Hereditary angioedema (HAE) is a very rare and potentially life-threatening genetic condition that occurs in about 1 in 10,000 to 1 in 50,000 people.
HAE symptoms include episodes of edema (swelling) in various body parts including the hands, feet, face and airway. In addition, patients often have bouts of excruciating abdominal pain, nausea and vomiting that is caused by swelling in the intestinal wall. Airway swelling is particularly dangerous and can lead to death by asphyxiation.
HAE patients have a defect in the gene that controls a blood protein called C1 Inhibitor. The genetic defect results in production of either inadequate or non-functioning C1-Inhibitor protein.
Normal C1-Inhibitor helps to regulate the complex biochemical interactions of blood-based systems involved in disease fighting, inflammatory response and coagulation.
Because defective C1-Inhibitor does not adequately perform its regulatory function, a biochemical imbalance can occur and produce unwanted peptides that induce the capillaries to release fluids into surrounding tissue, thereby causing edema.
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
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
Associated with normal or increased levels of a dysfunctional C1-INH protein resulting in reduced levels of C1-INH activity.
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.
It runs in the family
HAE is called hereditary because the genetic defect is passed on in families.
A child has a 50 percent possibility of inheriting this disease if one of the parents has it. The absence of family history does not rule out the HAE diagnosis, however.
Scientists report that as many as 20 percent of HAE cases result from patients who had a spontaneous mutation of the C1-Inhibitor gene at conception. Consequently, these patients can pass the defective gene to their offspring.
Because the disease is very rare, it is not uncommon for patients to remain undiagnosed for many years.
A large number of patients report that their frequent and severe abdominal pain was inappropriately diagnosed as psychosomatic, resulting in referral for psychiatric evaluation.
Unnecessary exploratory surgery has been performed on patients experiencing gastrointestinal edema, because abdominal HAE attacks mimic a surgical abdomen.
Before therapy became available, the mortality rate for airway obstruction was reportedly as high as 30 percent.