Acquired Angioedema: A Challenging Diagnosis

Angioedema is a hypersensitivity disorder that presents as edema of the subcutaneous tissues and mucosa, typically involving the upper airways or gastrointestinal tract, and often accompanied by urticaria. Although this condition could be either hereditary or acquired, the causes often overlap, with similar clinical manifestations. Diagnosis requires laboratory testing to determine serum complement levels. Treatment must be directed toward the resolution of the acute symptoms and prevention of recurrence.

Atul Kukar, DO, Fellow, Department of Cardiology, St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons; Rashmi Chawla, MD, Resident, Department of Medicine, St. Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons; Ira Finegold, MD, Assistant Clinical Professor of Medicine, Columbia University College of Physicians and Surgeons, Chief, Allergy and Immunology, St. Luke's-Roosevelt Hospital Center, New York, NY

Acquired angioedema is a unique disease characterized by repeated bouts of noninflammatory edema in the subcutaneous tissues or mucosa. The sites most often affected are the upper respiratory tract and the gastrointestinal (GI) tract. Angioedema can present with life-threatening airway obstruction or with abdominal symptoms that mimic an acute abdomen. The disease can be either hereditary or acquired. The nonfamilial (ie, acquired) form was first described in 1972,¹ and the hereditary form was described in 1882² and named by William Osler in 1888.³ The 2 types are similar in clinical presentation and both are caused by a deficiency or qualitative defect of, or antibody against C1 esterase inhibitor, a component of the complement system.

Etiology

Angioedema is caused by extravasation of fluid into interstitial tissue as a result of the release of inflammatory mediators that increase permeability and dilate capillaries and venules. In contrast, edema is caused by an alteration in Starling's forces, such as an increase in intracapillary pressure or decrease in capillary plasma oncotic pressure.⁴ Distinguishing between the 2 entities is often easy, because unlike edema, angioedema has a rapid onset (minutes to hours); is asymmetric in distribution; often involves the lips, throat, or bowel; and is usually not found in dependent areas.

Angioedema can be divided into 4 basic categories: immunologic, nonimmunologic, miscellaneous, and idiopathic. Immunologic etiologies are either immunoglobulin (Ig) E dependent or complement associated. In IgE-dependent cases, a specific antigen sensitivity is present, such as a sensitivity to drugs, foods (eg, fresh fruit), insect bites, or latex. The complement-associated type includes hereditary and acquired angioedema and immune-complex conditions, such as serum sickness or necrotizing vasculitis.

Nonimmunologic cases are usually caused by direct mast cell degranulation or interference with arachidonic acid metabolism by agents such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or food additives (eg, tetrazine, benzoates). Mast cell-mediated cases are due to the release, via degranulation, of inflammatory mediators, such as histamine, heparin, leukotriene C4, or prostaglandin D². The majority of these cases are associated with pruritus. Examples of agents that can induce mast cell degranulation include narcotics, muscle relaxants, vancomycin (Vancocin, Vancoled), and radiographic contrast media.

The non-mast cell induction of angioedema, another nonimmunologic cause, is not associated with pruritus. It is characterized by increased activity of the vasodilator kinin pathway or abnormalities of the complement pathway. For example, it is believed that angiotensin-converting enzyme (ACE) inhibitors may induce angioedema by raising bradykinin levels secondary to a decrease in angiotensin II and prevention of the metabolism of substance P, both of which are potent mediators of tissue inflammation.

Other causes of angioedema include physical stimuli, such as exercise, cold, water, or even light. A small proportion of patients with hypereosinophilic syndromes may develop angioedema. Despite the existence of a myriad of etiologies, most cases of angioedema remain idiopathic.

Acquired angioedema has a high correlation with malignancies. In one review, 14 of 22 patients with acquired C1 esterase inhibitor deficiency had a lowgrade lymphoproliferative disorder.⁵ Associated malignancies included lymphosarcoma, chronic lymphocytic leukemia, B-cell lymphoma, Waldenström's macroglobulinemia, and multiple myeloma. C1 inhibitor deficiency has also been linked to connective tissue disease. However, in the absence of clinical signs or symptoms, an extensive workup for occult malignancy or rheumatic disease is usually not necessary.

Pathophysiology

It is necessary to understand the complement pathway to appreciate how hereditary and acquired angioedema occur and which tests are appropriate. The complement system describes the multitude of proteins involved in sequential activation that culminates in cell lysis. The 3 known pathways of this cascade are the classic,⁶ alternative, and lectin-or mannan-binding pathway. The classic pathway (ie, the first one discovered) is mediated by the binding of an antibody to the first component (C1) of the complement system. The alternative pathway is mediated by the binding of an antigen to C3b. This pathway is considered to have existed before the classic pathway as a form of innate immunity, whereas the classic pathway is adaptive in nature. The lectin pathway is similar to the classic but is activated by lectin binding to certain proteases instead of an antibody binding to C1.

