Hereditary angioedema: Its diagnostic and management perspectives

doi:10.1016/0002-9343(90)90535-L

The American Journal of Medicine

Volume 88, Issue 6, June 1990, Pages 656-664

https://doi.org/10.1016/0002-9343(90)90535-L Get rights and content

Abstract

Although hereditary angioedema accounts for only a small fraction of all cases of angioedema, it is the most common genetically linked clinical disorder caused by the deficiency of a protein associated with complement activation. Attacks may be complicated by incapacitating cutaneous swelling, life-threatening upper airway impediment, and severe gastrointestinal colic. Recent physicochemical and genetic studies have contributed significantly to our understanding of the structure of the inhibitor protein. Measurement of serum C4 titer is an efficacious screening test. Normal levels during symptomatic periods rule out the diagnosis, whereas decreased levels warrant determination of C1 esterase inhibitor titer by immunoassay or functional assay. The functional assay is necessary to ascertain the genetic variant form.

The importance of making the correct diagnosis cannot be overemphasized. It can avert potentially fatal consequences, such as upper airway obstruction and unnecessary abdominal surgery. The application of short-term preventive measures can avoid complications associated with trauma. Finally, abatement or elimination of symptoms in patients with incessant and disabling attacks can be attained by long-term therapy with currently available attenuated androgens.

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Cited by (93)

