Diagnostic and Therapeutic Management of Hereditary Angioedema Due to C1-Inhibitor Deficiency

The Italian Experience

Mauro Cancian


Curr Opin Allergy Clin Immunol. 2015;15(4):383-391. 

In This Article

Pathophysiology and Diagnosis

To date, about 350 different mutations (Human Genome Mutation Database, http://www.hgmd.cf.ac.uk/ac) in C1-INH gene (SERPING1, OMIM #608660) have been demonstrated to cause C1-INH deficiency, but no genotype/phenotype correlation has been found so far.[14–19] C1-INH belongs to the superfamily of the serin protease inhibitors (SERPIN) and controls several proteases in the complement, coagulation, contact and fibrinolytic systems.[6,20,21,22] Uncontrolled local activation of the contact system leads to overproduction of bradykinin (BK) that binds BK-B2 receptor (BK-B2r) on endothelial cells. Stimulation of these receptors opens cell junctions allowing plasma outflow and angioedema formation[23] in the deep dermis and subcutaneous or submucosal layers of the face, larynx, abdomen and extremities. C1-INH-HAE is not associated with urticarial wheals and acute attacks resolve in 1–5 days.[24]

Symptoms tend to recur life-long and significantly affect patients' quality of life by limiting scholastic, working and social activities. Gastrointestinal involvement is typical of C1-INH-HAE and may help to differentiate this form from other angioedema.[25] It is characterized by bowel occlusion with severe crampy pain, vomiting and diarrhoea, so closely mimicking surgical emergencies to prompt unnecessary operations[26–28] (Fig. 1). Laryngeal attacks represent roughly 5% of all symptoms and can easily be lethal in undiagnosed patients.[29] Precipitating factors for HAE attacks may include medications such as oral estrogens or angiotensin-converting enzyme inhibitors, infection, trauma, hormonal changes, and surgical, endoscopic, or dental procedures.[24] Nevertheless, in most cases angioedema occurs spontaneously and the unpredictable onset of symptoms may worsen the burden of illness.[30,31]

Figure 1.

Abdominal CT-scan of an acute attack of C1-INH-HAE in a woman.

The worldwide prevalence is estimated between 1 : 10 000 and 1 : 50 000.[32–36] Data recently collected by the Italian network for HAE provided a prevalence of 1 : 64 935 for our country, with no sex differences.[13]

Whenever a patient reports a history of recurrent, nonhistaminergic subcutaneous or upper airway angioedema and/or abdominal pain attacks of unknown etiology, C1-INH deficiency should be taken into account.[25] Gastrointestinal involvement as the only symptom of the disease is rare, and the diagnosis is particularly challenging in this situation. A positive family history further strengthens the suspicion of C1-INH deficiency, but even in the absence of family history HAE needs to be considered as up to 20–25% of cases represent de-novo mutations.[32,33,37]

Laboratory assay includes C4, quantitative and functional C1-INH assessment. For diagnosis of C1-INH-HAE type I both plasma C1-INH antigen and function need to be less than 50% of normal control population. In the Italian HAE cohort, this variant accounts for 87% of patients whereas in the remaining 13% only C1-INH activity is below 50% of normal (C1-INH-HAE type II),[13] a finding similar to those reported in other series.[4,38] Screening with C4 plasma levels, a cheap assay available in most laboratories, may also be very helpful because values more than 50% of the reference range exclude diagnosis with 96% accuracy.[13,38,39] SERPING1 sequencing may be necessary when family analysis does not prove existence of genetic basis for C1-INH deficiency and for prenatal/perinatal diagnosis. In Italy, we chose to centralize C1-INH genotyping in a single referral centre to optimize costs and standardize quality of tests.

Although diagnostic criteria are well established and easy to apply, the delay between onset of symptoms, which typically present in childhood, and diagnosis of C1-INH-HAE is still substantial[30,32,33,40] and in Italy amounts to about 10 years.[13]

More rarely, C1-INH deficiency is caused by increased catabolism in patients with no mutation affecting the SERPING1 gene and in whom lack of a family history is constant. C1-INH-acquired angioedema (C1-INH-AAE) is usually associated with lymphoproliferative or immune diseases and commonly starts later than C1-INH-HAE, e.g. in middle or advanced age. Skin and mucosal involvement is otherwise similar to hereditary angioedema, but in addition to low levels of C4, antigen and functional C1-INH also C1q is usually reduced and anti-C1-INH autoantibodies may be detected.[20,41]