Emerg Radiol DOI 10.1007/s10140-014-1242-0

PICTORIAL ESSAY

Hereditary angioedema: imaging manifestations and clinical management Mandip S. Gakhal & Gregory V. Marcotte

Received: 16 April 2014 / Accepted: 19 May 2014 # Am Soc Emergency Radiol 2014

Abstract Hereditary angioedema is a genetic disorder typically related to insufficient or dysfunctional C1-esterase inhibitor. Patients present with episodic swelling of various body parts, such as the face, neck, bowel, genitals, and extremities. Acute or severe symptoms can lead to patients presenting to the emergency room, particularly when the neck and abdominopelvic regions are affected, which is often accompanied by radiologic imaging evaluation. Patients with hereditary angioedema can pose a diagnostic challenge for emergency department physicians and radiologists at initial presentation, and the correct diagnosis may be missed or delayed, due to lack of clinical awareness of the disease or lack of its consideration in the radiologic differential diagnosis. Timely diagnosis of hereditary angioedema and rapid initiation of appropriate therapy can avoid potentially lifethreatening complications. This article focuses on the spectrum of common and characteristic acute imaging manifestations of hereditary angioedema and provides an update on important recent developments in its clinical management and treatment. Keywords Hereditary angioedema . Diagnostic imaging . Computed tomography . Magnetic resonance imaging . Angioedema . Treatment . Therapy

Introduction Hereditary angioedema (HAE) affects approximately 1 in 50,000 to 100,000 patients, and has been classified into three types. In type I HAE, which accounts for approximately 85 % M. S. Gakhal (*) : G. V. Marcotte Christiana Care Health System, 4755 Ogletown-Stanton Rd, Newark, DE 19718, USA e-mail: [email protected]

of patients, and is the focus of this article, there is a defective allele expression, and thus deficient amount of C1-esterase inhibitor. In type II HAE, the C1-esterase inhibitor levels are normal or increased, but it is dysfunctional. Type III HAE occurs rarely; its pathophysiology is poorly understood, with symptoms despite normal C1-esterase levels and function, has a female predominance, and can be exacerbated by estrogen [1]. Hundreds of mutations have been described in the C1esterase inhibitor gene, with autosomal dominant inheritance in approximately 75 % of patients, and de novo occurrence without a family history in approximately 25 % of patients [2].

Pathophysiology, clinical presentation, and diagnosis C1-esterase inhibitor regulates pathways of complement activation, the contact system, and the intrinsic coagulation pathway. C1-esterase inhibitor has the ability to inhibit several proteases. Lack of C1-esterase inhibitor function results in uncontrolled activation of activated C1 and associated consumption of C4 and C2. Resultant increased bradykinin is thought to be a key mediator leading to the development of HAE. Bradykinin is a vasodilator and increases vascular permeability [1]. HAE symptoms are episodic, with variable frequency, and most commonly involve swelling of the subcutaneous or submucosal tissues in the extremities, face, oropharynx, larynx, gastrointestinal tract, genitals, buttocks, and trunk. Approximately half of patients become symptomatic by age of 10 and another third by age of 20 years. In two-thirds of patients, there is a family history of the disease. Symptoms can last from a few hours to a few days. There is considerable variation in frequency of attacks of HAE between different patients and in the same patient. Emotional stress and any type of trauma can trigger HAE, including any surgical procedure or prolonged repetitive activity [1]. Lack of urticaria, presence

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of abdominal symptoms, family history, and relatively slow evolution of symptoms distinguishes HAE from allergic or anaphylactic angioedema and urticarial vasculitis [3]. Prodromal symptoms may be present before attacks and include erythema marginatum, rash, severe fatigue, myalgia, arthralgia, abdominal cramps, and local numbness, tingling, and discomfort at the site of attack [3]. Half of patients with HAE have had at least one episode of laryngeal edema. Laryngeal edema can be life-threatening and, in the past, has been a major cause of death in patients with HAE. Abdominopelvic episodes of HAE may involve the duodenum, small bowel, or colon with variable degrees of abdominal pain, nausea, vomiting, ascites, and diarrhea [1]. Despite its episodic nature, the disease can have a substantial negative impact on the social life, family, and employment of affected patients. Clinical features alone can often lead to the diagnosis of HAE, assuming that the entity is considered in the differential diagnosis by the clinician. Laboratory tests used in the diagnosis of HAE include C1-esterase inhibitor concentration, C1esterase inhibitor function, and C4 level. In type I hereditary angioedema, C1-esterase inhibitor levels and function are decreased. In type II hereditary angioedema, C1-esterase inhibitor level is normal or increased, and C1-esterase inhibitor function is decreased. C4 is decreased in both types I and II HAE. Obtaining C1q level can be useful as it is normal in HAE but decreased in acquired forms of angioedema [1].

