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1.
Hedner  TSamuelsson  OLunde  HLindholm  LAndren  LWiholm  BE Angioedema in relation to treatment with angiotensin converting enzyme inhibitors.  BMJ. 1992;304941- 946Google ScholarCrossref
2.
Bork  KBarnstedt  SKoch  PTraupe  H Hereditary angioedema with normal C1-inhibitor activity in women.  Lancet. 2000;356213- 217Google ScholarCrossref
3.
Cicardi  MAgostini  A Hereditary angioedema.  N Engl J Med. 1996;3341666- 1667Google ScholarCrossref
4.
Quincke  H Über akutes umschriebenes Hautodem.  Monatsh Prakt Dermatol. 1882;1129- 131Google Scholar
5.
Osler  W Hereditary angioneurotic oedema.  Am J Med Sci. 1888;95362- 367Google ScholarCrossref
6.
Donaldson  VHEvans  RR A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C1-esterase.  Am J Med. 1963;3537- 44Google ScholarCrossref
7.
Borum  MLHoward  DE Hereditary angioedema: complex symptoms can make diagnosis difficult.  Postgrad Med. 1998;103 (251) 255- 256Google ScholarCrossref
8.
Cunningham  DSJensen  JT Hereditary angioneurotic edema in the puerperium: a case report.  J Reprod Med. 1991;36312- 313Google Scholar
9.
Frank  MMGelfand  JAAtkinson  JP Hereditary angioedema: the clinical syndrome and its management.  Ann Intern Med. 1976;84580- 593Google ScholarCrossref
10.
Sofia  SCasali  ABolondi  L Sonographic findings in abdominal hereditary angioedema.  J Clin Ultrasound. 1999;27537- 540Google ScholarCrossref
11.
Bork  KSiedlecki  KBosch  SSchopf  RKreuz  W Asphyxiation by laryngeal edema in patients with hereditary angioedema.  Mayo Clin Proc. 2000;75349- 354Google ScholarCrossref
12.
Bork  K Hypovolemic shock caused by ascites in hereditary angioedema [in German].  Med Klin. 1998;93554Google ScholarCrossref
13.
Heymann  WR Acquired angioedema.  J Am Acad Dermatol. 1997;36611- 615Google ScholarCrossref
14.
Krause  KHRentrop  UMehregan  U Cerebral manifestations in angioneurotic edema [author's translation; in German].  J Neurol Sci. 1979;42429- 435Google ScholarCrossref
15.
Brettle  RPDunmow  REMilne  LAYap  PL Angioneurotic oedema in the elderly.  Scott Med J. 1982;27309- 311Google Scholar
16.
Thorvaldsson  SESedlack  REGleich  GJRuddy  SJ Angioneurotic edema and deficiency of C′1 esterase inhibitor in a 61-year-old woman.  Ann Intern Med. 1969;71353- 357Google ScholarCrossref
17.
Landerman  NS Hereditary angioneurotic edema.  J Allergy. 1962;33316- 329Google ScholarCrossref
18.
Ogston  DWalker  JCampbell  DM C1 inactivator level in pregnancy.  Thromb Res. 1981;23453- 455Google ScholarCrossref
19.
Cohen  AJLaskin  CTarlo  S C1 esterase inhibitor in pregnancy.  J Allergy Clin Immunol. 1992;90412- 413Google ScholarCrossref
20.
Nielsen  EWGran  JTStraume  BMellbye  OJJohansen  HTMollnes  TE Hereditary angio-oedema: new clinical observations and autoimmune screening, complement and kallikrein-kinin analyses.  J Intern Med. 1996;239119- 130Google ScholarCrossref
21.
Halbmayer  WMHopmeier  PMannhalter  C  et al.  C1-esterase inhibitor in uncomplicated pregnancy and mild and moderate preeclampsia.  Thromb Haemost. 1991;65134- 138Google Scholar
22.
Davis  AE C1 inhibitor and hereditary angioneurotic edema.  Annu Rev Immunol. 1988;6595- 628Google ScholarCrossref
23.
Frank  MM Urticaria and angioedema. Goldman  LBennett  JC Cecil Textbook of Medicine. 21st ed. Philadelphia, Pa WB Saunders Co2000;1440- 1445Google Scholar
24.
