T3 intracellular calcium and caffeine

[Gingergrrl]

I've never had IVIG and this is an old study so I'm not sure what type they used.

No worries and when you said we were very similar, I thought it might have meant that you also had IVIG.

I don't think anyone really understand the mechanism by which IVIG works. It was developed to treat immune deficiency, not autoimmune conditions. It's a straightforward leap of faith that because it's an immunoglobulin it works via an immune pathway but not a proven one. And maybe in some cases it does work that way.

I agree that no one (even doctors) seem to fully understand the mechanism of how IVIG works, especially in autoimmunity. I know you are a doctor (not sure what specialty?) but this confirms it even further! I keep hearing a statistic that 75% of IVIG is now used for autoimmunity but am not sure if it is accurate. I agree it was a leap of faith but it worked miracles for me, and the combination of overlapping it with Rituximab was what put my most intractable symptoms into remission.

However, for most people with serious autoimmune conditions, the regular administration of IVIG does not appear to be necessary like for people with POTS and CFS. When I worked in the hospital, we would get people in critical condition in ICU, let's say something like thromocytopenic purpura, they get a course of IVIG and then they recover and can go years or the rest of their life without IVIG. While the impression I get from CFS/POTS crowd (and maybe I'm wrong) is that there is a dose dependent response that quickly tends to wear off it the dose is omitted.

My impression (which could be totally wrong) is that there are acute autoimmune conditions like Guillain Barre in which someone might have a five day cycle of IVIG and then never need it again and then there are also chronic autoimmune conditions in which someone might need it every three weeks, or every five weeks, etc, to maintain remission. I am not sure that there are any solid statistics re: for ME/CFS or POTS.

I know that many more doctors are now using it for POTS if they have evidence that the person has "Autoimmune POTS" like I do. I had many other autoimmune markers and auto-antibodies so it was ultimately a no-brainer for me (even though no guarantee that I would be a responder). Once I was on Rituximab for a good while, we were able to stretch out the IVIG interval to eight weeks and then stop it completely with no return of symptoms (but I am still on Rituximab which is the final piece of the puzzle and we don't know what happens to me when we stop it).

Jay Goldstein believed that IVIG worked for CFS in non-autoimmune mechanism.

What did he think was the mechanism?

As for my POTS, I only have it if I take thyroid hormone, especially Armour (which also has calcitonin in it to further complicate the calcium regulation, especially if you use it sublingually). I've done the start-stop experiment so many times that there's not a thread of doubt in my mind about the relationship between T3 and my dysautonomia. My choices have been essentially to take thyroid and have POTS and or not to take thyroid and have CFS, and I've spend the last 4.5 years trying to figure out this delicate balancing act.

We are actually completely different in this way (and my prior post might not have made sense)! I take Armour in pill form (and didn't even know that there was a sublingual- just as a side note). But back on topic, there was never any connection for me between taking Armour and having POTS. I first developed POTS (although not diagnosed until much later), literally overnight after a virus ended, in Jan 2013. I was not diagnosed with Hashi's and put on Armour until Oct 2013.

I tried many things for POTS (which was first diagnosed as IST or inappropriate sinus tachycardia). The first med that really helped AND that I tolerated very well was Atenolol. It stopped my HR from going into the 160's and 170's all throughout the day & night but I still had POTS. The only thing (for me) that led to remission of POTS was the combo of IVIG & later adding Rituximab. I still take Armour daily and have had no return of any POTS symptoms.

My illness in 2013 was totally different than in 2015 & 2016 (with each year progressively worse than the one before, until I began IVIG in July 2016). I still take Armour, Atenolol, and about seven meds total per day (plus many supplements). We do not think that I still need them all but since I've stopped IVIG and am tapering down on Cortef, we do not want to mess with too many things at once. I went from 15 mg/day Cortef to 13.75 to my current dose of 12.5 mg/day (with ultimate goal to get to zero but it is going to take a long time)! I see my Endo in 2 wks and the blood work will determine if I can start the next cut to get to 11.25 mg/day of Cortef.

 

[Iritu1021]

No worries and when you said we were very similar, I thought it might have meant that you also had IVIG.



I agree that no one (even doctors) seem to fully understand the mechanism of how IVIG works, especially in autoimmunity. I know you are a doctor (not sure what specialty?) but this confirms it even further! I keep hearing a statistic that 75% of IVIG is now used for autoimmunity but am not sure if it is accurate. I agree it was a leap of faith but it worked miracles for me, and the combination of overlapping it with Rituximab was what put my most intractable symptoms into remission.



