Hereditary Angioedema Workup
- Author: Michael M Frank, MD; Chief Editor: Michael A Kaliner, MD more...
Patients with hereditary angioedema (HAE) usually have normal results on most routine laboratory tests. An increased erythrocyte sedimentation rate or eosinophilia is not usually found. If either is present, the clinician should consider a coexisting or different diagnosis.
During attacks, patients can demonstrate hemoconcentration or prerenal azotemia, both of which reflect intravascular volume loss. The white blood cell count is usually not increased during attacks, although a leukocytosis may occur with gastrointestinal episodes.
The most reliable and cost-effective screening test for HAE is a serum C4 level.[13, 19, 21] The C4 concentration is almost always decreased during attacks and is usually low between attacks. If the C4 level is in the normal range but suspicion for angioedema is high, the test should be repeated. The concentrations of C3 and C1q are normal in patients with HAE, regardless of the clinical status of their disease.
During attacks, the total serum hemolytic complement (CH50) is typically decreased, but it returns to normal with recovery. Because a deficiency in any of several components of complement can cause a decrease in CH50, a decreased value is not a particularly helpful finding (ie, low positive predictive value). Keep in mind that patients can have antigenically present but nonfunctional C1 inhibitor (C1-INH). Therefore, functional tests may be useful. Unfortunately, functional testing has a high error rate.
Complement and Genetic Testing
The 3 types of HAE can be differentiated with complement testing and, in the case of type III, genetic testing.
Type I HAE is characterized by the following:
C1-INH level is low
C4 and C2 levels are low
C1q level is normal
Type II HAE is characterized by the following:
C1-INH level is normal or elevated but dysfunctional
C4 and C2 levels are low
C1q level is normal
Type III HAE is characterized by the following:
C1-INH level is normal
C1-INH functional assay is normal
C4 level may be normal
Factor XII mutation may be present [5, 6]
During attacks of gastrointestinal edema, abdominal radiographs may demonstrate features of ileus in HAE patients. Abdominal ultrasonography or computed tomography may show edematous thickening of the intestinal wall, a fluid layer around the bowel, and large amounts of free peritoneal fluid. Chest radiographs may demonstrate pleural effusions.
Very few histologic studies have been performed. Histologically, the angioedema of HAE is indistinguishable from other types of angioedema. Typically, perivascular mononuclear cell infiltrate and dermal edema similar to that seen with chronic urticaria or angioedema of other types are observed. Edema is found in the reticular dermis or subcutaneous or submucosal edema, without infiltrating inflammatory cells. Vasodilation may be present.
Craig T, Riedl M, Dykewicz MS, Gower RG, Baker J, Edelman FJ, et al. When is prophylaxis for hereditary angioedema necessary?. Ann Allergy Asthma Immunol. 2009 May. 102(5):366-72. [Medline].
Bankhead C. Another Drug for HAE Wins FDA Approval. MedPage Today. Jul 17 2014. [Full Text].
Riedl MA, Bernstein JA, Li H, Reshef A, Lumry W, Moldovan D, et al. Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. Ann Allergy Asthma Immunol. 2014 Feb. 112(2):163-169.e1. [Medline].
Starr JC, Brasher GW, Rao A, Posey D. Erythema marginatum and hereditary angioedema. South Med J. 2004 Oct. 97(10):948-50. [Medline].
Bork K, Wulff K, Hardt J, Witzke G, Staubach P. Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. J Allergy Clin Immunol. 2009 Jul. 124(1):129-34. [Medline].
Weiler CR, van Dellen RG. Genetic test indications and interpretations in patients with hereditary angioedema. Mayo Clin Proc. 2006 Jul. 81(7):958-72. [Medline].
US Food and Drug Administration (FDA). FDA Approves Berinert to Treat Abdominal Attacks, Facial Swelling Associated With Hereditary Angioedema. [Full Text].
Zuraw B, Yasothan U, Kirkpatrick P. Ecallantide. Nat Rev Drug Discov. 2010 Mar. 9(3):189-90. [Medline].
Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):532-41. [Medline]. [Full Text].
Lumry WR, et al. Results from FAST-3: A phase III randomized, double-blind, placebo-controlled, multicenter study of subcutaneous icatibant in patients with acute hereditary angioedema (HAE) attacks. American Academy of Allergy, Asthma, & Immunology Meeting. March 22, 2011; Abstract L2.
Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):513-22. [Medline]. [Full Text].
Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med. 1996 Jun 20. 334(25):1630-4. [Medline].
Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 4. 359(10):1027-36. [Medline].
Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009 Feb. 15(2):69-78. [Medline].
Bork K. Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations. Immunol Allergy Clin North Am. 2006 Nov. 26(4):709-24. [Medline].
Davis AE 3rd. Mechanism of angioedema in first complement component inhibitor deficiency. Immunol Allergy Clin North Am. 2006 Nov. 26(4):633-51. [Medline].
Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005 Mar. 139(3):379-94. [Medline]. [Full Text].
Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006 Mar. 119(3):267-74. [Medline].
Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med. 1976 May. 84(5):580-93. [Medline].
Nielsen EW, Gran JT, Straume B, Mellbye OJ, Johansen HT, Mollnes TE. Hereditary angio-oedema: new clinical observations and autoimmune screening, complement and kallikrein-kinin analyses. J Intern Med. 1996 Feb. 239(2):119-30. [Medline].
