A. J. Stangou

Progressive cardiac amyloidosis following liver transplantation for familial amyloid polyneuropathy - Implications for amyloid fibrillogenesis

BACKGROUND Circulating transthyretin (TTR) is derived from the liver, and orthotopic liver transplantation (OLT) is widely performed for variant TTR-associated familial amyloid polyneuropathy (FAP). The effect of OLT on FAP-related cardiac amyloid is of particular interest because wild-type TTR can itself be deposited as senile cardiac amyloid. METHODS Serial echocardiography was performed in 20 FAP patients, 14 of whom underwent OLT, and 10 other liver transplant patients. Follow-up included serum amyloid P component scintigraphy and measurement of plasma TTR before and after OLT. RESULTS Cardiac amyloidosis progressed rapidly in three FAP patients (TTR Pro52 and Thr84 mutations) after OLT, even though the deposits elsewhere had stabilized or regressed. Results of echocardiography improved in three transplant patients with TTR Met30 and remained normal in seven other patients. Plasma TTR levels were altered substantially after OLT, but they did not reflect the cardiac findings. CONCLUSIONS Although amyloid deposition in FAP is generally inhibited after OLT, cardiac amyloidosis can be exacerbated, probably due to enhanced deposition of wild-type TTR on a template of amyloid derived from variant TTR. The phenomenon may be mutation-dependent. These findings suggest that amyloid formation de novo and its subsequent accumulation can be promoted by different factors, which may be organ-specific.

Hereditary fibrinogen A α-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation

Variants of fibrinogen A alpha-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome. Twenty-one had E526V and 1, the R554L variant. Coronary atherosclerosis was identified in 68% and systemic atheromatosis in 55%. Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid. Half had autonomic neuropathy. Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up. Serial technetium-99m-labeled dimercaptosuccinic acid ((99m)Tc-DMSA) renal scintigraphy in 2 cases of preemptive LKT demonstrated preserved native kidney residual function at 5 years. Four explanted livers were used successfully for domino transplantation. Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement. LKT is curative; however, cardiovascular amyloidosis may preclude this option. Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation.

Proportion between wild-type and mutant protein in truncated compared to full-length ATTR : an analysis on transplanted transthyretin T60A amyloidosis patients

Familial ATTR amyloidosis is caused by point mutations in the transthyretin gene. The clinical manifestations are highly varied but polyneuropathy and/or cardiomyopathy are generally the main symptoms. The amyloid fibrils can either be composed of only intact ATTR molecules or intact together with fragmented ATTR species. As plasma TTR is almost exclusively synthesized in the liver, liver transplantation is performed in order to eliminate the mutant plasma TTR. The procedure has shown best results among patients with the V30M mutation, while a rapid continued cardiac deposition of wild-type (wt) TTR has been seen for many other mutations. In this paper we investigated the proportion of wtATTR in two TTRT60A patients that underwent liver transplantation; one patient died 3 weeks after surgery, the other patient survived for 12 months. As the role of fragmented TTR species in the pathogenesis is far from understood, we investigated the proportion of wt in these species separately to the full-length molecules, which has not been done before in transplanted patients. The results show a higher proportion of wtTTR in the 12-months-surviving patient than the 3-weeks-surviving patient, but interestingly this difference in wt proportion is mainly seen among the full-length, and not the fragmented, molecules.

Simultaneous combined liver and kidney transplantation: a single center experience

Chava SP, Singh B, Stangou A, Battula N, Bowles M, O’Grady J, Rela M, Heaton ND. Simultaneous combined liver and kidney transplantation: a single center experience.
Clin Transplant 2010: 24: E62–E68.

LIVER TRANSPLANTATION FOR TRANSTHYRETIN SYSTEMIC AMYLOIDOSIS DISORDERS: AN UPDATED REVIEW FROM THE FAMILIAL AMYLOIDOTIC POLYNEUROPATHY WORLD TRANSPLANT REGISTER (FAPWTR): 1930

Introduction/Methods: Several hereditary amyloidosis disorders can be treated with liver transplantation (Ltx). The FAPWTR exists since 1993 and gets data on these patients from centres all over the world. Results: By Dec 2009, a total of 70 centres from 18 different countries reported patients to the FAPWTR. A total of 1536 patients underwent 1660 liver transplantations. 37 patients received a combined liver/kidney graft and 25 patients a combined liverand heart transplantation. 81 LTx:s were done with grafts from living related donors. Patients with more than 45 different variants of TTR mutations have been transplanted, the most common being Val30Met (83%) followed by Ser77Tyr, Thr60Ala and Tyr114Cys (1-2% each, respectively). 1274 of the FAP patients had the Val30Met TTR mutation, 196 patients had a nonVal30Met variant, 11 were non-TTR variants and in 55 patients information was missing or unknown. Most transplantations have been done in Portugal (n=650), France (n=207), Sweden (n=130), USA (n=79), UK (n=78), Brazil (n=71) and Spain (n=72).