REFEEDING SYNDROME - The clues to healing via induced deficiencies

Eastman

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While potassium supplementation is often discussed here on Phoenix Rising, especially as a consequence of refeeding syndrome while on the methylation protocol, the potential role of vitamin B1/thiamine in maintaining electrolyte balance is not often appreciated.

Acute thiamine deficiency and refeeding syndrome: Similar findings but different pathogenesis
Abstract
OBJECTIVE:
Refeeding syndrome can occur in several contexts of relative malnutrition in which an overaggressive nutritional support is started. The consequences are life threatening with multiorgan impairment, and severe electrolyte imbalances. During refeeding, glucose-involved insulin secretion causes abrupt reverse of lipolysis and a switch from catabolism to anabolism. This creates a sudden cellular demand for electrolytes (phosphate, potassium, and magnesium) necessary for synthesis of adenosine triphosphate, glucose transport, and other synthesis reactions, resulting in decreased serum levels. Laboratory findings and multiorgan impairment similar to refeeding syndrome also are observed in acute thiamine deficiency. The aim of this study was to determine whether thiamine deficiency was responsible for the electrolyte imbalance caused by tubular electrolyte losses.

METHODS:
We describe two patients with leukemia who developed acute thiamine deficiency with an electrolyte pattern suggestive of refeeding syndrome, severe lactic acidosis, and evidence of proximal renal tubular dysfunction.

RESULTS:
A single thiamine administration led to rapid resolution of the tubular dysfunction and normalization of acidosis and electrolyte imbalance. This demonstrated that thiamine deficiency was responsible for the electrolyte imbalance, caused by tubular electrolyte losses.

CONCLUSIONS:
Our study indicates that, despite sharing many laboratory similarities, refeeding syndrome and acute thiamine deficiency should be viewed as separate entities in which the electrolyte abnormalities reported in cases of refeeding syndrome with thiamine deficiency and refractory lactic acidosis may be due to renal tubular losses instead of a shifting from extracellular to intracellular compartments. In oncologic and malnourished patients, individuals at particular risk for developing refeeding syndrome, in the presence of these biochemical abnormalities, acute thiamine deficiency should be suspected and treated because it promptly responds to thiamine administration.
Thiamin and folic acid deficiency accompanied by resistant electrolyte imbalance in the re-feeding syndrome in an elderly patient
Abstract
INTRODUCTION:
Re-feeding Syndrome (RS) is a deadly complication, which can be encountered during "refeeding" of malnourished patients. In these patients, thiamin deficiency may develop and "risk awareness" is the most significant factor in the management of these patients. In this case report, the treatment is presented of an elderly patient who was diagnosed with RS and followed-up in the intensive care unit (ICU) due to resistant fluidelectrolyte imbalance.

CASE:
An 87-year-old elderly woman was admitted to the hospital due to aspiration pneumonia. On day 4, during parenteral nutrition (30 kcal/kg/day), severe electrolyte imbalance developed. Total parenteral nutrition (TPN) was stopped, and enteral feeding together with potassium (90 mmol/day, i.v.) were started. During follow-up, plasma potassium values remained less than 3 mmol/L. Despite replacement therapy, hypoalbuminemia, hypomagnesemia, hypocalcemia, and hypophosphatemia persisted. Considering the parenteral nutrition (30 kcal/kg/day) during the hospitalization period, a diagnosis of RS was made. On day 10, thiamin (200 mg/day, i.v.) and folic acid (5 mg/day) were added, and the patient subsequently responded to electrolyte replacement treatment. The patient was discharged on day26 with a home-care plan.

CONCLUSION:
In patients with malnutrition, thiamin replacement should be given before starting nutrition to prevent RS. Energy intake should be 10kcal/kg/day at the start, and be gradually increased between days 4-10. Hemodynamic-laboratory parameters should be closely monitored. All these measures may be life-saving for patients at high risk.
 

Freddd

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I have been going through refeeding syndrome for 15 years now. It is become more clear that there are several forms of refeeding syndrome. The kind that is best known is the outright complete starvation of all nutrients with partial starvation. That can include a general extreme anorexia and/or lack of ability to eat during severe illnesses.


At the other end is a single item pinpoint starvation, such as somebody like me has. Because of genetic polymorphisms, I can't utilize CyCbl, HyCbl, folic acid, folinic acid and many vegetable folates. So those specific deficiencies slow or stop cell formation. The second effect is that the nutrient delivery pathways of other nutrients slows down delivery of other nutrients to match the need from the limited cell formation. This can go on for years. I ended up
So a single item like needing MeCbl or methylfolate ends up with a 4 way deadlock limited to the amount it had to deliver to go with the most limited item. Then secondary items pathways get tighter. I believe that is what happened to the patient in the case study above this.

Some items like B12 and folate are needed for all cell formation. B1, B2, B3 and other items can drive cell formation in certain directions. When my hematocrit was getting too high, I was able to reduce it by decreasing P5P which "drives" the hematocrit. So basically as my cell formation came on line, everything ended up being insufficient, mostly one at a time, the next one in order. After 6 years of healing and taking just a multi micromineral for those items I developed copper, boron. manganese, molybdenum, vanadium, lithium orotate (non-ionic trace mineral dose) and vanadium all had degrees of insufficiency that had been slowly building up. They all had a potassium need within a few days of starting. The vanadium (10 mg vanadyl sulphate, 2 mg vanadium worked wonderfully on trace mineral dose) also caused a relapse in copper insufficiency while it lowered cholesterol and improved insulin sensitivity according to tests. It also increase potassium need so the mechanism is at least in part cell formation.

The "wide" starvation refeeding syndrome hits harder because everything is missing but the pathways were not "narrowed" over the decades. The "narrow" pinpoint single item starvation (ie B12 and/or folate and others) appears to make for a long lasting one item at a time (and that is taking all needed nutrients in normal amounts) each nutrient comes to insufficiency that after correction, goes to the next item that gets utilized in the metabolism. And often as the pathways are rebuilt, other items become insufficient again as the rebuilt pathways become not wide enough a number of times.. This goes on potentially for the rest of one's life approximately.

