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 progression1,2,6,8  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).

Contribution: A.J.S. wrote the manuscript; N.R.B. and M.D.B. contributed to the drafting and editing of the manuscript; and B.M.H., M.R., B.P., J.W., M.M., P.M., M.B.-T., C.J.M., J.J.L., J.O., and N.D.H. have seen and approved the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Arie J. Stangou, King's College Hospital, Denmark Hill St, London SE5 9RS, United Kingdom; e-mail: [email protected].

1
Stangou
AJ
Banner
NR
Hendry
BM
et al
Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation.
Blood
2010
115
15
2998
3007
2
Gillmore
JD
Lachmann
HJ
Rowczenio
D
et al
Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen Aalpha-chain amyloidosis.
J Am Soc Nephrol
2009
20
2
444
451
3
Hawkins
PN
Pepys
MB
Imaging amyloidosis with radiolabelled SAP.
Eur J Nucl Med
1995
22
7
595
599
4
Gertz
MA
Comenzo
R
Falk
RH
et al
Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004.
Am J Hematol
2005
79
4
319
328
5
Mourad
G
Delabre
JP
Garrigue
V
Cardiac amyloidosis with the E526V mutation of the fibrinogen A alpha-chain.
N Engl J Med
2008
359
26
2847
2848
6
Serpell
LC
Benson
M
Liepnieks
JJ
Fraser
PE
Structural analyses of fibrinogen amyloid fibrils.
Amyloid
2007
14
3
199
203
7
Tavares
I
Moreira
L
Pinheiro
J
et al
Clinical and pathologic features of fibrinogen amyloidosis: an open question [abstract].
Presented at the VIIth International Symposium on Familial Amyloid Polyneuropathy and Ist International Workshop on Hereditary Amyloidosis
September 2-5, 2008
London, United Kingdom
8
Zeldenrust
S
Gertz
M
Uemichi
T
et al
Orthotopic liver transplantation for hereditary fibrinogen amyloidosis.
Transplantation
2003
75
4
560
561
9
de Carvalho
M
Linke
RP
Domingos
F
et al
Mutant fibrinogen A-alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy.
Amyloid
2004
11
3
200
207
10
Hawkins
PN
Richardson
S
MacSweeney
JE
et al
Scintigraphic quantification and serial monitoring of human visceral amyloid deposits provide evidence for turnover and regression.
Q J Med
1993
86
6
365
374
11
Elkayam
O
Hawkins
PN
Lachmann
H
Yaron
M
Caspi
D
Rapid and complete resolution of proteinuria due to renal amyloidosis in a patient with rheumatoid arthritis treated with infliximab.
Arthritis Rheum
2002
46
10
2571
2573
12
Holmgren
G
Ericzon
B-G
Groth
G
et al
Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis.
Lancet
1993
341
8853
1113
1116
Sign in via your Institution