My impression (which could be totally wrong) is that there are acute autoimmune conditions like Guillain Barre in which someone might have a five day cycle of IVIG and then never need it again and then there are also chronic autoimmune conditions in which someone might need it every three weeks, or every five weeks, etc, to maintain remission. I am not sure that there are any solid statistics re: for ME/CFS or POTS.

I know that many more doctors are now using it for POTS if they have evidence that the person has "Autoimmune POTS" like I do. I had many other autoimmune markers and auto-antibodies so it was ultimately a no-brainer for me (even though no guarantee that I would be a responder). Once I was on Rituximab for a good while, we were able to stretch out the IVIG interval to eight weeks and then stop it completely with no return of symptoms (but I am still on Rituximab which is the final piece of the puzzle and we don't know what happens to me when we stop it).



What did he think was the mechanism?



We are actually completely different in this way (and my prior post might not have made sense)! I take Armour in pill form (and didn't even know that there was a sublingual- just as a side note). But back on topic, there was never any connection for me between taking Armour and having POTS. I first developed POTS (although not diagnosed until much later), literally overnight after a virus ended, in Jan 2013. I was not diagnosed with Hashi's and put on Armour until Oct 2013.

I tried many things for POTS (which was first diagnosed as IST or inappropriate sinus tachycardia). The first med that really helped AND that I tolerated very well was Atenolol. It stopped my HR from going into the 160's and 170's all throughout the day & night but I still had POTS. The only thing (for me) that led to remission of POTS was the combo of IVIG & later adding Rituximab. I still take Armour daily and have had no return of any POTS symptoms.

My illness in 2013 was totally different than in 2015 & 2016 (with each year progressively worse than the one before, until I began IVIG in July 2016). I still take Armour, Atenolol, and about seven meds total per day (plus many supplements). We do not think that I still need them all but since I've stopped IVIG and am tapering down on Cortef, we do not want to mess with too many things at once. I went from 15 mg/day Cortef to 13.75 to my current dose of 12.5 mg/day (with ultimate goal to get to zero but it is going to take a long time)! I see my Endo in 2 wks and the blood work will determine if I can start the next cut to get to 11.25 mg/day of Cortef.

I came close to wanting to try IVIG but I was too sick at the time and had no energy to pursue it. I stopped all my prescription meds, took a ton of supplements and herbs and somehow POTS went away, and it would not come back until I started Armour again (same thing every time - great at first, then the periods of feeling good on it getting shorter and shorter until it stopped working). I've been checking my blood pressure religiously after every dose and found that blood pressure and pulse almost always would get better 30 min after the dose of thyroid and then the POTS would start getting worse about four hours after each dose. If I stay on the same dose for a while, the body would usually adjust and the negative effects become less pronounced but the positive effects would wear off too.

I think that I've also might have had short term episodes of POTS before I went on thyroid during acute flares of my thyroiditis which I believe felt like a viral illness. Or the thyroiditis itself might be caused by the viral activation within the thyroid gland, and the antibodies are just a "red herring". I have a friend who has anti-TPO antibodies >1000 and TSH 2.7 and she runs around all day like a champ without any thyroid medication. I have another friend with T3 of 2.3 and she has no issues whatsoever either. My antibodies even at my worst have only been around 300 and T3 around 3.1 - so go figure.

I guess I'm a "medical heretic", like Goldstein. He didn't really know what the mechanism of IVIG was, but he said that initially he used it for almost all of his CFS patients since it was the most effective drug, but then he figured it out that he could achieve the same effects through neurohacking so he stopped using it. I think he thought it had something to do with norepinephrine but I never found any study that would support that.

 

[Iritu1021]

@Gingergrrl , I forgot to tell you one more thing.
There is no such thing as sublingual Armour formulation. Allowing Armour pill to dissolve under the tongue is a trick I picked up from alt-thyroid websites. It tastes kinda yucky but you learn to get over it because of how good it makes you feel and how quickly it works. It's an equivalent of "snorting T3", it's the "thyroid crack".

 

[Learner1]

I've been trying desperately to understand all of the discussion above, as it seems significant...

First, some observations, then I'm hoping someone can answer a couple of questions...

1. From what I can tell, I acquired impaired mitochondrial function, causing my immune system to lack the energy to do its job, resulting in immunodeficiency (low IgG and IgM). This allowed EBV to reactivate and in time, triggered my POTS and MCAS autoimmunity. I have been on autoimmune dose IVIG for over a year.
   