There is very little research on these refeeding syndrome variations. Most of us are learning the hard way. It is possible to keep healing going for years. The other part of the trick is to learn to recognize the up and coming deficiency before it does more damage and correct it. Each of us has a pattern of how these develop. Keeping track of the symptoms each time they change can give one the answers..

I find that if one starts with the basics of cell formation, all basics in modest doses, MeCbl, AdoCbl, l-methylfolate and l-carnitine gets cells forming and then specific symptoms pop up for where the cell growth is stopping for some insufficient nutrient. None after that come up until that one is fixed allowing the healing to progress further. So until the basic cell formations are happening, copper deficiency doesn't show up, and similarly with the other trace minerals. Good luck.
 

Athene*

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While potassium supplementation is often discussed here on Phoenix Rising, especially as a consequence of refeeding syndrome while on the methylation protocol, the potential role of vitamin B1/thiamine in maintaining electrolyte balance is not often appreciated.

Acute thiamine deficiency and refeeding syndrome: Similar findings but different pathogenesis


Thiamin and folic acid deficiency accompanied by resistant electrolyte imbalance in the re-feeding syndrome in an elderly patient
I've read on a few forums now that ordinary forms of B1 (HCL, mononitrate) and the synthetic form, Benfotiamine really suck up potassium, but that Alliathimin does not and can even help to normalise potassium. I wonder if you've found that? I'm going to try it, given my drastic low potassium response to refeeding syndrome from Methylb12 & methylfolate. Being coeliac and possibly having some odd B1 transporter defect and now B1 deficiency symptoms, I hope I can manage to take Allithiamin and that it's not going to be difficult to tolerate, side effect wise.

I haven't read those links you provided yet, but will do, thanks.
 
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Athene*

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I have been going through refeeding syndrome for 15 years now. It is become more clear that there are several forms of refeeding syndrome. The kind that is best known is the outright complete starvation of all nutrients with partial starvation. That can include a general extreme anorexia and/or lack of ability to eat during severe illnesses.


At the other end is a single item pinpoint starvation, such as somebody like me has. Because of genetic polymorphisms, I can't utilize CyCbl, HyCbl, folic acid, folinic acid and many vegetable folates. So those specific deficiencies slow or stop cell formation. The second effect is that the nutrient delivery pathways of other nutrients slows down delivery of other nutrients to match the need from the limited cell formation. This can go on for years. I ended up
So a single item like needing MeCbl or methylfolate ends up with a 4 way deadlock limited to the amount it had to deliver to go with the most limited item. Then secondary items pathways get tighter. I believe that is what happened to the patient in the case study above this.

Some items like B12 and folate are needed for all cell formation. B1, B2, B3 and other items can drive cell formation in certain directions. When my hematocrit was getting too high, I was able to reduce it by decreasing P5P which "drives" the hematocrit. So basically as my cell formation came on line, everything ended up being insufficient, mostly one at a time, the next one in order. After 6 years of healing and taking just a multi micromineral for those items I developed copper, boron. manganese, molybdenum, vanadium, lithium orotate (non-ionic trace mineral dose) and vanadium all had degrees of insufficiency that had been slowly building up. They all had a potassium need within a few days of starting. The vanadium (10 mg vanadyl sulphate, 2 mg vanadium worked wonderfully on trace mineral dose) also caused a relapse in copper insufficiency while it lowered cholesterol and improved insulin sensitivity according to tests. It also increase potassium need so the mechanism is at least in part cell formation.

The "wide" starvation refeeding syndrome hits harder because everything is missing but the pathways were not "narrowed" over the decades. The "narrow" pinpoint single item starvation (ie B12 and/or folate and others) appears to make for a long lasting one item at a time (and that is taking all needed nutrients in normal amounts) each nutrient comes to insufficiency that after correction, goes to the next item that gets utilized in the metabolism. And often as the pathways are rebuilt, other items become insufficient again as the rebuilt pathways become not wide enough a number of times.. This goes on potentially for the rest of one's life approximately.

There is very little research on these refeeding syndrome variations. Most of us are learning the hard way. It is possible to keep healing going for years. The other part of the trick is to learn to recognize the up and coming deficiency before it does more damage and correct it. Each of us has a pattern of how these develop. Keeping track of the symptoms each time they change can give one the answers..

I find that if one starts with the basics of cell formation, all basics in modest doses, MeCbl, AdoCbl, l-methylfolate and l-carnitine gets cells forming and then specific symptoms pop up for where the cell growth is stopping for some insufficient nutrient. None after that come up until that one is fixed allowing the healing to progress further. So until the basic cell formations are happening, copper deficiency doesn't show up, and similarly with the other trace minerals. Good luck.
'I can't utilize CyCbl, HyCbl, folic acid, folinic acid and many vegetable floates.' I have the same problems and multiple genetic mutations that show reduced function in B12 & Folate absorption, transportation & recycling. I also have pernicious anaemia diagnosis and have OAT testing that shows difficulty with Krebs and low B2 and raised MMA (slowly improving). I have been following your regimen for two years now @Freddd and am very grateful to you for the improvement in function it has given me (bedridden to housebound to small amount of walking outside).

I don't know how you manage with all those refeeding challenges and I'm not sure I'm up to the task but will keep trying. The last few months I'm having some low thiamine concerns (I'm coeliac so can't get any from food and have odd genetics around B1 as well as folate & B12).

Because of your reaction to higher dose thiamine, I have been reluctant to take anything more than the low dose thiamine in the low dose B complex you recommend.

