Residency · Residency · Allergy Immunology

Hereditary Angioedema

Overview and Classification

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent, self-limited episodes of subcutaneous and submucosal edema. A fundamental distinction from histamine-mediated angioedema is that HAE is bradykinin-mediated, meaning it does not respond to antihistamines, epinephrine, or corticosteroids. The clinical presentation is characteristically non-pruritic, with patients experiencing pain or a pressure sensation rather than itching, and urticaria is absent. The condition is potentially fatal, as laryngeal edema causing asphyxiation occurs in approximately 25 to 30 percent of patients over their lifetime. Before the availability of modern targeted therapies, mortality from HAE was estimated at 15 to 33 percent.

Classification

HAE Type I, accounting for 85 percent of cases, results from autosomal dominant mutations in the SERPING1 gene, which encodes C1-inhibitor (C1-INH). More than 700 SERPING1 mutations have been described, with approximately 25 percent arising de novo. Type I disease is characterized by both reduced C1-INH protein levels and reduced function. HAE Type II, representing 15 percent of cases, also results from autosomal dominant SERPING1 mutations but is characterized by normal or even elevated C1-INH protein levels with reduced functional activity. These are typically missense mutations affecting the reactive center loop, often at the Arg444 residue, producing a dysfunctional protein.

HAE with normal C1-INH (HAEnCI) is a more recently recognized category encompassing multiple genetic subtypes. HAE-FXII results from gain-of-function Factor XII mutations (Thr309Lys being most common) and is notably estrogen-sensitive. Other identified subtypes include HAE-ANGPT1 (angiopoietin-1 mutations), HAE-PLG (plasminogen mutations, particularly Lys330Glu), HAE-KNG1 (kininogen-1 mutations), HAE-MYOF (myoferlin mutations), and HAE-HS3ST6 (heparan sulfate 3-O-sulfotransferase 6 mutations). Some patients display a clinical HAE phenotype with normal C1-INH but no identifiable genetic mutation (HAE-unknown).

Pathophysiology

Bradykinin Pathway

C1-INH is a serine protease inhibitor (serpin) that serves as a critical regulatory brake on multiple protease cascades. In the contact and kinin system, it inhibits kallikrein and activated Factor XII (Factor XIIa). In the complement system, it inhibits C1r and C1s. In the coagulation cascade, it inhibits Factor XIa. In the fibrinolytic system, it inhibits plasmin.

In HAE, reduced C1-INH function leads to uncontrolled activation of the contact system. Factor XII undergoes autoactivation upon contact with negatively charged surfaces, generating Factor XIIa. Factor XIIa then converts prekallikrein to its active form, kallikrein, which in turn cleaves high-molecular-weight kininogen (HMWK) to release bradykinin. A positive feedback loop amplifies this cascade, as kallikrein itself activates additional Factor XII. C1-INH serves as the primary physiologic brake on this entire cascade, and its deficiency allows runaway activation.

Bradykinin binds the B2 receptor on endothelial cells, activating endothelial nitric oxide synthase (eNOS), phospholipase A2 (producing prostacyclin), and phospholipase C-beta (triggering calcium flux). These signals converge to disrupt VE-cadherin-mediated cell-cell junctions, causing rapid-onset vascular permeability and tissue edema without significant inflammatory cell infiltration. The enzyme ACE (also known as kininase II) is the major physiologic degradation pathway for bradykinin, which explains the mechanistic overlap between HAE and ACE inhibitor-induced angioedema. Because C1-INH also regulates the classical complement pathway by inhibiting C1, its deficiency leads to constitutive consumption of C4, providing the basis for using C4 as a screening test.

