eMedicine Specialties > Dermatology > Allergy & Immunology

Angioedema, Hereditary

Author: Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey
Coauthor(s): Amanda Carolfi, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School
Contributor Information and Disclosures

Updated: Oct 22, 2009

Introduction

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.

A related eMedicine article is Angioedema, Acquired.

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. For example, 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
 
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.² This hypothesis encompasses the role of illness or tissue injury in the generation of bradykinin.^3,4

Hereditary angioedema (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 caused by mutations occurring throughout the gene, which result in either a truncated or misfolded protein. This protein is not secreted efficiently, resulting in low antigenic and functional plasma levels of a normal C1-INH protein. Even though one normal allele is present, less than 50% of functional C1-INH is present. A possible explanation is that the normal C1-INH protein is down-regulated, and this is supported by the finding of decreased levels of C1-INH mRNA in patients with HAE.¹

Type II HAE is caused by mutations that involve the active site of exon 8. These mutations result in a dysfunctional protein.¹ Therefore, patients with type II HAE have 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, thus the term "estrogen-dependent" should be avoided. One theory suggests that estrogen plays a role in up-regulating the production of bradykinin and decreasing its degradation by angiotensin-converting enzyme (ACE). More recently, mutations in factor XII have been identified in some, but not all patients. These factor XII mutations allow for the inappropriate activation of the kinin cascade.⁵

Frequency

United States

Hereditary angioedema (HAE) incidence is 1 case in 10,000-50,000 people.⁶

International

Hereditary angioedema (HAE) is estimated to occur in 1 in 50,000-150,000 individuals.

Mortality/Morbidity

Mortality rates for hereditary angioedema (HAE) are estimated at 15-33%, resulting from laryngeal edema and asphyxiation.

HAE leads to 15,000-30,000 emergency department visits per year. An abdominal attack can lead to unnecessary surgery and delay in diagnosis, as well as narcotic dependence due to severe pain. Cutaneous attacks are both disfiguring and disabling, resulting in a diminished quality of life.⁶

Race

Persons of any race can be affected by hereditary angioedema (HAE), with no reported bias in different ethnic groups.

Sex

Men and women are equally affected for hereditary angioedema (HAE) types I and II, although women tend to have more severe attacks.⁶ 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 hereditary angioedema (HAE) experience their first episode before age 5 years, and 75% present before age 15 years.⁷ Patients typically experience minor swelling in childhood that may go unnoticed, with increased severity around puberty. However, type III HAE is found in the second decade of life or later and occurs only rarely before puberty.⁵   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.

Clinical

History

• A family history of hereditary angioedema (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 of hereditary angioedema (HAE) 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. Type III HAE patients tend to have more facial attacks.⁸   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.⁹
• 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 hereditary angioedema (HAE) 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.¹⁰
• 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.

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