Friday, March 18, 2011

Lupus Tests: C3 and C4


            One of the most common tests for lupus activity is a blood test that measures the level of C3 and C4 in the blood. Here’s a brief description of what these proteins are, and why they serve as a marker for lupus activity:

Short answer: 

C3 and C4 are proteins produced by the immune system to fight infection. If your C3 and C4 levels are low then it means that the immune system is actively trying to kill something. In a healthy person this means that there’s an infection, but in someone with lupus the immune system is trying to kill cells in the body. This is obviously a bad thing, so doctors will try to calm down (by which I mean kill) the immune response by giving the patient steroids, methotrexate, and/or other immunosuppressants.

Long Answer:

            In the immune system there is something called the “Complement Cascade.” This is a sequential immune reaction that can be started by antibodies or by bacterial molecules. In the complement cascade that is triggered by antibodies, what happens is the antibodies bind to something they think is foreign. When multiple antibodies have bound, a protein floating around in the blood recognizes the antibodies, and grabs on to them. This protein is called C1 (for Complement 1, I presume).

Once C1 binds, another protein in the blood, C4, sees it and grabs on to C1. When it does this part of C4 gets chopped off, and it floats away. C4 has to be cut in two, or it doesn’t work… think of it as taking the sheath off of a knife. Once C4 has been cut, C2 recognizes it, binds, and is also cut. This C4/C2 combination can then cut C3, which is a major player in the complement cascade. When C3 is cut, part of it stays with  C4/C2, but the part that floats away tells the immune system that there’s a problem, and the immune system had better get activated. The rest of the complement cascade is just a sequence of proteins being bound, cut, and binding more proteins. The order is C5, C6, c7, C8 and then finally C9. When C9 binds to the cell that the original antibodies grabbed on to, it punches a hole in the cell, which causes the cell to die.

Since C4 is an early protein in the complement cascade and C3 is important in both the complement reaction itself and in activating the immune system, these are used as markers of an immune response. If you’re not fighting anything, your levels of C3 and C4 should be steady. If your immune system is fighting something (which often means cells in your body if you have lupus) then C3 and C4 get used up binding to cells and trying to kill them, and the levels in your blood drop. This is why the C3 and C4 test is used to measure whether the immune system is active or not.

28 comments:

  1. awesome article Sam! Thanks! LJK

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  2. Thanks! I found that I was answering the same questions repeatedly in different discussion boards and the like, and figured it would be easier to make it so I can just link to one site.

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  3. 62 year old female
    Four years ago I was diagnosed with chronic active Epstein Barr Syndrome. All the symptoms of mono, including never ending fatigue. Was started on 10mg prednisone. As time went by more symptoms such as chest pain, shortness of breath, numbness and tingling in the right arm and leg, strange headaches.
    a neurologists conducted an ANA tested and the result was positive for Systemic Lupus but no butterfly rash. Prednisone was still the drug of choice. During a recent exam and blood work by a rheumatologist she performed the c3 & c4 compliment tests and the results were on the high side of normal.
    also TSH and vitamin D3 were normal. She is leaning toward the idea of chronic fatigue. I had had some time enduring some extreme stress six years ago from family and evidently infected with Epstein Barr. I have read in an article from the Mayo Clinic that a serious viral infection combined with extreme
    stress and some degree of depression can be the precursor to chronic fatigue. I am wondering if I could have both Chronic Fatigue and SLE at the same time. Feel physically terrible and very confused. can you comment on this for me. thank you.

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  4. It is absolutely possible to have chronic fatigue and SLE at the same time. Honestly, I don't think it's possible to have active lupus without having chronic fatigue, as a matter of fact. And when you feel like ****, which you do with either or both diseases, of course you're more likely to have depressive symptoms. Every time I see a new study "demonstrating" this completely obvious fact I want to smack the researcher upside the head with my Captain Obvious baseball bat.

    As for the lupus symptoms: I was diagnosed with lupus 12 years ago, and I have NEVER had a true butterfly rash. And blood tests are not great diagnostic tools, in my opinion. I normally have very few markers of active lupus even when I am obviously very sick. As for prednisone, for me it has two drawbacks: 1) If I take it for more than 3 days I get suicidal, and 2) It only works when I get 1000mg or higher doses. I'm not a clinician, so I can't give you a diagnosis, but I can say that I have had similar blood results even after my lupus diagnosis.

