A detailed history concerning angioedema should be done. The following should warrant suspicion of HAE [9] [10]:

• Family history of HAE
• Reccurent angioedema that is non-responsive to antihistamine, glucocorticoid or epinephrine and produces various cutaneous sensations an hour prior to attack (prodromal)
• Onset of symptoms during childhood
• Recurrent abdominal pain
• Occurrence of difficulty of breathing

The most frequent presentation is asymmetric, non-pitting, cutaneous swelling [1]. The sites of predilection are the face, genitalia, buttocks, and extremities. The most common site of swelling in the face is the periorbital area and the lips [1]. There are prodromal signs (e.g. tingling sensation) in the affected area several hours prior to swelling. The swelling is self-limiting and resolves in 12 to 36 hours [1]. There is no discoloration in the affected site after the attack has elapsed. GI involvement of HAE may present with or without nausea and vomiting [1]. The abdominal pain is severe and mimics the presentation of a surgical abdomen.

Laryngeal edema is the most severe presentation of HAE. Complete upper airway obstruction may commence without immediate medical attention. Progressive upper airway obstruction warrants immediate emergency intubation. In the pediatric population, frequent GI disturbances are common; therefore, it is an unreliable symptom to consider HAE. Flat, erythematous, non-pruritic lesions occur as a prodromal sign to angioedema. This is also known as erythema marginatum and is observed in 42 to 58% of cases [11].

Newborn screening for HAE is not advisable. Complement protein levels erratically increase and reach the normal value at 1 year of age [12]. The best time to screen for HAE is after 1 year of age.

Complement testing

Measurements of C4, C1-INH, C1-INH functional activity, and C1q are laboratory test to diagnose HAE. The C4 is the single best screening test to detect HAE [13]. Uncontrolled C1 activity permanently depletes the C4 stores in all types of HAE. The levels decrease further during acute episodes. However, the C4 level is not highly specific or sensitive for diagnosis of HAE [14].

The C1-INH level and functional activity distinguishes the three types of HAE. The C1-INH level is low due to innate deficiency in type 1 HAE [14] [15]. The C1-INH level is normal but dysfunctional in type 2 HAE due to a mutation in the protein [14] [15]. Both C1-INH level and functional activity is normal for type 3 HAE because the defect lies in a mutation not related to the C1-INH protein.

The C1q level distinguishes HAE from acquired angioedema. All types of HAE will have normal C1q levels [15] [16]. Acquired angioedema will present will low C1q levels because the autoantibodies attach to both the C1-INH and C1q rendering them inactive.

On-demand treatment

Early treatment of acute attacks is warranted because the symptoms are debilitating and severely painful as a result of uncontrolled pro-inflammatory chemical release and nociceptive receptor stimulation. Upper airway obstruction should be treated immediately to avoid asphyxiation [17]. The same can be said for abdominal pain which mimics surgical abdomen and may result in superfluous surgical management. Peripheral swelling limits functionality of the patient. HAE attacks are treated with C1-INH, kallikrein inhibitor, or bradykinin receptor antagonist [18].

• C1-INH

Administration of C1-INH concentrate resolves the underlying cause [19]. The concentrate restores activity regulation of the complement, clotting, fibrinolytic, and kinin systems. The result is reduction of bradykinin, factor XII, and eicosanoid derivative levels that cause angioedema.

• Kallikrein inhibitor

Kallikrein’s function of cleaving HMWK to bradykinin is inhibited and prevents edema progression during attacks [20]. The only commercial kallikrein inhibitor available is ecallantide [21]. The medication is administered by subcutaneous injection. A 30 mg dose is indicated for HAE patients ≥ 16 years old for acute attacks [18] [21].

• Bradykinin receptor antagonist

The synthetic peptide icatibant competitively binds at the bradykinin B2 receptors to inhibit the effects of bradykinin. It is administered subcutaneously with a recommended dose of 30mg for on-demand treatment [18]. A side effect of transient erythema, wheal, pruritus, or burning sensation may occur at the site of administration [22].

