- Email: [email protected]
Hereditary angioedema and normal C1-inhibitor activity in women
CORRESPONDENCE
the presence of activated platelets trapped in the microcirculation of the infarct zone and not apoptotic cardiomyocytes. This could explain why the uptake of 99Tc annexin V was noted in the whole infarct region, not only at its borders (where it would have been expected in accordance with human necropsy findings after thrombolysis). Furthermore, we did an experimental study with I-123-labelled annexin V in four Franco-Anglaise dogs, in which myocardial infarction was created by 1·5 h balloon occlusion of the proximal left circumflex artery, followed by reperfusion.4 In this model, activated platelets play only a minor part in the process of myocardial injury. The presence of myocardial infarction after the occlusion was documented by a perfusion defect in the circumflex region on 99Tc sestamibi images. No significant uptake of 123I annexin V could, however, be documented in the infarct zone on early (3 h) and late (24 h) images obtained after intravenous injection 3 weeks after myocardial infarction. Since we have shown that 123I annexin V binds to apoptotic cells in vitro,5 this is a further argument against the presence of large numbers of apoptotic cardiomyocytes 3 weeks after myocardial infarction treated with reperfusion. We believe, therefore, that Hofstra and co-workers’ results should be interpreted cautiously. Further experimental studies are needed before this tracer can be presented as a marker of apoptosis in patients with acute myocardial infarction. *Johan De Sutter, Christophe Lahorte, Yves Taeymans, Rudi Dierckx, Guido Slegers Departments of *Cardiology and Nuclear Medicine, Ghent University Hospital, 9000 Ghent, Belgium, and Department of Radiopharmacy, University of Ghent, Ghent (e-mail: [email protected])
1
2
3
4
5
Hofstra L, Liem IH, Dumont EA, et al. Visualisation of cell death in vivo in patients with acute myocardial infarctions. Lancet 2000; 356: 209–12. Stratton JR, Dewhurst TA, Kasina S, et al. Selective uptake of radiolabelled annexin V on acute porcine left atrial thrombi. Circulation 1995; 92: 3113–21. Topol EJ, Yadav JS. Recognition of the importance of embolisation in atherosclerotic vascular disease. Circulation 2000; 101: 570–80. Lahorte C, De Sutter J, Van de Wiele C, et al. Evaluation of 123I-labelled annexin V in normal and infarcted myocardium in dogs. Nucl Med Comm 1999; 20: 948 (abstr). Lahorte C, Dumont F, Slegers G, et al. Synthesis and in vitro stability of 123I-labelled annexin V: a potential agent for SPECT imaging of apoptotic cells. J Labelled Cpd Radiopharm 2000; 43: 739–51.
1440
Hereditary angioedema and normal C1-inhibitor activity in women Sir—Konrad Bork and colleagues’ findings (July 15, p 213)1 on hereditary angioedema (HAE) motivated them to introduce a new variant of HAE (type III). We care for six unrelated families with HAE in Austria, and wish to criticise three points. First, although it seems unnecessary to await an attack of angioedema to obtain a diagnostic sample, assessment of C1-inhibitor activity and C4 concentrations during an attack in all 36, and not only four, of the Bork and colleagues’ female patients might have substantiated their conclusions. In our experience, gained over 10 years in female and male patients, C1-inhibitor activity can sometimes be normal or near normal in symptom-free periods, as Bork and colleagues show, but is substantially lowered during an attack. Moreover, even male HAE patients with normal C4 values in symptom-free periods have been described.2 Second, in the four women reported to have had episodes of acute laryngeal oedema, treatment with 1000 U C1-inhibitor concentrate was ineffective. Bork and colleagues classified this finding as an essential feature of the newly postulated variant of HAE, but the result might be more due to an underdosed therapeutic regimen than a pathogenetic concept.2 The manufacturer of C1-esterase inhibitor S-TIM 3 human haemoderivate (Immuno, Vienna, Austria) recommends a dose of 1000–1500 U during an acute attack, to be repeated if ineffective (total ⭐3000 U). Moreover, one patient in Bork and colleagues’ study became symptom-free under treatment with danazol, whereas this androgen was ineffective in another (in a daily dose of 200 mg). This finding allows no speculation on the pathogenesis, because androgen therapy shows a dissociation of clinical response from concentrations of C1-inhibitor and C4.3 Last, the proposed term HAE III is awkwardly chosen, since N K Day and R A Good identified and named a variant of HAE as HAE III more than 10 years ago.4 That type is characterised by an albumin-bound C1-inhibitor protein without functional activity, which can be differentiated from the C1-inhibitor protein of HAE II by electrophoresis. It seems more suitable, therefore, for
Bork and colleagues to name the type of angioedema they describe as HAE IV. *Birger Kränke, Wolfgang Salmhofer, Werner Aberer Department of Dermatology, University of Graz, A-8036 Graz, Austria (e-mail: [email protected]) 1
2
3
4
Bork K, Barnstedt S-E, Koch P, Traupe H. Hereditary angioedema with normal C1inhibitor activity in women. Lancet 2000; 356: 213–17. Visentin DE, Yang WH, Karsh J. C1-esterase inhibitor transfusions in patients with hereditary angioedema. Ann Allergy Asthma Immunol 1998; 80: 457–61. Warin AP, Greaves MW, Gatecliff M, et al. Treatment of hereditary angioedema by low-dose attenuated androgens: dissociation of clinical response from levels of C1 esterase inhibitor and C4. Br J Dermatol 1980; 103: 405–09. Day NK, Good RA. Inherited and acquired deiciencies of C1 esterase inhibitor in man. In: Rother K, Till GO, eds. The complement system. Heidelberg: Springer, 1988.
