eMedicine Specialties > Dermatology > Allergy & Immunology

Angioedema, Acquired

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey
Amanda Carolfi, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School

Updated: Aug 18, 2009

Introduction

Background

Angioedema is most commonly associated with acquired urticaria. The evaluation and management are similar to those for urticaria. Two distinct syndromes unassociated with urticaria are described below. Both distinct types of acquired angioedema (AAE) without urticaria are characterized by painless, nonpruritic, nonpitting swelling of the skin. They are classified into 2 forms: acquired angioedema type I (AAE-I) and acquired angioedema type II (AAE-II). Acquired angioedema type I is associated with other diseases, most commonly B-cell lymphoproliferative disorders. Acquired angioedema type II is an autoimmune process defined by the presence of an autoantibody directed against the C1 inhibitor molecule (C1-INH).

Pathophysiology

The gene for C1-INH (SERPING1) has been mapped to chromosome 11 (11q12-q13.1). C1-INH is a multifunctional serine protease inhibitor that is normally present in high concentrations in plasma. It is the only plasma inhibitor of C1r and C1s, the activated proteases of the first component of complement. It is also the major plasma inhibitor of activated Hageman factor, the first protease in the contact system. Additionally, C1-INH is one of the major inhibitors of plasma kallikrein, the contact system protease that cleaves kininogen and releases bradykinin.
Presumably, uncontrolled activation of the contact system allows for release of kininlike mediators, resulting in vascular permeability with edema of subcutaneous and mucosal tissues.

Although the issue of which vasoactive peptide is ultimately responsible for these changes remain controversial, direct evidence supports the importance of bradykinin in the clinical manifestations of angioedema. Other kinins may also be pathogenic. The specific trigger responsible for inducing the release of these vasoactive peptides is unclear. Factor XII activation (Hageman factor) may be secondary to phospholipid release from damaged or apoptotic cells and may be important in the generation of bradykinin from endothelial activation. This hypothesis encompasses the role of illness or tissue injury in the generation of bradykinin. 

Supporting the importance of bradykinin in acquired angioedema, vascular permeability has been shown to increase in mice deficient in C1-INH, but not in mice with a deficiency in both C1-INH and the bradykinin B2 receptor.¹ The precise pathophysiology of acquired angioedema type I remains to be defined. C1-INH levels diminish as a result of its increased catabolism and excessive activation of the classic complement pathway.

Although the current classification of acquired angioedema is being readdressed, in acquired angioedema type I, the associated disorders (usually lymphoproliferative malignancies) produce complement-activating factors, idiotype/anti-idiotype antibodies, or other immune complexes that destroy C1-INH function. Neoplastic lymphatic tissue has been found to play an active role in the consumption of C1-INH and the complement components of the classic pathway. The most commonly associated malignancy, B-cell lymphoma, has shown that anti-idiotypic antibody attached to immunoglobulin on the surface of B-cells causes C1-INH deficiency. Increased consumption of C1q followed by C2 and C4 results in subsequent release of vasoactive peptides that act on postcapillary venules.

In acquired angioedema type II, a normal 105-kd C1-INH molecule is synthesized in adequate amounts, but, because of an unknown event, a subpopulation of B cells secretes autoantibodies to the C1-INH molecule. This autoantibody, which may be any of the major immunoglobulin classes, binds to the reactive center of C1-INH. After binding to C1-INH and altering its structure, its regulatory capacity is diminished or abrogated.

In all reported cases of C1-INH deficiency caused by an autoantibody, C1-INH circulates in the blood in a form that has been cleaved by target proteases from its native molecule to a 95-kd fragment. Because of the higher affinity of the autoantibody for native C1-INH, the 95-kd antibody/C1-INH complex dissociates, and the freed antibody can bind to another native C1-INH molecule, allowing for the further depletion of C1-INH.

The distinction between acquired angioedema type I and acquired angioedema type II may be difficult to make at times and it is imperative to stress that overlap does occur. For instance, cases of monoclonal gammopathy of undetermined significance (MGUS) have shown the monoclonal immunoglobulin itself to be the C1-INH antibody. Regarding malignancies and/or other diseases associated with acquired angioedema type I, it has been demonstrated that these patients may initially present with autoantibodies to C1-INH, or they may develop as the disease progresses.

Frequency

International

Acquired angioedema is rare, with approximately 150 cases reported in the medical literature worldwide.

Mortality/Morbidity

Although mortality may occur because of laryngeal edema, it is more likely due to the complications of the associated disorder.

Race

Presumably, persons of any race can be affected by acquired angioedema.

Sex

Both men and women may be affected by acquired angioedema.

Age

The onset of acquired angioedema is most common after the fourth decade of life, whereas the onset of hereditary acquired angioedema (HAE) is in the second decade.

