Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema is due to either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and acquired angioedema can be life-threatening. Of the three types of HAE, type 1 is most common, occurring in approximately 85% of patients and characterized by decreased production of C1-INH, which results in reduced functional activity to 5-40% of normal. Type 2 occurs in 15% of cases; C1-INH is detectable in normal or elevated quantities but is dysfunctional. Also, HAE with normal CI-INH (previously called type 3 HAE) is rare and characterized by normal complement studies. Specific genetic mutations have been linked to factor XII, angiopoietin-1, and plasminogen gene. Patients with unknown mutations are classified as unknown. The screening test for types 1 and 2 is complement component C4, which is low to absent at times of angioedema and during quiescent periods. A useful test to differentiate HAE from acquired angioedema is C1q protein, which is normal in HAE and low in acquired angioedema. The management of HAE has been transformed with the advent of disease-specific therapies. On-demand therapy options include plasma and recombinant C1-INH for intravenous infusion; ecallantide, an inhibitor of kallikrein; and icatibant, a bradykinin β₂ receptor antagonist, both administered subcutaneously. For long-term prophylaxis, intravenous or subcutaneous C1-INH enzyme replacement and lanadelumab, a monoclonal antibody against kallikrein that is administered subcutaneously, are effective agents.

Hereditary angioedema is a rare autosomal dominant disease characterized by recurrent and unpredictable episodes of swelling, particularly of the skin and the gastric, oropharyngeal, and laryngeal mucosa, which can be life threatening. The majority of cases of hereditary angioedema are caused by genetic mutations that lead to a deficiency (type I) or dysfunction (type II) of C1 esterase inhibitor (C1-INH), a serine protease inhibitor that regulates multiple pathways, including the kallikrein–kinin and contact system. In an especially rare third type of hereditary angioedema, patients have normal levels of functional C1-INH and often have a distinct clinical presentation, including a higher frequency of facial, pharyngeal, and tongue swelling. The typical swelling in hereditary angioedema is caused by locally increased vascular permeability in response to excessive bradykinin formation, which results from inadequate control of the contact-system components factor XIIa and plasma kallikrein.

For decades, C1-INH–replacement therapies have been the predominant option for the treatment of hereditary angioedema attacks. Recently, inhibition of plasma kallikrein has also emerged as a promising strategy for the control of the condition. In 2018, lanadelumab (Takhzyro, Takeda), a monoclonal antibody targeting plasma kallikrein, was approved in the United States for prophylactic treatment of hereditary angioedema attacks. In addition, treatment with the oral plasma kallikrein inhibitor berotralstat has been reported to result in a 44% reduction in attack rate in a phase 3 trial (Biocryst press release, May 21, 2019) that followed a successful dose-finding phase 2 trial. However, injection-site reactions (with lanadelumab) and gastrointestinal side effects (with berotralstat) occurred in a substantial proportion of the patients.

Targeting of plasma prekallikrein expression at the messenger RNA level could potentially reduce plasma kallikrein activity and concomitant bradykinin release.

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by a mutation in the C1 esterase inhibitor gene. HAE affects 1/50,000 people worldwide. Three main types of HAE exist: type I, type II, and type III. Type I is characterized by a deficiency in C1-INH. C1-INH is important in the coagulation complement, contact systems, and fibrinolysis. Most HAE cases are type I. Type I and II HAE result from a mutation in the SERPING1 gene, which encodes C1-INH. Formally known as type III HAE is typically an estrogen-dependent or hereditary angioedema with normal C1-INH activity. Current guidelines now recommend subdividing hereditary angioedema with normal C1 esterase inhibitor gene (HAE-nl-C1-INH formerly known as HAE type III) based on underlying mutations such as in kininogen-1 (HAE-KNG1), plasminogen gene (PLG-HAE), myoferlin gene mutation (MYOF-HAE), heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6), mutation in Hageman factor (factor XII), and in angiopoietin-1 (HAE-ANGPT-1). The clinical presentation of HAE varies between patients, but it usually presents with nonpitting angioedema and occasionally abdominal pain. Young children are typically asymptomatic. Those affected by HAE usually present with symptoms in their early 20s. Symptoms can arise as a result of stress, infection, or trauma. Laboratory testing shows abnormal levels of C1-INH and high levels of bradykinin. C4 and D-dimer levels can also be monitored if an acute HAE attack is suspected. Acute treatment of HAE can include IV infusions of C1-INH, receptor antagonists, and kallikrein inhibitors. Short- and long-term prophylaxis can also be administered to patients with HAE. First-line therapies for long-term prophylaxis also include IV infusion of C1-INH. This review aims to thoroughly understand HAE, its clinical presentation, and how to treat it.

