Hereditary angioedema (due to C1 inhibitor deficiency): Epidemiology, clinical manifestations, exacerbating factors, and prognosis

INTRODUCTION — 

Hereditary angioedema (HAE) is a disease 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. Although the swelling is self-limited, laryngeal involvement may cause fatal asphyxiation. Prior to the availability of effective therapy, this disorder was associated with a mortality rate of approximately 30 percent due to asphyxiation from laryngeal swelling.

The epidemiology, clinical manifestations, triggering and exacerbating factors, and prognosis of HAE are discussed in this topic review. The laboratory evaluation, establishing definitive diagnosis, and acute and prophylactic therapies of this disorder are discussed separately:

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

●(See "Hereditary angioedema (due to C1 inhibitor deficiency): Acute treatment of angioedema attacks".)

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

TERMINOLOGY — 

HAE types 1 and 2 are the focus of this topic review. These disorders are caused by deficiency or dysfunction of the C1 inhibitor (C1INH) protein. They are referred to as HAE-C1INH or simply HAE in this review.

Other types of HAE are discussed separately. (See "Hereditary angioedema with normal C1 inhibitor".)

EPIDEMIOLOGY — 

The prevalence of HAE is estimated at approximately 1 individual per 50,000, with ranges between 1 in 30,000 to 92,000, varying by region and by study methodology [1-3]. Males and females are affected equally, and there are no known differences in prevalence among ethnic groups [4-6].

CLINICAL MANIFESTATIONS

Age of onset — The age at which attacks begin is variable, with rare reports of initial episodes of angioedema in the perinatal period [7]. Symptoms can start as early as age one to two years. Approximately 40 percent of patients experience their first HAE attack before age 5 years and 75 percent by age 15 years, although repeated attacks in preadolescent children are uncommon [7-10]. Thus, for the majority of patients, the disease first presents in childhood or adolescence. There may be some population differences as the average age of onset in a Chinese population was reported to be 21 years [11]. The time of the onset of the initial symptoms does not differ between the sexes [12,13]. Attack frequency usually increases after puberty [12]. In most cases, the diagnosis is eventually made in the second or third decade of life and can be further delayed if there is no family history.

Laboratory findings — Patients with HAE with C1 inhibitor (C1INH) deficiency demonstrate characteristic abnormalities in the complement system, upon which the diagnosis is based. These are discussed in detail separately. Other than abnormal complement studies, patients with HAE are usually healthy and most commonly have normal routine laboratory values. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis".)

Characteristic features of angioedema attacks — Attacks most often affect three anatomical locations:

●The skin (subcutaneous attacks)

●The gastrointestinal tract (abdominal attacks)

●The upper airway (usually referred to as laryngeal attacks)

Many HAE attacks involve only one site at a time, although multilocational attacks may also occur. HAE attacks are self-limited, lasting two to five days, and range in severity from inconvenient subcutaneous swelling to life-threatening upper airway edema [14,15]. Approximately 50 percent of patients experience all three manifestations during the course of their lives [8]. Other general observations about HAE include the following:

●HAE attack frequency varies from weekly to one or two episodes per year [15]. Untreated, patients with frequent attacks may miss up in excess of 100 work days per year [8]. A few subjects remain asymptomatic and are identified as having HAE only as a result of family screening [7,16].

●Disease severity differs markedly among affected members within families despite the presence of the same mutation [7]. Disease severity may also vary significantly in the same patient over time. Early symptoms may predict a more severe disease course.

Prodromal symptoms and skin changes — Prodromal symptoms include fatigue, nausea or other gastrointestinal symptoms, and myalgias and flu-like symptoms [17,18]. Some patients develop skin changes that are usually described as a serpentine, mottled, and/or "chicken-wire" pattern of erythematous discoloration (picture 1) [19-22]. Erythema marginatum occurs in approximately 42 to 58 percent of cases [19,23,24]. Prodromal symptoms usually occur within 24 hours before the onset of angioedema, although not all prodromal symptoms are followed by an angioedema episode [18].