Authors’ reply Sir—In nearly all patients with HAE due to C1-inhibitor deficiency (HAE type I and II) C1-inhibitor plasma activity is low during the oedema attacks and in the symptom-free period. Very few patients have normal C1-inhibitor activity in plasma between oedema attacks and lowered activity only during attacks. Such a pattern is exceptional and concerns only a few individual patients, but never all family members affected by HAE. By contrast, we consistently found normal C1-inhibitor concentrations and activity in up to seven affected family members. We measured C1-inhibitor during ten oedema episodes in four patients and found normal C1inhibitor concentration and activity. We have had the opportunity to measure C1-inhibitor activity in a further six attacks in four other patients and obtained the same results. We believe that 1000 U C1-inhibitor concentrate is not underdosed in laryngeal oedema. We have treated 193 episodes of life-threatening laryngeal oedema with C1-inhibitor concentrate in 18 patients.2 In 48 episodes only 500 U were needed, and in the other 145 laryngeal oedemas 1000 U were necessary. No patient needed more than 1000 U. All patients survived and no patient needed intubation or tracheostomy. In HAE type II, or variant forms, a normal and a mutated allele of the structural gene is present. HAE II includes two phenotypes; in one a functionally inactive C1-inhibitor protein circulates in normal concentrations and the normal protein
THE LANCET • Vol 356 • October 21, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
the presence of activated platelets trapped in the microcirculation of the infarct zone and not apoptotic cardiomyocytes. This could explain why the uptake of 99Tc annexin V was noted in the whole infarct region, not only at its borders (where it would have been expected in accordance with human necropsy findings after thrombolysis). Furthermore, we did an experimental study with I-123-labelled annexin V in four Franco-Anglaise dogs, in which myocardial infarction was created by 1·5 h balloon occlusion of the proximal left circumflex artery, followed by reperfusion.4 In this model, activated platelets play only a minor part in the process of myocardial injury. The presence of myocardial infarction after the occlusion was documented by a perfusion defect in the circumflex region on 99Tc sestamibi images. No significant uptake of 123I annexin V could, however, be documented in the infarct zone on early (3 h) and late (24 h) images obtained after intravenous injection 3 weeks after myocardial infarction. Since we have shown that 123I annexin V binds to apoptotic cells in vitro,5 this is a further argument against the presence of large numbers of apoptotic cardiomyocytes 3 weeks after myocardial infarction treated with reperfusion. We believe, therefore, that Hofstra and co-workers’ results should be interpreted cautiously. Further experimental studies are needed before this tracer can be presented as a marker of apoptosis in patients with acute myocardial infarction. *Johan De Sutter, Christophe Lahorte, Yves Taeymans, Rudi Dierckx, Guido Slegers Departments of *Cardiology and Nuclear Medicine, Ghent University Hospital, 9000 Ghent, Belgium, and Department of Radiopharmacy, University of Ghent, Ghent (e-mail: [email protected])
1
2
3
4
5
Hofstra L, Liem IH, Dumont EA, et al. Visualisation of cell death in vivo in patients with acute myocardial infarctions. Lancet 2000; 356: 209–12. Stratton JR, Dewhurst TA, Kasina S, et al. Selective uptake of radiolabelled annexin V on acute porcine left atrial thrombi. Circulation 1995; 92: 3113–21. Topol EJ, Yadav JS. Recognition of the importance of embolisation in atherosclerotic vascular disease. Circulation 2000; 101: 570–80. Lahorte C, De Sutter J, Van de Wiele C, et al. Evaluation of 123I-labelled annexin V in normal and infarcted myocardium in dogs. Nucl Med Comm 1999; 20: 948 (abstr). Lahorte C, Dumont F, Slegers G, et al. Synthesis and in vitro stability of 123I-labelled annexin V: a potential agent for SPECT imaging of apoptotic cells. J Labelled Cpd Radiopharm 2000; 43: 739–51.
