eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Angioedema

Author: Shih-Wen Huang, MD, Medical Director of Allergy Service, Professor, Department of Pediatrics, Division of Immunology and Infectious Diseases, University of Florida College of Medicine
Contributor Information and Disclosures

Updated: Jan 11, 2010

Introduction

Background

Angioedema is a subcutaneous extension of urticaria, resulting in deep swelling within subcutaneous sites. In contrast, urticaria results from transient extravasation of plasma into the dermis, causing a wheal characterized by tense edema with or without redness. Angioedema can occur with generalized urticaria if the tissue swelling has indistinct borders around the eyelids and lips. In addition, when the swelling of urticaria extends to the face, hands, feet, and genitalia, the clinical manifestation may be called angioedema. As many as 50% of children who have urticaria exhibit angioedema with swelling of the hands and feet.

Based on the current clinical understanding of angioedema, dividing cases into the following types is useful:

• Hereditary type 1 (HAE1)
• Hereditary type 2 (HAE2)
• Hereditary type 3 (HAE3)
• Acquired type 1 (AAE1) (very rare; only a few reported cases)
• Acquired type 2 (AAE2) (very rare; only a few reported cases)
• Nonhistaminergic angioedema (INAE) (may occur in approximately 1 of 20 angioedema cases)
• Idiopathic angioedema
• Allergic angioedema (most common form)
• ACE inhibitor–induced angioedema (4-8% of cases)

Hereditary angioedema (HAE) accounts for only 0.4% of angioedema cases; however, the specific diagnostic tests and high mortality rate associated with hereditary angioedema deserve special attention. In 1876, Milton described the first case. Six years later, Quincke introduced the term angioneurotic edema to describe this disease. Later, Osler described the disease as episodic bouts of well-circumscribed nonpitting subepithelial edema that primarily involved the extremities, larynx, face, and abdomen. Hereditary angioedema is an autosomal dominant disease usually associated with a positive family history of angioedema. However, numerous cases are due to a new mutation of the gene.

In approximately 80-85% of hereditary angioedema cases, serum levels of C1 inhibitor (C1INH) are decreased to approximately 30% of reference range values. In contrast, about 15% of patients with hereditary angioedema have reference range levels of antigenic C1NIH but mostly nonfunctional C1INH. Missing or nonfunctional C1INH leads to failure in controlling the enzymatic activity of C1, resulting in lower levels of the early acting complement components C4 and C2 because of overconsumption. HAE1 (low levels of functional C1INH) may be due to a wide range of gene mutations. In HAE2 (reference range or even increased levels of antigenic but nonfunctional C1INH), different point mutations have been described within or nearby the reactive center of the C1INH gene.

Recently, a new form of hereditary angioedema, hereditary angioedema type 3 (HAE3), has been described. In HAE3, C1INH function and complement components are normal.² Essential features of HAE3 include (1) a long history of recurrent skin swelling, attacks of abdominal pain, or episodes of upper airway obstruction; (2) familial occurrence, exclusively in female members of the family; (3) no history of urticaria in the patient or other family members; (4) normal C1INH and C4 concentrations in the plasma; and (5) a failure to respond to antihistamines, corticosteroids, or C1INH concentrate.

INAE angioedema is angioedema without urticaria. Patients usually do not respond to H1 blockers (antihistamines). Parasites, infections, and autoimmune diseases are not present.

The idiopathic form of angioedema may be associated with swelling, hives that persist longer than 6 weeks, or both. Thyroid dysfunction should be considered.

Allergic angioedema is characterized by swelling, hives, or both in reaction to environmental factors such as food, an insect sting or bite, cold, heat, latex, or a drug. Usually, these environmental factors provoke histamine release that leads to swelling, hives, or both.

Angioedema can also be caused by ACE inhibitors (eg, captopril, enalapril, genzapril, quinapril, ramipril) used to treat high blood pressure. Swelling may begin a few hours to years after first starting the medication.