    Epstien-Barr Virus (EBV) is a nasty one. It infects the same cells that produce the antibodies that damage the body when someone has lupus. There has been a lot of speculation that it may be a risk factor for developing lupus, but I don't think it has ever been proven. My own experience was that I developed autoimmunity after getting EBV.

    As a side note, there was a paper that just came out that showed that some cases of chronic fatigue syndrome are caused by undiagnosed autoimmune diseases. This was discovered when people with CF went on chemo for cancer (which kills the immune system), and found that their CF went away while they didn't have an active immune system.

    I hope all of that helps. If it doesn't, please let me know, and I'll try to help. I'm sorry you've had such a stressful time recently.

    ~Sam

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  5. thank you so very much for your information. it does shed some light on my situation. i have placed a shortcut on my desktop to stay up with your website. my next plight is which medication to investigate, as the rheumatologist has started to gradually reduce the prednisone by lowering the dose by 1mg per month.
    would love to be off of it because of the detrimental long term effects i've read about. but know yet how the pain will be like without it. i have read all of your site and everything rings so true.

    thanks again and wish you the best for each day

    maggie

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    1. You have my deepest sympathies...lupus drugs to replace prednisone are really frustrating. That's because they take weeks to work, so you get a friendly "Try this, and come back in a month!" from your rheumatologist....or at least, that's been my experience.

      I cannot tell you how glad I am that this blog has been helpful to you. Sometimes I feel like I'm just writing to vent, so it's nice to know that other people feel the same way.

      I hope that your rheumatologist finds something quickly that helps you. I know a lot of people do have good luck with the first or second drug they try. I'm just a nightmare patient.

      ~Sam

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  6. Very informative. Thank you.

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  7. Hi, Sam! What a great site you are providing to provide information and support for people! The way you explain things is very easy to understand.

    I am a nursing student and found your site while searching for info about the C3/C4 lab for my Lab and Diagnostics class. Here is a question I wonder if you might know the answer to: Why is C3 decreased in SLE, but elevated in Rheumatoid Arthritis, when they are both autoimmune disorders? Seems like they should both be low.

    I feel for you and others with chronic autoimmune disorders. The more I learn, the better advocate I can be for my patients who experience chronic pain. Thanks!

    Melissa

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    1. This question I'm not quite as certain about, but I will say that lupus is considered an immune complex disease, while RA (to my knowledge) is not. This may mean that other parts of the immune system are more involved in the pathogenesis of RA, whereas autoantibodies/complement complexes are the main actor in SLE. But, as I say, that's only an educated guess.

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  8. I have low c3 & c4 levels causing polyarthritis. This all happened after Barmah Forest virus then influenza A & meningitis. Not sure how to approach this but would appreciate any info. I don't want to take heavy meds as I am breastfeeding. Thanks

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    1. Any time you have low complement levels it means that your immune system is either 1) not producing complement (uncommon), or 2) using complement somewhere else (common). So in the case you mentioned, it sounds like there is inflammation that could be causing arthritis. That inflammation could decrease the complement levels in your blood.

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  9. Hi Sam,
    I recently had my C3 and C4 levels check the c3= 18 and c4=77.My WBC is 3.7 and ANA is positive speckled at titer of 1:40 this last time, before it was Nucleo at 1:64. My Rhuemy doesn't seem to find that I have been suffering for four years serious like I do... and how it is affecting my everyday living and my symptoms continue to worsen and change monthly. I do not see my Rheumy until July 1st. My pain level has increased incredibly in my toes, fingers, knees, hips and my Raynauds is still quite active, my toes and feet are like sausages that ulcer and feel broken to walk on... I have begun the process to set up an appt. at Hopkins. since it is only an hour drive for me... I am not sure what to think of my Bloodwork, I recently had echocardiogram and for chest pain and it is showing hyperinflated lungs and false tendon. I will be having a pulmonary test this week. I can't believe how my health has declined in the past 3 years... I would love your thoughts...I really enjoy reading your comments and insight on this crazy disease :)

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    1. Good luck! Isn't amazing how fast lupus can deteriorate one's quality of life? I hope that Hopkins has been able to help you. I found them frustrating on a personal basis, but helpful on a professional basis.

