Where to from here?

[Gingergrrl]

I've just learned that my Complement Component C3 and C4 are below normal range (C3 is more than 50% lower than the lowest end of normal range).

@TrixieStix Am hoping this is the right place to post this and I know we've been talking about C3 and C4 levels in a few threads (and we can continue to chat via PM, too).

It turns out that I was tested for C3 and C4 levels in early May 2016 by a rheumy who was ultimately unable to help me. My levels were low but were within range at that time. I have no idea what they are now almost a year later.

My C3 was "95" and range was 87-200 and my C4 was "21" and range was 19-52. Those same tests showed I had a positive ANA of 1:160, speckled pattern, and that I had the two Hashimoto's autoantibodies (which I already knew). My other tests (not done by the rheumy) showed paraneoplastic (or anti-neuronal) Abs which he did not know anything about and then much later I learned that I tested positive on 7 of the 9 Cell Trend Abs from Germany.

If you have any thoughts on my C3 or C4 levels or how they compare to yours, I'd love to learn more about it. On a side note I have to truly thank you (@TrixieStix) b/c in searching to see if I'd been tested for C3 & C4 levels so I could tell you, I found exactly what I was searching for (different test results) that my doctor very much needed for our phone consult tomorrow (and I do not think I ever would have searched the Rheumy tests for these) so you really helped me out without even knowing it!

 

[TrixieStix]

Your plan sounds sensible but if the ANA is negative lupus is unlikely. Low C3 and C4 go with lupus but in the absence of ANA they would be harder to interpret. Abnormal complement levels would certainly be a reason to re-investigate through a rheumatologist. ANA might turn out to have switched to positive.

Jonathan,

Thanks so much for your reply. My rheumatologist agreed I should see her again. Until then I've been researching the complement system so I can at least have a little bit of understanding.

I found the following statement...."ANA is generally negative in immune complex diseases caused by complement deficiency."

And also this statement...."Individuals lacking C3 are therefore highly susceptible to recurrent systemic bacterial infections and frequently suffer from immune complex-related disorders, such as glomerulonephritis and systemic lupus erythematosus. The deficiency is caused by mutations in the C3 gene, resulting in absence/markedly reduced levels, or dysfunction of the protein."

Like you said, normally a negative ANA would make Lupus highly unlikely, but according to the above information wouldn't a negative ANA be expected in someone with Lupus caused by a complement deficiency thus making it an exception to the rule? If I'm wrong please tell me as I'm just trying to understand.

Also what kind of tests are usually done to further investigate low levels of C3 and C4 in a patient who currently has no AI or IC disease diagnosis? Do you agree that testing a persons C1q level can tell you whether or not the hypocomplementemia is due to "classical pathway" activation?

Above quoted statements referenced from these links...

http://emedicine.medscape.com/article/886128-workup?pa=lKtnEcj94ilGF2++8OVTmzmUDqCZu7q2fhusG0Pzzc82UAKkvc8SAGSkiPANFcwgu1G9/9deUaLHm1a05gdTD0eb0T8SAO/pBjZvSxPL9fk=

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005321

 

[Jonathan Edwards]

I found the following statement...."ANA is generally negative in immune complex diseases caused by complement deficiency."

And also this statement...."Individuals lacking C3 are therefore highly susceptible to recurrent systemic bacterial infections and frequently suffer from immune complex-related disorders, such as glomerulonephritis and systemic lupus erythematosus. The deficiency is caused by mutations in the C3 gene, resulting in absence/markedly reduced levels, or dysfunction of the protein."

Like you said, normally a negative ANA would make Lupus highly unlikely, but according to the above information wouldn't a negative ANA be expected in someone with Lupus caused by a complement deficiency thus making it an exception to the rule? If I'm wrong please tell me as I'm just trying to understand.

Also what kind of tests are usually done to further investigate low levels of C3 and C4 in a patient who currently has no AI or IC disease diagnosis? Do you agree that testing a persons C1q level can tell you whether or not the hypocomplementemia is due to "classical pathway" activation?

