Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is an autosomal dominant disorder that affects approximately 1 in 50,000 individuals in the United States. It is due to a deficiency in functional C1-inhibitor (C1-INH), which results in recurrent episodes of nonpruritic edema beginning in childhood or adolescence and continuing throughout the patient’s lifetime. HAE attacks result in edema of the hands, feet, arms, legs, trunk, face, genitalia, bowels, and larynx.¹ 

Hereditary Angioedema Types

There are 3 forms of HAE. Type I HAE is caused by mutations in the gene that encodes for C1-INH, leading to truncated or misfolded C1-INH proteins that are not secreted efficiently. As a result, patients with HAE type I have low plasma levels of C1-INH and low C1-INH function. Type I HAE accounts for approximately 85% of cases. In HAE type II, mutations allow for the proper secretion of C1-INH; however, the protein functions suboptimally, resulting in low C1-INH function despite normal plasma levels. Type II affects approximately 15% of patients. Type III HAE (also known as HAE with normal C1-INH and estrogen-dependent HAE) is very rare and poorly understood.^1,2 It is characterized by normal levels of functioning C1-INH; however, patients exhibit the classic HAE phenotype and suffer recurrent attacks of angioedema that are unresponsive to antihistamines or corticosteroids. It appears to affect women more than men, and attacks may be preceded by elevated estrogen levels (eg, pregnancy or estrogen replacement therapy).¹

C1-INH is a member of the serpin family of serine proteases and serves as a major regulator of the complement, contact, and coagulation cascades via the inhibition of complement proteases (C1r, C1s, and mannose-binding lectin-associated serine proteases 1 and 2), contact proteases (plasma kallikrein and coagulation factor XIIa), and coagulation factors (XIa and XIIa). It is the runaway activation of the complement and contact systems due to the lack of its main inhibitor (C1-INH) that is thought to be the main driver of HAE attacks. Especially important is the increased expression of bradykinin – the primary mediator of vascular permeability in HAE. Kallikrein mediates a critical step in the contact pathway by converting kininogen into bradykinin. Low C1-INH activity leads to uninhibited conversion of kallikrein, which then results in increased vascular permeability manifesting as an HAE attack.¹ 

Since histamine and other mast cell mediators are not directly involved, HAE attacks do not respond to antihistamines. HAE attacks may be triggered by trauma, pressure, emotional stress, or medications (especially angiotensin-converting enzyme inhibitors).² The precise molecular event that initiates this cascade of events remains to be elucidated. It is believed that the activation of factor XII may be the leading molecular mechanism.³

Type III HAE was first reported in 2000 in women experiencing angioedema without wheals and no qualitative or quantitative C1-INH deficits. Additionally, the patients had an interesting common clinical history of estrogen exposure due to pregnancy or exogenous exposure. A case report of 3 patients in Brazil described the cessation of HAE attacks following the discontinuation of oral contraceptives, suggesting a strong link between estrogen exposure and type III HAE. Interestingly, this is not always the case, and some women appear to tolerate estrogen exposure with no correlation to disease activity. Genetic mutations in the factor XII gene have been identified in patients with type III HAE; however, male individuals that harbor this mutation are more likely to be asymptomatic, with up to 98.5% of patients being female. The precise role of estrogen in type III HAE remains unclear, but it is believed to be one reason why this disease primarily affects women. More research is therefore needed in this area.^2,4

References 

1. Lumry WR. Overview of epidemiology, pathophysiology, and disease progression in hereditary angioedema. Am J Manag Care. 2013;19(7 Suppl):s103-s110.

2. Miranda AR, de Ue APF, Sabbag DV, Furlani WdJ, de Souza PK, Rotta O. Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review. An Bras Dermatol. 2013;88(4):578-584. doi:10.1590/abd1806-4841.20131818

3. Cugno M, Cicardi M, Coppola R, Agostoni A. Activation of factor XII and cleavage of high molecular weight kininogen during acute attacks in hereditary and acquired C1-inhibitor deficiencies. Immunopharmacology. 1996;33(1-3):361-364. doi:10.1016/0162-3109(96)00086-0

4. Magerl M, Germenis AE, Maas C, Maurer M. Hereditary angioedema with normal C1 inhibitor: update on evaluation and treatment. Immunol Allergy Clin North Am. 2017;37(3):571-584. doi:10.1016/j.iac.2017.04.004

Reviewed by Harshi Dhingra, MA, on 6/26/2022.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.