Abstract:

ACE inhibitors are in widespread use for the treatment of hypertension and are generally well
tolerated. Angioedema is an infrequent complication, but potentially life-threatening with
airway obstruction, that can occur at any time point after the initiation of ACE inhibitors.
Medical management of angioedema includes antihistamines and corticosteroids, while
endotracheal intubation or tracheostomy might be required to maintain airway integrity. The
purpose of this report is to discuss a 64 year-old female with a history of ACE inhibitor use who
presented with acute oral angioedema with blue discoloration of the tongue, tonsils,
hypopharynx and supraglottic larynx.

Cases of angioedema have been previously described in literature, but the blue discoloration
accompanying the condition has not yet been reported to our knowledge.

Introduction:
Angioedema, also known as Quinckes Disease, was first described in the 19th century as a
sudden-onset, often erythematous, localized swelling. Acquired angioedema is a rare
classification characterized by bradykinin-mediated edema secondary to angiotensin converting
enzyme blockade by ACE inhibitors. Angioedema may present at any time following initiation of
ACE inhibitors. Incidence rates are between 0.1-0.6% in ACE inhibitor users, with the best
estimated incidence reported by the Omapatrilat Cardiovascular Treatment Assessment Versus
Enalapril (OCTAVE) trial that reported an incidence rate of 0.68% in subjects on Enalapril.
Angioedema can present with hoarseness, dysphagia, odynophagia, drooling, and respiratory
distress. Since the head and neck are the most common areas affected by ACE inhibitor-induced
angioedema, airway compromise, especially with lingual involvement, presents a potentially life-
threatening clinical scenario.

The purpose of this presentation is to discuss a patient with an acute episode of angioedema
with blue discoloration of the tongue, lingual tonsils, hypopharyngeal region, and the
supraglottic larynx. ACE inhibitor use in cases of angioedema has been thoroughly documented,
but the accompanying blue discoloration found in our patient appears to be a novel finding with
no prior cases reported.

Case Report:

A 64 y/o morbidly obese African American female presented to our hospital due to acute
worsening of shortness of breath. Past medical history revealed longstanding COPD and chronic
respiratory failure on home oxygen, CHF, Diabetes Mellitus Type 2, dyslipidemia and
hypertension. Patient was found to have pulmonary edema and elevated troponins and
creatinine and was treated for CHF exacerbation and NSTEMI. Subsequently, patients CXR
improved, cardiac perfusion study showed no evidence of ischemic heart disease, and ECHO
showed an ejection fraction of 55%. Patients urine was found to be positive for yeast infection
and was treated with Diflucan.

Following empiric treatment and significant improvement in symptoms, patient was planned for
discharge when she developed macroglossia with blue discoloration extending to the arytenoids
and developed respiratory distress. She was transferred to the ICU and ENT consult was
arranged. Diflucan was stopped, and CT scan of the neck showed macroglossia and a mass at
the base of the tongue. An endoscopic biopsy specimen of the left lateral tongue revealed an
irregularly shaped, elliptical soft tissue mass with smooth mucosal surface covered by a
lobulated lesion measuring 1.8 x 0.9 cm. The mass revealed hemorrhage with extensive fibrosis,
reactive changes and focal adipose tissue without lipoblasts or atypical features.

A Congo-red stain was performed on the specimen and was found to be negative for the
presence of amyloid. The features of the mass were not typical of a classical lipoma, but were
correlated clinically.

Following the biopsy, the patient continued to experience dysphagia and respiratory distress
secondary to an occluded oropharyngeal airway. A Dobhoff tube was placed, and tube feeding
was begun. The patient was continued on low-dose steroids and Diflucan was restarted. Patients
macroglossia gradually resolved and her post-discharge clinic follow-up revealed no further
evidence of disease.

Discussion:
Angioedema is a sudden-onset swelling within the mucosa and submucosa of the head and neck
that can become life-threatening secondary to airway obstruction. The most common affected
area is the face followed by the oral cavity and tongue, pharynx and larynx. The four main causes
are C1 esterase inhibitor deficiency, IgE-mediated allergic reaction, idiopathy and ACE inhibitor
use. This can lead to venular inflammation and resultant fluid egress into the surrounding
subdermal area. Angioedema following the use of ACE inhibitors is an uncommon complication
but has been well documented in literature.

Angioedema is a product of a biphasic process in which the first phase is an early response due
to histamine and leukotriene release, followed by the second, delayed phase response to serum
kinins. ACE inhibitor use is linked to the second phase whereby blocking angiotensin II
formation leads to bradykinin accumulation and the subsequent increase in permeability of
blood vessels. Up to 0.68% of patients taking ACE inhibitors present with angioedema. Risk
factors include female gender, age above 65 years, African-Americans and history of smoking.
More recently, NSAIDs, aspirin and immunosuppressive medication use have also been
suggested as risk factors. Furthermore, polypharmacy has become a commonplace occurrence,
so drug interactions become an important issue in clinical practice. The -gliptin class of
hypoglycemic medications not only inhibits dipeptidyl peptidase 4 (DPP-4), but it also prevents
breakdown of bradykinins by DPP-4. Used in conjunction with ACE inhibitors, gliptin use has
been studied and proposed as a risk factor for development of angioedema.

Treatment with the greatest efficacy in preventing recurrences of episodes is discontinuation

of ACE inhibitors. While antihistamines, corticosteroids and bradykinin antagonists have
been proposed for use in angioedema, none of them have been established for therapy and lack
trials to judge efficacy. Surgery is not frequently required but airway integrity is first priority so
endotracheal intubation or tracheostomy can be performed to maintain the airway.

The link between ACE inhibitor use and angioedema is well-established in current literature. We
present a 64-year-old patient on an ACE inhibitor who suddenly exhibited acute angioedema
and discoloration of the tongue, lingual tonsils, hypopharynx and the supraglottic larynx. What
makes this case unique and informative for the clinician is the regional blue discoloration of
unknown etiology that accompanied the patients swelling which, to our knowledge, has not yet
been reported with oral angioedema.

Conclusion:
ACE inhibitor induced angioedema is an uncommon but well documented phenomenon.
Associated blue discoloration is a novel finding that can accompany an episode of angioedema in
the oropharynx and larynx. Maintaining the airway becomes important with laryngeal
involvement therefore it is imperative to have a low clinical threshold to perform endotracheal
intubation or tracheostomy to prevent airway compromise.