Q:

1/22/2013
I was referred a 33 yo asian male with chronic urticaria and an incidental laboratory finding of undetectable C4 levels (verified with 3 separate lab draws over course of 2 months. Urticaria is well controlled on desloratidine 10mg bid. He has no symptoms of autoimmune disease with a normal physical exam. Family history revealed a male cousin with SLE. He does not have any history of angioedema or of frequent infections. He feels quite well.

I have ordered further laboratory evaluation which revealed normal C3 1.08 g/L, CH50 was undetectable, C1-inh level was undetectable < 0.5 g/L, C1q normal 162 mg/L (Done at Institute of Med and Vet Science Adelaide Australia). SPEP with no abnormalities, ANA negative, DsDNA negative, Urine analysis negative, antibodies to SS-A,B, RNP, Sm, Scl-70 and Jo 1 are negative. RF normal at 9.8 IU/mL, ESR 11. CBC, LFT and Renal function panel are all normal.

I understand that there are genetic causes for low C4 which can predispose a person to SLE. Is there any explanation for his low C4 and low C1-inh and no history of angioedema? Thank you for your help.

A:

Thank you for your inquiry.

I initially misread your question - for reasons totally unknown to me - as indicating the C1 inhibitor was "normal" rather than "undetectable." I therefore originally misinterpreted your question, thinking we were dealing with an isolated C4 deficiency, a very rare event, and thus sent it to Dr. John Atkinson, a world recognized expert in complement, especially complement deficiencies.

It wasn't until I received Dr. Atkinson's very rapid and extremely helpful response that this error was called to my attention since, in his response sent to me by Dr. Hyon Ju Park, it was noted that both the C4 and C1 inhibitor levels were undetectable. Had I interpreted your question correctly, I would have answered your inquiry myself and clearly agreed with Drs. Park and Atkinson's superb response. Their response is copied for you below.  

Unfortunately, I cannot explain why your patient is asymptomatic. It does call to our attention one more subtle element. As you know, patients with C1 inhibitor deficiency syndrome, especially with classical hereditary angioedema, oftentimes develop a serpiginous nonpruritic rash which can be confused with urticaria. I am of course not sure whether your patient's rash is of this nature, but if it does not itch and is not elevated, contrary to my original comment about urticaria, it may be related to the C1 inhibitor deficiency syndrome. I personally do not think any therapeutic action is indicated as long as he is asymptomatic.


Finally, I echo Drs. Atkinson and Park's statement about obtaining a C2 and possibly obtaining C1 inhibitor gene sequencing. I suppose there are other cases of asymptomatic patients with C1 inhibitor deficiency, but I have never seen one nor have I noted one in the literature.

We would greatly appreciate a follow-up on your patient if you notice any change in symptoms.  

Thank you again for your inquiry.

Sincerely,
Phil Lieberman, M.D.

Response from Drs. Atkinson and Park:
In terms of the 33 y.o. Asian male with undetectable levels of both C4 and C1 inh, he likely has either acquired or hereditary angioedema without any clinical manifestations. His rash is likely unrelated although pictures and details regarding frequency and duration of episodes and treatment response would be helpful. Obtaining a C2 antigenic level and a test for C1 inh antibodies would be important. If C2 is also low, the patient should have his C1 inh gene sequenced. We can certainly assist with the sequencing if needed.

Sincerely,
Hyon Ju Park, M.D.
John Atkinson, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology