Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis

INTRODUCTION — Acquired angioedema due to deficiency of C1 esterase inhibitor (AAE-C1-INH), also called acquired C1-INH deficiency (ACID), is a rare syndrome of recurrent episodes of angioedema, without urticaria, which is associated with B cell lymphoproliferative disorders in some patients [1]. Angioedema typically affects the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. The swelling is self-limited, although laryngeal involvement may cause fatal asphyxiation. Clinically, this disorder is very similar to hereditary angioedema (HAE), although AAE-C1-INH develops in older patients and is frequently associated with underlying disease, whereas the hereditary disorder presents in younger patients who are otherwise healthy [2].

This topic review will discuss the clinical manifestations, epidemiology, pathogenesis, and diagnosis of AAE-C1-INH. The management and prognosis of this disorder are reviewed separately. (See "Acquired C1 inhibitor deficiency: Management and prognosis".)

HAE is discussed separately. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis" and "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis" and "Hereditary angioedema: Acute treatment of angioedema attacks" and "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)

EPIDEMIOLOGY — AAE-C1-INH is rare, and the precise incidence is not known [3-5].

●In a large group of patients referred to a specialty center in Milan for angioedema due to C1-INH deficiency since 1976, 77 had acquired and 675 had hereditary forms of the disease with a ratio of 1:8.8 [3].

●Two national series found that between 6 and 10 percent of angioedema cases with C1-INH deficiency were attributable to AAE-C1-INH [6,7].

However, AAE-C1-INH is likely underdiagnosed, and there are several factors that may contribute to this. (See 'Obstacles to diagnosis' below.)

CLINICAL MANIFESTATIONS — AAE-C1-INH is characterized by recurrent episodes of angioedema, without urticaria or pruritus [8]. Episodes of angioedema typically last two to five days without treatment. Attacks are commonly triggered by trauma and psychological stress but may also occur without an apparent trigger. As in hereditary angioedema (HAE), swelling episodes in AAE-C1-INH can be characterized into three types, cutaneous, gastrointestinal, or upper airway, and the two disorders have very similar clinical manifestations. The important differences are summarized here. A more detailed discussion of each type of attack is found separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

Upper airway edema, frequently involving the larynx, is the most severe and potentially lethal site of angioedema in both disorders. Approximately 50 percent of patients with AAE-C1-INH experience upper airway edema, and anoxic brain injury or death from upper airway obstruction can occur [5,9]. (See "Acquired C1 inhibitor deficiency: Management and prognosis", section on 'Prognosis'.)

Differences between acquired and hereditary angioedema — The most consistent clinical difference between hereditary and acquired C1-INH deficiency is the age of onset. AAE-C1-INH typically presents in the fourth decade of life or later [10,11]. In a series of 77 patients with AAE-C1-INH, the earliest age of angioedema appearance was 39 years. In comparison, more than 90 percent of patients with HAE experience their first symptoms before the age of 20 years. A Spanish cohort with 46 AAE-C1-INH patients included 4 (8.7 percent) who presented at <40 years, with the youngest being 24 years of age [12].

Another important difference is that patients with AAE-C1-INH are often found to have an underlying lymphoproliferative, malignant, or autoimmune disorder, whereas most patients with HAE are otherwise healthy.

There are other more subtle differences between the clinical manifestations of the acquired and hereditary disorders:

●Gastrointestinal attacks appear to be less frequent in AAE-C1-INH compared with HAE. Angioedema of the gastrointestinal mucosa, which presents as recurrent colicky abdominal pain, distention, vomiting, and/or diarrhea, is reported by nearly 80 percent of patients with HAE, while less than 50 percent of AAE-C1-INH patients reported gastrointestinal attacks [3,5,13].

●Cutaneous angioedema in AAE-C1-INH seems to affect the face more than the limbs, while, in patients with HAE, swelling of the extremities is more typical [3,5]. However, both disorders can cause swellings in both locations.