2. I'd already had Hashimotos for 10 years, and was put on T3 only due to sky high reverse T3. A year and a half ago, we added T4 and reduced the T3, and I'm currently on 137mcg T4 and 50mcg split dose T3. I notice pretty immediate effects on taking T3. FT3 and FT4 are both midrange and TSH is always .01-.05 and don't ferl hypo or hyperthyroid (and am well aware of those symptoms...) I don't function on T4 only and can't take Armour, etc. due to allergens.
3. I also take 20mg hydrocortisone daily in 2 doses and drink about 3 cups of espresso daily and can't function without them.
4. Now, the calcium part. Serum calcium ranges from 9-9.4, low normal, but RBC calcium was at the 2nd percentile, which seems to mean that it isn't getting into cells. I also seem to be actively losing bone. I get 1200mg calcium daily in my diet and take another 1000mg with all the proper cofactors in supplement form, so I shouldn't be short.

My question is, where is all the calcium going? From what I've read in your dialog above, if my mitochondria don't have adequate calcium, they can't do OXPHOS, which brings me back to step 1.

How does one break out of this cycle?

 

[S-VV]

Well, we have two options. We can empirically try supplements like Lithium, Pregnenolone, Dandelion etc...

Or we can try to get some insight into what is going on: is it a deficiency of the Phospholipase C pathway, calcium ion channel disregulation, PTH aberrancies, or maybe even mutations in the VDR of cells, since vitamin D and calcium are very linked via calcitonin.

"Calcitonin is a hormone that is produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland.Calcitonin is involved in helping to regulate levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone"

 

[Learner1]

Or we can try to get some insight into what is going on: is it a deficiency of the Phospholipase C pathway, calcium ion channel disregulation, PTH aberrancies, or maybe even mutations in the VDR of cells, since vitamin D and calcium are very linked via calcitonin.

"Calcitonin is a hormone that is produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland. Calcitonin is involved in helping to regulate levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone"

Good questions. So, to test this, you'd test calcitonin and what else to get a good picture?

Thanks!

 

[Iritu1021]

Good questions. So, to test this, you'd test calcitonin and what else to get a good picture?

Thanks!

I've tried testing calcitonin but the test seems to be only designed to evaluate for really high doses in cases of medullary cell producing tumors.

Some people believe that calcitonin in Armour is not absorbed via GI tract but I suspect that in hyper-sensitive people like us it might still be enough to rock the boat. And certainly more so if you chew it or use it sublingually.

There's definitely some subtle difference in the effect that I observed from Armour which was not reproduced by any other form of thyroid.

I agree that there appears to be some reciprocal relationship between calcium and thyroid, and it's not a mere coincidence that both types of cells (thyroid and calcitonin) are localized to the same gland, with parathyroid gland working as an appendage.

If the IVIG article I quoted is correct, than IVIG releases large stores of calcium from the muscle cells but then the muscles runs out of their supply, and have to borrow calcium from the bone (which is like the Federal Reserve for body calcium needs). Plus high dose steroids impair bone remodeling so this might be why you're ending up in the negative balance.

I don't know if that's actually true but it's one possible explanation that I can think of. @Gingergrrl, have you noticed any change in your bone density after IVIG?

My bone density went up for the first time after I used lithium - but it's my personal anecdotal observation - could have been something else.

 

[drob31]

Well, we have two options. We can empirically try supplements like Lithium, Pregnenolone, Dandelion etc...

Or we can try to get some insight into what is going on: is it a deficiency of the Phospholipase C pathway, calcium ion channel disregulation, PTH aberrancies, or maybe even mutations in the VDR of cells, since vitamin D and calcium are very linked via calcitonin.

"Calcitonin is a hormone that is produced in humans by the parafollicular cells (commonly known as C-cells) of the thyroid gland.Calcitonin is involved in helping to regulate levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone"

VDR: rs731236 AG: 1/2
Notes:
Downregulated Vitamin D
receptor, can affect dopamine
levels


VDR: rs1544410 CT: 1/2



I'm heterozygous for those 2.

 

[Learner1]

If the IVIG article I quoted is correct, than IVIG releases large stores of calcium from the muscle cells but then the muscles runs out of their supply, and have to borrow calcium from the bone (which is like the Federal Reserve for body calcium needs). Plus high dose steroids impair bone remodeling so this might be why you're ending up in the negative balance.

