Hereditary Angioedema (HAE) is a rare, inherited condition that leads to unpredictable and recurrent episodes of severe swelling, known as angioedema. This disorder is caused by a biochemical imbalance, often involving a protein that regulates inflammation in the body. Diagnosing HAE is difficult because its symptoms frequently mimic common allergic reactions, often leading to years of misdiagnosis and ineffective treatments. Proper diagnosis relies on recognizing specific clinical patterns and conducting specialized blood tests to identify the underlying protein deficiency or dysfunction.
Clinical Clues That Suggest HAE
The swelling associated with HAE presents in a specific way that helps distinguish it from typical allergic reactions. A significant clinical clue is the nature of the swelling itself, which is non-pitting and does not respond to standard allergy medications like antihistamines, corticosteroids, or epinephrine. These HAE attacks usually last for two to five days before gradually resolving on their own.
A particularly telling feature is the near-complete absence of urticaria, or hives, and pruritus, or itching. Allergic angioedema, by contrast, is almost always accompanied by hives and intense itching because it is mediated by histamine release. The swelling in HAE is instead caused by the overproduction of a molecule called bradykinin, which increases vascular permeability without triggering the classic allergic response.
Attacks can occur in various body parts, including the limbs, face, and genitals, but the most concerning locations are the airway and the gastrointestinal tract. Swelling of the larynx is life-threatening as it can rapidly obstruct breathing and requires immediate medical attention. Gastrointestinal tract attacks cause severe, excruciating abdominal pain, often accompanied by vomiting and diarrhea. These symptoms can lead to unnecessary surgery if the HAE diagnosis is not considered.
The suspicion for HAE often arises when a patient experiences recurrent episodes of unexplained swelling, especially if a family history of similar episodes exists. Symptoms frequently begin in childhood or adolescence and may increase in severity around puberty. The failure of typical allergy treatments to alleviate the swelling further directs the diagnostic process toward non-histamine-mediated causes like HAE.
Standard Blood Tests for Initial Diagnosis
The laboratory investigation for HAE focuses on the complement system, where the regulatory protein C1-inhibitor (C1-INH) operates. HAE is linked to a deficiency or dysfunction of this protein, making its measurement the central component of the diagnostic pathway. Three specific blood tests are used to screen for and diagnose the majority of HAE cases.
The initial screening test is the measurement of the Complement 4 (C4) protein level in the blood. C4 is a protein that is consumed when C1-INH is deficient or non-functional. In most patients with HAE, the C4 level is low, often even between swelling attacks. This reflects the ongoing, uncontrolled activation of the complement pathway.
If the C4 level is low, or if there is a high clinical suspicion of HAE despite a normal C4, the next step involves measuring the C1-INH protein directly. This requires two distinct tests: the C1-INH quantitative level and the C1-INH functional assay. The C1-INH quantitative level measures the amount of the protein present in the blood, often expressed as an antigenic level.
The C1-INH functional assay measures how well the existing C1-INH protein is working. This test is highly informative because a patient may have a normal amount of the protein, but if that protein is structurally defective, it cannot perform its regulatory job effectively. A low functional activity is the common denominator in the two most frequent types of HAE.
Confirming Diagnosis and Identifying HAE Type
The results from the three blood tests are combined to confirm the diagnosis of HAE due to C1-INH deficiency and to classify the specific subtype. The most common form, Type I HAE, accounts for approximately 85% of cases. It is characterized by a low C4 level along with both a low C1-INH quantitative level and low C1-INH functional activity. This indicates the body is not producing enough of the protein.
Type II HAE is the second most common form, making up around 15% of cases. Patients with Type II HAE exhibit a low C4 level and low C1-INH functional activity. However, their C1-INH quantitative level is normal or sometimes elevated. This signifies that they produce enough of the protein, but a mutation renders it ineffective.
A distinct and rarer category is Hereditary Angioedema with Normal C1-INH (HAE-nC1-INH). In these patients, all three standard blood tests—C4 level, C1-INH quantitative level, and C1-INH functional activity—are within the normal range. Clinical suspicion remains high due to the presence of recurrent, bradykinin-mediated swelling episodes that lack hives and do not respond to allergy treatments.
Confirmation of HAE-nC1-INH relies on genetic testing, which looks for mutations in genes other than the SERPING1 gene responsible for Type I and II HAE. The most frequently identified mutation is in the Factor XII (F12) gene, although other genes, such as ANGPT1 and PLG, have also been implicated in this subtype. Genetic testing also confirms the SERPING1 mutation in Type I and II, and it is a valuable tool for screening family members, even those who are currently asymptomatic.