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Keywords:

  • Hereditary fibrinogen amyloidosis;
  • kidney transplantation;
  • liver transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References

Hereditary systemic amyloidosis comprises several autosomal dominant diseases caused by mutations in a number of plasma proteins, including the fibrinogen Aα-chain. Four mutations in the fibrinogen Aα-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 Aα-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.

Beside AL and AA amyloidosis, hereditary systemic amyloidosis is becoming of increasing importance. It is caused by the deposition of genetically variant proteins as amyloid fibrils. Currently known mutations concern transthyretin (familial amyloid polyneuropathy), apolipoprotein AI (apoAI), apolipoprotein AII, lysozyme, cystatin C, gelsolin, tumor necrosis factor receptor and the fibrinogen Aα-chain; these diseases are all inherited in an autosomal dominant manner with variable penetrance (1–3). The most common mutation in the fibrinogen Aα-chain gene results in the substitution of valine for glutamic acid at position 526 (4). Surprisingly, this seems to be a frequent cause of amyloidosis in northern Europeans since this variant was found to be the cause in 5% of patients referred to the UK National Amyloidosis Center with an apparent diagnosis of AL amyloidosis (5). Kidneys are the main site of amyloid deposition, which can sometimes also be observed in the spleen and the liver, but not in the heart. It has a low penetrance: most patients present in middle age with proteinuria and progress to end-stage renal failure within 4–8 years. Three other mutations have been described so far: two frame-shift deletion mutations, and a leucine for arginine substitution at codon 554 (6–9). Because of the small number of described cases, the natural history of such fibrinogen mutation-induced amyloidosis is poorly known. However, the amyloidosis in the French family described above with a frame-shift mutation in the fibrinogen Aα-chain gene producing a novel amyloid protein is characterized by the early age of onset and the rapid recurrence of amyloid deposits in successive renal transplants leading to graft loss (7). Fibrinogen, as transthyretin, is synthesized in the liver, thus it was logical to consider liver transplantation for this form of hereditary amyloidosis. We report the successful result of a combined kidney and liver transplantation in a member of this family.

Case Report

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References

We have previously reported in part the medical histories of a father and his son with hereditary renal amyloidosis (7).

Briefly, the father was a 31-year-old man who developed nephrotic syndrome in 1984. Kidney biopsy showed glomerular amyloid deposits that were birefringent under polarized light after Congo red staining. Hepatic, bone marrow and rectal biopsies showed no amyloid deposit. Echocardiography showed no sign of amyloid cardiomyopathy. At that time, he was thought to have AL amyloidosis and was treated with plasma exchange and chemotherapy without any improvement, and reached end-stage renal failure in 1987. In 1988, at the age of 35, the patient received a kidney transplant. Two years later, a biopsy revealed recurrence of amyloidosis in the renal graft. Maintenance hemodialysis was started again in 1994. The transplant was removed in 1995. A new immunohistochemical study showed a reaction of the amyloid deposits with antifibrinogen, anti-SAP, anti-IgG and anti-κ light chain antibodies. A liver biopsy showed mild vascular amyloid deposits. No other amyloid deposit was detected. A second renal transplantation was performed in November 1996. Recurrence of amyloid deposition still occurred quickly and the patient again reached end-stage renal failure requiring maintenance hemodialysis therapy since December 2001.

Amyloid fibril protein isolated from the first removed transplant was found to contain a novel, hybrid peptide of 49 residues whose N-terminal 23 amino acids were identical to residues 499–521 of normal fibrinogen Aα-chain, whereas the remaining 26 residues formed a completely new sequence for mammalian proteins. DNA sequencing from total genomic DNA isolated from peripheral blood cells revealed that this new sequence was the result of a single nucleotide deletion at position 4897 of the fibrinogen Aα-chain gene that gives a frameshift at codon 522 and premature termination at codon 548 (7).

