You are in: eMedicine Specialties > Dermatology > ALLERGY AND IMMUNOLOGY Angioedema, AcquiredArticle Last Updated: May 21, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  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 is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology Coauthor(s): Kathleen M Rossy, MD, Staff Physician, Department of Dermatology, New York Medical College, Metropolitan Hospital Editors: Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center; Paul Krusinski, MD, Director of Dermatology, Professor, Department of Internal Medicine, Fletcher Allen Health Care, University of Vermont; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System Author and Editor Disclosure Synonyms and related keywords: AAE, Caldwell syndrome, acquired angioedema INTRODUCTIONSection 2 of 10
  BackgroundAcquired angioedema (AAE) is characterized by painless, nonpruritic, nonpitting swelling of the skin that is classified into 2 forms: acquired angioedema type I (AAE-I) and acquired angioedema type II (AAE-II). AAE-I is associated with other diseases, most commonly B-cell lymphoproliferative disorders. AAE-II is an autoimmune process defined by the presence of an autoantibody directed against the C1 inhibitor molecule (C1-INH). PathophysiologyThe 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. The precise pathophysiology of AAE-I remains to be defined. Diminished levels of C1-INH are due to its increased catabolism. In AAE-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 AAE-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 AAE-I and AAE-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 AAE-I, it has been demonstrated that these patients may initially present with autoantibodies to C1-INH, or they may develop as the disease progresses. FrequencyInternationalAAE is rare, with approximately 150 cases reported in the medical literature worldwide. Mortality/MorbidityAlthough mortality may occur because of laryngeal edema, it is more likely due to the complications of the associated disorder. RacePresumably, all races are affected. SexMen and women may be affected. AgeThe onset of AAE is most common after the fourth decade of life, whereas the onset of hereditary acquired angioedema (HAE) is in the second decade. CLINICALSection 3 of 10
History
Physical
CausesAAE-I is most frequently associated with B-cell lymphoproliferative disease. To date, only 2 reports of a T-cell lymphoma associated with AAE-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, AAE-II is not associated with any specific disorder but rather by the presence of the autoantibody directed against C1-INH. However, the occasional existence of features of both AAE-I and AAE-II has been noted, most notably with a MGUS. One case of AAE 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 AAE was reported with acute upper airway angioedema in association with the local anesthetic articaine. DIFFERENTIALSSection 4 of 10
Angioedema, Hereditary Drug Eruptions Urticaria, Acute Urticaria, Cholinergic Urticaria, Chronic Urticaria, Contact Syndrome Urticaria, Dermographism Urticaria, Solar Urticarial Vasculitis
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| Drug Name | Cyclophosphamide (Cytoxan, Neosar) |
|---|---|
| Description | 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. |
| Adult Dose | 500-750 mg/m2 |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity; severely depressed bone marrow function |
| 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 |
| Pregnancy | D - Unsafe in pregnancy |
| 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 |
Act through the inhibition of plasmin.
| Drug Name | Aminocaproic acid (Amicar) |
|---|---|
| Description | 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. |
| Adult Dose | 8 g q4h IV, then 16 g/d in acute attacks 6-10 g/d PO maintenance |
| Pediatric Dose | 8-10 g/d PO Not recommended in newborns |
| 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) |
| 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 |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| 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 |
| Drug Name | Tranexamic acid (Cyklokapron) |
|---|---|
| Description | Alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin. |
| Adult Dose | 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 Dose | 12-25 mg/kg/dose (not to exceed 1.5 g) PO tid/qid for acute attack or as prophylaxis for 5 d |
| Contraindications | Documented hypersensitivity; active intravascular clotting process; acquired defective color vision; subarachnoid hemorrhage |
| Interactions | Not established |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| 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 |
These agents have immunosuppressive properties.
| Drug Name | Danazol (Danocrine) |
|---|---|
| Description | Increases levels of C4 component of complement and prevents attacks associated with angioedema. |
| Adult Dose | 200 mg PO bid/tid initially; if efficacious, taper dose by 50% over following 2-3 mo |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; seizure disorders; renal or hepatic insufficiency; cardiac disease; breastfeeding; conditions influenced by edema; undiagnosed genital bleeding; porphyria; carcinoma of the breast |
| 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) |
| Pregnancy | X - Contraindicated in pregnancy |
| 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 |
| Drug Name | Stanozolol (Winstrol) |
|---|---|
| Description | Synthetic androgen with immunosuppressive properties. Increases levels of C1 esterase inhibitor and C4 component of the complement. |
| Adult Dose | 2 mg PO tid and reduce to maintenance dose of 2 mg/d or 2 mg qod after 1-3 mo |
| Pediatric Dose | <6 years: 1 mg/d PO 6-12 years: 2 mg/d PO >12 years: Administer as in adults |
| Contraindications | Documented hypersensitivity; nephrosis; breast or prostate cancer |
| Interactions | Increases hypoprothrombinemic effects of oral anticoagulants and hypoglycemic effects of insulin and sulfonylureas |
| Pregnancy | X - Contraindicated in pregnancy |
| 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; adverse effects include cholestatic jaundice syndrome and/or hepatic necrosis (causing death); may cause premature epiphyseal closure in children; caution in diabetic patients and pediatric patients; may cause suppression of clotting factors II, V, VII, and X and an increase in prothrombin time |
Article Last Updated: May 21, 2007
