C1 Esterase Inhibitor Deficiency Research Articles

Hereditary Angioedema Therapy: Kallikrein Inhibition and Bradykinin Receptor Antagonism

Current strategies for the treatment of hereditary angioedema (HAE) include targeted inhibition or antagonism of the contact system, which is dysregulated in HAE patients by a C1 esterase inhibitor deficiency. Ecallantide, a plasma kallikrein inhibitor, and icatibant, a selective bradykinin-2 receptor antagonist, have recently been evaluated in clinical studies for the treatment of acute HAE attacks. Both drugs have demonstrated evidence of efficacy and safety in treating acute HAE episodes, with ecallantide approved for use in the United States and icatibant approved for use in Europe. As therapeutic options for HAE expand for both for prophylactic and acute treatment strategies, a number of patient-specific and drug-specific factors have emerged as important considerations when developing individualized HAE management plans. Optimization of HAE therapy will require further integration of new therapies into the current treatment paradigm.

Ecallantide: A plasma kallikrein inhibitor for the treatment of acute attacks of hereditary angioedema

Hereditary angioedema (HAE) is a debilitating, potentially fatal disease characterized by variable and unpredictable acute attacks of swelling affecting the subcutaneous tissue and mucosa. It is an autosomal dominant disorder resulting from a genetic deficiency of functional C1-esterase inhibitor. Available treatments include long-term prophylaxis, short-term prophylaxis and treatment of acute attacks. Ecallantide is a novel, specific and potent inhibitor of plasma kallikrein that was recently approved in the United States for the treatment of acute attacks of HAE in patients aged 16 years and older. In two phase III clinical trials, the subcutaneous administration of 30 mg ecallantide resulted in significantly greater symptom improvement than placebo for acute attacks of HAE. Ecallantide was generally well tolerated throughout the clinical development program. The main safety concern following ecallantide treatment is hypersensitivity reactions, including anaphylaxis. A Risk Evaluation and Management Strategy (REMS) has been implemented to minimize this risk and a long-term observational safety study is currently under way to collect more information about hypersensitivity and immunogenicity. Ecallantide represents a novel treatment option for patients with HAE.

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

Abdominal involvement in angioedema is often a challenge to diagnose. Acute onset abdominal pain is its most common presenting symptom, and misdiagnosis may lead to unnecessary surgical intervention. Familiarity with the types and presentations of angioedema can be invaluable to clinicians as they consider the differential diagnoses of a patient presenting with abdominal pain. Detailed personal and family histories, careful physical examination of the patient, combined with knowledge of angioedema types, can help clinicians perform their diagnostic evaluation. An accurate diagnosis is essential in order to provide appropriate treatment to patients with angioedema. Depending upon the diagnosis, treatment may be the avoidance of provoking factors (such as allergens or medications), inhibiting histamine-provoked reactions, or treating C1 esterase inhibitor deficiency.

A regional audit of experience managing C1 esterase inhibitor deficiency – cause of a potential airway emergency

Deficiency of C1 esterase inhibitor (hereditary, acquired or ACE-inhibitor-induced angioedema) is characterised by recurrent episodes of laryngeal, cutaneous and abdominal swelling. Attacks may occur spontaneously or in response to triggers such as the trauma caused by surgery or oral instrumentation. Best practice for the management of this condition, which has a prevalence of 1:50 000, has been published in a consensus document [1]. It advises that the treatment for acute attacks and prophylaxis for invasive procedures should include intravenous administration of the deficient C1 esterase inhibitor (C1-INH). Patients should carry treatment advice for their attending doctor and consider home possession of C1-INH to minimise the onset of symptoms-to-needle time. This audit aimed to determine the knowledge of this guidance by both patients and the doctors likely to manage them and assess the availability of C1-INH. With the approval of the clinical effectiveness units within local trusts, between April and May 2008 three surveys were conducted within Northern Ireland. An on-line survey was sent to doctors, a postal questionnaire was sent to patients and a telephone survey of laboratories was conducted. The overall response rate from the doctors’ survey was 40% (anaesthetists 41% (102/250), emergency medicine doctors 33% (35/107), oral surgeons 45% (4/7)). One in three emergency medicine doctors and one in six anaesthetist respondents had dealt with C1-esterase inhibitor deficiency (C1-INHD)-related laryngeal oedema. One in 10 anaesthetist respondents had managed procedure prophylaxis. The response rate of the patient questionnaire was 76% (16/21). Sixty-three per cent of respondents admitted to having experienced laryngeal angioedema (12% every 3–6 months). Two in every three respondents kept home supplies of C1-INH. Whilst 88% of respondents mentioned their condition on symptomatic presentation, only 50% did so on presentation for potentially triggering procedures. Despite the majority having undergone invasive procedures, prophylaxis had only been taken by ∼50% of respondents. All 12 laboratories surveyed were willing to stock C1-INH but due to budgetary constraints only three did so. C1-INHD-related laryngeal oedema is potentially life-threatening and unlikely to respond to adrenaline or steroids [1], yet only half of patients carry written treatment advice. The distribution of advice cards, alongside encouragement to present these to attending physicians, may expedite provision of appropriate treatment. Education is required to encourage patients to mention their need for procedure prophylaxis to prevent unnecessary and unpredicted peri-operative airway compromise. If not brought by the patient, C1-INH is unlikely to be obtained locally; an issue that could be addressed by promotion of universal home-possession. A significant minority of doctors have dealt with C1-INHD. This audit demonstrates the need for education and dissemination of clinical guidance on the emergency and peri-operative management of C1-INHD to acute care physicians who may only rarely encounter the condition.

