The Broad Spectrum Of Disorders That Make Up Pots

[ramakentesh]

Well prettymuch the conclusion of a few different research groups have - to some degree - painted a better picture of the varied forms of POTS:

Partial Dysautonomia:

1. Autoimmune peripheral neuropathy (long tract/small fiber) / High Flow POTS.

2. Splanchnic neuropathy (stomach pooling with reflex sympathetic activation).

Work on these forms of POTS started with Streeten et al publishing work in the New England Journal of Medicine regarding reduced norepinephrine release in the legs of 11 POTS patients. This is now generally accepted as a possible causal mechanism in POTS. Research conducted by MAYO found antibodies in around 6 POTS patients (13% of those tested) perhaps suggesting an autoimmune component to these forms of POTS.

Stomach pooling or increased vasodilation of the stomach cavity was first noted in work published by Dr Stewart in New York.

Characteristics: Pooling either in the hands and feet or stomach region - hands and feet generally mottled, sometimes warm to the touch, stomach pooling often causes peripheral vasoconstriction (raynauds) to compensate. In hand/feet poolers, decreased peripheral resistance and as a consequence reduced blood flow to thorax and head.

Cerebral vasoregulation abnormalities

1. possible Parasympathetic autoregulation abnormalities

Work on these forms of POTS is very new and started with a recent publication by Dr Stewart et al regarding impaired vascular circulatory cerebral control in a select group of patients. It appears that these patients dont have pooling in their stomach, but rather excessive or abnormal vasodilation of their cerebral arteries resulting in blood pressure fluctuations and dizziness without a great increase in heart rate and normal BP.

The parasympathetic nervous system is implicated but research is in its early stages so there is much more to come.

Characteristics If pooling, specific to the stomach. vasoconstriction of periphery under orthostatic stress. Possible symptoms of parasympathetic withdrawal.

Hyperadrenergic presentations - primary sympathetic activation driven

1. NET deficiency

2. Low Flow - increased angiotensin/reduced neuronal nitric oxide, Norepinephrine potentiated

3. Denervation of kidney Possibly the same as above

4. Receptor hypersensitivity

5. An Autoimmune variety with auto-antibodies that are binding to beta 1 receptors (Grubb, personal communication)

This is the confusing variety of POTS.

When we talk about hyperadrenergic POTS many people may think that these are patients more prone to anxiety, or specific symptoms. This isnt necessarily the case - presentations can be very similar to other forms of POTS (Grubb and Vanderbilt University).

According to the Vanderbilt website it appears Hyperadrenergic POTS encompasses a spectrum of mechanisms, from obvious hyperadrenergic states like NET deficiency (NE left at the synaptic cleft, increased transduction and excessive vasoconstriction and peripheral resistance, postural hypertension, cerebral vasospasm), and a form of low renin and obvious hypovolumia, with increased venous filtration into the stomach area.

The vanderbilt website concludes that many hyperadrenergic patients may have denervation of the part of the kidney that controls renin.

Unpublished work by the Baker Institute in Melbourne case doubt on the kidney denervation hypothesis.

Other hypothesis were that hyperadrenergic POTS patients also had partial denervation of peripheral nerves and resultant hyperactivity of remaining ones. This has yet to be proven or disproven.

Shannon et al found in 2000 that a patients and her sibling with obvious symptoms of POTS had a gene coding error that resulted in loss of function of the Norepinephrine transporter protein. The mechanism is outlined above.

Enough for now - more to come...

[firewatcher]

Part of the difficulty of these problems is that all these researchers seem to be concentrating on the neuro-cardio component and NOT investigating the endocrine and renal aspects of this dysautonomias. It would take a closely organized, cross-disciplinary team of cardiologists, neurologists, nephrologists, endocrinologists and rheumatologists to sort out the whole autoimmune/cardiac/neural/endocrine effects. The only common denominator is a sustained 30bpm increase on standing. All our other symptoms vary so dramatically from person to person and day to day that they are only loosely tied together under the acronym POTS.

[Rosie]

Interesting post. Rama. But this is me, from what I understand so far.

I developed an aneurysm in the brain and see a neurosurgeon periodically to watch it. Once he remarked that my cerebral arteries were very large, "As in really, really large." I also have high levels of NE. And I believe that I have some autoimmune/autoinflammatory stuff going on. Whether the latter is due to low levels of D3 or not is yet to be determined.

Seems I am a mix!! And I would assume I am not the only one.

Nice reading about the working theories, though. Thanks for the post.

[bjt22]

I do believe that some of us might be "hybrids"....we might have more than one of these processes going on. That might account for the severity is some cases. What if, for example, one is genetically predisposed AND develops an auto-immune type response as well? One could have significant neuropathy as well as an inborn NET type deficiency or something along that order.