Talavera  ALarraona  JLRamos  JL  et al.  Hereditary angioedema: an infrequent cause of abdominal pain with ascites.  Am J Gastroenterol. 1995;90471- 474Google Scholar
25.
Oltvai  ZNWong  ECCAtkinson  JPTung  KSK C1-inhibitor deficiency: molecular and immunological basis of hereditary and acquired angioedema.  Lab Invest. 1991;65381- 388Google Scholar
26.
Zuraw  BLLotz  M Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon gamma.  J Biol Chem. 1990;26512664- 12670Google Scholar
27.
Falus  ARokita  HWalcz  EBrozik  MHidvegi  TMeretey  K Hormonal regulation of complement biosynthesis in human cell lines, II: upregulation of the biosynthesis of complement components C3, factor B and C1 inhibitor by interleukin-6 and interleukin-1 in human hepatoma cell line.  Mol Immunol. 1990;27197- 201Google ScholarCrossref
28.
Dobo  JGal  PSzilagyi  K  et al.  One active C1r subunit is sufficient for the activity of the complement C1 complex: stabilization of C1r in the zymogen form by point mutations.  J Immunol. 1999;1621108- 1112Google Scholar
29.
Ziccardi  RJ Spontaneous activation of the first component of human complement (C1) by an intramolecular autocatalytic mechanism.  J Immunol. 1982;1282500- 2504Google Scholar
30.
Ziccardi  RJ A new role for C1-inhibitor in homeostasis: control of activation of the first component of human complement.  J Immunol. 1982;1282505- 2508Google Scholar
31.
Ziccardi  RJ The first component of human complement (C1): activation and control.  Springer Semin Immunopathol. 1983;6213- 230Google Scholar
32.
Bianchino  ACPoon  PHSchumaker  VN A mechanism for the spontaneous activation of the first component of complement, C1, and its regulation by C1 inhibitor.  J Immunol. 1988;1413930- 3936Google Scholar
33.
Colman  RWSchmaier  AH Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes.  Blood. 1997;903819- 3843Google Scholar
34.
Grunewald  T Acquired C1 esterase inhibitor deficiency [letter].  Ann Intern Med. 2000;133837Google ScholarCrossref
35.
Nussberger  JCugno  MAmstutz  CCicardi  MPellacani  AAgostoni  A Plasma bradykinin in angio-oedema.  Lancet. 1998;3511693- 1697Google ScholarCrossref
36.
Nussberger  JCugno  MCicardi  MAgostini  A Local bradykinin generation in hereditary angioedema.  J Allergy Clin Immunol. 1999;1041321- 1322Google ScholarCrossref
37.
Cugno  MCicardi  MBottaso  B  et al.  Activation of the coagulation cascade in C1-inhibitor deficiencies.  Blood. 1997;893213- 3218Google Scholar
38.
Shoemaker  LRSchurman  SJDonaldson  VHDavis  AE Hereditary angioneurotic edema: characterization of plasma kinin and vascular permeability–enhancing activities.  Clin Exp Immunol. 1994;9522- 28Google ScholarCrossref
39.
Curd  JGPrograis  LJCochrane  CG Detection of active kallikrein in induced blister fluids of hereditary angioedema patients.  J Exp Med. 1980;152742- 747Google ScholarCrossref
40.
Schapira  MSilver  LDScott  CF  et al.  Prekallikrein activation and high-molecular-weight kininogen consumption in hereditary angioedema.  N Engl J Med. 1983;3081050- 1053Google ScholarCrossref
41.
Nielsen  EWJohansen  HTGaudesen  O  et al.  C3 is activated in hereditary angioedema, and C1/C1-inhibitor complexes rise during physical stress in untreated patients.  Scand J Immunol. 1995;42679- 685Google ScholarCrossref
42.
Brickman  CMFrank  MMKaliner  M Urine-histamine levels in patients with hereditary angioedema (HAE).  J Allergy Clin Immunol. 1988;82403- 406Google ScholarCrossref
43.
Carpenter  CBRuddy  SShehadeh  IHMuller-Eberhard  HJMerrill  JPAusten  KF Complement metabolism in man: hypercatabolism of the fourth (C4) and third (C3) components in patients with renal allograft rejection and hereditary angioedema (HAE).  J Clin Invest. 1969;481495- 1505Google ScholarCrossref
44.
