Orthotopic liver transplantation for hereditary fibrinogen amyloidosis : Transplantation

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Orthotopic liver transplantation for hereditary fibrinogen amyloidosis

Zeldenrust, S.1; Gertz, M.1; Uemichi, T.2; Björnsson, J.3; Wiesner, R.4; Schwab, T.5; Benson, M.6

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Transplantation 75(4):p 560-561, February 27, 2003. | DOI: 10.1097/01.TP.0000046526.10003.EC
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Systemic amyloidosis is a group of related conditions in which insoluble protein fibrils are deposited in the extracellular space. The most common form is associated with deposition of immunoglobulin light-chain fragments. Several hereditary forms of amyloidosis have also been identified. Although most of the hereditary forms involve mutations in the transthyretin gene, several recent reports have identified mutations in the fibrinogen Aα chain gene in individuals with autosomal dominant amyloidosis and renal deposition resulting in renal failure (1–5).

Fibrinogen is a major plasma protein involved in the coagulation cascade. It is composed of two sets of three discrete polypeptide chains (α,β, and γ). Numerous mutations have been described in individuals with dysfibrinogenemia, but the reports cited previously are the first associated with amyloidosis (6). Synthesis of fibrinogen is exclusively hepatic, making liver transplant theoretically curative in hereditary fibrinogen amyloidosis. We report successful orthotopic liver transplantation in two patients with hereditary fibrinogen amyloidosis.

The subject of this report is a 62-year-old member of an Irish-American kindred with the Glu526Val mutation. He presented with hypertension in the fourth decade. At the time of presentation, the patient’s serum creatinine was 2.7 mg/dL with a creatinine clearance of 39 mL/min. A 24-hr urine collection was remarkable for the presence of 3 g of protein.

A renal biopsy was performed and revealed that the glomeruli were extensively replaced by diffuse nodular masses of eosinophilic, amorphous, and refractile material. Special stains for amyloid (Thioflavin T and Congo Red) were strongly positive with only minimal evidence of vascular amyloid deposition. Immunohistochemistry was weakly positive for fibrinogen and negative for serum amyloid A, β2 microglobulin, transthyretin, and λ immunoglobulin light chain. Electron microscopy showed extensive deposition of fibrillar material in glomerular mesangium with extension into peripheral capillary walls. High power views (×50,000) showed the presence of fibrils in irregular arrays with a mean diameter of 13.3 nm.

Over the next 12 months, the patient developed progressive renal failure with hyperkalemia. His serum creatinine rose to 4.5 mg/dL. He developed refractory nausea and vomiting. It was known that both his father and brother had been diagnosed with renal amyloidosis. DNA studies revealed the patient to be a carrier of the Glu526Val fibrinogen mutation. In an effort to improve renal function and prevent a similar recurrence of amyloid deposition, a combined orthotopic liver and renal transplantation was performed in September 1995.

Follow-up at 61/2 years reveals the patient has stable renal function with serum creatinine of 1.8 mg/dL and iothalamate clearance of 47 mL/min. Subsequent biopsies have shown no evidence of recurrent renal amyloid deposits, and serum fibrinogen level is normal. Graft rejection has been minimal on a standard regimen of immunosuppression. Nausea and vomiting resolved. The patient required a splenectomy for erythropoietin-refractory anemia, which has subsequently resolved. Analysis of the spleen showed extensive amyloid deposits composed of fibrinogen.

The older brother of our patient developed proteinuria at age 47 years. He underwent orthotopic renal transplantation at an outside facility in 1994, with diffuse amyloid deposits found in the native kidney. In April 1997, he developed recurrent renal failure and required a nephrectomy of his transplanted kidney for chronic rejection. Extensive amyloid deposition in the allograft was noted. He also required a splenectomy for erythropoietin-refractory anemia. There was extensive splenic amyloid deposition. He was also found to have a profound autonomic neuropathy, characterized by delayed gastric motility.

He received an orthotopic liver and kidney transplant in November 1999. Renal function has improved, with a creatinine of 1.2 mg/dL and corrected iothalamate clearance of 51 mL/min at 28 months of follow-up. Renal biopsy is negative for recurrent amyloid deposition, and liver function and serum fibrinogen levels are normal. His appetite is normal, with no evidence of delayed gastric emptying.

The first liver transplantation for hereditary amyloidosis was performed in a patient with transthyretin-associated amyloidosis in Sweden in 1990 (7). More than 350 liver transplants have been performed worldwide since that time, according to the Familial Amyloidotic Polyneuropathy World Transplant Register. Despite promising results in the Swedish population, which consists almost entirely of the V30M variant form of transthyretin, mixed results have been published from other centers. Clear progression of cardiac disease, peripheral neuropathy, vitreous deposits, and even central nervous system disease after transplant in non-V30M patients has been reported (8–12). This has resulted in more careful pretransplant assessment in familial amyloidotic polyneuropathy patients and greater reluctance to perform transplants in non-V30M patients with preexisting cardiac amyloidosis.

Combined hepatorenal transplantation has been reported successfully in other forms of hereditary amyloidosis. A single case report of hepatorenal transplantation in a patient with end-stage renal failure and progressive liver dysfunction as the result of apolipoprotein-AI–associated amyloidosis showed excellent results after 2 years of follow-up (13).

Similarly, excellent results were reported in a single patient after combined hepatorenal transplantation for fibrinogen-associated amyloidosis in a British patient (14). At 2 years of follow-up, the patient showed no evidence of recurrent amyloidosis on serum amyloid P scintigraphy, suggesting that liver transplantation was curative in this patient.

Renal transplantation has been used in the management of patients with systemic amyloidosis for more than 30 years, particularly in patients with amyloid A, or secondary, amyloidosis. Several recent reports claim that more than 400 patients with systemic amyloidosis have received transplants worldwide (15,16). A report from the United Network for Organ Sharing registry data documents 83 first-time renal allograft recipients with a diagnosis of amyloidosis between 1987 and 1996 (17). Posttransplant survival in amyloidosis patients remains poor, with 40% to 65% 5-year overall survival (15). Most deaths occur as a result of systemic infections or cardiovascular complications.

We report the first use of hepatorenal transplantation in hereditary fibrinogen amyloidosis and the successful long-term outcome in two patients. Both patients show excellent graft function, improved quality of life, and no evidence of recurrent amyloid deposition at 2.3 and 6.5 years posttransplant. The long-term success in these patients confirms the curative nature of hepatic transplantation in this disease. Hereditary fibrinogen-associated amyloidosis can be added to the list of genetic diseases that are cured by liver transplantation, which includes hyperoxaluria, Wilson’s disease, hemochromatosis, Crigler-Najjar syndrome, ornithine transcarbamoylase deficiency, homozygous hypercholesterolemia, familial intrahepatic cholestasis, urea cycle defects, and some forms of glycogen storage disease.


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