Case 151: Hereditary Angioedema in the Duodenum

HomeRadiologyVol. 253, No. 2 PreviousNext Case 151: Hereditary Angioedema in the DuodenumJesse Courtier, Kamran AliJesse Courtier, Kamran AliAuthor Affiliations1From the Department of Radiology, University of Kansas–Wichita, Wichita, Kan.Address correspondence to J.C., 1 St Francis Pl, Room 4606, San Francisco, CA 94107 (e-mail: [email protected]).Jesse CourtierKamran AliPublished Online:Nov 1 2009https://doi.org/10.1148/radiol.2532080598MoreSectionsFull textPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In AbstractTo reach the correct diagnosis of hereditary angioedema, it was necessary to integrate the patient's imaging findings with his clinical and family history, as well as his laboratory data; this case illustrates the necessity of the integration of clinical and radiologic findings, as well as the use of a pattern approach to complex small-bowel processes. References 1 Ghai S, Pattison J, Ghai S, O'Malley ME, Khalili K, Stephens M. Primary gastrointestinal lymphoma: spectrum of imaging findings with pathologic correlation. RadioGraphics 2007;27(5):1371–1388. Link, Google Scholar2 Fishman EK, Kuhlman JE, Jones RJ. CT of lymphoma: spectrum of disease. RadioGraphics 1991;11(4):647–669. Link, Google Scholar3 Macari M, Megibow A, Balthazar E. A pattern approach to the abnormal small bowel: observations at MDCT and CT enterography. AJR Am J Roentgenol 2007;188(5):1344–1355. Crossref, Medline, Google Scholar4 Buckley JA, Fishman EK. CT evaluation of small bowel neoplasms: spectrum of disease. RadioGraphics 1998;18(2):379–392. Link, Google Scholar5 Jayaraman MV, Mayo-Smith WW, Movson JS, Dupuy DE, Wallach MT. CT of the duodenum: an overlooked segment gets its due. RadioGraphics 2001;21(Spec Issue):S147–S160. Link, Google Scholar6 Bork K, Staubach P, Eckardt AJ, Hardt J. Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol 2006;101(3):619–627. Crossref, Medline, Google Scholar7 Hertz IH, Keller RJ. Paroxysmal nocturnal hemoglobinuria: small bowel findings. AJR Am J Roentgenol 1981;136(2):204–205. Crossref, Medline, Google Scholar8 Choudhary AM, Grayer D, Nelson A, Roberts I. Mesenteric venous thrombosis: a diagnosis not to be missed! J Clin Gastroenterol 2000;31(2):179–182. Crossref, Medline, Google Scholar9 Byun JY, Ha HK, Yu SYet al.. CT features of systemic lupus erythematosus in patients with acute abdominal pain: emphasis on ischemic bowel disease. Radiology 1999;211(1):203–209. Link, Google Scholar10 De Backer AI, De Schepper AM, Vandevenne JE, Schoeters P, Michielsen P, Stevens WJ. CT of angioedema of the small bowel. AJR Am J Roentgenol 2001;176(3):649–652. Crossref, Medline, Google Scholar11 Pekdemir M, Ersel M, Aksay E, Yanturali S, Akturk A, Kiyan S. Effective treatment of hereditary angioedema with fresh frozen plasma in an emergency department. J Emerg Med 2007;33(2):137–139. Crossref, Medline, Google Scholar12 Fisher AJ, Fleishman MJ, Hancock D. Angioedema of the small bowel: CT appearance. AJR Am J Roentgenol 2000;175(2):554. Crossref, Medline, Google Scholar13 Ciaccia D, Brazer SR, Baker ME. Acquired C1 esterase inhibitor deficiency causing intestinal angioedema: CT appearance. AJR Am J Roentgenol 1993;161(6):1215–1216. Crossref, Medline, Google ScholarArticle HistoryReceived April 1, 2008; revision requested June 2; revision received August 19; final version accepted August 27.Published in print: Nov 2009 FiguresReferencesRelatedDetailsCited ByTherapies, Vol. 75, No. 2La Presse Médicale, Vol. 44, No. 3Rude Awakening: Acute Abdominal Pain with Spontaneous ResolutionThe American Journal of Medicine, Vol. 125, No. 10Recommended Articles CT Findings of Acute Small-Bowel EntitiesRadioGraphics2018Volume: 38Issue: 5pp. 1352-1369Pearls, Pitfalls, and Conditions that Mimic Mesenteric Ischemia at CTRadioGraphics2020Volume: 40Issue: 2pp. 545-561Fluoroscopic Evaluation of Duodenal DiseasesRadioGraphics2022Volume: 42Issue: 2pp. 397-416Imaging Review of Gastrointestinal Motility DisordersRadioGraphics2022Volume: 42Issue: 7pp. 2014-2036Imaging of Drug-induced Complications in the Gastrointestinal SystemRadioGraphics2016Volume: 36Issue: 1pp. 71-87See More RSNA Education Exhibits Gastrointestinal Tract Dilation: How and Why it Happens. A Simplified Review of the Pathophysiologic Mechanisms and CausesDigital Posters2020Non-Neoplastic Diseases of the Small Intestine and Their Pattern of Mural InvolvementDigital Posters2018The Many Faces of Bowel IschemiaDigital Posters2019 RSNA Case Collection Jejunal diverticulitisRSNA Case Collection2021Superior Mesenteric Artery SyndromeRSNA Case Collection2021TrichobezoarRSNA Case Collection2021 Vol. 253, No. 2 Metrics Altmetric Score PDF download

