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Hereditary angioedema with normal C1 inhibitor

Hereditary angioedema with normal C1 inhibitor
Literature review current through: Jan 2024.
This topic last updated: Oct 11, 2021.

INTRODUCTION — Hereditary angioedema (HAE) is characterized by recurrent, self-limited episodes of swelling primarily involving the skin and the mucosa of the gastrointestinal tract and upper airway. There are several types.

HAE types I and II, which are characterized by impaired C1 inhibitor (C1-INH) activity (HAE-C1-INH) due to protein deficiency (type I) or dysfunction (type II) are discussed separately:

(See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

(See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis".)

(See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)

(See "Hereditary angioedema: Acute treatment of angioedema attacks".)

(See "Hereditary angioedema: Short-term prophylaxis before procedures or stressful events to prevent angioedema episodes".)

In 2000, a novel type of HAE was identified that was characterized by normal C1-INH activity in plasma [1,2]. This type was classified as "HAE with normal C1-INH" or "HAE type III." Over time, HAE with normal C1-INH was shown to result from a number of different genetic causes with similar phenotypes [3]. The clinical manifestations, pathogenesis, diagnosis, and management of this disorder will be reviewed here.

EPIDEMIOLOGY — Information about the incidence and prevalence of HAE with normal C1-INH is limited because it is a rare disorder. The prevalence has been estimated to be 1:100,000 among German patients [4]. HAE with normal C1-INH was initially assumed to be specific to females, but male members of affected families have since been reported [5]. In the largest single series, approximately 11 percent of patients were male [4].

BACKGROUND AND TERMINOLOGY — Historically, HAE was described as a familial disorder resulting from either deficiency or dysfunction of the inhibitor of the complement protein C1, termed C1 inhibitor (C1-INH). Types I and II are now collectively abbreviated as HAE-C1-INH. In 2000, two different groups published descriptions of another familial form of angioedema, in which affected individuals had normal C1-INH levels and activity [1,2].

Thirty-six patients from 10 families were detailed in the earliest study [1]. All of the affected individuals were women, and all of those tested had normal C1-INH function and plasma concentration.

In a second report published in the same year, seven females from a single family were described in whom episodes only occurred during pregnancy or with the use of exogenous estrogens [2].

Subsequently, a number of additional families were described [4,6-8]. The largest series included 265 patients from 88 families [4]. The terms "estrogen-dependent" and "estrogen-associated inherited angioedema" were initially proposed to describe this disorder, prior to the recognition that males can also be affected [9]. In an attempt to standardize nomenclature, a consensus statement from an international expert panel has recommended the disorder be designated "HAE with normal C1-INH" [10,11].

PATHOGENESIS

Mediators of angioedema — In types I and II HAE, excess generation of bradykinin, a potent vasoactive substance, has convincingly been shown to be the major mechanism leading to the formation of angioedema [12]. The pathophysiology of types I and II HAE is reviewed in more detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis", section on 'Pathogenesis'.)

In HAE with normal C1-INH, it is not as clear that bradykinin is the main mediator of angioedema, although the efficacy of icatibant, a bradykinin B2 receptor antagonist, is a strong indirect indicator that bradykinin is important [13]. The kinin-generating pathways interface with the coagulation (contact system) and fibrinolytic pathways, and abnormalities of proteins in these pathways could also lead to abnormal generation of angioedema (figure 1) [3].

Known HAE-specific mutations — Several HAE-specific mutations have been identified in families with HAE with normal C1-INH. The pattern of affected family members in successive generations supports an autosomal dominant mode of inheritance [2,4,6,8]. To date, HAE-specific mutations in the genes for the following proteins have been identified in families with HAE with normal C1-INH:

Coagulation factor XII

Plasminogen

Angiopoietin-1

Kininogen-1

Myoferlin

Heparan sulfate-glucosamine 3-O-sulfotransferase 6

Factor XII — Several mutations in the coagulation factor XII (FXII, Hageman factor) gene (F12) have clearly been identified in patients with HAE with normal C1-INH. This disorder is called HAE-FXII [8]:

