Introduction
Background
Angioedema is characterized by painless, nonpruritic, nonpitting, and well-circumscribed areas of edema due to increased vascular permeability. Angioedema is most apparent in the head and neck, including the face, lips, floor of the mouth, tongue, and larynx, but edema may involve any portion of the body. In advanced cases, angioedema progresses to complete airway obstruction and death caused by laryngeal edema. Angioedema may involve the gastrointestinal tract, leading to intestinal wall edema, which results in symptoms such as colicky abdominal pain, nausea, vomiting, and diarrhea.
Angioedema can occur as a result of (1) hereditary angioedema (HAE); (2) acquired angioedema (AAE); (3) angioedema associated with allergic reactions, which is often associated with urticaria; (4) angioedema secondary to medications; and (5) idiopathic angioedema. In this article, the hereditary and acquired forms are discussed in detail. Angioedema induced by drugs, specifically angiotensin-converting enzyme (ACE) inhibitors, is explored briefly. Angioedema related to reactions mediated by immunoglobulin E is discussed in Anaphylaxis.
In 1888, Osler first described HAE when he treated a 24-year-old woman for chronic episodic attacks of edema. By interviewing the woman’s 92-year-old grandfather, Osler learned that 5 successive generations of the family had a history of similar attacks. Osler proposed an inherited etiology and named the entity hereditary angioneurotic edema. In 1917, Crowder and Crowder determined that the condition is inherited as an autosomal dominant trait.
In 1963, Donaldson and Evans determined that an inherited deficiency of C1-esterase inhibitor (C1-INH) is at the core of this disease. C1-INH is one of the first components of the complement system. Classically, two phenotypic variants of this disorder have been described, and, more recently, a third type has been proposed.
In type I, which accounts for 80-85% of cases of HAE, serum levels of C1-INH (as determined by immunoassays) are low. In type II, patients have normal or elevated levels of C1-INH (as determined by immunoassay) but this C1-INH is dysfunctional (as determined by a functional assay). This deficiency in functioning C1-INH leads to autoactivation of the complement system and release of kininlike mediators, resulting in edema of the subcutaneous or submucosal tissues. The third, recently proposed variant has been labeled as HAE type 3. This type has been seen only in women and is thought to have an X-linked dominant mode of inheritance. These patients have normal C1-INH levels and function.
The exact mediators of this variant are unknown, but they are thought to act somewhere beyond kallikrein in the sequence of reactions.
AAE is a rare syndrome. Like HAE, AAE has 2 distinct forms. Type I is characterized by diminished levels of C1-INH secondary to its increased catabolism. Type I AAE is associated with lymphomas, chronic lymphocytic leukemia, and other lymphoproliferative diseases. Although the exact mechanism by which these lymphoproliferative diseases lead to angioedema is not clear, the underlying cause is thought to be the formation of immune complexes that increase consumption of C1-INH. In AAE type II, no lymphoproliferative or other underlying diseases are apparent but autoantibodies secreted by a subpopulation of B cells bind to the reactive center of C1-INH, altering its structure and regulatory capacity. Also worth noting is that autoantibodies have also been reported in type I AAE.
Approximately 94% of cases of angioedema presenting at the emergency department are drug induced. Most drug-induced angioedema is found in patients taking ACE inhibitors. As with HAE and AAE, life-threatening laryngeal edema and airway obstruction are major concerns. As many as 22% of patients with ACE inhibitor–induced angioedema require intubation, with an overall patient mortality rate of 11%. About 0.1-0.2% of patients treated with ACE inhibitors develop angioedema.
Pathophysiology
C1-INH is a serum alpha-2 globulin molecule and a member of the serpin family of protease inhibitors. The gene for C1-INH maps to chromosome 11. The gene is translated by hepatocytes as a single-chain glycoprotein containing 478 amino acids with a molecular weight of 105 kd. C1-INH is the only known plasma inhibitor of C1r and C1s, the activated proteases of the first component of the complement system. The complement system is a cascade reaction of approximately 20 components, which, when unopposed, results in increased vascular permeability and edema. C1-INH forms stable complexes with C1r and C1s by binding near or at their active sites, rendering them unable to cleave their natural substrates. Other targets of C1-INH include components of the coagulation cascade (eg, factors XIa, XIIa, XIIf), plasmin, and kallikrein, which is involved in the generation of bradykinin.
When C1-INH levels fall below 30% of the reference range, whether secondary to decreased production, dysfunction, or destruction, a domino effect occurs, leading to angioedema. Uncontrolled complement activation leads to the production of cleaved C2 kinin, a vasoactive molecule that causes angioedema. In addition, C1-INH is a major inhibitor of kallikrein, which converts high molecular weight–kinogen to bradykinin. The plasma bradykinin level rises substantially during acute attacks of hereditary, acquired, and ACE inhibitor–induced angioedema. Bradykinin has been shown to cause vasodilation, increased vascular permeability, and hypotension when injected intravenously into humans.