1440
Hereditary angioedema and normal C1-inhibitor activity in women Sir—Konrad Bork and colleagues’ findings (July 15, p 213)1 on hereditary angioedema (HAE) motivated them to introduce a new variant of HAE (type III). We care for six unrelated families with HAE in Austria, and wish to criticise three points. First, although it seems unnecessary to await an attack of angioedema to obtain a diagnostic sample, assessment of C1-inhibitor activity and C4 concentrations during an attack in all 36, and not only four, of the Bork and colleagues’ female patients might have substantiated their conclusions. In our experience, gained over 10 years in female and male patients, C1-inhibitor activity can sometimes be normal or near normal in symptom-free periods, as Bork and colleagues show, but is substantially lowered during an attack. Moreover, even male HAE patients with normal C4 values in symptom-free periods have been described.2 Second, in the four women reported to have had episodes of acute laryngeal oedema, treatment with 1000 U C1-inhibitor concentrate was ineffective. Bork and colleagues classified this finding as an essential feature of the newly postulated variant of HAE, but the result might be more due to an underdosed therapeutic regimen than a pathogenetic concept.2 The manufacturer of C1-esterase inhibitor S-TIM 3 human haemoderivate (Immuno, Vienna, Austria) recommends a dose of 1000–1500 U during an acute attack, to be repeated if ineffective (total ⭐3000 U). Moreover, one patient in Bork and colleagues’ study became symptom-free under treatment with danazol, whereas this androgen was ineffective in another (in a daily dose of 200 mg). This finding allows no speculation on the pathogenesis, because androgen therapy shows a dissociation of clinical response from concentrations of C1-inhibitor and C4.3 Last, the proposed term HAE III is awkwardly chosen, since N K Day and R A Good identified and named a variant of HAE as HAE III more than 10 years ago.4 That type is characterised by an albumin-bound C1-inhibitor protein without functional activity, which can be differentiated from the C1-inhibitor protein of HAE II by electrophoresis. It seems more suitable, therefore, for
Bork and colleagues to name the type of angioedema they describe as HAE IV. *Birger Kränke, Wolfgang Salmhofer, Werner Aberer Department of Dermatology, University of Graz, A-8036 Graz, Austria (e-mail: [email protected]) 1
2
3
4
Bork K, Barnstedt S-E, Koch P, Traupe H. Hereditary angioedema with normal C1inhibitor activity in women. Lancet 2000; 356: 213–17. Visentin DE, Yang WH, Karsh J. C1-esterase inhibitor transfusions in patients with hereditary angioedema. Ann Allergy Asthma Immunol 1998; 80: 457–61. Warin AP, Greaves MW, Gatecliff M, et al. Treatment of hereditary angioedema by low-dose attenuated androgens: dissociation of clinical response from levels of C1 esterase inhibitor and C4. Br J Dermatol 1980; 103: 405–09. Day NK, Good RA. Inherited and acquired deiciencies of C1 esterase inhibitor in man. In: Rother K, Till GO, eds. The complement system. Heidelberg: Springer, 1988.
Authors’ reply Sir—In nearly all patients with HAE due to C1-inhibitor deficiency (HAE type I and II) C1-inhibitor plasma activity is low during the oedema attacks and in the symptom-free period. Very few patients have normal C1-inhibitor activity in plasma between oedema attacks and lowered activity only during attacks. Such a pattern is exceptional and concerns only a few individual patients, but never all family members affected by HAE. By contrast, we consistently found normal C1-inhibitor concentrations and activity in up to seven affected family members. We measured C1-inhibitor during ten oedema episodes in four patients and found normal C1inhibitor concentration and activity. We have had the opportunity to measure C1-inhibitor activity in a further six attacks in four other patients and obtained the same results. We believe that 1000 U C1-inhibitor concentrate is not underdosed in laryngeal oedema. We have treated 193 episodes of life-threatening laryngeal oedema with C1-inhibitor concentrate in 18 patients.2 In 48 episodes only 500 U were needed, and in the other 145 laryngeal oedemas 1000 U were necessary. No patient needed more than 1000 U. All patients survived and no patient needed intubation or tracheostomy. In HAE type II, or variant forms, a normal and a mutated allele of the structural gene is present. HAE II includes two phenotypes; in one a functionally inactive C1-inhibitor protein circulates in normal concentrations and the normal protein
THE LANCET • Vol 356 • October 21, 2000
For personal use only. Not to be reproduced without permission of The Lancet.