Hereditary angioedema (HAE) is a heritable blood disorder that causes episodes of protracted swelling, which can be life threatening. It has three subtypes, with two known to be caused by a mutation in the C1-INH (C1 inhibitor) gene.
HAE causes angioedema, a condition in which fluid leaves the bloodstream and passes into the space between the deep dermis and subcutaneous tissue. Swelling episodes can last for up to five days and swelling resolves between attacks. About 30% of HAE patients also have a rash similar to erythema marginatum, pink, slightly raised rings that don’t itch or wheal. HAE patients do not have hives or itching, an important distinction that allows diagnostic separation from chronic urticaria and angioedema
Swelling can occur in any region of the body, but face, GI tract, limbs, penis and scrotum are the most common. Angioedema of the tongue and pharynx can compromise the airway, as can edema of the larynx. In these patients, a tracheostomy may need to be placed.
Over 90% of patients suffer severe abdominal swells lasting 2-4 days. Abdominal pain, nausea, vomiting and diarrhea are common symptoms in this group. It is not unusual for doctors to assess the patient as having an “acute abdomen” in need of surgical intervention. Likewise, unnecessary surgery is often performed looking for the source of the swelling. These symptoms occur as a result of edema in the bowel wall, with complete or partial obstruction, sometimes causing ascites, or free fluid in the abdomen.
Angioedema seen in HAE patients is caused by excessive production of bradykinin, which is initiated by factor XII (also called Hageman factor). There are three types of HAE:
- Patients with HAE type I (85% of cases) have too little C1 inhibitor which functions poorly.
- Patients with type II (15% of cases) have normal levels of C1 inhibitor but it does not function correctly.
- Patients with HAE type III have normal levels and function of C1 inhibitor, but have symptoms and treatment responses similar to those with types I and II. Current research indicates that these people sometimes have mutations in the gene for Factor XII, which is also involved in the production of bradykinin.
Bradykinin acts on B2 receptors to cause blood vessels to dilate, decreasing blood pressure. It also increases vessel permeability, allowing fluid and cells to leave the blood stream and become trapped in tissues, resulting in angioedema.
C1 inhibitor (C1INH) is a molecule with multiple regulatory functions. Its name derives from its relation to the complement protein C1, the activation of which is the initiating step in the classical pathway for the complement system, a mechanism for fighting infections. A side product of this pathway is the large scale production of complement proteins C3a and C5a, both of which can induce anaphylaxis. C1INH also regulates steps involving the formation of plasminogen and plasmin, which prevent the formation of blood clots.
C1INH also inhibits the molecule Factor XII, also called Hageman Factor. C1INH prevents Factor XII from activating itself, the first step in a pathway that produces bradykinin. Activation of Factor XII causes formation of molecules XIIa and XIIf. Factor XIIa induces conversion of prekallikrein to kallikrein, and kallikrein then acts on high molecular weight kininogen to release bradykinin. All of those steps are regulated by C1INH.
Zuraw, B. L., et al. A focused parameter update : Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013; 131(6); 1491-1493e25.
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.
Csuka, Dorottya, et al. Activation of the ficolin-lectin pathway during attacks of hereditary angioedema. J Allergy Clin Immunol 134 (6) 1388-1393.e3.
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.
Kajdacsi, E., et al. Endothelial cell activation during edematous attacks of hereditary angioedema types I and II. J Allergy Clin Immunol 133 (6); 1686-1691.
Triggianese, Paola, et al. The autoimmune side of hereditary angioedema: insights on the pathogenesis. Autoimmunity Reviews 2015 (ahead of press).
Madsen, Daniel Elenius, et al. C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: implication for a role in hereditary angioedema. Biochimica and Biophysica Act 1850 (2015) 1336-1342.
Lasek-Bal, Anetta, et al. Hereditary angioedema with dominant cerebral symptoms finally leading to chronic disability. Clinical Neurology and Neurosurgery 135 (2015) 38-40.