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Radiologic manifestations of angioedema
Insights into Imaging volume 5, pages 365–374 (2014)
The purpose of this pictorial review is to present imaging findings of angioedema involving the various organs.
The role of imaging for patients with angioedema includes the evaluation of the upper airway for obstruction and the exclusion of other possible aetiologies, such as neoplastic or infectious processes. Glossomegaly is a common finding of head and neck angioedema. Angioedema may involve organ systems beyond the superficial regions and the head and neck including the gastrointestinal and genitourinary tracts. Angioedema of the visceral organs is often accompanied by adjacent fluid, and it is commonly diffuse or concentric but can also be multifocal and asymmetric.
The evaluation of the upper airway obstruction is important for head and neck angioedema.
Glossomegaly with decreased attenuation is common in head and neck angioedema.
Angioedema of the visceral organs can be multifocal and asymmetric.
Angioedema of the visceral organs is often accompanied by adjacent fluid.
It is important to include clinical and laboratory findings for the diagnosis of angioedema.
Angioedema was first described by J.L. Milton in 1876. First named angioneurotic oedema by Quinckein 1882, it is sometimes referred to as Quincke’s oedema [1, 2]. There are various causes of angioedema . The incidence of angioedema varies with its causes. For example, the estimated incidence of angiotensin-converting enzyme (ACE) inhibitor-induced angioedema is 0.1 to 1.0 %  and that of hereditary angioedema (HAE) ranges from 0.002 to 0.01 % . It is clinically characterised as episodic localised and transient oedematous swelling, most commonly affecting superficial regions such as the face, genitals, and extremities. If angioedema only affected the superficial regions, imaging evaluation would not be necessary. Angioedema, however, may affect any part of the body, and intra-abdominal involvement can even occur without cutaneous involvement [3, 6, 7]. Angioedema can also present with life-threatening respiratory distress when the upper airway is involved . Angioedema involving the gastrointestinal tract may present as an acute abdominal pain resulting in unnecessary laparotomy [2, 9]. Although the diagnosis of angioedema is clinical, awareness of this entity and its characteristic imaging findings by radiologists will aid in raising the suspicion for angioedema, which may warrant further clinical workup and prevent unnecessary surgery. Additionally, for patients with known previous history of angioedema who have abdominal pain, contrast-enhanced CT of the abdomen and pelvis is the study of choice to evaluate for possible visceral involvement as well as to rule out other pathology.
The purpose of this pictorial review is to present imaging findings of angioedema involving the various organs. Differential diagnoses and complications of angioedema are discussed.
Classification and pathogenesis of angioedema
Classification of angioedema is summarised in Table 1.
The majority of cases of angioedema are idiopathic. When a trigger is identified, most often it is a medication, allergen, or a physical agent such as pressure or cold . Many medications can cause angioedema but those most commonly implicated are angiotensin-converting enzyme (ACE) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) .
A less common, but important cause of angioedema is deficiency or inactivation of C1 esterase inhibitor (C1-INH) in the complement system, which can be either hereditary  or acquired . Hereditary angioedema (HAE) is autosomal dominant, and is classified into three types [5, 10]. Acquired angioedema (AAE), a very rare condition is associated mainly with lymphoproliferative disorders and autoimmune diseases .
The mechanism of angioedema is the overproduction or failure to inactivate vasoactive stimulants such as histamine, bradykinin, and leukotrienes (Table 1), which lead to increased vascular permeability. Allergen-induced angioedema is due to histamine mediated by immunoglobulin E (IgE) [2, 3]. ACE inhibitor-induced angioedema is not entirely understood, but it is postulated that the use of ACE inhibitors increases bradykinin levels [2, 3], which is a potent vasodilator. Given the estimated incidence of ACE inhibitor-induced angioedema of 0.1 to 1.0 %  and the large number of patients on ACE inhibitors, one theory is that affected individuals have an underlying partial deficiency of C-1 esterase . NSAIDs inhibit cyclooxygenase 1 (Cox 1), which results in overproduction of leukotrienes . HAE types 1 and 2 and AAE (deficiency or inactivation of C1-INH) are characterised by uncontrolled complement activation and resultant increased bradykinin production [2, 3, 5, 10]. In addition, a rare form of HAE (type 3) mainly noted in female patients is associated with a mutation in the coagulation factor XII gene , which also ultimately results in increased levels of bradykinin.
