Patients with HAE may have normal bloodwork for routine tests. Blood counts, electrolytes and liver function tests are often unremarkable. Upon further testing, complement protein C4 is often low. This deficiency is most profound during attacks but often continues in interim periods. C3 is usually normal.
- In HAE type I, C1 inhibitor (C1INH), C4 and C2 levels are low, while C1q is normal.
- In HAE type II, C1INH is normal or marginally increased, C4 and C2 levels are low, and C1q is normal. C1INH functional tests yield low function.
- In HAE type III, CIINH is normal and functions normally and C4 is sometimes normal. Mutation for Factor XII is sometimes found. This is still largely a diagnosis of exclusion based upon similar clinical presentation as the other two types.
Hereditary angioedema (HAE) attacks carry the risk of significant danger as airway constriction can lead to suffocation. More than half of HAE patients will experience laryngeal swelling at least once in their lifetime. Swells typically last 2-3 days and then resolve over the following two days. Antihistamines and steroids are ineffective in mitigating swelling of this type.
HAE attacks have many triggers in the same way mast cell disease does. HAE was originally termed angioneurotic disease because patients frequently had a strong emotional event that activated the disease. In women, swells may correspond to changes in circulatory estrogen – pregnancy, menopause, puberty, menses. Psychological stress is a well characterized trigger for HAE and patients are strongly urged to eliminate sources of stress wherever possible. ACE inhibitors are known to interfere with regulation of the pathway to produce bradykinin and should therefore by avoided.
The last few years have seen several medications for acute angioedema attacks come to market. Cinryze, Berinert and Ruconest are C1INH solutions for intravenous infusion that can be administered at home. Kalbitor is a kallikrein inhibitor that is formulated for subcutaneous injection. Firazyr blocks the bradykinin receptor and is also available for injection. It is universally agreed that these medications should be available on demand in the event of a swell as they have been shown to safely and effectively reduce the risk to life.
With the advent of these targeted medications, more outmoded treatments are start to be phased out. Previous treatment modalities include fresh frozen plasma for acute attacks or short term prophylaxis, anabolic steroids like anabolic steroids, such as danazol, and antifibrinolytic medications, such as tranexamic acid. These medications often had difficult side effects, but still see some use for prophylaxis to avoid swell episodes. For short term prophylaxis for procedures, 1000-2000U of C1INH, 2U of freshly frozen plasma or a week of high dose danazol can be used.
References:
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Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.
Kaplan AP, et al. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 2010 Aug; 47(13):2161-9.
Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.
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Ohsawa, Isao, et al. Clinical manifestations, diagnosis, and treatment of hereditary angioedema: survey data from 94 physicians in Japan. Ann Allergy Asthma Immunol 114 (2015) 492-498.
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Lasek-Bal, Anetta, et al. Hereditary angioedema with dominant cerebral symptoms finally leading to chronic disability. Clinical Neurology and Neurosurgery 135 (2015) 38-40.