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

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: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

●(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".)

PATHOGENESIS — The best characterized forms of HAE arise from deficiency or dysfunction of C1 inhibitor (C1-INH). The swelling (ie, angioedema, sometimes called "giant" swelling) that occurs in HAE due to C1-INH deficiency (HAE-C1-INH) 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-C1-INH [1]. In bradykinin-mediated angioedema, histamine and other mast cell mediators are not directly involved, which explains the lack of response to antihistamines and distinguishes this form of angioedema from the histamine-mediated angioedema that is seen in allergic reactions and urticaria.

There are other forms of HAE in which C1-INH is normal (HAE-nl-C1-INH). 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 C1-INH is discussed in more detail separately. (See "Hereditary angioedema with normal C1 inhibitor".)

Functions of C1 inhibitor — C1-INH is an acute-phase reactant and a member of the "serpin" superfamily of serine protease inhibitors. The function of C1-INH in the kinin-generating pathway is most directly related to the pathogenesis of HAE-C1-INH (figure 1) [2-5]. However, C1-INH 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, C1-INH 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 — The initial molecular events in the genesis of an 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 [11]. Heat shock protein 90 generated during cell stress may enhance contact system activation. Activated factor XII (factor XIIa) and kallikrein catalyze the cleavage of high molecular weight kininogen (HMWK), with release of bradykinin. C1-INH normally plays a role in limiting bradykinin production by inhibiting both kallikrein and active factor XII, so when C1-INH is deficient or dysfunctional, bradykinin production is relatively unchecked (figure 1) [4,12,13]. Plasma prekallikrein has been reported to be capable of slowly catalyzing the cleavage of HMWK independently of factor XII. However, the clinical relevance of this is unclear [14,15].

The pathologic mechanisms of this disease have proven difficult to study. An animal model of HAE was produced in knockout mice [16]. However, despite profound deficiency of C1-INH due to homozygous gene defects, the mice do not develop spontaneous episodes of angioedema, but rather demonstrate a constitutive increase in vascular permeability. Minor localized swellings can be induced experimentally by the local application of mustard oil (an irritant) to the animal's skin. The increased vascular permeability observed in these mice can be reversed either by administration of C1-INH, blocking kallikrein, or blocking the bradykinin B2 receptor.

C1-INH 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 C1-INH is deficient (figure 2). C1-INH is only a significant inhibitor of C1r and C1s (table 1), so the result of C1-INH deficiency can be detected in this pathway easily as a low C4 level. Thus, low C4 is a sensitive test for detection of deficiency of C1-INH, even though it is not believed to be directly related to the pathogenesis of HAE-C1-INH.

SUBTYPES AND GENETICS — There are two types of HAE that arise from deficiency or dysfunction of C1-INH (types I and II, respectively) and can be detected by abnormal complement protein levels or function [9,17-19]. The other types of familial angioedema are characterized by normal C1-INH and normal complement studies. Specific mutations and diagnosis are reviewed separately. (See "Hereditary angioedema with normal C1 inhibitor".)

Patients with hereditary forms of angioedema have these defects from birth and generally present with recurrent angioedema as children or young adults. There is also an acquired form of C1-INH deficiency that presents in older patients (ie, age >40 years) without a family history of angioedema and is associated with underlying disorders or autoantibodies against C1-INH in most cases. Acquired C1-INH deficiency is reviewed in more detail separately. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis" and "Acquired C1 inhibitor deficiency: Management and prognosis".)

HAE with C1 inhibitor deficiency/dysfunction — HAE type I is due to C1-INH deficiency, and type II is caused by C1-INH dysfunction. Together, these two disorders are called HAE with C1-INH deficiency (HAE-C1-INH) (MIM #106100).

●HAE type I accounts for 85 percent of HAE-C1-INH kindreds and is characterized by reduced secretion of the C1-INH protein. Upon testing, plasma protein (antigenic) and functional C1-INH 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 I 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 [20,21].

●HAE type II results from the presence of a dysfunctional C1-INH protein, which is present in normal or elevated amounts. This type of HAE is found in about 15 percent of affected families. Upon testing, C1-INH function is low, but protein levels are normal or elevated. Protein levels may be elevated because the defective C1-INH is unable to form complexes with proteases, resulting in an increased plasma half-life [21].

