, since their liver function is typically fine and a person with liver failure would gladly take that liver since it would usually take many years for any amyloidosis symptoms to become evident. In the case of this particular patient, however, since they knew this mutation caused rapid failure of a transplanted kidney, they did not consider using his liver in another patient.


Although this article is about a fibrinogen amyloisosis mutation other than Glu526Val, it does add to the general discussion about a liver transplant being curative for fibrinogen amyloidosis. Upcoming articles will have more reports of transplants in the treatment of fibrinogen amyloidosis, and there will be more reports of patients in other countries being diagnosed with it. The number of articles per year definitely increased in 2006, so it will take awhile to catch up to the current day with article reviews.

Next up, we hear from the land down under.


(1) Hamidi Asl L., Liepnieks J.J., Uemichi T., Rebibou J.M., Justrabo E., Droz D., Mousson C., Chalopin J.M., Benson M.D., Delpech M., Grateau G. Renal amyloidosis with a frame shift mutation in fibrinogen a α-chain gene producing a novel amyloid protein. Blood. 1997;90:4799–4805.

(2) Mousson C, Heyd B, Justrabo E, et al. Successful hepatorenal transplantation in hereditary amyloidosis caused by a frame-shift mutation in fibrinogen A alpha-chain gene. Am J Transplant 2006; 6: 632-635.

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