Two missense mutations involving the F12 gene were detected in 6 of 20 index patients from unrelated German families [14]. Both mutations were single heterozygous nucleotide substitutions within exon 9 of the F12 gene. The first and most common point mutation c.983C>A (alternatively termed c.1032C>A) results in substitution of a threonine residue for lysine (Thr328Lys; alternatively Thr309Lys), and the second c.983C>G (alternatively termed c.1032C>G) results in substitution of the same threonine residue for arginine (Thr328Arg; alternatively Thr309Arg) [14,15]. Neither mutation was detectable in 145 healthy controls. The same mutations have subsequently been identified in multiple other affected families and appear to segregate with the disease [4,10,16-24].

A different F12 gene mutation resulting in deletion and insertion of a considerable number of base pairs (c.971_1018+24del72) was identified in a few families [15,24,25]. This large deletion is located in the same gene region as the previously identified missense mutations and was not detected in control subjects.

A duplication of 18 base pairs (c.892_909dup) in the F12 gene has also been reported [26]. The duplication occurs in the same region as the three mutations previously described and causes a repeated amino acid sequence (p.Pro283_Pro303) [26].

The observation that several different mutations involving the same F12 gene region are present in affected patients and not in controls supports an association between FXII protein modifications and the disorder [27]. In one study, mutations in the F12 gene were associated with normal plasma concentrations of FXII but an increase in its enzymatic activity when compared with healthy controls [16]. However, these findings could not be reproduced in a follow-up study using a more sensitive assay, and functional defects in FXII were not found [28]. In 2014, it was reported that due to the F12 gene mutations, O-glycosylation sites are lost in the FXII protein, resulting in an abnormal glycosylation [25]. In a later study, it was reported that the loss of glycosylation led to an increased rate of FXII activation resulting in activation of the kallikrein-kinin pathway and bradykinin formation [29]. The two missense mutations and the deletion mutation introduce new sites in the FXII protein that are sensitive to enzymatic cleavage by plasmin [30]. The FXII mutants rapidly activate after cleavage by plasmin, escape from inhibition through C1-INH, and elicit excessive bradykinin formation. The findings indicate that plasmin modulates disease activity in patients with HAE-FXII. In 2019, another study showed that the F12 variants Thr328Lys and Thr328Arg are cleaved after residue 328 by coagulation proteases like thrombin and FXIa, producing a truncated form of FXII (delta-FXII) [31]. The truncated delta-FXII converts prekallikrein to kallikrein more efficiently than native FXII. In addition, delta-FXII is a better substrate than FXII for kallikrein, resulting in greater delta-FXII production and further prekallikrein activation. This accelerated FXII/prekallikrein activation overwhelms the regulatory functions of C1-INH, and more kallikrein can cleave high molecular weight kininogen to bradykinin (figure 2) [31].

Not all members of a given family (not even all the females) who carry the F12 mutations are symptomatic, indicating that penetrance is incomplete, and other factors are necessary for disease development. Among 23 families affected by HAE with normal C1-INH, 35 (33.7 percent) of 104 carriers of F12 mutations were asymptomatic [4]. Results from another study suggest variations in enzymes involved in kinin metabolism may modify disease expression and severity in HAE with normal C1-INH associated with F12 mutations [32]. The study included symptomatic and asymptomatic carriers of F12 mutations, as well as noncarrier relatives and healthy controls. The study showed a significant inverse relationship between disease severity and both angiotensin-I-converting enzyme activity and carboxypeptidase-N activity [32].

F12 mutations do not appear to be equally prevalent in all populations. In the large German series of 265 patients, 69 (26 percent) demonstrated one of the four identified F12 mutations [4]. In other series by the same group, one of these mutations was present in 17 to 25 percent of the families tested [8,33]. However, neither of these mutations was found in 40 patients analyzed in the United States, although the study in which this was reported was an analysis of samples submitted to a specialty commercial laboratory, and the clinical features of the patients were not available to the researchers [34].

