Hereditary Angioedema 

Updated: Aug 30, 2018
Author: Michael M Frank, MD; Chief Editor: Michael A Kaliner, MD 

Overview

Practice Essentials

Although rare, hereditary angioedema (HAE) is associated with episodic attacks of edema formation that can have catastrophic consequences. Laryngeal edema can result in asphyxiation; abdominal angioedema attacks can lead to unnecessary surgery and delay in diagnosis, as well as to narcotic dependence due to severe pain; and cutaneous attacks can be disfiguring and disabling.[1]

Signs and symptoms

Physical signs of HAE include overt, noninflammatory swelling of the skin and mucous membranes. They are referable to the following prominent sites:

  • Subcutaneous tissues: Face, hands, arms, legs, genitals, and buttocks

  • Abdominal organs: Stomach, intestines, bladder, and urethra; may manifest as vomiting, diarrhea, or paroxysmal colicky pain and can mimic a surgical emergency

  • Upper airway (larynx) and tongue: May result in laryngeal edema and upper airway obstruction

In approximately 25% of patients, erythema marginatum may precede the occurrence of edema.[4]

See Clinical Presentation for more detail.

Diagnosis

Complement and genetic testing

The 3 types of HAE can be differentiated with complement testing and, in the case of HAE with normal C1 inhibitor levels, genetic testing. Type I HAE is characterized by the following:

  • Low C1 esterase inhibitor (C1-INH) protein level

  • Low C4 level

  • Normal C1q level

Type II HAE is characterized by the following:

  • Normal or elevated, but dysfunctional, C1-INH level

  • Low C4 level

  • Normal C1q level

HAE with normal C1 inhibitor levels is characterized by the following:

  • Normal C1-INH level

  • Normal C1-INH functional assay

  • Normal C4 and C1q level

  • Factor XII mutation may be present[5, 6]

Imaging studies

The following imaging studies can be used in the diagnosis of HAE:

  • Abdominal radiography: During attacks of gastrointestinal edema, features of ileus may be demonstrated

  • Chest radiography: Pleural effusions rarely may be seen

  • Abdominal ultrasonography or computed tomography scanning: Edematous thickening of the intestinal wall, a fluid layer around the bowel, and large amounts of free peritoneal fluid may be found

See Workup for more detail.

Management

Agents used in the treatment of acute attacks of HAE include the following:

  • C1-INH concentrate: Berinert was approved in September 2009 by the US Food and Drug Administration (FDA) for the treatment of acute abdominal and facial angioedema attacks in adolescents and adults with HAE[7] ; in January 2012, an additional indication for Berinert, for laryngeal angioedema, was approved by the FDA; in July 2014, the FDA approved the recombinant human C1-INH (rhC1-INH) Ruconest to treat acute attacks of HAE in adolescents and adults, although its effectiveness was not established in patients with HAE that involve laryngeal attacks[2, 3]

  • Kallikrein inhibitor: During HAE attacks, unregulated plasma kallikrein activity results in excessive bradykinin generation, resulting in swelling; ecallantide (Kalbitor) is a recombinant agent that is a potent, selective, reversible kallikrein inhibitor; the FDA approved ecallantide in December 2009 for treating acute HAE attacks in patients aged 16 years and older[8]

  • Selective bradykinin B2 receptor antagonist: Icatibant (Firazyr) was approved by the FDA in 2011 for treatment of acute HAE attacks in adults[9, 10]

Prophylaxis

The Medical Advisory Board of the HAE Patient's Association has recommended that patients be free to choose their preferred therapy. Prophylactic treatment includes attenuated androgens and the C1 inhibitor protein product Cinryze. If androgen therapy is used dosage should be minimized, balancing disease severity with minimizing adverse effects. The drug most commonly used is danazol, but all attenuated androgens are useful in treatment. The usual recommendation is to try to use 200 mg/day or less.

The nano-filtered C1-INH concentrate Cinryze was approved by the FDA in 2008 for HAE prophylaxis. It is reported to be effective in acute attacks, as well.[11]  The first subcutaneous C1-INH concentrate (Haegarda) was approved by the FDA in June 2017 for HAE prophylaxis in adults and adolescents.[51]  Lanadelumab, a monoclonal antibody that targets kallikrein, was approved for HAE prophylaxis in August 2018.[52]

See Treatment and Medication for more detail.

Background

Hereditary angioedema (HAE) is an autosomal dominant disease caused by low levels of the plasma protein C1 inhibitor (C1-INH).

Deficiencies in C1-INH allow unchecked activation of the classic complement pathway and other biochemical systems including the bradykinin system. Patients can present with any combination of painless, nonpruritic, nonpitting swelling of the skin (cutaneous angioedema); severe abdominal pain; or acute airway obstruction.

There are 3 types of HAE. Type I HAE is defined by low plasma levels of a normal C1-INH protein reflecting an abnormality of one of the gene alleles of the protein. Type II HAE is characterized by the presence of normal or elevated levels of a dysfunctional C1-INH. Again, one of the two gene alleles is abnormal but here the allele leads to the release of a non-functional protein. HAE with normal C1 inhibitor was identified as an estrogen-dependent inherited form of angioedema occurring mainly in women with normal functional and quantitative levels of C1-INH. There is still no clear understanding of its pathophysiologic mechanism

Prior to the development of effective therapy, the mortality rate from HAE was 20-30%. Although preventable and treatable, the complications of this disease do not respond well to the usual therapies for angioedema; therefore, establishment of the correct diagnosis is critical. The most reliable and cost-effective screening test for HAE is a serum C4 level (see Workup).

