Pediatrics

Hereditary Angioedema (HAE)

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Hereditary Angioedema? What are the typical findings for this disease?

Hereditary angioedema (HAE) is a disorder characterized by recurrent episodes of nonpruritic and nonpitting edema primarily of the peripheral extremities and the gastrointestinal mucosa. The attacks of swelling may be life-threatening when they also involve the airway. The swelling is self-limited and typically lasts 2-4 days.

The frequency of attacks is variable, and patients are typically well in between episodes. Attacks usually do not respond to antihistamine or glucocorticoid therapy.

There are currently three defined subtypes of HAE. The classic forms of HAE, types I and II, are autosomal dominant disorders caused by mutations affecting the plasma protein C1 inhibitor. HAE type I is due to low antigenic levels of C1 inhibitor, and HAE type II is due to a functional defect in C1 inhibitor. HAE type III is a recently described form, and affected patients have normal C1 inhibitor level and function. HAE type III is clinically similar to the classic forms of HAE, but facial and tongue swellings occur more frequently with HAE type III.

Typical findings for HAE

Episodic peripheral swelling, most commonly involving the hands and feet is almost universally present. Extremity swelling tends to be asymmetric and is rarely painful. Swelling may also involve the genitalia, trunk, face, tongue or larynx.

Most debilitating are attacks of abdominal pain due to swelling of the bowel wall. Attacks may be accompanied by vomiting and less commonly diarrhea or constipation.

Although attacks are sporadic and often occur without a clear trigger, precipitating factors include pressure or trauma and emotional stress. Other known triggers include estrogens, menstruation, and ACE inhibitors.

Some patients note a prodrome consisting of a tingling sensation in the area where an attack will start. A subset of patients also note erythema marginatum at the onset of an attack.

True urticaria and pruritis are typically absent.

On physical examination, the peripheral swelling during an acute attack is typically asymmetric and not well circumscribed. Facial edema and oral mucuous membrane swelling may be present. The abdomen may be distended and tender to palpation, and bowel sounds are often diminished. Abdominal attacks often lead to unnecessary imaging and surgical exploration.

What other disease/condition shares some of these symptoms?

50% of individuals with chronic idiopathic urticaria also suffer from angioedema. However, chronic urticaria usually responds to treatment with antihistamines and glucocorticoids, while hereditary angioedema does not respond to these therapies.

Idiopathic angioedema may also have a similar presentation as HAE, but individuals usually lack a family history of angioedema.

An HAE-like syndrome can be caused by a monoclonal gammopathy in which the patient makes antibody to C1 inhibitor. Similarly, patients with lymphoid malignancies and occasionally autoimmune disease may destroy a sufficient amount of C1 inhibitor to cause angioedema.

Other considerations include allergic angioedema and medication-induced angioedema, most commonly associated with ACE inhibitors and NSAIDs.

What caused this disease to develop at this time?

Classic HAE is an autosomal dominant disorder caused by mutations in the C1 inhibitor gene, located on chromosome 11. HAE type I accounts for 85% of classic HAE cases, and causative C1 inhibitor mutations result in failure to synthesize or secrete the protein. HAE type II accounts for 15% of classic HAE cases, and associated gene defects lead to a secreted but nonfunctioning protein. It is important to note that as many as 25% of patients have no family history and presumably have a new mutation. Attacks of swelling usually begin in childhood and become more severe during puberty, but they can begin anytime. Presumably, the biochemical abnormality responsible for the attacks is present from birth, and some factor or event activates the long-standing quiescent disease. The precipitating factor remains unknown.

Though a trigger often cannot be identified, well-described precipitating factors include trauma or application of pressure and emotional stress. For example, dental work is a common precipitant. Estrogens cause attack frequency and severity to increase in some patients, and many women note that attack frequency is highest at the time of menstruation.

A mutation in the coagulation Factor XII gene on chromosome 5 has been indentified in a subset of families with the novel HAE type III, but its relationship to pathogenesis is unknown. No genetic cause has been identified in other affected families. The clinical presentation is similar to that of classic HAE, but attacks tend to start later in adulthood and more often involve the face and tongue. Initial descriptions indicated an estrogen-dependence, with only women affected and onset or exacerbation of clinical symptoms following the use estrogen-containing birth control or hormone replacement therapy. Clinically affected males, however, have since been described.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Measurement of C1 inhibitor and complement protein C4 are the usual diagnostic tests for the classic forms of HAE. In patients with HAE type I, both quantitative and functional levels of C1 inhibitor are low. In patients with HAE type II, quantitative levels are normal, but functional levels are low. In HAE types I and II, C4 levels are also low, typically even between attacks. Though C4 levels are low, complement activation itself is not believed to contribute to disease pathogenesis. C3 levels are virtually always normal.