International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency
2012, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Pregnancy can mitigate, aggravate, or have no effect on HAE-C1-INH edematous attacks. The frequency of attacks during previous pregnancies is not useful for predicting HAE-C1-INH events in later pregnancies.10,12,21,28,29,71,86,100-108 Clinical symptoms are usually more severe during the first trimester.27-29,102
There are a limited number of publications on the management of gynecologic/obstetric events in female patients with hereditary angioedema caused by C1 inhibitor deficiency (HAE-C1-INH).
We sought to elaborate guidelines for optimizing the management of gynecologic/obstetric events in female patients with HAE-C1-INH.
A roundtable discussion took place at the 6th C1 Inhibitor Deficiency Workshop (May 2009, Budapest, Hungary). A review of related literature in English was performed.
Contraception: Estrogens should be avoided. Barrier methods, intrauterine devices, and progestins can be used. Pregnancy: Attenuated androgens are contraindicated and should be discontinued before attempting conception. Plasma-derived human C1 inhibitor concentrate (pdhC1INH) is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis. Tranexamic acid or virally inactivated fresh frozen plasma can be used for long-term prophylaxis if human plasma-derived C1-INH is not available. No safety data are available on icatibant, ecallantide, or recombinant human C1-INH (rhC1INH). Parturition: Complications during vaginal delivery are rare. Prophylaxis before labor and delivery might not be clinically indicated, but pdhC1INH therapeutic doses (20 U/kg) should be available. Nevertheless, each case should be treated based on HAE-C1-INH symptoms during pregnancy and previous labors. pdhC1INH prophylaxis is advised before forceps or vacuum extraction or cesarean section. Regional anesthesia is preferred to endotracheal intubation. Breast cancer: Attenuated androgens should be avoided. Antiestrogens can worsen angioedema symptoms. In these cases anastrozole might be an alternative. Other issues addressed include special features of HAE-C1-INH treatment in female patients, genetic counseling, infertility, abortion, lactation, menopause treatment, and endometrial cancer.
A consensus for the management of female patients with HAE-C1-INH is presented.
Enzymatic pathways in the pathogenesis of hereditary angioedema: The role of C1 inhibitor therapy
2010, Journal of Allergy and Clinical Immunology
A functional abnormality of C1 inhibitor (C1INH) is present in types I and II hereditary angioedema (HAE), and normal C1INH may be rendered ineffective in the newly described type III HAE. C1INH inhibits factor XIIa, factor XII fragment (XIIf), kallikrein, and plasmin. Thus, in its absence, there is marked activation of the bradykinin-forming cascade resulting in severe angioedema. Factor XII may autoactivate on binding to endothelial cell surface gC1qR (receptor for the globular heads of C1q) thus initiating the cascade. Alternatively, stimuli that activate endothelial cells may liberate (or express at the cell surface) heat shock protein 90 or the enzyme prolylcarboxypeptidase, either of which can interact with the prekallikrein–high-molecular-weight kininogen complex to convert prekallikrein to kallikrein stoichiometrically. The kallikrein produced can cleave high-molecular-weight kininogen to produce bradykinin and also recruit factor XII by enzymatically activating it. Patients with type I or II HAE have mutant C1INH so that control of C1 activation is lost. Autoactivation of C1r in the absence of C1INH leads to C1s activation followed by C4 cleavage and depletion. An attack of swelling is accompanied by conversion of factor XIIa to factor XIIf and further enzymatic activation of C1r so that C4 levels drop further and C2 is depleted. New therapies for HAE focus on the bradykinin-forming cascade and include a kallikrein inhibitor and a bradykinin B-2 receptor antagonist in addition to administration of purified C1INH.
Perioperative management of a patient with hereditary angioedema during off-pump coronary artery bypass graft surgery
2010, Journal of Clinical Anesthesia
Citation Excerpt :
The patient was restarted on maintenance doses of androgen therapy, he had an uneventful postoperative course, and he was discharged home 6 days after admission. The classical complement and clotting cascade, as well as antifibrinolytic systems, are inhibited by the C1 esterase inhibitor [1,2]. The disinhibited activation of complement leads to augmented production of C2 kinin and bradykinin, which are responsible for hereditary angioedema-induced edema.
The case of a patient with hereditary angioedema (HAE), a rare, life-threatening disorder caused by reduced activity of the C1 esterase inhibitor, and requiring off-pump coronary artery bypass graft (OP-CABG) surgery, is presented. Perioperative management of patients with HAE who undergo complex cardiac surgical procedures are discussed, including an OP-CABG surgical approach to decrease complement activation, fresh-frozen plasma administration to increase C1 esterase inhibitor activity, and administration of reduced doses of heparin and protamine to minimize heparin-protamine complex formation.
Anaesthesic management of vaginal delivery in a parturient with C1 esterase deficiency
2009, Annales Francaises d'Anesthesie et de Reanimation
L’œdème angioneurotique (OAN) est la traduction clinique d’un déficit qualitatif ou quantitatif en inhibiteur de C1 estérase. La fréquence et la sévérité des manifestations cliniques sont extrêmement variables, allant d’un œdème des extrémités modéré à l’obstruction des voies aériennes supérieures. Les anesthésistes réanimateurs peuvent être confrontés aux manifestations aiguës de cette pathologie en cas d’œdème laryngé menaçant le pronostic vital. La chirurgie, les traumatismes physiques et l’accouchement sont des facteurs déclenchants classiques de la maladie. Les anesthésistes sont donc au cœur de la stratégie prophylactique. Nous rapportons le cas d’une patiente atteinte d’un OAN découvert en cours de grossesse chez qui l’utilisation prophylactique et thérapeutique de concentré d’inhibiteur de C1 estérase a permis un accouchement par voie basse non compliqué. Une courte revue de la littérature rappelle la physiopathologie et les implications thérapeutiques.
Hereditary and acquired angioedema (HAE/AAE) are the clinical translation of a qualitative or a quantitative deficit of C1 esterase inhibitor (C1 INH). The frequency and severity of clinical manifestations vary greatly, ranging from a moderate swelling of the extremities to obstruction of upper airway. Anaesthesiologists and intensivists must be prepared to manage acute manifestations of this disease in case of life-threatening laryngeal edema. Surgery, physical trauma and labour are classical triggers of the disease. The anaesthesiologists should be aware of the drugs used as prophylaxis and treatment of acute attacks when considering labour and caesarean section. Androgens are contraindicated during pregnancy. If prophylaxis is required, tranexamic acid may be used with caution. The safest obstetric approach appears to be to administer a predelivery infusion of C1 INH concentrate. It is important to avoid manipulation of the airway as much as possible by relying on regional techniques. We report the case of a patient suffering from an HAE discovered during pregnancy. The management included administration of C1 INH during labor and early epidural analgesia for pain relief. A short review of the pathophysiology and therapeutic options follows.
Management of Hereditary Angioedema During Off-Pump Coronary Arterial Surgery
2008, Annals of Thoracic Surgery
Citation Excerpt :
Most patients with HAE experience their first attack during early childhood [1]. In a National Institutes of Health study, angioedema of the extremities, face, or oropharynx developed in 79% of HAE patients during attacks, but only 21% of patients had symptoms limited to the gastrointestinal tract [1, 2]. Hereditary angioedema-induced edema usually lasts between 24 and 72 hours, but may be limited to less than 4 hours or persist for as long as 1 week [1].
Hereditary angioedema: A decade of human C1-inhibitor concentrate therapy
2007, Journal of Allergy and Clinical Immunology
C1-inhibitor (C1-INH) is a serine protease inhibitor regulating the complement, kinin-kallikrein, coagulation, and fibrinolytic systems. Hereditary angioedema (HAE) is caused by an inherited deficiency of C1-INH characterized by sudden, recurrent edematous swellings of the subcutaneous or submucosal tissues. The optional therapy for the acute management of HAE is administration of human C1-INH (hC1-INH) concentrate. However, hC1-INH is not available in many countries, in which case fresh frozen plasma is an alternative.
To summarize our experience with hC1-INH concentrate in patients with HAE.
Clinical and laboratory information on the effectiveness and safety of hC1-INH administered to relieve 468 acute edematous attacks in 61 patients with HAE was analyzed.
Severe abdominal or subcutaneous attacks and laryngeal edema were consistently relieved by the administration of 500 U hC1-INH concentrate. Symptoms improved within 15 to 60 minutes of administration. Progression of the attacks was never observed, and there were no recurrent attacks within 72 hours. hC1-INH concentrate requirements did not change after repeated use. hC1-INH concentrate proved effective in the management of 94 attacks in 22 children and 6 attacks in 4 pregnant women. Adverse reactions, viral infections, and antibody formation against the purified protein did not occur.
The administration of hC1-INH concentrate in HAE is highly effective and safe for the treatment of acute attacks and short-term prophylaxis and in pediatric patients and pregnant women.
Human C1-INH concentrate is effective and safe for the treatment of acute HAE attacks as well as for short-term prophylaxis.

