Version July 2025
INTRODUCTION —
Hereditary angioedema (HAE) is a disease characterized by recurrent episodes of angioedema, without urticaria (also called wheals) or pruritus, which most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Although the swelling is self-limited and resolves in two to five days without treatment, laryngeal involvement may cause fatal asphyxiation.
The pathogenesis and diagnosis of hereditary forms of angioedema will be reviewed here. The clinical features, precipitating factors, and treatment of this disorder are discussed separately:
●(See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)
●(See "Hereditary angioedema (due to C1 inhibitor deficiency): Acute treatment of angioedema attacks".)
HAE with normal C1 inhibitor — Complement studies, including C4, C1 inhibitor (C1INH) protein level, and C1INH function, are normal in HAE with normal C1INH. Clinical manifestations, diagnosis, and treatment are reviewed in detail separately. (See "Hereditary angioedema with normal C1 inhibitor".)
PATHOGENESIS —
The best-characterized forms of HAE arise from deficiency or dysfunction of C1INH. The swelling (ie, angioedema, sometimes called "giant" swelling) that occurs in HAE due to C1INH deficiency (HAE-C1INH) results from excessive production of bradykinin, a potent vasodilatory mediator. Bradykinin also has important vascular permeability-enhancing effects. Plasma bradykinin levels were shown to be massively elevated during angioedema episodes in patients with HAE-C1INH [1]. In bradykinin-mediated angioedema, histamine and other mast cell mediators are not directly involved, which explains the lack of response to antihistamines or omalizumab and distinguishes this form of angioedema from the mast cell-mediated angioedema that is seen in allergic reactions and urticaria.
There are other forms of HAE in which C1INH is normal (HAE-nl-C1INH). A small but growing number of suspected pathogenic variants in genes for other proteins have been identified to explain the disease in some families, while the pathogenesis in other families remains unclear. The pathogenesis of HAE with normal C1INH is discussed in more detail separately. (See "Hereditary angioedema with normal C1 inhibitor".)
Functions of C1 inhibitor — C1INH is an acute-phase reactant and a member of the "serpin" superfamily of serine protease inhibitors. The function of C1INH in the kinin-generating pathway is most directly related to the pathogenesis of HAE-C1INH (figure 1) [2-5]. However, C1INH inhibits steps in the classical and lectin complement pathways, as well as of the intrinsic coagulation (contact system), fibrinolytic [6], and kinin-generating pathways. Within these different pathways, C1INH inhibits several plasma proteases: C1r and C1s, mannose-binding lectin-associated serine proteases (MASP1 and MASP2), coagulation factor XII (Hageman factor), coagulation factor XI, thrombin, plasma kallikrein, plasmin, and tissue plasminogen activator [7-10].
Molecular events leading to angioedema — Angioedema results primarily from a transient increase in vascular permeability. Multiple pathways encompassing a variety of different mechanisms may contribute to the increase in vascular permeability seen in HAE [11,12].
The initial molecular events in the genesis of an HAE attack are not entirely understood. Local activation of the contact system proteases factor XII and plasma prekallikrein on endothelial cell surfaces is important in initiation. The activation of factor XII, possibly by phospholipids released from damaged cells, is believed to be a leading mechanism [13]. Heat shock protein 90 generated during cell stress may enhance contact system activation. Activated factor XII (FXIIa) and plasma kallikrein catalyze the cleavage of high-molecular-weight kininogen (HMWK), with release of bradykinin. Bradykinin then binds to and activates the bradykinin B2 receptor, causing vasodilation, increased vascular permeability, and plasma leakage into the extracellular space, leading to edema formation.