But what do you think of Allithiamin (fat soluble form of B1 easy to absorb into cells and crosses BBB) that has been shown to normalise electrolytes (google Dr Lonsdale, Allithiamin if you're interested) and stop potassium loss which other forms of B1 caused you? Would that fit with your regimen?
 

Kathevans

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@Athene* I found that Thiamine HCL didn’t resolve my heart issues, and in fact initially aggravated them. It may have helped eventually, but on reading the B1 thread, I ordered and took Allithiamin for a month to six weeks up to about 150 mg/ day. What it caused, though, was more IBS and stomach upset, and I realized that the garlic/allicin was probably causing some of the symptoms and switched to Benfotiamin, again titrating up to the 150mg/day level. It seemed to help the IBS, at least initially. Neither one caused an increase in my need for potassium, and the Benfotiamin which I’m currently taking may lower potassium need somewhat even at the 150mg/day dose.

My heart chronic palpitations were resolved by the Benfotiamin. The other symptom that was helped was my sore and weak calves. In fact when I have tried to lower the dose, thinking it might be replete, the symptoms return, and I raise it again.

But dismayingly, I seem to be stuck in some form of refeeding where my IBS is fairly chronic though kept barely under control alternately by AdoB12, Carnitine, Folate and occasionally by Methyl B12. And I keep thinking more thiamine might also lower my fairly high Folate intake of about 18-20mg/ day. @Freddd has been at this for a long time, but I am still trying to parse the symptoms, ‘feel’ my way to the predominant symptom for each item.

The latest and most complex seems to be the carnitine for me. Strangely, once I started to take it last fall, I seem to absolutely need it. I can stay off it from days to a week or two and then horrible symptoms of insomnia (though my sleep has never been anything but haphazard) occur and a sort of anxious agitation and a tightness of my muscles, and only the carnitine will make things relax. Interestingly, in recent months, the carnitine has sometimes given me a three or four hour span of sleep that comes as a complete and welcome surprise.

Yet, raising the carnitine, even a bit might work briefly, but then backfire on me.

Well, I really can’t say. I’m flummoxed.

I am convinced that at least occasionally, the IBS which can become diarrhea is a form of detox—particularly since adding the carnitine. But this unsteady gut, sometimes burbling through the night is disturbing. I’ve been trying unsuccessfully to get the attention of my gastroenterologist. She has treated me for SIBO in the past, and perhaps I’m back in this place. I’ll have the try her again when sunlight hits this side of the planet...
 
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Kathevans

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@Athene* I may have said this before, but Looking back at some of my research, it seems I have the SLC19A1 snps as homozygous, which relates to folate transport, but NOT the SLC19 A2,relating to Thiamine. Though, of course, there may be others.

This might help a bit: https://www.ncbi.nlm.nih.gov/pubmed/1477031

The SLC19 gene family of solute carriers is a family of three transporter proteins with significant structural similarity, transporting, however, substrates with different structure and ionic charge. The three members of this gene family are expressed ubiquitously and mediate the transport of two important water-soluble vitamins, folate and thiamine. The concentrative transport of substrates mediated by the members of this gene family is energized by transcellular H(+)/OH(-) gradient. SLC19A1 is expressed at highest levels in absorptive cells where it is located in a polarized manner either in the apical or basal membrane, depending on the cell type. It mediates the transport of reduced folate and its analogs, such as methotrexate, which are anionic at physiological pH. SLC19A2 is expressed ubiquitously and mediates the transport of thiamine, a cation at physiological pH. SLC19A3 is also widely expressed and is capable of transporting thiamine. This review summarizes the current knowledge on the structural, functional, molecular and physiological aspects of the SLC19 gene family.
 

Kathevans

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I also posted this information on:
https://forums.phoenixrising.me/index.php?threads/transdermal-b12-oils.33172/page-33

I have been dealing with multiple deficiencies, as well as amalgam issues and my use of the B-12 Oils had increased to about 4 squirts, two of the simple Methyl and two of the Ado/Methyl combo. I've been cleared of amalgam for exactly three months and my current use has dropped to of squirt of each daily (the simple Methyl is less activating if I need something late in the day or at night...) (I find I can 'feel' the oils entering my system very fast, that is, within 15-20 minutes, actually; and I find they seem to last about 6 hours for me, though this may be shifting)

However, I've also been following Fred's protocol (as well as Greg's advice) and came finally--and very significantly--to Boron, which I had titrated up on over the past couple of months. According the Greg, it takes a month or possibly more for cells that haven't been functioning with a particular supplement to die off and new ones to begin to utilize it (or something like this!) and I have found this to be true on multiple occasions. It was only recently when a NutrEval Test showed that I STILL was deficient in B2--and therefore still missing something it needed to get going and thus wasn't recycling B-12 or Folate--that Greg recommended taking a multi that had some things that many people don't get around to (boron, vanadium, chromium). His recommendation was the Life Extension One per Day that had these things in it. In any case, because it also had alpha-lipoic-acid and folks who still have amalgam in their mouths should stay away from it until they are free and clear, I got what was still missing in a separate supplement, ie the boron, and began to titrate it.

Interestingly, as Fred describes in his REFEEDING thread, I had all the symptoms of refeeding--ibs, heart irregularities, higher potassium need, excruciating insomnia--and am still, even after two months, refeeding Boron. I have only just reached the 3mg that the NOW tablet contains (and the Life Extension multi) and I will say that Boron has changed my life. My host of symptoms, while still there, respond better, my arthritic, painful hands bend easily for at least portions of the day, I am sleeping more deeply most nights, my need for B-12 had dropped, as has my Folate dose (from about 15mg/day to about 5-6mg). All in all, it's amazing. And most of all, I have begun on some days to feel 'normal'. Not better, but headed in that direction. This after being ill for about 25 years.

So, I'll have to post this elsewhere, I think, or write a blog. I have been working on methylation issues for the past 3 years--it has been my life, and not happily so, I have to admit. But I have been faithful to it and, as much as I didn't want to be, patient...

