Association between CFS and the corticosteroid-binding globulin gene.

[Ema]

@Valentijn, is it possible to find this gene in the 23andme data?

Endocr Res. 2004 Aug;30(3):417-29.
Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism.
Torpy DJ1, Bachmann AW, Gartside M, Grice JE, Harris JM, Clifton P, Easteal S, Jackson RV, Whitworth JA.
Author information

Abstract
Chronic fatigue syndrome (CFS) is characterized by idiopathic fatigue of greater than 6 months' duration with postexertional exacerbation and many other symptoms. A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized thatCBG gene polymorphisms may act as a genetic risk factor for CFS. A total of 248 patients with CFS defined by Centers for Disease Control criteria, and 248 controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G-->T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls (chi2 = 5.31, P = 0.07). Immunoreactive-CBG(IR-CBG) levels were higher in Serine/Alanine (Ser/Ala) than Ala/Ala subjects and higher again in Ser/Ser subjects, this effect was strongest in controls; Ser/Ser: 46.1+/-1.8 (n = 31, P = 0.03) vs. Ser/Ala: 42.4+/-1.0 (n = 56, P = 0.05) vs. Ala/Ala: 40.8+/-1.7 microg/mL (n = 21). Despite higherCBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients, total cortisol: Ser/Ser: 13.3+/-1.4 (n = 34) vs. Ser/Ala: 14.0+/-0.7 (n = 66) vs. Ala/Ala: 15.4+/-1.0 (n = 23). Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.

Mol Cell Endocrinol. 2010 Mar 5;316(1):24-34. doi: 10.1016/j.mce.2009.07.015. Epub 2009 Jul 28.
Corticosteroid-binding globulin: the clinical significance of altered levels and heritable mutations.
Gagliardi L1, Ho JT, Torpy DJ.
Author information

Abstract
Corticosteroid-binding globulin (CBG) is the specific high-affinity plasma transport glycoprotein for cortisol. Stress-induced falls in CBG levels may heighten hypothalamic-pituitary-adrenal axis responses and CBG:tissue interactions may allow targeted cortisol delivery. Three genetic variants ofCBG have been identified that reduce cortisol binding affinity and/or CBG levels. These include the Leuven and Lyon mutations which reduceCBG:cortisol binding affinity 3- and 4-fold, respectively, and the null mutation resulting in a 50% (heterozygote) or 100% (homozygote) reduction inCBG levels. The three reported null homozygotes demonstrate that complete CBG deficiency is not lethal, although it may be associated with hypotension and fatigue. The phenotype of a CBG null murine model included fatigue and immune defects. One community-based study revealed that severe CBG mutations are rare in idiopathic fatigue disorders. The mechanisms by which CBG mutations may cause fatigue are unknown. There are preliminary data of altered CBG levels in hypertension and in the metabolic syndrome; however, the nature of these associations is uncertain. Further studies may clarify the functions of CBG, and clinical observations may validate and/or extend the phenotypic features of various CBGmutations.

Crown Copyright 2009. Published by Elsevier Ireland Ltd. All rights reserved.

 

[ukxmrv]

I looked and couldn't find it but Val is the expert!

I even thought about contacting Dr Torby to see if he was still looking at this but I could only find what was possibly a relative when I looked at Australian Uni or hospital he had been working at.

 

[merylg]

http://ghr.nlm.nih.gov/gene/SERPINA6

 

[alex3619]

There are old thead/s on PR about this. I have commented on it before. I was in one of these studies, but am negative for the gene. They found it in a family in which many people appear to have CFS (they were not using an ME diagnosis).

CBG is probably not just a binding molecule. It has molecular characteristics of a hormone. Yet I do not know the latest science on this.

I think, but I am not certain, that less than 1% of CFS patients have this problem.

Last time I was involved, more than a decade ago, there were at least 3 snps in this gene known to cause issues.

 

[Valentijn]

@Ema - There is no SEPRINA6 A224S that I can find, outside of being mentioned in some older research, but there is a A246S, also on exon 3 of SERPINA6 at rs2228541 . Naturally 23andMe doesn't test for it! But anyhow, the prevalence in the general population is very common for A224S according to the research, and 41.7% MAF according to http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=2228541 .

