Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant.

AIMS: Familial amyloid polyneuropathy (FAP) is a dominantly inherited multi-system disease associated with transthyretin (TTR) mutations. Previous series have predominantly described patients with the TTR variant Val30Met (V30M), which is the most prevalent cause of FAP worldwide. Here, we report the dominant cardiac phenotype and outcome of FAP associated with TTR Thr60Ala (T60A), the most common UK variant. METHODS AND RESULTS: Sixty consecutive patients with FAP associated with TTR T60A (FAP T60A) were prospectively evaluated in two centres between 1992 and 2009. Median (range) age of symptom development was 63 (45-78) years. A family history of amyloidosis was present in only 37%. Autonomic and peripheral neuropathy were present in 44 and 32 patients, respectively, at diagnosis. Cardiac involvement was evident on echocardiography at diagnosis in 56 patients, but was associated with reduced QRS voltages on electrocardiography in only 16% evaluable cases. Seventeen patients received implantable anti-arrhythmic devices. Median survival was 6.6 years following onset of symptoms and 3.4 years from diagnosis, and correlated with serum N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration and certain echocardiographic parameters at the latter. Orthotopic liver transplantation (OLT), performed to eliminate the predominant hepatic source of variant TTR T60A protein, was performed in eight patients including one who received a concomitant cardiac transplant. Cardiac amyloidosis progressed in all lone OLT recipients, of whom four died within 5 years. CONCLUSION: Cardiac amyloidosis is almost always present at diagnosis in FAP T60A, and is a major determinant of its poor prognosis. Outcome of liver transplantation in FAP T60A has been discouraging.

Hereditary fibrinogen A alpha-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.

Proliferation of antigen MIB-1 in metastatic carcinoid tumours removed at liver transplantation: relevance to prognosis.

BACKGROUND: Metastatic carcinoid tumours are difficult to manage. In spite of a multidisciplinary approach, including orthotopic liver transplantation, the recurrence rate is high with a poor prognosis. Histopathology generally fails to provide prognostic information, hence it is essential to try to identify markers of prognosis in these tumours before considering orthotopic liver transplantation. The MIB-1 antibody, which detects cell proliferative activity, has been shown to be a useful prognostic marker for a variety of neoplasms. AIMS: To assess the value of MIB-1 immunostaining as a prognostic marker of the duration to recurrence and the survival of patients undergoing orthotopic liver transplantation for metastatic carcinoid/neuroendocrine tumours of the liver. METHODS: Fourteen patients were included in the study. Formalin-fixed, paraffin-embedded tissue sections of the tumours were stained with routine haematoxylin and eosin and chromogranin. The cell proliferative activity was assessed by MIB-1 antibody labelling using the immunoperoxidase method. Results were correlated with the time of tumour recurrence and the length of patients' survival after transplantation. RESULTS: No correlation was found between MIB-1 labelling index and age, gender, clinical and histological type of tumour (i.e. carcinoid, APUDOMA, secreting or non-secreting). The patients with higher MIB-1 indices ( 5%) showed a trend toward earlier recurrence and poorer survival than those with low MIB-1 indices ( 5%). The predictive value of a MIB-1 index of 2 indicating patient survival of 24 months was 83% (five out of six patients). CONCLUSIONS: The correlation between MIB-1 index and patients' survival suggests that a high proliferative rate, as assessed by MIB-1 immunostaining, may detect those tumours with more aggressive biological behaviour. Prospective studies on a larger number of patients will be needed to determine if, in any individual tumour, this method will provide an additional parameter for a rational approach to therapy.

Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses.

Fibrinogen A α-chain (AFib) and apolipoprotein AI (AApoAI) amyloidosis due to variants in the AFib and ApoAI genes are the most common types of hereditary amyloidosis in Europe and the United States. Liver is the exclusive source of the aberrant amyloidogenic protein in AFib and responsible for supplying approximately half of the circulating variant ApoAI. Nephrotic syndrome and renal impairment due to renal amyloidosis are common disease manifestations; however, recent research provides evidence to support a more diverse and systemic disease phenotype, which in turn has implications in the management of the hereditary amyloidoses with solid organ transplantation and, in particular, liver transplantation.

Human plasma fibrinogen is synthesized in the liver.

Hereditary systemic amyloidosis caused by fibrinogen Aalpha-chain gene mutations is an autosomal dominant condition with variable penetrance, usually of late onset, and typically presents with nephropathy leading to renal failure. Amyloid deposits often develop rapidly in transplanted kidneys, and concomitant orthotopic liver transplantation has lately been performed in several patients with the hope of halting amyloid deposition. Fibrinogen is produced in vitro by hepatocytes but also by other human cell types, and although the liver is the source of plasma fibrinogen in vivo in rats, this is not known in humans. Transplantation of livers expressing wild-type fibrinogen into patients with variant fibrinogen amyloidosis provides a unique opportunity to establish the source of human plasma fibrinogen. We therefore characterized plasma fibrinogen Aalpha-chain allotypes by electrospray ionization mass spectrometry mapping of tryptic digests before and after liver transplantation. Before liver transplantation, fibrinogen amyloidosis patients with the Glu526Val Aalpha-chain variant had approximately equal proportions of peptide with the wild-type sequence TFPGFFSPMLGEFVSETESR, and with the amyloidogenic variant sequence TFPGFFSPMLGEFVSVTESR, as expected for individuals heterozygous for the mutation. After transplantation, only the wild-type sequence was detected, and the liver is thus the source of at least 98% of the circulation fibrinogen.

Liver transplantation in transthyretin-related familial amyloid polyneuropathy.

PURPOSE OF REVIEW: Familial amyloid polyneuropathy (FAP) associated with mutations in the gene for transthyretin is a rare, progressively disabling and ultimately fatal inherited disease. Transthyretin is produced predominantly in the liver, and orthotopic liver transplantation (OLT) eliminates more than 95% of variant amyloidogenic transthyretin from the circulation. Liver transplantation remains the only potentially curative treatment in this disorder, but many recent studies have suggested that outcome following transplantation may be poorer than previously considered in some groups of FAP patients. RECENT FINDINGS: We review here the available data on the use and clinical outcome of OLT in patients with FAP, and consider the significance of particular mutations and cardiac amyloid involvement. The practice of combined organ transplants and domino liver transplantation is also reviewed. SUMMARY: Published data generally support OLT as a treatment for FAP, particularly in younger patients with the most prevalent transthyretin (TTR) Met30 variant, who have mild symptoms. Although excellent outcomes have been reported, including improvement in autonomic and to a lesser extent peripheral nerve function coupled with regression of visceral amyloid deposits, the results of OLT are influenced by many factors that include properties of particular transthyretin variants, nutritional status, age, severity of neuropathy and cardiac amyloid involvement. Paradoxical acceleration of transthyretin amyloid deposition following OLT may occur in the heart and certain other sites in some patients. The combination of kidney or heart transplantation with OLT may occasionally be appropriate. The long-term outcome of patients with FAP who have undergone OLT, and recipients of FAP domino liver transplants, remain to be determined.