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Angioedema, Hereditary
Article Last Updated: May 18, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 9  
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:
hereditary angioedema, HAE, C1-INH, C1 inhibitor, swelling of the skin
Background
Hereditary angioedema (HAE) is an autosomal dominant disorder of C1 inhibitor (C1-INH) deficiency manifested by painless, nonpruritic, nonpitting swelling of the skin. Type I HAE is defined by low plasma levels of a normal C1-INH protein. Type II HAE is characterized by the presence of normal or elevated levels of a dysfunctional C1-INH. Type III HAE has been recently identified as an estrogen-dependent inherited form of angioedema occurring mainly in women with normal functional and quantitative levels of C1-INH.
Pathophysiology
The gene for C1-INH (SERPING1) has been mapped to 11q12-q13.1. C1-INH is a multifunctional serine protease inhibitor that is normally present in high concentrations in plasma. It is the only known plasma inhibitor of C1r and C1s, the activated proteases of the first component of complement. It is also the major plasma inhibitor of activated factor XII (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 the release of kininlike mediators, resulting in edema of subcutaneous or submucosal tissues. Although the issue of which vasoactive peptide is ultimately responsible for these changes remains controversial, direct evidence supports the importance of bradykinin in the clinical manifestations of angioedema. Other kinins may also be pathogenic. The inciting factor responsible for inducing the release of these vasoactive peptides is unclear. Factor XII activation may be secondary to a genetic mutation or 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. HAE is due to mutations within the C1-INH gene (C1NH) and is transmitted as an autosomal dominant trait. Approximately 150 different genetic mutations have been described in HAE, and a spontaneous mutation rate of 25% has been reported. The 2 variants of HAE related to C1-INH function are type I (85%) and type II (15%).
Type I HAE is characterized by low antigenic and functional plasma levels of a normal C1-INH protein. Type II HAE is characterized by the presence of normal or elevated antigenic levels of a dysfunctional mutant protein together with reduced levels of the functional protein. C1-INH deficiency allows autoactivation of C1, with consumption of C4 and C2. In type III HAE, the C1-INH protein is both qualitatively and functionally normal. The exact mechanism of action responsible for the link between estrogen and angioedema is unclear. One theory suggests that estrogen plays a role in up-regulating the production of bradykinin and decreasing its degradation by angiotensin-converting enzyme (ACE). A more recent theory suggests a mutation in factor XII that allows for the inappropriate activation of the kinin cascade.
Frequency
International
HAE is estimated to occur in 1 in 50,000-150,000 individuals.
Mortality/Morbidity
Mortality rates are estimated at 15-33%, resulting from laryngeal edema and asphyxiation.
Race
Persons of any race can be affected, with no reported bias in different ethnic groups.
Sex
Men and women are equally affected for HAE types I and II. HAE type III was initially thought to occur only in women, but recent family studies have described males with HAE and normal C1 inhibitor levels. Although a few male cases have been cited in the literature, HAE type III is still thought to predominantly affect women.
Age
C1-INH deficiency is present at birth, although only a few patients have been reported with perinatal angioedema. Symptoms usually become apparent in the first or second decade of life. Approximately 40% of people with HAE experience their first episode before age 5 years, and 75% present before age 15 years. Patients typically experience minor swelling in childhood that may go unnoticed, with increased severity around puberty. HAE is a lifelong affliction, although some report decreased symptoms with age. Five percent of adults with HAE are asymptomatic while carrying the C1NH mutation, and they are only identified after their children are found to be symptomatic.
History
- A family history of HAE is typically obtained, although spontaneous mutations may occur.
- Symptoms are referable to 3 prominent sites: subcutaneous tissues (face, hands, arms, legs, genitals, and buttocks); abdominal organs (stomach, intestines, bladder, and kidneys), which may manifest as vomiting, diarrhea, or paroxysmal colicky pain and mimic a surgical emergency; and the upper airway (larynx) and tongue, which may result in laryngeal edema and upper airway obstruction.
- Attacks usually occur at a single site, but simultaneous involvement of subcutaneous tissue, viscera, and the larynx is not uncommon. Nonpitting cutaneous swelling is the most commonly reported symptom, and it mainly affects the extremities, the genitalia, and the face. Acute abdominal pain, nausea, and vomiting are the dominant symptoms in 25% of patients with HAE and are rarely seen in people with other forms of angioedema. The lifetime incidence of a laryngeal attack is estimated at 70%.
- Mucosal edema of the bladder or urethra can result in urinary retention, stammering, pain, or anuria.
- Episodes of severe headaches, visual disturbances (eg, blurred vision, diplopia), and ataxia have been reported.
- Cases of painful muscle swelling and unilateral hip or shoulder involvement have also been cited.