If C1 esterase inhibitor (a factor participating in stopping the autoactivation of C1 and ceasing the conversion of C2 and C4) is lacking, nonfunctional, or autoantibodies against it exist, inhibition of the complement, kinin, and coagulation cascades is defective. Specifically, the proteases C1r, C1s, and kallikrein are no longer regulated appropriately. Triggering factors, such as local trauma or stress, activate the classic pathway, cleave high-molecularweight kininogen in the contact system, and generate plasmin, all leading to the release of vasoactive peptides that cause angioedema.⁷

Bradykinin, a potent vasodilator that increases vascular permeability, seems to play an important role in the pathogenesis of angioedema. Without C1 inhibitor, these triggers cause an abnormal, exaggerated response from these systems. Thus, histamine does not seem to play a role in the development of this type of angioedema and may help explain why antihistamine treatment for severe allergic reactions is not as effective in these cases.

Hereditary cases are divided into 2 types; most are caused by a low level of C1 inhibitor (type I); the remaining are caused by a nonfunctional C1 inhibitor (type II). Even though the hereditary form is autosomal dominant, only about half the patients have a positive family history.⁸

The acquired form also has 2 variants, either a low level of C1 inhibitor (<30% of normal) or an autoantibody directed against it. The former is believed to be secondary to excessive activation and consumption of the C1 inhibitor and is usually associated with lymphoproliferative disorders or other malignancies.

Signs and Symptoms

Signs and symptoms of angioedema include localized edema, abdominal cramping, and difficulty breathing. They could also include the sudden development of painful, pruritic wheals or welts associated with urticaria. Hereditary angioedema usually manifests in late childhood after trauma, dental procedures, or stress. An increased frequency is common during puberty, menses, ovulation, or the initiation of oral contraceptive therapy. In contrast, the acquired form often presents later in life and is usually not associated with a family history.

Both the hereditary and acquired types of angioedema present with acute, circumscribed, noninflammatory edema of the subcutaneous tissue that could have involvement of the mucosa of the respiratory and GI tracts. The subcutaneous edema can be anywhere in the body but is most common in the limbs, face, or genitals. When presenting elsewhere, the edema is usually painless, nonpruritic, nonerythematous, and without pitting, and often resolves within 2 to 3 days.

The GI tract is commonly involved, anywhere from the tongue to the colon. A majority of patients have abdominal pain, ranging from a dull ache to severe pain mimicking an acute surgical abdomen. Associated symptoms include nausea, vomiting, anorexia, and even distention. Some patients present with diarrhea alone. Rarely, obstruction or toxic megacolon occurs.

Physical examination findings vary from mild tenderness to peritoneal signs. A computed tomography (CT) scan will commonly demonstrate marked thickening of the bowel wall, as is seen in colitis (Figure 1). Many times, these patients undergo unnecessary surgery.

The genitourinary tract may also be involved, causing acute urinary retention, often with hematuria. Patients also often experience headaches, although the reason for this remains unclear. Angioedema itself is not known to cause a febrile illness.

Death is most likely to occur when the respiratory tract is involved. Without immediate intervention, acute airway closure can lead to asphyxiation and death. Before the introduction of prophylactic treatment, approximately 25% of patients died from this reaction.⁹

Diagnosis

In the initial screening of patients with angioedema, focus on the presence or absence of urticaria (Figure 2). Urticaria is caused by cutaneous mast cell degranulation in the superficial dermis, whereas angioedema involves the deeper layers of the dermis and the subcutaneous tissues. Urticaria is usually intensely pruritic, appearing as raised, erythematous lesions, often with a central pallor. When urticaria, generalized pruritus, or hypotension is present, the mast cell system is usually involved. In these cases, internal and external triggers (ie, foods, drugs, insects) should be sought. In contrast, chronic angioedema with urticaria is most often caused by autoimmune disease, such as Hashimoto's thyroiditis,¹⁰ or drug reactions (eg, NSAIDs). A patient with no urticaria will most likely either have a hereditary or acquired form of angioedema, or a reaction to medications (especially ACE inhibitors and angiotensin II receptor blockers).

Laboratory tests are essential in establishing the diagnosis of angioedema syndromes. Many assays of the complement system are available. The first assay usually performed is the total hemolytic complement (CH⁵⁰) screen, which measures the functional activity of C1 through C9. The level of a component must be reduced by more than 50% before CH⁵⁰ decreases. A normal result indicates that the classic pathway is functionally intact.

Measurement of serum C4 is the most reliable screening test in both hereditary and acquired angioedema, since its levels decrease even when the patient is asymptomatic. Angioedema can be excluded if C4 level is normal during an attack. Serum C3 concentration remains normal in both hereditary and acquired angioedema. Serum C1 and C1q (a subcomponent of C1) values remain normal in the hereditary form and are depressed in the acquired form.

