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

We thank Dr Gillmore and colleagues for their comments on our article describing the phenotype of fibrinogen alpha α-chain amyloidosis (AFib) and discussing the role of liver transplantation (LT).¹ 

Gillmore et al question our characterization of AFib as a systemic disease. However, in their own report,^2 123I-SAP scintigraphy demonstrated renal (100%), adrenal (21%), and splenic (89%) amyloid deposits. Among the latter, 4 patients required emergency splenectomy for spontaneous splenic rupture.¹  Visualization of amyloid deposits in the heart and nerves is beyond the resolution of SAP scintigraphy, a limitation acknowledged by the inventors of the technique themselves.³  Ten of our 20 mutual cases manifested echocardiographic features consistent with amyloidosis. The international criteria preclude a diagnosis of cardiac amyloidosis by echocardiography alone if hypertension is present⁴ ; however, the concomitant documentation of cardiac autonomic neuropathy justified, among other considerations, endomyocardial sampling. Cardiac histology revealed variant fibrinogen amyloid deposits, with a yield of 75% and specificity for Afib of 100%. One R544L patient's dilated left ventricle (LV) has remodeled toward normal after kidney transplantation (KT) and, presumably, resolution of the uremic/nephrotic component of LV dysfunction; but this patient must be followed carefully because the long-term course of her cardiac amyloid deposition is unknown.

Recently reported systemic AFib manifestations include amyloid cardiomyopathy, amyloid deposition in viscera, splanchnic vessels, adipose tissue, gut, and neuropathy.^1,2,5,,,–9  The international consensus criteria for distinguishing between localized and systemic amyloidosis support our characterization of AFib as systemic amyloidosis,⁴  and refute any analogy between our AFib findings and the incidental amyloid deposits seen in elderly persons, or the interpretation of cardiovascular and atheromatous disease in AFib as mere manifestations of renal failure.² 

Fibrinogen is produced by the liver. The 1-year 100% patient survival after isolated KT reported by Gillmore et al does not address the poor long-term outcomes in both renal allograft and patient survival associated with systemic amyloid progression^1,2,6,–8  and is surpassed by 100% survival at 6 years median follow-up in our 3 preemptive hepatorenal transplant recipients, who can reasonably be considered to be cured of amyloidosis. Advanced AFib disease manifestations and long-term hemodialysis side effects underlie the mortality in 3 of 6 patients who were transplanted late, highlighting the importance of selection and timing for transplantation.

Amyloid deposits undergo dynamic turnover, and interrupting the supply of amyloid precursors is a fundamental principle of treatment.¹⁰  We attribute the salvage of residual native kidney function in both our preemptive hepatorenal transplants to the elimination of variant fibrinogen by LT (analogous to renal and systemic improvement following treatment for AA, AL, and Transthyretin amyloidoses).^11,12  In AFib amyloidosis, the median time between proteinuria and end-stage renal failure is 4.6 years.²  We propose preemptive isolated LT at early stage of nephrotic syndrome with otherwise preserved kidney function as a feasible and rational approach to halt amyloid progression and facilitate regression. We recommend that this novel approach be developed in specialist transplantation centers with expertise in amyloidosis and evaluated through regular analysis of outcomes by the Familial Amyloid Polyneuropathy World Transplant Registry (FAPWTR; www.fapwtr.org).