Indications for Testing 

• Recurrent angioedema, laryngeal edema, or abdominal pain in the absence of urticaria
• Family history

Laboratory Testing

• Initial testing – C1 through C4
  • C4, C1-INH protein quantities normal
    • Confirm C4, C1-INH normal values during attack
    • Suspect other types of angioedema
  • C4, C1-INH protein quantities decreased – angioedema due to C1-INH deficiency
    • Confirm by second measurement of C4 and C1-INH
      • Family history of angioedema – hereditary angioedema
      • No family history of angioedema – measure C1Q binding assay and consider age of onset of symptoms
        • Earlier age of onset and/or C1Q normal – hereditary angioedema
        • Later age of onset and/or low C1Q – acquired angioedema
• C1-INH typing
  • Type 1 – low antigenic and functional levels; if C1Q is low, suspect acquired angioedema
  • Type 2 – normal antigenic level but low functional level
  • Type 3 – normal antigenic and functional levels
• Genetic testing not necessary

Differential Diagnosis

• Allergic urticaria or angioedema
• Idiopathic or cold-induced angioedema
• Angiotensin-converting enzyme (ACE)-associated angioedema
• Nonsteroidal anti-inflammatory drug (NSAID)-associated angioedema
• Angioedema with urticarial vasculitis
• Acquired angioedema
  • Lymphoproliferative disorders (lymphoma, B-cell, T-cell)
  • Autoimmune disease
  • Neoplasia

Hereditary angioedema (HAE) is an episodic swelling disease associated with the deficiency or malfunction of C1-esterase inhibitor.

Epidemiology

• Incidence – 1/50,000
• Age 
  • Congenital form – usually occurs in childhood
  • Acquired form – onset occurs later
• Sex – M:F, equal

Risk Factors

• Genetics
• Pressure applied to an extremity
• Stress
• Ingested estrogens, pregnancy
• Lymphoproliferative disorder 

Inheritance

• Autosomal dominant inheritance
  • 25% are spontaneous mutations
• Mutations in C1-INH gene

Pathophysiology

• C1-esterase inhibitor (C1-INH) is a multispecific, protease inhibitor
• C1-INH regulates the enzymes of the complement, coagulation, fibrinolytic and kinin-forming systems, including the following
  • C1r and C1s subunits of activated first component of complement
  • Activated Hageman factor (factor XIIa) and Hageman factor fragments
  • Activated plasma thromboplastin antecedent (PTA or factor XIa)
  • Prekallikrein (Fletcher factor)
  • Plasmin
• HAE is a hereditary quantitative deficiency in C1-INH
  • Type 1 or null – 85%
  • Type 2 or dysfunctional – 15%
  • Deficiency of functionally active component may lead to life-threatening angioedema
  • Rare type 3 defect (familial angioedema) associated with similar clinical presentation but normal C1-INH levels
• Acquired C1-INH deficiency is a qualitative (functional) deficiency of inhibitor
  • Associated with a variety of diseases, including lymphoid malignancies

Clinical Presentation

• Symptoms typically begin in childhood, worsen in puberty, and have an unpredictable course throughout adulthood
• Transient but recurrent attacks of non-pruritic, deep-seated swelling of various tissues occur throughout the body without the presence of urticaria
  • Typically involves arms, legs, hands, trunk, face, mouth, larynx, airway, genitals and tongue
• Gastrointestinal tract often involved, with recurrent episodes of cramping, abdominal pain, nausea and emesis (most frequent presenting complaint in children)
• Most frequent cause of death is airway obstruction secondary to laryngeal edema
• Presence of autoimmune diseases (especially glomerulonephritis) is higher in these patients
• Typical and predictable course
  • Many attacks, preceded by prodrome (tingling sensation)
  • Swelling gradually increases over the first 24 hours then gradually subsides over the next 48-72 hours

Treatment 

• Therapy for congenital defect is non-virilizing androgen treatment, which partially corrects the biochemical defect
• Aminocaproic acid
  • May be used for preoperative prophylaxis
  • Contraindicated in patients with thrombotic tendencies
• C1 inhibitor concentrate

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Bowen T, Cicardi M, Farkas H,et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010; 6 (1) :24-.PubMed
• Boyle RJ, Nikpour M, Tang ML. Hereditary angio-oedema in children: a management guideline. Pediatr Allergy Immunol. 2005; 16 (4) :288-294.PubMed
• Castaldo AJ. Hereditary angioedema: a current state-of-the-art review, IX: the US Hereditary Angioedema Association: a message from the president. Ann Allergy Asthma Immunol. 2008; 100 (1 Suppl 2) :S47-S48.PubMed
• Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, Fay AC, Longhurst HJ, Morrison L, Price A, Price M, Watters D. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005; 139 (3) :379-394.PubMed

General

• Bork K, Gul D, Hardt J, Dewald G. Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course. Am J Med. 2007; 120 (11) :987-992.PubMed
• Bork K. Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations. Immunol Allergy Clin North Am. 2006; 26 (4) :709-724.PubMed
• Cicardi M, Zanichelli A. Angioedema due to C1 inhibitor deficiency in 2010. Intern Emerg Med. 2010; 5 (6) :481-486.PubMed
• Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009; 15 (2) :69-78.PubMed
• Ebo DG, Verweij MM, De Knop KJ, Hagendorens MM, Bridts CH, De Clerck LS, Stevens WJ. Hereditary angioedema in childhood: an approach to management. Paediatr Drugs. 2010; 12 (4) :257-268.PubMed
• Frank MM. 8. Hereditary angioedema. J Allergy Clin Immunol. 2008; 121 (2 Suppl) :S398-S401.PubMed
• Johnston DT. Diagnosis and management of hereditary angioedema. J Am Osteopath Assoc. 2011; 111 (1) :28-36.PubMed
• Levy JH, Freiberger DJ, Roback J. Hereditary angioedema: current and emerging treatment options. Anesth Analg. 2010; 110 (5) :1271-1280.PubMed
• Temino VM, Peebles RS Jr. The spectrum and treatment of angioedema. Am J Med. 2008; 121 (4) :282-286.PubMed
• Weis M. Clinical review of hereditary angioedema: diagnosis and management. Postgrad Med. 2009; 121 (6) :113-120.PubMed
• Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008; 359 (10) :1027-1036.PubMed

Allergic Disease
Anaphylaxis
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