Hereditary Angioedema (C1 Esterase Inhibitor Deficiency)

Hereditary angioedema (HAE), also known as C1 esterase inhibitor (C1-INH) deficiency, is an autosomal dominant disorder characterized by recurrent episodes of severe swelling (angioedema). Hereditary angioedema commonly affects the limbs, face, intestinal tract, and upper airway. Swelling in the airway can restrict breathing and lead to a life-threatening airway obstruction. Hereditary angioedema has 3 subtypes distinguished by their underlying etiologies and levels of C1 inhibitor in the blood. Management includes treatment with danazol, kallikrein inhibitors, and C1-INHs. Hereditary angioedema is self-limiting, but may be fatal if the airway becomes compromised.

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Overview

Definition

Hereditary angioedema (HAE) is a hereditary condition featuring recurrent episodes of swelling (angioedema), usually of the mucosa of the respiratory and gastrointestinal (GI) systems, without urticaria or itching.

Epidemiology

  • Worldwide incidence: 
    • 1 in 50,000–150,000 people
    • Represents 2% of clinical angioedema
    • No difference in prevalence between genders
    • No difference in prevalence between ethnic groups
    • 75% of patients present by 15 years of age
  • Emergency department (ED) visits due to HAE: 15,000–30,000/year

Etiology

Genetic mutations are the cause of HAE:

  • Inherited mutations in the gene for the C1 esterase inhibitor (C1-INH): mapped to 11q12-13.1
  • Autosomal dominant disease
  • Transmission: 50% probability of transmission to children of either gender

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Pathophysiology and Types

The basic pathophysiology of swelling in HAE has to do with the overproduction of bradykinin.

HAE type I HAE type II HAE type III
Prevalence 80%–85% of cases 15%–20% Very rare; usually in women
Cause Reduced secretion of C1-INHs Production of non-functional C1-INH
  • Normal C1-INH levels
  • Unclear cause; contact with estrogens and hormone replacement therapy, such as oral contraceptives
  • Mutation in F12 gene, which encodes for a protein involved in blood clotting (disease-causing gene on chromosome 5q35.2-35.3)
Pathophysiology Excess production of inflammatory anaphylatoxins that affect the flow of body fluids between the vascular system and body tissues Excess production of inflammatory anaphylatoxins that affect the flow of body fluids between the vascular system and body tissues
  • Increased activity of the enzyme kininogenase, which leads to a rise in levels of bradykinin
  • Other patients with mutations in F12, encode defective protein functioning in blood coagulation

Clinical Presentation

Patients with HAE have recurrent attacks:

Angioedema attack

  • Cutaneous symptoms:
    • Swelling of skin in non-dependent areas
    • Seen most commonly on face and genitals
    • Swelling increases over 24 hours and subsists over the following 48 hours.
  • GI symptoms:
    • Symptoms of colic, nausea, vomiting, and diarrhea
    • Often preceded by prodromal symptoms of fatigue, hunger, irritability, and rash
  • Airway symptoms:
    • Swelling of the lips, tongue, uvula, or palate
    • Early symptoms may include voice changes, sore throat, and “barky” cough
    • Severe episodes may cause airway obstruction and suffocation.
    • More than ½ of patients will experience airway symptoms.

Triggers

  • Illness:
    • Upper respiratory infection
    • H. pylori infection
  • Trauma:
    • Intubation
    • Dental work
    • Piercings
  • Medication:
    • ACE inhibitors 
    • Tamoxifen
    • Some hormone replacement medications

Diagnosis

History and physical exam

Recognizing HAE is often difficult due to a wide variability in disease expression: 

  • May be similar to other types of angioedema resulting from allergies or other medical conditions 
  • HAE should be considered if the patient presents with:
    • Recurrent angioedema (without urticaria)
    • Recurrent episodes of abdominal pain and vomiting
    • Laryngeal edema
    • Positive family history of angioedema

Laboratory testing

Blood tests often used to confirm the diagnosis:

  • Serum complement factor 4 (C4): most reliable and cost-effective screening test
  • C1-INH antigenic protein
  • C1-INH functional level (if available)
Table: Common lab findings in HAE based on types
Type of angioedema without urticaria C1-INH protein C1q C4 & C2
HAE type I Normal
HAE type II N or ↑ (but dysfunctional) Normal
Acquired angioedema with C1-INH deficiency (type I)
Acquired angioedema with C1-INH deficiency (type II)

Management

There is no chronic preventive treatment; management focuses on treating attacks based on specific symptoms:

  • Medications used in all acute attacks as soon as symptoms start:
    • C1-INHs: 1st-line treatment:
      • Concentrates from human plasma
      • Recombinant forms
    • Bradykinin B2-receptor antagonist
    • Kallikrein inhibitors (available in the United States only)
  • Airway symptoms:
    • Airway management
    • Intubation should be considered early.
  • GI symptoms:
    • Supportive care and close monitoring
    • Rehydration may be necessary.
    • Monitor for signs of intestinal occlusion from swelling.
  • Cutaneous symptoms: usually with medication only
  • Preventative therapy: C1-INH is often administered 1–1.5 hours before surgery.

References

  1. Nordenfelt, P., Nilsson, M., Björkander, J., Mallbris, L., Lindfors, A., & Wahlgren, C.F. (2016). Hereditary Angioedema in Swedish Adults: Report From the National Cohort. Acta Derm Venereol. May;96(4):540-5. doi: 10.2340/00015555-2274. PMID: 26540175.
  2. Bork, K., Meng, G., Staubach, P., & Hardt, J. (2006). Hereditary angioedema: New findings concerning symptoms, affected organs, and course. Am J Med. Mar;119(3):267-74. doi: 10.1016/j.amjmed.2005.09.064. PMID: 16490473.
  3. Bork, K., Frank, J., Grundt, B., Schlattmann, P., Nussberger, J., & Kreuz, W. (2007). Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol. Jun;119(6):1497-503. doi: 10.1016/j.jaci.2007.02.012. Epub 2007 Apr 5. PMID: 17418383.

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