Donaldson  VHHess  EVMcAdams  AJ Lupus-erythematosus–like disease in three unrelated women with hereditary angioneurotic edema.  Ann Intern Med. 1977;86312- 313Google ScholarCrossref
45.
Brickman  CMTsokos  GCBalow  JE  et al.  Immunoregulatory disorders associated with hereditary angioedema, I: clinical manifestations of autoimmune disease.  J Allergy Clin Immunol. 1986;77749- 757Google ScholarCrossref
46.
Pacheco  TRWeston  WLGiclas  PC Three generations of patients with lupus erythematosus and hereditary angioedema.  Am J Med. 2000;109256- 257Google ScholarCrossref
47.
Theriault  AWhaley  KMcPhaden  ARBoyd  EConnor  JM Regional assignment of the human C1-inhibitor gene to 11q11-q13.1.  Hum Genet. 1990;84477- 479Google ScholarCrossref
48.
Carter  PEDunbar  BFothergill  JE Genomic and cDNA cloning of the human C1 inhibitor: intron-exon junctions and comparison with other serpins.  Eur J Biochem. 1988;173163- 169Google ScholarCrossref
49.
Eck  SLMorse  JHJanssen  DAEmerson  SGMarkovitz  DM Angioedema presenting as chronic gastrointestinal symptoms.  Am J Gastroenterol. 1993;88436- 439Google Scholar
50.
Agostini  ACicardi  M Hereditary and acquired C-1 inhibitor deficiency: biological and clinical characteristics in 235 patients.  Medicine (Baltimore). 1992;71206- 215Google Scholar
51.
Zuraw  BLHerschbach  BA Detection of C1 inhibitor mutations in patients with hereditary angioedema.  J Allergy Clin Immunol. 2000;105541- 546Google ScholarCrossref
52.
Aulak  KSPemberton  PARosen  FSCarrell  RWLachmann  PJHarrison  RA Dysfunctional C1-inhibitor(At), isolated from a type II hereditary angio-oedema plasma, contains a P1 "reactive centre" (Arg444 → His) mutation.  Biochem J. 1988;253615- 618Google Scholar
53.
Parad  RBKramer  JStrunk  RCRosen  FSDavis  AE Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site.  Proc Natl Acad Sci U S A. 1990;876786- 6790Google ScholarCrossref
54.
Levy  NJRamesh  NCicardi  MHarrison  PADavis  AE Type II hereditary angioneurotic edema that may result from a single nucleotide change in the codon for alanine-436 in the C1 inhibitor gene.  Proc Natl Acad Sci U S A. 1990;87265- 268Google ScholarCrossref
55.
Tosi  M Molecular genetics of C1 inhibitor.  Immunobiology. 1998;199358- 365Google ScholarCrossref
56.
Quastel  MHarrison  RCicardi  MAlper  CARosen  FS Behavior in vivo of normal and dysfunctional C1 inhibitor in normal subjects and patients with hereditary angioneurotic edema.  J Clin Invest. 1983;711041- 1046Google ScholarCrossref
57.
Melamed  JAlper  CACicardi  MRosen  FS The metabolism of C1 inhibitor and C1q in patients with acquired C1-inhibitor deficiency.  J Allergy Clin Immunol. 1986;77322- 326Google ScholarCrossref
58.
Farkas  HCsepregi  ANemesanszky  E  et al.  Acquired angioedema associated with chronic hepatitis C.  J Allergy Clin Immunol. 1999;103711- 712Google ScholarCrossref
59.
Grace  RJJacob  AMainwaring  CJMcVerry  BA Acquired C1 esterase inhibitor deficiency as manifestation of T-cell lymphoproliferative disorder [letter].  Lancet. 1990;336118Google ScholarCrossref
60.
Markovic  SNInwards  DJFrigas  EAPhyliky  RP Acquired C1 esterase deficiency.  Ann Intern Med. 2000;132144- 150Google ScholarCrossref
61.
Jackson  JSim  RBWhelan  AFeighery  C An IgG autoantibody which inactivates C1-inhibitor.  Nature. 1986;323722- 724Google ScholarCrossref
62.
