CLINICAL REVIEW
Gastrointestinal Manifestations, Diagnosis, and Management of Hereditary Angioedema Sujai Jalaj, MD and James S. Scolapio, MD
Abstract: Abdominal pain is one of the most common conditions in clinical practice and yet a challenging complaint to accurately diagnose due to the vast number of possible etiologies. When other health care providers cannot identify the cause of abdominal pain, gastroenterologists are often looked upon to help solve the diagnostic dilemma. Consequently, it is incumbent upon gastroenterologists to be well versed in the diagnosis and management of not only common but also rare causes of abdominal pain. One such uncommon but well-described cause of abdominal pain is angioedema of the intestinal tract due to hereditary angioedema. Acute onset, recurrent abdominal pain of varying severity is its most common presenting symptom, and misdiagnosis can not only lead to unnecessary surgical procedures but also death. The purpose of this review is to raise awareness among gastroenterologists about hereditary angioedema as a potential cause of recurrent, unexplained abdominal pain. Key Words: intestinal angioedema, hereditary angioedema, C1 esterase inhibitor concentrates, kallikrein inhibitors, bradykinin-2 receptor antagonists, androgens
(J Clin Gastroenterol 2013;47:817–823)
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32-year-old lady presented to the ER with nonbloody and nonbilious emesis and colicky, right lower quadrant abdominal pain. She had a documented history of irritable bowel syndrome in her medical records. She was afebrile and physical examination was notable for hypoactive bowel sounds and generalized abdominal tenderness with rebound. Labs including complete blood cell count with differential, comprehensive metabolic panel, amylase, and lipase were all within normal limits. Computed tomography (CT) scan of the abdomen and pelvis revealed diffuse bowel wall edema of the small intestine and right colon with what appeared to be an inflamed appendix. Given the presumed diagnosis of acute appendicitis, patient underwent an appendectomy. At the time of the appendectomy, the surgeon was concerned about Crohn’s disease due to significant bowel edema in terminal ileum and cecum. In addition to appendectomy, resection of the terminal ileum and cecum was also performed. Patient was seen in GI clinic 6 weeks postoperatively. Pathology was reviewed and consistent with bowel wall edema only with no evidence of Crohn’s disease or acute appendicitis. On further questioning, patient admitted to recurrent episodes of similar crampy abdominal pain
From the Department of Medicine, Division of Gastroenterology, University of Florida, Jacksonville, FL. The authors declare that they have nothing to disclose. Reprints: James S. Scolapio, MD, Department of Medicine, Division of Gastroenterology, University of Florida, 4555 Emerson Street, Suite 300, Jacksonville, FL 32207 (e-mail: james.scolapio@ jax.ufl.edu. Copyright r 2013 by Lippincott Williams & Wilkins
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associated with emesis and occasionally diarrhea with negative workup in past including normal EGD and colonoscopy. She denied taking any medications other than fiber supplements. Patient’s mother had similar bouts of abdominal pain attacks and had also been diagnosed with irritable bowel syndrome. Given patient’s personal and family history, a C1-esterase level and functional activity were checked. Both C1-esterase inhibitor (C1 INH) level and C1 INH functional activity were low. Given the probable diagnosis of hereditary angioedema (HAE), the patient was referred to an allergy and immunology specialist where a diagnosis of HAE was confirmed.
GASTROINTESTINAL CLINICAL MANIFESTATIONS OF HAE Symptomatic involvement of the gastrointestinal tract is an important clinical feature of HAE, as it is more distressing than the edema of the skin, and it occurs far more frequently than life-threatening laryngeal edema. Involvement of the gastrointestinal tract with resultant abdominal pain occurs in 43% to 93% of patients with HAE, and up to 80% of all patients have recurrent abdominal pain, whereas about 50% will have a potentially life-threatening laryngeal attack.1–3 Such abdominal pain symptoms may occur for many years without concomitant cutaneous or respiratory symptoms.4 Abdominal pain may manifest as severe acute onset abdominal pain, or as chronic recurrent abdominal pain of varying severity. The abdominal pain is often described as cramping or colicky and is rated as severe to excruciating in 87% of patients.5 Vomiting and diarrhea occur in 78% and 65%, respectively, of patients with abdominal symptoms.5 These symptoms of abdominal pain, vomiting, and diarrhea are caused by transient edema of small bowel wall leading to partial or complete intestinal obstruction. Although abdominal pain is the most common gastrointestinal manifestation of an attack, HAE can involve the entire GI tract leading to a bevy of other gastrointestinal symptoms during an acute attack (Table 1). Involvement of the oropharynx, and possibly of the esophagus, can cause dysphagia.3 The jejunum, ileum, duodenum, stomach, and colon are affected in descending frequency.6,7 Colonic involvement can lead to constipation, TABLE 1. Hereditary Angioedema Sites of Gastrointestinal Involvement and Their Clinical Manifestations
Site Oropharynx Small intestine Colon Liver Pancreas
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Clinical Manifestation Dysphagia Abdominal pain, ascites, vomiting, diarrhea Constipation Ascites Pancreatitis
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TABLE 2. Common Triggers of HAE Infection Trauma Emotional stress Medications (ie, ACE-I, estrogens) Menstruation Invasive procedures (ie, endoscopy, surgery, dental procedures) ACE-I indicates angiotensin-converting enzymes inhibitors; HAE, hereditary angioedema.
with occasional reports of colonic intussusception.8,9 Involvement of the liver has been reported, as suggested by elevated transaminase levels and reversible parenchymal changes on ultrasonography during acute attacks.10,11 A recent case report by Cutler and colleagues describes a case of recurrent pancreatitis in association with clinical attacks of HAE. Cutler et al12 have speculated that pancreatic edema leads to partial ductal obstruction, resulting in pancreatitis. Lastly, ascites frequently occurs in conjunction with small bowel mucosal edema in patients with HAE.13 If aspirated, the ascites is exudative.10,14 If an attack is severe enough, hypovolemic shock may rarely occur in the setting of extensive ascites and bowel wall edema.15 Attacks of angioedema typically occur due to an inciting event. A myriad of triggers have been indentified including fasting, infection, trauma, emotional stress, medical procedures (surgery or other invasive instrumentations), menstruation, exposure to estrogens, and certain medications (Table 2).16 The 1 class of medication classically associated with an increased risk of angioedema attacks includes angiotensin-converting enzymes (ACE) inhibitors. ACE inhibitors do not directly precipitate attacks, but act by increasing baseline concentrations of bradykinin, thereby reducing the threshold of an attack.17 Attacks are frequently accompanied by a prodromal phase. In the case of gastrointestinal manifestations, nonspecific complaints of fatigue, irritability, aggressiveness, or hunger may precede an attack.5 In the absence of treatment, attacks typically resolve over 2 to 5 days.
