Angioedema: Part 3

Acquired angioedema (AAE) is characterized by a deficiency of C1INH not associated with a genetic defect; overactivation of the classical complement pathway; and frequent angioedema episodes. AAE is rare, about ten times less common than HAE. However, the two conditions are clinically identical. AAE often presents with low CH50, C2, C4 and sometimes C1q, with low or poorly functioning C1INH.

AAE was originally associated with lymphoma and has since been found secondary to a number of autoimmune and hematologic diseases, particularly lymphoproliferative conditions and monoclonal gammopathy of unknown significance (MGUS, which often precedes multiple myeloma). Historically, AAE has been divided into two groups: type I, which I just described; and type II, in which there are IgG antibodies to C1INH that inactivate C1INH. However, further research found that anti-C1INH antibodies are also found in type I. It has since been recognized that these are really different presentations of the same condition, with lymphoma cells depleting C1INH more readily. There have been documented instances in which achieving remission from lymphoma cured the associated AAE.

There are other types of angioedema that are difficult to classify. Idiopathic angioedema is the instance of three episodes in 6-12 months without a clear trigger or pathology. It is distinguished from hereditary angioedema by the shorter duration of symptoms. Further testing demonstrates normal levels and function of C1INH in these patients. This is sometimes called “idiopathic non-histaminergic AAE” to distinguish from an allergic process.

Type III HAE patients are sometimes positive for mutations in the Factor XII gene. However, in some patients, no mutation is found. All type III patients demonstrate normal level and function of C1INH. Type III patients experienced four attacks per year on average, with 42.9% having swelling in the airway. 85% had abdominal attacks, with some severe enough to result in emergency (though unnecessary) surgical procedures and ascites, free fluid in the abdomen.

In the patients with the Factor XII mutation, attacks were most likely to occur during high estrogen states, but were not exclusive to these periods. Initial attacks for this patient group usually occurred while on oral contraceptives or during pregnancy. However, men and children were also found to have Factor XII mutations. Initial attacks were less likely to affected by estrogen state in type III HAE with no FXII mutation or in idiopathic non-histaminergic angioedema. .

23% of type III patients exhibited elevated D-dimer levels outside of attack periods. Some also had extended clotting times. In the FXII mutated group, bruising was seen in a number of patients when swelling in the swollen portions of anatomy, but strictly in the skin. 27.9% of pregnancies in this group terminated in spontaneous miscarriage. Two births were extremely premature and one liveborn child died shortly after birth with no obvious cause of death.


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.