C1INH normally plays a role in limiting bradykinin production by inhibiting both plasma kallikrein and activated factor XII, so when C1INH is deficient or dysfunctional, bradykinin production is relatively unchecked (figure 1) [4,14,15]. FXIIa can act as a plasminogen activator in the fibrinolytic system. Plasmin then cleaves HMWK to bradykinin. The permeability-increasing effects of plasmin can be blocked by C1INH, although the major inhibitor of plasmin is alpha 2-antiplasmin. Plasma kallikrein is also able to activate endothelial cells via protease-activated receptors (PAR) 1 and 2, thereby directly increasing endothelial permeability [16]. In addition, plasma kallikrein is capable of slowly catalyzing the cleavage of HMWK independently of factor XII, although the clinical relevance of this is unclear [17,18]. C1INH deficiency supports selective enhancement of contact pathway-mediated activation of coagulation [19]. Thrombin directly increases endothelial permeability via PAR1 activation. It can also be blocked by C1INH [20].
The pathologic mechanisms of this disease have proven difficult to study. An animal model of HAE was produced in knockout mice [21]. However, despite profound deficiency of C1INH due to homozygous gene defects, the mice do not develop spontaneous episodes of angioedema but rather demonstrate a constitutive increase in vascular permeability that was blocked by a plasma kallikrein inhibitor and by a bradykinin B2 receptor antagonist. Human umbilical vein endothelial cells monolayers may serve as a model to investigate molecular mechanisms on endothelial cells [16].
C1INH deficiency or dysfunction results in low levels of complement component 4 (C4) because the C1 complex normally cleaves C4 as part of the classical complement pathway, and this is exaggerated if C1INH is deficient (figure 2). C1INH is a significant inhibitor of C1r and C1s (table 1), so the result of C1INH deficiency can be readily detected in this pathway as a low C4 level. Thus, low C4 is a sensitive test for detection of deficiency of C1INH, even though it is not believed to be directly related to the pathogenesis of HAE-C1INH. The lectin complement activation pathway, similar to the classical one, is also activated in C1INH deficiency. MASP1 can directly activate endothelial cells via PAR1 and PAR4, resulting in increased endothelial paracellular permeability. The effect can be blocked by C1INH [16].
The role of the multiple cells of innate and adaptive immune system has also been investigated. Immune cells can exert directly or indirectly in the pathophysiology of angioedema [22].
SUBTYPES AND GENETICS —
There are two types of HAE that arise from deficiency or dysfunction of C1INH (types 1 and 2, respectively) and can be detected by abnormal complement protein levels or function [9,23-25]. The other types of familial angioedema are characterized by normal C1INH and normal complement studies. Specific mutations and diagnosis are reviewed separately. (See "Hereditary angioedema with normal C1 inhibitor".)
Patients with HAE-C1INH have a mutation in the SERPING1 gene from birth but generally develop recurrent angioedema as children (with symptoms starting as early as age one or two years) or young adults. Correlations between five common functional variants (F12-rs1801020, KLKB1-rs3733402, CPN1-rs61751507, and two in SERPING1 [rs4926 and rs28362944]) and HAE-C1INH severity have been confirmed [26]. In addition to the pathogenic variants in SERPING1, variants in genes encoding proteins involved in bradykinin metabolism or function may also impact disease severity.
HAE with C1 inhibitor deficiency/dysfunction — HAE type 1 is due to C1INH deficiency, and type 2 is caused by C1INH dysfunction. Together, these two disorders are called HAE with C1INH deficiency (HAE-C1INH; MIM #106100).
●HAE type 1 accounts for 85 percent of HAE-C1INH kindreds and is characterized by reduced secretion of the C1INH protein. Upon testing, plasma protein (antigenic) and functional C1INH levels are both low and range from undetectable to less than 30 percent of normal in most patients, although levels can occasionally be between 30 and 50 percent of normal. For example, if the lower limit of a normal protein level is 18 mg/dL, then a patient with HAE type 1 would typically have a level <6 mg/dL. These decrements are greater than would be predicted with one intact normal allele, even though the disorder is almost always heterozygous. Possible explanations for this include increased baseline catabolism or decreased expression of the normal allele product [27,28].
