Diagnosis and management of angioedema with abdominal involvement: A gastroenterology perspective

Table 1 Molecular mechanisms of angioedema[2,4,5]

Type of AE	Mediator	Mechanism
Allergic AE	Histamine (mast cells)	Allergens react with IgE antibodies on the surface of mast cells, causing degranulation and release of histamine
ACE-I-induced	Bradykinin	ACE-Is prevent the conversion of bradykinin to inactive metabolites, leading to bradykinin accumulation
NSAID-induced AE	Leukotrienes (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 1	Bradykinin	Genetic 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 2	Bradykinin	Genetic 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 INH	Bradykinin	Missense 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 AE	Bradykinin	Type 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 AE	Unknown	Unknown

AE: Adverse events; ACE-I: Angiotensin converting enzyme inhibitor; HAE: Hereditary angioedema; COX-1: Cyclooxygenase-1; NSAID: Non-steroidal anti-inflammatory drug; C1 INH: C1 esterase inhibitor.

Table 2 Distinguishing features of angioedemas[8,27,28,33]

	HAE	Inherited	AA	Idiopathic	ACE-I	NSAID	Allergic
Location	Anywhere	Anywhere	Anywhere	Especially lips and face	Especially lips, tongue, intestines	Especially face	Anywhere
Urticaria	No	No	No	Usually	Rare	Usually	Usually
Family history	Yes	Yes	No	No	No	No	No
Age of onset	6-20 yr	6-20 yr	> 40 yr	Any age	Any age	Any age	Any age
Trauma as trigger	Yes	Yes	Yes	No	No	No	No
C1q	Normal	Normal	Low (type 1)	Normal	Normal	Normal	Normal
			Low/normal (type 2)
C1 INH levels	Low (type 1)	Normal	Low (type 1)	Normal	Normal	Normal	Normal
	Normal (type 2)		Low/normal (type 2)
C1 INH function	Low (type 1)	Normal	Low	Normal	Normal	Normal	Normal
	Low (type 2)
C4	Low	Normal	Low	Normal	Normal	Normal	Normal
C3	Normal	Normal	Low/normal	Normal	Normal	Normal	Normal

HAE: Hereditary angioedema; AA: acquired angioedema; ACE-I: Angiotensin converting enzyme inhibitor; NSAID: Non-steroidal anti-inflammatory drug; C1 INH: C1 esterase inhibitor.

Table 3 Clinical studies of agents used in the treatment of hereditary angioedema

	Trial design	Primary efficacy outcome result	AE	Other safety notes
Routine prophylaxis
CINRYZE[34] C1 inhibitor (human) (1000 units every 3-4 d for 12 wk) IV	Randomized, 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 infection	Precautions: 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 route	Retrospective (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, headache	8 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 cholesterol	Warnings: 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) IV	Randomized, 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, vomiting	Treatment-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) SQ	Randomized, 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, rash	Precautions: 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) SQ	Randomized, 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, nasopharyngitis	Warnings: hypersensitivity reactions, including anaphylaxis
KALBITOR[40] Ecallantide (30 mg) SQ	Randomized, double-blind, placebo-controlled trial (n = 72)	Improved symptom response to treatment measured by Treatment Outcome Scores (36 placebo vs 63, P = 0.045)

AE: Adverse events; HAE: Hereditary angioedema; SQ: By subcutaneous route.

Table 4 Food and Drug Administration approved drugs for prophylaxis and treatment of hereditary angioedema attacks[18,34,35,37,38,40]

Drug	FDA approved indication	Usual adult dose	Range
Cinryze	Prophylaxis	1000 units IV	Every 3rd or 4th day
Danazol	Prophylaxis	200 mg/d	100 mg every 3rd day to 600 mg/d
Berinert	Acute attacks	20 units/kg body weight IV	Per attack
Icatibant	Acute attacks	30 mg SQ	Per attack
Ecallantide	Acute attacks	30 mg SQ	Per attack

FDA: Food and Drug Administration.