Confirmation of a genetic mutation in C1 inhibitor is typically not necessary for diagnosis.

Would imaging studies be helpful? If so, which ones?

A diagnosis of HAE may be made based on clinical presentation and supporting laboratory studies, and imaging studies are rarely helpful. Without a diagnosis, however, the pain of abdominal angioedema often leads to imaging, which may reveal bowel wall edema. Attacks involving the airway are an emergency and require direct visualization, only if immediate airway support is available. A lateral soft tissue neck x-ray may reveal soft tissue swelling.

Confirming the diagnosis

There are clinical decision algorithms available for the diagnosis, therapy and management of hereditary angioedema. The reader is referred to the following reference: Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010; 6 (1): 24.

If you are able to confirm that the patient has Hereditary Angioedema, what treatment should be initiated?

Treating acute HAE attacks requires a multifaceted approach. Most importantly, life-threatening attacks associated with oropharyngeal edema demand immediate airway support and rapid intubation may be necessary. Though often used, epinephrine has variable and often transient effect. There is no evidence that either corticoteroids or antihistamines provide meaningful benefit.

Management often includes fluid replacement and antiemetic therapy.

Pain associated with abdominal attacks requires judicious use of narcotics, as these patients are prone to narcotic addiction.

Within the last several years, the FDA has approved a series of treatment options for acute HAE attacks. Effective drugs include C1 inhibitor purified from plasma (Berinert), a kallikrein inhibitor (Kalbitor), and a bradykinin type 2 receptor antagonist (Firazyr). Their effectiveness has been demonstrated in placebo-controlled, double-blind studies. Patients usually begin to respond within 30-60 minutes of treatment.

Fresh frozen plasma has also been used in the past and is associated with remission in many patients; however, attacks may worsen in a minority of patients and is therefore no longer recommended for acute therapy.

Not all patients with HAE require prophylactic treatment to prevent attacks, and the decision requires a discussion with a health care provider. In addition, there are currently no standardized guidelines. Danazol, an impeded androgen and gonadotropin inhibitor, has proven highly effective in long-term prophylaxis. Side effects of Danazol therapy are noted in Table I. The only useful androgens are methylated substituted androgrens that must be administered orally (Table II). Their mechanism of action is still uncertain, but it is believed these androgens increase serum levels of C1 inhibitor.

Table I.

Side effects of Danazol therapy.

Table II.

Alkylated Anabolic Androgens

Epsilon-amincaproic acid and its derivative tranexamic acid are fibrinolysis inhibitors and are also effective in chronic therapy.

Most recently approved for long-term prophylaxis is an additional purified C1 inhibitor concentrate (Cinryze). Due to the short half-life of C1 inhibitor, the medication is administered twice weekly and is an intravenous infusion.

Avoidance of precipitating factors, including trauma and stress, are also mainstays in the long-term prophylaxis of HAE. If exogenous estrogen is a trigger, exposure should be avoided. Occasionally, a patient can be treated by simply stopping estrogen-containing birth control.

Short-term prophylaxis may be required to prevent HAE attacks following surgery or trauma, and options include administration of fresh frozen plasma, short burst of androgens, or infusion of purified C1 inhibitor.

What are the adverse effects associated with each treatment option?

All C1 inhibitor replacement therapies are plasma derived products and therefore carry the potential for transmission of infection.

Kalbitor is a 60 amino acid peptide synthesized in yeast and in a minority of patients (~3%) has been associated with anaphylaxis. It is given subcutaneously and requires administration by medical personnel.

Firazyy is a 10 amino acid peptide which causes local irritation, but otherwise has not been associated with serious side effects thus far. It is approved for self-administration subcutaneously.

All impeded androgens have many potentially important side effects, including masculinization, headaches, lack of libido or increased libido, hair gain or loss, liver function abnormalities, myopathy, and lipid abnormalities.

Serious side effects of EACA include severe muscle toxicity and theoretical promotion of thrombosis. Tranexamic acid is rarely used in the United States.

What are the possible outcomes of Hereditary Angioedema?