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Physical examination can be helpful but only during an acute attack. Particular attention should be focused on the skin examination. Skin should be inspected for external signs of cutaneous angioedema, which in HAE typically manifests as nonpitting edema in nondependent areas of the body without pruritus and urticaria.19 Thorough oropharyngeal examination is also important as tongue, lip, or intraoral swelling can be seen during an attack. With respect to the pulmonary examination, special attention should be paid to signs of respiratory distress, especially stridor. For episodes with acute abdominal involvement, the abdominal examination findings are very nonspecific. Palpation of the abdomen may reveal diffuse abdominal tenderness with or without rebound.18 Bowel sounds may be hypoactive or hyperactive.1 If an attack is severe enough, shifting dullness may be present signifying presence of ascites. Much like the physical examination, radiologic tests may be helpful but are not definitive in clinching a diagnosis of HAE. In severe cases of intestinal angioedema, plain abdominal radiographs may show dilated loops of bowel along with “thumbprinting,” which describes an area of mucosal edema (Fig. 1). Abdominal ultrasound may detect ascites and edematous viscera.11 The most sensitive diagnostic imaging study is a contrast-enhanced CT scan of the abdomen. CT is more useful for identifying milder degrees of intestinal edema, dilated loops of small or large bowel, and ascites than ultrasound and plain radiographs (Fig. 2).4 It is also useful in excluding other causes of acute abdominal pain such as mesenteric ischemia, appendicitis, or cholecystitis. Findings of intestinal edema with ascites
DIAGNOSIS Diagnosis of HAE requires a high index of clinical suspicion. When HAE attacks occur exclusively in the gastrointestinal tract without any swelling of visible body parts, the evaluating clinician might not consider HAE in the differential diagnosis of the patient’s abdominal pain resulting in missed or delayed diagnosis. In some instances, misdiagnosis of a severe abdominal pain attack may lead to inappropriate surgical interventions. One series of 235 patients with HAE has found up to a third of these patients had undergone exploratory laparotomies, appendectomies, or both, during their abdominal attacks.1 A detailed history is paramount. History should be obtained documenting the following: time of onset of current attack; whether there have been prior attacks; age at first attack; approximate intervals between attacks; presence or absence of triggering events or medications; a complete listing of all prescription and nonprescription drugs and supplements; presence of skin swelling during attacks; history of respiratory distress during attacks; and whether there is a history of similar attacks among family members.18
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FIGURE 1. Scout film revealing thumbprinting (arrow) of the colon. Reprinted with permission from Koruth et al.20 Copyright Elsevier, Philadelphia, PA. All permission requests for this image should be made to the copyright holder. r
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FIGURE 2. A, A noncontrast coronal image obtained at presentation shows isolated marked thickening of a small bowel segment in the left lower quadrant (arrows). B, A CT coronal view with contrast was performed 24 hours later, and it indicated resolution (arrows). C, Like the coronal image, an axial view taken upon presentation indicated thickening in the small bowel (arrows). D, An axial image with contrast acquired 24 hours later, also showed that edema had cleared (arrows). Reprinted with permission from Baines et al.21 Copyright Elsevier, Philadelphia, PA. All permission requests for this image should be made to the copyright holder.
are only seen during acute attacks. If imaging is delayed until after recovery, then radiologic imaging will only show normal results. An important point to remember is subtle or mild intestinal edema of any cause may be overlooked by interpreting radiologists even in symptomatic patients.18 Consequently, worsening pain severity after an earlier negative scan should not necessarily preclude consideration of HAE diagnosis or a repeat imaging study.18 In addition to a detailed history, physical examination and radiographic studies, laboratory tests are necessary to confirm a diagnosis of angioedema. If HAE is suspected, 4 laboratory tests should be obtained: C1 INH level, C1 INH activity, serum C4 level, and serum C1q, which is a byproduct r
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of C1 INH degradation.17,22,23 Low C4 is always present in HAE. In addition to low C4, a low C1 INH level and activity along with a normal C1q level is consistent with type I HAE. A normal C1 INH level with low functional activity and a normal C1q are consistent with type II HAE (Table 3). Endoscopy is not recommended for patients suspected to have HAE due to risk of inducing a potentially lifethreatening oropharyngeal or laryngeal attack. If endoscopy must be used for compelling clinical reasons, prophylactic measures to protect against the possibility of laryngeal swelling should be undertaken (see the “Prophylaxis” section). Nevertheless, endoscopic descriptions of HAE have been reported incidentally during www.jcge.com |
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TABLE 3. Laboratory Diagnostic Criteria of HAE
Type I HAE Type II HAE
C1 INH Quantitative Level
C1 INH Activity Level
C4
C1q
Low Normal
Low Low
Low Low
Normal Normal
C1 INH indicates C1-esterase inhibitor; HAE, hereditary angioedema.
undiagnosed HAE attacks (Fig. 3). Diffuse mucosal edema and erythema, and bulging areas of gastric mucosa (resembling a submucosal tumor), have been reported on upper GI endoscopy during acute abdominal attacks.24 Meanwhile, edematous colonic mucosa without gross signs of inflammation and normal histology on random colonic biopsies have been reported on colonoscopy during an acute attack of undiagnosed HAE.20
DEFINITION AND PATHOPHYSIOLOGY OF HAE Angioedema is a noninflammatory condition that is characterized by intermittent attacks of localized, nonpitting swelling of a body part. From a pathophysiological standpoint, it is important to remember that there are 2 broad categories of angioedema that must be distinguished: mast cell-mediated angioedema and bradykinin-mediated angioedema. Mast cell-mediated angioedema occurs as a result of allergic reactions to food or insect bites. The resultant symptoms include urticaria, flushing, bronchospasms, generalized pruritus, and/or anaphylaxis. In stark contrast to mast cell mediated, bradykinin-mediated angioedema is NOT associated with flushing, urticaria, bronchospasms, or pruritus.
