There are two subtypes of HAE based on the underlying genetic defect in the control of the blood protein C1-esterase inhibitor (C1INH) – and a third type HAE with normal C1INH:

HAE type I

HAE type I

Characterized by decreased levels of functional C1-INH protein; about 80-85 percent of patients suffer from this form of the disease.

HAE type II

HAE type II

Associated with normal or increased levels of a dysfunctional C1-INH protein resulting in reduced levels of C1-INH activity.

HAE with normal C1INH

HAE with normal C1INH

A new form of hereditary angioedema (HAE). Arises independently of a C1-INH deficiency; it is relatively rare and primarily affects women.

Type I HAE and Type II HAE is caused by a defect (mutation) in the gene responsible for producing the protein C1 esterase inhibitor (C1-INH). Unlike other hereditary diseases, the healthy gene cannot compensate for the defect in the other gene in patients with HAE.

Under normal conditions, C1-INH regulates the body’s production of bradykinin, a locally acting hormone that plays an important role in the control of the dilation (widening) and permeability of blood vessels – for example, in response to an injury or infection. If the C1-INH is not functioning properly or if its concentration is decreased, bradykinin is released excessively resulting in local swellings.

Besides the contact system, C1-INH is also involved in the so-called complement system, which is part of the immune defense. As in the contact system, an external stimulus, for example a foreign body or microbe, triggers a reaction cascade, which aims to eliminate the alien.

The cascade starts with the protein C1, whose direct counterpart is C1-INH. C1 is activated as soon as the immune system detects a foreign body, although the process is also self-activating to a lesser extent. Activated C1 activates a series of other factors in the complement system resulting in the elimination of the pathogen.

Infections, injuries, operations or stress may lead to consumption of C1-INH and may thus result in elevation of bradykinin levels with subsequent edema formation. Drugs that lower blood pressure (ACE inhibitors) can also cause edema: by inhibiting the degradation of bradykinin its level is increased.

A new form of hereditary angioedema (HAE) with normal C1 inhibitor (C1INH) was first described in 2000. The lack of clear diagnostic criteria, the heterogeneity among affected patients, and the varying names given to this disease have led to substantial confusion among both physicians and patients. This [scientific proceedings] was designed to bring more clarity to the diagnosis and potential treatment of HAE with normal C1INH. An international symposium of experts was convened to review the field and develop consensus opinions that could help clinicians who evaluate and manage these patients. Criteria were developed for the diagnosis of HAE with normal C1INH in patients with recurrent angioedema in the absence of concurrent urticaria. In addition, potential therapeutic strategies are discussed. The consensus criteria developed during this symposium will allow physicians to better diagnose and treat patients with HAE with normal C1INH.

“I try hard not to get upset about my symptoms or let them interfere with my daily routine. However, sometimes my HAE does prevent me from doing things because I am concerned I may have an attack.”
Renata Martins, Brazil
“I have had my appendicitis removed, have been brushed in the throat with adrenalin, and have been on a 14 days diet consisting of nothing but bread from rice and Tuborg beer – all just because the doctors couldn’t find out what was wrong with me.”
Erling Hess-Nielsen, Denmark
“My grandfather had severe HAE over many years and he died from a throat swelling at the age of 39, leaving four children, three of whom had HAE. My father suffered much until he was 30, when his symptoms suddenly ceased, never to return. Although many members of the family had the condition, my mother regarded it as ‘all down to nerves’ and ‘all in the mind’.”
Ann Price, United Kingdom