●HAE type 2 results from the presence of a dysfunctional C1INH protein, which is present in normal or elevated amounts. This type of HAE is found in approximately 15 percent of affected families. Upon testing, C1INH function is low, but protein levels are normal or elevated. Protein levels may be elevated because the defective C1INH is unable to form complexes with proteases, resulting in an increased plasma half-life [28].
Inheritance patterns — The inheritance of HAE is autosomal dominant, so the majority of affected patients have affected family members. However, in HAE-C1INH, approximately 25 percent of cases result from de novo mutations, so a positive family history helps to establish the diagnosis, but a negative family history does not exclude HAE [27,29]. Nearly all affected patients are heterozygotes with one abnormal allele, although a few patients with homozygous deficiency have been reported [30,31].
Having an abnormal C1INH allele does not result in symptoms of angioedema in all individuals [32]. However, approximately 95 percent of affected patients over the age of 20 years will have some symptoms [32]. A Spanish study describing the establishment of an HAE disease registry illustrated this phenomenon [33]. Patients with HAE were identified throughout the country, and family members were also tested. Up to 10 percent of individuals carrying the defective gene were asymptomatic, although this figure includes young subjects who may become symptomatic later in life.
The gene for C1INH is located on the long arm of chromosome 11 [29,34-36]. More than 700 variants in SERPING1 gene reported to be disease-causing mutations for HAE-C1INH have been described in the Human Genome Mutation Database (HGMD) and in the C1INH gene mutation database (HAEdb) [34,37-41]. The most common defects are single base-pair mutations, which can occur throughout the gene. Larger gene rearrangements, including partial gene deletions and duplications, account for another 20 percent of gene defects [42].
EVALUATION AND DIAGNOSIS
When to suspect HAE — HAE is characterized by recurrent episodes of angioedema, without urticaria or pruritus, which most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts.
HAE should be considered in any patient who demonstrates one or more of the following:
●Recurrent episodes of angioedema without urticaria (ie, wheals) or pruritus, lasting two to five days (without treatment).
●Unexplained recurrent episodes of self-limited, colicky, abdominal pain (typically lasting one to three days), especially in patients who also have had cutaneous angioedema.
●Unexplained upper airway edema (even a single episode).
●Recurrent episodes of angioedema in patients younger than 30 years of age.
●Angioedema episodes in patients taking angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs), or estrogens as these medications can both cause angioedema and "unmask" HAE.
●Angioedema that persists or worsens following the administration of therapy for mast cell- and histamine-mediated angioedema (antihistamines, omalizumab, glucocorticoids, or epinephrine).
●Angioedema episodes that initially present or occur more frequently during puberty or pregnancy.
●A family history of angioedema.
●A low complement C4 level (typically <50 percent of normal) in a patient with angioedema. Other causes of a low C4 are discussed below. (See 'Low C4 levels' below.)
The signs and symptoms of different types of HAE attacks are reviewed in greater detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Clinical manifestations'.)
Overview of diagnosis — The diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1INH) types 1 and 2 is based upon a suggestive clinical history and physical findings during episodes combined with consistent results from at least two sets of complement studies. Ideally, they should be separated in time by one month or more. Confirmation of HAE-C1INH requires low C4 plus decreased C1INH protein or function. A family history of angioedema strongly supports the diagnosis, but it is not required, since approximately one-quarter of patients have de novo mutations. Genetic testing is not required to establish the diagnosis of HAE-C1INH in most cases. A possible exception is newborns and young infants, as discussed below [43,44]. (See 'Accuracy of testing in infants' below.)
Trial of high-dose antihistamines if C4 is normal — Symptoms in patients with HAE do not improve with antihistamine therapy. Most patients with HAE have been given antihistamines and glucocorticoids multiple times in the past without benefit. However, if a therapeutic trial of high-dose antihistamines has not been given, this should be done if C4 is normal and there is no family history or if accurate complement testing is not available.