Treatment of HAE consists of prophylaxis, management of acute attacks, and prophylactic therapy in situations where attacks may occur. In HAE types I and II, the treatment of choice in acute attacks consists of replacement with commercially available C1 inhibitor (C1-INH) concentrates[12] , a kallikrein inhibitor or a bradykinin receptor type 2 antagonist. If there is no specific treatment available, fresh-frozen plasma has been used, but the physician should understand that, because the plasma may supply the substrate for bradykinin generation, attacks can at times worsen before they improve.

At the time of this report there is no consensus on best therapy for HAE with normal C1 inhibitor (See Treatment.)

For a discussion of acquired angioedema, which is caused by a consumption of C1-INH for any of a number of reasons leading to low levels of this protein, see Acquired Angioedema. For a discussion of angioedema in children, see Pediatric Angioedema. Additionally, go to Angioedema and Emergent Treatment of Angioedema for complete information on these topics.

Pathophysiology

C1-INH is a member of the serpin family of protease inhibitors, as are alpha-antitrypsin, antithrombin III, and angiotensinogen.[13] These proteins stoichiometrically inactivate their target proteases by forming stable, one-to-one complexes with the protein to be inhibited.

Synthesized primarily by hepatocytes, C1-INH is also synthesized by monocytes. The regulation of the protein production is not completely understood but, since patients respond clinically to androgen therapy and demonstrate increased serum levels of C1-INH, it is believed that androgens may stimulate C1-INH synthesis. C1-INH also blocks activation of the lectin pathway by binding to mannose-binding lectin-associated serine proteases (MASPs).

Although named for its action on the first component of complement (C1 esterase), C1-INH also inhibits components of the fibrinolytic, clotting, and kinin pathways. Specifically, C1-INH inactivates plasmin-activated Hageman factor (factor XII), activated factor XI, plasma thromboplastin antecedent (PTA), and kallikrein.

Within the complement system, C1-INH blocks the activation of C1 and the rest of the classic complement pathway by binding to C1r and C1s. Without C1-INH, unchecked activation of C1, C2, and C4 occur before other inhibitors (C4-binding protein and factors H and I) can halt the cascade.

Evidence is now overwhelming that bradykinin is the mediator responsible for capillary leakage.[13] Researchers have demonstrated activation of the kinin system with increased blood bradykinin levels associated with clinical flares. Bradykinin is an important inflammatory mediator formed by the action of the plasma enzyme kallikrein on the substrate high molecular weight kininogen that causes neutrophil chemotaxis, capillary dilation with plasma leakage, and smooth muscle relaxation, and it has been linked to other forms of angioedema.

In an animal model of C1-INH deficiency, bradykinin and bradykinin receptor antagonists prevent capillary leakage.[14] The US Food and Drug Administration has approved the use of a kallikrein enzyme inhibitor for acute treatment, and a bradykinin type 2 receptor antagonist also terminates edema fluid generation and thus terminates attacks.

There is no question that a relatively small subgroup of patients with HAE with normal C1 inhibitor have a factor XII mutation and it is presumed that this mutation is of importance in initiation of attacks. This may be closely related to endothelial cell activation and the initiation of attacks but further research is clearly needed.[15, 16, 17]

Genetics

Hereditary angioedema (HAE) is due to mutations within the C1-INH gene and is transmitted as an autosomal dominant trait. The gene for C1-INH (SERPING1) has been mapped to 11q12-q13.1.

Approximately 300 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.[14] Since the C1 inhibitor binds to the protein it inactivates and the complex is removed from the circulation, this may also be responsible for the low levels of C1 inhibitor. Half the normal level of C1-INH is believed to be insufficient to prevent attacks of angioedema.

Most type II HAE is caused by mutations that involve the active site of exon 8. These mutations result in a dysfunctional protein.[14] 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 HAE with normal C1 inhibitor, 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. The illness clearly is seen in males as well but at lower frequency. 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 presumably allow for the inappropriate activation of the kinin cascade.[5]

Epidemiology

Although urticaria and angioedema are common problems that affect nearly 20% of the population, HAE is a rare disorder. It accounts for approximately 2% of clinical angioedema cases and occurs in 1 per 50,000-150,000 population.[1] HAE leads to 15,000-30,000 emergency department visits per year in the United States.

Racial and sexual differences in incidence

Persons of any race can be affected by HAE, with no reported bias in different ethnic groups. Men and women are equally affected for HAE types I and II, although women tend to have more severe attacks.[1] HAE with normal C1 inhibitor levels was initially thought to occur only in women, but recent family studies have described males with HAE and normal C1 inhibitor levels. Nevertheless, HAE with normal C1 inhibitor levels is still thought to predominantly affect women.

Age-related differences in incidence

C1-INH deficiency is present at birth in HAE, 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.[18] Patients typically experience minor swelling in childhood that may go unnoticed, with increased severity around puberty. However, HAE with normal C1 inhibitor levels 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 adult HAE carriers are asymptomatic, and they are identified only after their children are found to be symptomatic.