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Bradykinin-mediated angioedema is mainly characterized by temporary swelling that can affect all layers of the skin or of the walls of hollow viscera such as the oropharynx, respiratory system, or gastrointestinal tract. Peripheral nonpitting edema of non–gravity-dependent areas of the body is typical of cutaneous manifestations.19 There are several causes of bradykinin-mediated intestinal angioedema. The most common causes include acquired angioedema due to acquired C1 INH deficiency, druginduced angioedema (most commonly ACE inhibitors), inherited angioedema with normal C1 INH, and HAE.18 HAE is a genetic disorder that results from mutations in the C1 INH gene on chromosome 11.22 These mutations are inherited in an autosomal dominant fashion in about 75% of cases, and approximately 25% result from spontaneous de novo mutations.25 “Classic” HAE is classified into 2 distinct types. Type I HAE is defined by subnormal levels of C1 INH along with subnormal functional enzymatic activity. Type II HAE is characterized by production of normal quantities of C1 INH but subnormal enzymatic function. A third type of HAE (type III) has been described but is not associated with a C1 INH deficiency and therefore, will not be discussed in this review. Type I HAE accounts for 85% of classic HAE cases.18 C1 INH plays an important role in complement, contact, and fibrinolytic pathways. One of the primary roles of C1 INH is to prevent activation of the classic complement and contact/bradykinin-generating systems. More specifically, within the contact/bradykinin-generating system, C1 INH regulates coagulation factor XII (Hageman factor) and kallikrein, which controls production of bradykinin—the main mediator of angioedema in HAE (Fig. 4).23 Consequently, the final result of subnormal levels of C1 INH and low functional activity that occurs in both types of HAE leads to massive bradykinin production, which causes symptomatic attacks of HAE.23 By binding to bradykinin-2 (B2) receptors which are constitutively expressed on many cells, bradykinin causes edema, ascites, and swelling through increased vascular permeability; congestion, hypotension, and erythema due to vasodilation; and cramps, spasms, and pain due to contraction of nonvascular smooth muscle.16
EPIDEMIOLOGY Surveys of patients suggest that HAE affects about 1 in 50,000 to 100,000 of any ethnic group, with many of those unaware of their diagnosis.26,27 Although HAE is a lifelong condition, attacks of angioedema rarely occur before the age of 2 years and are less frequent before adolescence.28 Incidence of symptoms varies from more than once per week to 5 days per month.29 In the United States, only 2 agents have been FDA approved for both short-term and long-term prophylaxis: oral attenuated androgens (mainly, danazol) and Cinryze, which is a nanofiltered C1 INH concentrate.25 Antifibrinolytics (eg, tranexamic acid) have also been shown to be effective and is still used in Europe but because of its prothrombotic side effects, it is no longer preferred therapy in the United States.34 Table 4 summarizes the FDA-approved drugs for acute treatment and prophylaxis of HAE. Attenuated androgen is the preferred therapy for longterm prophylaxis in nonpregnant adult patients because it is
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well tolerated and has very minimal reported breakthrough attacks. Unlike estrogen, androgens have been shown to increase the serum levels of C1 INH, thereby reducing the likelihood of HAE attacks.48,49 Danazol is the most commonly used agent mainly because availability of other attenuated androgens in the United States is variable. When used for preprocedure prophylaxis, androgen therapy should start 5 days before and 2 days after the procedure.34 Historically, side effects are common and relate mainly to androgenic properties of the drug, which is why these agents are not recommended for prepubescent children and pregnant women. Because of the myriad of potential side effects, consensus guidelines recommend regular liver function, cholesterol, and blood pressure monitoring, and biannual liver ultrasound to exclude hepatic adenoma, for patients who need these drugs long term.29 When used for long-term prophylaxis, dosage should be titrated to the lowest possible dose that provides reasonable freedom from symptoms.29 Cinryze, a C1 INH concentrate, is an alternative agent for long-term prophylaxis. Biweekly administration of Cinryze (every 3 to 4 d) has been shown to reduce angioedema attack rate, attack severity, and time to symptom resolution.29,38 Because of its high cost and occurrence of swellings reported in 2 of the 22 patients treated with Cinryze in phase III trials, Cinryze is considered an alternative agent for long-term prophylaxis.31,38 It is approved for patient selfadministration and is mainly useful for prepubescent children and pregnant women as androgens are contraindicated in these groups of patients. When used for preprocedure prophylaxis, consensus guidelines recommend Cinryze administration 1 hour before procedure.29 Some experts recommend a second dose postprocedurally.34 Side-effect profile is similar to its C1 INH concentrate counterpart, Berinert.