The son of this patient was referred to us in 1992 at the age of 12 for a nephrotic syndrome. Renal biopsy showed glomerular and vascular amyloid deposits. Immunofluorescence examination showed positive staining with antifibrinogen Aα, anti-IgM, anti-λ and anti-κ light chains’ antibodies, localized to glomerular deposits. Immunohistochemistry with antibodies to gelsolin, apoAI, lysozyme and transthyretin was negative. Bone marrow examination was normal, as was echocardiography. Renal failure progressed rapidly with severe hypertension, and continuous ambulatory peritoneal dialysis (CAPD) was begun 1 year after the diagnosis. DNA analysis showed the same single nucleotide deletion at position 4897 of the fibrinogen Aα-chain gene, as observed in his father (7). The boy received a cadaveric kidney transplant in 1995, at the age of 15. One year later, proteinuria of 1 g/day and hypertension recurred. Kidney transplant biopsy revealed the presence of marked amyloid deposits with the same immunofluorescence staining as seen in the native kidney. Renal failure progressed rapidly and CAPD was started again in February 1998. This was relieved by maintenance hemodialysis 2 years later. As three transplants were rapidly lost, two in the father and one in the son, it became evident that this particular form of hereditary amyloidosis recurred early on kidney transplants. It was ethically unreasonable to repeat the transplantation of a kidney alone. Although the liver function was normal, we decided to perform a combined kidney and liver transplantation. After informed consent, this double transplantation from a single cadaveric donor was performed in May 2002 with no technical problems. Renal and liver functions rapidly recovered. Microscopic examination of the removed liver showed mild amyloid deposits, which were Congo red positive, in some arteriolar walls and adjacent portal veins. Immunofluorescence examination with specific antibodies showed SAP but not SAA staining. Apart from these amyloid deposits, the liver parenchyma was normal. Three years later, the patient is doing well with low immunosuppressive therapy, and works full-time. Renal and liver functions remain perfectly normal. There is no proteinuria. Plasma fibrinogen level is normal. There are no coagulation abnormalities. A kidney transplant biopsy showed only mild lymphohistiocytic infiltrates in the interstitium. Congo red staining was negative. Immunofluorescence examination showed only IgM, κ and λ deposits in 10% of the glomeruli with no fibrinogen deposit. The patient refused a liver transplant biopsy.

The father is now waiting for combined liver and kidney transplantation, delayed because of the presence of a high level of anti-HLA antibodies.

Discussion

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References

Genetic diseases can be cured by liver transplantation when the synthesis of the mutant protein is exclusively hepatic, and could be improved when such mutant proteins are synthesized mainly by the liver. The first liver transplantation for familial amyloidosis was performed in 1990 in a patient with the Val30Met transthyretin-associated amyloidosis. Since that time, more than 500 patients have undergone liver transplantation worldwide for this disease with good results (10). Indeed, 5-year patient survival is 77%, comparable to the survival with liver transplantation performed for other chronic liver disorders. Nevertheless, longer follow-up is needed to compare the outcome after liver transplantation with the natural course of the disease. Indeed, though the majority of symptoms do not worsen after the procedure, they remain unchanged. In addition, progressive involvement of the heart, peripheral neuropathy, vitreous deposits and central nervous system disease have been reported, especially in non-Val30Met patients (11). Such outcomes could be explained by a spontaneous worsening of histological lesions in certain organs, especially in the heart, when the liver transplantation is performed too late, but also by the fact that transthyretin is also synthesized by the retina, the choroid plexus and the ependymal cells of the subcommissural organ (12,13). It has also been suggested that cardiac amyloidosis could be exacerbated by the increased deposition of wild-type transthyretin on a template of amyloid derived from variant transthyretin (14).

Among other types of familial amyloidosis, hepatorenal transplantation has been performed for apoAI Gly26Arg-induced systemic amyloidosis (15). Depending on the mutation, apoAI-induced amyloidosis can present diffuse involvement affecting the heart, kidney and liver and causing polyneuropathy (1). The majority of apoAI is synthesized in the liver and small intestine (16). Although it has not yet been possible to determine the precise contribution of these two sources of apoAI synthesis in the total synthesis of this protein, one can put forward the hypothesis that liver replacement can only partially correct the genetic abnormality. The above-mentioned patient underwent combined liver and kidney transplantation because of hepatic dysfunction associated with end-stage renal failure. Two years after surgery, he is asymptomatic and subclinical amyloid deposits detected by serum amyloid P component scintigraphy which were present in his spleen and heart pre-operatively have regressed and stabilized, respectively. The proportion of variant apoAI in the plasma, estimated by quantitative isoelectric focusing, decreased by 50% after liver transplantation. It was suggested that the excellent clinical outcome could be due to the fact that the balance between deposition and turnover of amyloid has been altered in favor of the latter.

