Transmission of Systemic Transthyretin Amyloidosis by Means of Domino Liver Transplantation
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《新英格兰医药杂志》
To the Editor: Familial amyloidotic polyneuropathy is a fatal autosomal dominant disease caused by amyloidogenic genetic variants of transthyretin. The liver is the predominant source of circulating transthyretin, and liver transplantation is the only treatment available for the disease.1 Livers explanted from patients with familial amyloidotic polyneuropathy contain only microscopic amyloid deposits in hilar vessels and nerves and are otherwise uninvolved. Since 1995, more than 300 such livers removed at transplantation have been used sequentially as donor grafts for recipients with liver cancer or end-stage liver disease, in so-called domino liver transplantation.2 We report here a case of systemic transthyretin amyloidosis in a 55-year-old man who had received a liver graft eight years earlier by means of domino transplantation from a 32-year-old patient with familial amyloidotic polyneuropathy who had the Val30Met variant of transthyretin.
The recipient had hepatitis C virus cirrhosis complicated by a 9-cm hepatocellular carcinoma, which precluded conventional cadaveric liver transplantation.3 In 1996, he consented to domino liver transplantation; preexisting amyloid and potentially amyloidogenic disorders were ruled out before surgery.4 He remained free from tumor recurrence but at eight years reported symptoms of dysesthesias in the lower extremities. Specimens from nerve and rectal biopsies contained transthyretin amyloid deposits as indicated by Congo red dichroism and immunohistochemical staining. In the ensuing six months, overt progressive peripheral neuropathy developed in the recipient, and according to provisions made in our initial counseling, he was listed for and subsequently underwent liver retransplantation in April 2005 with a standard graft from the cadaveric list. He was discharged home two weeks after transplantation and has had a smooth recovery with no complications.
Clinical disease is never present in systemic amyloidosis in the absence of amyloid deposits, and transformation of soluble proteins into amyloid fibrils in vivo is pivotal, but the precise molecular mechanisms are poorly understood. The penetrance of disease varies substantially, and amyloid deposition and symptoms occur in affected persons only in adulthood. Amyloid deposition may also depend on unknown age-related mechanisms that promote amyloid fibrillogenesis. In the present case, the rates at which amyloid appeared and the disease progressed in the recipient were accelerated as compared with the rates in the donor; it is possible that this is related to the recipient's older age or to inoculation with preformed amyloid fibrils that were present in the donor liver, which may be capable of triggering or promoting conversion of the acquired transthyretin variant into the pathogenic conformation of amyloid fibrils.
Subclinical cutaneous transthyretin amyloid deposits were recently reported in five other recipients of domino liver grafts.5 Although liver donors with familial amyloidotic polyneuropathy remain a valuable resource, our data reinforce the need for additional caution and vigilant long-term monitoring of recipients.
Arie J. Stangou, M.D.
Nigel D. Heaton, F.R.C.S.
Institute of Liver Studies
London SE5 9RS, United Kingdom
arie.stangou@kcl.ac.uk
Philip N. Hawkins, F.R.C.P.
National Amyloidosis Centre
London NW3 2PF, United Kingdom
References
Holmgren G, Ericzon BG, Groth CG, et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993;341:1113-1116.
Herlenius G, Wilczek HE, Larsson M, Ericzon BG. Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry. Transplantation 2004;77:64-71.
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-700.
Stangou AJ, Heaton ND, Rela M, Pepys MB, Hawkins PN, Williams R. Domino hepatic transplantation using the liver from a patient with familial amyloidotic polyneuropathy. Transplantation 1998;65:1496-1498.
Sousa MM, Ferrao J, Fernandes R, et al. Deposition and passage of transthyretin through the blood-nerve barrier in recipients of familial amyloidotic polyneuropathy livers. Lab Invest 2004;84:865-873.
The recipient had hepatitis C virus cirrhosis complicated by a 9-cm hepatocellular carcinoma, which precluded conventional cadaveric liver transplantation.3 In 1996, he consented to domino liver transplantation; preexisting amyloid and potentially amyloidogenic disorders were ruled out before surgery.4 He remained free from tumor recurrence but at eight years reported symptoms of dysesthesias in the lower extremities. Specimens from nerve and rectal biopsies contained transthyretin amyloid deposits as indicated by Congo red dichroism and immunohistochemical staining. In the ensuing six months, overt progressive peripheral neuropathy developed in the recipient, and according to provisions made in our initial counseling, he was listed for and subsequently underwent liver retransplantation in April 2005 with a standard graft from the cadaveric list. He was discharged home two weeks after transplantation and has had a smooth recovery with no complications.
Clinical disease is never present in systemic amyloidosis in the absence of amyloid deposits, and transformation of soluble proteins into amyloid fibrils in vivo is pivotal, but the precise molecular mechanisms are poorly understood. The penetrance of disease varies substantially, and amyloid deposition and symptoms occur in affected persons only in adulthood. Amyloid deposition may also depend on unknown age-related mechanisms that promote amyloid fibrillogenesis. In the present case, the rates at which amyloid appeared and the disease progressed in the recipient were accelerated as compared with the rates in the donor; it is possible that this is related to the recipient's older age or to inoculation with preformed amyloid fibrils that were present in the donor liver, which may be capable of triggering or promoting conversion of the acquired transthyretin variant into the pathogenic conformation of amyloid fibrils.
Subclinical cutaneous transthyretin amyloid deposits were recently reported in five other recipients of domino liver grafts.5 Although liver donors with familial amyloidotic polyneuropathy remain a valuable resource, our data reinforce the need for additional caution and vigilant long-term monitoring of recipients.
Arie J. Stangou, M.D.
Nigel D. Heaton, F.R.C.S.
Institute of Liver Studies
London SE5 9RS, United Kingdom
arie.stangou@kcl.ac.uk
Philip N. Hawkins, F.R.C.P.
National Amyloidosis Centre
London NW3 2PF, United Kingdom
References
Holmgren G, Ericzon BG, Groth CG, et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993;341:1113-1116.
Herlenius G, Wilczek HE, Larsson M, Ericzon BG. Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry. Transplantation 2004;77:64-71.
Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-700.
Stangou AJ, Heaton ND, Rela M, Pepys MB, Hawkins PN, Williams R. Domino hepatic transplantation using the liver from a patient with familial amyloidotic polyneuropathy. Transplantation 1998;65:1496-1498.
Sousa MM, Ferrao J, Fernandes R, et al. Deposition and passage of transthyretin through the blood-nerve barrier in recipients of familial amyloidotic polyneuropathy livers. Lab Invest 2004;84:865-873.