Case Presentation by Dr. Hannah Ferenchick, MD
Chief complaint: “My lip is swollen”
A 34-year-old man presents to the ED for lip swelling that has been present for several hours. The patient states that at work earlier today he was removing a car bumper. It came loose and popped up and hit the patient in the lip. At the time, the patient had no bleeding or pain in the area. However, 1-2 hours after this, the patient stated that his lip became irritated and then swollen. Patient states that for the last few hours his lip has stayed swollen. Patient denies pain in this area, trouble swallowing or trouble breathing. The patient states that for the last few months he has had periodic issues with swelling. He states he has swelling randomly occur on his side and under his arms. In addition, he has occasional scrotal swelling. These areas of swelling are self resolving. He has a history of hypertension, for which he previously was on lisinopril. However, his PCP switched him to amlodipine since these swelling episodes began. Patient denies any recent fevers, chills, chest pain, shortness of breath, abdominal pain, diarrhea, constipation, dysuria, penile discharge, headache, increased urination or thirst, hives or urticaria.
ROS: negative except as noted per HPI
PMH: Hx of hypertension
Meds: Amlodipine 5 mg BID
Allergies: No known medication allergies
SH: Drinks alcohol socially, denies cigarette smoking and illicit drug use
PE: vitals: T 98.7, HR 78, BP 156/89, RR 18, pulse ox 100% RA, weight 241, 5’ 9’’
General: Well-appearing, overweight male, appropriate for stated age, resting in bed comfortably, no acute distress
HEENT: Normocephalic, atraumatic. PERRLA. No erythema or exudates in posterior oropharynx. Patient’s upper lip is swollen and edematous, no erythema noted. No abrasions, lesions or urticaria noted. Tongue is non edematous, Mallampati grade II. No tracheal deviation or neck masses.
Cardio: RRR, S1 and S2 heard, no murmurs
Respiratory: Lungs clear to auscultation bilaterally
Abdomen: Soft, non tender, non distended. Positive bowel sounds
Musculoskeletal: +2 radial and DP pulses bilaterally. No pitting edema in lower extremities.
Skin: No rashes, hives or lesions noted
Neuro: Alert and orientated X3
1. Which of the following is the most likely diagnosis?
A. Allergic angioedema
B. Drug-induced angioedema
C. Hereditary angioedema
D. Idiopathic angioedema
2. Which of the following is considered an indication for screening for c1 inhibitor disorders?
A. Recurrent angioedema with urticaria
B. Recurrent unexplained episodes of colicky abdominal pain
C. History of angioedema with ACE-inhibitor use
D. History of refractory anaphylaxis
3. First line treatment of acute attacks of angioedema in adults with known c1-inhibitor deficiency includes which of the following?
A. 0.5 mg epipinephrine IM
B. Ranitidine 50 mg IV
C. C1-esterase inhibitor (Berinert®) 20 units/ kg
D. 2 units fresh frozen plasma
Answers and Discussion
1) The answer is C. The patient is having angioedema without related symptoms of a hypersensitivity reaction. Therefore, the most likely cause is a C1 inhibitor deficiency disorder, either hereditary angioedema or acquired C1 inhibitor deficiency (which is very rare and most commonly associated with lymphoproliferative disorders).
The patient has no signs of hypersensitivity reaction such as urticaria, wheezing or hypotension. Therefore, this is not likely due to an allergic-type reaction. The patient was taking lisinopril, which is known to cause angioedema due to the inhibition of ACE, and subsequent increased production of bradykinin. However, the patient stopped his ACE-I and continued to have symptoms which makes this diagnosis less likely. Finally, idiopathic angioedema is a diagnosis of exclusion.
2) The answer is B. GI attacks in hereditary angioedema (HAE) present as intermittent episodes of GI colic, nausea, vomiting and diarrhea. These symptoms result from bowel wall edema. GI attacks are experienced by most patients with HAE and may be the only presenting symptoms in up to ¼th of these patients. The presence of urticaria is associated with allergic angioedema, which is caused by hypersensitivity reactions. These are triggered by common allergens and rarely physical stimuli such as trauma or temperature changes. The inhibition of angiotensin-converting enzyme by ACE-inhibitors results in decreased metabolism of substance P and bradykinin, which contributes to tissue inflammation and can lead to angioedema. These patients often tolerate ARBs well. Refractory anaphylactic shock may require a continuous infusion of epipinephrine in the treatment if intramuscular epipinephine and volume expansion with normal saline have not succeeded in normalizing vital signs. However, it is not an indication for HAE screening.