Prognosis

Although rare, HAE is a disease with potentially catastrophic consequences. Laryngeal edema can result in asphyxiation. Abdominal attacks 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.[1]

HAE patients with an early onset of attacks have a worse prognosis than those with a late onset of attacks.

Prior to the development of effective therapy, the mortality rate was 20-30%. With appropriate use of prophylactic therapy, the prognosis for patients with HAE is now excellent. Judicious use of androgens reduces both short-term and long-term adverse effects. The advent of C1-INH concentrate and kinin pathway inhibitors will greatly enhance the care of these patients.

C1-INH is not needed for intact immune function, and patients with HAE have no increase in the incidence or severity of infections. Other biochemical pathways in which C1-INH is active, such as those for fibrinolysis and clotting, also function relatively normally without normal levels. Unlike other forms of angioedema, histamine is not involved in the pathogenesis of HAE.

Patient Education

Patients should be educated about possible triggering factors of their attacks. They should also be advised of the autosomal dominant inheritance pattern of HAE and that they should anticipate that 50% of their children will be affected. However, phenotypic expression of the condition may vary significantly within families.

For more information on hereditary angioedema (HAE), visit the United States Hereditary Angioedema Association. For patient education information, see the Allergy Center and Skin, Hair, and Nails Center, as well as Hives and Angioedema.

 

Presentation

History

Patients with hereditary angioedema (HAE) typically report episodic attacks that begin during childhood and become more severe during adolescence.[13, 19] Attacks in childhood usually are mild and infrequent and commonly manifest as abdominal involvement. A family history of HAE is typically obtained, although spontaneous mutations may occur.

Attacks are often preceded by a prodrome associated with a tingling in the area that will swell 1-2 hours before the swelling starts. Sudden mood changes, anxiety, sensory changes, or exhaustion may also occur several hours in advance of attacks.

Trauma precipitates attacks in about one third of patients. The trauma usually is pressure rather than sharp trauma. Patients who stand in one spot for a long time may have foot swelling; patients who used a lawn mower may have hand swelling. In some cases, infections may trigger attacks, and some women note attacks at the time of menses. However, most attacks have no clear inciting event.

The frequency of attacks varies greatly among affected individuals and at different times in the same individual, with some experiencing weekly episodes, while others might go longer than a year between attacks.

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.

Patients often report that episodes of swelling worsen 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.

Nonpitting cutaneous swelling is the most commonly reported symptom, and it mainly affects the extremities, the genitalia, and the face.[13, 19] Patients first notice a tightness or tingling of the skin, followed by the development of angioedema that evolves over several hours. In some patients, attacks are preceded by the development of a rash that is erythematous, not raised, and not pruritic, known as erythema marginatum. The angioedema typically resolves over 1-3 days.

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 abdominal pain is caused by edema of the mucosa of any portion of the gastrointestinal tract. The intensity can approximate that of an acute abdomen, often resulting in unnecessary surgery. Either constipation or diarrhea can be noted. The gastrointestinal edema generally follows the same time course to resolution as the cutaneous attacks.

Laryngeal edema is the most feared complication of HAE and can cause an immediate life-threatening emergency. The lifetime incidence of a laryngeal attack is estimated at 70%. The injection of a local anesthetic into the gums for the purpose of dental work is a common precipitant, but laryngeal edema can be spontaneous.

Laryngeal edema may progress rapidly through mild discomfort to complete airway obstruction, usually over a period of hours. Often, the pharyngeal swelling is difficult to visualize, in which case progression of the disease can best be evaluated by asking the patient if the attack is progressing. Difficulty with secretions and a change in the tone of the voice are good measures of progression. Emergency intubation or tracheostomy may be necessary to ensure an adequate airway.

Less common presentations reflect edema at other sites. Scrotal or even penile swelling is fairly common in males. Similarly, some women note swelling of the labia in attacks. 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.

Patients with HAE have a propensity to develop autoimmune disease.[20] This may range from inflammatory bowel disease to systemic lupus erythematosus (SLE) to thyroiditis, and, although these diseases are usually mild, they should be considered.

Physical Examination

Patients having acute attacks of HAE may appear severely ill. The first priority in the evaluation is to ensure an adequate airway. With severe attacks, patients can develop hypotension, owing to sequestration of fluid in the extravascular space.

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. Patients with HAE with normal C1 inhibitor levels tend to have more facial attacks.[13] In some patients with severe edema, tension vesicles or bullae may develop. Patients should not be febrile if HAE is their only active problem.

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.[4]

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.

 

DDx

Diagnostic Considerations

Other types of angioedema without urticaria, referred to as acquired angioedema (AAE), can complicate the diagnostic evaluation of patients with possible hereditary angioedema (HAE). In some cases, AAE may represent a response to an allergen and is treated like urticaria. In other cases, the pathophysiology may be similar to HAE.

As with patients with HAE, those with this type of AAE have decreased C1 inhibitor (C1-INH) activity and experience the same spectrum of clinical disease. However, the 2 conditions differ in several respects. Acquired angioedema is due to (1) an autoantibody to the C1-INH that prevents its function, (2) marked utilization of the normal C1 inhibitor by high levels of antigen-antibody complexes, or (3) factors formed by lymphoid tumors that destroy C1-INH activity.

