Hereditary angioedema: what the gastroenterologist needs to know

Figures & data

Figure 1 Dysregulation of coagulation, complement, and contact cascades in hereditary angioedema.

Notes: C1 inhibitor controls activation in the complement, coagulation, and contact cascades, and all three cascades are dysregulated in hereditary angioedema. Replacement of C1 inhibitor restores homeostasis. Ecallantide and icatibant specifically inhibit the contact cascade but have no direct effect on the complement or coagulation cascades.²⁵ Dashed arrows indicate enzyme cleavage steps; T bars indicate points of inhibition. Reprinted from The New England Journal of Medicine, Morgan BP. Hereditary angioedema: therapies new and old. N Engl J Med. 2010;363(6):581–583. Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.²⁵
Abbreviations: HAE, hereditary angioedema; MASP-2, mannose-binding lectin-associated serine protease 2.

Figure 2 Sites affected by angioedema in patients with clinical symptoms of hereditary angioedema.

Notes: Reprinted from The American Journal of Medicine. Volume 119(3), Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course pages 267–274; Copyright © 2006, with permission from Elsevier.²

Figure 3 Phases and time course for typical abdominal pain attacks in patients with hereditary angioedema.

Notes: Reprinted by permission from Macmillan Publishers Ltd on behalf of American Journal of Gastroenterology. Copyright © 2006. Bork K, Staubach P, Eckardt AJ, Hardt J. Symptoms, course, and complications of abdominal attacks in HAE to C1 inhibitor deficiency. Am J Gastroenterol. 2006;101(3):619–627.³⁰

Table 1 Differential diagnosis of intestinal angioedema

Initial presentation	Colicky abdominal pain, nausea, and vomiting
Possible gastrointestinal disorders	• Appendicitis
	• Hepatitis
	• Pancreatitis
	• Biliary obstruction
	• Diverticulitis
Test results
Biochemical	Suggestive of HAE
	• C1-INH level of <21 mg/dL
	• Decreased C2 and C4 levels
	Rules out biliary obstruction and hepatitis
	• Normal serum bilirubin, ALP, and ALT levels
Ultrasonography	Suggestive of HAE
	• Bowel mucosal thickening
	• Ascites
Computed tomography	Suggestive of HAE
	• Massive small bowel or colonic edema
	• Prominent mesenteric vessels
	• Thickened omentum
	• Moderate ascites
	Rules out appendicitis and diverticulitis
	• Normal pericolic fat
	Rules out pancreatitis
	• Normally shaped pancreas

Notes: Data from Bork, Fischer, and Dewald;²⁶ and Bork, Staubach, and Eckardt.³⁰ Reproduced from Locascio EJ, Mahler SA, Arnold TC. Intestinal angioedema misdiagnosed as recurrent episodes of gastroenteritis. West J Emerg Med. 2010;11(4): 391–394.³²

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; C1-INH, C1 esterase inhibitor; HAE, hereditary angioedema.

Figure 4 Abdominal computed tomography scan of patient with hereditary angioedema showing thickening of the small bowel (stacked-coin appearance) due to angioedema.

Notes: Curved arrow indicates prominent fold thickening; straight arrows indicate pelvic ascites. Reprinted with permission from the American Journal of Roentgenology. De Backer AI, De Schepper AM, Vandevenne JE, Schoeters P, Michielsen P, Stevens WJ. CT of angioedema of the small bowel. Am J Roentgenol. 2001;176(3):649–652.³⁹

Figure 5 Diagnostic algorithm for hereditary angioedema.

Notes: From Bowen T, Cicardi M, Farkas H, et al. 2010 international consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010;6(1):24.⁵⁰
Abbreviations: AE, adverse event; ACE, angiotensin-converting enzyme; C1-INH, C1 esterase inhibitor; C1q, complement component 1, q subcomponent; HAE, hereditary angioedema.

