Hereditary angioedema

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Hereditary angioedema

Malcolm W. Greaves

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Classic hereditary angioedema (HAE) is an autosomal dominantly inherited disease with a prevalence of 1 : 50 000 due to mutations in the C1-esterase inhibitor (C1-INH) gene on chromosome 11 (11q12-q13.1), though de novo mutations are frequent. It is mediated by the protease kallikrein and the nonapeptide bradykinin, acting on B₂ receptors, and is manifested by painless, non-pruritic swellings of subcutaneous and submucosal tissues, including abdominal organs and the upper airway. It is characterized by a quantitative (type 1, 85%) or functional (type 2, 15%) defect of the inhibitor of the first component of complement (C1-INH). Estrogen-dependent hereditary angioedema (type 3) has recently been reported predominantly in women with no detectable abnormality of complement components. A mutation in the gene encoding for factor 12 has been identified in some of these families. Acute abdominal pain simulating an ‘acute abdomen’ is an important presentation. Fatalities are possible in these hereditary angioedemas.

Management strategy

Therapy for HAE is dependent on three considerations:

Relief of acute angioedema, especially preservation of the airway

Long-term prophylaxis

Prevention of relapse due to dental and surgical interventions

Acute angioedema

Acute presentations of HAE are treated optimally with intravenous vapor-sterilized C1-INH concentrate. This treatment is safe, and no proven cases of viral transmission have been reported since this sterilization process was adopted. Reduction in swelling is usually significant within minutes, and substantial within two to three hours. Fresh frozen plasma (FFP), which contains C1-INH, can be used if concentrate is unavailable; however, FFP carries a higher risk of inadvertent viral transmission (HIV, hepatitis) and theoretically could exacerbate angioedema owing to the presence of C1 esterase substrate. The kallikrein–bradykinin mediator pathway is the target of new approaches to treatment of acute HAE. Ecallantide, a kallikrein inhibitor given subcutaneously in dosage 30 mg proved safe and effective for acute attacks. The swellings of HAE are mediated by bradykinin, a product of the action of kallikrein on its substrate kininogen. Bradykinin acts on B₂ receptors, and its specific antagonist icatibant, 30 mg subcutaneously, has been proven effective in acute attacks of HAE. The administration of subcutaneous icatibant for acute HAE in a domiciliary setting by health care professionals, or even by self-administration after suitable training, is being explored. Laryngeal edema may require tracheostomy, intubation, and/or other life-support measures. Patients should be admitted routinely for 24 hours after acute episodes, as relapses, which may be life-threatening, are common.

Long-term prophylaxis

Generally, long-term prophylaxis is appropriate in those patients with at least one or more attacks of angioedema per month, and in those with severe symptoms. However, patients could have infrequent attacks and still present with laryngeal edema. Even first-episode angioedema can be fatal. The 17α-alkylated androgens danazol and stanozolol are first-line prophylactic medications that are effective in preventing angioedema in types 1 and 2 HAE. The lowest possible dose of androgen should be used to obtain clinical remission, regardless of C1-INH or C4 levels. Side effects include hirsuties, deepening of voice, and menorrhagia. These attenuated androgens are unsuitable for long-term treatment of hereditary angioedema in children, in pregnant women, and for the treatment of acute attacks. However, they are safe and effective in adults, provided they are closely supervised with clinical biochemical and radiological assessments. In some patients alternate-day therapy can be achieved. Hepatocellular adenoma and hepatocellular carcinoma have been reported in patients on long-term danazol. Other prophylactic therapies include antifibrinolytics (e.g., tranexamic acid, epsilon-aminocaproic acid – EACA), but these are of less certain value. In patients with mild infrequent attacks avoidance of provoking factors, including estrogens and angiotensin-converting enzyme (ACE) inhibitors, may be sufficient. For long-term management in selected cases, patients’ carers can be trained to administer intravenous C1 inhibitor concentrate for occasional acute attacks if no medical facilities are at hand, thereby obviating the necessity for regular prophylaxis.

Prevention of relapse due to dental and surgical interventions

In all patients, prior to elective surgical, dental, or other invasive procedures, higher-dose androgens can be used for 5–10 days. If an emergency procedure is necessary, C1-INH concentrate or FFP can be administered.

Patients with HAE should all wear a MedicAlert disk stating the diagnosis and emergency treatment.

Specific investigations

Complement levels (C4, C2, C1q)

C1-INH immunoreactive level

Functional assay for C1-INH

Kaplan AP, Greaves MW. J Am Acad Dermatol 2005; 53: 373–88.

Type I HAE is characterized by low antigenic and functional plasma levels of normal C1-INH. Type II HAE is characterized by normal or elevated antigenic levels of a dysfunctional mutant C1-INH together with functional C1-INH. In those patients with a low C4 but normal C1-INH levels, a functional assay should be obtained to identify type II disease. A depressed C1q level in addition to low C4 and C1-INH levels is characteristic of acquired C1-INH-deficient angioedema. Causes include B-cell lymphoma, cryoglobulinemia, and the presence of autoantibodies against C1-INH itself.

Hereditary and acquired C1 inhibitor deficiency: biological and clinical characteristics in 235 patients.

Agostini A, Cicardi M. Medicine 1992; 71: 206–15.

C4 level is the best screening test. A reduced value is typical between attacks, and during an attack the value is almost undetectable. Rarely, the C4 level may fall within the normal range in between attacks. Therefore, if the clinical picture is highly suggestive of hereditary angioedema, the functional and quantitative C1 inhibitor levels should be determined even if the C4 level is unremarkable.

A multicentre evaluation of the diagnostic efficiency of serological investigations for C1 inhibitor deficiency.

Gompels MM, Lock RJ, Morgan JE, Osborne J, Brown A, Virgo PF. J Clin Pathol 2002; 55: 145–7.

All patients with suspected C1-INH deficiency should have serum C4 measured. If C4 is normal, it is unnecessary to proceed to C1-INH analysis unless the clinical picture is highly suggestive of hereditary angioedema. If C4 is low, then C1-INH function should be analyzed. A combination of low C4 and low C1-INH function has a 98% specificity and 96% predictive value for C1-INH deficiency and is a very effective screening procedure.

Missense mutations in the coagulation factor 12 (Hageman factor) gene in hereditary angioedema with normal C1 inhibition.

Dewald G, Bork K. Biochem Biophys Res Commun 2006; 343: 1286–89.

Although predominantly occurring in females, type 3 hereditary angioedema has occasionally been reported in males.

Acute Angioedema

First-line therapies

C1-INH concentrate

A

Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema.

Bork K, Barnstedt S-E. Arch Intern Med 2001; 161: 714–18.

A series of 193 episodes of laryngeal edema treated with 500–1000 units (500 units initially, then repeated in 30–60 minutes if necessary) of concentrate were compared to cases that did not receive concentrate. The relief of symptoms occurred, on average, at 42 minutes after injection.

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