Laurent  JGuinnepain  MT Angioedema associated with C1 inhibitor deficiency.  Clin Rev Allergy Immunol. 1999;17513- 523Google ScholarCrossref
63.
Csepregi  ANemesanszky  E Acquired C1 esterase inhibitor deficiency.  Ann Intern Med. 2000;133838- 839Google ScholarCrossref
64.
Chase  MPFiarman  GSScholz  FJMacDermott  RP Angioedema of the small bowel due to an angiotensin-converting enzyme inhibitor.  J Clin Gastroenterol. 2000;31254- 257Google ScholarCrossref
65.
Byrne  TJDouglas  DDLandis  MEHeppell  JP Isolated visceral angioedema: an underdiagnosed complication of ACE inhibitors?  Mayo Clin Proc. 2000;751201- 1204Google ScholarCrossref
66.
Farraye  FAPeppercorn  MASteer  MLJoffe  NRees  M Acute small-bowel mucosal edema following enalapril use [letter].  JAMA. 1988;2593131Google ScholarCrossref
67.
Mullins  RJShanahan  TMDobson  RT Visceral angioedema related to treatment with an ACE inhibitor.  Med J Aust. 1996;165319- 321Google Scholar
68.
Abdelmalek  MFDouglas  DD Lisinopril-induced isolated visceral angioedema: review of ACE-inhibitor–induced small bowel angioedema.  Dig Dis Sci. 1997;42847- 850Google ScholarCrossref
69.
Matsumura  MHaruki  KKajinami  KTakada  T Angioedema likely related to angiotensin converting enzyme inhibitors.  Intern Med. 1993;32424- 426Google ScholarCrossref
70.
Jacobs  RLHoberman  LJGoldstein  HM Angioedema of the small bowel caused by an angiotensin-converting enzyme inhibitor.  Am J Gastroenterol. 1994;89127- 128Google Scholar
71.
Guy  CCathebras  PRousset  H Suspected angioedema of abdominal viscera [letter].  Ann Intern Med. 1994;121900Google ScholarCrossref
72.
Gregory  KWDavis  RC Andioedema of the intestine.  N Engl J Med. 1996;3341641Google ScholarCrossref
73.
Skidgel  RAErdös  EG Cleavage of peptide bonds by angiotensin I converting enzyme.  Agents Actions Suppl. 1987;22289- 296Google Scholar
74.
Slater  EEMerrill  DDGuess  HA  et al.  Clinical profile of angioedema associated with angiotensin-converting enzyme inhibition.  JAMA. 1988;260967- 970Google ScholarCrossref
75.
Israili  ZHall  D Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy: a review of the literature and pathophysiology.  Ann Intern Med. 1992;117234- 242Google ScholarCrossref
76.
Inman  WHRawson  NSWilton  LVPearce  GLSpeirs  CJ Postmarketing surveillance of enalapril. I: results of prescription-event monitoring.  BMJ. 1988;297826- 829Google ScholarCrossref
77.
Jain  MArmstrong  LHall  J Predisposition to and late onset of upper airway obstruction following angiotensin converting enzyme inhibitor therapy.  Chest. 1992;102 ((3)) 871- 874Google ScholarCrossref
78.
Kaplan  AP Urticaria and angioedema. Middleton  EEllis  EFYunginger  JWReed  CEAdkinson  NFBusse  WW Allergy Principles & Practice. 5th ed. St Louis, Mo Mosby–Year Book Inc1998;1104- 1122Google Scholar
79.
Shinzato  TNakamura  HKuniyoshi  T  et al.  Hereditary angioedema: a case with ascites yet no symptoms in the family.  Intern Med. 1992;31633- 635Google ScholarCrossref
80.
Nzeako  UCFrigas  ETremaine  WJ Hereditary angioedema as a cause of transient abdominal pain: case report and literature review.  J Clin Gastroenterol. Google Scholar
81.
Nielsen  WEJohansen  HTStraume  BMollnes  TE Effect of time, temperature and additives on a functional assay of C1 inhibitor.  J Immunol Methods. 1994;173245- 251Google ScholarCrossref
82.
Hara  TShiotani  AMatsunaka  H  et al.  Hereditary angioedema with gastrointestinal involvement: endoscopic appearance.  Endoscopy. 1999;31322- 324Google ScholarCrossref
83.