Table 2 Hereditary Angioedema International Working Group consensus guidelines for the management of hereditary angioedema

Recommendations for acute treatment

1. All patients should have access to plasma-derived and recombinant C1-INH, icatibant, and ecallantide

2. Patients should keep medications at home and be trained to self-administer them

3. All attacks, regardless of their location on the body, should be treated as soon as recognized

4. Patients should report to a hospital if laryngeal symptoms persist following initial treatment

Recommendations for prophylactic treatment

1. Long-term prophylaxis is appropriate for patients in whom on-demand treatment is inadequate to control the disease

2. Androgens can be used in patients aged >16 years, and in women who are not pregnant or lactating

3. Androgens are not recommended if not tolerated by the patient or if the effective dose of danazol exceeds 200 mg/day

4. All patients can be considered for plasma-derived C1-INH

5. Treatment with plasma-derived C1-INH should be individualized to optimize clinical response

Note: Data from Cicardi et al.⁵⁴

Abbreviation: C1-INH, C1 esterase inhibitor.

Table 3 Specific agents for hereditary angioedema (HAE)

Drug (Trade name; manufacturer)	Approval for HAE	Age group	Dosage	Mechanism	Adverse events
Plasma-derived nanofiltered C1-INH (Berinert^® P; CSL Behring, Kankakee, IL, USA)^Citation54,Citation58,Citation59	In USA for acute facial, laryngeal, and abdominal attacks In Europe for all acute attacks and preprocedure prophylaxis	Adolescents and adults	20 U/kg IV	Inhibition of plasma kallikrein, coagulation factors XIIa, and XIa, C1s, C1r, MASP-1, MASP-2, and plasmin	Rare: risk of anaphylaxis Theoretical: transmission of infectious agent
Plasma-derived nanofiltered C1-INH (Cinryze^®; ViroPharma Biologics, Exton, PA, USA)^Citation38,Citation54,Citation60	In USA for routine prophylaxis In Europe for all acute attacks and short-term and long-term prophylaxis	Adolescents and adults	1000 U IV every 3–4 days	Inhibition of plasma kallikrein, coagulation factors XIIa, and XIa, C1s, C1r, MASP-1, MASP-2, and plasmin	Rare: risk of anaphylaxis Theoretical: transmission of infectious agent
Recombinant human C1-INH (Ruconest^®; Pharming Group NV, Leiden, the Netherlands)^Citation38,Citation62^–^Citation64	In Europe for acute attacks In USA, not yet approved, orphan drug, fast track status for acute attacks	NR	50–100 U/kg IV	Inhibition of plasma kallikrein, coagulation factors XIIa, and XIa, C1s, C1r, MASP-1, MASP-2, and plasmin	Uncommon: risk of anaphylaxis in rabbit-sensitized patients
Recombinant protein, ecallantide (Kalbitor; Dyax Corp, Burlington, MA, USA)^Citation66,Citation67	In USA for acute attacks	≥16 years	30 mg SC (3 injections of 10 mg each)	Inhibition of plasma kallikrein	Uncommon: risk of anaphylaxis; antidrug antibodies
Bradykinin B2 receptor antagonist, icatibant (Firazyr^®; Shire Orphan Therapies, Inc, Lexington, MA, USA)^Citation68^–^Citation70	In USA and Europe for acute attacks	≥18 years	30 mg SC	Inhibition of bradykinin	Common: injection site reactions

Notes: Data from Cicardi et al;⁵⁴ Epstein and Bernstein;⁵⁸ Berinert [C1 esterase inhibitor (human)] package insert;⁵⁹ Varga and Farkas;⁶² Ruconest (Rhucin in non-European territories). Recombinant human C1 esterase inhibitor;⁶³ Santarus Biologics License Application;⁶⁴ Kalbitor (ecallantide) package insert;⁶⁶ Levy et al;⁶⁷ Dubois and Cohen;⁶⁸ Firazyr (icatibant) package insert,⁶⁹ and Schmidt, Hirschl, Trautinger.⁷⁰ From The New England Journal of Medicine, Zuraw BL, Hereditary Angioedema, Volume 359, pp 1027–1036. Copyright © 2008 Massachusetts Medical Society. Adapted with permission from Massachusetts Medical Society.³⁸

Abbreviations: C1-INH, C1 esterase inhibitor; C1r, complement component 1, r subcomponent; C1s, complement component 1, s subcomponent; IV, intravenous; MASP, mannose-binding lectin serine protease; NR, not reported; SC, subcutaneous.

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