C1 Esterase Inhibitor Deficiency, Airway Compromise, and Anesthesia

Hereditary angioedema (HAE) is a serious genetic abnormality involving the complement system and characterized by episodic and sometimes life-threatening airway edema. In 1882, von Quincke [1] published the first detailed description, and 3 yr later, Strubing used the term angioedema to describe this disorder. By 1888, Osler [2] had demonstrated the hereditary nature of the clinical presentation. In the early 1960s, HAE was shown to be caused by deficiency of C1 esterase inhibitor, also called "C1 inhibitor" (C1 INH) [3,4]. In 1972, an acquired form of C1 INH deficiency was first reported [5]. Lack of C1 INH leads to uncontrolled activation of the classical pathway of complement and is thought to result in the release of C2 kinin, or perhaps bradykinin [6-10], which then causes increased vascular permeability and edema of the airway, trunk and extremities, and gastrointestinal tract [11,12]. Angioedema (Table 1) describes deep swelling of the dermis associated with a variety of disorders, including HAE, acquired C1 INH deficiency, angiotensin-converting enzyme inhibitor (ACE)-induced disorder, several conditions induced by allergens and drugs releasing histamine, and idiopathic and miscellaneous processes. Although these conditions share this one characteristic (angioedema), only the first two are caused by a complement abnormality.Table 1: Differential Diagnosis of AngioedemaHAE and acquired C1 INH deficiency are especially important to anesthesiologists because patients with these disorders are prone to developing massive swelling of the aerodigestive tract (especially the oral cavity, pharynx, and larynx) and life-threatening airway obstruction. Although angioedema may occur throughout the body, it has a proclivity for the extremities and gastrointestinal tissues, as well as the head and neck [12,13]. Pathophysiology A full understanding of C1 INH deficiency requires a brief review of the complement system (Figure 1) [12,14-16]. This system consists of approximately 20 proteins, many circulating as inactive enzyme precursors, with two pathways for activation: the classical pathway and the alternate pathway. The classical pathway is activated by antigen-antibody complexes, whereas the alternate pathway is activated by naturally occurring substances, such as bacterial cell walls and yeast walls [17,18]. Complement activation by either pathway may result in opsonization [19], lysis [20], anaphylatoxin activity [21,22], chemotactic activity [23], and immune complex clearance [24].Figure 1: The complement system consists of proteins and enzyme precursors. There are two pathways to activation, the classic (shown) and the alternate; activation by either can result in opsonization, lysis, chemotactic activity, and immune complex clearance. Angioedema describes deep swelling of the dermis and has many causes. Hereditary angioedema and acquired C1 esterase inhibitor deficiency specifically involve the complement system.C1, the first component of the classical pathway of complement, exists in serum as a macromolecular complex containing one C1q, two C1r, and two C1s molecules [25]. Activation of this macromolecule leads to cleavage of C1s to produce C1s, also called C1 esterase. C1s may then act on C4 and C2 to produce C4b2a in the fluid phase or on the cell, cleaving C4 and C2. Control proteins limit the amount of complement activation. C1 INH is a single-chain, highly glycosylated alpha2-globulin, serine-protease inhibitor (SERPIN) that contains 478 amino acids and specifically inhibits the spontaneous activation of the first component of complement [3,4,15]. C1 INH binds stoichiometrically (in a 1:1 ratio) to C1r and C1s and less well to their inactivated precursors, C1r and C1s [26-29]. Individuals who lack sufficient C1 INH cannot adequately control the activation of C1, which leads to the consumption of C4 and C2 with subsequent generation of C2 kinin or other biologically active products [8,30]. C2 kinin alone or in conjunction with bradykinin or other substances may then cause increased vascular permeability and subcutaneous and mucosal swelling characteristic of HAE [3,15]. The bradykinin receptor and genotype may have particular relevance to clinical status [31]. C4b2a formation and decay are controlled by complement receptor 1 (CR1, CD35) and C4 binding protein (C4BP), as well as factor I, which prevents C3 levels from decreasing as a result of C1 INH deficiency [14]. Unfortunately, C1 INH is the only known control protein that regulates the consumption of C4 and C2. C1 INH also can inhibit activated Hageman factor (factor XIIa), plasma thromboplastin antecedent (factor XIa), and plasma kallikrein [30]. Activation of the coagulation cascade in C1 INH deficiency has been described in detail [32]. Furthermore, C1 INH inhibits plasmin and tissue plasminogen activator [7] and is encoded by a gene on chromosome 11 [29]. The C1 INH gene consists of eight exons and seven introns and is approximately 1.7 x 104 base pairs in length [30,33]. Androgens may enhance the expression of C1 INH in vivo, whereas gamma-interferon, alpha-interferon, tumor necrosis factor alpha, interleukin-6, and monocyte colony-stimulating factor have been shown to do so in vitro [34-36]. Most C1 INH is synthesized