I looked at the other SNPs for the 31 23andMe ME patient profiles I have access to, and we were extremely normal, compared to the controls.

 

[Inara]

I know this thread is old. But does anyone know: If you turn out to have CBG deficiency, can you still have ME? Or is it CBG deficiency then, and not ME?

Is anybody here with CBG deficiency?

 

[Gingergrrl]

I know this thread is old. But does anyone know: If you turn out to have CBG deficiency, can you still have ME? Or is it CBG deficiency then, and not ME? Is anybody here with CBG deficiency?

I had not seen this thread before but was wondering if someone could explain what “CBG deficiency” means in basic non-scientific terms?

 

[Inara]

It can mean two things:
1) CBG is decreased in blood.
2) The binding affinity of CBG is reduced, i.e. its level is normal, but the protein can't bind as much as "normal" CBG (e.g. cortisol, progesterone to a lesser extent).

Its functions are still mostly unknown. There exists the so-called "free hormone hypothesis" saying only free hormones act because their transport proteins can't enter cells. I can't make an assessment of that hypothesis, but I know the stuff in our bodies wasn't there if it wasn't needed, so binding proteins will play their role. CBG seems to act more like a hormone than a transport protein alone, and it seems to modulate the HPA axis. It may act in the central nervous system. Newer research in mice indicated a role in the adrenal glands, and affected mice don't produce enough cortisol.

There exist people whose CBG gene is "missing", i.e. they can't produce CBG. These people live. It wasn't specified how well they lived, but it was assumed till then that you can't live without CBG.

I am not impressed by "wow, they live". To me, quality of life counts. I know of a boy who is lacking the ITPR3 gene. Well, yes, he lives, but he is nearly constantly in hospital and severely immuno-compromised.

That's maybe a general problem for me when it comes to finding phenotypes. In my view - that's how medicine likes it - they pick a few symptoms they deem relevant and don't report the others; or, they forcedly try to find ONE phenotype, i.e. one symptom/disease that is associated with a mutation. In my view, that's a bit narrow-minded. We already know that the genetic makeup as a whole plays a role, too. So variation in symptoms and severity shouldn't be too surprising. It is known that people with a mutation can have symptoms while others with the same mutation don't. That also holds inside of families. This knowledge already exists for some genetic diseases. It should be common knowledge by now. We simply don't know enough, I'd say.

I think that's what you can see in CBG deficiency as well. There seems to be agreement that pain is the most reported symptom (including headaches), next comes physical fatigue, which increases after exercise. If this includes activity in general like in PEM/PENE, I can't say. More generally, it seems preferred to correlate CBG deficiency with pain and fatigue syndromes. But I also found muscle aches ("muscle soreness"-like), fast muscle fatiguability - some would say: muscle weakness, some wouldn't - high and low blood pressure (maybe due to a dysfunctional vasoconstriction), obesity. Not much is known. I think research is lacking because CBG deficiency isn't viewed as "bad enough".

CBG deficiency can look like Addison's, so I would expect comparable symptoms in that case. But I don't know. And in CBG deficiency hydrocortisone doesn't seem to help.

Would really be interesting to hear what affected people say. That story might be very different than reported.

 

[Gingergrrl]

Thank you for your detailed answer @Inara and I Googled this and found a link (below) from Medline that explains it further (in case it is useful to anyone):

https://medlineplus.gov/genetics/condition/corticosteroid-binding-globulin-deficiency/#resources

It can mean two things:
1) CBG is decreased in blood.
2) The binding affinity of CBG is reduced, i.e. its level is normal, but the protein can't bind as much as "normal" CBG (e.g. cortisol, progesterone to a lesser extent).

This makes sense but I am still confused about a few things. Is this purely a genetic mutation that someone has from birth or is it something that can develop later in life in an adult? Meaning would CBG deficiency always be from birth/genetic cause or could it develop later in life from an environmental or viral cause, etc?

CBG deficiency can look like Addison's, so I would expect comparable symptoms in that case. But I don't know. And in CBG deficiency hydrocortisone doesn't seem to help.