Plasminogen — In 2018, the 161139762A>G mutation in the plasminogen gene (PLG) was identified by whole exome analysis in German patients with HAE with normal C1-INH. The mutation co-segregated with clinical symptoms and the disease was transmitted as an autosomal dominant trait [35]. The mutation was located in exon 9 leading to the missense mutation p.Lys330Glu (K330E) in the kringle 3 domain of the PLG protein. The mutation was found in 14 patients of four families and additionally in nine index patients of 38 other families with HAE with normal C1-INH. The exact function of the change in the kringle 3 domain is unknown at present. This disorder is called HAE with a specific mutation in the PLG gene (HAE-PLG).

Other HAE-specific mutations — HAE-specific mutations in other genes have been reported, each in one family with HAE with normal C1-INH.

Angiopoietin-1 – A variant was identified in the gene encoding angiopoietin-1 (ANGPT1) in one Italian family [36]. This disorder is termed HAE with a specific mutation in the ANGPT1 gene (HAE-ANGPT1). The mutation, which is rare in the general population, was present in four symptomatic females and absent in seven unaffected relatives. Angiopoietin-1 has been shown to decrease bradykinin-induced plasma leakage [37]. The mutation did not alter plasma levels of angiopoietin-1 but impaired its ability to interact with its receptor (tunica interna endothelial cell kinase 2 [TIE2]) on endothelial cells.

Kininogen-1 – A mutation in the kininogen-1 gene (KNG1) was present in all six affected patients with HAE with normal C1-INH in a German family, and it was not present in eight asymptomatic relatives [38]. The mutation causes an amino acid change of p.Met379 to p.Lys379 (p.Met379Lys; p.M379K) and is present in both high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK) isoproteins. Pedigree analysis revealed that clinical symptoms of HAE occurred in three generations and co-segregated with the KNG1 mutation c.1136T>A in all analyzed patients. The mutation was transmitted in a dominant inheritance pattern. The mutation is located in a functional domain, the cleavage region for kinins including bradykinin, which is the presumed direct mediator for the symptoms of HAE. The amino acid change is close to the N-terminal cleavage site of bradykinin. The disorder is called HAE with a specific mutation in the KNG1 gene (HAE-KNG1).

Myoferlin – A gain-of-function variant was identified in the gene for myoferlin (MYOF), a protein implicated in vascular endothelial growth factor (VEGF) signal transduction, in an Italian family. Three females with the MYOF-217S gain-of-function had angioedema symptoms affecting only the face, lips, and oral mucosa [39]. This disorder is called HAE with a specific mutation in the MYOF gene (HAE-Myoferlin).

Heparan sulfate glucosamine 3-O-sulfotransferase 6 – A mutation in the gene encoding heparan sulfate glucosamine 3-O-sulfotransferase 6 (3-OST-6), HS3ST6, was identified in one family [40]. This likely leads to incomplete synthesis of heparan sulfate, a glycosaminoglycan found on endothelial surfaces.

Patients without an HAE-specific mutation — The genetic background is still unknown in other patients with HAE with normal C1-INH. These individuals are said to have HAE of unknown background (HAE-unknown). There could be multiple mechanisms underlying HAE-unknown, and there could be subtle clinical and laboratory differences among those types [10].

Other laboratory abnormalities — Other laboratory abnormalities that have been identified in some patients with HAE with normal C1-INH include genetic mutations in other proteins and deficiency of plasminogen activator inhibitor-2 (PAI-2). The presence of these abnormalities, as well as their role in pathogenesis, remains to be confirmed.

Polymorphisms in the genes encoding aminopeptidase P and angiotensin-converting enzyme (ACE), two enzymes that degrade bradykinin, were reported in three female subjects with HAE with normal C1-INH. However, these patients also possessed the Thr328Lys mutation in the F12 gene [41].

PAI-2, a molecule that inhibits the activation of plasminogen, was found to be deficient in 23 patients with HAE with normal C1-INH, including patients both with and without a F12 mutation [42]. This abnormality was not present in 23 control patients with HAE-C1-INH.

Role of estrogens — The impact of estrogens in HAE with normal C1-INH is highly variable. An exacerbating effect of estrogens on female patients with this disorder was first highlighted in one of the original descriptions of the disease, in which females only experienced angioedema attacks during pregnancy or while using some form of exogenous estrogen, such as oral contraceptives or hormone replacement therapy [2]. Additional patients with estrogen-exacerbated angioedema have since been described [7,33,43,44]. However, other females with HAE with normal C1-INH can tolerate high levels of estrogen without a worsening of angioedema attacks [7,27,33].