●Patients with AAE-C1-INH may report antecedent changes in the skin (ie, similar in appearance to erythema marginatum) prior to cutaneous or gastrointestinal angioedema episodes, although it is not as prevalent as in patients with HAE. Skin findings are described separately. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis", section on 'Characteristic features of angioedema attacks'.)

ASSOCIATED DISORDERS — AAE-C1-INH was first described in 1972 in two patients with lymphoma [14]. Since this initial description, the majority of patients diagnosed with AAE-C1-INH have been found to have an underlying disorder [15-19]. Based on available reports, approximately 30 to 40 percent of patients are found to have some type of malignancy, predominantly affecting B lymphocytes. Another 30 to 40 percent are found to have monoclonal gammopathy of undetermined significance (MGUS), and another 5 to 10 percent have autoimmune conditions [20]. A small percentage of patients have no identifiable associated disorder, at least at the time of diagnosis.

To illustrate this, one extensive review of the literature identified 136 cases of AAE-C1-INH [20]. An underlying disease was identified in 85 percent of patients, including:

●Lymphatic malignancies in 35 percent

●MGUS in 32 percent

●Autoimmune diseases in 8 percent

●Adenocarcinoma and other malignancies in 6 percent (note that, other than lymphoma and adenocarcinoma, no other specific types of malignancies have been reported with regularity)

A 2021 literature review of 121 AAE-C1-INH patients reported an associated disease in 94 patients (77.7 percent), with lymphoproliferative disorder the most frequently reported (59 of 94, 62.8 percent) [21]. Anti-C1-INH autoantibodies were present in 45 of 71 patients (63.4 percent).

Lymphoproliferative disorders and B cell malignancies — The most frequently associated disorders are lymphoproliferative disorders and B cell malignancies (most often non-Hodgkin lymphomas and indolent lymphomas) [15-19,22,23]. Among patients with MGUS and AAE-C1-INH, the rate of progression to multiple myeloma does not appear to be increased [17,19].

In the Milan series of patients, 24 of 77 (31 percent) had non-Hodgkin lymphoma, and, in a French series, 44 of 92 (48 percent) had non-Hodgkin lymphoma [3,5]. Splenic marginal zone lymphoma was far more frequent (20 of 24 in the Italian series and 24 of 44 in the French series) than other types [3,5,24]. The predominance of splenic marginal cell lymphoma among patients with AAE-C1-INH was consistent with an earlier study mentioned above and suggests that these individuals may be at particular risk [25]. (See "Splenic marginal zone lymphoma", section on 'Managing autoimmune complications'.)

An estimate of the prevalence of AAE-C1-INH in lymphoma patients was provided by a retrospective study of 131 patients with different types of lymphomas in which patients were screened at the time of diagnosis for deficiency and dysfunction of C1-INH [23]. Four patients (3 percent) were symptomatic with episodic swelling, and all four had both functional tests and levels of C1-INH that were below 50 percent of normal. Three of these four patients had splenic marginal cell lymphoma. Another 10 patients had abnormal C1-INH function but normal levels and had not developed angioedema.

Autoimmune disorders — Autoimmune disorders are also identified in patients with AAE-C1-INH [26]. Reported conditions include systemic lupus erythematosus (SLE), autoimmune hemolytic anemia, and cryoglobulinemia [27-29].

Other implicated disorders — A small number of case reports have implicated infections, especially with Helicobacter pylori, in the development of AAE-C1-INH [30-32]. Eradication of H. pylori was followed by reversal of the clinical symptoms and biochemical abnormalities of AAE-C1-INH, suggesting the possibility that this infection could have a pathogenetic role in the development of AAE-C1-INH. A patient with Echinococcus and AAE-C1-INH who improved after treatment of the infection has been reported [33]. However, infections are unlikely to be related to pathogenesis in most patients, and we do not suggest an exhaustive search for infections unless there are suggestive clinical and laboratory findings.