- Attacks may be preceded several hours in advance by sudden mood changes, anxiety, sensory changes, or exhaustion.
- Patients often report episodes of swelling worsening over a period of 12-24 hours, usually with resolution within 72 hours. Symptoms can persist for up to 5 days, with migration of swelling to different sites. The edema is usually unresponsive to antihistamines. Attacks are usually periodic and are commonly followed by weeks of remission.
- Pediatric episodes are usually less frequent and commonly manifest as abdominal involvement.
Physical
- Physical signs include overt, noninflammatory swelling of the skin and mucous membranes. Typical involvement includes the face, hands, arms, legs, genitalia, and buttocks, although the edema can localize subcutaneously at any site. In some patients with severe edema, tension vesicles or bullae may develop.
- In approximately 25% of patients, erythema may precede the occurrence of edema. An estimated 30-50% of patients with HAE reportedly have erythema marginatum preceding or accompanying the attacks. Urticaria is not usually associated with HAE.
- Abdominal examination may reveal signs consistent with acute abdomen or abdominal obstruction. Ascites is often present with an abdominal attack associated with angioedema.
- Mucosal involvement with glossal, pharyngeal, or laryngeal edema may cause respiratory obstruction and signs of distress.
- Additional rare physical findings that have been reported are pleuritic symptoms with pleural effusions, seizures and hemiparesis secondary to cerebral edema, and bladder edema.
Causes
- Precipitating factors of attacks may include trauma (especially dental trauma), anxiety, menstruation, infection, exercise, alcohol consumption, and stress. Medications (eg, estrogen, ACE inhibitors, angiotensin II type 1 receptor antagonists) have also been shown to induce attacks.
- During pregnancy, symptoms may increase or decrease for HAE types I and II. In HAE type III, studies have reported first episodes or recurrences associated with estrogen-containing oral contraceptives, estrogen replacement therapy, or pregnancy.
- As many as 2% of patients with HAE may have systemic lupus erythematosus. Less commonly, other autoimmune disorders, such as glomerulonephritis, rheumatoid arthritis, thyroiditis, Sjögren syndrome, and pernicious anemia, may be associated with HAE.
- Those HAE patients infected with Helicobacter pylori have been found to be more symptomatic than those who are not infected.
Angioedema, Acquired
Drug Eruptions
Urticaria, Acute
Urticaria, Cholinergic
Urticaria, Chronic
Urticaria, Contact Syndrome
Urticaria, Dermographism
Urticaria, Pressure
Urticaria, Solar
Urticarial Vasculitis
Other Problems to be Considered
ACE inhibitor–induced angioedema
Episodic angioedema with eosinophilia
Vibratory- or pressure-induced angioedema
Lab Studies
Routine laboratory test results are usually normal, although a leukocytosis may occur with gastrointestinal episodes. Elevation of the hematocrit value may be observed because of intravascular fluid loss.
- Type I HAE
- C1-INH level is low.
- C4 and C2 levels are low.
- C1q level is normal.
- Type II HAE
- C1-INH level is normal or elevated but dysfunctional.
- C4 and C2 levels are low.
- C1q level is normal.
- Type III HAE
- C1-INH level is normal.
- C1-INH functional assay is normal.
- C4 level may be normal.
Imaging Studies
- Abdominal radiographs may demonstrate features of ileus.
- Abdominal ultrasonography or computed tomography may show edematous thickening of the intestinal wall, a fluid layer around the bowel, and large amounts of free peritoneal fluid.
- Chest radiographs may demonstrate pleural effusions.
Histologic Findings
Histologic features include edema in the reticular dermis or subcutaneous or submucosal edema without infiltrating inflammatory cells. Vasodilation may be present.
Medical Care
- Depending on the symptoms and the sites of the angioedema, intensive support may be necessary, including intravenous fluids. In cases of serious laryngeal edema causing respiratory obstruction, intubation or tracheostomy should be performed. In HAE types I and II, the treatment of choice in acute attacks consists of replacement with commercially available C1-INH concentrates or, if unavailable, fresh-frozen plasma. In HAE type III, infusion of C1-INH has proven to be ineffective.
- Prophylactic treatment is instituted if patients are afflicted with frequent and/or severe episodes.
- Danazol or stanozolol may be used at doses that prevent attacks; normalizing the levels of C1-INH is not necessary. The most significant complication of long-term use may be arterial hypertension. The 17-alpha-alkylated androgens rarely cause hepatotoxicity and liver tumors, but they should be used at the lowest effective dosage. Regular monitoring of liver function test results, lipid levels, and liver ultrasonography findings is recommended.
