AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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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

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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.

DIFFERENTIALS

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Other Problems to be Considered

Allergic
Inhalants
Bites and stings
Natural rubber latex
Foods (eg, milk, eggs, peanuts, tree nuts, soy, wheat, seafood, sulfites)

Drugs
ACE inhibitors
Beta-lactam antibiotics
Sulfonamides
Aspirin/nonsteroidal anti-inflammatory drugs
Insulin
Dilantin
Streptokinase

Viral infections
Herpes simplex
Hepatitis B
Hepatitis C
Mononucleosis
Coxsackieviruses A and B

Bacterial infections
Dental caries/abscesses
Pharyngitis
Tonsillitis
Sinusitis
Otitis media
Upper respiratory infection
Urinary tract infection

Parasitic infections
Ascaris species
Strongyloides species
Echinococcus species
Toxocara species
Fasciola species
Filaria species
Schistosoma species

WORKUP

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Lab Studies

• Laboratory evaluation of the complement system is essential to diagnose HAE or AAE.
• • In type I HAE, C1-INH and C4 levels are low. C4 levels are low during an attack; they may be normal in between attacks.
  • In type II HAE, which is characterized by normal levels of C1-INH that is dysfunctional, a functional or qualitative assay of C1-INH must be performed before the diagnosis can be excluded. C4 levels are low during an attack.
  • In type III HAE, C1-INH levels and function and C4 levels are normal at all times.
  • In HAE and AAE, C4 levels are low during angioedema episodes but may be normal in between episodes. C4 can be used for screening between angioedema episodes, with the understanding that a normal level does not rule out the diagnosis.
  • To differentiate between AAE and HAE, the C1q level should be measured. The hallmarks of AAE are low C1q, C2, C4, and C1-INH levels. In HAE, C1q levels are usually normal or only slightly decreased. Levels of C1q are rarely less than 50% of the normal values in HAE; in AAE, C1q levels are less than 10% of the normal values.
• Complete blood cell count: Leukocytosis should be absent. If leukocytosis is present, an infectious etiology should be sought. The white blood cell count may be elevated secondary to hemoconcentration.
• Electrolytes: Abnormalities may be present secondary to vomiting and diarrhea. Prerenal renal failure can also result from intravascular volume depletion.
• If time permits, a blood sample should be submitted for a type and crossmatch and for determination of the prothrombin time and activated partial thromboplastin time before surgical airway intervention is instituted.

Imaging Studies

• Plain abdominal films may show a "stacked coin" or "thumbprint" appearance of the intestines.
• A chest film may show pleural effusion.
• A soft tissue neck film may show soft tissue swelling.
• A CT scan image of the abdomen may show severe edema of the bowel wall.

Procedures

• Airway protection is the most important consideration in patients with angioedema. In cases of possible airway compromise, early intervention with intubation may be preferred. Intubation may be exceedingly difficult, and advanced techniques (eg, fiberoptic intubation) may be necessary. In severe cases of laryngeal edema, a surgical airway must be created via cricothyrotomy or tracheotomy.

TREATMENT

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Medical Care

• Acute attacks
• • Voice changes (eg, hoarseness, stridor, muffling) are indications that airway intervention should be strongly considered. In urgent but nonemergent cases, orotracheal intubation is the preferred method. When laryngeal edema is severe, a surgical airway must be created via cricothyrotomy or tracheotomy.
  • Attain intravenous access with large-bore line.
  • Fluid resuscitation may be necessary.
  • Continuously monitor vital signs.
  • Epinephrine, corticosteroids, and antihistamines are not effective in patients with HAE, AAE, and ACE inhibitor–induced angioedema. These agents are recommended as second-line therapy. In cases of angioedema due to allergic causes, these medications are first-line therapies (see Anaphylaxis).
  • Vapor-heated C1-INH concentrate (recommended dosage 500-2000 U IV) is the first-line therapy for acute attacks of HAE or AAE, and was recently approved by the FDA in the United States for routine prophylaxis. When vapor-heated C1-INH concentrate is unavailable, fresh frozen plasma (FFP) (2 U IV) may be used. FFP may worsen an attack by providing substrates of complement that may exacerbate angioedema; however, this treatment is being used by many centers in this situation, given the lack of other available therapies, and most do not report any difficulties.
  • Other treatment options for acute attacks include antifibrinolytic agents (eg, tranexamic acid, epsilon-aminocaproic acid). These agents probably act by inhibiting plasmin, which plays a role in initiating the complement cascade. Tranexamic acid is not approved for treatment of HAE or AAE in the United States.
• Long-term prophylaxis
• • Long-term prophylaxis is indicated when a person is experiencing more than 2 attacks per month or if the airway is compromised continuously. Some authors recommend that long-term prophylaxis be considered in any patient with HAE affecting any organ system, regardless of the number of previous episodes.
  • The agents of choice are the synthetic androgens danazol and stanozolol. Androgenic agents are effective because they induce messenger-RNA synthesis in the liver and directly increase C1-INH levels. Stanozolol and danazol have the same efficacy, but stanozolol has less masculinizing potential. In pediatric patients, antifibrinolytic agents are recommended as the first choice because of their favorable safety profile.
  • Epsilon-aminocaproic acid and tranexamic acid have been used successfully to prevent bouts of HAE and AAE.
• Short-term prophylaxis
• • Dental procedures or elective surgery of the oropharyngeal region often precipitates acute bouts of HAE or AAE. Therefore, short-term prophylaxis is necessary.
  • A combination of FFP, vapor-heated C1-INH concentrate (if available), and androgen therapy is the regimen of choice.
• Treatment of the underlying disorder associated with AAE (ie, malignancy) usually results in correction of the abnormality.
• Patients who have had angioedema related to an ACE inhibitor must be cautioned against resuming that drug or using another drug in the class at any time. In addition, it is becoming recognized that these patients may be at risk for angioedema if taking an angiotensin receptor antagonist; their use should be considered only if no other option is available.
• Therapies currently under investigation for HAE and AAE include the following (For more information, see United States Hereditary Angioedema Association.):
• • C1 inhibitor concentrates (Pharming and Lev Pharmaceuticals) are currently undergoing clinical testing.
  • A kallikrein inhibitor, DX-88 (Dyax/Genzyme), is currently undergoing an open-label trial for use in HAE and AAE.
  • B2 bradykinin receptor antagonist, Icatibant (Jerini Pharmaceutical), is also undergoing clinical trials.