If a trial of high-dose antihistamines is given, we use nonsedating H1 antihistamines (eg, cetirizine, levocetirizine, loratadine, desloratadine, or fexofenadine) given for at least one month or for a sufficient time period to appreciate a change, depending upon the patient's frequency of angioedema episodes. We start with twice the usual dose (eg, cetirizine 10 mg twice daily). If there is no improvement, we increase to four times the usual dose or add a second agent at twice the usual dose. Note that there is one report of a patient who did not respond to antihistamines and oral glucocorticoids but did respond to omalizumab, proving the patient did not have HAE, although it was not clear if antihistamines were administered in the manner described above [45].
●If high-dose antihistamine therapy does not prevent episodes of angioedema, then the evaluation for HAE can continue [46].
●If high-dose antihistamine therapy does prevent further episodes of angioedema, then the patient has histaminergic acquired angioedema, which is far more common than HAE (figure 3). If no cause can be found, the diagnosis is idiopathic histaminergic acquired angioedema (AAE-IH), which is also called idiopathic angioedema. (See "An overview of angioedema: Clinical features, diagnosis, and management", section on 'Recurrent, idiopathic angioedema'.)
Approach to complement testing — The approach to evaluation and testing depends upon whether the clinical suspicion is low or high because this determines how extensive complement testing should be and whether or not genetic testing is needed.
Diagnostic tests — The different types of HAE can be confirmed or excluded with complement testing. The critical diagnostic tests for patients with possible HAE-C1INH are:
●C4 (the natural substrate for C1 esterase)
●C1INH protein (or "antigenic") levels
●C1INH function
The diagnosis of HAE-C1INH requires low C4 plus decreased C1INH protein or function (table 2). Two sets of complement tests should be obtained, ideally at least one month apart.
At some centers, C4 and C1INH protein levels are measured first because these are adequate to make the diagnosis in most cases, and C1INH function is measured only if the C1INH protein level is normal or elevated. Other centers order all three tests together. In other parts of the world, accurate complement testing is not widely available. In such settings, it is common to refer patients to specialty centers, which typically perform complete complement studies in all patients to assure that cases are not missed [47]. (See 'Sources of diagnostic errors' below.)
C1q should also be ordered in patients older than 40 years of age to detect acquired forms of C1INH deficiency. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)
Low clinical suspicion — Clinical suspicion can be considered to be low when the episodes of angioedema are not characteristic of HAE, because one or more of the following is true:
●The attacks last 24 hours or less (because HAE episodes usually, though not always, last three to five days without treatment).
●The angioedema is sometimes accompanied by hives or pruritus (because the edematous episodes of HAE are not accompanied by hives or pruritus, although there can be prodromal maculopapular skin changes called erythema marginatum (picture 1).
●The angioedema attacks appear to improve or become less frequent with antihistamines, glucocorticoids, and epinephrine (because the angioedema of HAE does not respond to these medications).
●There is a potential medication (especially ACE inhibitors or NSAIDs) or allergy that could be causing or exacerbating the angioedema. Although it should be noted that ACE inhibitors may "unmask" or worsen symptoms of HAE.
If clinical suspicion is low, then a C4 is adequate for evaluation [48-50].
Interpretation of C4 levels — The normal range for C4 is extremely wide (from 10 to 40 mg/dL) and may be reported as a concentration, absolute level, or percentage of normal. A level below 50 percent of normal is strongly suggestive of HAE-C1INH. If the C4 level is presented in milligrams without a percent, 25 mg would be considered a normal level (100 percent), and levels <10 mg are strongly suggestive of C1INH deficiency (pathologic). Levels between 10 and 15 mg are possibly pathologic, and levels >15 mg are not pathologic.
A normal C4 during an episode of angioedema essentially excludes HAE-C1INH [49]. Between episodes of symptoms, C4 is low in between 81 to 96 percent of patients with HAE [51,52]. Because a normal C4 level in a patient during a symptom-free period does not exclude HAE with absolute certainty, C4 should be repeated during an angioedema episode if the clinical suspicion is moderate or high [53].
In summary, the C4 level can be interpreted as follows:
●If C4 is normal during an episode of angioedema, HAE-C1INH is highly unlikely, and other causes of angioedema should be considered. Other causes of a low C4 level are discussed below. (See 'Differential diagnosis' below.)