Idiopathic cases — In most series, fewer than 10 percent of patients have neither an associated disorder nor autoantibodies to C1-INH [20,33]. The mechanism underlying AAE-C1-INH remains unknown in such patients. We can hypothesize that these individuals have antibodies to C1-INH that elude detection in plasma because of a low titer or because they are bound to cell membranes. It is also possible that an entirely different mechanism exists in such patients.

PATHOGENESIS — AAE-C1-INH usually arises in the setting of an uncontrolled clonal proliferation of B lymphocytes. However, the mechanism by which clonal B cell disorders lead to depletion of C1-INH and angioedema remains incompletely understood. Clonal B cell proliferation appears the pathologic process underlying AAE-C1-INH that leads to production of C1-INH-neutralizing autoantibodies and to non-Hodgkin lymphomas. The postgerminal center origin of non-Hodgkin lymphoma suggests that immune stimulation may contribute to lymphomagenesis [25].

Role of bradykinin — The angioedema of AAE-C1-INH appears to be mediated largely by bradykinin, as in hereditary angioedema (HAE) [34]. Tissue insult or injury normally activates the contact system, leading to the generation of bradykinin and other proinflammatory mediators. Bradykinin, acting through bradykinin B₂-receptors, increases endothelial permeability via mechanisms involving nitric oxide, cyclic guanosine monophosphate (GMP), and other effector molecules [35,36]. Bradykinin production is normally regulated by C1-INH.

Antibodies to C1 inhibitor — Most (although not all) patients with AAE-C1-INH have identifiable autoantibodies against the C1-INH protein [27,37-39]. In a series of 73 AAE-C1-INH patients, autoantibodies against the C1-INH protein were detected in 48 patients (66 percent) [33]. One theory proposes that pathologic B lymphocyte proliferation results in expansion of a clone that produces antibodies that bind to C1-INH ("neutralizing antibodies"), causing steric hindrance and a functional deficiency of the C1-INH protein. Whether autoreactive clones may then evolve to lymphoma remains to be established. The unusually high prevalence of splenic marginal zone lymphoma in our population suggests that immune stimulation of postgerminal center B cells may contribute to the development of lymphoma [25]. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Normally, C1-INH interacts with its target proteases and is cleaved in the process. The cleaved and inactive inhibitor irreversibly binds to the protease and renders it inactive. However, in the presence of anti-C1-INH antibodies, C1-INH is still cleaved, but it cannot bind the protease, and the protease continues to function, leading to uncontrolled generation of bradykinin and angioedema. Most patients with AAE-C1-INH demonstrate profound depletion of components of the classical complement pathway, including a low C1q (the measurable component of the C1 complex, C1q-r-s), which is not seen in patients with HAE. In addition, not all AAE-C1-INH patients with low C1q values have detectable anti-C1-INH antibodies [33]. (See "Complement pathways".)

The relationship between autoantibodies to C1-INH and lymphoproliferative disorders in patients with AAE-C1-INH is not clear either. An early study identified these neutralizing antibodies in otherwise healthy AAE-C1-INH patients and hypothesized that AAE-C1-INH could arise from an autoimmune mechanism without an associated lymphoproliferative disease [37]. Based on this, two types of AAE-C1-INH were proposed: one paraneoplastic and the other autoimmune [40]. However, subsequent work revealed that patients with and without autoantibodies to C1-INH develop lymphatic malignancies over time and at similar rates, indicating that this distinction is not clinically or prognostically relevant [11,41]. Thus, the division of AAE-C1-INH into these two types has been abandoned [15].

Activation of the classical complement pathway — A second theory proposes that the pathogenesis of AAE-C1-INH involves massive activation of the classical complement pathway by the neoplastic lymphoid tissue or by the abnormal antibodies and subsequent depletion of normally functioning C1-INH [16,28,42,43]. Evidence includes increased in vivo turnover of radiolabeled C1q and C1-INH with concomitant normal C1-INH production by monocytes of the same patient [42,43]. In this theory, anti-C1-INH autoantibodies are either an aggravating factor or purely an epiphenomenon.