Above quoted statements referenced from these links...

http://emedicine.medscape.com/article/886128-workup?pa=lKtnEcj94ilGF2++8OVTmzmUDqCZu7q2fhusG0Pzzc82UAKkvc8SAGSkiPANFcwgu1G9/9deUaLHm1a05gdTD0eb0T8SAO/pBjZvSxPL9fk=

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005321

Good questions, but this is very confusing and complicated area. In lupus complement component (C3, C4, C1q etc) in blood are low as a result of consumption by immune complexes. That needs to be separated from genetic complement deficiency where the components are low because of faulty genes. But it gets complicated because the autoimmune loop in lupus that leads to consumption of complement components by immune complexes is predisposed to by defects in complement genes.

To ry to make that clearer: if you have major C3 deficiency you will get a lupus-like immune complex disease but not have ANA. Major C3 deficiency is rare. If you have defects in C4 genes, which are often subtle, or defects in the C1q gene, then you are likely to develop lupus with a positive ANA.

It is reasonably straightforward to work out whether low complement levels are due to consumption as part of a lupus like illness or of primary genetic origin, although as indicated above it may be both.

Immune complex mediated problems are reasonably easy to identify. Fatigue in lupus is almost certainly not an immune complex problem but perhaps due to ANA antibodies interfering with cell metabolism directly.

 

[TrixieStix]

Good questions, but this is very confusing and complicated area. In lupus complement component (C3, C4, C1q etc) in blood are low as a result of consumption by immune complexes. That needs to be separated from genetic complement deficiency where the components are low because of faulty genes. But it gets complicated because the autoimmune loop in lupus that leads to consumption of complement components by immune complexes is predisposed to by defects in complement genes.

To try to make that clearer: if you have major C3 deficiency you will get a lupus-like immune complex disease but not have ANA. Major C3 deficiency is rare. If you have defects in C4 genes, which are often subtle, or defects in the C1q gene, then you are likely to develop lupus with a positive ANA.

It is reasonably straightforward to work out whether low complement levels are due to consumption as part of a lupus like illness or of primary genetic origin, although as indicated above it may be both.

Immune complex mediated problems are reasonably easy to identify. Fatigue in lupus is almost certainly not an immune complex problem but perhaps due to ANA antibodies interfering with cell metabolism directly.

I guess I am starting to understand this a bit as everything you said makes sense Thanks!

However I am still a bit unclear as to whether a primary genetic complement deficiency of a single specific complement can in turn cause low levels of other complements? In short, could my low C3 and C4 be caused by a primary genetic deficiency of a different yet to be tested complement?

In a person with C3 and C4 levels such as mine would it be normal to do a full testing of all the complements or do they usually do just specific tests to pin point why the levels are low and which pathway is affected?

 

[Jonathan Edwards]

I guess I am starting to understand this a bit as everything you said makes sense Thanks!

However I am still a bit unclear as to whether a primary genetic complement deficiency of a single specific complement can in turn cause low levels of other complements? In short, could my low C3 and C4 be caused by a primary genetic deficiency of a different yet to be tested complement?

In a person with C3 and C4 levels such as mine would it be normal to do a full testing of all the complements or do they usually do just specific tests to pin point why the levels are low and which pathway is affected?

Yes, genetic C1q deficiency can lead on to a lupus-type illness with low C3 and or C4, I am fairly sure. It is not common to test all complement component levels and genes. Traditionally the functional tests have been C3, C4 and something called CH50. Genetic tests have been available more recently mostly on a research basis but things have probably moved on quite a lot since I retired.

 

[TrixieStix]

Yes, genetic C1q deficiency can lead on to a lupus-type illness with low C3 and or C4, I am fairly sure. It is not common to test all complement component levels and genes. Traditionally the functional tests have been C3, C4 and something called CH50. Genetic tests have been available more recently mostly on a research basis but things have probably moved on quite a lot since I retired.

Ah ok so indeed it is possible. I was tested for CH50 along with C3 and C4. My CH5o is 35 (normal range bottom is 31-60 so I at lower end of norm). I can't seem to find anything in reference to normal CH50 when C3 or C4 are low so perhaps that isn't of much significance.