Clinical Review of Hereditary Angioedema: Diagnosis and Management

Hereditary angioedema (HAE) is caused by a deficiency in C1 esterase inhibitor and is characterized by sudden attacks of edema associated with discomfort and pain. The disease places patients at risk for disability and death if left untreated. Symptom severity and frequency can be extremely variable even among affected members of the same family. Attacks are not associated with inflammation or allergy, with most occurring secondary to trauma or stress. Swelling can affect any part of the body or multiple sites at once. Commonly affected areas include the extremities, genitalia, trunk, gastrointestinal tract, face, and larynx. Swelling typically worsens over 24 to 36 hours and resolves within 48 hours in less severe cases. Attacks result in 15 000 to 30 000 emergency department visits each year. Many of these emergency cases will undergo unnecessary surgeries or medical procedures due to misdiagnosis. The hallmarks of HAE—recurrent episodes of swelling without urticaria, a family history of HAE, first attack in childhood, and worsening at puberty—can be identified by a thorough family history, and the diagnosis can be confirmed by laboratory studies. Nevertheless, diagnosis may be delayed by 2 decades. We review available therapies and clinical characteristics that will both help clinicians diagnose HAE and distinguish among emergencies and nonemergency cases.

Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks

Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder. To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema. This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours. Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus. C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.

Cerebral angioedema associated with enalapril

Cerebral angioedema associated with enalapril

Modern preoperative and intraoperative management of hereditary angioedema

Hereditary angioedema (HAE), deficiency of C1 esterase inhibitor, poses a risk of airway compromise during trauma, including surgery, due to activation of the complement cascade. Classical surgical management includes emergent/slash tracheostomy and cricothyrotomy, associated with high complication rates. We provide here an evidence-based review of available medical literature to construct guidelines for managing patients with HAE pre- and intra-operatively. We also describe our experience with a patient for whom we cared using these guidelines. Our objective was to explain new preventive measures to prevent airway compromise in HAE and their level of evidence for averting potential therapeutic misadventure. We analyzed PUBMED literature regarding airway management and etiology of angioedema and its prevention, followed by application of guidelines based on these data in a patient with HAE undergoing inguinal hernia repair. An analysis of contemporary literature yielded key points: (1) using a Cook Exchange catheter to facilitate re-intubation, (2) measuring cuff leak pressure to verify whether airway pressure had increased during surgery, (3) visualizing the airway directly using a fiberoptic laryngoscope connected to a digital flat-screen monitor for real-time assessment, (4) following conventional dictum to double stanozolol dosages 2 weeks before admission, (5) administering fresh frozen plasma pre- and intraoperatively, and (6) preparing recombinant C1 esterase inhibitor for instantaneous intraoperative use; and using FDA-approved human-derived C1-esterase inhibitor prophylactically. Biotechnology in the form of novel but currently available and in-practice medical devices, as well as new therapeutic agents, have expanded the armamentarium for safely managing patients with HAE pre- and intraoperatively.

