Diagnosis and management of hereditary angioedema: an American approach.

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent episodes of angioedema, and caused by a deficiency of the plasma protein C1 inhibitor. HAE attacks carry a substantial risk of morbidity or even mortality, making it imperative that the correct diagnosis be established and an appropriate management plan be in place. This report reviews the current diagnostic and therapeutic approaches available in the United States. Areas in which the diagnostic or therapeutic tools are deficient are discussed, and the prospects for improved therapeutic modalities highlighted.     

Unusual manifestations of hereditary angioedema.

Hereditary angioedema is a hereditary disorder transmitted as an autosomal dominant trait, characterized by reduced plasma concentration of C1 esterase inhibitor (type 1) or the presence of non functional C1 esterase inhibitor (type 2). We describe and discuss the case of a 35-year-old man who presented two unusual clinical manifestations of type 2 hereditary angioedema causing diverse emergency situations: acute abdomen and parasellar oedema.     

The pathogenesis of hereditary angioedema.

Hereditary angioedema (HAE), which is characterized by episodic localized angioedema of the skin or mucosa, results from heterozygous deficiency of the plasma protease inhibitor, C1 inhibitor (C1INH). The most obvious biologic role of C1INH, therefore, is prevention of excessive vascular permeability. A variety of data indicate that this role is primarily a product of regulation of the contact system proteases, factor XIIa and plasma kallikrein. The C1INH deficient mouse, although it does not have episodes of cutaneous angioedema, does have increased vascular permeability which is reversed by treatment with C1INH, with the plasma kallikrein inhibitor, DX88, and with the bradykinin 2 receptor (Bk2R) antagonist, Hoe140. In addition, mice deficient in both C1INH and the Bk2R do not have increased vascular permeability. These analyses strengthen the argument that angioedema is mediated by bradykinin. This mouse also provides a system to test new potential therapeutic approaches. In addition to its role in the regulation of vascular permeability, C1INH also is an important modulator of inflammatory responses via regulation of activation of both the contact and the complement systems, and very likely via activities unrelated to protease inhibition.     

Sonographic findings in abdominal hereditary angioedema.

Patients with hereditary angioedema (HAE) may suffer from abdominal pain severe enough to prompt unnecessary surgical intervention. The diagnostic approach to abdominal pain during HAE attacks is not established. We describe abdominal sonographic findings during severe colic in 2 patients with known HAE. Sonography demonstrated marked mucosal thickening and edema of the bowel wall with a variable amount of free peritoneal fluid. These findings are not specific but are consistent with the hypothesized mechanism of attack and resolve after therapy. Abdominal sonography is useful for evaluating acute abdominal pain in patients with known HAE to prevent unnecessary surgery. Conversely, if the described sonographic findings appear in a case of abdominal colic of unknown origin, HAE should be included in the differential diagnosis.     

Treatment of hereditary angioedema: a review (CME)

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent attacks of self‐limiting tissue swelling. The management of HAE has transformed dramatically with recently approved therapies in the United States. However, there is lack of awareness among physicians about these new modalities. The aim of this review is to update the practicing physician about various therapeutic options available for HAE patients. An exhaustive literature search of PubMed and OVID was performed to develop this article. Management of HAE is traditionally classified into treatment of acute attacks or on‐demand therapy, short‐term (preprocedural) prophylaxis, and long‐term prophylaxis. Newer therapies include C1 esterase inhibitor (C1‐INH) and contact system modulators, namely, ecallantide and icatibant. Recombinant C1‐INH, which is available in Europe, is awaiting approval in the United States. C1‐INH concentrate is approved for prophylaxis as well as on‐demand therapy while ecallantide and icatibant are approved for acute treatment only. Effective HAE management further includes patient education, reliable access to specific medications, and regular follow‐up to monitor therapeutic response and safety.     

Immunoblotting of plasma in a pregnant patient with hereditary angioedema.