Clinical

History

• A family history for hereditary angioedema is not obtained, which distinguishes acquired angioedema from hereditary acquired angioedema.
• Regarding angioedema, symptoms are referable to 3 prominent sites: subcutaneous tissues (eg, face, hands, arms, legs, genitals, buttocks); abdominal organs (eg, stomach, intestines, bladder), which may manifest as nausea, vomiting, and/or colicky pain and mimic a surgical emergency; and the upper airway (eg, larynx), which may result in laryngeal edema.
• Occasionally, acquired angioedema patients may experience heat and pain in the affected areas.
• Other symptoms of acquired angioedema may be related to underlying disorders, such as lymphoproliferative malignancies or connective tissue disease.

Physical

• Physical signs of acquired angioedema include overt, noninflammatory swelling of the skin and mucous membranes.
• Although urticaria does not usually occur, occasionally, erythema or mild urticarial eruptions may precede the edema.

Causes

Acquired angioedema type I is most frequently associated with B-cell lymphoproliferative disease. To date, only 2 reports of a T-cell lymphoma associated with acquired angioedema type I have been documented. Other disorders have included multiple myeloma, chronic lymphocytic leukemia, myelofibrosis, Waldenström macroglobulinemia, non-Hodgkin lymphoma, MGUS, rectal carcinoma, essential cryoglobulinemia, erythrocyte sensitization, livedo reticularis, cold urticaria, lupus anticoagulant, and infection with Helicobacter pylori or Echinococcus granulosis.

By definition, acquired angioedema type II is not associated with any specific disorder but rather by the presence of the autoantibody directed against C1-INH. Most of these antibodies work by binding the epitopes around the reactive center of INH.² However, the occasional existence of features of both acquired angioedema type I and acquired angioedema type II has been noted, most notably with a MGUS.

One case of acquired angioedema with C1-INH deficiency state was identified in association with liver transplantation. The status of the liver donor was unknown, but it is speculated that the donor may have been C1-INH deficient.

Another case of acquired angioedema was reported with acute upper airway angioedema in association with the local anesthetic articaine.

Differential Diagnoses

Other Problems to Be Considered

ACE inhibitor–induced angioedema
Episodic angioedema with angioedema
Leukocytoclastic vasculitis
Urticaria, cold

Workup

Laboratory Studies

• Acquired angioedema type I (AAE-I) and Acquired angioedema type II (AAE-II)
  • Low C1-INH levels
  • Low C1q levels (except 1 reported case)
  • Low C4 levels
  • Low C2 levels
• Acquired angioedema type II - Positive immunoblot assay findings for 95-kd C1-INH cleavage product

Imaging Studies

• Abdominal radiographs may demonstrate features of ileus. Other findings may be referable to an associated illness.

Other Tests

• Other laboratory findings are related to associated illnesses.

Histologic Findings

Histologic features include reticular dermal, subcutaneous, or submucosal edema without infiltrating inflammatory cells. Vasodilation may be seen.

Treatment

Medical Care

• Depending on the symptoms and the site of the angioedema, intensive support may be necessary, including intravenous fluids.
• When possible, the underlying disorder should be treated. The resolution of angioedema has been reported with the treatment of underlying disease, although recurrences have occurred despite appropriate treatment of the disorder.
• In acquired angioedema type I (AAE-I), treatment of the associated lymphoproliferative process may result in correction of the abnormality.

Surgical Care

• Intubation may be necessary in cases of laryngeal edema.

Medication

In acquired angioedema, therapy for acute attacks may be aborted with C1-INH concentrates or, if unavailable, fresh-frozen plasma. However, rapid catabolism of C1-INH occurs in acquired angioedema, so higher doses of C1-INH plasma concentrate may be needed.

Androgens, such as danazol or stanozolol, may be beneficial in acquired angioedema type I but are of no value in acquired angioedema type II (AAE-II). Prostate cancer and pregnancy preclude the use of androgens.

Antifibrinolytics, such as epsilon-aminocaproic acid and tranexamic acid, have been found to be more effective for long-term prophylaxis in those with acquired angioedema.

Immunosuppressive therapy directed toward decreasing autoantibody production may be of value in patients with acquired angioedema type II, which may be accomplished by the use of plasmapheresis with cyclophosphamide.

In recent years, 2 papers have reported effective treatment of acquired angioedema cases with a series of 4 weekly injections with rituximab (a chimeric monoclonal antibody to CD20). In one study, 3 patients with severe acquired angioedema were treated with rituximab, which resulted in normalization of C1-INH and C4 levels. Long-term remission of angioedema attacks was achieved.³ In a second study, a patient with acquired angioedema type II refractory to standard treatment was treated with rituximab, which allowed for a 6-month attack-free interval.⁴

New medications are currently being studied for the treatment of acquired angioedema. One such treatment is a synthetic kallikrein inhibitor, Ecallantide (DX-88), produced by Dyax (Cambridge, Mass). The drug is able to stop the generation of bradykinin by inhibiting kallikrein activation. This decreases the rate of C1-INH catabolism, allowing for C1-INH concentrate to be more effective. US Food and Drug Administration (FDA) approval for DX-88 is expected in December, 2009 (personal communication, Dyax; July 31, 2009).