With appropriate therapy, long-term prognosis is very good. The recent introduction and approval of various therapies has allowed the disease to be manageable, and affected patients may remain highly functioning and achieve an appropriate life-span. Death is rare, though life-threatening attacks require prompt management.

Patients with HAE do have a higher than normal incidence of autoimmune diseases, although the diseases are often mild. The type of autoimmune disease is variable, but may require further evaluation and management in conjunction with treatment of their HAE.

What causes this disease and how frequent is it?

There are no epidemiologic studies available on hereditary angioedema. HAE occurs equally in males and females, but females tend to be more severely affected. There is no known ethnic variability.

HAE type I is due to a genetic deficiency resulting in low quantity of C1 inhibitor and HAE type II is due to a genetic deficiency resulting in a functional defect in C1 inhibitor. Classic HAE is an inherited autosomal dominant disease, though family history is absent and de novo mutations may occur in approximately 25% of patients. The genetic cause has not been identified in a large proportion of patients with HAE type III, though a genetic mutation affecting Factor XII has been identified in a subset.

How do these pathogens/genes/exposures cause the disease?

C1 is a complement protein that circulated in an inactive form and is activated during immunologic reactions. It functions to activate the classical complement pathway and cleaves the next 2 proteins, C4 and C2. Their consumption leads to low levels. C1 inhibitor's main function is to inhibit this cascade activated by C1. C1 inhibitor also mediates the kinin-generating systems, and recent studies have indicated that the major mediator in angioedema attacks is bradykinin. Deficiency of C1 inhibitor therefore results in unregulated activation of the classical complement pathway and of the kinin-generating system. Angiotensin converting enzyme is important in the degradation of bradykinin, therefore explaining the contraindication of ACE inhibitor use in HAE patients.

What complications might you expect from the disease or treatment of the disease?

With appropriate therapy and monitoring for adverse effects associated with therapy, HAE is not associated with any long-term complications and carries a good prognosis.

Are additional laboratory studies available; even some that are not widely available?

A subset of patients with HAE type III possess a mutation in the coagulation Factor XII gene. Though testing is available, the authors do not recommend evaluating for the mutation since it is sufficiently rare.

How can Hereditary Angioedema be prevented?

Hereditary Angioedema cannot be prevented, but appropriate management includes measures that reduce attack frequency. As with all autosomal dominant diseases, 50% of the offspring of patients with classic HAE types I and II can be expected to have the disease. Affected families may elect to undergo genetic counseling. Similarly, family members of affected patients should be evaluated.

What is the evidence?

Zuraw, BL. "Clinical practice. Hereditary angioedema". N Engl J Med. vol. 359. 2008. pp. 1027-36.

Frank, MM, Gelfand, JA, Atkinson, JP. "Hereditary angioedema: the clinical syndrome and its management". Ann Intern Med. vol. 84. 1976. pp. 580-93.

Gelfand, JA, Sherins, RJ, Alling, DW, Frank, MM. "Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities". N Engl J Med. vol. 295. 1976. pp. 1444-8.

Bork, K, Gul, D, Hardt, J, Dewald, G. "Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course". Am J Med. vol. 120. 2007. pp. 987-92.

Gelfand, JA, Sherins, RJ, Alling, DW, Frank, MM. "Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities". N Engl J Med. vol. 295. 1976. pp. 1444-8.

Zuraw, BL, Busse, PJ, White, M. "Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema". N Engl J Med. vol. 363. 2010. pp. 513-22.

Craig, TJ, Levy, RJ, Wasserman, RL. "Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks". J Allergy Clin Immunol. vol. 124. 2009. pp. 801-8.

Cicardi, M, Levy, RJ, McNeil, DL. "Ecallantide for the treatment of acute attacks in hereditary angioedema". N Engl J Med. vol. 363. 2010. pp. 523-31.

Cicardi, M, Banerji, A, Bracho, F. "Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema". N Engl J Med. vol. 363. 2010. pp. 532-41.

Ongoing controversies regarding etiology, diagnosis, treatment

Considerable controversy surrounds the diagnosis and management of HAE type III. Because of the absence of a confirmatory laboratory test, many believe the diagnosis cannot be made without presence of a strong family history. In addition, there is only anecdotal evidence of optimal treatment at this time. In the authors' experience, patients with HAE type III respond to the same medications used for the treatment of classic forms of HAE. Since patients with HAE type III have normal levels of C1 inhibitor, however, the authors recommend C1 inhibitor replacement therapy not be used. Instead, we recommend treatment with danazol or products that target excess bradykinin production.

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