That said, this forum lead me down the path that brought me to here and I am beyond grateful. What I have learned is that it's all relevant! Right down to those microminerals. Another shoe could drop, of course. I'm by no means complacent... In fact, I'm working assiduously on my gut now (l-glutamine, probiotics, digestive enzymes, etc).

With a nod of ardent appreciation to @Athene* and @Johnmac and @garyfritz and @caledonia and @ahmo and @stridor and @Gondwanaland and @Eastman and many, many others.

Oh, and above all, to @Freddd and Dr. Gregory Russell-Jones.
 

Freddd

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'I can't utilize CyCbl, HyCbl, folic acid, folinic acid and many vegetable floates.' I have the same problems and multiple genetic mutations that show reduced function in B12 & Folate absorption, transportation & recycling. I also have pernicious anaemia diagnosis and have OAT testing that shows difficulty with Krebs and low B2 and raised MMA (slowly improving). I have been following your regimen for two years now @Freddd and am very grateful to you for the improvement in function it has given me (bedridden to housebound to small amount of walking outside).

I don't know how you manage with all those refeeding challenges and I'm not sure I'm up to the task but will keep trying. The last few months I'm having some low thiamine concerns (I'm coeliac so can't get any from food and have odd genetics around B1 as well as folate & B12).

Because of your reaction to higher dose thiamine, I have been reluctant to take anything more than the low dose thiamine in the low dose B complex you recommend.

But what do you think of Allithiamine (fat soluble form of B1 easy to absorb into cells and crosses BBB) that has been shown to normalise electrolytes (google Dr Lonsdale, Allithiamin if you're interested) and stop potassium loss which other forms of B1 caused you? Would that fit with your regimen?
HI Athene,

I just finished Benfotiamine trial. I did 2 months of it and got more and more potassium short. It was 150mg of Benfo and 100mg of B1. It's hard to say but it may have helped my peripheral neuropathy. But I can't stand to do it too long. It turned out I needed all the microminerals.

However, my Copper level is improving and may also be a contributor to improved neuropathies.

Every several months I have to change forms or brands of methylfolate to restore effectiveness. This has happened with all of the other 5 now who had the methylfolate symptoms coming back despite taking 15mg or whatever. I take 45mg/day. Suddenly I started getting angular cheilitis, first time in some years. A day or two of Quatrefolic, or a different generic salt of L-methylfolate or even a different maker did the trick, and the functionality of my usual mfolate continued relieve the cheilitis after the short use of the other folate brand.

I've also had to change copper type, l-carnitine (fumarate, tartrate, freebase). So for some reason which I can only hypothesize, I have to vary mfolate type or brand if effectiveness is lost. The interval for me has settled down to each 3 months or so after an initial occurrence of some years.

Allithiamine sounds worthwhile to try.

It's great to hear of your 2 years improvement and able to walk some outside. When I reached that point, after about 2 years, I started increasing my walk by 1 driveway (50-60 feet) in that neighborhood each day. In a year I was doing 5 mile walk starting at a few hundred feet. When I added the l-carnitine my Ski Trac device time went from 17 minutes, where I had been stuck for 3 years, to 34 minutes the first day and increased by 3 minutes per day after that. I put on 50 pounds of muscle replacing previously atrophied muscle.IUt was denser and I am a sinker instead of a floater in a pool.

I found that AdoCbl if in place of MeCbl gives the same response as HyCbl or CyCbl, methyltrap and lesions forming. So once a week for AdoCbl was completely adequate for me, 10mg sublingual dose, once a month 50mg for CNS penetration. My daughter had to have it every day.

As you collect your data your pattern will become more and more obvious. MeCbl and Mfolate make cells, ALL cells. So when cells should be getting made and not, look for what deficiency is occurring. Recognition of refeeding syndrome has made this so much easier for me becasue it is usually shuttling around between familiar things and occasionally something new. My copper deficiency first appeared about 6 years of healing. It hit just after healing from the glutathione trial which finally exhausted copper and boron giving me varicose veins, gum deterioration and unstopping decay from low boron.
 
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Athene*

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Thanks for this @Freddd

I seem to follow your experience so closely with everything you've done and I'm very grateful for your sharing of your Refeeding experience. I will keep on eye on the folate type and try changing if necessary. I mistakenly ordered a methylfolate with glycine (10 bottles!). Is glycine on the list of glutathione precursors? If so I'll just have to dump it.

Unbelievably I was diagnosed four weeks ago, after an operation, with Refeeding Syndrome.

I ended up in ICU with hypokalemia (I had warned them to look out for this) and hypophosphatemia (low phosphorous). It was an African visiting doctor who recognised the Refeeding Syndrome and we had a great discussion about B12 replacement etc. My consultant was prepared to trust him (and me!). He had seen Refeeding Syndrome in India. My magnesium was low too. It has since improved since using magnesium spray.

However there is nobody else medical in Ireland who recognises Refeeding Syndrome, apart from my primary care doc (GP) who is prepared to go along with the diagnosis and prescribe the phosphate (only available on prescription here), but she doesn't feel too comfortable treating this on her own. I need 1000mg of Phospate x 3 times daily. It has made a huge difference to my energy and blood counts (haemoglobin, red cell count, iron etc all in range now, and elevated ferritin I had for years has come into normal range). Doc is keeping an eye on blood phosphate levels.

I only realised last week that I had been barely in range for phosphorous (Inorganic phosphate on CBC blood tests) since 2012, when I first tried injecting B12. When I began your supplement advice in 2014 and got going on the protocol properly in 2015/16, the phosphorous markedly dropped without me noticing. It has made such a difference since I began taking the phosphate three weeks ago - unbelievable. I do find too much calcium makes phosphorous go low so I'm keeping calcium to 300mg for now (with boron and vitamin K as well).

