Angioedema

Angioedema: Excerpt from The 5-Minute Pediatric Consult

Mathew Fogg, MD

Angioedema - BASICS

Angioedema - description

Hereditary angioedema is an autosomal-dominant disorder in which mutations in the C1-INH (C1 esterase inhibitor) gene results in a deficiency or an inactive form of plasma C1-INH. This permits unregulated activation of the complement and plasma kinin-forming pathways, leading to angioedema.

Angioedema - risk factors

Angioedema - genetics

• Autosomal dominant
• Mutations may be in either of 2 genes for C1-INH, located on chromosome 11.
• Acquired forms lack a genetic predisposition (there is no mutation in the C1-INH gene).

Angioedema - pathophysiology

• Deficiency of C1-INH leads to unopposed activation of the 1st 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.

Angioedema - etiology

• Classic hereditary form: Defect in 1 of 2 genes on chromosome 11 that code for C1-INH
• Acquired forms:
  • In 1 form, normal amount and functionally normal C1-INH is secreted into the plasma, but it is bound to circulating antibodies that 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, resulting in increased degradation of C1-INH.

Angioedema - DIAGNOSIS

Angioedema - signs & symptoms

Decide if the patient’s symptoms are consistent with hereditary angioedema (recurrent angioedema after minor trauma, family history, onset at puberty, lack of hives, poor response to epinephrine).

Angioedema - history

• Age at onset of recurrent episodes of subcutaneous and submucosal edema (recurrent episodes of angioedema usually begin at puberty)
• Characterize episodes of angioedema. Angioedema episodes are characterized by edema of the upper airway, extremities, or bowels (can cause severe abdominal pain).
• Determine whether angioedema episodes are associated with hives. Episodes of hereditary angioedema are not associated with hives; however, patients may have a nonpruritic erythema marginatum rash.
• Duration of angioedema episodes usually last 1–4 days.
• Triggers:
  • Emotional stress
  • Physical trauma such as surgery or dental procedures
  • Infection
  • Menstruation
  • Pregnancy
  • Estrogen-containing oral contraceptives
• Family history:
  • Angioedema can be inherited in an autosomal-dominant fashion.
  • There may be other affected family members.
• Response to epinephrine, antihistamines, or corticosteroids: Angioedema related to hereditary angioedema responds poorly to epinephrine, antihistamines, and corticosteroids.

Angioedema - physical exam

Aside from angioedema, the physical examination is normal. Erythema marginatum, a nonpruritic eruption, may also be present in patients with hereditary angioedema.

Angioedema - tests

Angioedema - lab

• C1 esterase inhibitor level and function:
  • 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.
• Direct measurement of C1-INH level and function (study of choice to identify the hereditary form of C1-INH deficiency):
  • This is an antigenic assay.
  • Affected patients may have a minimal quantity of C1-INH detected, and heterozygotes (carriers) have ~1/2 of normal levels detected.
  • Some patients may have normal levels of protein with reduced function.
• C1q level:
  • In acquired C1-INH deficiency, levels of C1q will be reduced.
  • In the hereditary form, C1q will be normal.
• CH50 level:
  • A general screen of the complement system
  • If abnormal, can indicate a deficiency of any of the complement components

Angioedema - differencial diagnosis

• Toxic, environmental, drugs (patients on ACE inhibitors)
• Allergic inflammatory:
  • IgE-mediated allergic reactions: Drug, food, and contact allergies
  • Transfusion reaction
• Tumor (associated with neoplasms via unknown mechanism)
• Genetic/Metabolic:
  • Urticaria pigmentosa/mastocytosis
  • Familial cold urticaria
  • C3b-inactivator deficiency
  • Amyloidosis with deafness and urticaria
  • Hereditary vibratory angioedema
• Physical:
  • Urticarials: Cold urticaria, cholinergic urticaria, pressure urticaria (angioedema), vibratory angioedema, solar urticaria, aquagenic urticaria
  • Exercise-induced anaphylaxis
• Rheumatologic (collagen vascular disease)
• Psychologic:
  • Panic attacks
  • Globus hystericus
  • Vocal cord dysfunction
• Miscellaneous: Idiopathic angioedema