An interesting patient was reported who had HAE and then developed non-Hodgkin lymphoma [44]. With the appearance of the lymphoma, the patient's angioedema markedly worsened, and depletion of classical pathway complement components was apparent that had not been present before. This patient did not have detectable anti-C1-INH antibodies, and the case supports the role of lymphoma tissue as activator of the classical complement pathway and as the trigger of angioedema symptoms.

DIAGNOSIS — The diagnosis of AAE-C1-INH is based upon a suggestive clinical history and appropriate complement abnormalities.

Clinical history — AAE-C1-INH should be considered in patients with the following:

●Episodes of angioedema affecting the cutaneous tissues and mucous membranes of the upper respiratory and gastrointestinal tracts

●Symptoms beginning in the fourth decade of life or later

●No family history of angioedema

Patients with AAE-C1-INH generally demonstrate all three of the above characteristics. Absence of a family history of angioedema, in isolation, is not diagnostic of AAE-C1-INH, because more than 25 percent of patients with HAE carry a de novo mutation in C1-INH gene and therefore have no affected ancestors [1]. On the other hand, the presence of a family member with HAE essentially excludes the diagnosis of AAE-C1-INH.

Complement studies — An algorithm for the diagnosis of angioedema due to C1-INH deficiency (acquired or hereditary) was published by an international consensus group (algorithm 1) [45]. In patients with isolated angioedema who are suspected of having a disorder of C1-INH, the following tests should be obtained:

●C4 level.

●C1-INH antigenic level and function.

●C1q level may be obtained initially in patients older than 30 years of age and without a family history of angioedema.

Most patients with AAE-C1-INH demonstrate the following:

●Low C4

●Low C1q (usually <50 percent of normal)

●Low or normal C1-INH antigenic (or quantitative protein) level

If the patient demonstrates these laboratory abnormalities, then a test of C1-INH function should be obtained. Low function is required for the diagnosis, and it is usually <50 percent of normal (table 1).

C1q levels are usually <50 percent of normal in patients with AAE-C1-INH. However, approximately 30 percent of the patients in two large series had C1q levels that were decreased but >50 percent of normal [10,20]. Finally, there are rare cases in which C1q levels are normal.

Note that complement abnormalities may fluctuate between normal and abnormal when the disorder first develops, becoming more consistently abnormal over the ensuing months. For this reason, mild abnormalities associated with a consistent clinical presentation should be followed over time.

Additional studies — Other diagnostic tests are only occasionally required. These include genotyping, detection of antibodies directed against C1-INH, and detection of cleaved C1-INH by gel electrophoresis and immunoblotting. The indications for obtaining these tests are discussed below.

Genotyping — In rare cases of AAE-C1-INH in which C1q is normal, the complement findings of AAE-C1-INH are identical to those in HAE. Genotyping for mutations in the C1-INH gene (SERPING1), which are only found in HAE, would be the only definitive way to differentiate these disorders. However, genetic testing is not widely available. If testing is not available, we recommend screening and monitoring patients who appear to develop HAE over the age of 40 years for underlying lymphoproliferative diseases. (See 'Evaluation for underlying disorders' below.)

Detection of anti-C1-INH antibodies — The other biochemical finding that is characteristic of AAE-C1-INH is the presence of anti-C1-INH autoantibodies in plasma. By comparison, approximately 30 percent of patients with HAE have these antibodies, as well as 3 percent of normal controls [46]. As with other autoantibodies, the definition of a pathologic level is relatively arbitrary. Furthermore, these autoantibodies bind C1-INH protein with a low avidity and can be difficult to detect, making a negative test less useful than a positive test. At least one commercial assay for measuring these antibodies is available, and an enzyme-linked immunosorbent assay (ELISA) system can be set up in specialized laboratories and yields reliable results for investigational purposes [39,47]. Therefore, the finding of high titers of anti-C1-INH antibodies in a patient's serum is supportive of the diagnosis of AAE-C1-INH, but the absence of these antibodies does not exclude the disorder.

