Hereditary Angioedema (HAE) is a rare, life-long genetic condition characterized by unpredictable and recurrent episodes of severe swelling (angioedema). This swelling affects various parts of the body, including the face, limbs, and gastrointestinal tract, but is most dangerous in the upper airway. Misdiagnosis is common due to the condition’s rarity, often leading to significant delays in diagnosis. Timely diagnosis is crucial because laryngeal swelling can rapidly cause airway obstruction and death. HAE is caused by a failure to regulate the C1-Inhibitor (C1-INH) protein, resulting in the overproduction of bradykinin, the molecule responsible for the swelling.
Recognizing Symptoms and Clinical History
The initial step in diagnosing HAE relies heavily on a detailed review of the patient’s symptoms and medical history. Unlike common allergic reactions, HAE-related swelling is distinctively non-itchy, non-pitting, and not accompanied by hives (urticaria). The edema develops slowly over a period of 12 to 24 hours, often lasting between two and five days without treatment.
Swelling most frequently affects the extremities, face, and genitals, but gastrointestinal attacks are also common. These abdominal attacks can cause severe, cramping pain, nausea, and vomiting, sometimes mimicking a surgical emergency and leading to unnecessary surgeries. Swelling of the larynx is the most threatening manifestation, as it can cause airway closure and asphyxiation.
Many patients experience warning signs (prodromes) hours before an attack, such as fatigue, mood changes, or localized tingling. Identifying triggers is important, as episodes can be provoked by physical trauma, dental procedures, illness, or emotional stress. A family history of similar swelling is present in about 75% of HAE cases, though 25% arise from a spontaneous genetic mutation.
The lack of response to standard treatments for allergic angioedema—antihistamines, corticosteroids, and epinephrine—indicates the swelling is not histamine-mediated. This non-responsiveness, combined with the unique characteristics of the swelling, should raise suspicion of a bradykinin-mediated angioedema like HAE. The clinical picture guides the physician to order specific laboratory tests for confirmation.
Specific Laboratory Testing
Once the clinical history suggests HAE, the diagnosis is confirmed by measuring complement components. The initial screening test typically involves measuring the serum level of C4. In individuals with HAE Type I and Type II, C4 levels are almost always low, even when the patient is between swelling attacks.
If the C4 level is found to be low, the next step involves testing the C1-Inhibitor (C1-INH) protein. This protein is responsible for regulating the biochemical pathway that leads to bradykinin overproduction. Two separate measurements are needed for C1-INH: the antigenic level (total quantity) and the functional level (how well the protein works).
The results of these two C1-INH tests allow for the classification of the two primary types of HAE. HAE Type I, which accounts for approximately 85% of cases, is diagnosed when both the C1-INH antigenic level and the C1-INH functional level are low. HAE Type II is diagnosed when the C1-INH antigenic level is normal or sometimes elevated, but the C1-INH functional level is low, indicating the protein is present but defective.
It is recommended to repeat these laboratory tests one to three months after the initial abnormal result to confirm the diagnosis. While C4 and C1-INH functional levels are often lower during an acute episode, the tests are reliable for diagnosis even when the patient is asymptomatic.
Differentiating HAE from Other Forms of Angioedema
A crucial step following initial laboratory findings is to differentiate HAE from other conditions that can cause similar bradykinin-mediated swelling. Two main differential diagnoses are Acquired Angioedema (AAE) and angioedema induced by Angiotensin-Converting Enzyme (ACE) inhibitors.
Acquired Angioedema (AAE) also involves C1-INH deficiency but is typically a late-onset condition, presenting after the fourth decade of life, unlike HAE. The key test distinguishing AAE from HAE is the measurement of C1q. In HAE, the C1q level is typically normal, while in AAE, the C1q level is often low because the protein is consumed due to an underlying disorder.
Angioedema caused by ACE-inhibitor medications presents a challenge because it occurs even with normal C1-INH and C4 levels. This swelling is bradykinin-mediated, resulting from the drug preventing bradykinin breakdown. Diagnosis relies on the patient’s history of taking an ACE-inhibitor and the fact that swelling typically resolves upon discontinuing the medication.
Both HAE and ACE-inhibitor angioedema are often characterized by swelling of the lips, tongue, and larynx, which is less common in allergic angioedema. The absence of hives and the failure to respond to antihistamines and steroids remain the most important clinical clues. This careful exclusion process prevents misdiagnosis as a common allergic condition.
Genetic Confirmation and Family Screening
For patients diagnosed with HAE Type I or Type II based on the biochemical tests, the underlying cause is a mutation in the SERPING1 gene. Genetic testing can confirm this mutation and is particularly useful when the biochemical results are inconclusive or in newborns and young children where protein levels may be less reliable.
There is also a separate category known as HAE with normal C1-Inhibitor (HAE-nC1-INH), where the C4 and C1-INH levels and function are all normal. Genetic testing for this form targets other genes, most commonly the F12 gene, which codes for Coagulation Factor XII. Mutations in other genes, such as PLG or ANGPT1, are also being identified as causes of HAE-nC1-INH, requiring broader genetic testing panels.
Because HAE is an autosomal dominant disorder, an affected person has a 50% chance of passing the mutation to their children. Once a diagnosis is confirmed in a patient (the index case), family screening is recommended for all blood relatives. This proactive testing allows for early diagnosis and intervention, essential for preventing potentially fatal laryngeal attacks.