in the liver and blood monocytes [37]. Amino acid composition, physical characteristics, purification, and assays have been described in great detail [30,34,38,39]. In type I HAE, the region of the gene rich in alu repeats often contains the defective gene [33]. In type II HAE, the defect is usually at or near the active site, ARG 444, in exon 8. This explains why patients with type I HAE do not produce normal antigenic levels of C1 INH; their abnormal gene does not allow antigenic C1 INH to be expressed. Patients with type II HAE express nonfunctional protein. Types of C1 INH Deficiency and Laboratory Diagnosis The etiologies of IIAE and acquired C1 INH deficiency are quite different (Table 2). HAE is caused by a defective C1 INH gene that produces either no C1 INH (type I) or dysfunctional C1 INH, which is measurable for antigen but is inactive (type II). In both types of HAE, <50% of normal C1 INH is produced, which is insufficient. In contrast, acquired C1 INH deficiency is caused by the consumption of C1 INH or autoantibodies directed against C1 INH [16]. There are also two types of acquired C1 INH deficiency. Type I is characterized by a malignancy that activates complement or produces idiotype anti-idiotypes or other immune complexes. In contrast, type II is not associated with underlying disorders, except for the presence of an autoantibody that interferes with C1 INH activity.Table 2: Complement Levels in HAE and Acquired C1 INH DeficiencyThe cardinal feature of type I HAE is decreased antigenic and functional levels of C1 INH [12]. Type II HAE is characterized by normal or increased antigenic levels of C1 INH, half of which is dysfunctional [40]. The type II form afflicts approximately 15% of patients with HAE [15]. C1 levels are normal in both types of HAE. A C4 level is a rapid screening test for C1 INH deficiency [15,41-43]. Normal levels during an acute attack tend to exclude the diagnosis, whereas decreased levels of C4 warrant an assay for C1 INH. C4, C2, and C1 INH levels should all remain low between attacks. Low C1 and C1q levels suggest acquired C1 INH deficiency rather than HAE [13,43]. However, C1 INH levels do not necessarily correlate with the level of disease. For example, the C1 INH level may be very low and the patient may be unaffected [40], whereas higher levels may be seen in patients with massive angioedema. Natural History, Manifestations, and Clinical Presentation The importance of recognizing HAE cannot be overemphasized. Frank et al. [13] reported that the interval between onset of symptoms and diagnosis is approximately 20 yr, probably because HAE is an uncommon disorder. In the United States, HAE has a probable incidence of approximately 1:50,000 to 1:150,000, although there are large regional differences related to the presence of afflicted families in certain parts of the country. Acquired C1 INH deficiency is probably less common than HAE, but its prevalence is unknown. Compounding the rarity of the processes is the wide variety of presenting symptoms. Therefore, the natural history and clinical manifestation of C1 INH deficiency deserve careful attention. Most patients with this disorder have a family history [13]. Age of onset is usually not helpful in making the diagnosis, but the disease manifests itself by the age of 30 yr in approximately 98% of patients [44]. Although one half of patients with HAE are symptomatic by the age of 7 yr and two-thirds are symptomatic by the age of 13 yr [45], presentation after the age of 50 yr has been reported [13]. Presenting signs are usually cutaneous edema, abdominal pain, vomiting, and edema of the laryngeal or retropharyngeal area. Attack duration typically ranges from approximately 24 h to several days. Minor or even trivial trauma or emotional upset are the most consistent and frequent precipitators of attack. Trauma may be the trigger of one half of exacerbations [13]. Unlike HAE, acquired C1 INH deficiency is associated with onset at an older age and absence of family history. In addition, acquired C1 INH deficiency may be associated with a lymphoproliferative disorder, such as lymphoma or systemic lupus erythematosis [43,46-48]. HAE and acquired C1 INH deficiency are both characterized by the presence of angioedema and are not clearly distinguishable from each other on this basis [43]. The swelling involves the deep dermis and is nonpruritic, nonerythematous, circumscribed, cutaneous, and asymmetric [3,40,49]. Nearly one fourth of patients with HAE have a nonpruritic rash accompanying attacks of HAE, described as erythema marginatum [13,50]. Although urticaria (erythematous, pruritic, cutaneous elevations of the skin that blanch with pressure) can occur in patients who have C1 INH deficiency, urticaria that is always associated with angioedema suggests a diagnosis other than HAE [12,51]. HAE characteristically involves the extremities, face, airway, and gastrointestinal tract. In the series reported by Frank et al. [13], 96% had swelling of extremities, 93% had recurrent abdominal pain, 85% had angioedema of the face, and 64% had oropharyngeal involvement. Attacks involving the airway present the greatest threat. Obstruction generally begins slowly with voice change and dysphagia. Often it is preceded by peripheral swelling [13], but facial edema has also been