<image>A detailed pathway diagram of the contact activation system and bradykinin generation in hereditary angioedema. Start with Factor XII at the top, showing its autoactivation on contact surfaces. Factor XIIa activates prekallikrein to kallikrein (with positive feedback loop back to Factor XII). Kallikrein cleaves HMWK to release bradykinin. C1-INH shown as a red octagonal "STOP" sign at three points: inhibiting Factor XIIa, inhibiting kallikrein, and inhibiting C1r/C1s (complement arm). In HAE, C1-INH is reduced/dysfunctional (shown as faded/broken stop signs). Bradykinin binds B2 receptor on endothelial cell, activating nitric oxide, prostaglandins, and calcium signaling, leading to VE-cadherin disruption and vascular leakage/edema. Drug targets highlighted: lanadelumab (anti-kallikrein), ecallantide (kallikrein inhibitor), icatibant (B2 receptor antagonist), berotralstat (oral kallikrein inhibitor), C1-INH replacement. ACE shown degrading bradykinin, with ACE inhibitor blocking this degradation pathway.</image>

Clinical Manifestations

Attack Characteristics

HAE attacks develop gradually over hours, in contrast to the more acute onset of histamine-mediated angioedema. Swelling typically peaks at 24 to 36 hours and resolves spontaneously over 48 to 72 hours, though attacks may last up to 5 days. The frequency of attacks is highly variable, ranging from weekly to yearly, with an average of 1 to 2 attacks per month in untreated patients.

The most common sites of involvement are the skin of the extremities, face, and genitalia, producing non-pitting, non-pruritic, often asymmetric swelling. Abdominal attacks, occurring in approximately 50 percent of episodes, result from intestinal wall edema and cause severe crampy abdominal pain, nausea, vomiting, and diarrhea. These episodes can closely mimic a surgical acute abdomen, and undiagnosed patients may undergo inappropriate surgical exploration. Imaging with ultrasound or CT during abdominal attacks may reveal ascites and bowel wall thickening. Laryngeal attacks represent the most dangerous manifestation, producing stridor, voice changes, and dysphagia. Approximately 50 percent of HAE patients experience at least one laryngeal attack in their lifetime. Less common sites of involvement include urogenital and chest wall edema.

Prodromal symptoms are reported by 50 to 70 percent of patients and include erythema marginatum (a distinctive serpiginous, non-pruritic rash that is often mistaken for urticaria but lacks wheals) and tingling or tightness at the site where swelling will subsequently develop.

Triggers

Recognized triggers for HAE attacks include trauma and surgery (dental procedures being particularly common precipitants), emotional stress, infections, and estrogen exposure from both exogenous sources (oral contraceptive pills, hormone replacement therapy) and endogenous fluctuations (puberty, menstruation, pregnancy). Estrogen-containing contraceptives are contraindicated in HAE, especially in HAE-FXII; progestin-only or non-hormonal contraception should be used. ACE inhibitors are absolutely contraindicated. Many attacks occur spontaneously without an identifiable trigger.

Natural History

Symptom onset typically occurs in childhood or adolescence, with disease severity often worsening around puberty, particularly in females due to estrogen effects. The course during pregnancy is unpredictable, with some patients improving and others experiencing exacerbation. Without treatment, HAE causes significant morbidity from missed school and work, impaired quality of life, and the ever-present risk of fatal laryngeal edema.

Diagnosis

Laboratory Evaluation

The initial screening test for HAE Types I and II is the serum C4 level. C4 is low between attacks in more than 95 percent of patients with HAE Type I and II, giving it a high negative predictive value. A normal C4 level during an attack virtually excludes HAE Types I and II. It is important to understand that C4 is not directly related to bradykinin; rather, it is consumed by unopposed classical complement pathway activation resulting from the absence of C1-INH regulation of C1.

Confirmatory testing requires both a quantitative C1-INH level and a functional C1-INH level. In HAE Type I, both the level and function are reduced, typically below 50 percent of normal. In HAE Type II, the quantitative level is normal or elevated but function is reduced below 50 percent. Testing should be repeated to confirm the diagnosis, as the C1-INH functional assay is prone to false positives from technical issues.