Angioedema - TREATMENT

Angioedema - general measures

• Prophylaxis:
  • 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 (ε-aminocaproic acid or tranexamic acid) do not correct C2 and C4 levels, but are clinically effective.
  • Recombinant C1-INH concentrate is available outside the US and is highly effective. Prior to dental and surgical procedures, doses of androgen should be increased for 1–2 weeks. In addition, some experts recommend treatment with fresh frozen plasma shortly before and immediately after surgery, as this product contains C1-INH.
• Acute attacks:
  • Recombinant C1-INH concentrate (outside the US)
    • Increase dose of androgen at 1st symptoms of an attack.
    • Immediately seek medical care; airway should be protected if any compromise is imminent.
  • Intermittent administration of subcutaneous epinephrine (This type of angioedema is usually poorly responsive, but in an emergency situation this may be considered.)
• Medical management: Treatment of the underlying condition often results in resolution of the angioedema.

Angioedema - FOLLOW UP

Angioedema - disposition

Angioedema - issues for referral

• Any patient 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 management of acute attacks.
• Patients with difficult-to-control angioedema without an identified trigger: An allergist immunologist can assist with the appropriate evaluation.

Angioedema - prognosis

Good with prophylactic and recombinant C1-INH therapies; recombinant C1-INH is not available in the US despite its proven clinical efficacy for treatment of acute attacks.

Angioedema - complications

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

Angioedema - patient monitoring

• Patients should be seen at least annually.
• Follow-up should include the following:
  • 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 patients requiring androgen steroid therapy.

Angioedema - bibliography

1. Frigas E, Nzeako UC. Angioedema: Pathogenesis, differential diagnosis, and treatment. Clin Rev Allergy Immunol. 2002;23:217–231.
2. Gratten C, Powell S, Humphreys F. Management and diagnostic guidelines for urticaria and angio-edema. Br J Dermatol. 2001;144:708–714.
3. Kaplan AP. Clinical practice: Chronic urticaria and angioedema. N Engl J Med. 2002;346:175–179.
4. Kozel MM, Bossuyt PM, Mekkes JR, et al. Laboratory tests and identified diagnoses in patients with physical and chronic urticaria and angioedema: A systematic review. J Am Acad Dermatol. 2003;48:409–416.

Angioedema - CODES

Angioedema - icd9

• 277.6 Other deficiencies of circulating enzymes
• 277.6 Hereditary angioedema

Angioedema - PATIENT TEACHING-MED

Education regarding:

• Role of triggers
• Prospective genetic counseling
• Need for prophylaxis
• Need for regular follow-up with an endocrinologist is indicated for patients who require androgen steroid therapy.

Angioedema - FAQ

• Q: What is a good screening test for angioedema?
• A: CH50 is a good screening test. Patients with angioedema 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 prophylactic androgen therapy?
• A: Side effects include masculinization, menstrual irregularities, enhanced epiphyseal growth-plate closure, water retention, hypertension, cholestatic hepatitis, hepatic carcinoma, decreased spermatogenesis, and gynecomastia.

Book Source Details

• Book Title: The 5-Minute Pediatric Consult
• Author(s): M. William Schwartz MD; et al.
• Year of Publication: 2008
• Copyright Details: The 5-Minute Pediatric Consult, Copyright © 2008 Lippincott Williams & Wilkins.

More About Angioedema

• Back to disease: Angioedema: Introduction
• Next Book Extract About Angioedema: Urticaria (The 5-Minute Pediatric Consult)
• More Book Extracts: All Online Books for Angioedema

More Medical Textbooks Online about Angioedema

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Copyright notice for book excerpts: Copyright © 2008 Lippincott Williams & Wilkins. All rights reserved.

More About This Book: Title: The 5-Minute Pediatric Consult Authors: M. William Schwartz MD; et al. Publisher: Lippincott Williams & Wilkins Copyright: 2008 ISBN: 0-7817-7577-9

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