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/lp/ou_press/extremely-delayed-diagnosis-of-type-ii-hereditary-angioedema-case-RpneFraFol
- Publisher
- Oxford University Press
- Copyright
- Copyright © 2022 The Society of Federal Health Professionals
- ISSN
- 0026-4075
- eISSN
- 1930-613X
- DOI
- 10.1093/milmed/usy031
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- See Article on Publisher Site
Abstract
Downloaded from https://academic.oup.com/milmed/article/183/11-12/e765/4954103 by DeepDyve user on 19 July 2022 MILITARY MEDICINE, 183, 11/12:e765, 2018 Extremely Delayed Diagnosis of Type II Hereditary Angioedema: Case Report and Review of the Literature Capt Jeremy Berger, MC USAF*; 2d Lt Michael P. Carroll Jr, MC USAF†; Lt Col Edward Champoux, MC USAF‡; Lt Col Christopher A. Coop, MC USAF‡ ABSTRACT We present a case with extremely late diagnosis of type II hereditary angioedema (HAE). Given recent advances in HAE treatment, we want to bring physician awareness to this condition and aid in earlier detection. HAE is a disorder associated with episodes of angioedema of the face, larynx, lips, abdomen, or extremities. Late diagnosis of HAE can lead to significant morbidity and is severely impairing due to recurring attacks. The diagnosis of HAE is ordinarily made during childhood and adolescence. Delayed diagnoses in early and middle adulthood have been docu- mented in the literature. Gastrointestinal symptoms are common features of HAE and can be misdiagnosed as disease of primary gastrointestinal pathology, such as irritable bowel syndrome, recurrent pancreatitis, or appendicitis. These attacks are characterized by recurrent attacks of subcutaneous and submucosal edema without the presence of urticaria. We present a case of an elderly veteran whose diagnoses was extremely delayed into the eighth decade of life subse- quent to unexplained abdominal symptoms. After diagnosis, the patient’s symptoms were well controlled with medica- tion due to advances in HAE treatment. To prevent further atypically delayed diagnoses, physicians should consider HAE in patients with recurrent attacks of unexplained abdominal pain. INTRODUCTION weekly basis and lasting for several days. He described an Hereditary angioedema (HAE) is characterized by recurrent extensive history of constipation and occasional diarrhea, attacks of subcutaneous and/or submucosal edema without 1,2 including a significant, month-long episode in the spring of the presence of urticaria. The angioedema commonly 2014 associated with abdominal pain, anorexia, and weight involves the extremities, abdomen, and genitourinary tract. It loss. He has since regained his weight and has not had fur- also involves the face, oropharynx, and larynx, risking ther weight loss since. The patient’s review of systems was potential airway obstruction. Depending on the location and negative or noncontributory. The patient indicated that his degree of edema, the severity may range from a mild episode maternal grandfather, mother, daughters, and two nieces to a life-threatening emergency. The diagnosis of HAE is have a history of episodic limb swelling. His brother has ordinarily made during childhood and adolescence. Later diag- experienced similarly described recurrent abdominal pain. noses, however, can also be made in adulthood, with atypical There is no family history of airway involvement. One niece delayed diagnoses being made in the elderly. We present a case has been diagnosed with a type of hereditary angioedema of an extremely delayed diagnosis of type II HAE. and is being treated. The patient has undergone multiple evaluations for his abdominal pain, which revealed several polyps and minor CASE PRESENTATION diverticulosis. The patient has been on several medications A 78-yr-old military veteran presented with a long history of for gastroesophageal reflux disease and constipation, includ- intermittent abdominal pain and swelling of the hands, feet, ing lubiprostone, polyethylene glycol 3,350, and ranitidine, and scrotum since adolescence. The patient endorsed mid- all without symptom improvement. Given his symptoms, epigastric abdominal pain without radiation, occurring on a family history, and unsuccessful treatments, his primary phy- sician subsequently referred him to an allergist. Physical *Department of Medicine, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234. exam findings were unremarkable. Laboratory findings are †Morsani College of Medicine, University of South Florida, 12901 listed in Table I. Additional workup included several C4 Bruce B Downs Blvd, Tampa, FL 33612. levels documented as low–normal or low, a normal quantita- ‡Department of Allergy and Immunology, Wilford Hall Ambulatory tive complement C1q level, and a normal C1 esterase inhibi- Surgical Center, 2200 Bergquist Drive, Lackland Air Force Base, TX tor level. The C1 