Angioedema with inconsistent decrease in C1 esterase inhibitor
Question:
6/6/2019
I have a 32 year-old female patient who had angioedema a few times. Lips and then tongue swelled. First episode was around September 2018. Usually the episodes are lip swelling (upper and lower), but one episode included swelling of tongue and closing of throat along with the lip swelling requiring hospitalization but no intubation. Does not get hives. Not on any ACEI or NSAIDs. In hospital, C4 was normal (28) with normal range 15-57. C1 Esterase antigenic was normal at 26 (normal range 21-39). On 9/26/18; her C4 was 32 (15-57) - normal, but C1 esterase inhibitor functional was 24 LOW (with normal over 68%.). Her C-1 esterase inhibitor protein on that day (9-26-18) was normal @ 26 with normal 21 to 39. I repeated these and C4 =normal @ 26 (normal 10-40); C1 EST antigenic was normal @ 31 (normal 21-39); C1 EST functional indeterminate range @53% (indeterminate range 41-67%, normal over 68%, low 40% or less). C1Q pending. FHX: No swellings in family.
Do you feel she could have a mild HAE type II with low and then indeterminate C1EST functional despite normal C4 (and normal C1 EST protein level)? If so, do you feel we would need genetic testing to prove it? Exactly what genetic tests would prove or disprove HAE type II (no family history).
Answer:
I would favor that this is histamine dependent angioedema, most likely idiopathic, and the C1 esterase inhibitor function is falsely low, perhaps due to misadventure with the sample after collection. I base this on the probability being much greater for idiopathic angioedema compared to bradykinin dependent angioedema, the prior involvement of lips (more common with idiopathic), the patient’s age, the lack of family history and particularly the normal C4 while in hospital for facial and throat swelling. A normal C4 during an acute event virtually excludes the diagnosis of C1 esterase inhibitor deficiency, although reports are in literature of normal C4 with the deficiency when not having angioedema (1,2). It would be helpful to know the angioedema characteristics, with idiopathic being less brawny, more rapid in onset and resolution and responsive somewhat to antihistamine and/or corticosteroid therapy.
I would suggest the chromogenic assay for C1-inhibitor function as this is available at the National Jewish Laboratory and is more sensitive than the other commercial assay (3). Genetic testing for the SERPING1 gene has been described but I am not sure it is available commercially (4).
In summary, I favor a diagnosis of idiopathic angioedema and not bradykinin angioedema. For confirmation I would suggest the chromogenic C1-inhibitor assay.
1. Tarzi, M. D., et al. "An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio‐oedema." Clinical & Experimental Immunology 149.3 (2007): 513-516.
2. Gompels MM, Lock RJ. C1 inhibitor deficiency: diagnosis. Clin Exp Dermatol 2005; 30:460–2.
3. Wagenaar-Bos IG, Drouet C, Aygoren-Pursun E, Bork K, Bucher C, Bygum A, et al. Functional C1-inhibitor diagnostics in hereditary angioedema: assay evaluation and recommendations. J Immunol Methods 2008;338:14-20, IV.
4. Loules G, Zamanakou M et al. Targeted next-generation sequencing for the molecular diagnosis of hereditary angioedema due to C1-inhibitor deficiency. Gene 2018;667:76-82.
I hope this information is of help to you and your practice.
All my best.
Dennis K. Ledford, MD, FAAAAI