Cutaneous attacks — Cutaneous attacks are common and temporarily disfiguring, although not generally dangerous. Skin swelling was present in 97 percent of 131,110 angioedema episodes in a retrospective series of 221 patients [7]. The extremities, face, and genitals are most commonly affected, although any site can be involved (picture 2). Swelling occurs in nondependent areas and is not pitting or pruritic. Cutaneous attacks are often associated with pain and dysfunction in addition to swelling [25]. An episode typically begins in the skin with a peculiar tingling or sensation of fullness and irritation, followed by swelling and a sense of tightness in the next two to three hours. The angioedema builds over the first 24 hours, then gradually subsides over 48 to 72 hours [26]. Swelling may last up to five days in some patients. Attacks can also last longer if the swelling spreads from one site to another.

Face and lips — Angioedema of the face and lips comprises approximately 3 percent of the episodes of subcutaneous edema. Orofacial edema was the most common clinical presentation (76 percent) among Indian patients with HAE [27]. Swelling in these areas should be monitored closely by the patient because up to 30 percent of episodes of upper airway edema are preceded by facial/labial edema [26].

Upper airway attacks — Laryngeal swelling can occur in isolation or in association with swelling of the lips, tongue, uvula, and soft palate [7]. Initial signs and symptoms of upper airway attacks may include a sore, scratchy, or itchy throat; the sensation of tightness or a lump in the throat; dysphagia; voice changes; hoarseness; roughness of voice; or a resonant, "barky" cough [28].

Upper airway edema occurs in approximately one-half of all patients over their lifetimes; however, only a few percent experience recurrent episodes, and, in the large retrospective series mentioned above, laryngeal attacks accounted for less than 1 percent of all angioedema episodes [7]. Laryngeal attacks are less common in patients over the age of 45 years [26]. Tooth extraction and oral surgery are common triggers. (See 'Triggers and exacerbating factors' below.)

Laryngeal swelling usually develops over hours, with a reported mean of seven hours [29]. However, there are disturbing reports of fulminant laryngeal attacks, including a nine-year-old boy with a family history of HAE but no previous attacks who died of asphyxiation 20 minutes after the apparent onset of symptoms [29-31]. In comparison with adults, asphyxia may ensue more rapidly in children because of smaller airway diameter [32]. Although each laryngeal attack has the potential to become life threatening, the majority resolve before complete airway obstruction, and one large series documented only 2 intubations and 4 cricothyrotomies among 342 laryngeal attacks [26].

In a study of 70 fatal laryngeal attacks, researchers proposed that three phases of an attack can be distinguished [31]:

●The predyspnea phase, which starts with the first noticeable symptom and ends when dyspnea develops (average length: 3.7 hours; range: 0 to 11 hours). During this phase, patients typically reported the initial symptoms but not frank dyspnea. Six patients did not appear to have a predyspnea phase at all, as their initial symptom was dyspnea.

●The dyspnea phase, from onset of dyspnea to loss of consciousness (average length: 41 minutes; range: 2 minutes to 4 hours).

●The loss of consciousness phase, which starts with loss of consciousness and ends with death (average length: 9 minutes; range: 2 to 20 minutes).

Thus, there is a window of opportunity in the predyspnea phase in which patients can seek and receive help, followed by a much shorter period in the dyspnea phase. In this study, 63 patients had not been diagnosed with HAE at the time of death, and 7 had. Possible triggers were apparent in a minority of patients (eight had preceding upper respiratory tract infections, and six had tooth extractions). The mean age of death by asphyxiation in undiagnosed patients was 40.6 years [33]. Importantly, patients without a clear diagnosis were far more likely to die from an upper airway attack than those in whom HAE-C1INH had been previously diagnosed.

Gastrointestinal attacks — Gastrointestinal attacks present as varying degrees of gastrointestinal colic, nausea, vomiting, and/or diarrhea [34]. These symptoms result from bowel wall edema. Gastrointestinal attacks are experienced by a majority of patients with HAE-C1INH and can be the principal presentation in one-quarter of patients [7,15]. A few families have been reported in which bowel attacks were the only manifestation.