Unfortunately there were some cancer cells in the growth which was removed during the operation. It seems to be extremely rare in presentation. It has been sent away for a second opinion and the consultant said it 'may not even be cancer'. Fingers crossed.

So I'm hoping it's some odd malformation caused by low folate for decades, but hopefully not malignant. I won't know for another couple of weeks. There was some speculation about sarcoma but it didn't really match that either so they are flummoxed.

While I wait for results I have been busy researching immunotherapy, just in case, because there's no way I will ever agree to chemo (anti folate and anti metabolite). I want to keep my DNA turning over! I feel very well now, ironically, and my bloods are good, so I'm hoping that whatever it was has been taken away. The oncologist knows I'm on high dose Meb12 injections & Methylfolate and that if I stop I may not get methylation going again.

I'm placing my hope in new immunotherapy treatments (checkpoint inhibitors that allow the immune system to recognise and attack cancer cells) if the worst happens, and he is open to this. Freddd, I'm not asking you to give medical diagnoses but if you have any ideas at all or any caveats, they would be gratefully accepted, either here or possibly in a private message if you get time.

Thanks again, Freddd. I have had such improvement in quality of life over the past two years especially and it's all thanks to your generosity in sharing what has helped you. Before this I was in bed unable to support my head or lift my arms and with a hot water bottle for hypothermia even in high summer. I was very unsteady in my gait when I got up for the toilet and had bad neuropathy in my feet and had to crawl - all now long gone. I think we may have similar genes. My Dad died young and very slowly and agonisingly of a mysterious demyelinating disease, misdiagnosed as MS (first as ME) but no MS brain lesions were found on autopsy. The demyelination was found on lumbar puncture while he was alive in the 1980s. His serum B12 was high, like mine (600 or thereabouts for years) even with my high MMA & homocysteine and MCV of 105 for years...so he was never treated with B12.


PS
Re Allithiamine: I do find it helps (especially with tinnitus and hearing loss I had) and it seems to have helped potassium stabilise, though I still need 3.5K potassium gluconate daily. I find that I can only take half the Allithhiamine capsule daily so it's a small dose, otherwise too much potassium demand. But Allithiamine seems to have helped to be able to tolerate a little more LCF (now on 1/4 of Dr's Best 500mg capsule). And just as you have noted, I get dreadful low folate symptoms if I try to take Adocbl daily, even with multiple MeB12 injections I can only manage 2mg of Adocbl about an hour before my last MEb12 injection of the day and even then I will get some low folate symptoms next morning. I think I will go to weekly Adocbl now and the CNS dose regularly as you advise.

Continued success to you. Your regime definitely works, not that you need me to tell you that...
 
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Freddd

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Thanks for this @Freddd

I seem to follow your experience so closely with everything you've done and I'm very grateful for your sharing of your Refeeding experience. I will keep on eye on the folate type and try changing if necessary. I mistakenly ordered a methylfolate with glycine (10 bottles!). Is glycine on the list of glutathione precursors? If so I'll just have to dump it.

Unbelievably I was diagnosed four weeks ago, after an operation, with Refeeding Syndrome.

I ended up in ICU with hypokalemia (I had warned them to look out for this) and hypophosphatemia (low phosphorous). It was an African visiting doctor who recognised the Refeeding Syndrome and we had a great discussion about B12 replacement etc. My consultant was prepared to trust him (and me!). He had seen Refeeding Syndrome in India. My magnesium was low too. It has since improved since using magnesium spray.

However there is nobody else medical in Ireland who recognises Refeeding Syndrome, apart from my primary care doc (GP) who is prepared to go along with the diagnosis and prescribe the phosphate (only available on prescription here), but she doesn't feel too comfortable treating this on her own. I need 1000mg of Phospate x 3 times daily. It has made a huge difference to my energy and blood counts (haemoglobin, red cell count, iron etc all in range now, and elevated ferritin I had for years has come into normal range). Doc is keeping an eye on blood phosphate levels.

I only realised last week that I had been barely in range for phosphorous (Inorganic phosphate on CBC blood tests) since 2012, when I first tried injecting B12. When I began your supplement advice in 2014 and got going on the protocol properly in 2015/16, the phosphorous markedly dropped without me noticing. It has made such a difference since I began taking the phosphate three weeks ago - unbelievable. I do find too much calcium makes phosphorous go low so I'm keeping calcium to 300mg for now (with boron and vitamin K as well).

Unfortunately there were some cancer cells in the growth which was removed during the operation. It seems to be extremely rare in presentation. It has been sent away for a second opinion and the consultant said it 'may not even be cancer'. Fingers crossed.

So I'm hoping it's some odd malformation caused by low folate for decades, but hopefully not malignant. I won't know for another couple of weeks. There was some speculation about sarcoma but it didn't really match that either so they are flummoxed.

While I wait for results I have been busy researching immunotherapy, just in case, because there's no way I will ever agree to chemo (anti folate and anti metabolite). I want to keep my DNA turning over! I feel very well now, ironically, and my bloods are good, so I'm hoping that whatever it was has been taken away. The oncologist knows I'm on high dose Meb12 injections & Methylfolate and that if I stop I may not get methylation going again.

I'm placing my hope in new immunotherapy treatments (checkpoint inhibitors that allow the immune system to recognise and attack cancer cells) if the worst happens, and he is open to this. Freddd, I'm not asking you to give medical diagnoses but if you have any ideas at all or any caveats, they would be gratefully accepted, either here or possibly in a private message if you get time.

Thanks again, Freddd. I have had such improvement in quality of life over the past two years especially and it's all thanks to your generosity in sharing what has helped you. Before this I was in bed unable to support my head or lift my arms and with a hot water bottle for hypothermia even in high summer. I was very unsteady in my gait when I got up for the toilet and had bad neuropathy in my feet and had to crawl - all now long gone. I think we may have similar genes. My Dad died young and very slowly and agonisingly of a mysterious demyelinating disease, misdiagnosed as MS (first as ME) but no MS brain lesions were found on autopsy. The demyelination was found on lumbar puncture while he was alive in the 1980s. His serum B12 was high, like mine (600 or thereabouts for years) even with my high MMA & homocysteine and MCV of 105 for years...so he was never treated with B12.