CONCLUSIONS Symptomatic involvement of the gastrointestinal tract is an important clinical feature of HAE. When confronted with cases of unexplained abdominal pain, whether acute or recurrent, it is imperative that gastroenterologists add HAE to their list of potential etiologies. With several effective drugs available for acute and prophylactic treatment of HAE, prompt diagnosis is extremely crucial to prevent years of needless suffering, unnecessary surgical procedures, and life-threatening complications from laryngeal edema or hypovolemic shock. Lastly, it is important to remember that once HAE is diagnosed, a multidisciplinary approach to management is required. As HAE is an autosomal dominant inherited condition, referral to a geneticist should be made for testing of all first-degree relatives. A specialist in allergy and immunology should also be engaged to provide patients with long-term management. REFERENCES 1. Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore). 1992;71:206–215. 2. Winnewisser J, Rossi M, Spath P, et al. Type I hereditary angio-oedema. Variability of clinical presentation and course within two large kindreds. J Intern Med. 1997;241:39–46. 3. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med. 1976;84:580–593. r
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4. De Backer AI, De Schepper AM, Vandevenne JE, et al. CT of angioedema of the small bowel. AJR Am J Roentgenol. 2001; 176:649–652. 5. Bork K, Staubach P, Eckardt AJ, et al. Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol. 2006; 101:619–627. 6. Weinstock BL, Kothari T, Sharma NR, et al. Recurrent abdominal pain as the sole manifestation of hereditary angioedema in multiple family members. Gastroenterol. 1987;93:1116–1118. 7. Eck SL, Morse JH, Janssen DA, et al. Angioedema presenting as chronic gastrointestinal symptoms. Am J Gastroenterol. 1993;88:436–439. 8. Johnson HT Jr, Caldwell WK. Angioneurotic edema of the colon. Radiology. 1971;99:61–63. 9. Witschi A, Krahenbuhl L, Frei E, et al. Colorectal intussuception: an unusual gastrointestinal complication of hereditary angioedema. Int Arch Allergy Immunol. 1996;111:96–98. 10. Branco-Ferreira M, Pedro E, Barbosa MA, et al. Ascites in hereditary angioedema. Allergy. 1998;53:543–545. 11. Farkas H, Harmat G, Fekete B, et al. Acute abdominal attack of hereditary angioedema associated with ultrasound abnormalities suggestive of acute hepatitis. Acta Paediatr. 2002;91:971–974. 12. Cutler AF, Yousif EA, Blumenkehl ML. Hereditary angioedema associated with pancreatitis. South Med J. 1992;85:1149–1150. 13. Farkas H, Harmat G, Kaposi PN, et al. Ultrasonography in the diagnosis and monitoring of ascites in acute abdominal attacks of hereditary angioneurotic oedema. Eur J Gastroenterol Hepatol. 2001;13:1225–1230. 14. Talavera A, Larraona JL, Ramos JI, et al. Hereditary angioedema: an infrequent cause of abdominal pain with ascites. Am J Gastroenterol. 1995;90:471–474. 15. Cohen N, Sharon A, Golik A, et al. Hereditary angioneurotic edema with severe hypovolemic shock. J Clin Gastroenterol. 1993;16:237–239. 16. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161:2417–2429. 17. Cugno M, Nussberger J, Cicardi M, et al. Bradykinin and the pathophysiology of angio-oedema. Int Immunopharmacol. 2003;3:311–317. 18. Nzeako UC, Longhurst HJ. Many faces of angioedema: focus on the diagnosis and the management of abdominal manifestations of hereditary angioedema. Eur J Gastroenterol Hepatol. 2012;24:353–361. 19. Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol. 2005;53:373–388. 20. Koruth JS, Eckardt AJ, Levey JM. Hereditary angioedema involving the colon: endoscopic appearance and review of GI manifestations. Gastrointest Endoscopy. 2005;61:907–911. 21. Baines SN, Baines SS, Anis M, et al. Rude Awakening: Acute Abdominal Pain with Spontaneous Resolution. American Journal of Medicine. 2012;125:971–973. 22. Bowen T, Cicardi M, Bork K, et al. Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008;100:S30–S40. 23. Cugno M, Zanichelli A, Foieni F, et al. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009;15:69–78. 24. Hara T, Shiotani A, Matsunaka H, et al. Hereditary angioedema with gastrointestinal involvement: endoscopic appearance. Endoscopy. 1999;31:322–324. 25. Nzeako UC. Diagnosis and management of angioedema with abdominal involvement: a gastroenterology perspective. World J Gastroenterol. 2010;16:4913–4921. 26. Bygum A. Hereditary angio-oedema in Denmark: a nationwide survey. Br J Dermatol. 2009;161:1153–1158. 27. Roche O, Blanch A, Caballero T, et al. Hereditary angiooedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol. 2005;94:498–503. r
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28. Longhurst HJ, Cicardi M. Hereditary angio-oedema. Lancet. 2012;379:474–481. 29. Cicardi M, Bork K, Caballero T, et al. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012;67:147–157. 30. Bork K, Meng G, Staubach P, et al. Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angio-oedema. Transfusion. 2005;45:1774–1784. 31. US Food and Drug Administration. Summary basis for regulatory action—Cinryze. October 9, 2008. http://www.fda. gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ ApprovedProducts/LicensedProductsBLAs/FractionatedPlasma Products/UCM129918.pdf. Accessed on August 8, 2012. 32. Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patient with hereditary angio-oedema. Arch Int Med. 2001;161:714–718. 33. Bork K, Frank J, Grundt B, et al. Treatment of acute edema attacks in hereditary angio-oedema with a bradykinin receptor2-antagonist (icatibant). J Allergy Clin Immunol. 2007;119: 1497–1503. 34. 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;6:24. 35. Caballero T, Baeza ML, Cabanas R, et al. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part II. Treatment, follow-up, and special situations. J Investig Allergol Clin Immunol. 2011;21:422–441. 36. Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. 2009;124:823–829. 37. Craig TJ, Bewtra AK, Bahna SL, et al. C1 esterase inhibitor concentrate in 1085 hereditary angioedema attacks—final results of the I.M.P.A.C.T.2 study. Allergy. 2011;66:1604–1611. 38. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Eng J Med. 2010;363:513–522. 39. CSL Behring GmbH. Berinert (C1 Esterase Inhibitor [Human]) [package insert]. Marburg, Germany: CSL Behring GmbH; 2009. 40. Kaplan AP. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy. J Allergy Clin Immunol. 2010;126:918–925. 41. Longhurst HJ. Management of acute attacks of hereditary angioedema: potential role of icatibant. Vasc Health Risk Manag. 2010;6:795–802. 42. Deeks ED. Icatibant. Drugs. 2010;70:73–81. 43. Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010;363:523–531. 44. Levy RJ, Lumry WR, McNeil DL, et al. EDEMA4: a phase 3, double blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol. 2010;104:523–529. 45. Dyax Corp. Kalbitor (Ecallantide) [package insert]. Cambridge, MA: Dyax Corp; 2009. 46. Kreuz W, Fischer D, Martinez-Saguer I, et al. C1-esterase inhibitor substitution in hereditary angioedema. Biomed Prog. 1999;12:1–7. 47. Pekdemir M, Ersel M, Aksay E, et al. Effective treatment of hereditary angioedema with fresh frozen plasma in an emergency department. J Emerg Med. 2007;33:137–139. 48. Gelfand JA, Sherins RJ, Alling DW, et al. Treatment of hereditary angioedema with danazol: reversal of clinical and biochemical abnormalities. N Engl J Med. 1976;295:1444–1448. 49. Sheffer AL, Fearon DT, Austen KF. Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J Allergy Clin Immunol. 1981;68:181–187.