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. Four amyloidogenic mutations of the fibrinogen Aα-chain have been described so far. The most frequent, which concerns 5% of patients with an apparent diagnosis of AL amyloidosis in the United Kingdom, seems to be the substitution of valine for glutamic acid at position 526 (Glu526Val) (5). Other mutations include two frame-shift deletion mutations, including the family reported here (6,7), and a leucine for arginine substitution at position 554 (8). The commonest Glu526Val fibrinogenα-chain variant has low penetrance and most patients present in middle age with proteinuria and hypertension, and progress to end-stage renal failure within 2–8 years. However, though the kidneys are the main target of amyloid deposits, deposition in the spleen and the liver can also occur. Gillmore et al. (17) report the case of a 53-year-old woman who received a renal transplant for end-stage renal failure secondary to Glu526Val fibrinogenα-chain amyloidosis. This graft failed 6 years later due to the recurrence of amyloid deposits. Simultaneously, hepatic amyloidosis induced progressive liver failure, so that hepatorenal transplantation was performed in 1996, both to replace the failed organs and to suppress the hepatic source of the amyloidogenic variant fibrinogen. Three years later, the patient is doing well and has no amyloid deposit identifiable by serum amyloid P component scintigraphy. The first two cases of combined hepatorenal transplantation in patients with Glu526Val fibrinogen mutation-induced amyloidosis with end-stage renal failure, but without liver manifestation were reported in 2003 (18). A 62-year-old man with biopsy-proven renal amyloidosis and the Glu526Val fibrinogen mutation developed progressive renal failure without liver abnormalities. He underwent kidney graft in 1995 associated with liver transplantation purposely included to prevent the recurrence of amyloid deposition. Follow-up at 6.5 years reveals a good clinical state, stable renal function and kidney biopsy showed no recurrence of amyloid deposition. The serum fibrinogen level is normal. The brother of this man developed renal failure with diffuse amyloid deposits at the age of 47 years. A first kidney transplantation failed after 3 years because of chronic rejection and extensive amyloid deposition in the graft. The patient required splenectomy for erythropoietin-refractory anemia due to extensive amyloid deposition in the spleen, and suffered from an autonomic neuropathy characterized by delayed gastric motility. He received a combined liver and kidney transplantation in 1999. Twenty-eight months later, renal and liver functions are normal, the fibrinogen level is also normal, and there is no evidence of delayed gastric emptying. Kidney transplant biopsy showed no amyloid deposit.

Although only a small number of cases have been reported so far, it appears that liver transplantation can cure fibrinogen mutant-induced amyloidosis, whatever the kind of mutation involved. Indeed, we report the first case of liver transplantation for a non-Glu526Val fibrinogen mutation-induced amyloidosis. This mutation is particular since it consists in a frameshift at codon 522 and premature termination at codon 548, resulting in a novel, hybrid peptide as described above (7). This is the only case in the literature of a family with such a mutation. Amyloidosis developed early in life and concerned mainly the kidneys, but we also discovered mild amyloid deposits in the native liver of the father and in the removed liver of the son. Recurrence of amyloid deposition in transplanted kidneys was fast and massive since, for the father and son together, three transplants failed within 3–6 years. Recurrence in allografted kidneys has also been observed in the Glu526Val fibrinogen mutation-induced amyloidosis, but the frequency of such relapses remains unknown (5). Consequently, the only solution was to perform hepatorenal transplantation. As in the cases described by Gillmore et al. (17) and by Zeldenrust et al. (18) in Glu526Val fibrinogen mutation-induced amyloidosis, clinical and histological results after a 3-year follow-up suggest that liver replacement can really cure hereditary fibrinogen amyloidosis.

Clearly, as emphasized by Zeldenrust et al. (18), hereditary fibrinogen-associated amyloidosis can be added to the list of genetic diseases that can be cured by liver transplantation, whatever the mutation may be. A question is: must combined hepatorenal transplantation be systematically performed in end-stage renal failure patients without liver failure? It is probably too early to answer this question. Indeed, the rate of progression of hereditary amyloidosis caused by variants of the fibrinogen Aα-chain is slow in many patients and kidney transplantation alone can lead to an excellent outcome, at least in the Glu526Val variant (5). Thus, it could be suggested that a decision of combined liver and kidney transplantation depends on the mutation and must be considered only in patients or families in whom fast recurrence has occurred in a first kidney transplant, or when the involved mutation is known to result in fast recurrence in the graft, as in the mutation reported in the present family, all the more so because heart involvement is not a feature of this kind of hereditary amyloidosis. It is impossible to know if early liver transplantation could result in the regression of amyloid deposits in native or transplanted kidneys because no data have yet been published.

A last question concerns the possibility of retransplanting the removed liver into another nonamyloidotic patient requiring liver transplantation, the so-called domino procedure. About 30–35 domino liver transplantations are performed each year worldwide with livers explanted from patients with familial amyloidotic polyneuropathy (10). Although after 6–7 years post-transplant, most recipients have no clinical symptoms of amyloidotic polyneuropathy, amyloid deposits have been found in the skin and nerve biopsies of the first domino recipients (19). In addition, the appearance of overt symptoms leading to liver retransplantation with a standard graft from a cadaveric donor has recently been reported (20). Therefore, a case by case approach is now recommended, taking into account individual prognosis, urgency and recipient age. We have chosen not to use the liver explanted in our patient for such a domino procedure. Indeed, the particular mutation in this family results in early manifestations in life, and the recurrence on the kidney transplants was very fast. Thus, it was feared that the same process would occur in the liver recipient, and we preferred to be cautious.

References

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References
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