The condition angioedema is characterized as recurrent, nonpitting, nonpruritic swelling of the deep layers of the skin and mucosal tissues. It may be hereditary, acquired, drug induced, or idiopathic. Hereditary angioedema, an autosomal dominant condition, results from deficiency of the C1 esterase inhibitor, which may reflect inadequate levels (type I) or function (type II). Deficiency of the C1 esterase inhibitor changes activation of the complement and contact systems and also affects the regulation of coagulation and fibrinolysis, although to a lesser extent. Table 2 summarizes the differences among hereditary angioedema, acquired angioedema, and angioedema that is associated with angiotensin-converting–enzyme (ACE) inhibitors. ACE inhibitors are thought to cause angioedema through an effect on the kallikrein–kinin system that reduces the catabolism of bradykinin and increases its activity, leading to the inflammatory effect seen in angioedema.

A recent change in guidelines recommends that patients carry on-demand treatment for hereditary angioedema at all times and consider short-term prophylaxis before undergoing procedures that can induce an attack. The revised guidelines recommend consideration of on-demand treatment (with self-dosing of a C1 esterase inhibitor) for all attacks, treatment of attacks affecting the upper airway, early treatment, and initiation of treatment with a C1 inhibitor — either ecallantide (a kallikrein inhibitor) or icatibant (a bradykinin receptor antagonist). Ecallantide should be administered subcutaneously by a health care professional in three 10-mg (1-ml) injections; if the attack persists, an additional dose of 30 mg may be administered within a 24-hour period. The recommended dose for icatibant is 30 mg injected subcutaneously in the abdominal area; additional doses may be administered at intervals of at least 6 hours if the response is inadequate or if symptoms recur, but no more than 3 doses may be administered in any 24-hour period.

Table 2:
Caption: Subtypes of Angioedema and Related Laboratory Abnormalities.*
Content:
Diagnosis,C4 Level,C1 Inhibitor Function,C1 Inhibitor Level,C1q Level
Hereditary angioedema,,,,
Type I,Low,Low,Low,Normal
Type II,Low,Low,Normal,Normal
Acquired angioedema,Low,Low,Normal or low,Low
ACE-inhibitor–associated angioedema,Normal,Normal,Normal,Normal

Hereditary angioedema is a disabling and potentially fatal condition characterized by recurrent episodes of swelling without urticaria or pruritus. The condition is caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. Patients have insufficient C1 inhibitor function to prevent bradykinin production by the contact system, leading to episodes of increased capillary hyperpermeability and swelling. These episodes manifest clinically as angioedema attacks.

Low levels of C1 inhibitor protein antigen or low functional levels of C1 inhibitor activity, as well as low levels of complement C4, are diagnostic for hereditary angioedema, and baseline C1 inhibitor function has been reported to correlate with disease severity. According to clinical observations, a sustained threshold level of approximately 40% functional C1 inhibitor activity has been reported to confer certain protection against recurrent attacks.

Regular intravenous C1 inhibitor replacement is effective at reducing the frequency and severity of attacks and has an acceptable safety and side-effect profile. A double-blind, placebo-controlled, crossover trial involving 22 patients with frequent attacks showed a 50% reduction in the frequency and severity of attacks with the use of an intravenous C1 inhibitor at a dose of 1000 IU twice weekly. However, because of the technical difficulties of regular venous access, risks with the use of indwelling venous catheters, and patient considerations, the development of a C1 inhibitor concentrate suitable for regular subcutaneous administration is of interest.

A phase 2 trial showed that administration of CSL830 (CSL Behring), a low-volume, human plasma–derived, pasteurized, nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in a dose-dependent and constant increase in trough plasma levels of functional C1 inhibitor activity above 40%, a biochemical finding expected to provide effective prophylaxis of attacks.

The critical functional threshold for C1 inhibitor control of the plasma contact system is approximately 40%. Functional C1 inhibitor levels in hereditary angioedema with C1 inhibitor deficiency are generally 5 to 30% of the normal level, despite the presence of one normal gene. The cause of this discrepancy has been proposed to involve enhanced clearance of C1 inhibitor–protease complexes, cleavage of C1 inhibitor into an inactive, 94-kD form, and inhibition of the normal gene product by the abnormal one, designated as “transinhibition.” A dominant negative effect on C1 inhibitor protein secretion has also been reported.