●If C4 is low (typically <50 percent of normal) [51], then the clinical suspicion for HAE is increased, and C1INH protein level and C1INH function should be measured. (See 'High clinical suspicion' below.)
High clinical suspicion — Clinical suspicion can be considered high in patients with the following features:
●The patient develops recurrent episodes of angioedema without wheals/urticaria lasting two to five days (without treatment).
●Episodes of angioedema do not correlate with administration of NSAIDs.
●History does not suggest food, latex, or other allergic cause.
●A clearly positive family history is another factor that strongly suggests the presence of HAE, although the accuracy of reports of angioedema in family members can be variable.
Patients on ACE inhibitors — Note that patients with underlying HAE are especially susceptible to developing angioedema while taking an angiotensin-converting enzyme (ACE) inhibitor, and ACE inhibitors can therefore "unmask" the disease, resulting in a first episode of angioedema in a previously asymptomatic individual. If clinical suspicion is high for other reasons in a patient taking an ACE inhibitor, then it is appropriate to obtain complement studies at the time of presentation, while simultaneously stopping the ACE inhibitor. Complement studies are not affected by the presence of ACE inhibitors. In a study of 149 patients who developed angioedema (most often of the face, lips, and tongue) during treatment with ACE inhibitors, complement testing revealed the presence of hereditary C1INH deficiency in two patients and acquired C1INH deficiency in three [54]. The mean interval between starting ACE inhibitor therapy and the occurrence of angioedema (most often of the face, lips, and tongue) was 43 months.
Algorithm for interpretation of complement results — Complement studies obtained in a patient with high clinical suspicion can be interpreted as follows (algorithm 1):
●If C4 is low and C1INH protein level and function are normal, then other causes of a low C4 should be considered. (See 'Low C4 levels' below.)
●If C4 is low and C1INH protein level is normal or elevated, C1INH function should be measured. If function is low, the patient has HAE-C1INH, type 2. C1INH function is usually below 30 percent of normal. Family history should be revisited, and, if truly negative, the patient has a de novo case of HAE-C1INH, type 2.
●If C4 is low and C1INH protein level is low, further evaluation depends upon the age at which symptoms began.
If symptoms began before age 30 years or there is a positive family history of angioedema, the most likely explanation is HAE-C1INH, type 1. Levels of C1INH protein in untreated HAE-C1INH type 1 often range from undetectable to less than 30 percent of normal (eg, if the lower limit of normal is 18 mg/dL, then a typical value would be <6 mg/dL). C1INH function is typically less than 30 percent of normal, although this is not needed for the diagnosis of HAE type 1. If symptoms began after age 40 years, C1q should be measured to detect acquired C1INH deficiency, although C1q is normal in 30 percent of cases. Any patient with low C4, low C1INH protein level and/or C1INH function, and low C1q should be evaluated for an underlying hematologic or lymphoproliferative disorder, and the complement testing should be completed with measurement of antibodies against C1INH. Note that patients with HAE-C1INH occasionally have low C1q, so this is not an infallible marker for acquired C1INH deficiency. (See "Acquired C1 inhibitor deficiency: Management and prognosis", section on 'Associated disorders'.)
Patients older than 30 years of age could have either disorder, and genotyping of the C1INH gene (SERPING1) should be considered to help establish the diagnosis.
●If C4 is normal and C1INH protein level is low, the most likely explanation is laboratory error, and complement studies should be repeated. Less commonly, patients may have baseline C4 levels that are slightly higher than normal, such that a low normal C4 for that patient is actually low. In addition to repeating complement studies during an angioedema episode, sequencing SERPING1 would be reasonable.
●If C4 and C1INH functional levels are normal, then the diagnoses of HAE with normal C1INH and idiopathic non-mast cell-mediated angioedema need to be considered. These disorders are discussed in detail separately. (See "Hereditary angioedema with normal C1 inhibitor" and "An overview of angioedema: Clinical features, diagnosis, and management", section on 'Idiopathic angioedema'.)