Inheritance patterns — The inheritance of HAE is autosomal dominant, so the majority of affected patients have affected family members. However, in HAE-C1-INH 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 [20,22]. Nearly all affected patients are heterozygotes with one abnormal allele, although a few patients with homozygous deficiency have been reported [23,24].

Having an abnormal C1-INH allele does not result in symptoms of angioedema in all individuals [25]. However, approximately 95 percent of affected patients over the age of 20 years will have some symptoms [25]. A Spanish study describing the establishment of an HAE disease registry illustrated this phenomenon [26]. 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 C1-INH is located on the long arm of chromosome 11 [22,27-29]. More than 500 variants in SERPING1 gene reported to be disease-causing mutations for HAE-C1-INH have been described in the Human Genome Mutation Database (HGMD) and in the C1-INH gene mutation database (HAEdb) [27,30-34]. 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.

HAE with normal C1 inhibitor — Complement studies, including C4, C1-INH protein level, and C1-INH function, are normal in HAE with normal C1-INH. Clinical manifestations, diagnosis and treatment are reviewed in detail separately. (See "Hereditary angioedema with normal C1 inhibitor".)

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 patients who demonstrate 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 the absence of angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), or history to suggest an allergic cause.

●Angioedema that persists or worsens following the administration of therapy for mast cell- and histamine-mediated angioedema (antihistamines, glucocorticoids, or epinephrine).

●Angioedema episodes that occur more frequently during puberty, pregnancy, or while taking estrogen-containing medicines.

●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: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Clinical manifestations'.)

Overview of diagnosis — The diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) types I and II 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, these should be separated in time by one month or more. Confirmation of HAE-C1-INH requires low C4 plus decreased C1-INH protein and/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-C1-INH in most cases. A possible exception is newborns and young infants, as discussed below. (See 'Accuracy of testing in infants' below.)

Trial of high-dose antihistamines — 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.

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 that 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 [35].

●If high-dose antihistamine therapy does not prevent episodes of angioedema, then the evaluation for HAE can continue [36].

●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 — 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 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-C1-INH are:

●C4 (the natural substrate for C1 esterase)

●C1-INH protein (or "antigenic") levels, and

●C1-INH function

The diagnosis of HAE-C1-INH requires low C4 plus decreased C1-INH protein and/or function (table 2). Two sets of complement tests should be obtained, ideally at least one month apart.

At some centers, C4 and C1-INH protein levels are measured first because these are adequate to make the diagnosis in some cases, and C1-INH function is measured only if the C1-INH 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 [37]. (See 'Sources of diagnostic errors' below.)

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 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, or 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.

If clinical suspicion is low, then a C4 is adequate for evaluation [38,39].

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-C1-INH. 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 C1-INH 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-C1-INH [39]. Between episodes of symptoms, C4 is low in between 81 to 96 percent of patients with HAE [40,41]. 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 [42].

In summary, the C4 level can be interpreted as follows:

●If C4 is normal during an episode of angioedema, HAE-C1-INH 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) [40], then the clinical suspicion for HAE is increased and C1-INH protein level and C1-INH 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 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 C1-INH deficiency in two patients and acquired C1-INH deficiency in three [43]. 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 C1-INH 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 C1-INH protein level is normal or elevated, C1-INH function should be measured. If function is low, the patient has HAE-C1-INH, type II. C1-INH 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-C1-INH, type II.

●If C4 is low and C1-INH protein level is low then C1q should be measured. If C1q is normal, then further evaluation depends upon the age at which symptoms began. If symptoms began before age 30 or there is a positive family history of angioedema, the most likely explanation is HAE-C1-INH, type I. Levels of C1-INH protein in untreated HAE-C1-INH type I 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). C1-INH function is typically less than 30 percent of normal, although this is not needed for the diagnosis of HAE type I.

If symptoms began after age 40, acquired C1-INH deficiency (AAE-C1-INH) is the most likely explanation (C1q is normal in 30 percent of cases), and the patient should be evaluated for an underlying hematologic or lymphoproliferative disorder.

Patients older than 30 years of age could have either disorder, and genotyping of the C1-INH gene (SERPING1) should be considered for definitive diagnosis.

A low C1q level suggests AAE-C1-INH, which usually presents in patients >40 years of age with underlying hematologic or lymphoproliferative disorders. Any patient with low C4, low C1-INH protein level and/or C1-INH 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 C1-INH. Note that patients with HAE-C1-INH occasionally have low C1q, so this is not an infallible marker for AAE-C1-INH. (See "Acquired C1 inhibitor deficiency: Management and prognosis", section on 'Associated disorders'.)