Symptoms and patterns of symptom development were analyzed in a large, mostly retrospective, observational study of over 33,000 gastrointestinal attacks in 153 patients with HAE [35]. The patients included in this series had received treatment with analgesics or spasmolytics only. At least one prodromal symptom occurred at the onset of 70 percent of the attacks and included fatigue, irritability, hunger, sensitivity to noise, and erythema marginatum. All attacks were painful, with a mean pain score of 8.4 on a subjective scale of 1 (minimal) to 10 (maximal). Three-quarters included nausea, vomiting, and abdominal distension, and 41 percent involved diarrhea. Four percent of patients experienced circulatory collapse, which can result from hypovolemia. Attacks lasted four days on average, from the onset of prodromal symptoms to complete resolution, and peaked on the second day.

Gastrointestinal attacks can be challenging to diagnose, and the clinician must determine if the abdominal symptoms are due to angioedema or to an unrelated process. Recurrent abdominal complaints of unknown etiology should always raise the suspicion of HAE. Patients who have had previous gastrointestinal attacks should be questioned carefully to ascertain if their current symptoms are similar to past episodes. Because of the clinical similarities between bowel attacks of angioedema and true surgical emergencies, as many as one-third of patients with undiagnosed HAE may undergo unwarranted abdominal surgery [8,36,37].

Objective findings

●Most abdominal attacks are not associated with fever, peritoneal signs, or an elevated white blood cell count. However, during severe abdominal attacks, elevations of neutrophils (without increased bands), hypovolemia from fluid losses, or hemoconcentration from plasma extravasation and/or vasodilation have been reported [38-40]. Neutrophils have been reported to be elevated and activated but without a left shift (ie, without an increase in bands) [40,41].

●Imaging is not routinely needed during an abdominal attack in a patient with known HAE who is reporting characteristic symptoms. However, if the cause of the patient's presentation is unclear, an abdominal ultrasound or computed tomography (CT) scan is useful in confirming the findings of gastrointestinal angioedema. Ultrasound findings include edema of the intestinal wall and free peritoneal fluid, which resolve after the attack. Although not specific to HAE, these findings can be a sensitive, rapid, and noninvasive means of excluding other disorders [40,42,43].

Unusual manifestations of HAE — Unusual forms of HAE attacks include episodic swelling of the bladder and urethra, pancreatic duct, gallbladder, circumscribed induration of muscles, chest tightness or pain, renal colic, cephalalgia, joint swelling, and pleural or pericardial fluid accumulations [7,44]. There is sometimes accompanying or preceding cutaneous swelling.

Associated conditions — Most patients with HAE are otherwise healthy. However, the following conditions are reported in association with HAE in some individuals:

●Depression – Those with severe or frequent HAE attacks have impaired quality of life and may suffer from depression [45,46].

●Venous thromboembolism – Venous thromboembolic disease, including deep vein thrombosis of the lower extremities and pulmonary embolism, was more prevalent in a study of Swedish patients with HAE compared with their family members without HAE [47]. The incidence of venous thromboembolism was 9.6 and 4.1 percent in individuals with and without HAE, respectively, an effect size similar to that of factor V Leiden (rs6025) and the prothrombin G20210A variant (rs1799963). Further investigation of the impact of C1INH deficiency on activation of coagulation and thrombosis using patient samples and mouse models showed that plasmas from patients with HAE-C1INH and whole blood from C1INH-deficient mice had significantly increased contact pathway-mediated thrombin generation. Purified human C1INH normalized contact pathway-mediated thrombin generation and venous thrombosis in C1INH-deficient mice. Endogenous C1INH is an important negative regulator of venous thrombus formation [48]. However, further mechanistic study is needed.

●Pancreatitis – Acute pancreatitis has been reported in patients with HAE, although it is not clear if the two disorders are pathologically related [49-57]. Although HAE attacks are rarely associated with pancreatitis, a review of literature suggested that HAE (due to mutations in either C1INH or factor XII) should be considered in the differential diagnosis of patients with idiopathic pancreatitis [58].

