What is hereditary angioedema?
Hereditary angioedema (HAE) is a rare genetic condition that causes recurring episodes of severe swelling beneath the skin and in the body’s tissues. The swelling is driven by an excess of bradykinin, a protein that causes blood vessels to expand and leak fluid. That mechanism is what makes HAE so different from the angioedema most people are familiar with.
In allergic angioedema, histamine is the problem. Antihistamines and epinephrine work because they address that. In HAE, histamine is not the issue at all, which is why those same treatments largely don’t work. HAE requires its own medications.
Episodes can affect the limbs, abdomen, face, throat, and genitals. Throat swelling is the most serious complication; it can obstruct the airway. Before effective treatments existed, HAE carried a real risk of death from asphyxiation during severe attacks.
About 1 in 50,000 people worldwide have HAE. It follows an autosomal dominant inheritance pattern, meaning one copy of the abnormal gene is enough to cause the condition. Around 25% of cases arise with no family history, from a spontaneous gene mutation.
How HAE differs from other types of angioedema
Angioedema is swelling of the deeper skin layers. Most people with angioedema have the allergic or medication-induced type, where histamine is the driver and antihistamines are the first line of treatment.
HAE is in a different category entirely. The swelling comes from a deficiency or dysfunction of C1-inhibitor (C1-INH), a protein that regulates the contact activation pathway and complement system. Without enough functional C1-INH, bradykinin builds up and causes repeated swelling episodes.
Getting this distinction right is what leads to the right treatment. HAE patients are sometimes misdiagnosed with allergic angioedema for years, going through treatments that do nothing for them, which is one reason a proper specialist workup matters so much.
Types of HAE
Type I is the most common form, accounting for roughly 85% of cases. The body simply doesn’t produce enough C1-inhibitor protein.
Type II is less common. C1-INH levels can be normal or even elevated, but the protein doesn’t function correctly.
Type III (HAE with normal C1-INH) is rare and less well understood. It is more common in women and has been linked to estrogen exposure, including oral contraceptive use. Some cases are associated with mutations in the F12 gene (factor XII).
Acquired angioedema (AAE) is not hereditary but shares features with HAE. It tends to appear later in life and can be associated with autoimmune conditions or certain malignancies.
Symptoms of hereditary angioedema
Attacks can appear without warning. Many patients notice a prodrome beforehand: a tingling sensation or a non-itchy, snake-like rash called erythema marginatum in the hours before swelling begins.
Limb and peripheral swelling Swelling of the hands, feet, arms, or legs is common. Triggers can be surprisingly minor: typing, sports, a blood draw. Any physical pressure or trauma on the body can set an attack off.
Abdominal attacks Abdominal swelling causes severe cramping, nausea, vomiting, and diarrhea. These episodes are frequently mistaken for appendicitis or other surgical emergencies. Some HAE patients have had unnecessary abdominal surgeries before anyone recognized what was actually happening.
Facial and throat swelling Swelling around the lips, tongue, and throat is the most serious presentation. Laryngeal attacks can progress to airway obstruction and are life-threatening. Any throat tightness or change in voice during an attack should be treated as a medical emergency.
One useful distinguishing feature: HAE swelling is typically not itchy. If hives are present alongside the swelling, that points more toward allergic urticaria than HAE.
What triggers HAE attacks?
Attacks can be spontaneous or provoked. Common triggers include:
- Physical trauma or pressure (dental work, surgery, injury)
- Emotional stress or anxiety
- Illness or infection
- Estrogen, including oral contraceptives and hormone replacement therapy
- ACE inhibitor medications
- Menstruation
- Fatigue
How often attacks occur varies enormously from person to person. Some patients have them every few weeks; others go months without one. Without treatment, attacks typically last 2 to 5 days.
How is HAE diagnosed?
HAE is diagnosed through blood testing. The key markers are:
- C4 levels: almost always low in Type I and II, even between attacks. This is usually the first test ordered.
- C1-INH antigenic level: measures how much C1-inhibitor protein is in the blood. Low in Type I.
- C1-INH functional level: measures whether the C1-inhibitor actually works. Low or absent in both Type I and Type II.
- C1q levels: usually normal in hereditary HAE; low C1q suggests acquired angioedema instead.
Genetic testing for SERPING1 mutations (the gene that encodes C1-INH) can confirm the diagnosis and is useful when lab values are borderline but family history is suggestive.
If you have a first-degree relative with HAE, testing is worth doing even if you have no symptoms. Children can inherit the condition and benefit from early diagnosis.
Standard allergy skin testing is not useful here. HAE is not an IgE-mediated allergic condition.
Treatment for hereditary angioedema
HAE treatment falls into three categories: on-demand treatment for acute attacks, short-term prophylaxis before planned procedures, and long-term prophylaxis for patients with frequent or severe attacks.
Acute (on-demand) treatment
Patients with HAE should carry their acute medication at all times. Attacks can progress quickly, and waiting to see how bad it gets is not a safe approach.
Sebetralstat (Ekterly) is the first oral on-demand treatment for HAE attacks, approved in 2025 for patients 12 and older. It’s a plasma kallikrein inhibitor taken as a pill at the first sign of an attack, which means patients no longer have to rely on an injection to start treatment. Updated international guidelines now recommend it as a first-line option for acute attacks.
C1-inhibitor concentrate (Berinert, Ruconest) are plasma-derived or recombinant C1-INH concentrates given by injection during an attack. They work by restoring normal C1-INH activity and bringing bradykinin levels back down.