3) The answer is C. Cinryze and berinert are C1 inhibitor concentrates derived from plasma. They are among first line therapies for C1 inhibitor deficiency angioedema. Other medications that are also considered first line include icatibant, which is a synthetic bradykinin receptor antagonist and ecallantide, a recombinant plasma kallikrein inhibitor that blocks the production of bradykinin by inhibiting plasma kallikrein. It is approved in US for treatment of acute attacks of HAE in patients 16 yrs and older. Cinreyze is technically not FDA approved for acute angioedema attacks, but is being has been used in Europe with success. IM epinephrine is typically not thought to be helpful in C1-inhibitor deficiency cases. It does not address the known pathophysiologic mechanism of underlying C1ID, although it may help decrease mucosal edema. It is considered first line in the treatment of allergic angioedema. H2 antihistamines are indicated in the treatment of allergic angioedema. Finally, FFP has c1 inhibitor and has been reported to be effective in acute attacks. It is considered 2nd line in treatment of HAE, to be used when first line medications are not available.
The differential diagnosis for this patient includes allergic reaction/anaphylaxis, drug-induced angioedema, allergic contact dermatitis, hereditary angioedema, acquired C1-esterase deficiency angioedema and idiopathic angioedema. Allergic reactions and anaphylaxis often present with systemic symptoms involving multiple organ systems simultaneously, such as wheezing, urticaria, and hypotension. The patient does not exhibit any of these, which makes this diagnosis unlikely. Drug induced angioedema is associated with ACE-inhibitors and NSAIDs. However, the patient had stopped his ACE-inhibitor without resolution of his angioedema. Allergic contact dermatitis often presents as erythematous, scaly plaques and occurs in association with cosmetic and topical pharmaceuticals. Idiopathic angioedema is a diagnosis of exclusion and therefore not appropriate in this case. The most likely cause of this patient’s presentation is a bradykinin-induced angioedema, either hereditary angioedema or acquired C1-esterase deficiency.
Angioedema results from vasodilation and edema of the deeper dermal and subcutaneous layers of the skin. The skin may appear normal color or pink due to the swelling being located in deeper layers of the skin. Angioedema may cause pain and is not necessarily associated with pruritus. The majority of angioedema is caused by hypersensitivity reactions commonly triggered by allergens, referred to as allergic angioedema (or mast cell mediated angioedema). Mast-cell mediated angioedema often presents with other systemic signs of mast cell mediator release: urticaria, pruritus, bronchospasm, and hypotension. The patient had none of these symptoms; therefore the most likely cause of this patient’s presentation is a bradykinin-induced angioedema. These are nonallergic types of angioedema and are caused by bradykinin excess. The distinction between mast-cell mediated angioedema and bradykinin induced angioedema is crucial for treatment and management of the disease. The causes of bradykinin-induced angioedema include hereditary angioedema (HAE), acquired C1 inhibitor deficiency and ACE inhibitors. In the case of HAE and ACID, the deficiency of C1 inhibitor results in increased bradykinin levels. These types of angioedema do not respond to the typical treatments for allergic hypersensitivity reactions such as steroids, antihistamines and IM epipinephrine. As always, early airway stabilization is key in management.
Although this patient was not currently demonstrating any signs of airway compromise, ENT was consulted in the emergency department. They did a bedside bronchoscopy, which showed some signs of edema at the base of the tongue. Therefore, they recommended that the patient be observed in the ICU for 24 hours, with a low threshold for intubation and cricothyroidotomy tray at bedside. Patient was given methylprednisone 125 mg IV, zantac 25 mg IV and Benadryl 25 mg IV push in the emergency department and was admitted to the ICU. Patient was given Decadron 10 mg q8hr, zantac 50 mg Q8 hours and Benadryl 50 mg IV Q8 hours. Patient did well overnight, with no signs of airway compromise. Repeat bronchoscopy was done the following day which showed significant improvement in edema. Therefore, patient was cleared by ENT and discharged home with a 5-7 day course of Zantac and Benadryl, as well as a prescription for Medrol dose pack and close follow-up with allergy/immunology for evaluation of possible genetic or environmental causes of his angioedema.
Atkinson, JP., Cicardi, M, Zuraw, B. Hereditary angioedema: Treatment of acute attacks. In: UpToDate, Saini S (Ed), UpToDate, Waltham, MA, 2013.
Atkinson, JP., Cicardi, M, Zuraw, B. Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis. In: UpToDate, Saini S (Ed), UpToDate, Waltham, MA, 2013.
Cicardi, M. Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis. In: UpToDate, Saini S (Ed), UpToDate, Waltham, MA, 2013.
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