Copyright copy;2010 Baishideng Publishing Group Co.
World J Gastroenterol. Oct 21, 2010; 16(39): 4913-4921
Published online Oct 21, 2010. doi: 10.3748/wjg.v16.i39.4913
Table 1 Molecular mechanisms of angioedema[2,4,5]
Type of AEMediatorMechanism
Allergic AEHistamine (mast cells)Allergens react with IgE antibodies on the surface of mast cells, causing degranulation and release of histamine
ACE-I-inducedBradykininACE-Is prevent the conversion of bradykinin to inactive metabolites, leading to bradykinin accumulation
NSAID-induced AELeukotrienes (mast cells)Inhibition of COX-1 leads to overproduction of vasoactive substances by shunting arachidonic acid metabolism through the lipoxygenase pathway, creating leukotrienes. Vasoactive leukotrienes act on cell-surface receptors to increase vascular permeability and promote inflammation
HAE type 1BradykininGenetic mutations in the C1 INH gene result in low levels of C1 INH. Major roles of C1 INH include inactivating coagulation factors XIIa, XIIf and XIa; blocking C1 complement autoactivation; and inhibiting activated kallikrein. Removal of these inhibitory actions results in complement activation and elevated bradykinin levels
HAE type 2BradykininGenetic mutations in the C1 INH gene result in normal levels of C1 INH, but the C1 INH is dysfunctional. Plasma cascades are unregulated in the presence of dysfunctional C1 INH, leading to bradykinin accumulation as in HAE type 1
Inherited AE with normal C1 INHBradykininMissense mutation in factor XII gene confers a significant increase in the protease activity of each activated factor XII molecule, which increases bradykinin generation. Decreased activity of enzymes such as ACE and aminopeptidase P have also been noted
Acquired AEBradykininType 1: Immune complex formation associated with rheumatologic, lymphoproliferative, and neoplastic disorders continuously activate C1, causing C1 INH depletion and bradykinin accumulation
Type 2: Autoantibodies inactivate C1 INH, leading to bradykinin accumulation
Idiopathic recurrent AEUnknownUnknown
Table 2 Distinguishing features of angioedemas[8,27,28,33]
LocationAnywhereAnywhereAnywhereEspecially lips and faceEspecially lips, tongue, intestinesEspecially faceAnywhere
Family historyYesYesNoNoNoNoNo
Age of onset6-20 yr6-20 yr> 40 yrAny ageAny ageAny ageAny age
Trauma as triggerYesYesYesNoNoNoNo
C1qNormalNormalLow (type 1)NormalNormalNormalNormal
Low/normal (type 2)
C1 INH levelsLow (type 1)NormalLow (type 1)NormalNormalNormalNormal
Normal (type 2)Low/normal (type 2)
C1 INH functionLow (type 1)NormalLowNormalNormalNormalNormal
Low (type 2)
Table 3 Clinical studies of agents used in the treatment of hereditary angioedema
Trial designPrimary efficacy outcome resultAEOther safety notes
Routine prophylaxis
CINRYZE[34] C1 inhibitor (human) (1000 units every 3-4 d for 12 wk) IVRandomized, double-blind, placebo-controlled, cross-over study (n = 24)Decreased the number of attacks (mean 12.7 for placebo vs 6.1, P < 0.0001)Sinusitis, rash, headache, upper respiratory tract infectionPrecautions: hypersensitivity reactions, thrombotic events, and risk of transmission of infectious agents
DANOCRINE[35,36] Danazol (range, 40-1000 mg, mean: 171.2 mg/d) oral routeRetrospective (n = 118)Decreased the number of attacks (33.3 per year when untreated vs 9.7 per year when treated)Clinical: weight gain, menstrual irregularities, virilization in women, headache8 patients with long-term therapy had serious adverse events (i.e. myocardial infarction, stroke, deep vein thrombosis, acute pancreatitis, hepatocellular adenoma)
Laboratory: elevated liver enzymes, elevated cholesterolWarnings: use in pregnancy is contraindicated. Thrombotic events, peliosis hepatis, benign hepatic adenoma, and intracranial hypertension have been reported
Acute attacks
BERINERT[37] C1 esterase inhibitor (human) (10 or 20 units/kg body weight) IVRandomized, double-blind, placebo-controlled study (n = 124)20 mg/kg dose: reduction in time to onset of symptom relief (> 4 h for placebo vs 50 min, P = 0.0016)Headache, nausea, abdominal pain, dysgeusia, vomitingTreatment-emergent AEs: laryngeal edema, facial attack with laryngeal edema, swelling (shoulder and chest) exacerbation of HAE, and laryngospasm
Precautions: hypersensitivity reactions, thrombotic events, and risk of transmission of infectious agents
FIRAZYR[38,39] Icatibant (30 mg) SQRandomized, double-blind, comparator-group study [n = 56 (placebo comparator study)] [n = 74 (tranexamic acid comparator study)]Decreased time to onset of symptom relief (4.6 h placebo vs 2.5 h, P = 0.142; 12 h tranexamic acid vs 2 h, P < 0.001 )Injection site reactions; common events include recurrent attacks, nausea, abdominal pain, headache, asthenia, rashPrecautions: caution should be used in patients with acute ischemic heart disease or unstable angina pectoris, and in patients in the weeks following a stroke
KALBITOR[40] Ecallantide (30 mg) SQRandomized, double-blind, placebo-controlled trial (n = 96)Decreased symptom severity measured by Mean Symptom Complex Severity scores (-0.4 placebo vs -0.8, P = 0.010)Headache, nausea, diarrhea, pyrexia, injection site reactions, nasopharyngitisWarnings: hypersensitivity reactions, including anaphylaxis
KALBITOR[40] Ecallantide (30 mg) SQRandomized, double-blind, placebo-controlled trial (n = 72)Improved symptom response to treatment measured by Treatment Outcome Scores (36 placebo vs 63, P = 0.045)
Table 4 Food and Drug Administration approved drugs for prophylaxis and treatment of hereditary angioedema attacks[18,34,35,37,38,40]
DrugFDA approved indicationUsual adult doseRange
CinryzeProphylaxis1000 units IVEvery 3rd or 4th day
DanazolProphylaxis200 mg/d100 mg every 3rd day to 600 mg/d
BerinertAcute attacks20 units/kg body weight IVPer attack
IcatibantAcute attacks30 mg SQPer attack
EcallantideAcute attacks30 mg SQPer attack