Sources of diagnostic errors — Complement tests are susceptible to laboratory error and should be performed by accredited laboratories that have demonstrated competence in these assays [55]. In addition, clinicians should be vigilant for the following sources of error [47]:
●Complement studies should be done with fresh or freshly frozen serum that has not been standing for more than four hours.
●C4 and C1INH protein levels are relatively reliable. In contrast, tests of C1INH function are particularly prone to error and can be falsely low (chromogenic assay) or falsely normal (enzyme-linked immunosorbent assay [ELISA]) [47]. Both methods demonstrate high sensitivity and specificity in diagnosing C1INH deficiency, particularly when combined with C4 concentrations. If C4 is normal and C1INH function is low, the most likely explanation is that the C1INH function is falsely low due to laboratory error, and testing should be repeated [56].
●Complement studies for diagnosis must be performed when the patient is not receiving C1INH concentrate, because it will alter results. If it has been initiated, it should be discontinued for one week before diagnostic complement studies are obtained, or genotyping can be performed. Patients receiving androgens will often still have low C4 and C1INH levels, but if complement results are normal, androgens should be withheld for one week and testing repeated. Therapies for HAE are discussed in detail separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Acute treatment of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)
Additional tests — In HAE types 1 and 2, C1q is usually normal and antibodies against C1INH are not present, although there are rare exceptions (table 2). C1q and anti-C1INH antibodies are abnormal in acquired C1INH deficiency, as discussed separately. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis".)
Genetic testing — Genetic testing is not required for the diagnosis of HAE-C1INH in most patients. However, it is essential for preimplantation genetic testing and prenatal diagnosis and can also be helpful for selected HAE-C1INH cases where complement results are ambiguous, such as pregnancy. Pregnancy can decrease complement levels, making the diagnosis more difficult. Genetic testing can also be useful in diagnosing infants and very young children, in whom complement studies are less reliable. (See 'Accuracy of testing in infants' below.)
In approximately 5 percent of patients with HAE-C1INH, no mutation in the SERPING1 gene is detected with conventional genotyping.
Dried blood spot test — Dried blood spot (DBS) testing has been developed, which enables both C1INH and C4 quantitation and genetic analysis from dried blood samples, enabling testing of HAE patients living in remote locations [57].
TESTING FAMILY MEMBERS —
Once a diagnosis of HAE has been made, all first-degree relatives with or without angioedema symptoms should be screened by complement testing. Asymptomatic family members may develop symptoms in the future and may transmit the mutation, and it is preferable to identify the disorder before the onset of clinical symptoms. Early diagnosis is essential and improves the quality of life of patients. The impact of a late diagnosis can be high as initiation of appropriate therapy is delayed, putting patients at increased risk of morbidity and mortality. In HAE-C1INH, approximately 25 percent of cases result from de novo mutations, so affected descendants are usually but not always identified. HAE-C1INH does not skip generations, although it can occasionally appear to do so if affected individuals are asymptomatic [42].
Accuracy of testing in infants — In newborns and infants younger than one year of age, the complement system is immature, resulting in lower C1INH and C4 levels, even in the absence of HAE-C1INH. Both C1INH levels and function are normally 30 to 50 percent lower than adult levels. Complement levels are also influenced by birth weight and gestational age [58,59]. Both false positives and false negatives may occur in infants screened in the manner suggested for adults [60]. Because C4 levels are also variable in this age group, measuring C4 levels as a test for HAE-C1INH is also not recommended in patients less than one year of age [61]. Genetic testing from peripheral/umbilical cord blood or buccal smear is occasionally performed in infants under the age of one year if a definitive diagnosis is required and the disease-causing mutation in the family is known [62]. However, in most cases, testing is simply postponed until the infant is older, and the diagnosis can be made using complement studies [9,63]. All asymptomatic newborns or infants with a parent or sibling who has HAE-C1INH should be considered to have C1INH deficiency until this diagnosis is excluded.