Pathophysiology

The pathophysiology of urticaria-associated angioedema is fully discussed in Urticaria.

The cause of angioedema in patients with hereditary angioedema is still unknown. One hypothesis involves persistent activation of C1, resulting in ongoing cleavage of the next 2 components of the complement cascade: C4 and C2. According to this hypothesis, cleaved C2 is acted on by other proteolytic enzymes (possibly plasmin), generating a kinin-like molecule that causes angioedema. Involvement of local mediators is virtually uncertain.

A second hypothesis is that angioedema attacks are caused by activation of the kinin-generating system, which involves cleavage of high-molecular-weight kininogen by activated kallikrein with attendant formation of bradykinin. Bradykinin is believed to be responsible for angioedema episodes.

In hereditary angioedema, 2 phenotypic variants have been described. HAE1 may be due to a wide range of gene mutations, resulting in either a lack of messenger RNA transcription or transcription in abnormal messenger RNAs that are not translated into a stable protein. In HAE2, different point mutations have been described within or near the reactive center, resulting in different dysfunctional proteins.

AAE is due to the production of a C1INH-consuming factor by malignant cells. In fact, most cases of acquired C1INH-deficient angioedema have been associated with the presence of a lymphoid or other malignancy. In rare cases, C1INH deficiency could be due to consumption by the immune complex during the course of an autoimmune disease. Another type of C1INH deficiency is the result of monoclonal or oligoclonal production of antibodies that appear to recognize C1INH and destroy its functional activity.

The fluctuations in sex hormone levels at the beginning of adolescence, in the perimenopausal period, during pregnancy, or during the use of oral contraceptives can precipitate edematous attacks in hereditary angioedema. One study indicated that the number of attacks was significantly higher in females with high progesterone levels (>4 nmol/L); a significantly lower attack frequency was noted in patients with a higher (40 nmol/L) sex hormone–binding globulin (SHBG) level.³ Thus, monitoring these 2 hormonal levels may be useful in predicting attacks in patients with hereditary angioedema.

Studies in the function of C1INH have helped further the understanding of angioedema's pathophysiology. C1INH controls activation of the complement system by inhibiting the esterase activity of C1r and C1s in the classic pathway and the esterase activity of MASP2 in the mannose-binding lectin pathway.

The second major physiological role of C1INH is now believed to be regulation of the contact system, where it intervenes and inhibits activated coagulation factor XII and kallikrein. In addition to these 2 major functions, C1INH inhibits factor XI, plasmin, and the tissue plasminogen activator (tPA). The relevance of these activities in vivo remains controversial. However, convincing in vivo evidence supports the activation of plasminogen in human beings by factor XIIa.

HAE3 has been exclusively observed in women, in whom it appears to be correlated with high estrogen levels (eg, pregnancy, the use of oral contraceptives). One report proposed 2 missense mutations (ie, c.1032C --> A and c.1032C -->G) in F12, the gene that encodes human coagulation factor FXII (Hageman factor), as a possible cause of HAE3.⁴ Transcription of F12 is positively regulated by estrogens, which may explain why only women are affected by HAE3.

Another extensive family study of HAE3 was reported. In this family a missense mutation Thr309Lys was identified in factor XII gene with a heterozygotic pattern.⁵ This mutation was also identified in the mother of the patient, her daughter, and her son. Other than 5 German and French families that have been reported for HAE3, a large Italian family was also reported from Canada.⁶ A missense mutation in F12 was present in the 3 affected female subjects of this family who had estrogen-dependent inherited angioedema. In addition, these affected females have polymorphisms associated with lower level of both aminopeptidase and angiotensin-1 converting enzyme, the major enzymes responsible for bradykinin degradation. Thus, multiple genes may contribute to estrogen-dependent or estrogen-associated angioedema, leading to the observed heterogeneity of clinical features.

Frequency

United States

Urticaria-associated angioedema occurs in nearly 50% of children who have urticaria. Because urticaria occurs in 2-3% of children, urticaria-associated angioedema is estimated to occur in 1-2% of the general population.