It is not entirely clear how estrogens would induce attacks, although they may influence expression of factors important in the synthesis and degradation of bradykinin. High levels of estrogens are reported to reduce plasma C1-INH levels, increase transcription of FXII protein, and increase plasma prekallikrein levels, all favoring an increase in bradykinin production (figure 2). In keeping with some interaction between estrogens and FXII, patients with HAE-FXII were found to be more sensitive to estrogens than patients with HAE-unknown in one study [4]. ACE is important in degradation of bradykinin and its metabolite, and estrogens may reduce expression of ACE and allow bradykinin accumulation. Estrogens may also increase the expression of bradykinin type 2 receptors [45].

The negative influence of estrogens is not specific to HAE with normal C1-INH, since estrogen is a well-established trigger in some females with HAE-C1-INH. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Triggers and exacerbating factors'.)

CLINICAL PRESENTATION — HAE with normal C1-INH has signs and symptoms similar to those of HAE associated with C1-INH defects, with some distinguishing features.

Similarities between HAE-C1-INH and HAE with normal C1-INH include the occurrence of self-limited episodes of subcutaneous and submucosal angioedema lasting two to five days in the absence of treatment. All disorders affect the skin and the mucosa of the gastrointestinal and upper respiratory tract. Cutaneous attacks are most common, and episodes affecting the upper airway are less common but potentially life-threatening [8,46]. Affected skin is nonpruritic and the edema is nonpitting, and urticaria is not seen. Some patients report a prodrome of numbness or tingling at the affected site. There is significant heterogeneity in the types of HAE with normal C1-INH. Members of an affected family may be asymptomatic or symptomatic to varying degrees [8,33].

Unique characteristics of HAE with normal C1-INH — Differences have been noted between HAE with normal C1-INH and HAE-C1-INH:

Later age of onset – HAE with normal C1-INH usually presents in adulthood (after puberty). In a large series of 138 patients with the disorder, the mean age at disease onset was 26.8 years [8]. In contrast, more than one-half of patients with HAE-C1-INH present during childhood with a mean age at disease onset of 11.7 years [8,10,46].

More prominent involvement of the tongue, uvula, and face – In HAE with normal C1-INH, angioedema of the tongue, uvula, and facial skin occurs with higher frequency, and tongue swelling may be a diagnostic clue to its presence [8,47]. In the series of 138 patients mentioned previously, 54 percent experienced tongue swelling, compared with 12 percent in a series of patients with HAE-C1-INH [8]. Tongue swelling may herald laryngeal edema. Among 35 patients with laryngeal edema, 13 had experienced episodes associated with tongue swellings [8]. Four of 138 patients in this series died due to asphyxiation. In a series of 60 patients with one specific type of HAE with normal C1-INH, namely HAE-PLG, tongue swellings were a frequent sign [35]. Many of the tongue swellings were associated with voice changes and dyspnea as signs of the beginning upper airway obstruction [35].

Less frequent abdominal attacks – Approximately 50 percent of patients with HAE with normal C1-INH experience abdominal attacks, compared with at least 90 percent in patients with types I and II [8,46-48].

Females are affected more often and more severely – Within families affected by HAE with normal C1-INH, females are more often symptomatic and have more severe symptoms than males [8].

Less intense and more variable disease activity – Patients with HAE with normal C1-INH usually have a decreased frequency of symptoms and a greater number of disease-free intervals. Many patients with the disorder experience prolonged periods (ie, one to several years) without symptoms [8]. In addition, attacks more often involve a single location in HAE with normal C1-INH compared with HAE-C1-INH [49].

Different cutaneous findings – Hemorrhages into skin swellings and easy bruising have rarely been reported in patients with HAE with normal C1-INH, although not in patients with types I and II [8]. The prodromal skin changes, erythema marginatum, which is reported by up to one-third of patients with HAE-C1-INH, has not been observed in HAE with normal C1-INH.