DIFFERENTIAL DIAGNOSIS —
A number of disorders share clinical or laboratory features of HAE [64,65].
Cutaneous and/or upper airway swelling — Cutaneous and/or upper airway swelling without urticaria (wheals) can also result from non-bradykinin-mediated processes. These include the following:
●Allergic reactions and anaphylaxis – Allergic reactions and anaphylaxis can involve cutaneous and upper airway swelling. There are often associated symptoms affecting multiple organ systems simultaneously, such as urticaria, wheezing, vomiting, diarrhea, and hypotension. The onset of allergic reactions is rapidly progressive or even explosive, and the patient can often identify a precipitating event, such as a meal, an insect sting, or administration of a new medication. Thus, compared with attacks of HAE, allergic reactions are generally more rapid in onset, involve multiple organ systems, and can include urticaria and wheezing (which are never seen in attacks of HAE).
If upper airway edema is present, airway assessment and management must always take precedence over any other treatments. If anaphylaxis is a diagnostic possibility, the patient should be given epinephrine without delay. Complement studies and/or serum tryptase levels should be obtained after the patient is stabilized. Any elevation in serum tryptase is consistent with anaphylaxis, although a normal level does not exclude it. (See "Anaphylaxis: Emergency treatment".)
●Idiopathic angioedema – By definition, idiopathic angioedema is a diagnosis of exclusion. Complement studies are normal in this condition. (See "An overview of angioedema: Clinical features, diagnosis, and management", section on 'Recurrent, idiopathic angioedema'.)
●Drug-induced angioedema – Medications, particularly angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal antiinflammatory drugs (NSAIDs), may be associated with angioedema. ACE inhibitors create a predisposition to angioedema, and patients have occasional episodes. In contrast, NSAIDs trigger angioedema with nearly every administration in patients who are susceptible to angioedema with these drugs.
The mouth and throat are commonly affected in drug-induced angioedema. Complement studies, including C4 and C1INH protein and function are normal. Drug-induced angioedema is reviewed in greater detail separately. (See "An overview of angioedema: Pathogenesis and causes", section on 'Causes' and "ACE inhibitor-induced angioedema".)
●Allergic contact dermatitis – Allergic contact dermatitis can be confused with facial angioedema. Contact dermatitis can cause dramatic swelling of the facial and periorbital skin when it develops in response to cosmetic or topical pharmaceuticals. Microvesiculation and/or deep erythema of the skin can help distinguish this from complement-mediated angioedema. Patients with contact dermatitis may complain of pain and burning of the skin. Poison ivy can cause a similar clinical picture, but linear patterns of vesiculations are often detectable, and pruritus is prominent. Contact dermatitis responds to oral glucocorticoids and does not involve complement abnormalities. (See "Allergic contact dermatitis: Clinical features and diagnosis".)
●Autoimmune conditions – Facial, periorbital, and sometimes hand edema can be seen in systemic lupus, polymyositis, dermatomyositis, and Sjögren's disease. Early stages of both scleredema and systemic sclerosis can present as swelling. However, the swelling of these conditions is persistent. Scleredema often involves the posterior neck, and systemic sclerosis often affects the hands and may be accompanied by Raynaud phenomenon [64]. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)
●Thyroid disorders – Both hypothyroidism and hyperthyroidism can cause skin changes that could be mistaken for angioedema but develop over a period of weeks to months and are not episodic. (See "Clinical manifestations of hypothyroidism" and "Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease".)
●Superior vena cava syndrome and tumors – Occasionally, edema of the face, neck, or upper extremities is observed with rapidly developing superior vena cava syndrome (see "Malignancy-related superior vena cava syndrome"). Tumors of the head and neck and lymphoma can also cause localized edema. Unlike the C1INH disorders, protracted or progressive swelling would be expected with these entities.