Short-term prophylaxis

Dental, minor, and major surgical procedures may trigger acute attacks of HAE due to physical trauma and/or emotional stress [23]. The site of attack is often near the site of surgery [18]. This poses an increased risk of upper airway obstruction for dental procedures.

C1-INH concentrate is the first line drug for short-term prophylaxis. 10 to 20 units/ kilogram of body weight should be given 1 to 6 hours prior to procedure [18]. Androgens such as danazol, stanozolol are a viable alternative if risk of attack is low. Prophylaxis starts 5 days prior to 2 days post-procedure. The recommended dose for danazol is 2.5-10 mg/kilogram/day with a maximum dose of 600mg. Stanozol’s recommended dose is 4-6 mg/day [18].

Prophylactic treatment

Prophylactic long-term treatment with Danazol is necessary if patients are afflicted with frequent and/or severe episodes.

The main concern lies with laryngospasm or laryngoedema. Both should be treated immediately with administration of C1-INH concentrate, kallikrein inhibitor, and bradykinin receptor antagonist treatment. Progressive obstruction of the upper airways warrants intubation to avoid asphyxia. Abdominal and cutaneous attacks should be treated on demand as well since there is uncontrolled cascade of pro-inflammatory chemicals that evoke severe pain.

HAE is an autosomal dominant disorder that involves a defect in the C1-INH protein. The deficient or dysfunctional protein cannot fulfill its function of regulating the release of bradykinin. Bradykinin produces venodilation and edema, laryngospasm and gastrointestinal (GI) disturbances, and cytokine and eicosanoid pathway derivative release. Some attacks may be triggered by trauma, psychological stress situations (Christmas, weddings, etc.), menstruation, ovulation and infectious diseases.

• The offspring of a person with HAE has a 50% chance of inheriting the disorder due to its autosomal dominant pattern of inheritance.
• The ratio of C1-INH deficiency occurrence is 1 in every 50,000 persons [2]. 
• De novo mutation of the C1-INH occurs in 20-25% of HAE [3].
• The onset of symptoms occurs between 5-11 years of age in 50% of HAE patients [1].

The C1-INH is a protein involved in the regulation of the complement, clotting, fibrinolytic, and kinin systems. The defect in C1-INH regulation with HAE allows spontaneous activation of complements C1, C2, and C4, kallikrein, factor XII, mannose-binding lectin associated proteases (MASP) 1 and 2, plasmin and factor XI [1]. Of the activated systems involved, it is the uncontrolled stimulation of the kinin system that primarily evokes angioedema [4].

HAE is a type of bradykinin-mediated angioedema due to a deficiency or dysfunction of the C1-INH gene. Uncontrolled activity of factor XII (Hageman Factor) activates pre-kallikrein into kallikrein. Kallikrein then cleaves the high molecular weight-kininogen (HMWK) to produce the vasoactive polypeptide bradykinin [1].

Excess in bradykinin promotes increased vascular permeability, venodilation and increased nitric oxide synthesis, smooth muscle contraction in airways and gastrointestinal (GI) tract, pain stimulation, and stimulation of various cytokines and eicosanoid derivatives release [1]. The result is the clinical picture of HAE. Increased permeability and venodilation [5] [6] leads to localized edema involving the deep layer of the dermis and subcutaneous tissue. Recurrent GI symptoms and laryngospasm may occur as a result of bradykinin-induced smooth muscle contraction. Pain and swelling arises from increased release of eicosanoid pathway products and cytokines.

Types of HAE

• Type 1 (null)

It is transmitted in an autosomal dominant genetic pattern and constitutes 85% of HAE [1]. The available protein is low antigenicity and functional levels.

• Type 2 (dysfunctional)

Mutations result in a dysfunctional protein. C1-INH is secreted in adequate amount and normal in terms of antigenicity. However, the function of the protein is impaired leading to angioedema.