Lower penetrance – The inheritance pattern of HAE with normal C1-INH shows generally low penetrance compared with HAE-C1-INH, and obligate, asymptomatic carriers appear to be relatively common.

DIAGNOSIS

When to suspect — HAE should be suspected in a patient with recurrent, self-limited angioedema without urticaria or pruritus, recurrent episodes of abdominal pain or laryngeal edema, and a family history of similar symptoms. However, a family history will not be present if the patient has a de novo mutation or is the first family member to display clinical features of the disorder.

Evaluation — In contrast to those patients with HAE-C1-INH, patients with HAE with normal C1-INH have normal plasma C1-INH levels and activity, as well as normal plasma C4 levels. Because there is no specific biochemical test for HAE with normal C1-INH at present, it is generally accepted that either a family history of angioedema or the presence of a mutation known to be specific for HAE with normal C1-INH is required for diagnosis. Clinical features that help differentiate this disorder from HAE-C1-INH are reviewed above. (See 'Unique characteristics of HAE with normal C1-INH' above.)

Thus, the following elements are necessary to make the diagnosis [11]:

Episodic angioedema affecting characteristic organs, without urticaria

Normal C1-INH level and function and normal C4

A family history of angioedema or the presence of a mutation specific for HAE with normal C1-INH  

Excluding other forms of angioedema — When evaluating a patient with recurrent episodes of angioedema without urticaria, other causes of angioedema must be excluded. This is particularly important in a patient with an uncertain or negative family history of angioedema. A diagnostic algorithm is provided for patients with suggestive clinical features and no family history (algorithm 1).

Patients on angiotensin-converting enzyme (ACE) inhibitors should discontinue these medications and be treated with a different type of antihypertensive. It is important to note that the impact of discontinuation may only be clear after several months, as some patients will have a small number of recurrent episodes, particularly in the first few months after the ACE inhibitor was discontinued. This is discussed in more detail separately. Angiotensin II receptor blockers (ARBs) are usually tolerated. (See "ACE inhibitor-induced angioedema".)

Patients on estrogens should have these medications discontinued. We also discontinue daily aspirin but continue other nonsteroidal anti-inflammatory drugs (NSAIDs) used as needed.

If an allergic cause is suspected, the patient should be referred to an allergy specialist, if possible, or tested for immunoglobulin E (IgE) to the suspected allergen. A trial of strict avoidance is another option.

If no medication or allergy can be implicated, then the patient can be said to have idiopathic angioedema. Complement studies are normal in idiopathic angioedema. Idiopathic angioedema can be classified to histaminergic angioedema (responding to antihistamines) and nonhistaminergic angioedema (not responding to antihistamines).

A trial of antihistamine therapy is helpful in distinguishing histaminergic from nonhistaminergic idiopathic angioedema. Histaminergic idiopathic angioedema often improves with antihistamines, alone or in combination with glucocorticoids. The evidence supporting the use of H1 antihistamines in idiopathic angioedema is reviewed separately. (See "An overview of angioedema: Clinical features, diagnosis, and management", section on 'Recurrent, idiopathic angioedema'.)

The following represents our approach to differentiate histaminergic from nonhistaminergic idiopathic angioedema, which has not been formally studied:

We treat patients with a nonsedating H1 antihistamine for at least one month (or an appropriate amount of time, depending on the frequency of attacks in that individual). Options include cetirizine (10 mg daily), loratadine (10 mg daily), fexofenadine (180 mg daily), or a similar agent. If this does not prevent episodes of angioedema, we double or quadruple the dose for another one to three months (cetirizine up to four times daily or an equivalent for one month or an interval long enough to expect three or more angioedema attacks) [10].

In addition, we instruct patients to treat with additional medications at the first sign of symptoms. Some patients have identifiable sensations in the skin or tissue just before the onset of angioedema, and the medications should be taken when these sensations appear. In this setting, we ask patients to self-administer 40 mg of prednisone and 25 to 50 mg of diphenhydramine all at once at the first sign of swelling, with no further doses.

If there is a strong suspicion for a histaminergic cause and a trial of high dose antihistamines does not clearly reduce angioedema episodes, a trial of omalizumab (eg, four months) has also been used.