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^☆: This study was supported in part by Grant AI-22940 from the National Institutes of Health, Bethesda, Maryland.

^∗: Dr. Sim is a recipient of the Marvin Lee Graves Fellowship in Clinical Research.

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ReviewHereditary angioedema: Its diagnostic and management perspectives☆

Abstract

J Biol Chem

Am J Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Thromb Res

J Allergy Clin Immunol

J Allergy Clin Immunol

Gene

Clin Immunol Immunopathol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Hereditary angioneurotic edema

Am J Med Sci

Five generations of angioneurotic edema

Arch Intern Med

Observations on a proesterase associated with partially purified first component of complement (C1)

Assay and properties of serum inhibitor of C1 esterase

Hereditary angioneurotic edema. II. Deficiency of inhibitor for serum globulin permeability factor and or plasma kallikrein

J Allergy

Hereditary angioedema: the clinical syndrome and its management

Ann Intern Med

Allergic urticaria and hereditary angioedema: independent association in the same patient

Clin Allergy

Hereditary angioedema: clinical and biochemical heterogeneity

Ann Allergy

Management of the airway in patients with angioedema

Laryngoscope

Complement in the pathophysiology of human disease

N Engl J Med

Serum inhibitor of C1 esterase in health and disease

J Lab Clin Med

Rapid fibrinolysis, augmented Hageman factor titers and decreased C1 esterase inhibitor titers in women taking oral contraceptives

J Lab Clin Med

Lupus erythematosus-like disease in three unrelated women with hereditary angioneurotic edema

Ann Intern Med

Hereditary angioneurotic edema and systemic lupus erythematosus in one of identical twin girls

J Allergy Clin Immunol

Discoid lupus erythematosus and the variant form of hereditary angioneurotic edema

Arch Dermatol

Studies of the mechanism of solubilization of immune precipitates by serum

J Exp Med

The role of complement and its receptor in the elimination of immune complexes

N Engl J Med

Permeability-increasing activity in hereditary angioneurotic edema plasma: II. Mechanism of formation and partial characterization

J Clin Invest

Cleavage of C2 by C1s into the antigenically distinct fragment C2a and C2b: demonstration of binding of C2b to C4b

Review
Hereditary angioedema: Its diagnostic and management perspectives☆