Angioedema attacks can last from 1 to 5 days depending on the causes and symptoms . Importantly, acute attacks of HAE and AAE do not respond to epinephrine, antihistamines, or steroid . Consequently, treatment is often mainly supportive, consisting of intravenous fluids and upper airway management. Allergen and drug induced angioedema are treated with elimination of causative agents [2, 12]. For acute attacks of HAE and AAE, C1-INH concentrate, kallikrein inhibitor ecallantide, bradykinin B2 antagonist icatibant, or fresh frozen plasma are administered [2, 3, 9, 10].
Head and neck
Upper airway obstruction can be a life-threatening complication from angioedema. In emergent cases, airway management precludes imaging. In less urgent cases, lateral plain radiograph of the neck could be used for the initial imaging assessment (Fig. 1). On plain film, care should be paid to the presence or absence of swelling of the retropharyngeal soft tissue, epiglottis, aryepiglottic folds, and soft palate . Computed tomography (CT)—with lateral scanogram of the neck and multiplanar reformatted (MPR) images—is also useful in the evaluation upper airway obstruction (Fig. 2).
On CT, facial or neck swelling with subcutaneous fat stranding is occasionally recognised (Figs. 3 and 4). The swelling is usually diffuse but can be focal or asymmetric. Similarly, narrowing of the upper airway and tongue swelling can be focal or asymmetric (Figs. 2 and 5). Glossomegaly (swelling of the tongue) is a common finding of angioedema (Figs. 6 and 7), with isolated glossomegaly reportedly more common in patients with ACE inhibitor-induced angioedema than HAE .
The differential diagnosis of upper airway obstruction includes neoplasms, parapharyngeal abscess, and infection (e.g., tonsillitis, laryngitis, and cellulitis) and these should be excluded by the imaging findings, laboratory data, clinical course, and laryngoscopy [14, 15]. Glossomegaly may also be seen in patients with amyloidosis (Fig. 8). Angioedema-induced glossomegaly typically shows a low-density tongue, while the one caused by amyloidosis shows soft tissue density. In addition, angioedema has an acute onset with short duration whereas amyloidosis is chronic.
Although it is rare, cases of central nervous system involvement have been reported in patients with HAE and ACE inhibitor-induced angioedema [16–18]. Imaging findings vary from unremarkable to extensive white matter oedema [16–18].
Gastrointestinal involvement can be seen in HAE, AAE, and ACE inhibitor-induced angioedema [2, 7, 9, 19, 20] (Figs. 9, 10, and 11). In addition, a case of small bowel angioedema triggered by intravenous iodinated contrast medium has been reported . Gastrointestinal involvement of angioedema clinically presents as acute abdominal pain, nausea, vomiting, diarrhea, and various degrees of obstruction. A flare of angioedema can even predispose patients to acute pancreatitis likely because of duct obstruction and/or oedema of the ampulla of Vater  (Figs. 10 and 12).
Abdominal radiographs are of limited value for the evaluation of abdominal involvement of angioedema. Contrast-enhanced CT is the imaging modality of choice for patients with possible angioedema involving the gastrointestinal tracts. MPR of the involved bowel can show mural stratification or the halo sign because of a thickened low-density submucosal layer reflecting submucosal oedema with mucosal and subserosal enhancement (Fig. 11) [7, 20]. Involved small bowel folds show regular thickening with low density (Figs. 9 and 11). This finding has also been likened to a stack of coins on barium studies because of the uniformly thickened folds with a relatively parallel arrangement  (Fig. 11). Oedematous bowel wall thickening is commonly accompanied by adjacent free fluid (Figs. 9 and 10). It should be emphasised that wall thickening may not always be circumferential and may be asymmetric (Fig. 10). In addition, gastrointestinal involvement can be multifocal (Fig. 11). Oral contrast is not necessary in emergent situations and also may obscure mural stratification of the involved bowel wall .