A patient not responsive to antihistamines is presumed to fall into the category of nonhistaminergic idiopathic angioedema. A limitation to the proposed diagnostic criteria is the inability to distinguish HAE with normal C1-INH of unknown cause (HAE-unknown) from nonhistaminergic idiopathic angioedema, highlighting the need for a valid confirmatory diagnostic test.

Genetic testing — The majority of the patients with HAE with normal C1-INH do not have identifiable F12, PLG, or other mutations, based on available data. The prevalence of the F12 mutation appears to be particularly low in the United States [50]. However, mutational testing is available through some commercial laboratories and establishes the diagnosis if positive [51,52]. Focused next-generation sequencing panels that can interrogate for the known mutations are increasingly available from several Clinical Laboratory Improvement Amendments (CLIA)-certified labs [53].

Differential diagnosis — The primary disorder in the differential diagnosis of HAE with normal C1-INH is idiopathic angioedema. An approach to excluding other causes of angioedema is outlined above. (See 'Excluding other forms of angioedema' above.)

Conditions that can mimic angioedema are discussed in detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis", section on 'Differential diagnosis'.)

MANAGEMENT — Reported treatment options for HAE with normal C1-INH are overall similar to those for HAE-C1-INH and may also be divided into management of acute attacks and prophylactic therapy [3,54]. However, treatment experience is limited, because there are no placebo-controlled clinical trials, and most evidence is anecdotal. (See "Hereditary angioedema: Acute treatment of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis" and "Hereditary angioedema: Short-term prophylaxis before procedures or stressful events to prevent angioedema episodes".)

Avoidance of triggers — Triggers for episodes of angioedema include local trauma or physical pressure to the affected area, emotional stress, and certain medications [33]. Exogenous estrogens are the most consistently reported medication to worsen symptoms [2]. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have been implicated in case reports [46,55]. In some patients, withdrawal of aggravating medications is sufficient to prevent most attacks, and no other prophylactic therapy is needed [56].

Treating acute attacks

Airway attacks — Patients with acute symptoms involving the upper airway are at risk for fatal asphyxiation. Assessment and protection of the upper airway is the first and most important management issue in the patient with an acute attack involving any part of the airway, because none of the available therapies are universally effective. In addition, these agents take time to work, and the patient's airway must be protected in the interim. (See "Hereditary angioedema: Acute treatment of angioedema attacks".)

Intubation should be performed immediately if stridor or signs of respiratory arrest are present. A clinician trained in difficult airway management should be summoned, if possible, because failed attempts can lead to fatal obstruction. Emergency cricothyroidotomy may be required in rare cases. (See "Emergency cricothyrotomy (cricothyroidotomy) in adults".)

Once the patient is assessed and either intubated or deemed stable, additional therapies can be considered. Transfer to the intensive care unit should be arranged. Frequent and meticulous monitoring of airway status should continue throughout the course of the attack until complete resolution, and patients should not be discharged until all airway symptoms have resolved.

Specific agents — Unlike with HAE-C1-INH, data on the effectiveness of different therapies for HAE with normal C1-INH are limited to small, uncontrolled trials and case reports. At present it is not clear whether all types of HAE with normal C1-INH respond equally to available treatments. The clinical experience of the authors is that icatibant appears to be effective in the majority of acute attacks of all types of HAE with normal C1-INH, and its mechanism of antagonizing the bradykinin 2 receptor suggests that it would be helpful regardless of the precise cause of excessive bradykinin generation.

IcatibantIcatibant is a bradykinin type 2 receptor antagonist that has been effective in treating acute symptoms in small numbers of patients [57-59].

In an open-label, prospective uncontrolled study that included eight patients with HAE with normal C1-INH, most symptoms improved rapidly following icatibant self-administration, although some attacks required a second or third injection of the drug [58]. Two of 19 attacks could be classified as failures with a time of initial improvement ≥4 hours.

In a retrospective study of 13 patients with HAE-PLG, icatibant was given for 201 acute swelling attacks, including 104 tongue swellings [13]. The mean duration of the treated attacks was significantly shorter than that of the previous 149 untreated attacks.