esterase inhibitor function, however, was The views expressed are solely those of the authors and do not reflect found to be low. His liver function tests were normal. the official policy or position of the US Army, US Navy, US Air Force, the The patient was diagnosed with type II HAE based on his Department of Defense, or the US Government. symptom history, family history of angioedema, and low doi: 10.1093/milmed/usy031 levels of C4 and functional C1 esterase inhibitor. In 2016, Published by Oxford University Press on behalf of Association of he was prescribed Icatibant, a bradykinin receptor blocker, Military Surgeons of the United States 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US. which helped resolve six episodes of abdominal angioedema MILITARY MEDICINE, Vol. 183, November/December 2018 e765 Downloaded from https://academic.oup.com/milmed/article/183/11-12/e765/4954103 by DeepDyve user on 19 July 2022 Extremely Delayed Diagnosis of Type II Hereditary Angioedema TABLE I. Relevant Patient Laboratory Findings anaphylaxis. Patients can give themselves up to three doses in a 24-h period if needed to reduce edema. Test Findings Reference Range Complement C1Q level, serum 18.0 mg/dL 11.8–23.8 mg/dL Complement C1-INH functional 28%, 31% Normal > 67% CONCLUSION level, serum This case presentation is unique because of the extremely late Complement C1-INH level, serum 24 mg/dL 21–39 mg/dL diagnosis of type II HAE. There are other reports present in the literature of patients with recurrent abdominal pain result- ing from HAE but having a delay in their diagnosis. Patients and pain in 2016 and five episodes in 2017. In each case of with recurrent abdominal pain may be misdiagnosed with a its use, his pain resolved over several hours, rather than over disease of primary gastrointestinal pathology, such as irritable days or weeks in which he would experience pain without bowel syndrome, recurrent pancreatitis, appendicitis, or colon treatment. The patient desires to continue using on-demand intussusception, with an eventual diagnosis of HAE. Icatibant as needed for future episodes of HAE. With the Individualized treatment plans for patients of all ages should low frequency of symptoms at this time in his management, address preventive, home, and emergency measures for disease prophylactic medications are not being used. Regular moni- management, including long-term prophylaxis and on-demand toring of transaminases is performed, as elevations are less medication with HAE identification and instructions. To best common side effects of Icatibant. The patient was educated accomplish this, several general HAE guidelines have been pub- on the risk of using ACE inhibitors with a diagnosis of HAE lished and are available; examples include the World Allergy and to avoid this class of medication. Organization Guideline for the Management of Hereditary 3,8 Angioedema and the US Hereditary Angioedema Association DISCUSSION Medical Advisory Board 2013 Recommendations for the The mechanism by which HAE occurs is through a heredi- Management of Hereditary Angioedema Due to C1 Inhibitor tary deficiency in functional levels of C1 esterase inhibitor Deficiency. (C1-INH) activity. C1-INH is a serine protease inhibitor, The World Allergy Organization (WAO) in collabora- normally functioning as a suicide inhibitor by forming com- tion with the European Academy of Allergy and Clinical plexes with its target proteases: kallikrein, factor XIa, factor Immunology (EAACI) recently proposed new guidelines XIIa, C1s, and C1r. Pathogenesis of HAE involves the kal- in 2017 for the management of hereditary angioedema. likrein–kinin and complement pathways, with activated fac- Specifically, they recommend that attacks are treated as early tor XII initiating a cascade that produces bradykinin, the as possible and HAE attacks are treated with either C1-INH, primary mediator of swelling via the enhancement of vascu- Ecallantide, or Icatibant. If these three agents are not avail- 2,3 lar permeability. able, then soluble detergent plasma or fresh frozen plasma HAE is an autosomal dominant disease, and roughly 75% can be given. The new guidelines recommend that patients of patients with HAE have a positive family history of have sufficient medication for on-demand treatment of two angioedema. Three important subtypes of HAE have been attacks and patients should carry this medication at all times. recognized: type I, type II, and HAE with normal C1-INH The advantages of using an on-demand medication are short- (HAE-nC1 INH). More than 275 different mutations have er time to resolution of symptoms and shorter total attack been identified and are responsible for these diseases. Type duration. The following is a review of currently available I HAE involves a mutation in the C1-INH gene, SERPING1, options. Plasma-derived C1-INH concentrate