Electrophoresis for inactive inhibitor — An additional test that may help to refine the diagnosis of AAE-C1-INH is the detection of cleaved C1-INH by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting [48]. C1-INH normally interacts with its target protease and is cleaved by this interaction. Cleaved C1-INH then irreversibly binds to the protease, rendering it inactive. However, in the presence of anti-C1-INH antibodies, C1-INH is cleaved but cannot bind the protease [49]. The protease then continues to function while cleaved, but inactive C1-INH remains in the circulation. The cleaved, inactive form can be distinguished by electrophoresis [49]. In contrast, the routine quantitative assay for antigenic levels of C1-INH cannot distinguish between cleaved inactive and uncleaved active C1-INH, which explains why patients with AAE-C1-INH can have normal C1-INH antigenic levels and low function with standard complement tests.

Obstacles to diagnosis — It is our clinical impression that AAE-C1-INH frequently evades diagnosis for a period of years. We believe there are several obstacles to diagnosis:

●Even among specialists, awareness of the existence of an acquired form of C1-INH deficiency is not widespread, and uncertainties regarding the pathogenesis and laboratory features of the disorder further complicate diagnosis.

●Patients with AAE-C1-INH lack a family history, so cases are not detected through family screenings, as with the hereditary form.

●The diagnosis of a coexisting lymphoproliferative malignancy can overshadow other medical issues, including recurrent angioedema, which may be attributed to a paraneoplastic phenomenon and not evaluated further.

●Because the disorder begins later in life, many patients are taking multiple medications, and the episodes of angioedema are attributed to drug-allergic reactions. Similarly, patients may have multiple comorbidities, and the evaluation of angioedema may not take precedence until a severe attack occurs.

●Complement abnormalities may fluctuate between normal and abnormal when the disorder first develops, becoming more consistently abnormal over the ensuing months. For this reason, mild abnormalities associated with a consistent clinical presentation should be followed over time.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of AAE-C1-INH includes:

●In patients with no complement abnormalities:

•Angioedema induced by angiotensin-converting enzyme (ACE) inhibitors

•Hereditary angioedema with normal C1-INH (which has also been called type III HAE or, previously, estrogen-dependent HAE)

•Isolated angioedema as a manifestation of an allergic reaction

•Idiopathic angioedema (ie, angioedema with no associated complement abnormalities)

●In patients with complement abnormalities:

•Hereditary angioedema with deficient C1-INH (type I HAE)

•Hereditary angioedema with dysfunctional C1-INH (type II HAE)

However, most patients with AAE-C1-INH have low levels of C1q, while patients with HAE have normal C1q (table 1). Patients with AAE-C1-INH develop angioedema later in life and do not have a family history of angioedema, while HAE usually presents in young people, and approximately 75 percent of HAE patients have a family history of angioedema.

The differential diagnosis of angioedema in general is reviewed separately. (See "An overview of angioedema: Clinical features, diagnosis, and management", section on 'Differential diagnosis'.)

Low C1q levels — Low levels of C1q are not exclusive to AAE-C1-INH. Autoantibodies to C1q causing depressed C1q levels can be seen in hypocomplementemic urticarial vasculitis syndrome (HUVS) and systemic lupus erythematosus (SLE). Levels of C1q less than 30 percent of normal are typical of both conditions. However, HUVS usually includes urticaria, which is not observed with inherited or acquired C1-INH deficiency. The diagnosis of HUVS and SLE are reviewed elsewhere. (See "Urticarial vasculitis" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults".)

