Why Hereditary Angioedema testing

A rare autosomal dominant disorder that is characterized by frequent episodes of painful, usually asymmetric, swellings without urticaria, Hereditary Angioedema (HAE) may lead to significant morbidity and at times mortality if a laryngeal attack is not treated appropriately.

HAE must be considered in all patients with recurrent episodes of angioedema without urticaria and unexplained abdomen pain. Measurements of serum C4 and C1 inhibitor (C1-INH) levels and C1-INH function are used to confirm the diagnosis of HAE. Given the rarity of the disorder, delays in diagnosis and misdiagnosis are common. The pregnancy and postpartum periods are especially important for patients with HAE.

Early Diagnosis is essential

Diagnosing HAE as early as possible is essential to avoid morbidity and mortality associated with this disease. Once the diagnosis of HAE is confirmed in a patient, it is essential to screen parents, children, and siblings, even if they are asymptomatic. It has been observed that the risk of mortality is higher when the diagnosis of HAE is unknown. It has also been observed that a few patients may remain asymptomatic for several years and at times the first episode may prove to be fatal.

HAE is of three types. Type 1 HAE is characterized by decreased levels and/or function of C1-INH protein while type 2 HAE has normal levels of C1-INH protein but C1-INH is functionally abnormal. Patients with type 3 HAE have normal C1-INH levels and normal C1-INH function. Management of HAE has been divided into 1. On demand treatment (i.e., to abort an acute attack of angioedema); 2. Long-term prophylaxis (i.e., to prevent an episode of angioedema in patients who
have very frequent episodes); and 3. Short-term prophylaxis (i.e., given to prevent an episode of angioedema during certain procedures such as dental extraction where the risk of laryngeal oedema is very high).

Implications of HAE during Pregnancy

Because of influence of hormones, the clinical course of HAE may exacerbate during pregnancy and during post-partum period. Moreover, there are limited therapeutic options that can be used during pregnancy because of their concern of side effects on the foetus. HAE may rarely present for the first-time during pregnancy or during post-partum. In women with
normal C1-INH-HAE (type 3 HAE), it is not rare for the first symptom to develop during pregnancy or post-partum. It is important to keep a high index of suspicion in these cases.

During pregnancy, serum C1-INH testing must be interpreted cautiously because transiently low levels of C1-INH may be seen in normal pregnant females. This may be linked to a rise in plasma volume during pregnancy. Moreover, reduced functional levels of plasma C1-INH have also been reported in females with nC1-INH-HAE during pregnancy. Hence, it is important to repeat these tests, whenever in doubt.

Genetic testing of patients with HAE

HAE is a genetic disorder and genetic testing should ideally be done in all patients with HAE. Genetic test not only helps in confirming the diagnosis, it also helps in doing genetic counselling; may also facilitate testing of the foetus (antenatal diagnosis) and testing during the first year of life as plasma C4 and C1-INH levels may not be reliable during the first year of life. Genetic testing of foetus is usually done by either using amniotic fluid or a chorionic villus sample (CVS). Preimplantation genetic diagnosis is now being increasingly utilized for several genetic disorders including HAE. Genetic testing of parents is a must before opting for a preimplantation genetic diagnosis.

It is, however, important to note that a genetic defect may only be identified in approximately 90% of patients with type 1 and type 2 HAE.

Successful and safe delivery in patients with HAE
With advancements in medical technologies and the availability of plasma-derived C1-INH therapy, it is possible to have a successful pregnancy and safe delivery for all patients with HAE. However, patients must be cautioned about the risk of increased frequency of episodes in pregnancy and lactation and limitations about use of certain drugs such as androgens during pregnancy.

Androgens are a commonly used