Molina  CBrun  JCoulet  MBetail  GWahl  DHartmann  L Diagnostic and therapeutic problems associated with hereditary deficiency of the C1 esterase inhibitor.  Clin Allergy. 1977;7127- 135Google ScholarCrossref
84.
Waytes  ATRosen  FSFrank  MM Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate.  N Engl J Med. 1996;3341630- 1634Google ScholarCrossref
85.
Alsenz  JLambris  JDBork  KLoos  M Acquired C1 inhibitor (C1-INH) deficiency type II: replacement therapy with C1-INH and analysis of patients' C1-INH and anti-C1-INH autoantibodies.  J Clin Invest. 1989;831794- 1799Google ScholarCrossref
86.
Markovic  SNInwards  DJFrigas  EPhyliky  RP Acquired C1 esterase inhibitor deficiency.  Ann Intern Med. 2000;132144- 150Google ScholarCrossref
87.
Sheffer  ALFearon  DTAusten  KF Clinical and biochemical effects of stanozolol therapy for hereditary angioedema.  J Allergy Clin Immunol. 1981;68181- 187Google ScholarCrossref
88.
Gelfand  JASherins  RJAlling  DWFrank  MM Treatment of hereditary angioedema with danazol: reversal of clinical and biochemical abnormalities.  N Engl J Med. 1976;2951444- 1448Google ScholarCrossref
89.
Castaldo  AJ The case for oxandrolone (OxandrineTM) as an alternative for preventing attacks of hereditary angioedema (HAE). Available at: http://www.hereditaryangioedema.com/oxscott.htm. Accessed December 8, 2000
90.
Agostini  ACicardi  M Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients.  Medicine (Baltimore). 1992;71206- 215Google Scholar
91.
Cicardi  MCastelli  RZingale  LCAgostini  A Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients.  J Allergy Clin Immunol. 1997;99194- 196Google ScholarCrossref
92.
Bork  KPitton  MHarten  PKoch  P Hepatocellular adenomas in patients taking danazol for hereditary angio-oedema.  Lancet. 1999;3531066- 1067Google ScholarCrossref
93.
Crampon  DBarnoud  RDurand  M  et al.  Danazol therapy: an unusual aetiology of hepatocellular carcinoma.  J Hepatol. 1998;291035- 1036Google ScholarCrossref
94.
Cicardi  MBisiani  GCugno  MSpath  PAgostini  A Autoimmune C1 inhibitor deficiency: report of eight patients.  Am J Med. 1993;95169- 175Google ScholarCrossref
95.
Cugno  MCicardi  MAgostini  A Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid.  J Allergy Clin Immunol. 1994;93870- 876Google ScholarCrossref
96.
Nomura  HTsugawa  YKoni  I  et al.  Hereditary angioedema complicated with chronic renal failure: report of sibling cases.  Intern Med. 1992;3194- 97Google ScholarCrossref
97.
Ewald  GAEisenberg  PR Plasmin-mediated activation of contact system in response to pharmacological thrombolysis.  Circulation. 1995;9128- 36Google ScholarCrossref
98.
Lynch  MPentecost  BLLittler  WAStockley  RA Why do patients develop reactions to streptokinase?  Clin Exp Immunol. 1993;94279- 285Google ScholarCrossref
99.
Francis  CWBrenner  BLeddy  JPMarger  VJ Angioedema during therapy with recombinant tissue plasminogen activator.  Br J Haematol. 1991;77562- 563Google Scholar
100.
Rais  MUnzeitig  JGrant  JA Refractory exacerbations of hereditary angioedema with associated Helicobacter pylori infection.  J Allergy Clin Immunol. 1999;103713- 714Google ScholarCrossref
Review
November 12, 2001

Hereditary Angioedema: A Broad Review for Clinicians

Author Affiliations

From the Divisions of Gastroenterology (Drs Nzeako and Tremaine), Hepatology (Drs Nzeako and Tremaine), and Allergy (Dr Frigas), Mayo Clinic and Foundation, Rochester, Minn.

Arch Intern Med. 2001;161(20):2417-2429. doi:10.1001/archinte.161.20.2417
Abstract

Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10 000 to 1 in 150 000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named "type 3" HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain.

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