Systemic Diseases

Hereditary fibrinogen A -chain amyloidosis: Phenotypic characterization of a systemic disease and the role of liver transplantation. Blood 115: 2998–3007, 2010 Arie J. Stangou, Nicholas R. Banner, Bruce M. Hendry, Mohamed Rela, Bernard Portmann, Julia Wendon, Mark Monaghan, Philip MacCarthy, Muriel Buxton-Thomas, Christopher J. Mathias, Juris J. Liepnieks, John O’Grady, Nigel D. Heaton, and Merrill D. Benson Fibrinogen amyloidosis due to mutations in the fibrinogen -chain gene (AFib) localized on chromosome 4 and composed of six exons belongs to the group of nonneuropathic hereditary renal amyloidoses. It is the most common type of all hereditary renal amyloid diseases in the United States and Europe. Like other forms of amyloidosis, AFib amyloidosis is a protein misfolding disorder. Fibrinogen production is exclusively hepatic. Liver transplantation was therefore considered as a logical mode of treatment, whereas isolated renal transplantation was followed by kidney amyloid recurrence in most patients. Stangou et al. have first revisited the current phenotypic description of AFib amyloidosis and second performed a systematic evaluation for liver and kidney transplantation (LKT) in a series of 22 patients (8 women, 14 men). Three of them had been misdiagnosed as primary systemic AL amyloidosis—a diagnostic error already reported (1). The median age at presentation was 55 years (range 33 to 63 years). Proteinuria was the most common presenting feature (median 24-hour urine protein 7.2 g; range 0 to 11.8 g). At the time of assessment, median GFR was 16 ml/min (range 0 to 52 ml/min). Renal biopsy was performed in 21 of 22 patients and revealed amyloidosis in all patients, with enlarged glomeruli replaced by amyloid with minimal or no extraglomerular involvement—a finding suggestive of this type of amyloidosis (1). Twenty of 22 patients progressed to ESRD. Two patients had liver amyloidosis, complicated in one by end-stage liver disease. Coronary atherosclerotic disease was documented in 15 patients (68%), in half of the patients predating evolution of kidney impairment. Twelve patients had severe systemic vascular disease, involving aorta, splanchnic, or carotid arteries. Two patients underwent carotid endarterectomy. Of interest, the excised material contained amyloid purely consistent of mutant fibrinogen A -chain. Cardiac amyloidosis was not a rare localization. Echocardiography was abnormal in 11 of 21 patients (52%). Three of the four endomyocardial biopsies revealed substantial amyloid deposition. One patient developed dilated amyloid cardiomyopathy in association with coronary disease and myocardial amyloidosis, whereas cardiac amyloidosis usually leads to restrictive cardiomyopathy. In addition, cardiac parasympathetic dysfunction and risk of bradycardia were identified in 12 patients. Seven of them had pacemaker insertion. Autonomic involvement of the gastrointestinal tract was a feature in 15 patients. Only 24% of patients had family history of renal disease. However, 81% had family history of systemic or coronary vascular disease. Family members who had such cardiovascular history were indeed carriers of AFib mutations. Spontaneous splenic rupture occurred in four patients (one during hemodialysis and three during transplantation). The excised spleen contained widespread amyloid. Nine of 14 patients accepted on the waiting list received combined liver and kidney allografts. At a median follow-up of 67 months, six of nine patients are alive and well with normal liver function. Five patients have good renal function. Cardiac amyloidosis has not progressed after LKT. I-labeled serum amyloid P component (SAP) scintigraphy showed regression of systemic visceral amyloid deposits as early as at the first annual follow-up scan after LKT, whereas scintigraphy documented progressive amyloid deposition in two patients who had previously undergone isolated kidney transplant. Serial 99mTcDMSA renal scintigraphy after preemptive LKT in two patients demonstrated stable native renal uptake. Four patients with various liver diseases received, after full information, explanted livers from AFib patients. Only one “domino” recipient had SAP scans and echocardiography for up to 5 years with no evidence of de novo amyloid deposition. The study by Stangou et al. extends the clinical scope of AFib amyloidosis. Stangou et al. encourage evaluation of isolated liver transplant early in the course of amyloid nephropathy to prevent systemic deposition and renal progression to ESRD. Amyloid fibrils in AFib contain exclusively variant fibrinogen. Circulating total fibrinogen consists of a mixture of wild-type/ variant fibrinogen in a ratio of 1:1 to 3:2. Wild-type fibrinogen does not perpetuate amyloid disease. After liver transplant, the variant fibrinogen is eliminated and promptly replaced by Published online ahead of print. Publication date available at www.cjasn.org.