reported as the initial presenting sign [52]. Although the differential diagnosis of airway and extremity swelling is quite extensive (Table 1), sudden airway compromise leading to the death of a relative should raise suspicion of HAE. Because HAE may also cause swelling during head and neck or dental surgery, the diagnosis should be made before these procedures are performed. Abdominal and orthopedic procedures may not trigger an attack unless the patient is also tracheally intubated, whereas dental surgery is more likely to provoke obstructive laryngeal edema in patients with C1 INH deficiency [13,45,53]. Frank et al. [13] reported life-threatening pharyngeal swelling after dental surgery in many patients with untreated HAE. In addition to swelling of the extremities and airway, the gastrointestinal tract is also vulnerable to attacks of HAE. Osler [2] wrote, "Associated with the edema, there is almost invariably gastrointestinal disturbance: colic, nausea, vomiting, and sometimes diarrhea." Unexplained episodic edema in a patient with recurrent abdominal pain or even ascites should raise suspicion of HAE [54]. Unfortunately, as noted above, the diagnosis is often missed, as exemplified by the case of one middle-aged woman who underwent almost 50 extensive evaluations for unexplained abdominal pain occurring almost bimonthly. It was not until HAE was diagnosed in her grandson during a military entrance examination that the etiology of her problem was finally determined [55]. One 52-yr-old man experienced three to four attacks of intermittent abdominal pain per year for 40 yr before HAE was diagnosed. Three exploratory laparotomies for presumed bowel obstruction had been performed during this period [52]. It should be emphasized that recurrent abdominal pain can be the sole manifestation of HAE [56]. Gastrointestinal distress may easily be misinterpreted as representing an acute abdomen, and HAE may be present in patients with a history of multiple negative abdominal operations [52,56,57]. Unexplained abdominal pain has historically led to narcotic use and dependence, as well as psychiatric diagnoses. The traditional name of hereditary angioneurotic edema reflects this presumed psychiatric component. However, major psychiatric illness may not be more frequent in patients with HAE than in the general population [45]. The abdominal pain caused by HAE is best characterized as crampy, colicky, and often excruciating [13,40]. Usually patients have diffuse abdominal tenderness characterized by normal to high-pitched bowel sounds without rigidity and peritoneal signs [12]. The pain may be secondary to intestinal obstruction caused by localized swelling [55], and the radiographic appearance is of stacked coins or a thumbprint [58]. Loss of fluid from the gut wall into the lumen may result in vomiting and copious accompanying watery diarrhea often late in the course of attack [12,45]. Diarrhea can be so severe as to cause hemoconcentration, hypotension, and shock [59]. Significant extraluminal intraperitoneal fluid sequestration can also develop [59]. Leukocytosis may be present [12,57]. Although attacks of HAE during pregnancy are unpredictable, the risk of an attack seems to decrease after the first trimester and during delivery [13]. When attacks occur, however, they are often accompanied by acute abdominal pain mimicking acute appendicitis or peritonitis. HAE should be considered in the differential diagnosis of acute abdominal pain in pregnant patients when no other cause is apparent [45,60]. Pregnancy may worsen symptoms of HAE, but the condition does not seem to adversely affect fetal viability. In one of all to term [44]. Most do not at patients with HAE may also have or especially and has been the HAE early of this disorder. This is because airway obstruction is the most common cause of it is important to C1 INH deficiency from other causes of and pharyngeal such as localized and swelling caused by HAE may slowly from of and to airway obstruction. One should not that airway compromise caused by HAE either or a and because airway compromise can also occur and be Osler [2] described by one death from a sudden edema of HAE in families and that most from acute laryngeal of secondary to acute laryngeal edema. The age at death was yr to In by the from acute airway obstruction was as as reported seven families afflicted with HAE in from acute airway edema, and each had a of abdominal pain, peripheral edema, and laryngeal edema. approximately one half to two of patients with HAE an of airway and may from laryngeal edema There is a of laryngeal symptoms in both hereditary and acquired of C1 INH in the facial laryngeal edema, [13]. et al. reported patients with HAE at the of 85% had of head and neck edema. was in only although symptoms of airway compromise present in more than obstruction was reported to have also seen airway obstruction to the of with C1 inhibitor described had been the patient likely have and are necessarily trauma during may worsen laryngeal edema and [45]. A patient described in an early case at two for HAE and from airway obstruction In 7 of the families by and [40], one or more from acute airway obstruction. In one three as of airway obstruction. One man a in the for to use should to the patient from an attack of HAE is not of C1 INH