In general, patients with AAE have low levels of C1q. This distinguishes them from patients with HAE, who have normal levels of the protein.

Although HAE is a treatable disease, the agents used to treat more common forms of angioedema are not effective. Thus, the diagnosis of HAE should be considered when angioedema is not associated with urticaria or when cutaneous or laryngeal attacks do not respond to the usual therapy. Once the diagnosis has been made, efforts should be made to prevent attacks associated with dental and surgical procedures.

Usually, the swelling of HAE does not resemble that of rheumatic disease. Occasionally, when the swelling surrounds a joint and movement of the joint becomes difficult, the difference between HAE and rheumatic disease becomes more difficult to distinguish.

Other problems to be considered in the evaluation of patients with possible HAE are ACE inhibitor–induced angioedema, episodic angioedema with eosinophilia, and vibratory- or pressure-induced angioedema.

Differential Diagnoses

 

Workup

Approach Considerations

Patients with hereditary angioedema (HAE) usually have normal results on most routine laboratory tests. An increased erythrocyte sedimentation rate or eosinophilia is not usually found. If either is present, the clinician should consider a coexisting or different diagnosis.

During attacks, patients can demonstrate hemoconcentration or prerenal azotemia, both of which reflect intravascular volume loss. The white blood cell count is usually not increased during attacks, although a leukocytosis may occur with gastrointestinal episodes.

The most reliable and cost-effective screening test for HAE is a serum C4 level.[13, 19, 21] The C4 concentration is almost always decreased during attacks and is usually low between attacks. If the C4 level is in the normal range but suspicion for angioedema is high, the test should be repeated.[1] The concentrations of C3 and C1q are normal in patients with HAE, regardless of the clinical status of their disease.

During attacks, the total serum hemolytic complement (CH50) is typically decreased, but it returns to normal with recovery. Because a deficiency in any of several components of complement can cause a decrease in CH50, a decreased value is not a particularly helpful finding (ie, low positive predictive value). Keep in mind that patients can have antigenically present but nonfunctional C1 inhibitor (C1-INH). Therefore, functional tests may be useful. Unfortunately, functional testing has a high error rate.

Complement and Genetic Testing

The 3 types of HAE can be differentiated with complement testing and, in the case of HAE with normal C1 inhibitor levels, genetic testing.

Type I HAE is characterized by the following:

  • C1-INH level is low

  • C4 and C2 levels are low

  • C1q level is normal

Type II HAE is characterized by the following:

  • C1-INH level is normal or elevated but dysfunctional

  • C4 and C2 levels are low

  • C1q level is normal

HAE with normal C1 inhibitor levels is characterized by the following:

  • C1-INH level is normal

  • C1-INH functional assay is normal

  • C4 level may be normal

  • Factor XII mutation may be present[5, 6]

Imaging Studies

During attacks of gastrointestinal edema, abdominal radiographs may demonstrate features of ileus in HAE patients. 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

Very few histologic studies have been performed. Histologically, the angioedema of HAE is indistinguishable from other types of angioedema. Typically, perivascular mononuclear cell infiltrate and dermal edema similar to that seen with chronic urticaria or angioedema of other types are observed. Edema is found in the reticular dermis or subcutaneous or submucosal edema, without infiltrating inflammatory cells. Vasodilation may be present.

 

Treatment

Approach Considerations

Treatment of hereditary angioedema (HAE) consists of prophylaxis, management of acute attacks, and prophylactic therapy in situations where attacks may occur. Patients with hypotension due to sequestration of fluid in the extravascular space require intravascular fluid replacement may require large amounts of intravenous fluids to maintain hemodynamic stability. Abdominal pain is treated with narcotics. In cases of serious laryngeal edema causing respiratory obstruction, intubation or tracheostomy should be performed.

For information on treatment of acute angioedema episodes, see Emergent Treatment of Angioedema.

In HAE types I and II, the treatment of choice in acute attacks consists of replacement with commercially available C1 inhibitor (C1-INH) concentrates[12] or kallikrein inhibitor or, if those are unavailable, fresh-frozen plasma. In HAE with normal C1 inhibitor levels, infusion of C1-INH has proven to be ineffective.[22, 23]

For prophylaxis, attenuated androgens are currently the initial mode of treatment. Therapy should be minimized, balancing disease severity with minimizing adverse effects. The drug most commonly used is danazol, but all attenuated androgens are useful in treatment. C1-INH concentrates have become available for prophylaxis and treatment of acute attacks.

A discussion of future plans, such as pregnancy, should be routine. Guidelines on the management of gynecologic/obstetric events in female patients with hereditary angioedema caused by C1 inhibitor deficiency have been published based on roundtable discussions at the 6th C1 Inhibitor Deficiency Workshop.[24] Briefly, estrogens and androgens should be mostly avoided while planning and throughout pregnancy. Plasma-derived human C1 inhibitor concentrate is the preferred treatment for these patients. See the International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency.