PS
Re Allithiamine: I do find it helps (especially with tinnitus and hearing loss I had) and it seems to have helped potassium stabilise, though I still need 3.5K potassium gluconate daily. I find that I can only take half the Allithhiamine capsule daily so it's a small dose, otherwise too much potassium demand. But Allithiamine seems to have helped to be able to tolerate a little more LCF (now on 1/4 of Dr's Best 500mg capsule). And just as you have noted, I get dreadful low folate symptoms if I try to take Adocbl daily, even with multiple MeB12 injections I can only manage 2mg of Adocbl about an hour before my last MEb12 injection of the day and even then I will get some low folate symptoms next morning. I think I will go to weekly Adocbl now and the CNS dose regularly as you advise.

Continued success to you. Your regime definitely works, not that you need me to tell you that...


'I mistakenly ordered a methylfolate with glycine (10 bottles!). Is glycine on the list of glutathione precursors? If so I'll just have to dump it." - That is the MethylPro l-methylfolate. I take TMG, trimethylglycine, and various things that use the glycine. It appears to be no problem at all. My usual order from them is 4x90 15mg caps and 1 bottle of their Quatrefolic product. I think both of them are quite excellent. Either one works for about 3 months for me and then suddenly it doesn't and I have to switch to the other for a day or two and then the effectiveness of returns of the original. I take 15mg 3 times daily, one on wakeup, one at bedtime and one with my late afternoon medications. I don't take it with food and and the stack of everything else becasue I have some things blocking other things and I didn't know whether the mfolate was being blocked by anything else. Then I switch to the MethylPro Quatrefolic. It's more expensive so I and my partner both use it as our 1-2 day refresh mfolate that gives back the effectiveness of the original product used. She has quite a different problem than I do but has the same thing happening with the mfolate.

The CblC disease is my trigger into the 4-way deadlock of MeCbl, AdoCbl, L-methylfolate and L-carnitine (best personal typer and it can change; fumarate is most often the one to start with). However folate related polymorphisms can be a trigger. For some people like me glutathione is a trigger. It ties up the MeCbl/AdoCbl and excretes it promptly causing methyltrap when a cell needs MeCbl and doesn't get it, then the methylfolate is kicked out of the cell and the symptoms of the cell failure are paradoxical folate deficiency symptoms. It quickly casues various types of lesions in epithelial tissues very rapidly.

I'm in the USA. I checked out the phosphate situation in the USA and it was rarely a problem, the writer saying becasue the usual diet has high amounts of phosphorus becasue of dough conditioners, phosphoric acid in soft drinks, and so on. I don't eat those but I take lecithin with phosphatidylcholine and/or phosphatidylserine and such.

One time a person posting mentioned she had ended up in the ER with hypokalemia. They tested and it showed 4.2, about midrange. However, her symptoms worsened and they tested every hour an in 3 hours it was down to 3.5. In me, the CblC has problems with electrolytes. It seems that for me the potassium can't get pulled from the tissue and I need to keep a relatively level serum level by drinking water with potassium gluconate.

I do subcutaneous MeCbl injections. The overlapping series keeps my serum level pretty constant.

600pg/ml of serum cobalamin is actually quite low. I need to maintain > 220,000 pg/ml to keep my nerves from demyelinating and/or keep up with the repairs.


"I ended up in ICU with hypokalemia (I had warned them to look out for this) and hypophosphatemia (low phosphorous). It was an African visiting doctor who recognised the Refeeding Syndrome and we had a great discussion about B12 replacement etc." - You were fortunate to see a doctor who had seen the aftermath of starvation, refeeding syndrome, and recognize the "slow" version of it rather than the acute form gotten with starvation.

The high MMA and HCY are functional proof of deficiencies affecting the methylation-ATP process. There is also a methylation process inside the mitochondria based on AdoCbl withTMG instead of the MeCbl with methylfolate methylation. The one internal to the mitochondria and the external process can happen at different rates and can affect the balance. TMG with the carnitine works in the mitochondria and and reduces the energized-edginess of the MeCbl-methylfolate pathway. They are both needed. The important thing to remember with these things is on the first day of adding or increasing something with symptoms shows what is being positively affected and the refeeding symptoms typically start on the 3rd day for the clues to what is next. The microminerals are the most difficult. The deficiency symptoms can be diminishing the next couple of days (benefits) and on day 5 or 6 the next induced deficiency symptoms start popping up, some very slowly. Most of these things happen in a 5-6 day cyclke if you can spot them with the first symptom up from the usual group. My first folate deficiency symptom is putting on 2-3 pounds of water in a day (edema). Increasing folate (or switching methylfolate form) starts the water pouring out and that takes potassium with it. Watch out for that.

Do you have copies of the refeeding symptoms list as it currently is? Can you specify the phosphate deficiency symptoms that come on fast and then slow, and how much phosphate the doctor prescribed?

One thing I have found is that things keep on going, getting more subtle and fewer symptoms that are affected by anything I have found. Some of the changes are not noticeable in less than some months or a year. And changes keep on going. While some things get better. You can't count on anybody being able to say "Oh, that looks like deficiency symptoms". That unfortunately goes for almost anything and especially trace minerals.
 
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CCC

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There is also a methylation process inside the mitochondria based on AdoCbl withTMG instead of the MeCbl with methylfolate methylation. The one internal to the mitochondria and the external process can happen at different rates and can affect the balance.
@Freddd - you mentioned this in another reply to someone (well, to me). Do you have something you can point me to to help visualise it? I'm wondering if it might explain a few things for us.
 