A critical distinguishing test is the C1q level, which is normal in HAE but low in acquired C1-INH deficiency (AAE). This distinction is clinically essential because acquired C1-INH deficiency is associated with lymphoproliferative disease or anti-C1-INH autoantibodies and requires a fundamentally different diagnostic and therapeutic approach. Genetic testing is confirmatory and is especially important for establishing the diagnosis of HAE with normal C1-INH.

Differential Diagnosis

The differential diagnosis of recurrent angioedema without urticaria includes acquired C1-INH deficiency, which typically presents in adults over age 40 and is associated with lymphoproliferative disease or anti-C1-INH autoantibodies with a low C1q level. ACE inhibitor-induced angioedema is identified through medication history and normal complement studies. Idiopathic angioedema is a diagnosis of exclusion with normal C4 and C1-INH that may respond to antihistamines. Histamine-mediated angioedema often accompanies urticaria, is pruritic, and responds to antihistamines.

<image>A diagnostic algorithm for recurrent angioedema without urticaria. Starting box: "Recurrent angioedema WITHOUT urticaria." Step 1: "Is patient on an ACE inhibitor?" If Yes: "Discontinue ACEi; if resolves = ACEi-induced angioedema." If No: Step 2: "Measure serum C4." If C4 is low: "Measure C1-INH level + C1-INH function + C1q." Three possible results: (A) Low C1-INH level + Low function + Normal C1q = HAE Type I. (B) Normal C1-INH level + Low function + Normal C1q = HAE Type II. (C) Low C1-INH level + Low function + Low C1q = Acquired C1-INH deficiency (evaluate for lymphoproliferative disease). If C4 is normal: "Consider: HAE with normal C1-INH (genetic testing for FXII, PLG, ANGPT1, KNG1, etc.), idiopathic angioedema (trial of antihistamines), histamine-mediated angioedema." Each diagnosis box includes recommended next steps and treatments.</image>

Treatment

On-Demand (Acute Attack) Treatment

All HAE attacks should be treated early, without waiting to assess severity, as the trajectory of any given attack is unpredictable. Laryngeal attacks require immediate treatment, and preparation for intubation or cricothyrotomy should be made concurrently. Plasma-derived C1-INH concentrate (Berinert at 20 IU/kg intravenously) is FDA-approved for acute attacks, while Cinryze (1000 IU intravenously) is approved for both acute treatment and prophylaxis. Recombinant C1-INH (Ruconest/conestat alfa) at 50 IU/kg intravenously (maximum 4200 IU) provides an alternative, though it is contraindicated in patients with rabbit allergy, as it is produced in transgenic rabbits.

Icatibant (Firazyr) is a synthetic bradykinin B2 receptor antagonist administered as 30 mg subcutaneously via a pre-filled syringe that can be self-administered by the patient. Onset of action is 30 to 60 minutes, with approximately 10 percent of attacks requiring a repeat dose at 6 hours. Ecallantide (Kalbitor) is a kallikrein inhibitor administered as 30 mg subcutaneously (three 10 mg injections), but must be given by a healthcare provider due to a 3 percent risk of anaphylaxis. Fresh frozen plasma, which contains C1-INH, may be used when specific therapies are unavailable, though there is a theoretical risk of worsening by providing additional substrate for bradykinin generation.

Short-Term (Preprocedural) Prophylaxis

Before dental procedures, surgery, intubation, or other known triggers, preprocedural prophylaxis with C1-INH concentrate (Cinryze 1000 IU or Berinert 20 IU/kg intravenously) should be administered 1 to 6 hours before the procedure. Alternatively, on-demand therapy should be immediately available. Danazol at 200 to 600 mg daily, started 5 days before and continued 2 to 3 days after the procedure, is a less preferred option.

Long-Term Prophylaxis

Long-term prophylaxis is indicated when patients experience one or more attacks per month, have impaired quality of life, have a history of laryngeal edema, or have inadequate access to acute treatment. Lanadelumab (Takhzyro), a fully human anti-kallikrein monoclonal antibody, has emerged as first-line long-term prophylaxis in most guidelines. Administered as 300 mg subcutaneously every 2 weeks (with extension to every 4 weeks possible in well-controlled patients), the HELP trial demonstrated an 87 percent reduction in attack rate versus placebo, with 44 percent of patients becoming completely attack-free.