World Allergy Organization guidelines

The World Allergy Organization (WAO) issued the following 2013 recommendations for the management of hereditary angioedema types I and II (HAE-I/II)[25] :

  • Assess all patients suspected of having HAE-I/II for blood levels of C4, C1 esterase inhibitor (C-INH) protein, and C1-INH function

  • Consider on-demand treatment for all HAE attacks that (1) result in debilitation/dysfunction and/or (2) involve the face, neck, or abdomen; attacks affecting the upper airways must be treated

  • Treat all HAE attacks as early as possible with C1-INH, ecallantide, or icatibant; do not use oral antifibrinolytics as on-demand treatment

  • Consider intubation or tracheotomy early in progressive upper airway edema

  • Administer adjuvant therapy in HAE attacks when indicated, but use specific therapies without delay when indicated

  • All HAE-I/II patients should (1) have on-demand treatment for 2 attacks and (2) carry their on-demand treatment at all times

  • Plasma-derived (pd)C1-INH is the preferred on-demand therapy for HAE-I/II attacks in children and for pregnant or breastfeeding women

  • All patients should have an action plan, product available to treat HAE attacks, and an HAE identification card

  • Self-administration of treatment should be taught to all patients given on-demand treatment that is licensed for self-administration

  • All patients should have at least 1 annual assessment by an HAE specialist

The WAO’s 2013 recommendations regarding prophylaxis and screening in HAE are as follows:

  • Consider administering short-term preprocedural prophylaxis, particularly in cases involving dental/intraoral surgery, bronchoscopy or endoscopy, endotracheal intubation, or manipulation of the upper airway or pharynx

  • Before beginning long-term prophylaxis with androgens, assess the patient for cardiac risk factors and obtain a complete blood count (CBC), urine analysis, liver function test results, a lipid profile, and liver ultrasonography

  • During the use of androgens for long-term prophylaxis and for 6 months after cessation of therapy, monitor the patient’s CBC, urine analysis, lipid profile, liver function test results, and blood pressure every 6 months; perform annual ultrasonography of the liver

  • Defer screening children for HAE-I/II until the age of 12 months; test all offspring of an affected parent

  • Family members of HAE-I/II patients should be screened so that appropriate therapy can be available for treatment

  • Administer hepatitis A and B vaccinations to HAE-I/II patients receiving blood products, including pdC1-INH; administer influenza vaccine to all HAE-I/II patients

Specific Treatments

Until recently, no effective agent for acute attacks of HAE existed in the United States. Now, several agents have been approved, and others are in the midst of the US Food and Drug Administration (FDA) approval process.[26] The new therapeutic agents are leading to a reevaluation of the best approaches to therapy. These new agents are all much more expensive than attenuated androgens.

The nano filtered C1 inhibitor concentrate Cinryze was approved by the FDA in 2008 for prophylaxis of HAE attacks and is reported to be effective in acute attacks as well. In 2 randomized trials by Zuraw et al, use of the nanofiltered C1 inhibitor concentrate shortened the duration of acute attacks in patients with HAE and, when used for prophylaxis, reduced the frequency of acute attacks.[11]

The C1 esterase inhibitor Berinert was approved in September 2009 by the FDA for the treatment of acute abdominal and facial angioedema attacks in adolescents and adults with HAE.[7] In January 2012, an additional indication for laryngeal angioedema was approved by the FDA. Use was expanded to include children younger than 12 years in July 2016. Berinert is also approved for patient self-administration after proper training by a healthcare professional.

During HAE attacks, unregulated plasma kallikrein activity results in excessive bradykinin generation, resulting in swelling. Ecallantide (Kalbitor) is a recombinant agent that is a potent, selective, reversible kallikrein inhibitor. This drug decreases the rate of C1-INH catabolism, allowing for C1-INH concentrate to be more effective.

The FDA approved ecallantide in December 2009 for treating acute HAE attacks in patients aged 16 years and older.[8] Two randomized, double-blind, placebo-controlled trails, EDEMA4 and EDEMA3, established the safety and efficacy of ecallantide.[27] After multiple drug administrations, some patients developed antidrug antibodies and experienced allergic or anaphylactic-like reactions. Thus, the FDA issued a black box warning and recommends that the drug only be administered by a healthcare professional who can treat anaphylaxis.[8]

A more recent study demonstrated that ecallantide can be safely used to treat multiple episodes of HAE.[28] The trial involved 147 patients who received treatment for 625 HAE episodes. Patients received 30 mg of subcutaneous ecallantide for acute HAE attack symptoms, with no limit on the number of episodes treated. The primary end point was change in patient-reported mean symptom complex severity (MSCS) score at 4 hours. Results showed no reduction of efficacy with repeated use of ecallantide. In addition, no new safety signals were detected.[28]

In 2010, Cicardi et al reported significantly better outcome scores in patients treated for acute attacks of angioedema with ecallantide compared with placebo.[29] This was a double-blind, placebo-controlled trial in 71 patients.