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Gastrointestinal Manifestations, Diagnosis, and Management of Hereditary Angioedema Sujai Jalaj, MD and James S. Scolapio, MD
Abstract: Abdominal pain is one of the most common conditions in clinical practice and yet a challenging complaint to accurately diagnose due to the vast number of possible etiologies. When other health care providers cannot identify the cause of abdominal pain, gastroenterologists are often looked upon to help solve the diagnostic dilemma. Consequently, it is incumbent upon gastroenterologists to be well versed in the diagnosis and management of not only common but also rare causes of abdominal pain. One such uncommon but well-described cause of abdominal pain is angioedema of the intestinal tract due to hereditary angioedema. Acute onset, recurrent abdominal pain of varying severity is its most common presenting symptom, and misdiagnosis can not only lead to unnecessary surgical procedures but also death. The purpose of this review is to raise awareness among gastroenterologists about hereditary angioedema as a potential cause of recurrent, unexplained abdominal pain. Key Words: intestinal angioedema, hereditary angioedema, C1 esterase inhibitor concentrates, kallikrein inhibitors, bradykinin-2 receptor antagonists, androgens
(J Clin Gastroenterol 2013;47:817–823)
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32-year-old lady presented to the ER with nonbloody and nonbilious emesis and colicky, right lower quadrant abdominal pain. She had a documented history of irritable bowel syndrome in her medical records. She was afebrile and physical examination was notable for hypoactive bowel sounds and generalized abdominal tenderness with rebound. Labs including complete blood cell count with differential, comprehensive metabolic panel, amylase, and lipase were all within normal limits. Computed tomography (CT) scan of the abdomen and pelvis revealed diffuse bowel wall edema of the small intestine and right colon with what appeared to be an inflamed appendix. Given the presumed diagnosis of acute appendicitis, patient underwent an appendectomy. At the time of the appendectomy, the surgeon was concerned about Crohn’s disease due to significant bowel edema in terminal ileum and cecum. In addition to appendectomy, resection of the terminal ileum and cecum was also performed. Patient was seen in GI clinic 6 weeks postoperatively. Pathology was reviewed and consistent with bowel wall edema only with no evidence of Crohn’s disease or acute appendicitis. On further questioning, patient admitted to recurrent episodes of similar crampy abdominal pain
From the Department of Medicine, Division of Gastroenterology, University of Florida, Jacksonville, FL. The authors declare that they have nothing to disclose. Reprints: James S. Scolapio, MD, Department of Medicine, Division of Gastroenterology, University of Florida, 4555 Emerson Street, Suite 300, Jacksonville, FL 32207 (e-mail: james.scolapio@ jax.ufl.edu. Copyright r 2013 by Lippincott Williams & Wilkins
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associated with emesis and occasionally diarrhea with negative workup in past including normal EGD and colonoscopy. She denied taking any medications other than fiber supplements. Patient’s mother had similar bouts of abdominal pain attacks and had also been diagnosed with irritable bowel syndrome. Given patient’s personal and family history, a C1-esterase level and functional activity were checked. Both C1-esterase inhibitor (C1 INH) level and C1 INH functional activity were low. Given the probable diagnosis of hereditary angioedema (HAE), the patient was referred to an allergy and immunology specialist where a diagnosis of HAE was confirmed.
GASTROINTESTINAL CLINICAL MANIFESTATIONS OF HAE Symptomatic involvement of the gastrointestinal tract is an important clinical feature of HAE, as it is more distressing than the edema of the skin, and it occurs far more frequently than life-threatening laryngeal edema. Involvement of the gastrointestinal tract with resultant abdominal pain occurs in 43% to 93% of patients with HAE, and up to 80% of all patients have recurrent abdominal pain, whereas about 50% will have a potentially life-threatening laryngeal attack.1–3 Such abdominal pain symptoms may occur for many years without concomitant cutaneous or respiratory symptoms.4 Abdominal pain may manifest as severe acute onset abdominal pain, or as chronic recurrent abdominal pain of varying severity. The abdominal pain is often described as cramping or colicky and is rated as severe to excruciating in 87% of patients.5 Vomiting and diarrhea occur in 78% and 65%, respectively, of patients with abdominal symptoms.5 These symptoms of abdominal pain, vomiting, and diarrhea are caused by transient edema of small bowel wall leading to partial or complete intestinal obstruction. Although abdominal pain is the most common gastrointestinal manifestation of an attack, HAE can involve the entire GI tract leading to a bevy of other gastrointestinal symptoms during an acute attack (Table 1). Involvement of the oropharynx, and possibly of the esophagus, can cause dysphagia.3 The jejunum, ileum, duodenum, stomach, and colon are affected in descending frequency.6,7 Colonic involvement can lead to constipation, TABLE 1. Hereditary Angioedema Sites of Gastrointestinal Involvement and Their Clinical Manifestations
Site Oropharynx Small intestine Colon Liver Pancreas
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Clinical Manifestation Dysphagia Abdominal pain, ascites, vomiting, diarrhea Constipation Ascites Pancreatitis
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TABLE 2. Common Triggers of HAE Infection Trauma Emotional stress Medications (ie, ACE-I, estrogens) Menstruation Invasive procedures (ie, endoscopy, surgery, dental procedures) ACE-I indicates angiotensin-converting enzymes inhibitors; HAE, hereditary angioedema.
with occasional reports of colonic intussusception.8,9 Involvement of the liver has been reported, as suggested by elevated transaminase levels and reversible parenchymal changes on ultrasonography during acute attacks.10,11 A recent case report by Cutler and colleagues describes a case of recurrent pancreatitis in association with clinical attacks of HAE. Cutler et al12 have speculated that pancreatic edema leads to partial ductal obstruction, resulting in pancreatitis. Lastly, ascites frequently occurs in conjunction with small bowel mucosal edema in patients with HAE.13 If aspirated, the ascites is exudative.10,14 If an attack is severe enough, hypovolemic shock may rarely occur in the setting of extensive ascites and bowel wall edema.15 Attacks of angioedema typically occur due to an inciting event. A myriad of triggers have been indentified including fasting, infection, trauma, emotional stress, medical procedures (surgery or other invasive instrumentations), menstruation, exposure to estrogens, and certain medications (Table 2).16 The 1 class of medication classically associated with an increased risk of angioedema attacks includes angiotensin-converting enzymes (ACE) inhibitors. ACE inhibitors do not directly precipitate attacks, but act by increasing baseline concentrations of bradykinin, thereby reducing the threshold of an attack.17 Attacks are frequently accompanied by a prodromal phase. In the case of gastrointestinal manifestations, nonspecific complaints of fatigue, irritability, aggressiveness, or hunger may precede an attack.5 In the absence of treatment, attacks typically resolve over 2 to 5 days.