So if someone had a CBG deficiency, does that mean that their Cortisol levels are always low but in spite of this, taking hydrocortisone does NOT help them? Also, would their ACTH levels be abnormal, too, or only their Cortisol levels? I am trying to figure out if this could possibly pertain to my situation but I am thinking that it does not since my issue developed later in life as an adult AND taking hydrocortisone helps me.

 

[Inara]

Meaning would CBG deficiency always be from birth/genetic cause or could it develop later in life from an environmental or viral cause, etc?

The knowledge till now is related to mutations starting from birth. I don't know if changes in later life are possible, too.
I'd say CBG deficiency can make a "milieu" that's not too optimal, e.g. re. stress, which includes infections.

So if someone had a CBG deficiency, does that mean that their Cortisol levels are always low but in spite of this, taking hydrocortisone does NOT help them?

In some and I think most patients, cortisol levels can be low (in others it's normal or even slightly elevated), and yes, mostly hydrocortisone does not help.
A typical constellation, as far as I understood, would be normal to lowish total cortisol and low to lowish free cortisol and normal cortisol in 24h-urine, plus "cortisol jumps" ("pulsatility"). In case of the Leuven variant, e.g., CBG is produced normally, i.e. its levels are normal to normal-low, but its binding capacity is reduced (which can't be measured in a normal lab).

I know of one reported case where an ACTH stimulation test was abnormal and indicated Addison's, but hydrocortisone didn't help which would be very untypical for Addison's.

I didn't always have symptoms like fatigue and fatiguability and PEM-like stuff and muscle issues (which also come from the periodic paralysis), they came with an infection although I had minor symptoms beforehand (like tiredness und early burning muscles). I have A SERPINA6 variant, called the Leuven variant. That's what I mean with "non-optimal milieu", but I can only speculate.

Since not much is known I wouldn't exclude other mechanisms per se. Also, I wouldn't exclude variability.

 

[Gingergrrl]

@Inara I got my blood test results back this morning and when I reviewed the results, I was surprised to find that my main doctor had ordered a test for "Corticosteroid Binding Globulin" or "CBG"! I had not even realized that I was tested for this when I was asking you questions in this thread! Does this mean that I was tested for a genetic issue or only for the amount of CBG in my blood? I'm sorry that this still confuses me!

In either case, the "normal" reference range for CBG with the lab was 1.7 to 3.1 and my result was 3.0 which means that I was "normal" on this test and just inside of the range. Does this mean anything to you? My gut instinct is that the issues that I have re: ACTH & Cortisol have nothing to do with CBG and I assume that this tests confirms that?

The knowledge till now is related to mutations starting from birth. I don't know if changes in later life are possible, too. I'd say CBG deficiency can make a "milieu" that's not too optimal, e.g. re. stress, which includes infections.

That makes sense and the issues that I have are not from birth and all started as an adult.

In some and I think most patients, cortisol levels can be low (in others it's normal or even slightly elevated), and yes, mostly hydrocortisone does not help.

That is interesting and I have never had elevated Cortisol (only very low, slightly low, or normal). And hydrocortisone helps me.

I know of one reported case where an ACTH stimulation test was abnormal and indicated Addison's, but hydrocortisone didn't help which would be very untypical for Addison's.

That is interesting, too.

I didn't always have symptoms like fatigue and fatiguability and PEM-like stuff and muscle issues (which also come from the periodic paralysis), they came with an infection although I had minor symptoms beforehand (like tiredness und early burning muscles). I have A SERPINA6 variant, called the Leuven variant. That's what I mean with "non-optimal milieu", but I can only speculate.

So in your case, are you thinking that you have both periodic paralysis and the CBG mutation as the cause of your symptoms?

Since not much is known I wouldn't exclude other mechanisms per se. Also, I wouldn't exclude variability.

What do you mean by "variability"?

 

[sometexan84]

Interesting. Might be why some develop ME/CFS after corticosteroid shots, as apparently they will decrease CBG as well.

 

[Inara]

Hey @Gingergrrl, I'm reading stuff on cortisol, and it's not as simple as doctors (and I) seem to think it is. I find it complex.
I found these papers helpful:

https://academic.oup.com/jes/article/1/2/96/2897141
It's about diagnosing Adrenal Insufficiency via salivary cortisol. It compares serum to salivary cortisol and also talks about problems when measuring (total) serum cortisol that arise due to binding proteins (CBG, albumin). Salivary cortisol measures free cortisol, and that mirrors serum free cortisol relatively well. The problem is that no consensus on normal ranges exist.