There is also congenital C1q deficiency, which is rare (10 to 50 reported cases). More than 90 percent of reported patients with this have SLE, and the deficiency is also associated with glomerulonephritis and pyogenic infections [50].

EVALUATION FOR UNDERLYING DISORDERS — All patients with AAE-C1-INH disorders should be evaluated for an underlying B cell lymphoproliferative disorder. This evaluation begins with a thorough review of systems and physical examination. Any abnormalities identified should be investigated further. Referral to a hematology expert can help with this evaluation. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)

If the review of systems and physical examination is unrevealing, we usually obtain the following studies:

●Complete blood count (CBC), white blood cell differential, platelet count, and examination of the peripheral smear for the presence of atypical cells.

●Biochemical tests, including blood urea nitrogen (BUN), creatinine, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH).

●Serum protein electrophoresis and immunofixation.

●Serum-free light chain assay. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)

●Screening for lymphadenopathy and masses with imaging studies of the chest and abdomen. We usually perform chest radiograph and abdominal ultrasound, although computed tomography (CT) scans are also an option.

●All age-appropriate cancer screening. (See "Screening for lung cancer" and "Screening for colorectal cancer: Strategies in patients at average risk" and "Screening for breast cancer: Strategies and recommendations".)

●A bone marrow biopsy to look for underlying lymphoreticular disease may be done in patients with AAE-C1-INH who do not have other identifiable causes for the C1-INH deficiency.

If no associated condition is identified, then we monitor patients by repeating studies for B cell malignancies annually. Monitoring is discussed in more detail separately. (See "Acquired C1 inhibitor deficiency: Management and prognosis", section on 'Monitoring for development'.)

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: Urticaria and angioedema (excluding hereditary angioedema)".)

SUMMARY

●Epidemiology and clinical manifestations – Acquired angioedema due to deficiency of C1 esterase inhibitor (AAE-C1-INH; also known as acquired C1 inhibitor deficiency [ACID]) is a rare disorder characterized by recurrent episodes of angioedema, without urticaria or pruritus. Swelling most often involves the subcutaneous tissues of the face and the submucosa of the upper airway and small bowel. AAE-C1-INH presents in the fourth decade of life or later. (See 'Epidemiology' above and 'Clinical manifestations' above.)

●Associated disorders – Approximately 70 percent of patients with AAE-C1-INH are found to have an associated disorder. In one-half of these cases, the disorder is malignant (most often non-Hodgkin lymphoma), and, in the other one-half, the associated condition is benign (most often monoclonal gammopathy of undetermined significance [MGUS]). (See 'Associated disorders' above.)

●Pathogenesis – Angioedema in AAE-C1-INH is bradykinin mediated, but the precise pathogenesis is undefined. Most patients have autoantibodies against the C1-INH protein. These autoantibodies may impede the normal functioning of C1-INH and cause a functional deficiency. Alternatively, the antibodies, or perhaps neoplastic tissue in some cases, may cause activation of the classical complement pathway, leading to depletion of normally functioning C1-INH. (See 'Pathogenesis' above.)

●In whom to suspect – AAE-C1-INH should be considered in a patient who presents with isolated angioedema (without urticaria) in the fourth decade of life or later and has no family history of angioedema. (See 'Diagnosis' above.)

●Complement abnormalities – Initial testing should consist of levels of C4, C1q, and C1-INH (antigenic level). If C4 and C1q are low and C1-INH antigenic level is low or normal, then C1-INH function should be obtained. Low C1-INH function confirms the diagnosis (algorithm 1 and table 1). Other studies are usually not needed. (See 'Complement studies' above.)

●Evaluation for underlying disorders – All patients with acquired C1-INH disorders should be evaluated for an underlying B cell lymphoproliferative disorder at the time of diagnosis. If no disorder is found, we recommend repeating an evaluation annually. (See 'Evaluation for underlying disorders' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marco Cicardi, MD, who contributed to earlier versions of this topic review.