Thank you for translating! Wow! I'll have to ask my doctor on Monday about this...

Due to some confluence of some genetic predisposition and external stressors, patients with CFS might develop states of cytosolic calcium depletion which in turn leads to mitochondrial calcium depletion which leads to hypometabolic cellular failure that makes it very difficult to climb out from.

This sounds reasonable...wonder what the solution is? Wonder if lipid membrane replenishment would help, or if it's the transporters/channels that are the problem...

Oh, I think.i forgot to mention that a week on amlodipine, a calcium channel blocker gave me pancytopenia, which lowered my platelets, RBCs and WBCs to dangerous levels and caused severe fatigue, enough to stop taking it even before the alarming labs finally showed up.

VDR: rs731236 AG: 1/2
Notes:
Downregulated Vitamin D
receptor, can affect dopamine
levels

VDR: rs1544410 CT: 1/2

I'm heterozygous for those 2.

Me too. But COMT and DRD SNPs affect dopamine too. I became depleted in dopamine (and was VERY lethargic) but now take 3-4g of tyrosine a day, which has kept my dopamine normal.

 

[Inara]

I read that IVIG also causes sarcoplasmic calcium release, a pretty massive one actually

This is an interesting thread. I'm just at the beginning, but I don't want to forget my questions. Do you have a reference for this by chance?

 

[Iritu1021]

hi @Inara

here's the reference for IVIg
https://www.ncbi.nlm.nih.gov/pubmed/9559984

@Gingergrrl
I went on Wikipedia page to look up rituximab and this is what I found:

The antibody binds to the cell surface protein CD20. CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cells. CD20 does not shed, modulate or internalise. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.

 

[drob31]

Taking calcium (2 grams a day, 1 gram is of calcium orate with magnesium) and 1/4 dose HTCZ, while I think my T4 levels are stabilizing (125 mcg levoxyl, switched over to this 5 weeks ago), and I'm pacing myself. Also have avoided any sort of extreme dopamine releasing activities (like orgasm) for a month.

 

[Gingergrrl]

here's the reference for IVIg
https://www.ncbi.nlm.nih.gov/pubmed/9559984

Thank you for the reference and I am very curious what my doctor thinks of it.

The antibody binds to the cell surface protein CD20. CD20 is widely expressed on B cells, from early pre-B cells to later in differentiation, but it is absent on terminally differentiated plasma cells. CD20 does not shed, modulate or internalise. Although the function of CD20 is unknown, it may play a role in Ca2+ influx across plasma membranes, maintaining intracellular Ca2+ concentration and allowing activation of B cells.

I am not sure if I understand this correctly... is it saying that Rituximab plays a role in the Ca2+ ions going across the plasma membranes, maintaining intracellular Ca2+ concentration, and allowing activation of B-cells or that the CD20 protein itself plays this role?

I was a huge responder to Rituximab and having my B-cells and CD-protein at zero played a huge role in my remission. I have many auto-antibodies with one of them being the N-type calcium channel autoantibody. I'm not sure how to put all of this information together but I assumed that the Rituximab was so helpful b/c it stopped autoantibody production, especially of this autoantibody.

But if CD20 plays a role in maintaining proper calcium levels, then wouldn't having CD20 at zero be a bad thing? (even though it was not in my particular case)? I hope my question makes sense?

 

[Inara]

The MCU has a very low affinity for calcium, so the cytosolic calcium concentration needs to be approximately 5-10 uM for significant transport of calcium into the mitochondria. Mitochondria are closely associated with the endoplasmic reticulum (ER), at contact sites, which contains stores of cellular calcium ions for calcium signaling. The presence of 1,4,5-triphosphate (IP3) triggers the release of calcium from these intracellular stores, which creates microdomains of high calcium concentration between the ER and the mitochondria, creating the conditions for the MCU to take up calcium

The Ryanodine Receptors (with calcium channel) and the inositol trisphosphate (IP3) receptors (with calcium channel) sit on the membrane of the ER/SR and regulate the calcium flux.

 

[Iritu1021]

Thank you for the reference and I am very curious what my doctor thinks of it.



I am not sure if I understand this correctly... is it saying that Rituximab plays a role in the Ca2+ ions going across the plasma membranes, maintaining intracellular Ca2+ concentration, and allowing activation of B-cells or that the CD20 protein itself plays this role?