Hereditary angioedema (HAE), an autosomal disorder caused by a deficiency of C1 inhibitor, is characterized by attacks of localized swelling, laryngeal edema, or abdominal pain. Plasma samples from one pregnant patient were studied serially by functional and quantitative immunochemical assays as well as immunoblot assays for high molecular weight kininogen (HMWK) and/or prekallikrein/kallikrein (PK/K). An immunoblot of this patient's HMWK from plasma obtained before she became pregnant and when she was well revealed that it was mostly an intact protein of 120 kd, similar to immunoblot results of normal plasma HMWK. In plasma samples taken throughout her pregnancy, before, during, and after clinical attacks of angioedema, all of her plasma HMWK was shown to be cleaved into the 45 kd light chain form. After delivery of the infant the 120 kd form of intact plasma HMWK returned to her plasma. In comparison, immunoblot studies on 21 normal and abnormal pregnancies revealed that plasma HMWK was an intact protein at 120 kd. That this patient's plasma during her pregnancy was contact activated was determined by additional immunoblot studies for PK/K. Immunoblot assay for plasma PK/K revealed kallikrein-alpha 2-macroglobulin complexes and a 50 kd PK/K form seen only in activated plasma samples. The findings of kallikrein-alpha 2-macroglobulin complexes and a 50 kd PK/K form disappeared after delivery. These combined studies on this patient show that the structures of HMWK and prekallikrein as indicated by immunoblot assays were altered during pregnancy. Immunoblot assays for detection of changes in the structure of HMWK and prekallikrein may be objective laboratory studies for documenting clinical attacks of hereditary angioedema, their onset, and their resolution.     

Treatment of laryngeal hereditary angioedema

Background

In the emergency department, patients with laryngeal swelling and an inconclusive patient history may receive treatment for allergy-mediated angioedema. Intubation may be necessary if the patient does not respond to treatment. Because angioedema subtypes respond to different interventions, a correct diagnosis is vital.

Objectives

Review the differential diagnosis of angioedema and characteristics differentiating subtypes. Discuss therapies for angioedema subtypes. Introduce therapies for prevention and acute treatment of hereditary angioedema (HAE).

Case Report

A 10-year-old girl presented with laryngeal swelling unresponsive to diphenhydramine, methylprednisolone, and epinephrine. It was later revealed that she had a family history of HAE, was C1 inhibitor deficient, and enrolled in a clinical study of acute HAE treatment. She was given 1000 units of nanofiltered C1 inhibitor and was able to swallow within 30 min. She was prescribed routine prophylaxis with C1 inhibitor concentrate and has had no subsequent severe HAE swelling attacks.

Conclusion

This case illustrates the need for providers to consider HAE in light of available diagnostic testing and recent Food and Drug Administration approval of specific therapies for HAE.     

Urticaria and angioedema: a practical approach

Urticaria (i.e., pruritic, raised wheals) and angioedema (i.e., deep mucocutaneous swelling) occur in up to 25 percent of the U.S. population. Vasoactive mediators released from mast cells and basophils produce the classic wheal and flare reaction. Diagnosis can be challenging, especially if symptoms are chronic or minimally responsive to therapy. A thorough medical history, physical examination, and methodical investigation are necessary to uncover diagnostic clues. Although serious medical illness can occur concurrently with chronic urticaria, acute urticaria generally is benign and self-limited. The mainstay of therapy for urticaria is avoidance of known triggering agents, judicious use of oral corticosteroids, and treatment with long-acting second-generation antihistamines, H2-receptor antagonists, tricyclic antidepressants, and anti-inflammatory leukotriene antagonists. Consultation for investigative therapy may be necessary if symptoms continue despite a stepwise approach to diagnosis and therapy.     

Erythema marginatum and hereditary angioedema

OBJECTIVE: To search for anaphylatoxin activity in plasma during episodes of erythema marginatum, and to evaluate the histology of erythema marginatum by electron microscopy and immunohistologic techniques. METHODS: Plasma samples were studied for C5a activity by granulocyte aggregation, and C3 conversion by immunoelectrophoresis. A skin biopsy of erythema marginatum was done, and the tissue stained with a rabbit antibody to bradykinin. RESULTS: No plasma anaphylatoxin was found. Dense deposits of bradykinin were discovered in stromal tissue and lining endothelial cells. CONCLUSIONS: Bradykinin may be important in the causality of the erythema marginatum associated with hereditary angioedema.     

Protease inhibitors in the treatment of hereditary angioedema.

Deficiency of C1 Inhibitor leads to unopposed activation of complement, with localized, unpredictable, and sometimes life-threatening attacks of angioedema. Treatment with plasma-derived C1 Inhibitor rapidly aborts attacks, and may be lifesaving, but is expensive, requires use of a pooled blood product, may need to be repeated and may not be effective in autoantibody mediated angioedema. The antifibrinolytic agents aprotinin, tranexamic acid, and epsilon-aminocaproic acid are useful for prophylaxis and treatment of angioedema, likely by inhibiting plasmin. Specific drugs to replace the deficient C1 Inh have not been reported. The kallikrein inhibitor DX-88 (Dyax) has received orphan drug status in Europe and is undergoing clinical trial in Europe and the USA.     