●Celiac disease – A higher prevalence of celiac disease is observed among patients with HAE compared with the general population (18.1 versus 1.2 percent) [59].

●Autoimmunity – There appears to be an association between HAE and both autoimmune diseases and enhanced autoantibody production. Autoimmune conditions were reported in 19 of 157 patients (12 percent) in one series of patients with HAE [49]. Associated disorders include thyroiditis, systemic lupus erythematosus (SLE), Sjögren's disease, inflammatory bowel disease, glomerulonephritis, and a nonrheumatoid erosive arthritis of the wrists and hips [60-62]. Small but significant differences in T cell subpopulations and B cell activation were also seen [63]. It has been proposed that the depressed levels of C4 seen in patients with HAE may contribute to the development of autoimmune disease since C4 is important in the solubilization and clearance of immune complexes [64,65]. Chronic overactivation of B cells (as determined by heightened expression of Toll-like receptor 9) has also been demonstrated [66]. High rates of positivity for antinuclear antibodies were found in two series (16 and 28 percent compared with 5 percent in the general population) [66,67]. Autoantibodies against C1INH, which are characteristic of acquired C1INH deficiency, have also been noted in HAE [68].

TRIGGERS AND EXACERBATING FACTORS — 

Patients report a variety of triggers for episodes of angioedema. Stress (either mental or physical) and dental procedures are the most common.

Physical triggers — Mild trauma, including dental work, is a common trigger and will precipitate episodes of angioedema in many patients. Intubation is another important trigger. Prophylaxis for prevention of attacks associated with dental work or surgery is discussed elsewhere. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis".)

Tongue piercing and snoring-induced local trauma of the soft palate have been implicated in isolated case reports [69,70]. Genital swelling in women can be precipitated by sexual intercourse, as well as bicycle or horse riding [71]. The reason one type of insult precipitates attacks while another does not is poorly understood.

Infections and other stressors — Other triggers that have been reported (although not all necessarily validated) include excitement, sleep deprivation, viral upper respiratory tract infections, bacteriuria, cold exposure, prolonged sitting or standing, ingestion of certain foods, and menstruation [64,72,73].

Helicobacter pylori infections can trigger gastrointestinal attacks, and eradication of this infection can lead to significant reduction in the frequency of gastrointestinal attacks [74,75].

Medications — The following medications can exacerbate the frequency and/or severity of HAE attacks:

●Estrogen-containing medications, such as hormone replacement therapy and contraceptives [76]. (See 'Hormonal changes in females' below.)

●Tamoxifen, a selective estrogen-receptor modulator (SERM) that has mixed agonist/antagonist actions on the estrogen receptor. In one reported case, a patient with HAE who developed increased episodes on tamoxifen was successfully treated with the aromatase inhibitor letrozole [77].

●Angiotensin-converting enzyme (ACE) inhibitors [72]. In contrast, angiotensin II receptor blockers (ARBs) are generally well tolerated.

Hormonal changes in females — The impact of hormonal fluctuations, including pregnancy, on females with HAE is variable [23,78-81]. The largest study was a retrospective questionnaire-based survey of 150 postpubertal females with HAE (both on and off therapy) from eight European countries, which reported the following observations [79]:

●Disease worsened with puberty in 62 percent and did not change for the others.

●Attacks were associated with the perimenstrual or menstrual period in 35 percent.

●Use of oral contraceptives containing both estrogen and progesterone worsened disease severity in 80 percent of respondents. In contrast, progesterone-only contraceptives improved disease in 64 percent. Intrauterine devices were well tolerated by 83 percent.

●Pregnancy was associated with more attacks in 38 percent, fewer in 30 percent, and no change in 32 percent [79]. Most females reported that the effects during an initial pregnancy were similar in subsequent pregnancies. Females who had attacks in association with menses were more likely to have worsening of disease during pregnancy, indicating that a subset is particularly sensitive to hormonal triggers [82].

