Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis

Abstract

Mutations in the fibrinogen A alpha-chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen A alpha-chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0-12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.

Figure 1.

Renal biopsy in fibrinogen Aα-chain amyloidosis. Panel A shows striking glomerular enlargement and almost complete obliteration of the normal glomerular architecture by extensive amyloid deposition. The vessels and renal tubular interstitium, in contrast, contain almost no amyloid at all (Congo red stain ×100). Panel B shows red-green birefringence when the same section is viewed under cross-polarized light. Panel C shows immunohistochemical staining of the same patient's biopsy with a monoclonal sheep anti-human fibrinogen antibody (Helena Bioscience) confirming the presence of fibrinogen within the amyloid deposits.

Figure 2.

Posterior whole-body scintigraphic images after intravenous injection of ¹²³I-labeled SAP in hereditary AFib. Panel A shows abnormal uptake into renal and splenic amyloid deposits in a 56-yr old patient with AFib associated with the previously reported fibrinogen E526V variant. Panel B shows abnormal uptake into renal, adrenal and splenic amyloid deposits in a 53-yr old German woman with AFib associated with a novel fibrinogen variant, E540V. Panel C shows abnormal uptake into renal, adrenal, and splenic amyloid deposits in a 72-yr old Afro-Caribbean man with AFib associated with a novel fibrinogen variant, P552H. The scan findings were corroborated by histologically proven renal amyloid deposits in all three patients.

Figure 3.

Four novel amyloidogenic mutations of the fibrinogen Aα-chain gene. Panel E shows the wild-type sequence for the portion of exon 5 of the fibrinogen Aα-chain gene that encodes the amyloid fibril subunit peptide fragment. (A) Frame-shifting mutation p.Thr525ThrfsX24 resulting from the deletion of T in the ACT codon (c.1632delT). (B) C-to-A single base substitution (c.1670C>A) encoding the p.Thr538Lys variant. (C) A-to-T single base substitution (c.1676A>T) encoding the p.Glu540Val variant. (D) C-to-A single base substitution (c.1712C>A) encoding the p.Pro552His variant. The arrows indicate the positions of the novel mutations.

Figure 4.

Panel A shows the family tree of two German sisters with AFib (arrows) caused by a novel amyloidogenic point mutation that encodes the E540V fibrinogen Aα-chain variant. The sisters’ father had died aged 47 yr but had been dialysis-dependent with proven renal amyloid. Panel B shows the family tree of a patient with AFib who presented at the age of 55 yr (arrow). Two paternal uncles were each shown to be heterozygous for the relevant mutation encoding the E526V fibrinogen variant but did not have renal dysfunction on testing aged 76 and 81 yr, respectively.

Figure 5.

Panel A shows a Kaplan-Meier plot of patient survival from diagnosis of AFib. Panel B shows Kaplan-Meier plots of survival on dialysis to 6 yr (censored at transplantation) among patients with AFib (dotted line) compared with all U.K. nondiabetic nephropaths aged less than 55 yr (gray line) and aged 55 to 64 yr (black line). Estimated survival among the AFib cohort, whose median age at commencement of dialysis was 60 yr, was no different from U.K. patients aged less than 55 yr and was significantly better than that in patients aged 55 to 64 yr (P < 0.02, log-rank test28).