Haegarda, a subcutaneous C1-INH concentrate, is administered at 60 IU/kg twice weekly. The COMPACT trial demonstrated a 95 percent reduction in attacks. It is self-administered with common injection site reactions as the principal adverse effect. Berotralstat (Orladeyo), an oral kallikrein inhibitor at 150 mg daily, represents the first oral prophylactic agent for HAE. The APeX-2 trial showed a 44 percent reduction in attacks versus placebo. Gastrointestinal side effects (abdominal pain, diarrhea) are the primary adverse effects, and drug interactions through CYP3A4 and CYP2D6 pathways must be considered. Donidalorsen (Odrya), an antisense oligonucleotide targeting prekallikrein mRNA, is administered subcutaneously monthly.

Attenuated androgens (danazol, stanozolol, oxandrolone) increase hepatic C1-INH synthesis and are effective but carry significant side effects including hepatotoxicity (hepatic adenoma, peliosis hepatis), virilization, and lipid abnormalities. They are contraindicated in pregnancy, children under 16 (growth plate effects), and hepatic disease, and have been largely replaced by modern targeted therapies. Tranexamic acid, an antifibrinolytic agent, has modest efficacy and is primarily used where other options are unavailable or as a pediatric option.

Special Populations

Pediatric HAE

Children of an affected parent should be screened with C4, C1-INH level, and C1-INH function at age 1 year or older, as neonatal levels are unreliable. Genetic testing can confirm the diagnosis at any age. On-demand treatments approved in pediatrics include C1-INH concentrate (Berinert from birth) and icatibant (from age 2 years). Prophylactic options include lanadelumab (from age 2 years), Haegarda (from age 6 years), and berotralstat (from age 12 years).

Pregnancy

Danazol is teratogenic and must be avoided during pregnancy. ACE inhibitors are similarly contraindicated. For acute attack treatment during pregnancy, C1-INH concentrate is considered safe, and icatibant has been used with limited data. For prophylaxis during pregnancy, C1-INH concentrate is the preferred agent. Peripartum management includes prophylaxis with C1-INH concentrate before delivery and ensuring on-demand therapy is immediately available. During breastfeeding, C1-INH concentrate is safe, while danazol is contraindicated.

Key Clinical Pearls

• HAE does NOT respond to antihistamines, epinephrine, or corticosteroids; these should not delay definitive HAE-specific treatment
• C4 is the best screening test for HAE Types I/II; it is low between attacks in >95% of patients
• C1q is NORMAL in HAE but LOW in acquired C1-INH deficiency; this distinction guides evaluation for lymphoproliferative disease
• ACE inhibitors are absolutely contraindicated in HAE and acquired angioedema with C1-INH deficiency
• Estrogen-containing contraceptives worsen HAE; use progestin-only or non-hormonal methods
• Laryngeal attacks are life-threatening; treat immediately with on-demand therapy; do not observe and wait
• Lanadelumab (anti-kallikrein mAb) has largely replaced androgens as first-line long-term prophylaxis
• All HAE patients should carry on-demand therapy at all times (icatibant auto-injector is convenient for self-administration)

References

1. Maurer M, et al. The international WAO/EAACI guideline for the management of hereditary angioedema - the 2021 revision and update. Allergy. 2022;77(7):1961-1990.
2. Banerji A, et al. Lanadelumab for prevention of attacks of hereditary angioedema (HELP). N Engl J Med. 2018;379(4):352-362.
3. Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036.
4. Craig TJ, et al. WAO guideline for the management of hereditary angioedema. World Allergy Organ J. 2012;5(12):182-199.
5. Bork K, et al. Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course. Am J Med. 2007;120(11):987-992.

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