Imaging of hereditary angioedema Patients with established diagnosis of HAE may undergo imaging for acute symptoms involving the neck to define the Fig. 1 A 30-year-old female with HAE presented with throat swelling and difficult swallowing. Lateral radiograph (a) shows extensive swelling of the cervical prevertebral soft tissues (arrows in a). Correlative axial (b) CT image also demonstrates diffuse low attenuation and soft tissue edema in the prevertebral region (arrows in b), but no organized or drainable fluid collection

degree of airway compromise from soft tissue swelling, but at initial presentation, the differential diagnosis includes other processes such as abscess and tumor. HAE affecting the abdomen and pelvis, usually involving the bowel, can present as a surgical abdomen and be indistinguishable from other emergent conditions such as appendicitis, bowel obstruction, and diverticulitis, thus often triggering imaging evaluation, initially via X-rays and followed by computed tomography (CT), to exclude other potential etiologies as the source of patient symptoms. In pediatric patients, ultrasound may be done as the next imaging study, as an alternative to CT. Notably, the imaging manifestations are only present when the patient has acute symptoms, and radiologic studies will be falsely negative if done too early or too late relative of the peak of symptom severity. Imaging findings in HAE can be similar to angioedema from other etiologies such as angiotensinconverting enzyme inhibitor therapy [4]. Edema of the larynx and oropharynx, as well as prevertebral soft tissue swelling can be detected on radiographs, CT scans, and MRI examinations (Fig. 1). Lack of abscess, lack of pathologic adenopathy, and absence of focal soft tissue mass are other factors that can imply angioedema as the underlying etiology. Facial soft tissue edema is apparent clinically, but if it occurs in conjunction with neck or airway swelling, it can be coincidentally depicted on radiographic studies (Fig. 2). Radiographs and conventional barium studies may demonstrate thumbprinting due to bowel wall thickening in HAE. Bowel lumen narrowing or occasionally bowel distention can be present. Computed tomography (CT) and magnetic resonance imaging (MRI) manifestations of angioedema can include bowel wall thickening, mural enhancement, target sign from mucosal, and muscularis propria hyperemia with relative

Emerg Radiol Fig. 2 A 23-year-old female with acute episode of HAE presented with facial swelling. Axial (a and b) MR images demonstrate swelling and edema in the anterior facial soft tissues (arrows in a and b)

lower attenuation of the submucosa, mesenteric edema, retroperitoneal edema, omental edema and thickening, ascites, prominent mesenteric vessels, fluid accumulation in the lumen of the affected segment, and bowel dilation [5]. Circumferential uniform mural thickening of bowel, but with preservation of the normal mucosal fold pattern, and stacked coin appearance can be a clue to the diagnosis. Also, if rapid complete Fig. 3 A 56-year-old male presented with abdominal pain, nausea, and vomiting. Axial (a) and coronal (b) CT images demonstrate extensive mural thickening of a segment of the duodenum (arrows in a) and jejunum (large arrow in b) with preservation of the normal fold pattern, and small amount of adjacent fluid and edema (small arrow in b). Axial (c) and coronal (d) T2-weighted single-shot MR images acquired 1 day after the CT study demonstrate near complete resolution of the mural thickening in the duodenum (arrows in c) and jejunum (arrows in d). In this instance, the imaging documentation of rapid reversal of the abnormalities led to the prospective radiologic diagnosis of hereditary angioedema, which was subsequently confirmed with further clinical workup and laboratory tests

resolution of the findings is documented on imaging, in the time frame of hours or 1 to 2 days, it is highly suggestive of angioedema and does not occur with other entities such as bowel infection and primary inflammatory bowel disease (Fig. 3). The jejunum and duodenum are the most frequently affected bowel segments, with the colon, ileum, and stomach involved much less frequently (Figs. 4, 5, 6, 7, and 8) [5]. The

Emerg Radiol Fig. 4 Two examples of hereditary angioedema affecting the jejunum. Axial (a and b) and coronal (c) CT images from a 41year-old female with abdominal pain reveal jejunal mural thickening (arrowheads in a, b, and c) and ascites (small arrows in a and c). Axial (d and e) images from a 25-year-old female with HAE demonstrate localized wall thickening in a segment of the jejunum (arrow in d and e)

gastrointestinal tract represents the only site of involvement by HAE in up to 21 % of patients [6]. Subcutaneous edema and swelling of the abdominal and pelvic wall, if present, can

be readily seen on both CT and MRI examinations. Swelling of the genitals and abdominal wall can be demonstrated on imaging examinations done for gastrointestinal symptoms if it