Calcium Channel Blocker-associated Small Bowel Angioedema

Isolated angioedema of the small intestine is a rare entity. The cases described have been related with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or C1 esterase inhibitor deficiency. We present a case of small intestine angioedema caused by calcium channel blockers (CCBs) and a review of the literature. Over the course of approximately 2 years, a 56-year-old African American woman presented to our hospital with 8 similar episodes of diffuse, intermittent abdominal pain, nausea, vomiting, and diarrhea. The diagnostic workup was extensive and included normal stool studies, anticardiolipin antibodies, antinuclear antibodies, antineutrophil cytoplasmic antibodies, cryoglobulin studies, complement levels, urinary 5-hydroxyindoleacetic acid, and serum markers for inflammatory bowel diseases. A computed tomographic angiogram was normal. Abdominal computed tomographic scans showed prominent mural thickening of different intestinal segments, always involving the ileum. An esophagogastroduodenoscopy showed patchy edematous, violaceous folds in the second portion of the duodenum. Colonoscopy revealed a markedly edematous and erythematous distal ileum. The recurrences subsided after CCBs were discontinued in this patient and reoccurred when they were incidentally restarted. Our case demonstrates that CCBs can cause isolated intestinal angioedema with distinctive endoscopic findings. The discontinuation of the involved medication is the key for both diagnosis and treatment.

New drugs: C1 inhibitor (human), romiplostim, and eltrombopag olamine

Hereditary angioedema (HAE) is a severely debilitating genetic disorder that is caused by a deficiency of C1 esterase inhibitor (C1 inhibitor), a plasma protein. C1 inhibitor regulates clotting and inflammatory reactions and, when this protein is deficient or not functioning properly, inflammation of tissues can result. Patients with C1 inhibitor deficiency may experience unpredictable, recurrent, and potentially life-threatening attacks of inflammation of the larynx, face, abdomen, and extremities, and asphyxiation may occur as a consequence of swelling of the larynx.

67-jähriger Patient mit Sprech- und Schluckstörung

A 67-year-old man who had been heart transplanted ten years before was admitted to our hospital because of diarrhea. During his stay he developed a severe lingual and facial angioedema. After excluding hereditary angioedema caused by a deficiency in functional C1 esterase inhibitor we focused on adverse effects of his drugs. The medication was composed of Aspirin, Enalapril, Diltiazem, Everolimus, Mycophenolate Mofetil, Bisoprolol, Pravastatin, Esomeprazol and Allopurinol. The angioedema disappeared with anti-allergic treatment. The administration of the suspected trigger enalapril was stopped. However weeks later the patient was admitted again with angioedema. Due to missing urticaria Aspirin was unlikely the causer. The only new drug the patient had been medicated with was Everolimus for 30 days. We assumed a link between the angioedema and Everolimus. Consequently we changed the immunosuppressive regime. After stopping Everolimus no angioedema occurred. Everolimus is a potential trigger of angioedema.

Functional C1-Inhibitor diagnostics in hereditary angioedema: Assay evaluation and recommendations

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of potentially life-threatening angioedema. The most widespread underlying genetic deficiency is a heterozygous deficiency of the serine protease inhibitor C1 esterase inhibitor (C1-Inh). In addition to low C4 levels, the most important laboratory parameter for correct diagnosis of HAE or angioedema due to acquired C1-Inh deficiency is reduced C1-Inh function (fC1-Inh). No direct recommendations about the assays for fC1-Inh or sample handling conditions are available, although this would prove especially useful when a laboratory first starts to offer assays on fC1-Inh for HAE diagnosis. In the present study we evaluated the performance of fC1-Inh assays in the 15 different laboratories that are specialised in HAE diagnostics and assessed inter-laboratory variation with each laboratory using their own assays and standards. A double-blind survey was conducted using plasma/serum samples from healthy donors and HAE patients and the uniformity of HAE diagnosis was evaluated. It can be concluded that the diagnosis of fC1-Inh deficiency was made correctly in most cases in this survey. We can recommend the chromogenic assay for the determination of fC1-Inh, while the complex ELISA needs further investigation.

A Case of Angioedema Due to Acquired C1 Esterase Inhibitor Deficiency Masquerading as Suspected Peritonitis: A Case Report

Angioedema due to acquired C1 esterase deficiency is a rare condition and a non-inflammatory disease characterized by episodes of edema of the mucosa of the upper airway or gastrointestinal tract. The purpose of this case report is to heighten awareness among emergency physicians of a peritonitis-like condition that can develop into angioedema due to acquired C1 esterase inhibitor deficiency, and thereby help to prevent false diagnosis resulting in unnecessary surgical intervention. We report the case of a 21-year-old man who presented to the Emergency Department (ED) with abdominal pain. He was later diagnosed with angioedema of the gastrointestinal tract due to acquired C1 esterase deficiency that was initially suspected as peritonitis. Careful evaluation of the acute abdomen in acquired C1 esterase deficiency is very important in the ED to distinguish between medical and surgical causes of an acute abdomen.

Angioedema caused by C1 esterase inhibitor deficiency

Angioedema caused by C1 esterase inhibitor deficiency

Hereditäres Angioödem Typ II mit vorwiegend abdomineller Symptomatik

For two years a 19-year-old patient had been complaining of recurrent abdominal symptoms consisting of severe colicky pain, nausea, vomiting and diarrhoea. Occasionally he noticed concomitant subcutaneous swellings in the limbs. There were no swellings in the face or the region of the upper airway. The symptoms occurred once or twice a month, spontaneously receding within 3-4 days. These signs and symptoms indicated hereditary angio-oedema. Serum concentration of C1-esterase inhibitor was normal (13 mg/dl), but its serum activity was reduced to 16% (normal range 80-125%). This is thus a case of type II C1-esterase inhibitor deficiency. Since starting low-dosage treatment with Danazol (initially, for two months, 200 mg daily, then 200 mg five times per week) the patient has been symptom-free.

8. Hereditary angioedema

Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by brawny, self-limited, nonpruritic edema of the deep dermal layers of the skin that most often involve the hands and feet. They usually begin in childhood and become more severe after puberty. Patients also have episodic attacks of severe abdominal pain caused by edema of the gastrointestinal mucosa. Swelling attacks are life threatening when they involve the airway. Estrogens exacerbate attacks, and in some patients attacks are precipitated by trauma or psychologic stress. The disease is caused by a mutation in one of the 2 copies of the gene for the plasma protein C1 inhibitor, with the product of 1 gene unable to control generation of bradykinin. Eighty-five percent of patients have low antigenic levels of C1 inhibitor, and 15% have normal levels of poorly functioning protein. Most patients have decreased plasma complement protein C4 levels. Impeded androgens and, less frequently, epsilon-aminocaproic acid are currently the mainstays of chronic treatment. These agents or fresh frozen plasma are also used for prophylaxis. At this time, acute therapy is mostly supportive. There are currently ongoing multiple trials of new therapeutic agents. In half a century, a life-threatening disease has become one that is manageable and rarely causes death.

Emergency management of upper airway angio-oedema after routine dental extraction in a patient with C1 esterase deficiency

Hereditary angio-oedema is rare and potentially life-threatening, being characterised by recurrent episodes of perioral or laryngeal oedema. We describe a 28-year-old woman who developed stridor, orofacial swelling, and drooling several hours after a routine dental extraction. This was initially diagnosed as a spreading dental infection. Only after early oral and maxillofacial review and taking a thorough family history was C1 esterase-inhibitor deficiency diagnosed. She was immediately given C1 esterase-inhibitor concentrate, made a complete recovery and was discharged next day.

Acute upper airway obstruction from acquired angioedema

C1 esterase inhibitor deficiency is an unusual cause of acute upper airway angioedema. This case of angioedema is secondary to acquired C1 esterase inhibitor deficiency associated with neoplastic disease and triggered by the use of angiotensin converting enzyme inhibitors. It was sufficiently severe to require emergency airway management. A guide to the evaluation and management of angioedema is presented.

Acquired C1 Esterase Inhibitor Deficiency in a Patient with Systemic Lupus Erythematosus (SLE)

Acquired C1 Esterase Inhibitor Deficiency in a Patient with Systemic Lupus Erythematosus (SLE)