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Myocardial involvement in fibrinogen A–alpha chain amyloidosis
European Journal of Internal Medicine 19 (2008) e54 – e56 www.elsevier.com/locate/ejim
Case report
Myocardial involvement in fibrinogen A–alpha chain amyloidosis G. Gahide a,⁎, F. Roubille b , J.C. Macia b , V. Garrigue c , H. Vernhet a a
Service de radiologie, France Service de cardiologie A, France c Service de Néphrologie, France
b
Received 18 January 2008; accepted 7 February 2008 Available online 14 April 2008
Keywords: Amyloidosis; Hereditary; Cardiac; Fibrinogen; MR
1. Introduction Amyloidosis is a rare, chronic disease resulting in permanent organ damage. Prognosis and treatment are related to the etiology. 2. Clinical case A 53-year-old patient was referred for a myocardial hypertrophy in the context of fibrinogen A–alpha chain amyloidosis, revealed by an asymptomatic nephrotic syndrome. His mother had died from renal amyloidosis. Clinical examination demonstrated an isolated hepatomegaly. Both renal and hepatic functions were normal. A renal biopsy demonstrated a typical amyloid deposit. Amyloidosis was first diagnosed as AL. Given the family history, genotyping was performed. There was a heterozygous point mutation (Glu 526 Val substitution) in the gene encoding the fibrinogen A–alpha chain. Echocardiography demonstrated a biventricular hypertrophy with an interventricular septum thickness estimated at 20 mm. Left Ventricle Ejection Fraction was mildly altered to 48%, with a significant intraventricular gradient. An MR-scan was performed prior to myocardial biopsy. Morphological sequences confirmed a diffuse biventricular, and valvular thickening. Delayed-enhanced sequences depicted a centrimetric posteroinferior nodular enhancement (Fig. 1). Multiple cardiac biopsies were obtained directed to the enhanced area. ⁎ Corresponding author. Hopital A de Villeneuve, Centre HospitaloUniversitaire de Montpellier, Avenue du Doyen Gaston Giraud, 34000 Montpellier, France. Tel.: +33 4 67 33 59 87; fax: +33 4 67 33 62 75. E-mail address: [email protected] (G. Gahide).
Pathological findings demonstrated a myocardial amyloid deposit, which is stained specifically with antifibrinogen antibodies. The intraventricular gradient was treated with a dual chamber pacemaker. A few months later, he presented a syncope. An implanted defibrillator was proposed and he was referred for a hepatorenal transplantation). 3. Discussion Amyloidosis refers to a group of diseases featuring an extracellular deposition of proteinaceous material that when stained with Congo red demonstrates apple-green birefringence under polarized light. AL, AA and hereditary amyloidoses differ in features, prognoses and treatments [1]. The AL form is the most common. Cardiac involvement is usually the worst prognosis factor with a median lifespan inferior to 6 months in untreated patients once congestive heart failure occurs [2]. Hereditary amyloidosis is due to the production of a mutant amyloid protein. Most of them result from a mutation of the transthyretin protein or fibrinogen A–alpha chain. Penetrance is variable and first manifestations usually occur in the third and fourth decades. They may be misdiagnosed and Lachmann et al. proposed that a genetic ground should be sought in all patients with amyloidosis that is not the reactive systemic amyloid A type and in whom confirmation of the AL type cannot be obtained [3]. This distinction is of paramount importance because the treatment differs completely, relying on a liver transplantation when necessary and possible for the hereditary form, also called a “surgical gene therapy”.
0953-6205/$ - see front matter © 2008 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2008.02.005
G. Gahide et al. / European Journal of Internal Medicine 19 (2008) e54–e56
e55
Fig. 1. Cardiac MR-scan. Systolic (A) and Diastolic (B) Short Axis CineMR showing homogenous biventricular myocardial thickening. C: Horizontal Long Axis TSE-T1 demonstrating a normal spontaneous myocardial signal. D: Post gadolinium Short Axis T1 revealing a posteromedial nodular enhancement (arrow) and mild diffuse anterior enhancement (arrowhead).