Alternatively, the frequency rate of hereditary angioedema diseases is currently unknown. Current estimates suggest that the disease affects 1 in 10,000-50,000 persons. An estimated 5,000-25,000 patients in the United States have HAE1.

The exact frequency of HAE2 is unknown, but the ratio of HAE1 to HAE2 is 85:15.

No epidemiologic data are available for acquired C1INH deficiency because these patients have only been described in case reports. In the past 5 years, the number of spontaneous mutations in newly diagnosed hereditary angioedema cases has increased 50%, indicating the need for more accurate epidemiologic data.

No epidemiologic data are currently available regarding patients with HAE3.

International

International frequency is similar to US frequency.

Mortality/Morbidity

Mortality may occur because of laryngeal swelling and subsequent asphyxiation. In the past, the mortality rate for attacks involving the upper airways exceeded 25%.

Urticaria-associated angioedema is generally self-limited in pediatric patients. In patients with hereditary angioedema, the onset of symptoms frequently occurs during the teenage years. Morbidity varies from case to case. In some patients, acute attacks occur once every several years, whereas attacks in others occur several times a year. Morbidity changes after therapy begins.

Race

No racial differences are known.

Sex

Urticaria-related angioedema has no known sex differences. Hereditary angioedema is an autosomal dominant disorder and affects both sexes. HAE3 has been exclusively reported in females. In this group, the influence of an X-linked gene on the generation of vasoactive peptides has been speculated.

Age

Urticaria-related angioedema has no known age differences. Clinical manifestations of hereditary angioedema are more common beyond the teenaged years.

Clinical

History

• If the patient has urticaria-associated angioedema, occurrence coincides with the cause of urticaria.
• Hereditary angioedema (HAE) accounts for only 0.4% of cases of urticaria but is associated with a high mortality rate.
  • The initial manifestations of hereditary angioedema in children occurred at a median age of 4.8 years (range, 3-9.7 y).
  • Hereditary angioedema attacks are characterized by episodic angioedema that usually involves the extremities. Swelling is usually brawny and is not associated with urticaria or pruritus. Patients also have episodic attacks of severe abdominal pain that are sometimes associated with vomiting but are not associated with diarrhea; they persist until the angioedema attacks subside. Abdominal pain may resemble that of acute abdomen.
  • Occasionally, attacks are precipitated by trauma, particularly the injection of an anesthetic (eg, in dental procedures, during tooth extraction). Attacks may be life-threatening. Approximately one half of patients with hereditary angioedema have attacks precipitated by trauma; interestingly, the other half do not.
  • Hereditary angioedema attacks generally last 1-4 days. Swelling of the extremities is typically painless. Abdominal attacks due to edema in the submucosa and serosa of the bowel wall are often associated with nausea, vomiting, and severe pain. Edema of the upper airway may result in asphyxiation.
  • Only 25% of patients provide a positive family history.
  • The disease may be present in childhood, but for reasons that are still not fully defined, it often becomes more severe at the time of puberty.
  • No close relationship between plasma C1INH levels and the severity of attacks has been noted; some patients with very low C1INH levels have few attacks, whereas others with much higher levels of C1INH have much more severe disease.
• Many patients have a family history of sudden death from asphyxia. In the past, the mortality rate for attacks involving the upper airways exceeded 25%. Patients live with the constant threat of life-threatening laryngeal obstruction.
• The location of swelling may be characteristic in some forms of angioedema. For instance, in HAE1 and HAE2, swelling can occur in the extremities, abdomen, throat, and other organs. Airway swelling can be fatal. Abdominal swelling usually involves pain, vomiting, and diarrhea. Symptoms (angioedema attacks) occur by age 13 in most hereditary angioedema cases and may increase in severity after puberty. Angioedema episodes may spontaneously occur or may be triggered by physical trauma or even emotional stress. HAE2 or HAE3 may present like HAE1.
• The acquired form of angioedema (AAE1 or AAE2) may present like classic hereditary angioedema, except for the age of onset. Usually, this type of angioedema occurs in the fourth decade of life or later. Because it is an acquired defect, a family history is negative for angioedema.
• The idiopathic form of angioedema may cause swelling anywhere in or on the body and may be accompanied by urticaria (hives).
• Swelling due to nonhistaminergic angioedema (INAE) may occur anywhere, including the face, arms, legs, genitalia, throat, and abdomen, although abdominal symptoms are far less common than in those with hereditary angioedema. Furthermore, symptoms do not change with menstrual period or pregnancy.
• Allergic angioedema may cause swelling, most often in the face and throat. Urticaria (hives) is often present. If the condition persists longer than 6 weeks, it is considered chronic idiopathic urticaria and is not a classic allergic reaction.
• In patients with ACE-inhibitor–induced angioedema, swelling may occur just about anywhere, including the throat, face, lips, tongue, hands, feet, genitalia, and intestines. Urticaria (hives) is very rare in this form of angioedema.
• Swelling of the gastrointestinal mucosa results in nausea, vomiting, diarrhea, and severe pain that can mimic a surgical emergency.
• Subcutaneous swelling is disfiguring but is not erythematous, pruritic, or painful.
• During attacks, angioedema remains limited to the area in which it begins.
• Symptoms last 1-4 days, and most patients have one or more attacks per month, leaving them unable to engage in normal social activities for 20-100 days a year.
• The cause of acquired angioedema in patients using ACE inhibitors is believed to be the accumulation of bradykinin, which is subject to breakdown by ACE. ACE inhibitors help build up bradykinin levels in the tissue.
• Onset usually follows trauma such as surgery, dental manipulation, an accident, or mental stress. In HAE2, attacks occur more often with sex hormone fluctuation.
• Onset is usually in adolescence, with more severe symptoms associated with menses.