I'm looking forward to figuring out why I have these abnormalities and whether or not they have anything to do with my decline in function and symptoms that doctors have yet to figure out a cause for.

Oh and I came across this article I thought was interesting. Another thing to perhaps check given my history of recurrent bacterial infections?

"CFI (complement factor I) deficiency is possibly an underestimated defect and the eventual existence of this deficiency should be tested in those patients exhibiting low C3 and recurrent bacterial infections."

https://www.ncbi.nlm.nih.gov/pubmed/22710145

 

[TrixieStix]

Yes, genetic C1q deficiency can lead on to a lupus-type illness with low C3 and or C4, I am fairly sure. It is not common to test all complement component levels and genes. Traditionally the functional tests have been C3, C4 and something called CH50. Genetic tests have been available more recently mostly on a research basis but things have probably moved on quite a lot since I retired.

Thanks again Jonathan for your replies. Since my exchange with you I've been researching the possibilities of why my C3 is so low and have concluded that while my C4 in one test was slightly below normal range the CH50 was normal so really only my C3 is actually "low". I read that if both C3 and C4 are low then CH50 will be low but if only of them is low then CH50 will be within normal range, as mine is. This information was gleaned from a 1981 medical journal so hoping that it still holds true.

Being a C3 deficiency this I believe moves it away from being an issue with the classical pathway and instead points to a problem in the alternative pathway, Factor H or Factor I deficiency, or possibly C3Nef. A little concerned about the possibility for these things to cause kidney disease given my mother died at age 53 of kidney failure of which I do not know the cause. But not stressing about it. I also have come to understand that there can be "functional" deficiencies adding yet another layer to the complication of the complement system and figuring out the cause of my low C3. My low C3 (only 30% of normal) likely explains my recent history of serious bacterial infections.

I have an appointment with an immunologist in a few months and the doctors bio say he deals with primary immune deficiencies so hoping he will be able to suss out the cause of my low C3. I'm so anxious to know the answer! Although I have been warned by other people with complement caused PIDD that not all immunologists are well versed in complement issues. I will let you know what it turns out to be.

As a side note. I was reading that doctors are seeing more and more PIDD patients become symptomatic for the first time in adulthood rather than in childhood and one explanation they gave was changing epigenetics. Interesting stuff. In another life I would choose to be a scientist/medical researcher!

 

[bspg]

@Cohen2 were you able to get any diagnosis? Reading your posts I'm wondering if I might have UCTD.

 

[TrixieStix]

Yes, genetic C1q deficiency can lead on to a lupus-type illness with low C3 and or C4, I am fairly sure. It is not common to test all complement component levels and genes. Traditionally the functional tests have been C3, C4 and something called CH50. Genetic tests have been available more recently mostly on a research basis but things have probably moved on quite a lot since I retired.

Thought I would post what I ended up finding out about my low C3.

I saw an immunologist at the University of Washington (Seattle) last month. He ran C3, C4, CH50 and AH50 tests. He also ran a Pneumococcal Titer test and a T-Cell Subset Panel.

My C3 came back exactly the same as it has 2 other times (30% of normal) and CH50 is also low (11 points below normal range). C4 still normal and AH50 was normal. Pneumococcal titers normal, CD4/CD8 Ratio inverted due to elevated CD8.

He said he considers my inverted CD4/CD8 Ratio to be normal and that my elevated CD8 is normal and means my immune system is working well. He also did not think that my low NK Cell Function test (this was run by ME/CFS specialist) result of 4% was of much clinical significance or that it was anything to worry about.

As for my low C3 and CH50 he said it's his opinion that it's most likely a partial genetic deficiency of C3 itself, but that he is not aware of any further testing that can establish this with 100% certainty (ie: genetic testing). I still feel a genetic Factor H or Factor I deficiency need to be ruled out at a deficiency of either one causes low C3 and CH50 as a result. My 23andme results do show that I am homozygous for at least 2 C3 gene variants, both of which aren't all that common, and I also have at least 1 homozygous CFH (factor H) variant.