Usually fibrinogen A–alpha chain amyloidosis first results in a severe kidney dysfunction. The liver may be affected subsequently. In our case the patient presented a concomitant myocardial hypertrophy. To our knowledge, it's the first reported case of myocardial involvement. A biopsy was essential to rule out another aetiology, mostly likely a hypertrophic cardiomyopathy. Fibrinogen A–alpha chain cardiac amyloidosis was confirmed with immunostaining. An MR-cardiac scan has been reported as a valuable tool to evaluate cardiac amyloidosis in many studies [4–6]. It perfectly depicts the morphological alterations, showing ventricular hypertrophy, valvular thickening and atrial dilatation. Delayed-enhancement sequences necessitate the nulling of the normal myocardial signal, increasing the contrast between normal and pathological areas. The impossibility of finding a nulling point has previously been reported as highly suggestive of AL amyloidosis. In our case, the null point was achieved, showing a nodular enhancement in the posterobasal area. This could suggest that AL and hereditary amyloidoses may have a distinctive delay-
ed enhancement pattern, which could be useful for their diagnosis. 4. Learning points • Fibrinogen A-alpha amyloidosis usually results in a severe renal dysfunction but may also involve the liver or the heart. • Amyloidoses are divided into three groups: AL, AA and familial. Due to its rarity, familial amyloidosis may be misdiagnosed as AL amyloidosis with clinical and therapeutic implications. • Symptomatic myocardial involvement in familial amyloidosis may benefit from a liver transplantation. • Cardiac MR-scan depicts amyloidosis involvement, showing specific findings. Acknowledgement The authors would like to thank Mr. Tom Moore-Morris (PhD, Institute of Functional Genomics, Montpellier, France) for his language editing.
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G. Gahide et al. / European Journal of Internal Medicine 19 (2008) e54–e56
References [1] Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112(13):2047–60. [2] Dubrey S, Mendes L, Skinner M, Falk RH. Resolution of heart failure in patients with AL amyloidosis. Ann Intern Med 1996;125(6):481–4. [3] Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002;346(23):1786–91.
[4] Maceira AM, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111(2):186–93. [5] vanden Driesen RI, Slaughter RE, Strugnell WE. MR findings in cardiac amyloidosis. AJR Am J Roentgenol 2006;186(6):1682–5. [6] Sueyoshi E, Sakamoto I, Okimoto T, Hayashi K, Tanaka K, Toda G. Cardiac amyloidosis: typical imaging findings and diffuse myocardial damage demonstrated by delayed contrast-enhanced MRI. Cardiovasc Interv Radiol 2006;29(4):710–2.
Case report
Myocardial involvement in fibrinogen A–alpha chain amyloidosis G. Gahide a,⁎, F. Roubille b , J.C. Macia b , V. Garrigue c , H. Vernhet a a
Service de radiologie, France Service de cardiologie A, France c Service de Néphrologie, France
b
Received 18 January 2008; accepted 7 February 2008 Available online 14 April 2008
Keywords: Amyloidosis; Hereditary; Cardiac; Fibrinogen; MR
1. Introduction Amyloidosis is a rare, chronic disease resulting in permanent organ damage. Prognosis and treatment are related to the etiology. 2. Clinical case A 53-year-old patient was referred for a myocardial hypertrophy in the context of fibrinogen A–alpha chain amyloidosis, revealed by an asymptomatic nephrotic syndrome. His mother had died from renal amyloidosis. Clinical examination demonstrated an isolated hepatomegaly. Both renal and hepatic functions were normal. A renal biopsy demonstrated a typical amyloid deposit. Amyloidosis was first diagnosed as AL. Given the family history, genotyping was performed. There was a heterozygous point mutation (Glu 526 Val substitution) in the gene encoding the fibrinogen A–alpha chain. Echocardiography demonstrated a biventricular hypertrophy with an interventricular septum thickness estimated at 20 mm. Left Ventricle Ejection Fraction was mildly altered to 48%, with a significant intraventricular gradient. An MR-scan was performed prior to myocardial biopsy. Morphological sequences confirmed a diffuse biventricular, and valvular thickening. Delayed-enhanced sequences depicted a centrimetric posteroinferior nodular enhancement (Fig. 1). Multiple cardiac biopsies were obtained directed to the enhanced area. ⁎ Corresponding author. Hopital A de Villeneuve, Centre HospitaloUniversitaire de Montpellier, Avenue du Doyen Gaston Giraud, 34000 Montpellier, France. Tel.: +33 4 67 33 59 87; fax: +33 4 67 33 62 75. E-mail address: [email protected] (G. Gahide).