Icatibant (Firazyr), a selective bradykinin B2 receptor antagonist, was approved by the US Food and Drug Administration for treatment of acute attacks HAE in adults. Approval was based on 3 double-blind, randomized, controlled clinical trials known as For Angioedema Subcutaneous Treatment (FAST) 1, 2, and 3.[9, 10]

FAST 3 was a placebo-controlled study of 98 adult patients with a median age of 36 years. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), composed of averaged assessments of skin swelling, skin pain, and abdominal pain. The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with icatibant (n=43) compared with placebo (n=45) was 2 hours (95% confidence interval [CI], 1.5, 3.0) versus 19.8 hours (95% CI, 6.1, 26.3), respectively (P< .001). The median times to almost complete symptom relief were 8 versus 36 hours for icatibant and placebo, respectively. Additional rescue medications were used by 3 patients (7%) treated with icatibant and 18 patients (40%) treated with placebo.[10]

With all of these agents, the time to response is in part determined by the duration of the attack. The response is more rapid early in an attack. Response is also determined by attack severity and location, in that peripheral edema responds more slowly to treatment. The time to onset of response appears roughly similar with all of the agents and the average response is often noted in about an hour.

Prophylactic Treatment

Prophylactic treatment is instituted if patients are afflicted with frequent and/or severe episodes.[30]

Danazol 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.

C1-INH products that are approved for prophylaxis include Cinryze (IV administration) and Haegarda (SC administration). In June 2017, the FDA approved the first subcutaneous C1 esterase inhibitor (Haegarda) for prevention of HAE attacks in patients aged 12-72 years. Approval was based on the phase 3 COMPACT trial (n=90), which showed C1-INH 60 IU twice weekly SC reduced the median number of HAE attacks by 90% compared with placebo. The study also showed use of rescue medication was reduced by >99% versus placebo.[51]

In August 2018, the FDA approved lanadelumab, a monoclonal antibody that targets kallikrein, for prophylaxis of HAE. Approval was based on the HELP clinical trial, which investigated the efficacy and safety of lanadelumab for long-term prophylaxis against angioedema attacks in HAE. Of 125 patients, 113 completed the trial. All lanadelumab dosing regimens significantly reduced the mean monthly attack rates of HAE compared to placebo (P < 0.001) over the 26-week duration of the study. The 300 mg SC every 2 week regimen reduced attacks by 92.8% from baseline in patient with < 2 attacks per month and by 88.2% in patients whose baseline was 2 to < 3 attacks per month.[52]

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. More reliably fresh frozen plasma (FFP) infusions can be given the day of surgery or the day before.[13, 19]

Treatment of Underlying Causes

Eradication of the underlying cause of the attack, such as Helicobacter 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 angiotensin-converting enzyme (ACE) inhibitors.

Investigational Agents

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.[19, 34, 35, 36]

Diet and Activity

No particular dietary restrictions are necessary. Activity is not limited with HAE, but it is prudent for patients to try to avoid activities such as camping that take them many hours away from possible emergency treatment.

Consultations

Primary care physicians who are unfamiliar with HAE may want to consult an allergist/immunologist to aid with the diagnosis and management of these patients. Once the diagnosis of HAE is made, patients and their families may benefit from discussions with a genetic counselor.

A clinical guideline summary from the American Academy of Allergy, Asthma & Immunology, Consultation and referral guidelines citing the evidence: how the allergist-immunologist can help, may be helpful.[37]

Long-Term Monitoring

Once recovery is achieved, proper referral for education and long-term management should be arranged. Anticipatory guidance with respect to oral surgery or any major procedure that will involve airway instrumentation should be stressed during follow-up care.

 

Medication

Medication Summary

The goals of pharmacotherapy for hereditary angioedema (HAE) are to reduce morbidity and to prevent complications. Medication may be used for acute or preventive treatment.

In Europe, purified C1 inhibitor (C1-INH) has been available for treatment of acute attacks for decades, but it has not been available in the United States until recently.[13, 38, 39] In October 2008, the US Food and Drug Administration (FDA) approved the use of C1-INH (Cinryze) at a dose of 1000 units IV 2-3 times/week for prophylaxis to prevent attacks. In October 2009, the FDA approved C1-INH (Berinert) at a dose of 20 units/kg IV for the treatment of acute abdominal and facial angioedema attacks in adolescents and adults with HAE.[7] In January 2012, an additional indication for laryngeal angioedema was approved by the FDA. Use was expanded to include children younger than 12 years in July 2016. The first subcutaneous C1-INH concentrate (Haegarda) was approved by the FDA in June 2017 for HAE prophylaxis in adults and adolescents.[51]

The recombinant C1 esterase inhibitor (rhC1-INH), Ruconest, was approved by the FDA in July 2014. It is indicated for adolescents and adults to treat acute attacks of HAE. Effectiveness was not established in patients with HAE that involved laryngeal attacks. Approval was supported by a phase 3 trial (n=75) that showed relief of symptoms of HAE attacks was achieved faster with rhC1-INH compared with placebo as assessed by patient questionnaire and visual analog scale.[2, 3]

Berinert and Ruconest are also approved for patient self-administration after proper training by a healthcare professional.

In December 2009, ecallantide (Kalbitor), a kallikrein inhibitor, at a dose of 30 mg SC was approved for the treatment of acute attacks.[8] A 2013 study showed that ecallantide can be safely used to treat multiple episodes of acute HAE.[28] The trial involved 147 patients who received treatment for 625 HAE episodes. Patients received ecallantide 30 mg SC for acute HAE attack symptoms, with no limit on the number of episodes treated.[28] The primary end point was change in patient-reported mean symptom complex severity (MSCS) score at 4 hours. Results showed no reduction of efficacy with repeated use of ecallantide. In addition, no new safety signals were detected.[28]

In August 2011, icatibant (Firazyr), a selective bradykinin B2 receptor antagonist, was approved for treatment of acute attacks of HAE in adults at a dose of 30 mg SC in the abdominal area.