I was a huge responder to Rituximab and having my B-cells and CD-protein at zero played a huge role in my remission. I have many auto-antibodies with one of them being the N-type calcium channel autoantibody. I'm not sure how to put all of this information together but I assumed that the Rituximab was so helpful b/c it stopped autoantibody production, especially of this autoantibody.

But if CD20 plays a role in maintaining proper calcium levels, then wouldn't having CD20 at zero be a bad thing? (even though it was not in my particular case)? I hope my question makes sense?

Your question sure makes sense but I don't know what to make of it either. Did you say that you had different types of issues before and after IVIG? Which symptoms were helped by IVIG and which ones by rituximab - were they the same or different?

Did the level of your calcium blocking antibody go down after rituximab?

 

[Iritu1021]

The Ryanodine Receptors (with calcium channel) and the inositol trisphosphate (IP3) receptors (with calcium channel) sit on the membrane of the ER/SR and regulate the calcium flux.

So to summarize, I see four levels through which the mitochondrial calcium flux can be regulated:

a) low serum levels of calcium (lack of dietary calcium or Vitamin D, malabsorption, hypoPTH, VDR defect, CaSR defect, genetic hypercalciuria)

b) at the level of plasma membrane entry into the cell (autoblockade or iatrogenic regulation of calcium channels in neurons, or CD20 receptor in lymphocytes)

c) at the level of the release from the ER/SR stores via IP3 (lithium) or ryanodine receptors (IVIG and caffeine) or lysosomes (Ambroxol); this step also appears to be potentiated by T3 by effect on Ca/ATPase

d) at the level of entry into the mitochondria (usually related directly to "c" but might involve dysfunction of the mitochondrial calcium uniporter); experimental drugs only

 

[S-VV]

That's a very nice summary. There are a few things that come to mind: Can we trace specific test results (ie low ionic calcium, bone osteoporosis) to the specific stage of the dysfunction?

Also, activating those G-coupled receptors that catalyze IP3 could be interesting. I'm going to try to find out what upregulates it

 

[Iritu1021]

That's a very nice summary. There are a few things that come to mind: Can we trace specific test results (ie low ionic calcium, bone osteoporosis) to the specific stage of the dysfunction?

Also, activating those G-coupled receptors that catalyze IP3 could be interesting. I'm going to try to find out what upregulates it

Yes, good idea, let us know what you find!

I've updated the summary with T3 effect on Ca/ATPase from @pattismith's quote in the beginning of the thread

 

[S-VV]

Phospholipase C in living cells: activation, inhibition, Ca2+ requirement, and regulation of M current

We have further tested the hypothesis that receptor-mediated modulation of KCNQ channels involves depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphoinositide-specific phospholipase C (PLC). We used four parallel assays to characterize the agonist-induced PLC response of cells (tsA or CHO cells) expressing M1 muscarinic receptors: translocation of two fluorescent probes for membrane lipids, release of calcium from intracellular stores, and chemical measurement of acidic lipids. Occupation of M1 receptors activates PLC and consumes cellular PIP2 in less than a minute and also partially depletes mono- and unphosphorylated phosphoinositides. KCNQ current is simultaneously suppressed. Two inhibitors of PLC, U73122 and edelfosine (ET-18-OCH3), can block the muscarinic actions completely, including suppression of KCNQ current. However, U73122 also had many side effects that were attributable to alkylation of various proteins. These were mimicked or occluded by prior reaction with the alkylating agent N-ethylmaleimide and included block of pertussis toxin-sensitive G proteins and effects that resembled a weak activation of PLC or an inhibition of lipid kinases. By our functional criteria, the putative PLC activator m-3M3FBS did stimulate PLC, but with a delay and an irregular time course. It also suppressed KCNQ current. The M1 receptor-mediated activation of PLC and suppression of KCNQ current were stopped by lowering intracellular calcium well below resting levels and were slowed by not allowing intracellular calcium to rise in response to PLC activation. Thus calcium release induced by PLC activation feeds back immediately on PLC, accelerating it during muscarinic stimulation in strong positive feedback. These experiments clarify important properties of receptor-coupled PLC responses and their inhibition in the context of the living cell. In each test, the suppression of KCNQ current closely paralleled the expected fall of PIP2. The results are described by a kinetic model

 

[S-VV]

Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome

... Autoantibodies against the M1 acetylcholine receptor (AChR) were shown in CFS patients and were associated with reduced binding of a M AChR ligand in brain detected by PET ...