Pathological findings demonstrated a myocardial amyloid deposit, which is stained specifically with antifibrinogen antibodies. The intraventricular gradient was treated with a dual chamber pacemaker. A few months later, he presented a syncope. An implanted defibrillator was proposed and he was referred for a hepatorenal transplantation). 3. Discussion Amyloidosis refers to a group of diseases featuring an extracellular deposition of proteinaceous material that when stained with Congo red demonstrates apple-green birefringence under polarized light. AL, AA and hereditary amyloidoses differ in features, prognoses and treatments [1]. The AL form is the most common. Cardiac involvement is usually the worst prognosis factor with a median lifespan inferior to 6 months in untreated patients once congestive heart failure occurs [2]. Hereditary amyloidosis is due to the production of a mutant amyloid protein. Most of them result from a mutation of the transthyretin protein or fibrinogen A–alpha chain. Penetrance is variable and first manifestations usually occur in the third and fourth decades. They may be misdiagnosed and Lachmann et al. proposed that a genetic ground should be sought in all patients with amyloidosis that is not the reactive systemic amyloid A type and in whom confirmation of the AL type cannot be obtained [3]. This distinction is of paramount importance because the treatment differs completely, relying on a liver transplantation when necessary and possible for the hereditary form, also called a “surgical gene therapy”.
0953-6205/$ - see front matter © 2008 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2008.02.005
G. Gahide et al. / European Journal of Internal Medicine 19 (2008) e54–e56
e55
Fig. 1. Cardiac MR-scan. Systolic (A) and Diastolic (B) Short Axis CineMR showing homogenous biventricular myocardial thickening. C: Horizontal Long Axis TSE-T1 demonstrating a normal spontaneous myocardial signal. D: Post gadolinium Short Axis T1 revealing a posteromedial nodular enhancement (arrow) and mild diffuse anterior enhancement (arrowhead).
Usually fibrinogen A–alpha chain amyloidosis first results in a severe kidney dysfunction. The liver may be affected subsequently. In our case the patient presented a concomitant myocardial hypertrophy. To our knowledge, it's the first reported case of myocardial involvement. A biopsy was essential to rule out another aetiology, mostly likely a hypertrophic cardiomyopathy. Fibrinogen A–alpha chain cardiac amyloidosis was confirmed with immunostaining. An MR-cardiac scan has been reported as a valuable tool to evaluate cardiac amyloidosis in many studies [4–6]. It perfectly depicts the morphological alterations, showing ventricular hypertrophy, valvular thickening and atrial dilatation. Delayed-enhancement sequences necessitate the nulling of the normal myocardial signal, increasing the contrast between normal and pathological areas. The impossibility of finding a nulling point has previously been reported as highly suggestive of AL amyloidosis. In our case, the null point was achieved, showing a nodular enhancement in the posterobasal area. This could suggest that AL and hereditary amyloidoses may have a distinctive delay-
ed enhancement pattern, which could be useful for their diagnosis. 4. Learning points • Fibrinogen A-alpha amyloidosis usually results in a severe renal dysfunction but may also involve the liver or the heart. • Amyloidoses are divided into three groups: AL, AA and familial. Due to its rarity, familial amyloidosis may be misdiagnosed as AL amyloidosis with clinical and therapeutic implications. • Symptomatic myocardial involvement in familial amyloidosis may benefit from a liver transplantation. • Cardiac MR-scan depicts amyloidosis involvement, showing specific findings. Acknowledgement The authors would like to thank Mr. Tom Moore-Morris (PhD, Institute of Functional Genomics, Montpellier, France) for his language editing.
e56
G. Gahide et al. / European Journal of Internal Medicine 19 (2008) e54–e56
References [1] Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112(13):2047–60. [2] Dubrey S, Mendes L, Skinner M, Falk RH. Resolution of heart failure in patients with AL amyloidosis. Ann Intern Med 1996;125(6):481–4. [3] Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 2002;346(23):1786–91.
[4] Maceira AM, et al. Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation 2005;111(2):186–93. [5] vanden Driesen RI, Slaughter RE, Strugnell WE. MR findings in cardiac amyloidosis. AJR Am J Roentgenol 2006;186(6):1682–5. [6] Sueyoshi E, Sakamoto I, Okimoto T, Hayashi K, Tanaka K, Toda G. Cardiac amyloidosis: typical imaging findings and diffuse myocardial damage demonstrated by delayed contrast-enhanced MRI. Cardiovasc Interv Radiol 2006;29(4):710–2.