In August 2018, the FDA approved lanadelumab, a monoclonal antibody that targets kallikrein, for prophylaxis of HAE. Approval was based on the HELP clinical trial which investigated the efficacy and safety of lanadelumab for long-term prophylaxis against angioedema attacks in hereditary angioedema (HAE). Of 125 patients, 113 completed the trial. All lanadelumab dosing regimens significantly reduced the mean monthly attack rates of HAE compared to placebo (P < 0.001) over the 26-week duration of the study. The 300 mg SC every 2 week regimen reduced attacks by 92.8% from baseline in patient with < 2 attacks per month and by 88.2% in patients whose baseline was 2 to < 3 attacks per month.[52]

Purified C1-INH, fresh frozen plasma (FFP), or attenuated androgen is given prophylactically prior to surgery.

Blood Products

Class Summary

These agents are used to improve the clinical aspects of the disease.

Fresh frozen plasma

Infuse prior to airway manipulation (eg, dental extraction) to prevent angioedema. Administering 2 units of FFP sustains complement control and prevents development of angioedema. Improved screening programs greatly reduce risk of hepatitis. FFP is not recommended for treatment of acute attacks.

Androgens and Androgen Derivatives

Class Summary

Some agents in this class may increase levels of C1 inhibitor and C4 component of complement.[40, 41, 42]

Danazol (Danocrine)

Danazol reduces the frequency of attacks in most patients, especially those involving the airway. For prophylaxis, the dose is adjusted to lowest dose that controls symptoms.

C1-Inhibitor Concentrates

Class Summary

Depending on the particular brand, these concentrates are approved by the U.S. FDA for routine prophylaxis against angioedema attacks and as treatment for acute attacks.

C1 esterase inhibitor recombinant (Ruconest)

Human recombinant C1 esterase inhibitor purified from the milk of genetically modified (transgenic) rabbits; restores level of functional C1 esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling. It is indicated for treatment of acute HAE attacks in adults and adolescents. It is administered as an IV infusion over 5 minutes.

 

C1 inhibitor human (Berinert, Cinryze, Haegarda)

Serine proteinase inhibitor that increases plasma concentration of C1 inhibitor activity. Berinert is indicated for treatment of acute abdominal, facial, or laryngeal attacks of HAE in adults and children. Cinryze and Haegarda are indicated for routine prophylaxis in adults and adolescents. Berinert and Cinryze are administered as an IV infusion, whereas, Haegarda is administered as a SC injection.

C1 inhibitor human (Berinert, Cinryze, Haegarda)

Serine proteinase inhibitor that increases plasma concentration of C1 inhibitor activity. Berinert is indicated for treatment of acute abdominal, facial, or laryngeal attacks of HAE in adults and children. Cinryze and Haegarda are indicated for routine prophylaxis in adults and adolescents. Berinert and Cinryze are administered as an IV infusion, whereas, Haegarda is administered as a SC injection.

C1 esterase inhibitor recombinant (Ruconest)

Human recombinant C1 esterase inhibitor purified from the milk of genetically modified (transgenic) rabbits; restores level of functional C1 esterase inhibitor in a patient’s plasma, thereby treating the acute attack of swelling. It is indicated for treatment of acute HAE attacks in adults and adolescents. It is administered as an IV infusion over 5 minutes.

Kallikrein Inhibitors

Class Summary

Kallikrein converts kininogen to bradykinin. Bradykinin is a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. Arresting this conversion can be used for treatment and prophylaxis of HAE.

Ecallantide (Kalbitor)

A human plasma kallikrein inhibitor, ecallantide binds to plasma kallikrein and blocks its binding site. It reduces conversion of kininogen to bradykinin. This agent is indicated for acute attacks of HAE. It is available as an injectable solution; 10 mg/mL per single-use vial.

Lanadelumab (Takhzyro, lanadelumab-flyo)

Human monoclonal antibody (IgG1 kappa-light chain) that targets plasma kallikrein and inhibits proteolytic activity to control excess bradykinin generated with HAE. It is indicated for prophylaxis to prevent attacks of HAE in adults and adolescents aged 12 years or older. Self-administered as a SC injection every 2-4 weeks.

Bradykinin Receptor Antagonists

Class Summary

Bradykinin receptor antagonists such as icatibant inhibit bradykinin from binding the B2 receptor and thereby treat the clinical symptoms of an acute attack. Recommended dose of icatibant is 30 mg SC in the abdominal area. It is available as a single-use, prefilled syringe, which delivers a dose of 30 mg (10 mg/mL).

Icatibant (Firazyr)

Bradykinin B2 receptor antagonist indicated for acute attacks of hereditary angioedema (HAE).

Antifibrinolytic Agents

Class Summary

These agents act through the inhibition of plasmin. They are potent inhibitors of fibrinolysis and can reverse states that are associated with excessive fibrinolysis.[19]

Aminocaproic acid (Amicar)

Aminocaproic acid is a lysine analog that inhibits fibrinolysis via inhibition of plasminogen activator substances; to a lesser degree, through antiplasmin activity.