El-Farhan et al., Measuring cortisol in serum, urine and saliva – are our
assays good enough? 2014, doi: 10.1177/0004563216687335
The answer may be: no. There exist several different measurement methods for serum cortisol. (That may explain the "jumps" in cortisol I see in my case. I don't think these jumps exist in me, they exist due to different measurement methods of different labs.) It is pretty difficult to measure free cortisol in serum. That's why it's computed from total cortisol and CBG, using assumed standard values. Also, the equations used will assume a certain model that might not hold for an individual. This computation will not take into account changes in CBG, and therefore, the computed free cortisol could be falsely higher or lower.
@Gingergrrl, that may be the reason why your doctor measured CBG, too, to have serum free cortisol computed more accurately? If so, you should have a result for free cortisol. I can't say if he assessed you for sth. else.

That paper compares the different hormone hypotheses, favoring the free and reservoir hormone hypothesis:
https://doi.org/10.1016/j.mce.2020.110857
It's quite illuminating.

In either case, the "normal" reference range for CBG with the lab was 1.7 to 3.1 and my result was 3.0 which means that I was "normal" on this test and just inside of the range. Does this mean anything to you?

It should because I read about it, but forgot it. I know that (oral) estrogen can increase CBG.

My gut instinct is that the issues that I have re: ACTH & Cortisol have nothing to do with CBG and I assume that this tests confirms that?

I have not read about higher CBG in CBG deficiency, but I ask myself: Why not having CBG deficiency with higher CBG? Binding affinity doesn't have to affect CBG level.
What might confirm adrenal insufficiency in your case is that hydrocortisone helps, plus all the other clinical findings.

Interesting. Might be why some develop ME/CFS after corticosteroid shots, as apparently they will decrease CBG as well.

I can't say. But hydrocortisone binds to CBG, and thus decreases CBG levels. Dexamethasone does not influence CBG levels because it doesn't bind to CBG. Stuff like sepsis, fasting, other stress leads to lower CBG levels.

So in your case, are you thinking that you have both periodic paralysis and the CBG mutation as the cause of your symptoms?

I asked an CBG expert about this (Prof. Torpy), and he said the lab results would fit Leuven CBG deficiency, so I view CBG deficiency as confirmed. Consensus seems to be that CBG deficiency doesn't cause severe disease states, but I read a case report where a woman was disabled, so I wouldn't totally agree to that. I think not enough is known.
I believe that CBG deficiency created a "non-optimal" milieu, so I think it's a contributor. So yes, it may be that the periodic paralysis is the top problem, plus CBG deficiency, and all its downstream effects. I can't say if I have ME or not, if the CBG deficiency led to ME which would be an extra diagnosis in addition to all the other stuff, or if CBG deficiency excludes ME. Therefore my question above.

What do you mean by "variability"?

Oh sorry, I mean "symptom variability". Like some with a CBG variant have symptoms, some don't, in some it's mild, in some it's more severe. And the set of symptoms isn't clear.

 

[Gingergrrl]

Hey @Gingergrrl, I'm reading stuff on cortisol, and it's not as simple as doctors (and I) seem to think it is. I find it complex.

I agree that it is very complex and thank you for the articles.

El-Farhan et al., Measuring cortisol in serum, urine and saliva – are our assays good enough?... The answer may be: no. There exist several different measurement methods for serum cortisol. (That may explain the "jumps" in cortisol I see in my case. I don't think these jumps exist in me, they exist due to different measurement methods of different labs.)

I just experienced having dramatically different results on blood tests for ACTH & (Total) Cortisol from two different labs (LabCorp & Quest in the US) so this is really of interest to me. Also, in your case, when you test for blood Cortisol, do you also test for ACTH?

@Gingergrrl, that may be the reason why your doctor measured CBG, too, to have serum free cortisol computed more accurately? If so, you should have a result for free cortisol. I can't say if he assessed you for sth. else.