[janiedelite]

Yeah, my mom developed neuroendocrine cancer in her 30's, my brother got a neurofibroma at age 30, and I came down with neuropathic POTS at 32 so there is a strong genetic component in my case. As far as my POTS symptom presentation goes, I don't really "fit" totally into anyone's category, but there doesn't seem to be any life-threatening underlying cause so far...

[flop]

thankful, although it is very unusual for 3 first degree relatives to develop neuro problems in their 30s I don't think that there is anything to show that the three different illnesses that you have are genetically linked. Most inherited / genetic problems are due to one error in a tiny part of the body's DNA, this would result in a similar problem happening in all the affected family members.

For example it is known that there is a family tendancy to atopy - family members may get one or more of asthma, eczema or hayfever. Or a genetic problem with BRACA1 or BRACA2 leads to high risk of breast or ovarian cancer. But the conditions are linked through the mechanism of the problem, I don't think there is a link between POTS, Carcinoid and Neurofibroma.

Flop

[ramakentesh]

Part of the difficulty of these problems is that all these researchers seem to be concentrating on the neuro-cardio component and NOT investigating the endocrine and renal aspects of this dysautonomias. It would take a closely organized, cross-disciplinary team of cardiologists, neurologists, nephrologists, endocrinologists and rheumatologists to sort out the whole autoimmune/cardiac/neural/endocrine effects. The only common denominator is a sustained 30bpm increase on standing. All our other symptoms vary so dramatically from person to person and day to day that they are only loosely tied together under the acronym POTS.

Yeah a good point, but in some ways not necessarily so - the kidney angle in particular has been evaluated pretty strongly; you have work that indicates that the hypovolumia found in some POTS patients with unusually low renin responses to thoratic hypovolumia is tied to increased angiotensin II levels from low ACE2 activity limiting metabolism - and then the Vandy website talks about this observation as a possible result of kidney denervation.

There isnt really any evidence of kidney denervation and it was investigated by a few groups without anything being found. They could at least pay lip service to the angiotensin II angle. This is also an area of active research. So the renin paradox in 'hyperadrenergic' patients is yet to be explained.

Hypovolumia could also just be the result of excessive sympo-excitation.

Endocrine abnormalities are probably only being evaluated where they are implicated due to their vasoactive properties. Still your observations of estrogen is yet to be explained. My doctor basically said that this angle proved a dead end, beacuse most POTS patients have fairly normal endocrine activity so no abnormalities were present to investigate.

In my opinion POTS is probably not the result of multiple simultaneous problems. Particularly in cases - like mine - where the onset was totally abrupt. What people may forget is that many of these proposed mechanisms would have profound effects on other bodily functions: Elevated norepinephrine levels would have a profound effect on glucose storage and metabolism just as an example; constant hypovolumia wouldnt be fun for the kidneys, constant reduced blood flow to the liver and pancreas might cause problems (my liver doc doubted anyone had ever bothered to think of this angle).

NET deficiencies seem strange in itself - the original work on this angle found that this person had family members with the same functional mutation, but without POTS, which they concluded demonstrated that other genes and environmental factors were also at play.

The new autoimmune variety - the Beta 1 receptor angle seems very interesting. It might explain some of the presentations found on this website and I look forward to Grubb et al publishing it when they are able to (hopefully by the end of the year).

As for hybrids - no doubt - they say its a spectrum of presentations, not so much fixed subsets, although some subsets are obvious (stomach poolers).

At the end of the day - i dont have any firm answers, just thought Id collate where all the research was at in regards to patho-physiology.

[firewatcher]

"Yeah a good point, but in some ways not necessarily so - the kidney angle in particular has been evaluated pretty strongly; you have work that indicates that the hypovolumia found in some POTS patients with unusually low renin responses to thoratic hypovolumia is tied to increased angiotensin II levels from low ACE2 activity limiting metabolism - and then the Vandy website talks about this observation as a possible result of kidney denervation."

I disagree, the kidney angle has been explored, but not by nephrologists and the exploration looked rather one sided. Lack of perfusion to the kidneys could wreak all kinds of havoc that is unseen for many years, and the adrenals (those lovable little epinephrine makers that sit on top of the kidneys) have to have some insult if the kidneys don't get enough blood. I've seen Vandy's docs publish in Nephrology journals, but I have not seen reciprocal articles coming from Nephs.

"Endocrine abnormalities are probably only being evaluated where they are implicated due to their vasoactive properties. Still your observations of estrogen is yet to be explained. My doctor basically said that this angle proved a dead end, beacuse most POTS patients have fairly normal endocrine activity so no abnormalities were present to investigate."