Angioedema attacks can last from 1 to 5 days without treatment , and intestinal angioedema typically subsides in 12–24 h . Recurrent episodes of unexplained acute abdominal pain (e.g., three or more episodes within 3–6 months ) and the imaging finding of oedematous bowel wall thickening may warrant an initial workup for angioedema including detailed family and medication (e.g., ACE inhibitors) histories and laboratory evaluation of the complementary system. Although imaging follow-up may not usually be indicated, complete remission of abnormal imaging findings may support the clinical diagnosis of angioedema, and vice versa.
Differential diagnoses of gastrointestinal angioedema consist of other pathologies that may cause bowel wall oedema, including ischaemia, vasculitis, and hypoproteinaemia [7, 23]. Since there are numerous entities that may present as mural stratification or the halo sign, the diagnostic approach is based on the exclusion of other potential causes clinically and radiologically. For example, it is possible to suggest venous ischaemia based on the presence of mesenteric venous thrombus (Fig. 13). However, making the differential diagnosis of intestinal angioedema versus non-occlusive mesenteric ischaemia may be difficult based solely on imaging findings because both entities show a halo sign without mesenteric fat stranding . In non-occlusive mesenteric ischaemia, diffuse narrowing of mesenteric arterial branches may be recognised , and patients with non-occlusive mesenteric ischaemia present clinically with hypovolaemia, hypotension, and low cardiac output . Associated skin findings may be recognised in patients with vasculitis such as lupus enteritis and Henoch-Schönlein purpura [7, 26]. In Crohn’s enteritis, mesenteric fat stranding, engorgement of vasa recta (comb sign), luminal narrowing, and the degree of wall enhancement are more striking than intestinal angioedema (Fig. 14). Additionally, the presence of fistula, abscess, and findings to suggest coexisting chronic inflammation such as submucosal fatty infiltration and creeping fat may be helpful for the differential diagnosis. Furthermore, clinical history and laboratory data can exclude radiation enteritis, hypoproteinaemia, portal hypertensive enteropathy, and infection.
Genitourinary involvement may be rarely encountered. The clinical symptom of renal involvement may simulate renal colic . Urinary bladder involvement clinically presents as lower abdominal pain, urinary stammering, and urinary bladder retention . Similar to gastrointestinal involvement of angioedema, renal and urinary bladder involvement can show oedematous wall thickening with adjacent fluid (Figs. 7 and 10). Although imaging findings may mimic those of urinary tract infection, it is possible to exclude this by clinical symptoms and urinalysis.
Pulmonary involvement of angioedema has not been well documented. A case of acute respiratory distress syndrome has been reported . Chest symptoms may be associated with upper airway obstruction or oesophageal involvement such as breathing or swallowing difficulties . Chest radiographs are utilised for the monitoring of endotracheal tube placement, lung aeration, and the presence or absence of pleural effusion and air space diseases.
The major role of imaging of angioedema in the head and neck is to evaluate for the presence of upper airway obstruction and exclusion of other causes. Glossomegaly with low attenuation is commonly present in head and neck angioedema. Angioedema may involve the gastrointestinal tracts and more rarely the genitourinary system. Angioedema of the visceral organs is often accompanied by adjacent fluid, and the involvement may be multifocal or asymmetric (may not always be diffuse or concentric). As the clinical presentation can mimic surgical and inflammatory causes of abdominal pain, the exclusion of these aetiologies is an important role in the imaging evaluation for visceral organ involvements in patients who present with angioedema in any organ system.
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Ishigami, K., Averill, S.L., Pollard, J.H. et al. Radiologic manifestations of angioedema. Insights Imaging 5, 365–374 (2014). https://doi.org/10.1007/s13244-014-0329-1
- Upper airway obstruction
- Head and neck angioedema
- Visceral angioedema