Physical

• If a patient has urticaria-related angioedema, lesions appear as large swellings with indistinct borders around the eyelids and lips. They may also appear on the face, trunk, genitalia, and extremities. The face, hands, and feet are involved in 85% of patients; other areas are involved in 15%. 
• As many as 50% of children with urticaria exhibit angioedema with swelling of the hands and feet.
• Patients with hereditary angioedema have associated repeated attacks of swelling of extremities, face, and throat accompanied by abdominal pain. Edematous swelling of the skin is not accompanied with itching but causes an unpleasant sensation of distension within the involved lesion.⁷
• A generalized, nonpruritic skin rash (erythema marginatum) may be observed in 8% of children prior to the onset of an angioedema attack.
• Onset usually follows trauma such as surgery, dental manipulation, an accident, or mental stress.
• Angioedema manifests as a diffuse brawny swelling of the extremities in 75% of patients, abdominal pain in 52%, and swelling of the face and throat in 30%.
• Abdominal pain eventually becomes a major symptom in 93% of patients.
• Patients do not have typical urticarial wheals but exhibit targetlike lesions. Severe airway edema accounts for the almost 30% mortality rate in untreated patients.
• Fewer than 5% of patients taking ACE inhibitors experience episodic swelling of the lip or face or tissue swelling on any part of the body; it is not usually accompanied by pruritus or pain.

Causes

• Hereditary angioedema is an autosomal dominant condition.
• Risk factors for hereditary angioedema episodes include trauma, such as surgery, dental manipulation, or accidents. Episodes of hereditary angioedema are the result of unopposed complement activation and/or activation of the kinin generating system due to the C1INH deficiency.
• Acquired forms of angioedema are commonly associated with lymphoproliferative disorders or malignancy. They are relatively uncommon in pediatric patients. Patients who are using ACE inhibitors, which are uncommonly in children, may experience episodic swelling of the tissue due to the accumulation of bradykinin.
• In HAE3, a fluctuation of sex hormones has been speculated to precipitate hereditary angioedema attacks.

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