is available in resulting in a truncated or misfolded protein that is not intravenous formulation (Cinryze) and subcutaneous formu- 2,3 secreted, accounting for about 85% of patients with HAE. lation (Haegarda); however, both have been associated with Type II HAE is caused by a missense mutation, resulting in anaphylactic adverse reactions. Ruconest is the only avail- a normal C1-INH level but defective function. Finally, able recombinant human C1-INH (rhC1-INH) and is only HAE-nC1 INH is due to either an increased activity of factor available in intravenous formulation, which is not ideal for XII or is through an unidentified cause. In addition to the on-demand home treatment. Ecallantide (a kallikrein inhibi- symptoms and signs previously described, HAE-nC1 INH tor) can be used on demand in the United States; however, may also include hemorrhage at the site of edema. In 20% 3–4% of patients have reported hypersensitivity reactions to of HAE-nC1 INH patients, the diagnosis can be made include anaphylaxis. This makes Icatibant (a bradykinin through identification of two known mutations in the factor receptor antagonist) a more practical option as it can be XII gene; otherwise, it is a diagnosis of exclusion. given at home subcutaneously and the main adverse reaction We chose Icatibant for this patient for two reasons. First, is local injection site irritation according to the safety data. it has been proven effective in acute attacks for HAE type II, The authors see three potential solutions to prevent future due to its antagonistic effect on bradykinin receptors. extremely delayed diagnosis. First, increasing physician Second, it is readily available in 3-mL prefilled syringes that awareness of the signs and symptoms of HAE may lead to a can be administered subcutaneously at home without risk of timelier diagnosis and reduce patient suffering. Two, once e766 MILITARY MEDICINE, Vol. 183, November/December 2018 Downloaded from https://academic.oup.com/milmed/article/183/11-12/e765/4954103 by DeepDyve user on 19 July 2022 Extremely Delayed Diagnosis of Type II Hereditary Angioedema 3. Craig T, Pürsün EA, Bork K, et al: WAO guideline for the management the diagnosis has been made, provide family screening. In of hereditary angioedema. World Allergy Organ J 2012; 5(12): 182–99. this case, our patient had a niece diagnosed with HAE; how- 4. LoVerde D, Files DC, Krishnaswamy G: Angioedema. Crit Care Med ever, our patient remained undiagnosed until an extended 2017; 45(4): 725–35. doi:10.1097/CCM.0000000000002281. abdominal flare led to further workup and referral to an 5. Zuraw BL, Bernstein JA, Lang DM, et al: A focused parameter allergy specialist. As evident with the presented case, clinical update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. suspicion for HAE in later stages of life is a paramount to J Allergy Clin Immunol 2013; 131(6): 1491–3. doi:10.1016/j.jaci.2013. prevent unnecessary patient suffering and potential serious 03.034. and preventable disease manifestations. Third, consider 6. Bouillet L, Boccon‐Gibod I, Launay D, et al: Hereditary angioedema referral to an allergist or immunologist once the diagnosis with normal C1 inhibitor in a French cohort: clinical characteristics and has been made for definitive treatment. response to treatment with icatibant. Immun Inflamm Dis 2017; 5(1): 29–36. doi:10.1002/iid3.137. 7. Patel N, Suarez LD, Kapur S, Bielory L: Hereditary angioedema and gas- REFERENCES trointestinal complications: an extensive review of the literature. Case Rep Immunol 2015; 2015: 925861. doi:10.1155/2015/925861. 1. Jose J, Zacharias J, Craig T: Review of select practice parameters, 8. Maurer M, Markus M, Ignacio A, et al: The international WAO/EAACI evidence-based treatment algorithms, and International Guidelines for guideline for the management of hereditary angioedema – the 2017 revi- Hereditary Angioedema. Clinic Rev Allerg Immunol 2016; 51: 193. sion and update. Allergy 2018. doi:10.1111/all.13384. doi:10.1007/s12016-016-8546-7. 9. Zuraw BL, Banerji A, Bernstein JA, et al: US Hereditary Angioedema 2. DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995. Association Medical Advisory Board 2013 recommendations for the Record No. 114672, C1 inhibitor deficiency; [updated 2017 Apr 05, cited management of hereditary angioedema due to C1 inhibitor deficiency. May 9, 2017]; [about 18 screens]. Available from http://search.ebscohost. J Allergy Clin Immunol Pract 2013; 1(5): 458–67. doi:10.1016/j.jaip. com.ezproxy.hsc.usf.edu/login.aspx?direct=true&db=dnh&AN=114672& 2013.07.002. site=dynamed-live&scope=site. MILITARY MEDICINE, Vol. 183, November/December 2018 e767
Journal
Military Medicine – Oxford University Press
Published: Nov 5, 2018
Keywords: angioneurotic edema, hereditary; delayed diagnosis; diagnosis; edema; abdomen; abdominal pain; angioedema; adolescent; limb