In hereditary angioedema with C1 inhibitor deficiency, activation of the plasma contact system generates bradykinin, which transduces its biologic effect through the engagement of G protein–coupled receptors. The bradykinin B2 receptor is constitutively expressed on endothelial cells and is considered to be principally responsible for the active transfer of fluid into localized tissues, with resultant angioedema. Mechanistically, activation of the bradykinin B2 receptor results in dissolution of the adherens junction, which plays a critical role in limiting vascular permeability (Figure 1). After bradykinin B2 receptor engagement, downstream signaling phosphorylates the transmembrane vascular endothelial cadherin molecules, which are then internalized and degraded. The ensuing actin cytoskeleton contraction increases pore sizes between endothelial cells, with consequent vascular leakage. In addition to the bradykinin B2 receptor, speculation has centered on the role of the bradykinin B1 receptor. Although the bradykinin B1 receptor is not expressed in normal tissue, inflammatory stimuli, as well as engagement of the bradykinin B2 receptor, can induce its expression. Unlike the bradykinin B2 receptor, which is rapidly desensitized, the bradykinin B1 receptor is only slowly and partially desensitized after binding with its agonist. Ex vivo experiments have provided evidence that bradykinin B1 receptor may be expressed during angioedema attacks, which could explain the protracted duration of the swelling episodes.

Figure 1:
Caption: Contact, Complement, and Fibrinolytic Systems in Hereditary Angioedema (HAE) and Targets for Available Therapy.
Description: The plasma contact system consists of coagulation factor XII, plasma prekallikrein, and high-molecular-weight kininogen (HMWK). Also shown are mechanisms of action for drugs that are currently approved for the treatment of HAE with C1 inhibitor (C1-INH) deficiency; sites of inhibition by C1-INH, ecallantide, lanadelumab, and icatibant in the plasma contact system activation cascade are shown in red. Coagulation factor XII and the prekallikrein–HMWK complex have weak intrinsic enzymatic activity; an absence of C1-INH produces their active forms, factor XIIa and plasma kallikrein, respectively. Autoactivation, kallikrein, and plasmin produce additional factor XIIa. Factor XII fragment (factor XIIf) weakly stimulates the prekallikrein–HMWK complex to produce the kallikrein–HMWK complex (black dashed arrow). Without sufficient levels of functional C1-INH to inhibit plasma kallikrein, HMWK is cleaved, producing bradykinin. Cleaved HMWK may be a biomarker of disease activity. Heat shock protein 90 (HSP90), which is constitutively secreted by endothelial cells, also activates the prekallikrein–HMWK complex. C1-INH regulates the lectin pathway. Levels of mannose-binding lectin–associated serine protease 1 (MASP-1), MASP-1–C1-INH, and ficolin-3 may correlate with HAE activity; further validation is required. Factor XII–independent activation of HMWK cleavage occurs through HSP90 and potentially through MASP-1. Bradykinin, generated through the plasma contact system, binds to the bradykinin B2 receptor on endothelial cells. Bradykinin B2 receptor activation produces angioedema (fluid transfer) through several mechanisms, including increased endothelial-cell permeability, enhanced phosphorylation and inactivation of vascular endothelial cadherin, and expression of vascular permeability factors (vascular endothelial growth factor [VEGF]), all of which create vascular pores. Endothelial-cell activation promotes vasodilation and increased plasma osmolality. Induction and activation of bradykinin B1 receptor through inflammation and through engagement of bradykinin B2 receptor may be involved in angioedema. Bradykinin (BK) that is unbound and Lys-BK (not shown) are rapidly inactivated by angiotensin-converting enzyme and carboxypeptidases N and M to des-Arg-BK and des-Arg-Lys-BK (not shown), respectively. Des-Arg-BK is a weak ligand for bradykinin B1 receptor (indicated by the gray dashed arrow) and is of uncertain importance in HAE. Tissue kallikrein cleaves low-molecular-weight kininogen, releasing Lys-BK, which is acted on by carboxypeptidase, generating des-Arg-Lys-BK, a potent ligand for bradykinin B1 receptor (not shown). There is no evidence that the tissue kallikrein system is activated in HAE. Mutations in angiopoietin-1 prevent Tie2 from inhibiting vascular permeability. The classic complement pathway, rather than the alternative complement pathway, is shown. VEGFR denotes vascular endothelial growth factor receptor.