Dosing and administration are reviewed separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Icatibant dose and administration'.)

EcallantideEcallantide is a plasma-kallikrein inhibitor, which has been used successfully to treat HAE with normal C1-INH in a limited number of reports [60,61]. It is only available in the United States. Dosing is found separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Kallikrein inhibitor (United States only)'.)  

C1 inhibitor concentrate – C1-INH concentrate has also been used and presumably acts by raising the threshold for activation of kallikrein and generation of bradykinin [13,33,56,62]. Only plasma-derived (pd) C1-INH concentrate has been used in this manner. Retrospective case series include the following:

In a series of 21 patients with HAE with normal C1-INH, 22 of 38 attacks showed improvement within one hour of administration of pdC1-INH, and another nine, within three hours [62]. However, other series reported a lack of effect [1].

Eleven females with HAE-FXII were treated with pdC1-INH for 143 facial attacks [56]. The duration of treated attacks was significantly shorter than that of 88 untreated facial attacks in the same individuals.

Twelve patients with HAE-PLG were treated with pdC1INH for 74 acute swelling attacks [13]. The duration of the treated attacks was significantly shorter than that of the previous 129 untreated in the same patients.

Dosing and administration of C1-INH are reviewed separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'C1 inhibitor (plasma derived)'.)

Plasma – Fresh frozen plasma (or solvent detergent-treated plasma) has not been reported for treatment of this disorder, to our knowledge. Use of plasma in other types of HAE is reviewed separately. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Plasma'.)

Patients with HAE with normal C1-INH would not be expected to respond to epinephrine, antihistamines, or glucocorticoids, similar to those with HAE-C1-INH [33,54]. However, if the diagnosis is uncertain, these therapies should certainly not be withheld. (See "Hereditary angioedema: Acute treatment of angioedema attacks", section on 'Ineffective therapies'.)

Short-term prophylaxis prior to medical/dental procedures — Dental and medical procedures can trigger episodes of angioedema. The goal of short-term prophylaxis is to prevent these episodes with premedications. Prophylactic therapy has not been carefully studied in HAE with normal C1-INH, although management is extrapolated from that used in patients with HAE types I and II, which is discussed separately. (See "Hereditary angioedema: Short-term prophylaxis before procedures or stressful events to prevent angioedema episodes".)

Long-term prophylaxis — Long-term prophylaxis is given to decrease the overall number of attacks.

Indications — Long-term prophylaxis is indicated for patients who do not achieve adequate control of their disease with trigger avoidance and on-demand therapy alone. The decision to start long-term prophylactic treatment should be individualized, and the approach may differ somewhat around the world. Most experts would consider initiating prophylaxis for the following:

Patients with more than one severe event per month

Patients who are disabled (ie, unable to perform their usual activities) more than five days per month

The need for prophylaxis should take into account several other factors, including the availability of effective therapies for acute attacks (ie, icatibant or others), the patient's proximity to emergency care, the likelihood of side effects from long-term prophylactic therapies, and the patient's preferences. Each case must be considered individually.

Choice of prophylactic agent — Tranexamic acid, progesterone, C1-INH concentrate, and androgens have been administered to HAE with normal C1-INH patients for prevention of angioedema attacks with reported success, but responses are variable. There appear to be differences in the degree to which patients with one mutation or another respond to various therapies, and data are limited [3]. In pregnant patients, C1-INH concentrate is preferred because of its history of safety in pregnancy.

Tranexamic acid – Multiple series have described successful use of tranexamic acid in patients with HAE with normal C1-INH [1,24,33,63-66]. Doses of 30 to 50 mg per kg body weight are given, to a maximum of 3 grams daily. Adverse effects are reviewed separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis", section on 'Antifibrinolytics'.)  

Progesterone – Progesterone-only contraceptives have been reported to be helpful for some premenopausal females with HAE with normal C1-INH, and in one series, they were associated with a 100 percent attack reduction in 15 of 16 women with HAE-FXII [33,56]. However, it has not been demonstrated conclusively that the improvement in symptoms was attributable to use of progesterone or avoidance of estrogens.  

