Hereditary angioedema: Pathogenesis and diagnosis
- Marco Cicardi, MD
Marco Cicardi, MD
- Professor of Medicine
- Università degli Studi di Milano, Italy
- Bruce Zuraw, MD
Bruce Zuraw, MD
- Professor of Medicine
- University of California San Diego
Hereditary angioedema (HAE) is a disease characterized by recurrent episodes of angioedema, without urticaria or pruritus, which most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Although the swelling is self-limited and resolves in two to five days without treatment, laryngeal involvement may cause fatal asphyxiation.
The pathogenesis and diagnosis of hereditary forms of angioedema will be reviewed here. The clinical features, precipitating factors, and treatment of this disorder are discussed elsewhere. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis" and "Hereditary angioedema: Treatment of acute attacks" and "Hereditary angioedema: General care and long-term prophylaxis".)
The swelling (ie, angioedema, sometimes called "giant" swelling) that occurs in hereditary angioedema (HAE) results from excessive production of bradykinin, a potent vasodilatory mediator. Bradykinin also has important vascular permeability-enhancing effects. During episodes of angioedema in patients with HAE, plasma bradykinin levels have been shown to be sevenfold higher than normal . In bradykinin-mediated angioedema, histamine and other mast cell mediators are not directly involved, which explains the lack of response to antihistamines and distinguishes this form of angioedema from the histamine-mediated angioedema that is seen in allergic reactions and urticaria.
Some forms of HAE arise from deficiency or dysfunction of C1 inhibitor (C1INH), while others do not. In those that do not, specific mutations in the factor XII gene have been identified in some families, while the etiopathogenesis of the disease in other families is unknown.
Functions of C1 inhibitor — C1 inhibitor (C1INH) is an acute-phase reactant and a member of the "serpin" superfamily of serine protease inhibitors. C1INH is an inhibitor of two complement pathways (classical and lectin), as well as of the intrinsic coagulation (contact system) fibrinolytic  and kinin-generating pathways. The function of C1INH in the kinin-generating pathway is most directly related to the pathogenesis of HAE [3-5]. C1INH inhibits the following plasma proteases (figure 1) [6,7]:
- Bork K, Frank J, Grundt B, et al. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol 2007; 119:1497.
- van Geffen M, Cugno M, Lap P, et al. Alterations of coagulation and fibrinolysis in patients with angioedema due to C1-inhibitor deficiency. Clin Exp Immunol 2012; 167:472.
- Davis AE 3rd. The pathophysiology of hereditary angioedema. Clin Immunol 2005; 114:3.
- Beinrohr L, Harmat V, Dobó J, et al. C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease. J Biol Chem 2007; 282:21100.
- Kaplan AP, Joseph K. The bradykinin-forming cascade and its role in hereditary angioedema. Ann Allergy Asthma Immunol 2010; 104:193.
- Morgan BP. Hereditary angioedema--therapies old and new. N Engl J Med 2010; 363:581.
- Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet 2012; 379:474.
- Agostoni A, Aygören-Pürsün E, Binkley KE, 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; 114:S51.
- Bracho FA. Hereditary angioedema. Curr Opin Hematol 2005; 12:493.
- Cugno M, Cicardi M, Coppola R, Agostoni A. Activation of factor XII and cleavage of high molecular weight kininogen during acute attacks in hereditary and acquired C1-inhibitor deficiencies. Immunopharmacology 1996; 33:361.
- Cugno M, Zanichelli A, Foieni F, et al. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med 2009; 15:69.
- Joseph K, Tholanikunnel BG, Kaplan AP. Factor XII-independent cleavage of high-molecular-weight kininogen by prekallikrein and inhibition by C1 inhibitor. J Allergy Clin Immunol 2009; 124:143.
- Joseph K, Tholanikunnel BG, Kaplan AP. Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. Proc Natl Acad Sci U S A 2002; 99:896.
- Joseph K, Tholanikunnel BG, Kaplan AP. Activation of the bradykinin-forming cascade on endothelial cells: a role for heat shock protein 90. Int Immunopharmacol 2002; 2:1851.
- Han ED, MacFarlane RC, Mulligan AN, et al. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 2002; 109:1057.
- Cicardi M, Aberer W, Banerji A, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy 2014; 69:602.
- LANDERMAN NS, WEBSTER ME, BECKER EL, RATCLIFFE HE. Hereditary angioneurotic edema. II. Deficiency of inhibitor for serum globulin permeability factor and/or plasma kallikrein. J Allergy 1962; 33:330.
- ROSEN FS, PENSKY J, DONALDSON V, CHARACHE P. HEREDITARY ANGIONEUROTIC EDEMA: TWO GENETIC VARIANTS. Science 1965; 148:957.
- Tosi M. Molecular genetics of C1 inhibitor. Immunobiology 1998; 199:358.
- Prada AE, Zahedi K, Davis AE 3rd. Regulation of C1 inhibitor synthesis. Immunobiology 1998; 199:377.