Bradykinin has been proposed as the primary mediator involved in angioedema caused by ACE inhibitors. ACE inhibitors work by blocking the action of the enzyme kinase II, which is involved in the conversion of angiotensin I to angiotensin II. Angiotensin II, a potent vasoconstrictor, is involved in the inactivation of bradykinin. When ACE inhibitors are used, angiotensin I is not converted to angiotensin II, leading to increased levels of bradykinin and angioedema. Angioedema is rare in patients taking angiotensin II AT1 receptor antagonists
Frequency
United States
Angioedema that is not secondary to HAE or AAE affects 10-20% of the population at some time in their lives. HAE is a rare condition, found in 1 per 150,000 persons. By some estimates, HAE may account for 15,000-30,000 emergency department visits yearly. AAE is even more rare; until 1997, fewer than 50 cases had been reported in the literature. The incidence of angioedema with the use of ACE inhibitors is reported to be 1-2 cases per 1000 persons.
International
Occurrence rates are believed to be similar to those in the US reports.
Mortality/Morbidity
Acute laryngeal edema is the major cause of angioedema-related mortality. Two thirds of people with HAE experience an episode of airway compromise. Unfortunately, 14-33% of persons die during these episodes because of airway compromise. In addition, life-threatening airway obstruction requiring intubation has been reported in as many as 22% of cases of ACE inhibitor–induced angioedema, leading to an overall mortality rate of 11%.
Race
No racial predilection is found in HAE or AAE. ACE inhibitor–induced angioedema is reported to be more common in African Americans than in individuals of other racial groups.
Sex
An equal distribution exists between males and females.
Age
The onset of HAE usually occurs by the first or second decade, but diagnosis in the fourth and fifth decades is not unusual. Most cases of AAE occur in individuals aged 50 years or older.
Clinical
History
Patients with HAE and those with AAE present with similar symptoms. Two thirds of the people with HAE present by age 13 years, and the onset of AAE usually occurs after the fourth decade.
The classic symptom triad involves severe colicky abdominal pain, peripheral edema, and laryngeal edema in the absence of urticaria.
Abdominal pain is accompanied by vomiting in 88% of patients and diarrhea in 22% of patients. Diarrhea is caused by intraluminal fluid in the edematous gut.
Extremity swelling is found in 75% of patients.
In 25% of patients, a prodromal rash resembling erythema marginatum occurs and blossoms over 1-4 days into true angioedema. This rash must be distinguished from urticaria. Urticaria is not associated with either HAE or AAE. If urticaria is present, consider a diagnosis other than HAE or AAE.
The most dreaded complication of angioedema is complete airway obstruction caused by laryngeal edema. This type of airway swelling is usually less acute than that associated with anaphylaxis. Patients with upper airway involvement present with hoarseness and dysphagia, which may gradually progress to upper airway obstruction over a period of hours.
In general, a course of angioedema develops fully within a few hours and fades in 48-72 hours, but it can persist for as long as 1 week.
Other symptoms include urinary bladder retention, pleural effusion with cough, and pleuritic chest pain.
Central nervous system symptoms (eg, headache, hemiparesis, seizures) may occur secondary to focal cerebral edema.
Physical
Angioedema of the submucosal and subcutaneous tissue is tense, nonpitting, nonpruritic, and nonerythematous.
Angioedema involves the extremities in 75% of patients and the face in 36% of patients.
Abdominal pain may be severe. Examination of the abdomen may reveal bowel sounds that vary from normal to high-pitched. Pain is usually diffuse, with no rigidity or peritoneal signs.
ACE inhibitor–induced angioedema most commonly affects the face but can affect any area of the body. In milder cases, a facial rash is present. When facial involvement progresses, edema of the soft palate, tongue, and larynx develops.
Causes
Several precipitants of angioedema in HAE are known, including the following:
Mental and physical stress
Trauma
Dental or surgical procedures
Infections
Menstruation
Pregnancy
Oral contraceptives containing estrogens
In AAE type I, diminished levels of C1-INH are associated with lymphoproliferative malignancies, including the following:
Chronic lymphocytic leukemia
Waldenström macroglobulinemia
Lymphosarcoma
Non-Hodgkin lymphoma
Essential cryoglobulinemia
Lymphocytic lymphoma
Myeloma
No underlying disease is present in patients with type II AAE, but patients have autoantibodies directed at C1-INH. The result is depletion of C1-INH, precipitating angioedema.
At the core of angioedema induced by ACE inhibitors is a decreased level of angiotensin II, which leads to increased levels of bradykinin. No correlation exists between the initiation of ACE inhibitor therapy and the clinical findings of angioedema. Although symptoms can occur within a few hours to several years, most patients (69-100%) are symptomatic within the first week of therapy. An otherwise stable patient developing angioedema after the ACE inhibitor dose is increased is not an unusual occurrence.