Hereditary fibrinogen A α-chain amyloidosis: clinical phenotype and role of liver transplantation

To the editor:

Having had the opportunity to follow up 71 patients with hereditary fibrinogen A α-chain amyloidosis (AFib) at the United Kingdom National Amyloidosis Centre,¹  our perspective on this disease differs substantially in several important respects from that of Dr Stangou and colleagues, despite our series including 20 of the 21 patients reported in their recent Blood paper.²  Our experience is that AFib is, for all intents and purposes, a renal disease that is neither associated with cardiac amyloidosis nor autonomic neuropathy in any clinically meaningful way. Furthermore, we do not believe that the authors' preliminary findings justify their concluding statement encouraging preemptive solitary orthotopic liver transplantation (OLT).

Dr Stangou states, “echocardiography was abnormal in 10 of 20 patients (50%), demonstrating impaired relaxation pattern, increased wall thickness, and/or reduced ejection fraction, findings consistent with amyloidosis.”²  Our wider experience supports the observation that these various individual abnormalities are common in the AFib population, but few if any such patients have the necessary combination of these features required to fulfill the international consensus definition for cardiac amyloidosis.³  The common entity of uremic cardiomyopathy would account for the echocardiographic features described by Stangou, and this is uniquely supported by complete reversal of the echocardiographic abnormalities in the reported AFib R554L patient after a recent kidney transplant. Histologic demonstration of amyloid deposits in tissues does not by itself confirm a diagnosis of amyloidosis, which is the clinical disease that may occur as a consequence of amyloid deposition. For example, incidental amyloid deposits occur very commonly in elderly persons, most of whom do not have amyloidosis.⁴  Similarly, despite some abnormalities on formal autonomic function testing, we have never encountered a patient with AFib who has developed clinically significant autonomic disease.

Treatment of AFib by combined renal and hepatic transplantation, as opposed to renal transplantation alone, is highly contentious due to its evident high early mortality and the current lack of sufficient follow-up demonstrating either renal or overall survival benefit. The procedure-related mortality of 33% reported by Stangou et al for combined liver and kidney transplantation compares poorly with 1-year patient survival of 100% among 10 AFib patients under our care who received 12 isolated renal transplants. Furthermore, only 3 of 12 isolated renal allografts have failed due to recurrent amyloidosis, the earliest after 5.8 years, and one graft continues to function more than 12 years after transplantation. Although we acknowledge that concomitant OLT protects kidney grafts from “recurrent” AFib amyloid deposition, the scanty available data regarding long-term kidney graft survival among combined liver-kidney recipients over the age of 50 years are not overly encouraging.

Whereas combined liver-kidney transplantation for AFib is merely contentious, the authors' encouragement for preemptive solitary OLT to prevent development of AFib-associated renal failure is completely unfounded. Fibrinogen A α-chain mutations associated with AFib are poorly penetrant, and most carriers never develop any disease. Among those who do develop proteinuric renal dysfunction, substantial chronic kidney damage is usually evident at the time of clinical presentation. Significant renal dysfunction occurs in approximately 35% of OLT recipients generally, and preexisting renal damage is a risk factor for irreversible renal decline after OLT.⁵  Amyloidotic kidneys are extremely susceptible to irreversible acute kidney injury from even minor stresses, and preemptive OLT involving prolonged anesthesia, and long-term anti-rejection therapy would undoubtedly place amyloidotic AFib kidneys at grave risk.