Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor, University of Chicago
Reviewer: S. Randhawa, M.D.
A 12-year-old Caucasian female is seen as a new patient by the allergy and immunology clinic for abdominal pain for 3 months. She has a family history of hereditary angioedema (HAE) diagnosed in her maternal grandfather, mother, and brother.
As a part of family screening, she had a C1 esterase inhibitor level checked 2 years ago and it was 15 mg/dL (normal 19 to 37 mg/dL). The level was repeated several months later and was was in the range of 32% to 10% of the normal.
The patient had no symptoms until 3 months ago when she started to have daily abdominal pain below the umbilicus. The pain lasts a whole day and she has night symptoms as well. There is no consistent relief provided by pain medications.
Maternal grandfather with hereditary angioedema with abdominal attacks. Mother with hereditary angioedema with cutaneous attacks. Younger brother with hereditary angioedema with attacks manifesting with “throat closing” symptoms.
C1 esterase inhibitor level 2 years ago was 15 mg/dL (normal 19 to 37 mg/dL). C4 level was 13 mg/dL (normal 10-40 mg/dL). The C1 esterase level was 14 mg/dL (normal 16-33 mg/dL).
What is the most likely diagnosis?
This is a patient with hereditary angioedema, which affected multiple members of her family including her mother, brother, and maternal grandfather. Her hereditary angioedema manifests with abdominal symptoms.
What prophylaxis and treatment would you recommend?
She was given a prescription for a C1 inhibitor, Cinryze 1,000 units IV every four days. The rate of infusion is 1 ml/min and the infusion takes 10 minutes. She was given a prescription to discuss the administration of the medication as a prophylaxis with her primary care physician.
She is to return to our clinic in three months.
Hereditary Angioedema (HAE)
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
In most cases (85%), hereditary angioedema (HAE) is an autosomal dominant condition associated with episodic attacks of nonpitting edema. Patients with HAE have low levels of C1 inhibitor (a serine protease inhibitor). Edema is caused by unregulated generation of bradykinin.
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
There are 2 preparations of C1 inhibitor purified from plasma which have been used in Europe for decades (Cinryze and Berinert P). There is also a recombinant C1 inhibitor (not obtained from plasma). A kallikrein inhibitor (Ecallantide) and a bradykinin type 2 receptor antagonist (Icatibant) are in testing phases. It is likely that HAE treatment will change dramatically in near future.
New therapies for hereditary angioedema (HAE)
In summary, the new products for acute treatment and prophylaxis of hereditary angioedema (HAE) are:
- C1 inhibitor purified from plasma (Cinryze and Berinert P)
- recombinant C1 inhibitor
- kallikrein inhibitor (Ecallantide)
- bradykinin type 2 receptor antagonist (Icatibant)
What is the difference between hereditary angioedema (HAE) type I, II and III?
C1 Inhibitor Cinryze Approved by FDA for Prophylaxis Against Hereditary Angioedema Attacks
New therapies for hereditary angioedema (HAE)
Biomarkers to help diagnose abdominal attacks in angioedema due to C1-inhibitor deficiency, prevent unnecessary surgeryJournal News: Icatibant for treatment of hereditary angioedema
Hereditary Angioedema: Prophylaxis and Long-Term Management http://goo.gl/l9bY
HAE: annual drug cost alone for prophylactic C1 esterase inhibitor is $450k - nearly $5 mln for every decade of life http://goo.gl/BCVtu
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.