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Physical examination can be helpful but only during an acute attack. Particular attention should be focused on the skin examination. Skin should be inspected for external signs of cutaneous angioedema, which in HAE typically manifests as nonpitting edema in nondependent areas of the body without pruritus and urticaria.19 Thorough oropharyngeal examination is also important as tongue, lip, or intraoral swelling can be seen during an attack. With respect to the pulmonary examination, special attention should be paid to signs of respiratory distress, especially stridor. For episodes with acute abdominal involvement, the abdominal examination findings are very nonspecific. Palpation of the abdomen may reveal diffuse abdominal tenderness with or without rebound.18 Bowel sounds may be hypoactive or hyperactive.1 If an attack is severe enough, shifting dullness may be present signifying presence of ascites. Much like the physical examination, radiologic tests may be helpful but are not definitive in clinching a diagnosis of HAE. In severe cases of intestinal angioedema, plain abdominal radiographs may show dilated loops of bowel along with “thumbprinting,” which describes an area of mucosal edema (Fig. 1). Abdominal ultrasound may detect ascites and edematous viscera.11 The most sensitive diagnostic imaging study is a contrast-enhanced CT scan of the abdomen. CT is more useful for identifying milder degrees of intestinal edema, dilated loops of small or large bowel, and ascites than ultrasound and plain radiographs (Fig. 2).4 It is also useful in excluding other causes of acute abdominal pain such as mesenteric ischemia, appendicitis, or cholecystitis. Findings of intestinal edema with ascites
DIAGNOSIS Diagnosis of HAE requires a high index of clinical suspicion. When HAE attacks occur exclusively in the gastrointestinal tract without any swelling of visible body parts, the evaluating clinician might not consider HAE in the differential diagnosis of the patient’s abdominal pain resulting in missed or delayed diagnosis. In some instances, misdiagnosis of a severe abdominal pain attack may lead to inappropriate surgical interventions. One series of 235 patients with HAE has found up to a third of these patients had undergone exploratory laparotomies, appendectomies, or both, during their abdominal attacks.1 A detailed history is paramount. History should be obtained documenting the following: time of onset of current attack; whether there have been prior attacks; age at first attack; approximate intervals between attacks; presence or absence of triggering events or medications; a complete listing of all prescription and nonprescription drugs and supplements; presence of skin swelling during attacks; history of respiratory distress during attacks; and whether there is a history of similar attacks among family members.18
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FIGURE 1. Scout film revealing thumbprinting (arrow) of the colon. Reprinted with permission from Koruth et al.20 Copyright Elsevier, Philadelphia, PA. All permission requests for this image should be made to the copyright holder. r
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FIGURE 2. A, A noncontrast coronal image obtained at presentation shows isolated marked thickening of a small bowel segment in the left lower quadrant (arrows). B, A CT coronal view with contrast was performed 24 hours later, and it indicated resolution (arrows). C, Like the coronal image, an axial view taken upon presentation indicated thickening in the small bowel (arrows). D, An axial image with contrast acquired 24 hours later, also showed that edema had cleared (arrows). Reprinted with permission from Baines et al.21 Copyright Elsevier, Philadelphia, PA. All permission requests for this image should be made to the copyright holder.
are only seen during acute attacks. If imaging is delayed until after recovery, then radiologic imaging will only show normal results. An important point to remember is subtle or mild intestinal edema of any cause may be overlooked by interpreting radiologists even in symptomatic patients.18 Consequently, worsening pain severity after an earlier negative scan should not necessarily preclude consideration of HAE diagnosis or a repeat imaging study.18 In addition to a detailed history, physical examination and radiographic studies, laboratory tests are necessary to confirm a diagnosis of angioedema. If HAE is suspected, 4 laboratory tests should be obtained: C1 INH level, C1 INH activity, serum C4 level, and serum C1q, which is a byproduct r
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of C1 INH degradation.17,22,23 Low C4 is always present in HAE. In addition to low C4, a low C1 INH level and activity along with a normal C1q level is consistent with type I HAE. A normal C1 INH level with low functional activity and a normal C1q are consistent with type II HAE (Table 3). Endoscopy is not recommended for patients suspected to have HAE due to risk of inducing a potentially lifethreatening oropharyngeal or laryngeal attack. If endoscopy must be used for compelling clinical reasons, prophylactic measures to protect against the possibility of laryngeal swelling should be undertaken (see the “Prophylaxis” section). Nevertheless, endoscopic descriptions of HAE have been reported incidentally during www.jcge.com |
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TABLE 3. Laboratory Diagnostic Criteria of HAE
Type I HAE Type II HAE
C1 INH Quantitative Level
C1 INH Activity Level
C4
C1q
Low Normal
Low Low
Low Low
Normal Normal
C1 INH indicates C1-esterase inhibitor; HAE, hereditary angioedema.
undiagnosed HAE attacks (Fig. 3). Diffuse mucosal edema and erythema, and bulging areas of gastric mucosa (resembling a submucosal tumor), have been reported on upper GI endoscopy during acute abdominal attacks.24 Meanwhile, edematous colonic mucosa without gross signs of inflammation and normal histology on random colonic biopsies have been reported on colonoscopy during an acute attack of undiagnosed HAE.20
DEFINITION AND PATHOPHYSIOLOGY OF HAE Angioedema is a noninflammatory condition that is characterized by intermittent attacks of localized, nonpitting swelling of a body part. From a pathophysiological standpoint, it is important to remember that there are 2 broad categories of angioedema that must be distinguished: mast cell-mediated angioedema and bradykinin-mediated angioedema. Mast cell-mediated angioedema occurs as a result of allergic reactions to food or insect bites. The resultant symptoms include urticaria, flushing, bronchospasms, generalized pruritus, and/or anaphylaxis. In stark contrast to mast cell mediated, bradykinin-mediated angioedema is NOT associated with flushing, urticaria, bronchospasms, or pruritus.