Deficiency to C1 INH Deficiency The only the of patients with C1 INH deficiency Therefore, describe the major that have been used to HAE and these are used acid an that inhibits plasminogen activation and plasmin activity, was thought to be in of HAE This probably by the formation of which can is not often used because it may cause hypotension, and In one however, use of decreased the and of symptoms in two patients with C1 inhibitor deficiency with no apparent or inhibitor of plasminogen activation and of has also been used in the of HAE It may limit the activation of C1, but it is used In demonstrated that with may be in the of HAE. Androgens such as and act by the of C1 INH by the liver are clearly in attacks but may cause serious including liver and [45]. have especially use of may also be in pregnant patients and secondary to [13]. is the and then as to control attacks. In the of that is prevents serious attacks but attacks as swelling of an to occur Patients should liver approximately plasma contains C1 INH but also contains the and C2 and that may complement activation also a risk of by blood Although and are the for C1 INH deficiency, C1 INH is one of the most for the C1 INH has been only in the its use that C1 INH can of symptoms 1 h and 24 C1 INH is from and the is can C1 INH levels by in C1 INH rapid and can be used to acute attacks. It may also be used for acute for which the of other is more lack of in the United States, the for and of or the C1 INH be to that it does not a C1 INH has not been by the and for use in the United and is only on an basis C1 INH can be and may be for approximately or perhaps during the of and for have also been described is to airway obstruction or when the of attacks is than or per and is severe to and have clearly been shown to attacks. A oral is or Patients with acquired C1 INH deficiency may than to patients with HAE. patients with HAE may be or C1 INH has been used alone or in with other is typically four a for before may be several or the before dental procedures when C1 INH is not In one dental procedures serious or life-threatening swelling in of untreated but when with of was 1 before dental no swelling was [13]. causes only a in C1 INH serum C1 INH levels decrease to levels days. of and should be for in which has not been and C1 INH is not its when C1 INH is for use in the United States, it probably be for in which is or The best for before an is C1 INH although this is an in the United of may be before an [13]. However, when is in this a attack may perhaps because contains C2 and and have not been shown to be when before an of Attacks attacks do not to with or in this are but it is important to be for The most seems to be C1 INH In in which C1 INH is not may be and C1 INH is for use in the United States, patients with HAE be with to the risk from an attack. Patients with a history of severe disease airway should be in a so that C1 INH can be used to life-threatening attacks. are also the have known that can inhibit complement in on both the classical and pathways of complement has been shown to the activity of C1 INH in vitro in are to the and of and in attacks of HAE. be to the airway of patients with HAE in three when the airway is not when or airway edema is and when airway swelling is In the or general can be performed The presence of angioedema does not for the of either general or regional or the use of including There are no known the use of of the It is important to of the airway as as by on regional or the for the and from and one important trigger for an attack. and reported the use of for a and reported a no form of and are and However, is not necessarily The of the laryngeal airway in the these patients is not but it is to that its may to airway edema. When is so is perhaps form of should also be There are no but the of for before surgery, as described above, and C1 INH is not before surgery are most often generally but they may not be This was by a of a of angioedema in a patient with HAE after who had been the before surgery with four and then C1 INH before Patients with HAE can usually be tracheally but they even after with and C1 INH the this is not generally Patients with HAE who are and One case describes a patient with acquired C1 INH deficiency with a C1 INH level of of normal who underwent during surgery these levels even and the patient of symptoms related to uncontrolled complement activation In contrast, in the C1 INH level increased to approximately of normal after and the patient underwent with a The limit for C1 INH is not but of normal has been When HAE attacks involve the airway, the may be called on to In of airway edema, symptoms can without usually a days. Patients should be in the may be and should be In a by is The use of is the patient the to even When and the of an is should a be The laryngeal airway has no or demonstrated in this the for laryngeal secondary to edema, probably be in most The presence of severe airway swelling and the for acute can limit the of of the airway is best performed in the in which full can most be This may not always be and the risk of from the to the be on the basis of the of of airway this risk is an should be performed without swelling may so severe that even may be in a may into the airway to such an that death is in the absence of (C1 INH