Other new products in trial are a genetically engineered C1 esterase inhibitor and a bradykinin B2 receptor antagonist. The recombinant C1 esterase inhibitor, a drug called Rhucin produced by Pharming (Leiden, The Netherlands), is still in a dialogue with the FDA regarding the anticipated approval time. Pharming is expected to submit a Biologic License Application to the FDA sometime in the second half of 2009.⁵ The bradykinin B2 receptor antagonist, a drug called Icatibant produced by Jerini (Berlin, Germany), received a "nonapprovable" letter from the FDA in April 2008. Phase III clinical trials are anticipated in the United States, but the drug is currently only available in Europe.⁶

Two clinical trials include C1-Esteraseremmer-N for the Treatment of Hereditary (and Acquired) Angioedema (completed) and Effectiveness of Bradykinin Receptor Blocker at Reducing Swelling Associated With Angiotensin Converting Enzyme (ACE) Inhibitor-Associated Angioedema (recruiting).

Alkylating agents

Some agents in this class have potent immunosuppressive activity.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Dosing

Adult

500-750 mg IV

Pediatric

Administer as in adults

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; hematologic myelosuppression, primarily leukopenia, is most common adverse effect; thrombocytopenia and anemia occur less frequently; gastrointestinal adverse effects include anorexia, nausea, emesis, and stomatitis; urologic adverse effects include dysuria, urgency, hematuria, bladder fibrosis, and necrosis; death from hemorrhagic cystitis has occurred; encourage excessive fluid intake; interferes with oogenesis and spermatogenesis; may cause irreversible sterility in both sexes

Antifibrinolytic agents

Act through the inhibition of plasmin; tend to be more effective than androgens for prophylaxis.¹

Aminocaproic acid (Amicar)

Lysine analog that inhibits fibrinolysis via inhibition of plasminogen activator substances; to a lesser degree, through antiplasmin activity.
Widely distributed. Half-life is 1-2 h. Peak effect occurs within 2 h. Hepatic metabolism is minimal. Can be used PO/IV.

Dosing

Adult

8 g q4h IV, then 16 g/d in acute attacks
6-10 g/d PO maintenance

Pediatric

8-10 g/d PO
Not recommended in newborns

Interactions

Coadministration with estrogens may cause increase in clotting factors, leading to a hypercoagulable state; coadministration with tretinoin my increase risk of both venous and arterial thrombosis

Contraindications

Documented hypersensitivity; evidence of active intravascular clotting process; coadministration with factor IX complex concentrates or anti-inhibitor coagulant complexes; injection in premature neonates (injectable product contains benzyl alcohol)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not administer unless a definite diagnosis of hyperfibrinolysis has been made; caution in cardiac, hepatic or renal disease; because aminocaproic acid can be fatal in patients with DIC, important to differentiate between hyperfibrinolysis and DIC; thrombi that form during treatment are not lysed and effectiveness is uncertain; associated adverse effects are postural hypotension, thrombosis, and muscular pain and weakness; monitor CK levels; caution in patients with upper urinary tract bleeding; caution with rapid infusions; do not administer with factor IX complex concentrates or anti-inhibitor coagulant complexes; adverse effects include bradyarrhythmia, drug-induced myopathy, and hypotension

Tranexamic acid (Cyklokapron)

Alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin.

Dosing

Adult

Up to 8 g PO/IV for acute attacks
1-2 g PO for maintenance
3-4.5 g PO/IV qd divided tid/qid pc; continue for period long enough for at least 3-4 attacks to have normally occurred

Pediatric

12-25 mg/kg/dose (not to exceed 1.5 g) PO tid/qid for acute attack or as prophylaxis for 5 d

Interactions

Not established

Contraindications

Documented hypersensitivity; active intravascular clotting process; acquired defective color vision; subarachnoid hemorrhage

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal impairment; adverse effects are not common but include headaches, nausea, abdominal pain, and diarrhea; evidence of tumor formation in retina and liver found in experimental animal models after long-term use; although no evidence has supported these findings in humans, annual funduscopic examinations and LFT monitoring recommended q6mo if on long-term therapy; perform baseline ophthalmologic examination before initiating therapy; caution in history of thromboembolic disease and disseminated intravascular coagulation

Antigonadotropic agents

These agents have immunosuppressive properties.

Danazol (Danocrine)

Increases levels of C4 component of complement and prevents attacks associated with angioedema.