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  10. I am totally confused by what is going o with me. i have many symptoms of Lupus but no tests results confirm it. I have an elevated sed rate and elevated c4 that have been elevated for 3 months. Had many blood tests for lupus and all show nothing. I am extremely fatigued, in quite a bit of pain, and feel ill most of the time. Help!!

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  11. Is Sam a doctor?

    You had better discuss with your doctor or absorb different comments form other doctors.

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    1. Sam is a PhD doctor, not an MD doctor. And anyway, no physician can diagnose someone over the internet. You're quite right to advise seeing a physician in person!

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  12. I love your explanations they are perfect but here is a question.

    I am under a Rheumy's care and my first C3 level was 143 now it is 108 is this just a normal range or are my levels droppping due to possible disease activations?

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  13. Thank you for the information, Sam. May mother is diagnose Lupus Nephritis her medicine is Prednisone, mygraft mycophenolic acid 2x a day, and blopress once a day, plus Coxibitor for pain only, sometimes if she missed her medicine she suffer pain in her upper extremeties like in hand and finger also. I think rheumatoid arthritis is also combine? Can we go to another doctor for second option?

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    1. You can always, always go to another doctor for a second opinion. If you're uncomfortable with what one physician has said, don't hesitate to see another. That's just generally good advice.

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  14. My daughter is diagnosed overlapping syndrome One morning she got painful swollen middle three fingers of a hand and pains in various joints. After investigation her TSH was found 9.78 something so she has been given thyroid medicine she improved but the physician advised to see Rheumy who in turn advised to conduct ANAon speakel which come positive 1:2560 titter due to this higher activity the Rheumy inferred overlapping syndrom since no other symptoms are present in her body not even abnormal fatigue. She was advised prednisone after taking last one year now she is quite right The physician advised C3 test which is normal he advised to discontinue Prednisone and other antimalerials. I have not received answer to my question whether my daughter was suffering from Lupus or not.

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    1. I can't diagnose anybody, but I would encourage you to pin down the physician you are seeing and ask him or her point blank a) whether your daughter has lupus and b) if (s)he doesn't know, what other tests could be run to find out.

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  15. I have a quick question. Does a low C3 and C4 always indicate kidney involvement, or could it just be an indicator that someone has lupus? Thanks so much for your time and helpful comment.

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    1. I can't diagnose you or anybody else, but in general low C3/C4 levels can mean that lupus is active (not necessarily involving the kidneys). It can also mean other things, though, like that you're fighting an infection.

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  16. How long does the blood test results take to get back to the Doctor . They said 14,15 days?

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  17. with imeges pleas

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  18. Hi Sam,
    thanks for this helpful information. I have been seeing a rheumatologist for 2yrs. She diagnosed me with SLE, though I feel fine albeit a bit tired and sometimes achey in my joints. According to my bloodwork, my anti-double strand DNA and ANA are elevated, and my compliments are low (C3 & C4). I've been taking plaquenil for the last two years to keep my symptoms at bay. So far, so good ... (Touch wood). I'm a teacher, so life can be stressful during the school year, but have some reprieve during the summer. I feel fortunate, after reading others' struggles with the disease. That said, my aunt died of SLE when she was 59. What might you suggest to boost my compliments, and flip my anti-DS-DNA/ANA? Thanks once again?

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  19. Thanks so much for the breakdown , this will help when i need to explain it to other in a way they can understand what is happening to our bodies internally to cause what we go through!!!
    Xoxo, L.

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  20. Hello I am 33 year old woman, I've had a lot of the lupus symptoms for several years. I've had a butterfly rash lately for several months straight, sometimes it gets very red and irritated. Makeup does not help:/ my mom has SLE. I had labs done these last couple weeks and my ANA is positive so they ran another test which was a panel that included Anti DSDNA which I tested positive. The lab says normal range is <=4.0 IU/Ml mine was 12, I don't know how significant that number is but my doctor had referred me to a rheumatologist. Does anyone know about those lab numbers and what they could mean? I know different labs use different measurements, ranges etc.....

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