Fig. 5 A 44-year-old female with acute abdominal pain and HAE involving the duodenum. Axial (a) CT image shows mural thickening of the duodenum (arrowhead) with a small amount of ascites (small

arrows). Axial (b) CT image of the same patient from examination performed 2 months earlier demonstrates the duodenum in its normal state for comparison (arrowhead)

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Fig. 6 A 23-year-old female with HAE affecting the colon. Axial (a and b) CT images demonstrate mural thickening in portions of the transverse colon (white arrow in a), descending colon (black arrow in a), and the

Fig. 7 Hereditary angioedema involving ileum in a 48-year-old female. Axial CT image demonstrates a short segment of ileal mural thickening (arrowhead) accompanied by mesenteric edema and fluid (small arrows)

occurs at the same time, or those regions may be specifically evaluated on the basis of clinical suspicion for other inflammatory or infectious process (Fig. 9). In some cases, mesenteric fluid, mesenteric edema, and ascites may be the only manifestations of the HAE without any discernible involvement of bowel or other organs (Fig. 10). Since patients with HAE often present to the ER with symptoms resembling a surgical abdomen, they are not only at risk for undergoing unnecessary surgical procedure but also at risk for multiple repeat CT examinations, and thus potentially high exposure to ionizing radiation. If the diagnosis has already been established, but based on clinical evaluation Fig. 8 A 27-year-old female with HAE affecting the stomach. Axial (a and b) T2-weighted MR images demonstrate gastric mural thickening and mural edema (arrow in a and b) and perigastric fluid (arrowhead in a and b)

sigmoid colon (white arrows in b). Axial (c) T2-weighted MR image acquired 4 years later demonstrates mural edema, mural thickening, and minimal pericolonic fluid, at the hepatic flexure of the colon (arrows in c)

further imaging is required, a MRI examination should be considered as an alternative to CT. Detection of most of the aforementioned abnormalities with ultrasound during acute episodes of HAE has been reported, but given the potential for low sensitivity in adults, ultrasound is more suitable as an initial examination in pediatric patients [7, 8]. Rare cases of hereditary angioedema involving unusual sites have been reported. These include pleural involvement resulting in pleuritic symptoms and cough with radiographically documented transient pleural effusions [9]. Pancreas and liver involvement, leading to pancreatitis and hepatitis, have been reported (Fig. 11) [10]. Occurrence of seizures and hemiparesis attributable to cerebral edema has been reported [9]. Intracranial edema in the parasellar region has been documented on CT, in conjunction with severe neurologic symptoms that rapidly reversed with intravenous C1 inhibitor administration [11]. Cases of urinary bladder involvement and urethral involvement, with urinary tract symptoms, have been published (Fig. 12) [12, 13]. HAE symptoms referable to muscles, joints, kidneys, chest, and esophagus have also been reported. Abnormalities occurring in the aforementioned rare sites can also be potentially detected on MRI or CT examinations. Clinical management and treatment of hereditary angioedema HAE is an episodic disease. Patients can be asymptomatic for days, months, or years between attacks. Avoidance of triggers is recommended, and the most common triggers are trauma

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Fig. 9 A 46-year-old female with HAE presented with abdominal pain. Axial (a and b) and coronal (c) CT images demonstrate hereditary angioedema affecting the left anterior abdominal wall subcutaneous adipose tissues with edema and planar fluid (arrows in a, b, and c), along

Fig. 10 A 49-year-old female with nausea and abdominal pain. Transverse CT image demonstrates localized mesenteric edema and fluid (arrowhead) and ascites (arrows) as the only manifestations of acute episode of HAE, with no visceral organ involvement