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Bradykinin-mediated angioedema is mainly characterized by temporary swelling that can affect all layers of the skin or of the walls of hollow viscera such as the oropharynx, respiratory system, or gastrointestinal tract. Peripheral nonpitting edema of non–gravity-dependent areas of the body is typical of cutaneous manifestations.19 There are several causes of bradykinin-mediated intestinal angioedema. The most common causes include acquired angioedema due to acquired C1 INH deficiency, druginduced angioedema (most commonly ACE inhibitors), inherited angioedema with normal C1 INH, and HAE.18 HAE is a genetic disorder that results from mutations in the C1 INH gene on chromosome 11.22 These mutations are inherited in an autosomal dominant fashion in about 75% of cases, and approximately 25% result from spontaneous de novo mutations.25 “Classic” HAE is classified into 2 distinct types. Type I HAE is defined by subnormal levels of C1 INH along with subnormal functional enzymatic activity. Type II HAE is characterized by production of normal quantities of C1 INH but subnormal enzymatic function. A third type of HAE (type III) has been described but is not associated with a C1 INH deficiency and therefore, will not be discussed in this review. Type I HAE accounts for 85% of classic HAE cases.18 C1 INH plays an important role in complement, contact, and fibrinolytic pathways. One of the primary roles of C1 INH is to prevent activation of the classic complement and contact/bradykinin-generating systems. More specifically, within the contact/bradykinin-generating system, C1 INH regulates coagulation factor XII (Hageman factor) and kallikrein, which controls production of bradykinin—the main mediator of angioedema in HAE (Fig. 4).23 Consequently, the final result of subnormal levels of C1 INH and low functional activity that occurs in both types of HAE leads to massive bradykinin production, which causes symptomatic attacks of HAE.23 By binding to bradykinin-2 (B2) receptors which are constitutively expressed on many cells, bradykinin causes edema, ascites, and swelling through increased vascular permeability; congestion, hypotension, and erythema due to vasodilation; and cramps, spasms, and pain due to contraction of nonvascular smooth muscle.16
EPIDEMIOLOGY Surveys of patients suggest that HAE affects about 1 in 50,000 to 100,000 of any ethnic group, with many of those unaware of their diagnosis.26,27 Although HAE is a lifelong condition, attacks of angioedema rarely occur before the age of 2 years and are less frequent before adolescence.28 Incidence of symptoms varies from more than once per week to 5 days per month.29 In the United States, only 2 agents have been FDA approved for both short-term and long-term prophylaxis: oral attenuated androgens (mainly, danazol) and Cinryze, which is a nanofiltered C1 INH concentrate.25 Antifibrinolytics (eg, tranexamic acid) have also been shown to be effective and is still used in Europe but because of its prothrombotic side effects, it is no longer preferred therapy in the United States.34 Table 4 summarizes the FDA-approved drugs for acute treatment and prophylaxis of HAE. Attenuated androgen is the preferred therapy for longterm prophylaxis in nonpregnant adult patients because it is
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well tolerated and has very minimal reported breakthrough attacks. Unlike estrogen, androgens have been shown to increase the serum levels of C1 INH, thereby reducing the likelihood of HAE attacks.48,49 Danazol is the most commonly used agent mainly because availability of other attenuated androgens in the United States is variable. When used for preprocedure prophylaxis, androgen therapy should start 5 days before and 2 days after the procedure.34 Historically, side effects are common and relate mainly to androgenic properties of the drug, which is why these agents are not recommended for prepubescent children and pregnant women. Because of the myriad of potential side effects, consensus guidelines recommend regular liver function, cholesterol, and blood pressure monitoring, and biannual liver ultrasound to exclude hepatic adenoma, for patients who need these drugs long term.29 When used for long-term prophylaxis, dosage should be titrated to the lowest possible dose that provides reasonable freedom from symptoms.29 Cinryze, a C1 INH concentrate, is an alternative agent for long-term prophylaxis. Biweekly administration of Cinryze (every 3 to 4 d) has been shown to reduce angioedema attack rate, attack severity, and time to symptom resolution.29,38 Because of its high cost and occurrence of swellings reported in 2 of the 22 patients treated with Cinryze in phase III trials, Cinryze is considered an alternative agent for long-term prophylaxis.31,38 It is approved for patient selfadministration and is mainly useful for prepubescent children and pregnant women as androgens are contraindicated in these groups of patients. When used for preprocedure prophylaxis, consensus guidelines recommend Cinryze administration 1 hour before procedure.29 Some experts recommend a second dose postprocedurally.34 Side-effect profile is similar to its C1 INH concentrate counterpart, Berinert.