My doctor did test for Free Cortisol (this time) but normally does not test for this. It was in the normal range just like the CBG was in the normal range. I will be speaking with my endocrinologist in a few days and hope to learn more about this.

I can't say. But hydrocortisone binds to CBG, and thus decreases CBG levels. Dexamethasone does not influence CBG levels because it doesn't bind to CBG.

Is that why some doctors order the "Dexamethasone Suppression Test" or "Dex Test"? Have you ever had this test?

I believe that CBG deficiency created a "non-optimal" milieu, so I think it's a contributor. So yes, it may be that the periodic paralysis is the top problem, plus CBG deficiency, and all its downstream effects. I can't say if I have ME or not, if the CBG deficiency led to ME which would be an extra diagnosis in addition to all the other stuff, or if CBG deficiency excludes ME. Therefore my question above.

It is all so confusing and I hope you will be able to figure out your correct diagnoses in the future. I think it takes a life-time to sort all of this stuff out!

Oh sorry, I mean "symptom variability". Like some with a CBG variant have symptoms, some don't, in some it's mild, in some it's more severe. And the set of symptoms isn't clear.

Thx and that makes sense.

 

[Inara]

I just experienced having dramatically different results on blood tests for ACTH & (Total) Cortisol from two different labs (LabCorp & Quest in the US)

Yes, I had that, too. I think it's most probably due to different measurement methods.
I find that questionable. Medicine is becoming an "uncertainty field" more and more to me, where you often come into situations where all that is left is a guesstimate? I wonder on what grounds doctors make diagnoses. Is it gut alone, in the end? If you don't know if a lab value or another test result (like EMG) is really correct...or if you assume it's correct while it isn't...at what does that leave you?

Also, in your case, when you test for blood Cortisol, do you also test for ACTH?

It was lowish at two time points, otherwise normal.

I will be speaking with my endocrinologist in a few days and hope to learn more about this.

If you care to share - I'll be interested.

Is that why some doctors order the "Dexamethasone Suppression Test" or "Dex Test"? Have you ever had this test?

I think doctors order that test to check for Cushing's. I don't know for what else it can be used.
The assumption is: dexamethasone increases cortisone levels, ACTH production is decreased so that the adrenal glands reduce cortisol production. If that doesn't happen, it is said it's Cushing's. It assumes that ACTH is really decreased during that test. If that doesn't happen, the source might be the pituitary gland? Some tumor then? But I think the CRH test is better suited then.

I think it takes a life-time to sort all of this stuff out

I hope not.

For me, the picture is relatively clear, I am only unsure about the ME.

 

[Thehealthofholly]

This is an interesting thread. I’ve been researching CBG deficiency over the past few months. I’ve found a few risk SNPs in my genetic data.

The symptom of CBG deficiency that really stood out to me is the physical exhaustion after emotional stress. Yes, I feel exhausted after physical activity, but no where close to how bedridden I am after a fight with a sister or a work call.

For those who have this confirmed - has anything helped with the symptoms?

 

[Inara]

For those who have this confirmed - has anything helped with the symptoms?

No, sorry to say.

Exception: dexamethasone. But if this is connected to CBG deficiency, I can't say.

 

[Thehealthofholly]

I would think that’s related. There were a few articles in how CBG deficiency causes increased inflammation, I didn’t exactly understand the theory, but the clinical evidence was there. If you’re taking a glucocorticoid and it’s reducing inflammation, I think it would be related.

I don’t have pain or inflammation. I just have insane fatigue and muscle fatigue. I wake up everyday feeling like I just finished a 13 hour labor intensive shift (like when I waitressed as a teen).

 

[Inara]

The clinical or biomedical implications of CBG deficiency are mainly unclear. There might be a connection to, let's say, low-grad inflammatory processes. I speculate that might be one reason for dexamethasone having an effect. But I have other traits as well that could be connected to low-grade inflammation so that CBG deficiency doesn't play a role.

Also, dexamethasone is not bound to CBG and is transported directly into tissue. It does not decrease CBG in contrast to other glucocorticoids. That might be another reason why dexamethasone helps.

But it's pure speculation, and I find it equally possible the effect of dexamethasone has nothing got to do with CBG.