C1-INH concentrate — Regular injections of pdC1-INH concentrate have been used successfully in a few females during pregnancy [21,67-69].

Androgens — The attenuated androgen danazol has been used with success in some patients with HAE with normal C1-INH [1,6,24,70]. However, we do not use androgens in females of child-bearing age or in adolescents due to the potential side-effects of androgens in long-term use. Androgens increase the levels of C1-INH in humans and FXII in rats, and they increase ACE levels in other animal studies [45]. Dosing and adverse effects are reviewed separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis", section on 'Attenuated androgens'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary angioedema and other forms of nonhistaminergic angioedema".)

SUMMARY AND RECOMMENDATIONS

Hereditary angioedema with normal C1 inhibitor (HAE with normal C1-INH, previously called HAE type III) was first described in 2000 and is characterized by recurrent, self-limited episodes of skin swelling, tongue swelling, and/or abdominal pain. It is distinguished from other forms of HAE (ie, types I and II, together called HAE-C1-INH) by the presence of normal complement studies. (See 'Background and terminology' above.)

Patients with HAE with normal C1-INH have normal function and plasma concentrations of C1-INH, in contrast to those with HAE-C1-INH. Patients from many families have specific mutations in the coagulation factor XII gene (F12), the plasminogen gene, or several other genes. Many female patients have more severe disease when pregnant or taking exogenous estrogens, while others are not influenced by hormonal factors. (See 'Pathogenesis' above.)

HAE with normal C1-INH is clinically similar to HAE-C1-INH, although there are several differences. Patients with HAE with normal C1-INH have onset later in life (typically in adulthood), more frequent facial and tongue swellings, and less prominent abdominal symptoms. (See 'Clinical presentation' above.)

In the absence of a validated biochemical diagnostic test, diagnosis of HAE with normal C1-INH is based on characteristic clinical features, a family history of angioedema, and normal complement studies. Genetic testing, if available, may serve to differentiate the various types of HAE with normal C1-INH (algorithm 1). In patients who lack a family history of angioedema, it is important to exclude idiopathic histaminergic angioedema, a disorder in which complement studies are also normal. Idiopathic histaminergic angioedema often responds to therapy with antihistamines (frequently at supratherapeutic doses), alone or in combination with glucocorticoids. (See 'Diagnosis' above.)

Triggers for episodes of angioedema include local trauma or physical pressure to the affected area, emotional stress, and certain medications (ie, exogenous estrogens, angiotensin-converting enzyme [ACE] inhibitors and possibly angiotensin II receptor blockers [ARBs]). In some patients, avoidance of triggers is sufficient to prevent most attacks, and no other prophylactic therapy is needed. (See 'Avoidance of triggers' above.)

For patients with acute angioedema involving the tongue or upper airway, assessment and protection of the airway is the first and most important management issue, because none of the available therapies can be considered universally effective. (See 'Airway attacks' above.)

For treatment of acute attacks, we suggest icatibant (which is a bradykinin type 2 receptor antagonist) in preference to other acute treatments (Grade 2C). Plasma-derived C1 inhibitor concentrate has also been used successfully. However, information about the efficacy of various treatments for acute symptoms is limited. (See 'Specific agents' above.)

Long-term prophylaxis is indicated for patients who do not achieve adequate control of their disease with trigger avoidance and on-demand therapy alone. The decision to start long-term prophylactic treatment should be individualized, and the approach may differ somewhat around the world. (See 'Indications' above.)

The options for prophylactic therapy for HAE with normal C1-INH include oral tranexamic acid, regular infusions of plasma-derived C1 inhibitor concentrate, progesterone-only contraceptives (in premenopausal females), and androgens (generally in adult males). For most nonpregnant patients, we suggest tranexamic acid in preference to other agents (Grade 2C). Plasma-derived C1 inhibitor is preferred during pregnancy. (See 'Long-term prophylaxis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Michael M Frank, MD, who contributed to an earlier version of this topic review.

We also acknowledge Eveline Wu, MD, who co-authored previous versions of this topic with Dr. Frank.

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Topic 16529 Version 21.0

References

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