●If C4 is normal and C1-INH protein level is low, the likely explanation is laboratory error and complement studies should be repeated.

●If C4 and C1-INH protein levels are normal, the next step in evaluation is a trial of daily high-dose antihistamines, if not already performed. In patients with idiopathic histaminergic acquired angioedema (AAE-IH), these interventions result in a dramatic decrease or complete cessation of angioedema episodes. (See 'Trial of high-dose antihistamines' above.)

If angioedema episodes continue, the patient possibly has either HAE with normal C1-INH, which can be caused by one of several disease-specific mutations, or idiopathic. This disorder is discussed in detail separately. (See "Hereditary angioedema with normal C1 inhibitor".)

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 [44]. In addition, clinicians should be vigilant for the following sources of error [37]:

●Complement studies should be done with fresh or freshly frozen serum that has not been standing for more than four hours.

●C4 and C1-INH protein levels are relatively reliable. In contrast, tests of C1-INH function are particularly prone to error and can be falsely low (chromogenic assay) or falsely normal (enzyme-linked immunosorbent assay [ELISA]) [37]. Both methods demonstrate high sensitivity and specificity in diagnosing C1-INH deficiency, particularly when combined with C4 concentrations. If C4 is normal and C1-INH function is low, the most likely explanation is that the C1-INH function is falsely low due to laboratory error, and testing should be repeated [45].

●Complement studies for diagnosis must be performed when the patient is not receiving C1-INH concentrate, because it will alter results. If it has been initiated, it should be discontinued for one week before diagnostic complement studies are obtained. Patients receiving androgens will often still have low C4 and C1-INH 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: Acute treatment of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)

Additional tests — In HAE types I and II, C1q is normal and antibodies against C1-INH are not present, although there are rare exceptions (table 2). These tests do not need to be obtained in most cases. C1q and anti-C1-INH antibodies are abnormal in acquired C1-INH 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-C1-INH in most patients. However, it is essential for preimplantation genetic diagnosis and prenatal diagnosis and can also be helpful for selected HAE-C1-INH 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 about 5 percent of patients with HAE-C1-INH, no mutation in the SERPING1 gene is detected with conventional genotyping.

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 due to C1-INH deficiency (HAE-C1-INH), approximately 25 percent of cases result from de novo mutations, so affected descendants are usually but not always identified. HAE-C1-INH does not skip generations, although it can occasionally appear to do so if affected individuals are asymptomatic.

Accuracy of testing in infants — In newborns and infants younger than one year of age, the complement system is immature, resulting in lower C1-INH and C4 levels, even in the absence of HAE-C1-INH. Both C1-INH levels and function are normally 30 to 50 percent lower than adult levels. Complement levels are also influenced by birth weight and gestational age [46,47]. Both false-positives and false-negatives may occur in infants screened in the manner suggested for adults [48]. Because of C4 levels are also variable in this age group, measuring C4 levels as a test for HAE-C1-INH is also not recommended in patients less than one year of age [49]. Genetic testing 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. However, in most cases, testing is simply postponed until the infant is older, and the diagnosis can be made using complement studies [9,50]. All asymptomatic newborns or infants with a parent or sibling who has HAE-C1-INH should be considered to have C1-INH deficiency until this diagnosis is excluded.

DIFFERENTIAL DIAGNOSIS — A number of disorders share clinical or laboratory features of HAE [51].

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 anti-inflammatory 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 C1-INH 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 "Clinical features and diagnosis of allergic contact dermatitis".)

●Autoimmune conditions – Facial, periorbital, and sometimes hand edema can be seen in systemic lupus, polymyositis, dermatomyositis, and Sjögren syndrome. 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 [51]. (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 C1-INH 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 [52]. Complement studies are normal.

●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 I and II result from deficiency or dysfunction of C1 inhibitor (C1-INH), respectively, and are collectively called HAE with C1-INH deficiency (HAE-C1-INH). C1-INH 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-C1-INH. In at least 90 percent of patients with HAE-C1-INH, 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-C1-INH 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. (See 'When to suspect HAE' above.)

●High-dose antihistamine trial if uncertain – Patients with HAE (of any type) do not respond to 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 in cases where there is no evidence of a deficiency or defect in C1-INH and no suggestive family history. (See 'Trial of high-dose antihistamines' 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, C1-INH protein level, and (in most centers) C1-INH 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.