Rosen FS, Alper CA, Pensky J, Klemperer MR, Donaldson VH. Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema. J Clin Invest. 1971 Oct. 50(10):2143-9. [Medline]. [Full Text].
Kreuz W, Martinez-Saguer I, Aygören-Pürsün E, Rusicke E, Heller C, Klingebiel T. C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis. Transfusion. 2009 Sep. 49(9):1987-95. [Medline].
Sachse MM, Khachemoune A, Guldbakke KK, Kirschfink M. Hereditary angioedema. J Drugs Dermatol. 2006 Oct. 5(9):848-52. [Medline].
Caballero T, Farkas H, Bouillet L, Bowen T, Gompel A, Fagerberg C, et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012 Feb. 129(2):308-20. [Medline].
Craig T et al. WAO Guideline for the Management of Hereditary Angioedema. Available at http://ainotes.wikispaces.com/file/view/WAO+Guideline+for+the+Management+of+HAE+-+2012.pdf. Accessed: February 8, 2013.
Morgan BP. Hereditary angioedema--therapies old and new. N Engl J Med. 2010 Aug 5. 363(6):581-3. [Medline].
US Food and Drug Administration. Advisory Committee Briefing Document:Kalbitor (ecallantide)For Acute Attacks of Hereditary Angioedema. [Full Text].
Lumry WR, Bernstein JA, Li HH, Macginnitie AJ, Riedl M, Soteres DF, et al. Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: Open-label continuation study. Allergy Asthma Proc. 2013 Mar. 34(2):155-61. [Medline].
Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):523-31. [Medline].
Cicardi M, Castelli R, Zingale LC, Agostoni A. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J Allergy Clin Immunol. 1997 Feb. 99(2):194-6. [Medline].
Krause K, Metz M, Zuberbier T, Maurer M, Magerl M. Successful treatment of hereditary angioedema with bradykinin B2-receptor antagonist icatibant. J Dtsch Dermatol Ges. 2010 Apr. 8(4):272-4. [Medline].
Bouillet L, Boccon-Gibod I, Ponard D, Drouet C, Cesbron JY, Dumestre-Perard C, et al. Bradykinin receptor 2 antagonist (icatibant) for hereditary angioedema type III attacks. Ann Allergy Asthma Immunol. 2009 Nov. 103(5):448. [Medline].
Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010 Aug 5. 363(6):532-41. [Medline].
Bracho FA. Hereditary angioedema. Curr Opin Hematol. 2005 Nov. 12(6):493-8. [Medline].
Zuraw BL. Current and future therapy for hereditary angioedema. Clin Immunol. 2005 Jan. 114(1):10-6. [Medline].
Zuraw BL. Novel therapies for hereditary angioedema. Immunol Allergy Clin North Am. 2006 Nov. 26(4):691-708. [Medline].
American Academy of Allergy, Asthma & Immunology. Consultation and referral guidelines citing the evidence: how the allergist-immunologist can help. J Allergy Clin Immunol. 2006 Feb. 117(2 Suppl Consultation):S495-523. [Medline].
Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004 Sep. 114(3 Suppl):S51-131. [Medline].
Bork K, Witzke G. Long-term prophylaxis with C1-inhibitor (C1 INH) concentrate in patients with recurrent angioedema caused by hereditary and acquired C1-inhibitor deficiency. J Allergy Clin Immunol. 1989 Mar. 83(3):677-82. [Medline].
Cicardi M, Bergamaschini L, Cugno M, Hack E, Agostoni G, Agostoni A. Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience. J Allergy Clin Immunol. 1991 Apr. 87(4):768-73. [Medline].
Gelfand JA, Sherins RJ, Alling DW, Frank MM. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med. 1976 Dec 23. 295(26):1444-8. [Medline].
Sheffer AL, Fearon DT, Austen KF. Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J Allergy Clin Immunol. 1981 Sep. 68(3):181-7. [Medline].
A Study of Icatibant in Patients With Acute Attacks of Hereditary Angioedema (FAST-3). [Full Text].
Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet. 2000 Jul 15. 356(9225):213-7. [Medline].
EASSI - Evaluation of the Safety of Self-Administration With Icatibant. [Full Text].
Johnson K. Real-world use of icatibant improves angioedema. Medscape Medical News. November 12, 2013. [Full Text].
Leiden, The Netherlands. Biotech company Pharming Group NV ("Pharming" or "the Company") (NYSE Euronext: PHARM) today announces that, in agreement with the European Medicines Agency (EMEA), the dossier for the European Marketing Authorisation Application (MAA) of Rhucin(R) will be submitted in September 2009. [Full Text].
Lumry WR, Li HH, Levy RJ, et al. Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol. 2011 Dec. 107(6):529-37. [Medline].
Maurer M, Aberer W, Bouillet L, et al. Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. PLoS One. 2013. 8(2):e53773. [Medline]. [Full Text].
Riedl M, Longhurst H, Fabien V, Lumry WR, Maurer M. Icatibant for the treatment of non-laryngeal hereditary angioedema attacks: comparison of outcomes from a controlled phase III trial and a real-world setting (abstract P85). Presented at: The American College of Allergy, Asthma & Immunology (ACAAI) 2013 Annual Scientific Meeting; November 9, 2013; Baltimore, Maryland.