- Pappalardo E, Cicardi M, Duponchel C, et al. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema. J Allergy Clin Immunol 2000; 106:1147.
- Blanch A, Roche O, Urrutia I, et al. First case of homozygous C1 inhibitor deficiency. J Allergy Clin Immunol 2006; 118:1330.
- López-Lera A, Favier B, de la Cruz RM, et al. A new case of homozygous C1-inhibitor deficiency suggests a role for Arg378 in the control of kinin pathway activation. J Allergy Clin Immunol 2010; 126:1307.
- Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 1992; 71:206.
- Roche O, Blanch A, Caballero T, et al. Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol 2005; 94:498.
- Bissler JJ, Cicardi M, Donaldson VH, et al. A cluster of mutations within a short triplet repeat in the C1 inhibitor gene. Proc Natl Acad Sci U S A 1994; 91:9622.
- Cicardi M, Agostoni A. Hereditary angioedema. N Engl J Med 1996; 334:1666.
- Bowen B, Hawk JJ, Sibunka S, et al. A review of the reported defects in the human C1 esterase inhibitor gene producing hereditary angioedema including four new mutations. Clin Immunol 2001; 98:157.
- Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005; 139:379.
- Cicardi M, Igarashi T, Rosen FS, Davis AE 3rd. Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema. J Clin Invest 1987; 79:698.
- Davis AE 3rd, Aulak K, Parad RB, et al. C1 inhibitor hinge region mutations produce dysfunction by different mechanisms. Nat Genet 1992; 1:354.
- Kalmár L, Hegedüs T, Farkas H, et al. HAEdb: a novel interactive, locus-specific mutation database for the C1 inhibitor gene. Hum Mutat 2005; 25:1.
- Bork K, Gül D, Hardt J, Dewald G. Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course. Am J Med 2007; 120:987.
- Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006; 343:1286.
- Cichon S, Martin L, Hennies HC, et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet 2006; 79:1098.
- Bouillet L, Ponard D, Rousset H, et al. A case of hereditary angio-oedema type III presenting with C1-inhibitor cleavage and a missense mutation in the F12 gene. Br J Dermatol 2007; 156:1063.
- Björkqvist J, de Maat S, Lewandrowski U, et al. Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. J Clin Invest 2015; 125:3132.
- de Maat S, Björkqvist J, Suffritti C, et al. Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations. J Allergy Clin Immunol 2016.
- Bork K, Wulff K, Witzke G, Hardt J. Hereditary angioedema with normal C1-INH with versus without specific F12 gene mutations. Allergy 2015; 70:1004.
- Duan QL, Binkley K, Rouleau GA. Genetic analysis of Factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema. J Allergy Clin Immunol 2009; 123:906.
- Zuraw BL, Bork K, Binkley KE, et al. Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel. Allergy Asthma Proc 2012; 33 Suppl 1:S145.
- Wagenaar-Bos IG, Drouet C, Aygören-Pursun E, et al. Functional C1-inhibitor diagnostics in hereditary angioedema: assay evaluation and recommendations. J Immunol Methods 2008; 338:14.
- Karim Y, Griffiths H, Deacock S. Normal complement C4 values do not exclude hereditary angioedema. J Clin Pathol 2004; 57:213.
- Gompels MM, Lock RJ, Morgan JE, et al. A multicentre evaluation of the diagnostic efficiency of serological investigations for C1 inhibitor deficiency. J Clin Pathol 2002; 55:145.
- Tarzi MD, Hickey A, Förster T, et al. An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema. Clin Exp Immunol 2007; 149:513.
- Nielsen EW, Johansen HT, Holt J, Mollnes TE. C1 inhibitor and diagnosis of hereditary angioedema in newborns. Pediatr Res 1994; 35:184.
- Weiler CR, van Dellen RG. Genetic test indications and interpretations in patients with hereditary angioedema. Mayo Clin Proc 2006; 81:958.
- Charlesworth EN. Differential diagnosis of angioedema. Allergy Asthma Proc 2002; 23:337.
- Levenson MJ, Ingerman M, Grimes C, Anand KV. Melkersson-Rosenthal syndrome. Arch Otolaryngol 1984; 110:540.
- Functions of C1 inhibitor
- Molecular events leading to angioedema
- Subtypes and genetics
- - Hereditary angioedema with C1 inhibitor deficiency/dysfunction
- Inheritance patterns
- - Hereditary angioedema with normal C1 inhibitor
- When to suspect hereditary angioedema
- Trial of high-dose antihistamines
- Complement testing
- Algorithmic approach to evaluation
- - Low clinical suspicion
- - High clinical suspicion
- Interpretation of complement tests
- TESTING FAMILY MEMBERS
- Accuracy of testing in infants
- DIFFERENTIAL DIAGNOSIS
- Cutaneous and/or laryngeal swelling
- Low C4 levels
- SUMMARY AND RECOMMENDATIONS