Again, I disagree. Many of the women here have menstrual issues, and the Hypothalamus and especially the Pituitary are particularly susceptible to lack of perfusion. Many of the "idiopathic" Diabetes Insipidus patients have been found to have reduced cerebral blood flow (sounds like POTS to me!) Again, I've seen where the POTS docs are published in Endocrine journals, but not that much from endocrinologists on POTS and they see ALOT of dysautonomia through their thyroid and diabetic patients. My primary endo said he saw orthostatic intolerance all the time, just not independent of a recognizable endocrine disorder or mitral valve prolapse. I was very surprised that Vandy's team did not have a dedicated Endo or Neph on the team.

"In my opinion POTS is probably not the result of multiple simultaneous problems. Particularly in cases - like mine - where the onset was totally abrupt. What people may forget is that many of these proposed mechanisms would have profound effects on other bodily functions: Elevated norepinephrine levels would have a profound effect on glucose storage and metabolism just as an example; constant hypovolumia wouldnt be fun for the kidneys, constant reduced blood flow to the liver and pancreas might cause problems (my liver doc doubted anyone had ever bothered to think of this angle)."

I don't think that POTS is a combination of disorders, it is a combination of responses to a few, specific (yet to be discovered) abnormalities. No kidding that these crazy responses can have profound effects, ON EVERY SYSTEM IN THE BODY! From our mental functioning and mood all the way down to skin conditions! I think that those "other angles" need to be investigated, not just the 30 bpm increase side of things. The whole EDS connection is yet to be properly explained as well as the Mast Cell angle. Again, they tend to study the younger patients, before the effects of long terms POTS has taken any kind of toll. At that point it becomes impossible to tell whether the other conditions are comorbid or caused by POTS.

"At the end of the day - i dont have any firm answers, just thought Id collate where all the research was at in regards to patho-physiology."

No but by taking a different view, you might get more firm answers than someone who is convinced by their own medical specialty. Keep looking, it would not be the first time that a patient figured out the answer before the doctor did!

[ramakentesh]

I found the fact that this study got completing ignored by most researchers in POTS/OI quite surprising. It was messaged to me from a friend who likes the alternative to partial dysautonomia/neuropathy:

Norepinephrine resistance:

http://hyper.ahajournals.org/cgi/content/full/36/4/553

The partial dysautonomia/peripheral neuropathy angle suggests that due to a reduction in either noradrenergic release in the lower vasculature or a reduction in Alpha 1 receptors in the lower body, the sympathetic nervous system has to shoot of more NE to get the legs to do what they are supposed to do, and because the rest of the body often not desensitized, it is subject to the full ramifications of this increased NE release.

However, instead of the neuropathy being the primary problem - perhaps there is a plasma-born factor that is desensitizing 1 specific type of receptor or alpha receptors only in one specific area, requiring more NE to active the receptors and leaving the rest of the body and the other non-effected receptors (beta 1) subject to the full effects of NE potentiation.

It could be an antibody that is attaching to alpha 2 receptors, mediating a downregulation of one type of receptor, competing with NE for alpha receptors, etc. And potentially quite easy to treat.

Denervation could then occur as a result of disuse; desensitation could effect alpha receptors through the entire body or be specific to the kidneys or lower body - and when tested the receptors presense may be intact.

[ramakentesh]

The angiotensin II angle is an attractive angle in relation to the menstrual fluctation of symptom levels in female POTS patients - it also fluctuates in this cycle.

[firewatcher]

The angiotensin II angle is an attractive angle in relation to the menstrual fluctation of symptom levels in female POTS patients - it also fluctuates in this cycle.

Yes, but a LOT of things fluctuate in relation to menstrual flow! Neurotransmitters don't work as well in the brain with the lack of estrogen, melatonin secretion changes and water retention will play with blood pressure responses....

As I am sure you know, Women are completely different creatures!

[firewatcher]

A meatier explanation and discussion of POTS-flow.

[sue1234]

How did you find this old post?? I can't find anything older than May 2010. I've searched different topics and only can go back a year.

[firewatcher]

How did you find this old post?? I can't find anything older than May 2010. I've searched different topics and only can go back a year.

I put in insanely narrow search parameters because I knew what I was looking for. I can't get further than last year on general searches though.

[sue1234]

I hope we haven't lost access to all the old info and posts. It is a wealth of information!! I can Google something specific about POTS and end up in one of our old posts about it. But, on this board I can't search any of the old stuff.

[issie]

I'm sure I don't understand but about half of this, but wish that more people would have these in-depth discussions and maybe we could get more things figured out. Thanks for posting this.

[skiberthoud]

I second issies post! I'm loving these meatier topics! All I have to say is that i'm not sure that we will ever truly figure out the neuro-endocrine system, but it's so fun trying...

[nunntrio]

A meatier explanation and discussion of POTS-flow.

Thanks for bumping this up. Do you know if there have been any new studies to elaborate on this? This post is 1 1/2 years old. Rama has not posted much lately. I always like reading Rama's posts because they were full of this type of stuff.

[sue1234]

Raising my hand here for agreeing to liking these kinds of posts!!