It is widely distributed. Half-life is 1-2 h. For inhibition of angioedema, several days of treatment may be required. Hepatic metabolism is minimal. This agent can be used PO/IV.

Tranexamic acid (Cyklokapron)

An alternative to aminocaproic acid, tranexamic acid inhibits fibrinolysis by displacing plasminogen from fibrin.

 

Questions & Answers

Overview

What is hereditary angioedema (HAE)?

What are the signs and symptoms of hereditary angioedema (HAE)?

How is hereditary angioedema (HAE) diagnosed?

What is the role of imaging in the evaluation of hereditary angioedema (HAE)?

Which medications are used in the treatment of hereditary angioedema (HAE)?

What is included in prophylaxis for hereditary angioedema (HAE)?

What is hereditary angioedema (HAE)?

What are the types of hereditary angioedema (HAE)?

What is the mortality rate for hereditary angioedema (HAE)?

What is included in the treatment of hereditary angioedema (HAE)?

What is the pathophysiology of hereditary angioedema (HAE)?

What role of bradykinin in the pathogenesis of hereditary angioedema (HAE)?

What is the role of genetics in the pathogenesis of hereditary angioedema (HAE)?

Which genetic mutations cause type I hereditary angioedema (HAE)?

Which genetic mutations cause type II hereditary angioedema (HAE)?

What is the pathogenesis of hereditary angioedema (HAE) with normal C1 inhibitor?

What is the prevalence of hereditary angioedema (HAE)?

What are the racial and sexual predilections of hereditary angioedema (HAE)?

How does the incidence of hereditary angioedema (HAE) vary by age?

What is the prognosis of hereditary angioedema (HAE)?

What should be included in patient education about hereditary angioedema (HAE)?

Presentation

Which medical history is characteristic of hereditary angioedema (HAE)?

What are possible triggering events in hereditary angioedema (HAE)?

How frequently do attacks of hereditary angioedema (HAE) occur?

How does site of hereditary angioedema (HAE) affect the presentation?

How is swelling characterized in hereditary angioedema (HAE)?

What is the most common symptom of hereditary angioedema (HAE)?

What are the signs and symptoms of hereditary angioedema (HAE)?

What is the most serious complication of hereditary angioedema (HAE)?

What are less common presentation of hereditary angioedema (HAE)?

Which physical findings are characteristic of hereditary angioedema (HAE)?

What are less common physical findings suggestive of hereditary angioedema (HAE)?

DDX

What is acquired angioedema (AAE) and how is it differentiated from hereditary angioedema (HAE)?

Which conditions should be included in the differential diagnoses of hereditary angioedema (HAE)?

What are the differential diagnoses for Hereditary Angioedema?

Workup

What is the role of lab testing in the diagnosis of hereditary angioedema (HAE)?

Which tests are performed to differentiate the types of hereditary angioedema (HAE)?

What is the role of imaging studies in the diagnosis of hereditary angioedema (HAE)?

Which histologic findings suggest hereditary angioedema (HAE)?

Treatment

What is included in the treatment of hereditary angioedema (HAE)?

What are the World Allergy Organization (WAO) guidelines for prophylaxis and screening in hereditary angioedema (HAE)?

What are the treatment options for hereditary angioedema (HAE) types I and II?

How is pregnancy managed in patients with hereditary angioedema (HAE)?

What are the World Allergy Organization (WAO) guidelines for managing hereditary angioedema (HAE) types I and II?

Which medications are used in the treatment of acute hereditary angioedema (HAE)?

What is the role of ecallantide in the treatment of hereditary angioedema (HAE)?

What is the role of icatibant (Firazyr) in the treatment of hereditary angioedema (HAE)?

What is the role of prophylaxis in the treatment of hereditary angioedema (HAE)?

Which medications are used in the prophylactic treatment of hereditary angioedema (HAE)?

How are the underlying causes of hereditary angioedema (HAE) managed?

What is the role protease inhibitors in the treatment of hereditary angioedema (HAE)?

What is the role of diet and activity modifications in the treatment of hereditary angioedema (HAE)?

Which specialist consultations are needed for the treatment of hereditary angioedema (HAE)?

What long-term monitoring is required for hereditary angioedema (HAE)?

Medications

What are the goals of drug treatment for hereditary angioedema (HAE)?

What is the role of C1-INH in the treatment of hereditary angioedema (HAE)?

What is the role of recombinant C1 esterase inhibitor (Ruconest) in the treatment of hereditary angioedema (HAE)?

Which medications are used in the treatment of acute hereditary angioedema (HAE)?

Which medications in the drug class Antifibrinolytic Agents are used in the treatment of Hereditary Angioedema?

Which medications in the drug class Bradykinin Receptor Antagonists are used in the treatment of Hereditary Angioedema?

Which medications in the drug class Kallikrein Inhibitors are used in the treatment of Hereditary Angioedema?

Which medications in the drug class C1-Inhibitor Concentrates are used in the treatment of Hereditary Angioedema?

Which medications in the drug class Androgens and Androgen Derivatives are used in the treatment of Hereditary Angioedema?

Which medications in the drug class Blood Products are used in the treatment of Hereditary Angioedema?