- Although virilization may be an issue with women, keeping to the lowest possible dose usually obviates this concern.
- Contraindications to the use of androgens include prostate cancer, pregnancy, childhood, and breastfeeding.
- Antifibrinolytic agents such as epsilon-aminocaproic acid or tranexamic acid can also be used for prophylaxis, although they have not been found to be as effective as the androgenic agents. These agents are the option for pregnant women.
- Short-term prophylaxis for surgical procedures, especially dental work, is necessary. C1-INH infusions can be given 24 hours before the procedure or just prior to it. Alternatives, such as antifibrinolytics or androgens, can be used, and they should be started 5 days before the procedure and continued for 2 days afterwards.
- Eradication of the underlying cause of the attack, such as H pylori or another infectious agent, may lead to resolution of symptoms. Careful attention should be given to medications being taken by the patient that may have contributed to an attack, such as contraceptives, hormone replacement therapy, or ACE inhibitors.
- Clinical trials are currently underway for several new therapies for acute attacks of angioedema. The new therapies, such as recombinant human C1-INH, recombinant kallikrein inhibitor (DX-88), and bradykinin-2 receptor antagonist (icatibant), may offer safer and more effective treatment options. Several protease inhibitors have been found to have functional overlap with C1-INH (eg, antithrombin III, beta-macroglobulin, alpha1-antitrypsin) and may be therapeutic options in the future.
Surgical Care
Intubation may be necessary in cases complicated by laryngeal edema.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Antigonadotropic agents
These agents may be used at doses that prevent attacks.
| Drug Name | Danazol (Danocrine) |
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| Description | Increases levels of C4 component of complement and reduces attacks associated with angioedema. In HAE, danazol increases level of deficient C1 esterase inhibitor. |
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| Adult Dose | Short-term prophylaxis: 100-600 mg/d PO
Long term prophylaxis: 200 mg PO tid; taper to lowest effective dose
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; seizure disorders; renal or hepatic insufficiency; cardiac disease; breastfeeding; conditions influenced by edema; undiagnosed genital bleeding; porphyria |
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| Interactions | Decreases insulin requirements and increases effects of anticoagulants; may increase carbamazepine levels |
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| Pregnancy | X - Contraindicated in pregnancy
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| Precautions | Caution in renal, hepatic, or cardiac insufficiency and seizure disorders; peliosis hepatitis and benign hepatic adenoma have been observed with long-term therapy (>10 y); thromboembolic events and pseudotumor cerebri reported; androgenlike effects, including weight gain, acne, hirsutism, edema, hair loss, voice changes, and menstrual disturbances, occur |
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| Drug Name | Stanozolol (Winstrol) |
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| Description | Synthetic androgen with immunosuppressive properties. Increases levels of C1 esterase inhibitor and C4 component of complement. |
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| Adult Dose | 2 mg PO tid and reduce to maintenance dose of 2 mg/d PO or 2 mg PO qod after 1-3 mo |
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| Pediatric Dose | <6 years: 1 mg/d PO
6-12 years: 2 mg/d PO
>12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity; nephrosis; breast or prostate cancer |
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| Interactions | Increases hypoprothrombinemic effects of oral anticoagulants and hypoglycemic effects of insulin and sulfonylureas |
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| Pregnancy | X - Contraindicated in pregnancy
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| 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 |
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Drug Category: Antifibrinolytic agents
Act through the inhibition of plasmin.
| Drug Name | Epsilon-aminocaproic acid (Amicar) |
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| Description | Lysine analog that inhibits fibrinolysis via inhibition of plasminogen activator substances and, 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.
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| Adult Dose | Acute attack: 8 g q4h IV, then 16 g/d
Maintenance: 6-10 g/d PO
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| Pediatric Dose | 8-10 g/d PO
Not recommended in newborns |
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| Contraindications | Documented hypersensitivity; evidence of active intravascular clotting process; coadministration with factor IX complex concentrates or anti-inhibitor coagulant complexes |
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| Interactions | Coadministration with estrogens may cause increase in clotting factors, leading to a hypercoagulable state |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| 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 |
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| Drug Name | Tranexamic acid (Cyklokapron) |
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| Description | Alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin. |
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| Adult Dose | Acute attack: Up to 8 g PO/IV
Maintenance: 1-2 g PO
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| Pediatric Dose | 12-25 mg/kg/dose (not to exceed 1.5 g) PO tid/qid recommended |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Not established |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| 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 |
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Prognosis
- Patients with an early onset of attacks have a worse prognosis than those with a late onset of attacks.
- With appropriate use of prophylactic therapy, the prognosis for patients with HAE is excellent.
Patient Education
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Angioedema, Hereditary excerpt Article Last Updated: May 18, 2007
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