Fig. 11 HAE affecting the pancreas in a 26-year-old female. Axial (a) MR image demonstrates mild enlargement of the pancreas with interstitial edema and small amount of peripancreatic edema and linear fluid consistent with acute pancreatitis (arrows in a). Axial (b) CT image from

with involvement of the ascending and transverse colon manifesting as mural thickening (arrowheads in a, b, and c), accompanied by mild ascites (small arrows in b and c)

and emotional stress. Angiotensin-converting enzyme inhibitors increase bradykinin levels and should be avoided. Contraceptives and hormone replacement therapy can increase disease severity and should be used cautiously. HAE therapies are traditionally thought of in three broad categories: acute therapies, long-term prophylactic therapies, and short-term prophylactic therapies [14]. Acute angioedema (non-HAE) patients are traditionally treated with H1- and H2-receptor blockers and corticosteroids. These will have no effect on HAE types I and II since bradykinin, not histamine, is the mediator causing the edema. Epinephrine is very effective for angioedema but of limited value for HAE. Therapy must stop the action of bradykinin, either by blocking its production or blocking its receptors. One of the actions of C1 esterase inhibitor (C1-INH) is to block the production of bradykinin [15]. Fresh frozen plasma (FFP), which contains C1-INH, is a treatment for acute attacks. However, FFP also contains other bradykinin precursors, so there are reports of FFP-exacerbating attacks [14]. FFP also carries the risk of blood-borne infections. Tranexamic acid and aminocaproic acid, antifibrinolytic agents, have been used

another episode of HAE pancreatitis demonstrates edema and linear fluid around the pancreatic tail region (arrows in b). This patient had no other plausible etiology for the recurrent episodes of pancreatitis

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Fig. 12 A 47-year-old female with known HAE presented with pelvic and abdominal pain with initial clinical diagnosis of urinary tract infection and infectious cystitis. The urinalysis and culture results were negative for infection, but the CT examination demonstrated urinary bladder wall thickening with mild edema in the surrounding fat planes, consistent with hereditary angioedema involving the bladder (arrows)

for acute attacks but carry the risk of hypercoagulability. All of these older agents are less expensive but have more side effects. Of course, supportive care such as intravenous fluids, pain control, and airway management is used to manage symptoms [16–18]. Newer, more expensive agents for acute attacks include purified plasma-derived human C1-INH (Berinert), the kallikrein inhibitor ecallantide (Kalbitor), and the bradykinin-receptor blocker icatibant (Firazyr) [19, 20]. Purified plasma-derived human C1-INH (Berinert) is administered intravenously and replaces the missing C1INH, decreases bradykinin production, and aborts acute attacks. Side effects include a theoretical risk of bloodborne illness, but other side effects are rare. Ecallantide (Kalbitor) is a molecule that is administered subcutaneously and blocks kallikrein, an upstream step in bradykinin production, thereby treating acute attacks. Side effects include reports of anaphylaxis, so it is recommended that the dose be given by a health care professional and that the patient be observed for 1 h after the dose. Finally, there is the subcutaneously administered icatibant (Firazyr) which aborts acute attacks by blocking the bradykinin receptor directly. Side effects include pain and swelling at the injection site [19, 21]. Long-term prophylaxis is required for patients with more frequent attacks. Attenuated androgens such as danazol, stanazolol, and oxandrolone have been used for decades as prophylaxis. Baseline low C1-INH and C4 levels can be shown to rise with therapy. Problems include lack of efficacy for some patients, virilizing side effects that are often unacceptable to women, hepatotoxicity, and other side effects including menstrual abnormalities, acne, altered libido, mood alteration,

hypertension, and lipid abnormalities [14, 18]. Purified plasma-derived human C1-INH (Cinryze) was approved for twice weekly infusion and significantly decreases the number of attacks in HAE patients. Of note, both Cinryze and Berinert are purified plasma-derived human C1-INH products, made by different manufacturers and given different FDA-approved indications: acute attacks only for Berinert (weight-based dosing, 20 units per kilogram) and prophylaxis only for Cinryze (dosed at 1,000 units twice per week, regardless of weight) [20, 21]. Short-term prophylaxis therapy is given prior to surgeries or dental procedures which are known precipitants for attacks. There are no FDA-approved products for short-term prophylaxis. High-dose anabolic androgen 1 week before surgery can produce modest results. There are reports of FFP or purified plasma-derived human C1-INH administered several hours before the procedure being helpful [22].

Conclusion An abnormal imaging examination in a patient presenting to the emergency room with acute symptoms can be the first clue to the presence of hereditary angioedema, which requires awareness of this entity and inclusion in the differential diagnosis. A timely diagnosis in the setting of recent development of effective therapies leads to optimized care for patients with hereditary angioedema.

Conflict of interest The authors declare that they have no conflict of interest.

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Hereditary angioedema: imaging manifestations and clinical management.

Hereditary angioedema is a genetic disorder typically related to insufficient or dysfunctional C1-esterase inhibitor. Patients present with episodic s...
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