Life with hereditary angioedema: then and now

Originally identified in 1882, hereditary angioedema (HAE) is a debilitating and potentially fatal disorder. Although a number of therapies have been identified, many are relatively ineffective or are associated with significant side effect concerns that limit their efficacy. Fortunately, the 2008 approval of plasma-derived C1 esterase inhibitor concentrate for disease prophylaxis provides clinicians with a novel and effective treatment unencumbered with severe side effect concerns for those with this debilitating disorder. However, despite advances in modern medicine, HAE remains a condition marked by a myriad of symptoms that mimic a range of other disorders, from allergic angioedema to acute abdomen, and accurate diagnosis remains a concern. Using articles from the medical literature from the late nineteenth and early twentieth centuries documenting families with HAE, we will review its history and pathophysiology as well as describe current trends in its diagnosis and treatment. Additionally, we will emphasize the humanistic impact of the disorder by describing the real-life experiences of a contemporary family who has documented their experience with HAE across 7 generations.     

How do we treat patients with hereditary angioedema.

Hereditary angioedema (HAE) is due to the inherited deficiency of C1-Inhibitor (C1-Inh). When specific treatment was not available, the mortality rate for this disease was as high as 50% and the disability up to 100-150 days per year (Agostoni and Cicardi, Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients). Such a worrying scenario dramatically improves upon appropriate treatment. Nevertheless, the disease still frequently goes undiagnosed or misdiagnosed as an allergic condition. Both circumstances prevent patients from receiving drugs that could save and/or improve the quality of their life. The interest of our group for patients with HAE goes back to the early seventies. Since that time, 441 such patients have been examined and treated at our department; 403 are still actively followed. Here we present our experience on the treatment of HAE.     

Sudden upper airway obstruction in patients with hereditary angioedema.

Hereditary angioedema (HAE) is clinically characterized by recurrent and self-limiting skin, intestinal, and life-threatening laryngeal edema. This study describes the age at which laryngeal edema first occurred, the time between onset and full development, and the effectiveness of therapy and prophylaxis in 123 HAE patients. 61 (49.7%) patients experienced a total of 596 laryngeal edema episodes. The ratio of laryngeal edema episodes to skin swellings and abdominal pain attacks was approximately 1:70:54 in patients who had laryngeal edema. The mean (SD) age at the first laryngeal edema was 26.2 (15.3) years. Nearly 80% of the laryngeal edemas occurred between age 11 and 45. The mean interval between onset and maximum development of laryngeal edema was 8.3 hours. A total of 354 laryngeal edemas cleared spontaneously without treatment and 208 laryngeal edemas were successfully treated with C1 inhibitor concentrate. Despite long-term prophylactic treatment with danazol, 6 patients developed subsequent laryngeal edemas. Laryngeal edema may occur at any age, although young adults are at greatest risk. In adults, the interval between onset of symptoms and acute risk of asphyxiation is usually long enough to allow for use of appropriate emergency procedures. It is essential to instruct patients and their relatives about the first signs of laryngeal edemas and the necessary procedures to follow.     

Diagnosis and management of hereditary angioedema: an emergency medicine perspective

Background

Hereditary angioedema (HAE) is a rare and often debilitating condition associated with substantial morbidity and mortality in the absence of appropriate intervention. An underlying deficiency in functional C1-inhibitor (C1-INH) protein induces a vulnerability to unchecked activation of the complement, contact, and coagulation/fibrinolytic systems. The clinical consequence is a pattern of recurring attacks of non-pitting, non-pruritic edema, the urgency of which varies by the affected site. Laryngeal edema can escalate rapidly to asphyxiation, and severe cases of abdominal swelling can lead to hypovolemic shock.

Objectives

This report reviews the emergency diagnosis and treatment of hereditary angioedema and the impact of recently introduced treatments on treatment in the United States.

Discussion

Until recently, emergency physicians in the United States were hindered by the lack of rapidly effective treatment options for HAE attacks. In this article, general clinical and laboratory diagnostic procedures are reviewed against the backdrop of two case studies: one patient presenting with a known history of HAE and one with previously undiagnosed HAE. In many countries outside the United States, plasma-derived C1-INH concentrate has for decades been the first-line treatment for acute attacks. The end of 2009 ushered in a new era in the pharmacologic management of HAE attacks in the United States with the approval of two new treatment options for acute treatment: a plasma-derived C1-INH concentrate and a kallikrein inhibitor.

Conclusion

With access to targeted and effective treatments, emergency physicians are now better equipped for successful and rapid intervention in urgent HAE cases.