CONCLUSIONS Symptomatic involvement of the gastrointestinal tract is an important clinical feature of HAE. When confronted with cases of unexplained abdominal pain, whether acute or recurrent, it is imperative that gastroenterologists add HAE to their list of potential etiologies. With several effective drugs available for acute and prophylactic treatment of HAE, prompt diagnosis is extremely crucial to prevent years of needless suffering, unnecessary surgical procedures, and life-threatening complications from laryngeal edema or hypovolemic shock. Lastly, it is important to remember that once HAE is diagnosed, a multidisciplinary approach to management is required. As HAE is an autosomal dominant inherited condition, referral to a geneticist should be made for testing of all first-degree relatives. A specialist in allergy and immunology should also be engaged to provide patients with long-term management. REFERENCES 1. Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore). 1992;71:206–215. 2. Winnewisser J, Rossi M, Spath P, et al. Type I hereditary angio-oedema. Variability of clinical presentation and course within two large kindreds. J Intern Med. 1997;241:39–46. 3. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med. 1976;84:580–593. r
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4. De Backer AI, De Schepper AM, Vandevenne JE, et al. CT of angioedema of the small bowel. AJR Am J Roentgenol. 2001; 176:649–652. 5. Bork K, Staubach P, Eckardt AJ, et al. Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol. 2006; 101:619–627. 6. Weinstock BL, Kothari T, Sharma NR, et al. Recurrent abdominal pain as the sole manifestation of hereditary angioedema in multiple family members. Gastroenterol. 1987;93:1116–1118. 7. Eck SL, Morse JH, Janssen DA, et al. Angioedema presenting as chronic gastrointestinal symptoms. Am J Gastroenterol. 1993;88:436–439. 8. Johnson HT Jr, Caldwell WK. Angioneurotic edema of the colon. Radiology. 1971;99:61–63. 9. Witschi A, Krahenbuhl L, Frei E, et al. Colorectal intussuception: an unusual gastrointestinal complication of hereditary angioedema. Int Arch Allergy Immunol. 1996;111:96–98. 10. Branco-Ferreira M, Pedro E, Barbosa MA, et al. Ascites in hereditary angioedema. Allergy. 1998;53:543–545. 11. Farkas H, Harmat G, Fekete B, et al. Acute abdominal attack of hereditary angioedema associated with ultrasound abnormalities suggestive of acute hepatitis. Acta Paediatr. 2002;91:971–974. 12. Cutler AF, Yousif EA, Blumenkehl ML. Hereditary angioedema associated with pancreatitis. South Med J. 1992;85:1149–1150. 13. Farkas H, Harmat G, Kaposi PN, et al. Ultrasonography in the diagnosis and monitoring of ascites in acute abdominal attacks of hereditary angioneurotic oedema. Eur J Gastroenterol Hepatol. 2001;13:1225–1230. 14. Talavera A, Larraona JL, Ramos JI, et al. Hereditary angioedema: an infrequent cause of abdominal pain with ascites. Am J Gastroenterol. 1995;90:471–474. 15. Cohen N, Sharon A, Golik A, et al. Hereditary angioneurotic edema with severe hypovolemic shock. J Clin Gastroenterol. 1993;16:237–239. 16. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161:2417–2429. 17. Cugno M, Nussberger J, Cicardi M, et al. Bradykinin and the pathophysiology of angio-oedema. Int Immunopharmacol. 2003;3:311–317. 18. Nzeako UC, Longhurst HJ. Many faces of angioedema: focus on the diagnosis and the management of abdominal manifestations of hereditary angioedema. Eur J Gastroenterol Hepatol. 2012;24:353–361. 19. Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol. 2005;53:373–388. 20. Koruth JS, Eckardt AJ, Levey JM. Hereditary angioedema involving the colon: endoscopic appearance and review of GI manifestations. Gastrointest Endoscopy. 2005;61:907–911. 21. Baines SN, Baines SS, Anis M, et al. Rude Awakening: Acute Abdominal Pain with Spontaneous Resolution. American Journal of Medicine. 2012;125:971–973. 22. Bowen T, Cicardi M, Bork K, et al. Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008;100:S30–S40. 23. Cugno M, Zanichelli A, Foieni F, et al. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009;15:69–78. 24. Hara T, Shiotani A, Matsunaka H, et al. Hereditary angioedema with gastrointestinal involvement: endoscopic appearance. Endoscopy. 1999;31:322–324. 25. Nzeako UC. Diagnosis and management of angioedema with abdominal involvement: a gastroenterology perspective. World J Gastroenterol. 2010;16:4913–4921. 26. Bygum A. Hereditary angio-oedema in Denmark: a nationwide survey. Br J Dermatol. 2009;161:1153–1158. 27. Roche O, Blanch A, Caballero T, et al. Hereditary angiooedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol. 2005;94:498–503. r
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28. Longhurst HJ, Cicardi M. Hereditary angio-oedema. Lancet. 2012;379:474–481. 29. Cicardi M, Bork K, Caballero T, et al. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012;67:147–157. 30. Bork K, Meng G, Staubach P, et al. Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angio-oedema. Transfusion. 2005;45:1774–1784. 31. US Food and Drug Administration. Summary basis for regulatory action—Cinryze. October 9, 2008. http://www.fda. gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ ApprovedProducts/LicensedProductsBLAs/FractionatedPlasma Products/UCM129918.pdf. Accessed on August 8, 2012. 32. Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patient with hereditary angio-oedema. Arch Int Med. 2001;161:714–718. 33. Bork K, Frank J, Grundt B, et al. Treatment of acute edema attacks in hereditary angio-oedema with a bradykinin receptor2-antagonist (icatibant). J Allergy Clin Immunol. 2007;119: 1497–1503. 34. 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;6:24. 35. Caballero T, Baeza ML, Cabanas R, et al. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part II. Treatment, follow-up, and special situations. J Investig Allergol Clin Immunol. 2011;21:422–441. 36. Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. 2009;124:823–829. 37. Craig TJ, Bewtra AK, Bahna SL, et al. C1 esterase inhibitor concentrate in 1085 hereditary angioedema attacks—final results of the I.M.P.A.C.T.2 study. Allergy. 2011;66:1604–1611. 38. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Eng J Med. 2010;363:513–522. 39. CSL Behring GmbH. Berinert (C1 Esterase Inhibitor [Human]) [package insert]. Marburg, Germany: CSL Behring GmbH; 2009. 40. Kaplan AP. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy. J Allergy Clin Immunol. 2010;126:918–925. 41. Longhurst HJ. Management of acute attacks of hereditary angioedema: potential role of icatibant. Vasc Health Risk Manag. 2010;6:795–802. 42. Deeks ED. Icatibant. Drugs. 2010;70:73–81. 43. Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010;363:523–531. 44. Levy RJ, Lumry WR, McNeil DL, et al. EDEMA4: a phase 3, double blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol. 2010;104:523–529. 45. Dyax Corp. Kalbitor (Ecallantide) [package insert]. Cambridge, MA: Dyax Corp; 2009. 46. Kreuz W, Fischer D, Martinez-Saguer I, et al. C1-esterase inhibitor substitution in hereditary angioedema. Biomed Prog. 1999;12:1–7. 47. Pekdemir M, Ersel M, Aksay E, et al. Effective treatment of hereditary angioedema with fresh frozen plasma in an emergency department. J Emerg Med. 2007;33:137–139. 48. Gelfand JA, Sherins RJ, Alling DW, et al. Treatment of hereditary angioedema with danazol: reversal of clinical and biochemical abnormalities. N Engl J Med. 1976;295:1444–1448. 49. Sheffer AL, Fearon DT, Austen KF. Clinical and biochemical effects of stanozolol therapy for hereditary angioedema. J Allergy Clin Immunol. 1981;68:181–187.
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