C1 inhibitor may be directly evaluated by radioimmunoassay for level and functional capacity. Alow level (&#8804;30% of normal) is usually helpful in confirming the diagnosis of deficient C1 inhibitor. The functional test helps distinguish between the 2 types of hereditary angioedema. In the 85% of patients with type I hereditary angioedema, serum C1 inhibitor levels are low (5%-30% of normal), while C1 inhibitor structure and function are normal.¹¹ The 15% of patients with type II hereditary angioedema have normal or sometimes elevated serum levels but abnormal C1 inhibitor structure and function.¹¹

Treatment

Treatment of angioedema always begins with an assessment of the airway to prevent life-threatening complications. When the larynx is involved, laryngoscopy is usually necessary to evaluate the extent of internal swelling. Epinephrine (1:1000 in 0.3-0.5 mL doses every 15 minutes) may sometimes be required. Antihistamines, both H¹ and H² blockers, can also be administered. The addition of an H² blocker has been shown to have some added benefit and is thus recommended as adjunctive therapy.¹² Corticosteroids are usually administered to help deter any delayed swelling.

In contrast to the allergic types of angioedema, C1 esterase inhibitor deficiency usually responds poorly to such treatment modalities. A concentrate of C1 inhibitor, delivered intravenously, is believed to be the most effective treatment. One concern is that this product can transmit hepatitis or HIV infection. It should therefore be limited to patients with laryngeal involvement or with severe abdominal pain.⁷ However, a study using C1 inhibitor concentrate that was vapor-heated (to destroy the viral contaminants) showed a vast decrease in the time to resolution of symptoms and was deemed to be safe.¹³ Fresh frozen plasma contains C1 inhibitor and has been used with mixed results; some case reports have shown efficacy in ACE inhibitor-induced angioedema.¹⁴ However, it may worsen angioedema since it also contains the complement substrates.

Aside from airway management and research agents, the standard treatment of acquired angioedema consists of attenuated androgens, which are thought to increase the hepatic synthesis of C1 esterase inhibitor. Stanozolol (Winstrol) or danazol (Danocrine) may be used for both an acute episode and prophylaxis. For example, 4 doses of stanozolol, 4 mg, can be given initially and then continued at 4 mg/day. Response to therapy can be determined by a reduction in symptoms and an increase in C4 levels. As the C4 level returns to normal, the patient should be symptom free. In a few studies, prophylactic danazol showed marked efficacy in averting attacks.¹⁵ Although the C1 inhibitor level will not approach normal, once it is more than 30% of normal, symptoms usually subside. The amount of androgen necessary to maintain a clinical response is usually less than the initial dose and can be tapered based on a lack of symptoms and an increase in serum C4 level. Even patients with dysfunctional C1 inhibitor respond to this treatment.

Helicobacter pylori

H pylori

Some novel approaches using antifibrinolytic agents, including epsilon-aminocaproic acid (Amicar) or tranexamic acid (Cyklokapron), have been effective in treating both the hereditary and acquired forms of angioedema. However, these are associated with intravascular thrombosis and thus are dangerous. Some cases of refractory angioedema have been associated with infections. In one study, only after the infection had been eradicated were androgens effective in curtailing the attacks.¹⁶

Prophylaxis

Once diagnosed, prophylaxis becomes an essential part of angioedema management. Because trauma is one of the most common triggers, elective operations—especially head and neck surgery, intubation, upper endoscopy, bronchoscopy, or dental work are usually preceded by an increase in the dosage of the androgen 5 days before surgery. Some protocols advocate the preoperative use of concentrated C1 inhibitor, especially when emergency intervention is required.

Conclusion

Angioedema is often coupled with urticaria. Recurrences are common, and once the condition is recognized, long-term prophylaxis is indicated. Early recognition of respiratory tract involvement is essential to prevent life-threatening complications. Patients taking medications that have been shown to induce angioedema are susceptible to additional attacks. Discontinuing the medication whenever possible is advised. Patients with hereditary angioedema should be referred to an immunologist.

SELF-ASSESSMENT TEST

1. All these features are characteristic of angioedema, except:

1. Rapid onset
2. Symmetrical distribution
3. Lip involvement
4. No edema in dependent areas

2. Which of these medications that can induce angioedema is NOT associated with pruritus?

1. ACE inhibitors
2. Muscle relaxants
3. Narcotics
4. Vancomycin

3. All these statements about angioedema are true, except:

1. Most cases are idiopathic
2. Hereditary angioedema is frequently associated with malignancy
3. Hereditary angioedema usually manifests in late childhood
4. Headache is a common symptom

4. Which of these laboratory findings is most characteristic of acquired angioedema?

1. Normal C1 level and decreased C4 level
2. Normal C2 level and decreased C1 level
3. Normal C3 level and decreased C1 level
4. Normal C4 level and decreased C3 level

5. All these treatments are usually safe and effective, except:

1. Epinephrine
2. Stanozolol
3. Epsilon-aminocaproic acid
4. Danazol

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Answers:

1. B; 2. A; 3. B; 4. C; 5. C