•  Type 3 (factor XII mutation)

Type 3 HAE is very rare. The recent theory is a factor XII mutation causes angioedema [7]. The mutation allows factor XII to activate kallikrein. Kallikrein in turn produces excessive amounts of bradykinin. The diagnosis of type 3 HAE necessitates a family history of angioedema [8] since the genetic defect of the disease is still inconclusive.

The disease itself is not preventable as it is autosomal dominant in origin in majority of cases. A person with HAE should avoid using angiotensin converting enzyme (ACE) inhibitors to prevent acute attacks. ACE inhibitors suppress bradykinin dehydrogenase activity [1] thereby promoting bradykinin accumulation.

Women with HAE should be cautious with the hormonal replacement therapy or oral contraceptive (OCP) use. High levels of estrogen increase the levels of factor XII [24] available and decrease both C1-INH [25] and ACE [25] [26] levels. As a consequence, bradykinin accumulation occurs.

Angioedema is a well-demarcated, localized, nonpitting edema that may involve the deep dermis, subcutaneous or submucosal tissue [1]. Edema may also occur at the mucosal lining of the upper airways and the gastrointestinal (GI) tract. Angioedema may be inherited with an autosomal dominant trait known as hereditary angioedema (HAE). The main cause of HAE is a defect in C1 inhibitor (C1-INH) protein [1]. This protein is mainly responsible for regulation of complement, kinin, clotting, and fibrinoltyic pathway activities. Defect or dysfunction of C1-INH impairs the regulation of the aforementioned systems. As a result, excessive products by the various systems circulate in the bloodstream. One of the products is bradykinin which promotes tissue swelling and mucosal edema of the airways and GI tract. Reccurent angioedema without pruritus characterizes the disorder.

Advances in treatment decreased the mortality rate of HAE. Treatment with C1-INH concentrate, kallikrein inhibitor, and bradykinin receptor antagonist regulates the level of bradykinin in the body; hence, life-threatening complications such as upper airway obstruction secondary to laryngeal edema are prevented.

Hereditary angioedema (HAE) is a type of rare inherited disorder that typically involves localized swelling of various body parts. A patient with the disease can pass it on to his/her child 50% of the time.

HAE is due to a defect in an important protein, C1 inhibitor (C1-INH), of the body. This protein regulates the release of bradykinin, a chemical that evokes multiple bodily reactions including increase in blood flow, leakiness of blood vessels, and release of chemicals that cause pain and tissue swelling. The protein defect allows accumulation of bradykinin. Thus, it imposes its uncontrolled effects on the body that result in angioedema.

Symptoms

• Swelling of various body parts

Swelling usually involves the face, buttocks, reproductive organs, and limbs. The lips and skin surrounding the eyes are the areas that usually get swollen in the face. The typical characteristic of swelling is asymmetric that does not blanch under pressure. It is sometimes preceded by a tingling or burning sensation a few hours before the attack.

• Tummy ache

Tummy ache occurs because the lining of the stomach and intestines become swollen. The tummy ache is often described as severe in pain and mistaken for a disease that warrants immediate surgery.

• Difficulty of breathing

Bradykinin causes swelling of the upper airways. It often presents as difficulty of breathing. This warrants immediate medical attention to prevent suffocation from a complete upper airway obstruction.

Treatment

Treatment involves three drugs that prevent the accumulation of bradykinin– C1-INH concentrate, kallikrein inhibitor, and bradykinin receptor antagonist. C1-INH concentrate administration is the treatment of choice for acute attacks of HAE because it solves the underlying problem which is a defect in C1-INH.

Intubation is necessary for patients who are at risk for complete airway obstruction.

Prevention

The disease per se is not preventable since it is an inherited disorder.

The use of drugs such as angiotensin converting enzyme (ACE) inhibitor and oral contraceptive pills should be avoided by HAE patients. These drugs trigger acute attacks of HAE by promoting accumulation of bradykinin in the body.

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