Freddd

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@Freddd - you mentioned this in another reply to someone (well, to me). Do you have something you can point me to to help visualise it? I'm wondering if it might explain a few things for us.
I came across a one of those methylation etc diagrams. I was looking into NAD, NMN, NR (I hope I got these things right), it's getting a lot of play in the anti aging folks and various people have different results from the various forms that come in a precursor or closer to active substance. The methylation is I think it was the process before the NAD (NR? "Niagen"? (I think) gets used.

In any case the effects for me and others is that instead of intense energetic occurrences when I started with L-carnitine fumarate, when I added TMG. Instead of making that SAM-e that is available for methylation for all sorts of purposes which feels very energetic, the methylation produced for producing ATP is used where it is made and doesn't produce that excessive energy feeling. I'm sorry I don't know where the exact diagram is located.
 

alicec

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There is also a methylation process inside the mitochondria based on AdoCbl withTMG instead of the MeCbl with methylfolate methylation. The one internal to the mitochondria and the external process can happen at different rates and can affect the balance. TMG with the carnitine works in the mitochondria and and reduces the energized-edginess of the MeCbl-methylfolate pathway.
I came across a one of those methylation etc diagrams. I was looking into NAD, NMN, NR (I hope I got these things right), it's getting a lot of play in the anti aging folks and various people have different results from the various forms that come in a precursor or closer to active substance. The methylation is I think it was the process before the NAD (NR? "Niagen"? (I think) gets used.
I don't think that is quite right.

For now, set aside NMN and NR - I think that is a red herring.

What I think is being referred to with TMG and methylation in the mitochondrion is the following series of reactions.

Consider Fig 1 in this paper. On the right hand side of the mitochondrial compartment, you will see that oxidation of choline, where TMG > DMG is an intermediate step, leads to generation of CH2-THF from THF. Reactions with serine and glycine also feed in to this step. CH2-THF then feeds in to a series of transformations which lead to formate production.

The cytoplasmic and mitochondrial compartments are metabolically connected by transport of serine, glycine and formate across mitochondrial membranes in an almost unidirectional flow - clockwise, according to the figure. The flow is from serine, through glycine and then formate to methionine.

Thus the source of the majority of 1C units for cytoplasmic methylation reactions is mitochondrial formate. Dietary serine is an important ultimate source of this formate, but choline oxidation, and hence TMG>DMG, makes an important contribution.

This paper helps to relate this to energy production, as illustrated in Fig 1.

Collectively, choline oxidation to CO2 may convert one homocysteine to methionine and produce three 5,10-CH2 THF as well as NADH and ubiquinol (UQH2), electron carriers that are reoxidized by the ETC (Fig. 1)
In other words, the generation of CH2-THF is coupled to NADH production and electron transfer that ultimately leads to ATP production, using the mechanism we are familiar with in the Kreb's cycle.

Carnitine and adoB12 are not directly linked to these reactions, but play a related role in energy generation as follows.

Carnitine is essential to carry fatty acids into the mitochondrion where they are broken down by beta oxidation. Even chain fatty acids end up as acetylCoA and are fed directly into the Kreb's cycle to produce energy.

Odd chain fatty acids end up as acetylCoA and propionylCoA. Some amino acids (methionine, valine, isoleucine and threonine), along with cholesterol side chains also end up as propionylCoA. The latter must be processed further before it can be used for energy and this is where adoB12 comes in.

First propionylCoA carboxylase converts it to methylmalonylCoA, then the enzyme MUT which uses adoB12 as cofactor converts methylmalonylCoA to succinylCoA. This molecule feeds directly into the Kreb's cycle where it is first converted to succinate.

If you look at Fig 1 in the second link you will see where succinate feeds in to the ETC, at complex II, or see the Wikipedia entry.

In terms of the overall B12 economy of the cell, the MUT reaction is overwhelmingly favoured since most B12 in the cell ends up in the adoB12 form.

I can't make any sense of the introduction of NMN, NR and methylation to the topic and think this is a mistake.

NADH/NAD+ of course is critically important to electron transfer reactions and ATP production but NMR and NR are merely part of the salvage cycle that ensures that these nucleotides are used efficiently.

Methylation here is a terminal reaction which removes excess niacinamide and is done by the enzyme N niacinamide methyltransferase (NNMT).

This paper shows the clearance pathway and the salvage pathways - 1st and 3rd Fgis in the abstract or Fig 1 and Box 2 in the full paper.
 

Freddd

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I don't think that is quite right.

For now, set aside NMN and NR - I think that is a red herring.

What I think is being referred to with TMG and methylation in the mitochondrion is the following series of reactions.

Consider Fig 1 in this paper. On the right hand side of the mitochondrial compartment, you will see that oxidation of choline, where TMG > DMG is an intermediate step, leads to generation of CH2-THF from THF. Reactions with serine and glycine also feed in to this step. CH2-THF then feeds in to a series of transformations which lead to formate production.

The cytoplasmic and mitochondrial compartments are metabolically connected by transport of serine, glycine and formate across mitochondrial membranes in an almost unidirectional flow - clockwise, according to the figure. The flow is from serine, through glycine and then formate to methionine.

Thus the source of the majority of 1C units for cytoplasmic methylation reactions is mitochondrial formate. Dietary serine is an important ultimate source of this formate, but choline oxidation, and hence TMG>DMG, makes an important contribution.

This paper helps to relate this to energy production, as illustrated in Fig 1.



In other words, the generation of CH2-THF is coupled to NADH production and electron transfer that ultimately leads to ATP production, using the mechanism we are familiar with in the Kreb's cycle.

Carnitine and adoB12 are not directly linked to these reactions, but play a related role in energy generation as follows.

Carnitine is essential to carry fatty acids into the mitochondrion where they are broken down by beta oxidation. Even chain fatty acids end up as acetylCoA and are fed directly into the Kreb's cycle to produce energy.

