Hereditary Angioedema - C1-INH Deficiency

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

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

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 (eg, autoimmune disorder)
    • 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, consider subtyping
        • No family history of angioedema – measure C1Q
          • 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

  • Cutaneous edema
    • Allergic urticaria/angioedema
    • Drug induced angioedema (eg, ACE inhibitors NSAIDS)
    • Contact dermatitis
    • Acquired angioedema
    • Urticarial vasculitis associated with angioedema
    • Idiopathic or cold-induced angioedema
    • Cellulitis
    • Parasitic infection (eg, Trichinella spp)
    • Autoimmune conditions
  • Laryngeal edema
    • Peritonsillar abscess

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 de novo mutations
  • Mutations in SERPING1 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 or qualitative defect in C1-INH
    •  Deficiency of functionally active component may lead to life-threatening angioedema
    • Types
      • Type 1 – 85%
        • Low production or absence of C1-INH levels
      • Type 2 – 15%
        • Dysfunctional C1-INH
      • Type 3 (familial angioedema) – rare
        • Normal C1-INH levels
  • Acquired C1-INH deficiency – qualitative defect in C1-INH

Clinical Presentation

  • Symptoms typically begin in childhood, worsen in puberty, and have an unpredictable course throughout adulthood
  • Transient, recurrent attacks of nonpruritic, 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

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

C-1-Esterase Inhibitor Panel 0050139
Method: Immunoturbidimetry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Nephelometry

Follow Up

May want to test for C2 to confirm C1-esterase deficiency and rule out complement deficiency

Complement Component 1Q Level 0099130
Method: Radial Immunodiffusion

Complement Component 4 0050155
Method: Quantitative Immunoturbidimetry

Related Tests

Guidelines

Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B, Aygoeren-Pürsün E, Craig T, Binkley K, Hebert J, Ritchie B, Bouillet L, Betschel S, Cogar D, Dean J, Devaraj R, Hamed A, Kamra P, Keith PK, Lacuesta G, Leith E, Lyons H, Mace S, Mako B, Neurath D, Poon M, Rivard G, Schellenberg R, Rowan D, Rowe A, Stark D, Sur S, Tsai E, Warrington R, Waserman S, Ameratunga R, Bernstein J, Björkander J, Brosz K, Brosz J, Bygum A, Caballero T, Frank M, Fust G, Harmat G, Kanani A, Kreuz W, Levi M, Li H, Martinez-Saguer I, Moldovan D, Nagy I, Nielsen EW, Nordenfelt P, Reshef A, Rusicke E, Smith-Foltz S, Späth P, Varga L, Xiang ZYu. 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 K. Hereditary angio-oedema in children: a management guideline. Pediatr Allergy Immunol. 2005; 16(4): 288-94. 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): S47-8. 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): 379-94. PubMed

Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D, Hsieh F, Khan D, Sheikh J, Weldon D, Bernstein DI, Blessing-Moore J, Cox L, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller DE, Spector SL, Tilles SA, Wallace D, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013; 131(6): 1491-3. PubMed

Zuraw BL, Bork K, Binkley KE, Banerji A, Christiansen SC, Castaldo A, Kaplan A, Riedl M, Kirkpatrick C, Magerl M, Drouet C, Cicardi M. Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel. Allergy Asthma Proc. 2012; 33 Suppl 1: S145-56. PubMed

General References

Banerji A. Hereditary angioedema: classification, pathogenesis, and diagnosis. Allergy Asthma Proc. 2011; 32(6): 403-7. PubMed

Bork K, Gül D, Hardt J, Dewald G. Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course. Am J Med. 2007; 120(11): 987-92. 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): 709-24. PubMed

Cicardi M, Johnston DT. Hereditary and acquired complement component 1 esterase inhibitor deficiency: a review for the hematologist. Acta Haematol. 2012; 127(4): 208-20. 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): 257-68. PubMed

Frank MM. 8. Hereditary angioedema. J Allergy Clin Immunol. 2008; 121(2 Suppl): S398-401; quiz S419. PubMed

Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet. 2012; 379(9814): 474-81. PubMed

Tse K, Zuraw BL. Recognizing and managing hereditary angioedema. Cleve Clin J Med. 2013; 80(5): 297-308. PubMed

Medical Reviewers

Last Update: December 2015