REVIEW ARTICLE Hereditary Angioedema A Broad Review for Clinicians Ugochukwu C. Nzeako, MD, MPH; Evangelo Frigas, MD; William J. Tremaine, MD ereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10000 to 1 in 150000 persons; HAE has been reported in all races, and no sex predomi- nance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known trig- Hgers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named “type 3” HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal sys- tems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corti- costeroids, antihistamines, and epinephrine can be useful adjuncts but typically are not effica- cious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential di- agnosis of unexplained, episodic cutaneous angioedema or abdominal pain. Arch Intern Med. 2001;161:2417-2429 Angioedema is an intense, usually disfig- prescribed for common ailments, such as uring, temporary swelling of a localized angiotensin-converting enzyme (ACE) body area. It most commonly occurs as inhibitors for hypertension, renal dis- part of an allergic response to exogenous ease, and cardiac disease, can also induce substances and conditions. Such sub- an adverse reaction in apparently healthy stances may be dietary in origin, eg, shell- individuals and result in angioedema. fish and other seafood, or may be envi- ronmental, as is the case with tempera- See also page 2406 ture-related angioedema. The sporadic exogenous phenomena that result in an- In a few individuals, angioedema oc- gioedema may be prevalent in up to 10% curs because of an intrinsic defect that abol- of the population.1 Use of some drugs ishes one of the body’s several safeguards against such occurrences. This defect al- From the Divisions of Gastroenterology (Drs Nzeako and Tremaine), Hepatology lows a cascade of events that culminates in (Drs Nzeako and Tremaine), and Allergy (Dr Frigas), Mayo Clinic and Foundation, symptoms. This form of angioedema oc- Rochester, Minn. curs as a result of either an inherited defect (REPRINTED) ARCH INTERN MED/ VOL 161, NOV 12, 2001 WWW.ARCHINTERNMED.COM 2417 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 in C1 esterase inhibitor (C1-INH) ac- pathophysiology, and genetic basis of in individuals as young as 4 weeks and tivity or an acquired deficiency of C1- the various forms of angioedema has as old as 78 years. Patients with no INH. The inherited form of the broadened considerably. previous history of upper airway in- disease, known as hereditary angio- volvement during acute HAE exac- edema (HAE), is rare, although it is CLINICAL PRESENTATION erbations still run a risk of asphyxi- more common than acquired angio- ating. In a recent study,11 5of6 edema (AAE). Symptoms of HAE are usually mild individuals who asphyxiated during Traditionally, 2 types of HAE or nonexistent during early child- acute HAE had never experienced up- have been described. Type 1 HAE, hood, typically first manifesting dur- per airway involvement during pre- which is estimated to occur in 80% to ing the second decade of life. How- vious attacks. The time from symp- 85% of patients, is caused by the de- ever, a few patients present during tom onset to asphyxiation also varies, creased production of C1-INH, result- their first decade. Although some at- ranging from as little as 20 minutes ing in subnormal blood and tissue in- tacks lack an identifiable trigger, most to as long as 14 hours. Transient pleu- hibitor activity. In type 2 HAE, which are associated with trauma, medical ral effusions, sometimes with cough occurs in the remaining 15% to 20% procedures, emotional stress, men- and mild pleuritic chest pain, can also of patients, normal or elevated quan- struation, oral contraceptive use, in- occur.9 titiesoffunctionallyimpairedC1-INH fections, or the use of medications Gastrointestinal tract symp- are produced. Recently, a third type such as ACE inhibitors.7 toms of HAE, caused by visceral of HAE in which C1-INH levels and Typically, acute HAE mani- edema, result in varying degrees of in- function are normal has been de- fests as marked diffuse edema involv- testinal obstruction. Thus, typical scribed, so far only in women.2 ing all skin layers and layers of the symptoms of gastrointestinal tract in- All types of HAE have identical walls of hollow visceral organs and volvement are anorexia, vomiting, symptoms characterized by edema of solid organs. Most visceral organs are and crampy abdominal pain that can 1 or several organ systems. The skin, susceptible and can be affected sin- be severe. The abdomen is typically gastrointestinal tract, and respira- gly or in any combination. Typical at- tender to palpation, usually without tory tract are most commonly in- tacks of angioedema last approxi- guarding. Ascites, as a result of fluid volved. Cutaneous angioedema in- mately 2 to 5 days before resolving extravasation into the peritoneal cav- volves deeper layers such as the inner spontaneously. Skin edema is non- ity, occurs occasionally. In one dermis and subcutaneous tissue, un- pitting, with ill-defined margins, and study,12 ascites from acute HAE was like urticaria, which is common in most commonly affects areas of the significant enough to cause hypovo- angioedema from other causes and face, extremities, and genitals. Fa- lemic shock; however, the concomi- involves the epidermis and upper der- cial areas typically involved are the tant vasodilation known to occur dur- mis. The absence of pruritus, and the lips, eyelids, and tongue. More of- ing acute exacerbations probably often-present associated visceral ten, genital edema occurs as a result played an additive role. Diarrhea can symptoms, makes angioedema dis- of trauma during intercourse, partu- also occur, particularly as the acute tinguishable from urticaria. rition, and even horseback riding.8,9 episode resolves. Gastrointestinal tract During acute attacks, patients may HAE presenting as severe cramps, HISTORY OF HAE develop a rash similar to that seen in nausea, and vomiting, and unaccom- urticaria. Unlike urticaria, however, panied by cutaneous symptoms, can J. L. Milton first described angio- the skin lesions associated with HAE be mistaken for an acute abdomen. edema in 1876.3 The subsequent ar- are erythematous but not warm, pain- This occasionally leads to unneces- ticle by Quincke in 18824 was the first ful, or pruritic. sary surgical abdominal exploration to assign the name angioneurotic When edema occurs in the walls and the excision of otherwise nor- edema to the disease. A review of the of the respiratory and gastrointesti- mal gallbladders and appendixes. In literature suggests that the word neu- nal tract systems, the most ominous fact, without a high index of suspi- rotic was used as part of the name in and distressing symptoms of HAE oc- cion, gastrointestinal tract HAE may an attempt to describe the observed cur. Thus, laryngeal, nasal, and si- be undiagnosed for decades despite effect of mental stress on exacerba- nus edema may lead to respiratory patients presenting repeatedly to the tions of this disease. In 1888, Wil- tract compromise and death from suf- emergency department with these liam Osler5 published the first ar- focation. In such circumstances, tra- complaints. In such circumstances, ticle describing a hereditary form of cheostomy can be lifesaving because symptoms have occasionally been at- angioneurotic edema; however, dis- the edema associated with acute epi- tributed to psychosomatization, with covery of the biochemical basis for the sodes typically occurs at, or above, the patients inappropriately referred for disease did not occur until several de- larynx. If undiagnosed, mortality from psychiatric assessment. Attacks of gas- cades later. A seminal study pub- HAE can be as high as 30% to 40%, trointestinal tract angioedema gener- lished in 1963 by Donaldson and mostly due to upper airway obstruc- ally subside within 12 to 24 hours, Evans6 first described the biochemi- tion.10,11 Even in those with known whereas cutaneous angioedema per- cal abnormality responsible for HAE: HAE, unnecessary delay in seeking or sists for several days.13 the absence of C1-INH in patients administering appropriate medical Two case reports14,15 describe with the disease. Since that study, the treatment has often resulted in as- migrainelike and transient ische- body of knowledge regarding the phyxiation.