Hereditary angioedema (HAE) is a rare genetic disorder that causes episodes of severe swelling throughout your body. It is caused by abnormal immune responses. But unlike allergic swelling, HAE is not typically accompanied by itchiness.

In most cases, symptoms of HAE begin during childhood or early adolescence, typically before 20 years of age. Some types may develop later in life. But because HAE is so rare and swelling can be a nonspecific symptom, many cases are initially missed or misdiagnosed, leading to delays in diagnosis.

You may not receive an accurate diagnosis until years after your first HAE episode, and even longer delays are possible for rarer types of HAE.

Diagnosis and classification of HAE is a multistep process that requires recognition of HAE symptoms along with follow-up laboratory testing and, in some cases, genetic testing. Read on to learn more about each of these steps in the diagnosis of HAE.

The process of diagnosing HAE typically begins when a doctor recognizes signs and symptoms of HAE during a physical examination and reviews your clinical history. It’s possible to experience multiple episodes over several years before healthcare professionals suspect that HAE may be the cause.

Swelling in HAE can affect several parts of your body, including your skin, gastrointestinal tract, and respiratory system. This can lead to a variety of additional symptoms, such as:

  • pain
  • nausea or vomiting
  • difficulty swallowing
  • difficulty speaking
  • noisy breathing

In serious cases, swelling of your airways can lead to laryngeal edema, a potentially life threatening complication that can affect breathing. This condition requires immediate medical attention to treat.

During an HAE episode, symptoms typically build over several hours and usually last about 3 to 5 days.

Because the signs and symptoms of HAE may mimic those of a variety of other conditions, certain features may help healthcare professionals rule out other conditions. For instance, HAE episodes typically do not respond to antihistamines, corticosteroids, or epinephrine, and the swelling is not usually associated with itchiness, rashes, or fever.

The episodic nature of the swelling may also help point to a diagnosis of HAE.

Episodes may be triggered by a variety of physical or emotional factors. Triggers vary from person to person but may include:

  • stress
  • infections
  • trauma or injury, including from surgical or dental procedures
  • hormonal factors, such as oral contraceptives or pregnancy
  • certain medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or angiotensin converting enzyme (ACE) inhibitors

Not all HAE episodes will have an identifiable trigger.

If healthcare professionals suspect HAE, laboratory testing is necessary to confirm the diagnosis. This usually involves a blood test to check for levels of two types of proteins found in your blood: complement protein (C4) and complement inhibitor (C1-INH).

Low C4 levels are a strong indicator of HAE, especially during an episode. A normal C4 level during an episode of swelling is typically enough to suggest that HAE is not the cause.

The effects on C1-INH levels depend on the type of HAE you have. In almost all cases, HAE is caused by a defect in C1-INH activity. This defect can have one of two possible causes: insufficient C1-INH production (type 1) or dysfunctional C1-INH protein (type 2).

Type 1 HAE is more common, affecting about 85% of people who have the condition. In these cases, C1-INH blood test results are low. In type 2 HAE, which makes up most of the remaining cases, C1-INH levels may appear normal or elevated.

In a rare, third type of HAE (type 3), C4 and C1-INH levels are normal, which can make the condition difficult to diagnose through laboratory testing. In these cases, genetic testing can help identify the cause.

Type 3 HAE, also known as HAE-nl-C1INH, has been linked to changes in several genes that affect immune responses, inflammation, and blood clotting, including:

  • F12
  • ANGPT1
  • PLG
  • KNG1

In some cases, the cause is unknown. This is known as HAE-unknown (HAE-U).

The genetic changes that lead to HAE with normal C1-INH levels are distinct from those that cause HAE with C1-INH deficiency. Both type 1 and type 2 HAE are caused by changes in the SERPING1 gene.

Healthcare professionals may recommend genetic testing if you have symptoms of HAE without abnormal C4 or C1-INH levels, especially if you have a family history of HAE or unexplained angioedema.

Because HAE is a genetic disorder, people with a family history of HAE are more likely to develop it. However, up to 25% of HAE cases arise from spontaneous, non-inherited genetic changes.

Because HAE is a rare condition and the symptoms can be nonspecific, it is often misdiagnosed. Results from an international study found that nearly half of people with HAE had received at least one misdiagnosis before getting a diagnosis of HAE.

In this study, the most common misdiagnoses were allergic angioedema and appendicitis. Other people received misdiagnoses of other gastrointestinal disorders or other, nonallergic types of angioedema. A variety of other disorders can cause swelling, including:

  • autoimmune disorders
  • some types of cancer
  • infections

Because HAE is a relatively rare genetic condition with nonspecific symptoms, diagnosis is often delayed for several years after the start of symptoms. Many people receive at least one incorrect diagnosis before getting a correct diagnosis of HAE. Diagnosing this condition requires laboratory testing and, in some cases, additional genetic testing.