As for health effects of a partial C3 deficiency. The immunologist says he does not consider me to have a primary immune deficiency because of it, but that I should inform my doctors that I have low complement, and any time there is suspicion that I may have a bacterial infection to always err on the side of caution and take antibiotics. This seems smart to me as I do seem to have a slightly higher susceptibility to bacterial infections than most people.

He has referred me to a colleague of his who specializes in both immunodeficiency and rheumatology as he does think it's within the realm of possibilities that my low C3 could be causing me to experience autoimmune or autoimmune-like symptoms (ex: lupus-like illness). He said he already discussed my case with this colleague, and he had some suggestions for further testing that could be done. I'm hoping this other doctor will be great and will be able to help me sort this low C3 thing out a bit more in relation to my symptoms. Plus hopefully agree to check my Factor H and Factor I, and C2 levels also which has yet to be done. If it is indeed an isolated partial C3 deficiency then it is within the realm of possibility that it could cause autoimmune symptoms. I've found cases in medical journals in which someone with a partial C3 deficiency (with levels similar to mine) who developed autoimmune/autoimmune like symptoms. I've also read that it's thought that the potential for C3 deficiency to cause autoimmune problems is subestimated.

UPDATE: I've secured an appointment with the immunodeficiency/rheumatology specialist for the beginning of November. Which is great seeing as this doctor only sees patients 1 day a week for half a day. I should also be getting the results of my skin nerve biopsies my neurologist had done on my left hip and leg to look for evidence of Small Fiber Peripheral Neuropathy as I have had the classic symptoms of it in my my feet for many years now (I'm in my late 30's) and in the past year it seems to have spread to one side of my face and my hands as well.

 

[Valentijn]

My 23andme results do show that I am homozygous for at least 2 homozygous C3 gene variants, both of which aren't all that common.

Have you run it through the Analyze My Genes program? I've seen rare-ish C3 missense mutations on (1-2% prevalence) turn up in a lot of ME patients who I have 23andMe data from.

 

[TrixieStix]

Have you run it through the Analyze My Genes program? I've seen rare-ish C3 missense mutations on (1-2% prevalence) turn up in a lot of ME patients who I have 23andMe data from.

This is the first I've heard of it. I just downloaded the program and ran by data thru it. It came up with 1 homozygous variant. rs34258285 (E-197-A) in the PMM2 gene.
Enlis considers this variant to have a frequency of 1.93% so not under 1% as Analyze My Genes does.

What is the significance of the data set of Analyze My Genes?

 

[Valentijn]

What is the significance of the data set of Analyze My Genes?

It just pulls out rare SNPs from your results. If you unzip remarks.zip and ten_percent.zip into the same file, it'll included less rare results, which is useful for finding homozygous results. It'll also label genes and mutations.

MAF might vary a bit, and it could be out of date in the program. dbSNP is down, so I can't check

 

[aquariusgirl]

@Valentijn
I just did this...I got one file with homozygous snps present in less than 1% of the population. Are there other analyses I could run?

 

[Gingergrrl]

Would 'undifferentiated connective tissue disease' be possible without having much joint pain? I only get joint pain occassionally, more often I have stiffness or weakness in joints same with my knees. As for other symptoms the list is long and has varied over the years. Some of my current symptoms are severe fatigue, muslce weakness, Orthostatic Intolerence

I am re-reading this thread, since someone bumped it to the top, and I am now curious if UCTD is possible without ANY joint pain or stiffness vs. some of the other symptoms that you mentioned like muscle weakness and orthostatic intolerance.

@Cohen2 were you able to get any diagnosis?

I was wondering, too, @Cohen2, were you able to see the Rheumy and get a diagnosis?

 

[Cohen2]

@bspg @Gingergrrl Thanks for asking. I was never able to see a rheumatologist through the public system. I did ask last time I was in hospital but there is a shortage of rheumatologists in my area. I do actually get occasional joint pain and have stiff knees most of the time. However I'm pretty confident that it is ME, because I get PEM and relate so much to others here.