• Defect in one of the two genes coding for C1-INH on chromosome 11.

• In one form, normal amount and functionally normal C1-INH is secreted into the plasma, but it is bound to circulating antibodies which inactivate it (associated with benign and malignant monoclonal B cell lymphoproliferative disorders)
• In the other form, an autoantibody not associated with lymphoproliferative disorders binds to C1-INH, which makes the C1-INH-C1s complex unstable resulting in increased degradation of C1-INH.

• Deficiency of C1-INH leads to unopposed activation of the first complement component, resulting in the formation of bradykinin, which produces angioedema.
• Angioedema may occur in the upper airway, gastrointestinal tract, and extremities.
• Life-threatening upper airway obstruction may develop.

• Autosomal dominant
• Mutations may be in either of two genes for C1-INH located on chromosome 11.
• Acquired forms lack a genetic predisposition (there is no mutation in the C1-INH gene).

• Life-threatening upper airway obstruction.
• Severe abdominal pain often mistaken for a surgical abdomen.

• IgE-mediated allergic reactions
  • Drug allergy
  • Food allergy
  • Contact allergy
• Transfusion reaction

• Urticaria pigmentosa/mastocytosis
• Familial cold urticaria
• C3b inactivator deficiency
• Amyloidosis with deafness and urticaria
• Hereditary vibratory angioedema

• Physical urticarias
  • Cold urticaria
  • Cholinergic urticaria
  • Pressure urticaria (angioedema)
  • Vibratory angioedema
  • Solar urticaria
  • Aquagenic urticaria
• Exercise-induced anaphylaxis

• Panic attacks
• Globus hystericus
• Vocal cord dysfunction

Question: At what age did the recurrent episodes of subcutaneous and submucosal edema begin?
Significance: Recurrent episodes of angioedema usually begin at puberty.

Question: How are the episodes of angioedema characterized?
Significance: Angioedema episodes are characterized by edema of the upper airway, extremities or bowels (can cause severe abdominal pain).

Question: Are the angioedema episodes associated with hives?
Significance: Episodes of angioedema are not associated with hives.

Question: How long do the episodes of angioedema last?
Significance: The duration of an angioedema episode usually last 1 to 4 days.

Question: What triggers the angioedema episode?
Significance: Episodes of angioedema can be triggered by emotional stress and physical trauma.

Question: Do other familial members have similar episodes of angioedema?
Significance: Angioedema can be inherited in an autosomal dominant fashion. There may be other affected familial members.

Question: Do the episodes of angioedema respond to epinephrine, antihistamines, or corticosteroids?
Significance: Angioedema related to angioedema responds poorly to epinephrine, antihistamines, and corticosteroids.

• Measure C1 esterase inhibitor level.
• If C1 esterase inhibitor level is normal, and an acquired deficiency is suspected, order a functional assay of C1 esterase inhibitor. Samples for complement assays must be placed on ice immediately, otherwise, the results may be falsely low.

Test: Direct measurement of C1-INH (study of choice to identify the hereditary form of C1-INH deficiency).
Significance: This is an antigenic assay. Affected patients will have a minimal quantity of C1-INH detected, and heterzygotes (carriers) will have approximately one-half normal levels detected.

Test: Direct measurement of C4 and C2 during attacks.
Significance: In acquired C1-INH deficiency the direct measurement of C1-INH is normal, but the C2 and C4 levels are decreased during attacks.

Test: CH50
Significance: The CH50 is a general screen of the complement system, and if abnormal can indicate a deficiency of any of the complement components.

• Any patient diagnosed with angioedema. An allergist can help evaluate these patients for possible androgen prophylaxis therapy. In addition, they can assist in the creation of an emergency plan for recombinant C1 esterase infusion.
• Patients with difficult to control angioedema without an identified trigger. An allergist/immunologist can assist with the appropriate evaluation.

• Anabolic steroids (Danazol or Stanozolol) cause increased production of C1-INH resulting in near normal C2 and C4 levels (decreased degradation by activated C1), and a significantly decreased episode frequency. This therapy is indicated in patients with frequent or life-threatening episodes.
• Plasmin inhibitors (Epsilon-Aminocaproic acid or Tranexamic acid) do not correct C2 and C4 levels, but are clinically effective.
• Recombinant C1-INH concentrate recently available.

• Recombinant C1-INH concentrate
• Intermittent administration of subcutaneous epinephrine (this type of angioedema is usually poorly responsive, but in an emergent situation this may be considered).

• Patients should be seen at least annually.
• Follow-up should include:
  • Review of triggers
  • Prospective genetic counseling
  • Reinforcement of the need for prophylaxis
  • Review of attacks during the previous year
  • Creation of an emergency plan for the administration of recombinant C1 esterase inhibitor during severe attacks
• Regular follow-up with an endocrinologist is indicated for patient’s requiring androgen steroid therapy

Q: What is a good screening test for angio-edema?
A: The CH50 is a good screening test. Patients with angioedema will have a low CH50. Remember that the specimen must be placed on ice immediately. Failure to ice the specimen will result in a falsely low CH50.

Q: What are the side effects of the prophylactic androgen therapy?
A: The side effects include: masculinization, menstrual irregularities, enhanced epiphyseal growth plate closure, water retention, hypertension, cholestatic hepatitis, hepatic carcinoma, decreased spermatogenesis, and gynecomastia.

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Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med 1976;84:580–593.

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