●Cheilitis granulomatosa (Miescher's cheilitis) and Melkersson-Rosenthal syndrome – These are rare disorders of persistent lip angioedema that lead to eventual permanent enlargement of the lips. The Melkersson-Rosenthal syndrome is also characterized by facial paralysis, facial swelling, and a fissured tongue, typically beginning in adolescence [66]. Complement studies are normal. (See "Cheilitis", section on 'Cheilitis granulomatosa'.)
●Systemic capillary leak syndrome (Clarkson's disease) – It is a rare, potentially fatal disorder characterized by unpredicted episodes of extensive edema and unexplained, recurrent shock caused by capillary hyperpermeability [67]. (See "Idiopathic systemic capillary leak syndrome".)
●Trichinosis – Infection with Trichinella spiralis can cause periorbital edema and abdominal symptoms, including abdominal pain, vomiting, and diarrhea. Eosinophilia is usually present. (See "Trichinellosis".)
Low C4 levels — Patients with HAE typically have C4 levels that are <50 percent of normal. Less dramatic reductions in C4 are seen in autoimmune diseases (eg, lupus and others) and inherited C4 deficiency. C3 is often also low in autoimmune disease and should be normal in HAE. These disorders are discussed separately. (See "Acquired disorders of the complement system", section on 'Increased consumption by immune complexes' and "Inherited disorders of the complement system", section on 'C4 deficiency'.)
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
●Pathogenesis – Hereditary angioedema (HAE) is a rare condition characterized by recurrent episodes of angioedema without urticaria (also called wheals) or pruritus, which most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Swelling is predominantly mediated by bradykinin, a potent vasodilatory peptide, although other mediators may be involved. (See 'Pathogenesis' above.)
●Subtypes and genetics – There are several types of HAE:
•Types 1 and 2 result from deficiency or dysfunction of C1 inhibitor (C1INH), respectively, and are collectively called HAE with C1INH deficiency (HAE-C1INH). C1INH plays a role in regulating bradykinin production. However, the precise mechanisms by which these defects predispose to episodic angioedema are not understood. Complement studies are abnormal in HAE-C1INH. In at least 90 percent of patients with HAE-C1INH, plasma levels of complement component 4 (C4) are always low, even during asymptomatic periods, and thus, C4 is a useful single test to obtain initially. The inheritance pattern of HAE-C1INH is autosomal dominant, although 25 percent of cases result from de novo mutations, and occasional affected individuals may be asymptomatic. (See 'HAE with C1 inhibitor deficiency/dysfunction' above.)
•The other types of HAE are characterized by normal complement studies. A detailed discussion of these forms of HAE is found separately. (See "Hereditary angioedema with normal C1 inhibitor".)
●Whom to evaluate – Indications for evaluation for HAE include recurrent angioedema without urticaria, unexplained recurrent episodic abdominal pain, a family history of angioedema, any episode of unexplained upper airway edema, and a low C4 level. Most patients with HAE have been given antihistamines and glucocorticoids multiple times in the past without benefit. (See 'When to suspect HAE' above.)
●Complement testing – Our approach to evaluation and testing depends upon whether the clinical suspicion is low or high because this determines how extensive complement testing should be. When clinical suspicion is high, the evaluation is further influenced by the presence or absence of a family history of angioedema. (See 'Approach to complement testing' above.)
•If clinical suspicion is low, C4 alone is sufficient for evaluation. If C4 is normal when the patient is not experiencing angioedema and no other explanation is apparent, C4 should be repeated during an episode of angioedema. (See 'Low clinical suspicion' above.)
•If clinical suspicion is high, C4, C1INH protein level, and (in most centers) C1INH function should be measured. An algorithm for interpretation of results is provided (algorithm 1).
●Testing of family members – Once a patient has been diagnosed with HAE, testing should be offered to family members. (See 'Testing family members' above.)
●Differential diagnosis – The differential diagnosis of HAE includes other causes of angioedema, as well as other conditions that cause similar complement abnormalities. (See 'Differential diagnosis' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Marco Cicardi, MD, who contributed to earlier versions of this topic review.
