Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU
A 58-year-old Caucasian male with past medical history of hypertension (on ACE-inhibor and HCTZ) and diverticulosis was referred to our clinic for work-up of angioedema.
Past medical history (PMH)
Hypertension and diverticulosis.
Two months ago, he developed severe abdominal pain after returning from a trip to Ecuador. He was hospitalized and had an EGD which showed erosions, swelling and edema in the area of the esophagus and stomach. He was placed on PPI. Pancreatitis, cholecystitis and hepatitis were ruled out. Hydrochlorothiazide (HCTZ) and Advil were stopped. He was discharged home only to be readmitted 10 days later with abdominal pain and small bowel obstruction (SBO). Altace was stopped and SBO resolved. He was discharged home and hospitalized again 2 weeks later with similar symptoms of abdominal pain and small bowel obstruction. A CT scan of the abdomen showed dilated small bowel loops with edema in the area of the duodenum and small bowel. Symptoms resolved and he was discharged home. He has never had similar symptoms of abdominal pain in the past.
During laboratory workup, C1 esterase inhibitor level was found to be normal, but the functional activity was 29% of the normal level during his last hospitalization (3 weeks prior to the clinic visit). The test was repeated a week ago: the C1 esterase inhibitor level was again normal and the functional capacity was 87% of the normal levels.
The patient was referred to us for work-up of suspected abdominal angioedema secondary to functional C1 esterase inhibitor deficiency.
Norvasc 5 mg po daily, Protonix 40 mg po daily, Toprol XL 100 mg daily, Colace 100 mg po daily.
Negative for smoking, no pets. Alcohol: He used to drink a 6-pack of beer per week, but he stopped drinking two months ago after his symptoms started.
Negative for angioedema, childhood asthma.
Normal, no rash.
Lymph nodes: Not palpable.
Respiratory system: Clear to auscultation bilaterally.
Cardiovascular system: Clear S1, S2. Abdomen is soft, non-tender, non-distended, no masses. Neurological exam: Normal strength.
Extremities: No cyanosis, clubbing, or edema.
What is the most likely diagnosis?
Abdominal angioedema secondary to acquired C1 esterase functional deficiency. The C1 esterase functional deficiency is probably secondary an infection such as Helicobacter pylori acquired in Ecuador.
What laboratory tests would you order?
Liver enzymes, ANA, CBC with manual differential, hepatitis B core antibody, hepatitis B surface antigen and hepatitis C antibodies for workup of remote hepatitis in conjunction with his travel to Ecuador.
We checked PSA level and specific tests for angioedema work-up including C1Q, C4, C2, CH50, C1 esterase inhibitor qualitative and C1 esterase inhibitor quantitative levels.
What happened next?
The patient was due to have a repeat EGD with biopsy to rule out eosinophilic esophagitis and colonoscopy next week. He has no symptoms, signs or laboratory findings of a lymphoproliferative disorder or any other malignancy.
All the tests came back normal and he was diagnosed with transient C1 esterase functional deficiency. He had no symptoms at his most recent follow-up 2 months after the initial visit.
Abdominal angioedema secondary to acquired C1 esterase functional deficiency. Our patient has acquired angioedema (AAE) type II (see below for explanation).
What did we learn from this case?
Acquired C1 esterase inhibitor deficiency is a rare condition which is associated with autoimmune or low-grade lymphoproliferative disorders. The angioedema may precede the lymphoma by many years. Optimal management requires that both angioedema and the underlying lymphoma be recognized and treated.
Adults (after the 4th decade) or elderly patients are most commonly affected.
It often presents with recurrent angioedema and low serum levels of C4 with normal levels of C3. Low levels of C1q and low C1 esterase inhibitor activity confirm the diagnosis.
There are 2 forms of acquired angioedema (AAE): type I and II.
AAE type I is a very rare syndrome associated with lymphoproliferative disorder, autoimmune disease or paraproteinemia. Complement-activating process acts to increase consumption of C1 esterase inhibitor.
In AAE type II, an autoantibody is produced against the C1 esterase inhibitor. The antibodies adhere to the C1 esterase molecule and cause a conformational change leading to decreased function or enhanced metabolism. AAE is differentiated from HAE by decreased C1q, C1r, and C1s levels and decreased functional activity of C1 esterase inhibitor.
Angioedema (AE) Classification (click to enlarge the image):
Angioedema (AE) can be allergic or non-allergic. There are 5 types of non-allergic angioedema (AE):
- acquired AE
- hereditary AE (HAE)
- ACE-inhibitor induced AE
- idiopathic AE, can occur with chronic urticaria
- pseudoallergic AE, e.g. reaction to NSAIDs
There are 3 types of HAE that are differentiated by C4 and C1-INH levels
- type I HAE - low C4, low C1-INH function, low C1-INH antigen level
- type II HAE - low C4, low C1-INH function, normal C1-INH antigen level
- type III HAE - all normal
Treatment of acute HAE attacks
- C1-INH, 20 units/kg, IV infusion
- Icatibant, 30 mg SC, bradykinin B2 receptor antagonist
- Ecallantide, 30 mg SC, kallikrein receptor antagonist
Prophylaxis of HAE attacks
- C1-INH, 1,000 units, IV infusion every 3-4 days
- attenuated androgen, e.g. danocrine 200 mg PO TID
Acquired C1 Esterase Inhibitor Deficiency. Svetomir N. Markovic, MD, PhD; David J. Inwards, MD; Evangelos A. Frigas, MD; and Robert P. Phyliky, MD. Ann of Int Med, 18 January 2000 | Volume 132 Issue 2 | Pages 144-150. Full text PDF.
Acquired C1-esterase inhibitor deficiency: Three case reports and commentary on the syndrome. TK Lipscombe, DI Orton, AG Bird 1 JD Wilkinson. Australasian Journal of Dermatology, Volume 37 Issue 3, Pages 145 - 148, 2007.
C1 Esterase Inhibitor Deficiency. 5-Min Clinical Consult. Unbound Medicine, Inc.
New Directions in the Treatment of Angioedema. Medscape, 2012.
35 years ago: “We probably will never know why you swell, but it’s called Angioneurotic Edema” - things have changed a lot since then. HAEA.org.