Consultations

Consultation with an allergist or an immunologist is recommended in the management of HAE or AAE.

MEDICATION

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The goal of medical treatment for HAE and AAE is to either increase levels of C1-INH (eg, C1-INH concentrate, androgens) or to limit mediators of the complement cascade (eg, antifibrinolytic agents).

Drug Category: Androgens

Induce messenger-RNA synthesis in the liver and directly increase C1-INH. Agents of choice for long- and short-term prophylaxis.

Drug Category: Hemostatic agents

Mechanism of action in the treatment of HAE and AAE is unknown. Most likely related to inhibition of plasmin.

Drug Category: Vasopressors

In angioedema caused by drugs and foods, catecholamines improve vascular permeability, vascular resistance, and bronchodilation. Less effective in HAE and AAE, but used as second-line therapy.

Drug Category: Antihistamines

Histamine causes increased vascular permeability. Blocking this effect at the receptor level provides symptomatic relief.

Drug Category: Glucocorticoids

Anti-inflammatory actions inhibit the late-phase response to allergens. Inhibit inflammatory cell proliferation and release of mediators that can cause increased capillary permeability and bronchoconstriction observed in anaphylaxis.

Drug Category: Serine Proteinase Inhibitors (serpins)

Used for routine prophylaxis against angioedema attacks.

FOLLOW-UP

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Further Inpatient Care

• Patients with oropharyngeal involvement should be admitted to either an intensive care unit or an intermediate care unit, depending on the severity of the angioedema (ie, lip vs tongue and soft palate involvement).
• If available, an in-house ear, nose, and throat specialist should be notified of the patient's condition and the possibility that a surgical airway or use of equipment for direct laryngoscopy may be needed. In this regard, an anesthesiologist should also be notified of the potential for airway compromise.
• All hospitalized patients should be monitored continuously with pulse oximetry.
• Continued analgesia and fluid resuscitation are also concerns in patients with HAE or AAE.

Further Outpatient Care

• Patients with HAE or AAE should follow up with an allergist and an immunologist as soon as possible.

In/Out Patient Meds

• Long-term prophylaxis with androgens is needed for patients with monthly attacks or a history of airway compromise.
• In children, long-term prophylaxis with aminocaproic acid reduces attacks by 80%.
• Prophylaxis is needed before any dental or oropharyngeal procedure (ie, 5-10 d preoperatively and 3 d postoperatively). Shortly before the intervention, FFP should be administered.
• Before emergent procedures, purified C1-INH may be administered. In addition, women who are pregnant may receive C1-INH before delivery. This has no effect on C1-INH levels in the newborn because C1-INH does not cross the placenta.

Complications

• The most dreaded complication of angioedema is complete airway obstruction caused by laryngeal edema. This type of airway swelling is usually less severe 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.

Patient Education

• More information is available from the United States Hereditary Angioedema Association.
• For excellent patient education resources, visit eMedicine's Allergy Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Hives and Angioedema.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to consider the diagnosis, especially in patients with the classic triad of abdominal pain, peripheral edema, and laryngeal edema
• Failure to intervene early by securing the airway in patients with oropharyngeal involvement
• Failure to instruct patients who have had ACE inhibitor–related angioedema that they have a lifelong prohibition from taking the drug again as well as any others in the class is a pitfall. This information must also be communicated to the patient's primary care provider.

MULTIMEDIA

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Media file 1:  The mechanism of angioedema resulting from C1-esterase inhibitor deficiency.
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Media type:  Graph

Media file 2:  Man with angioedema involving the lips.
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Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Oct 20, 2008