Icatibant (Firazyr) is a bradykinin B2 receptor antagonist given as a subcutaneous injection. It blocks bradykinin from acting on blood vessel receptors and typically provides relief within 30 to 60 minutes.
Ecallantide (Kalbitor) is a plasma kallikrein inhibitor given by subcutaneous injection that blocks the enzyme responsible for producing bradykinin.
Epinephrine can be used as a temporary measure if the airway is involved while definitive treatment is being arranged, but it does not address the bradykinin mechanism and should not be relied on as a standalone treatment. Antihistamines do not work for HAE attacks.
Short-term prophylaxis
Before surgery, dental procedures, or other predictable triggers, C1-INH concentrate or fresh frozen plasma can be given to reduce attack risk. Your allergist will coordinate timing and dosing with your care team ahead of the procedure.
Long-term prophylaxis
For patients with frequent or severe attacks, ongoing preventive therapy can reduce how often attacks occur and how bad they are when they do.
Garadacimab (Andembry) is a factor XIIa inhibitor approved in 2025, given as a monthly self-injection. It works upstream of the other prophylactic options, blocking the contact system before bradykinin generation even begins.
Donidalorsen (Dawnzera) is an antisense oligonucleotide approved in 2025, the first RNA-targeted therapy for HAE. It’s dosed every 4 or 8 weeks and works by reducing prekallikrein production.
Lanadelumab (Takhzyro) is a monoclonal antibody given as a subcutaneous injection every 2 to 4 weeks. It inhibits plasma kallikrein, cutting off the bradykinin production that drives attacks. It’s now also approved for children as young as 2.
Berotralstat (Orladeyo) is a once-daily oral capsule that inhibits plasma kallikrein. It was the first oral long-term prophylactic option for HAE, which matters for patients who prefer not to inject.
Subcutaneous C1-INH (Haegarda) is a self-injected C1-INH concentrate given twice weekly to maintain adequate enzyme levels between attacks.
Attenuated androgens like danazol were used for prophylaxis historically but are now generally a last resort given their side effect profiles.
With multiple mechanisms now available, from injectable to oral to RNA-targeted therapy, choosing the right long-term option comes down to attack frequency, patient preference around dosing route and schedule, and how someone tolerates a given mechanism. This is where a specialist who tracks the full landscape makes the difference.
What’s on the horizon
Research into HAE treatment continues to move quickly. A one-time gene-editing therapy is currently in late-stage trials and has shown strong results in reducing attacks, though it is still under FDA review and not yet available. A new oral on-demand option is also in trials. Neither is approved yet, but both point to a treatment landscape that keeps expanding for HAE patients.
Living with HAE
HAE is a lifelong condition. With a solid management plan, most patients do well, but that plan has to be followed consistently.
Carry your emergency medication everywhere. Not most places. Everywhere. Attacks can start in minutes, and having acute treatment accessible (and making sure people close to you know how to use it) is part of managing this condition.
Wear a medical ID. In an emergency, healthcare providers need to know upfront that standard angioedema treatments may not apply to you.
Tell your care team before any procedure. Your dentist, surgeon, and any other provider needs to know about your HAE before they do anything invasive. Pre-procedure prophylaxis can prevent what would otherwise be a serious post-procedure attack.
Think carefully about contraception choices. Estrogen is a known trigger for many HAE patients. Progestin-only methods are generally a safer option. This is worth discussing with both your allergist and your gynecologist.
Keep a symptom log. Tracking when attacks happen, how long they last, and what preceded them helps your allergist refine your treatment plan. It can also be relevant for insurance documentation for certain medications.
Frequently asked questions
Is HAE the same as allergic angioedema? No. The swelling can look similar, but the mechanism is completely different. Allergic angioedema is histamine-mediated. HAE is bradykinin-mediated. Antihistamines, steroids, and epinephrine are largely ineffective for HAE attacks, which is exactly why getting the right diagnosis matters.
Can HAE be cured? Not currently. It is a genetic condition managed with medication. With modern treatments, most patients can achieve good attack control and live normally.
Is HAE always inherited from a parent? In most cases, yes. A child of a parent with HAE has a 50% chance of inheriting it. About 25% of cases arise from a new mutation with no family history, so the absence of family history doesn’t rule it out.
Can women with HAE use hormonal birth control? Estrogen-containing contraceptives worsen HAE in many women. Progestin-only pills, hormonal IUDs, and other non-estrogen options are generally preferred. Your allergist and gynecologist should both be involved in that conversation.
What should I do if I think I’m having a throat attack? Use your on-demand medication immediately and go to the nearest emergency room. Do not wait to see if it resolves on its own. Laryngeal attacks can progress to airway obstruction faster than people expect.
Can stress actually trigger an attack? Yes. Emotional stress is one of the most commonly reported triggers. Managing stress through sleep, exercise, and other strategies can help reduce attack frequency in some patients, though it is not a substitute for medication.
Get expert HAE care in New York
HAE is rare and needs a specialist who knows it well, both for accurate diagnosis and for staying current on a treatment landscape that’s expanded significantly in just the past year. Patients today have access to more than a dozen FDA-approved options for on-demand treatment, procedural prophylaxis, and long-term prevention. Our allergists see patients with HAE across multiple NYC locations and can put together a management plan built around the therapies that fit your attack history and your life.
Call (212) 686-6321 or book an appointment online.