Dosing

Adult

200 mg PO bid/tid initially; if efficacious, taper dose by 50% over following 2-3 mo

Pediatric

Not established

Interactions

Decreases insulin requirements and increases effects of anticoagulants; concomitant administration with carbamazepine may result in toxicity; coadministration with HMG-CoA reductase inhibitors may increase risk for rhabdomyolysis; cyclosporine and/or tacrolimus toxicity may increase if coadministered with danazol; concomitant use with carbamazepine may increase risk of carbamazepine toxicity; concomitant administration with cyclosporine or tacrolimus and anabolic steroids may result in increased cyclosporine or tacrolimus blood levels and toxicity; may result in increased lovastatin plasma concentrations when administered concurrently (use only if potential benefit justifies potential risk of developing myopathy/rhabdomyolysis)

Contraindications

Documented hypersensitivity; seizure disorders; renal or hepatic insufficiency; cardiac disease; breastfeeding; conditions influenced by edema; undiagnosed genital bleeding; porphyria; carcinoma of the breast

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in renal, hepatic, or cardiac insufficiency and seizure disorders; peliosis hepatitis and benign hepatic adenoma have been observed with long-term therapy; thromboembolic events and pseudotumor cerebri reported; androgenlike effects, including weight gain, acne, hirsutism, edema, hair loss, voice change, and menstrual disturbances, occur; temporary alteration of lipoproteins may occur; consider the impact on the risk of atherosclerosis and coronary artery disease; serum total testosterone values may be falsely elevated if radioimmunoassay done to measure testosterone in women taking danazol

Anabolic Steriod

Stanozolol

Synthetic androgen with immunosuppressive properties. Increases levels of C1 esterase inhibitor and C4 component of the complement. No longer available in the United States.

Dosing

Adult

2 mg PO tid and reduce to maintenance dose of 2 mg/d or 2 mg qod after 1-3 mo

Pediatric

<6 years: 1 mg/d PO
6-12 years: 2 mg/d PO

Interactions

Increases hypoprothrombinemic effects of oral anticoagulants and hypoglycemic effects of insulin and sulfonylureas; concomitant administration with carbamazepine may result in toxicity; coadministration with HMG-CoA reductase inhibitors may increase risk for rhabdomyolysis; cyclosporine and/or tacrolimus toxicity may increase if coadministered with danazol; concomitant use with carbamazepine may increase risk of carbamazepine toxicity; concomitant administration with cyclosporine or tacrolimus and anabolic steroids may result in increased cyclosporine or tacrolimus blood levels and toxicity; may result in increased lovastatin plasma concentrations when administered concurrently (use only if potential benefit justifies potential risk of developing myopathy/rhabdomyolysis)

Contraindications

Documented hypersensitivity; nephrosis, breast or prostate cancer

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

May cause peliosis hepatitis, liver cell tumors, and blood lipid changes with increased risk of arteriosclerosis; caution in cardiac, renal, or hepatic disease or epilepsy; may increase PT; phallic or clitoral enlargement, hirsutism, gynecomastia, acne, edema, nausea, vomiting, and diarrhea may occur

Follow-up

Prognosis

• The prognosis for acquired angioedema is variable, and, in most patients, it depends on control of the underlying disorder. However, even with appropriate treatment of the underlying disease, patients may only be free of symptoms temporarily. Additionally, some patients who have had their underlying disease treated will be free of symptoms related to angioedema but will continue to have biochemical abnormalities.⁷
• Compared with the general population, patients with acquired angioedema have a higher incidence of B-cell malignancies.
• Patients with acquired angioedema and a concurrent diagnosis of monoclonal gammopathy of undetermined significance (MGUS) do not have an increased risk for progression to malignancy compared with patients with a sole diagnosis of MGUS.

Patient Education

• 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

Special Concerns

• Tranexamic acid may be used during pregnancy.

References

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3. Levi M, Hack CE, van Oers MH. Rituximab-induced elimination of acquired angioedema due to C1-inhibitor deficiency. Am J Med. Aug 2006;119(8):e3-5. [Medline].

4. Ziakas PD, Giannouli S, Psimenou E, Evangelia K, Tzioufas AG, Voulgarelis M. Acquired angioedema: a new target for rituximab?. Haematologica. Aug 2004;89(8):ELT13. [Medline].

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Keywords

angioedema, acquired angioedema, AAE, Caldwell syndrome, acquired angioedema

Contributor Information and Disclosures

Author

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey
Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Amanda Carolfi, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School
Amanda Carolfi is a member of the following medical societies: American Medical Association, American Medical Student Association/Foundation, and Society for Pediatric Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Paul Krusinski, MD, Director of Dermatology, Professor, Department of Internal Medicine, Fletcher Allen Health Care, University of Vermont
Paul Krusinski, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Kathleen M. Rossy, MD, and previous Chief Editor, William D. James, MD, to the development and writing of this article.

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