●Delivery did not precipitate attacks in most patients, as noted in other studies [23,80]. The majority (89 percent) were not given prophylactic treatment in preparation for delivery, and yet attacks during or within two days of delivery occurred in only 6 percent.

●Of the 29 percent of participants who had experienced menopause, 55 percent noticed no change in disease activity. A worsening of attacks was reported by 32 percent.

●There were no detectable differences in the rates of gynecologic disease, infertility, or spontaneous abortion in females with HAE compared with those in the general population.

Another study followed 22 females with HAE through 35 pregnancies and found an increase in attack rates during pregnancy or in the postpartum period in 83 percent [81]. All patients received replacement C1INH therapy during pregnancy and just prior to delivery, and none experienced attacks during labor or delivery. These patients were followed at a referral center, and so the severity of their disease may have been greater than that of patients with HAE treated elsewhere.

Recommendations for the gynecologic and obstetric care of females with HAE are reviewed elsewhere. (See "Hereditary angioedema (due to C1 inhibitor deficiency): General care and long-term prophylaxis", section on 'Gynecologic and obstetric care'.)

PROGNOSIS — 

The prognosis for patients with HAE-C1INH is variable. Once attacks have begun, they generally continue throughout the patient's life, although the frequency of attacks can be dramatically reduced by therapy.

Prior to the introduction of effective therapies for HAE, up to one-third of patients died of asphyxiation [23]. However, despite effective therapies, deaths secondary to laryngeal attacks still occur with some regularity, although data are limited. A series of Austrian, Swiss, and German patients published in 2004 cited a mortality rate as high as 13 percent [64]. Similar results have been observed in the Hungarian population [33].

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

●Epidemiology – Hereditary angioedema with C1 inhibitor deficiency (abbreviated here as HAE-C1INH or simply HAE) is a rare disorder characterized clinically by recurrent episodes of angioedema, without accompanying hives or pruritus, which most commonly affects the skin, bowel, or upper airway. HAE affects males and females equally. Although symptoms often begin in childhood, the disease is commonly diagnosed during puberty or early adulthood, when attacks become more frequent and show inter- and intraindividual differences. (See 'Epidemiology' above.)

●Clinical manifestations – An attack of HAE usually involves one site at a time (skin, upper airway, or gastrointestinal tract). A prodrome of fatigue or erythematous rash is noticed by some patients. Attacks build in severity for 24 hours and then subside over the next one to five days. (See 'Clinical manifestations' above.)

•Upper airway swelling – The most life-threatening type of attack involves the upper airway, and any swelling in this area should be regarded as an emergency. Laryngeal attacks usually develop over hours, but there are reports of precipitous airway closure. Laryngeal edema occurs in approximately one-half of all patients over their lifetimes, although only a few percent experience recurrent episodes. (See 'Upper airway attacks' above.)

•Subcutaneous swelling – Subcutaneous attacks are common and temporarily disfiguring, although not generally dangerous. The extremities, face, and genitals are most commonly affected, although any site can be involved (picture 2). Swelling occurs in nondependent areas and is nonpitting. (See 'Cutaneous attacks' above.)

•Bowel wall swelling – Gastrointestinal attacks are experienced by a majority of patients with HAE and present as varying degrees of gastrointestinal colic, nausea, vomiting, and/or diarrhea, which result from bowel wall edema. (See 'Gastrointestinal attacks' above.)

●Triggers and exacerbating factors – Mild trauma, including dental work, is the most common trigger for cutaneous and laryngeal attacks. Other triggers that have been reported include angiotensin-converting enzyme (ACE) inhibitors, stress, exogenous estrogens, infections, and changes in sex hormones (menstruation, pregnancy). (See 'Triggers and exacerbating factors' above.)

●Prognosis – Once attacks have begun, they generally continue throughout the patient's life, although the frequency of attacks can be dramatically reduced by therapy. The mortality rate for patients with HAE, despite effective therapies, has been estimated to be as high as 13 percent. (See 'Prognosis' above.)

ACKNOWLEDGMENT — 

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