Odd chain fatty acids end up as acetylCoA and propionylCoA. Some amino acids (methionine, valine, isoleucine and threonine), along with cholesterol side chains also end up as propionylCoA. The latter must be processed further before it can be used for energy and this is where adoB12 comes in.

First propionylCoA carboxylase converts it to methylmalonylCoA, then the enzyme MUT which uses adoB12 as cofactor converts methylmalonylCoA to succinylCoA. This molecule feeds directly into the Kreb's cycle where it is first converted to succinate.

If you look at Fig 1 in the second link you will see where succinate feeds in to the ETC, at complex II, or see the Wikipedia entry.

In terms of the overall B12 economy of the cell, the MUT reaction is overwhelmingly favoured since most B12 in the cell ends up in the adoB12 form.

I can't make any sense of the introduction of NMN, NR and methylation to the topic and think this is a mistake.

NADH/NAD+ of course is critically important to electron transfer reactions and ATP production but NMR and NR are merely part of the salvage cycle that ensures that these nucleotides are used efficiently.

Methylation here is a terminal reaction which removes excess niacinamide and is done by the enzyme N niacinamide methyltransferase (NNMT).

This paper shows the clearance pathway and the salvage pathways - 1st and 3rd Fgis in the abstract or Fig 1 and Box 2 in the full paper.
Hi Alicec,

Thank you for a thorough understanding and explanation. So here is the point. I was trying to illustrate, first that TMG makes a substantial perceptual difference in methylation for many people. Second, the type of fail symptoms depend where the cycle breaks down. MeCbl lack (deficiency or insufficiency) OR a different cobalamin is in place causes methyltrap which causes a folate symptom fail at making the cell. If there is insufficiency of AdoCbl there are typical AdoCbl fail symptoms because the ATP process fails. With genes like mine AdoCbl and MeCbl are very different things and are easy distinguishable. TMG insufficiency causes some fails. AdoCbl fails in neurons (limbic system it appears by effect and MRI evidence in patients).in the brain over a period of years to decades appears to be responsible for causing the damage to the neurons typical of Parkinson's disease. The right for the person l-carnitine form is a very effective ATP accelerator, the wrong type puts on the brakes. When there are "the usual group of symptoms" and anxiety, adding more than micro doses of the right carnitine, causes extreme neuropsych mood series over up to 36 hours or so; from anxiety to extreme anxiety to fear and extreme fear to anger to extreme anger to rage to homicidal rage to deep depression Starting with microdoses of 100 mcg orally and increasing at 33 mcg/day for a while increasing that as you proceed can work up to normal responses at normal doses. Now for this everything nutritionally for all the cycles of MeCbl-methylfolate methylation and ATP generation have to be present and complete for this to happen. If any of the subroutines break, the whole thing breaks.if there is no alternative pathway available. How the cycles break gives specific nutrient related combinations of symptoms that gives generally good clues for macro nutrients and more difficult for micronutrients and even more difficult for minor components in sub routines. And as far recycling goes, D-ribose is very helpful for getting the cycle running sufficiently for some people. And people with the right enzymes and enough ATP can recycle used broken down MeCbl (HyCbl, CyCbl) to some degree. The people that can recycle inactive cobalamins and process folic acid and vegetable folates to l-methylfolate have more dietary choices and less fragile body systems When I started work on this was 1978 and at that time "almost all CblC babies die as infants. The 3 known adult survivors are institutionalized due to neurological damage." Then in 2011 a review article announced adult onset CblC disease and the puzzle was solved. The solution wasn't available generally until the first 5 years of this century.

This process happens to solve the sequence of nutrients needed in refeeding syndrome which underlies most of the symptoms of many chronic diseases.

I'm a systems analyst. I spent decades consulting and designing HMO/insurance software and essentially catching all the accidental or intentional screwups of the software and/or people that gives wrong answers that cost the group insurance either in quality and money. I have built a system based on deficiency symptoms patterns and combinations and nutrient patterns and combinations. The biochemistry and chemistry is not the level I work at. I don't have Rich ( a great resource and researcher who posted here before he died) anymore to explain the biochemical processes underlying symptoms and nutrients responses or lack thereof. I have primary pathways for MeCbl, AdoCbl and L-methylfolate and nothing that works with CyCbl, HyCbl and folic acid. Glutathione treats MeCbl and AdoCbl like cyanide and gives "catastrophic B12 deficiency" in hours with bodywide inflammation (severe methyltrap) and demyelination in 2 weeks.

I had to work all this out in realtime on the fly as I played this real life game of YOU BET YOUR LIFE. I didn't have time to figure out more than what fixed the cell making fails. The whole thing runs on 5 day data cycles of solving the next nutrient, having it increase healing for 3 days and on the third day the next layer of induced deficiency symptoms pop up to the top, and two days to correct those and uncover the next deficiency. My internist watched all this as I changed visually each three weeks for a year that everybody in the office (or out) could see each 3 weeks. and he said "I've never seen anybody come back from so far over the line." I was just ahead of death for years. My ex wife of 33 1/3 years didn't recognize (face to face coming in my front door that I opened for her) .me after not seeing me for 9 months in the second year of healing.

So I have cured myself of FMS, CFS, CHF, IBS, MCS, lots of neuropathies but not all, and well over 200 symptoms and signs in all. My main problem lately has been getting

Lots of details, updated as needed, symptoms affected by nutrients, in healing order and a separate list of refeeding symptoms for many nutrients that they then correct.

https://www.quora.com/Has-someone-u..._filter__=all&__nsrc__=1&__snid3__=1808215186

So knowing all this what pragmatic clues can you glean of nutrient failure points and how to fix them and things like that?
 

Athene*

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'I mistakenly ordered a methylfolate with glycine (10 bottles!). Is glycine on the list of glutathione precursors? If so I'll just have to dump it." - That is the MethylPro l-methylfolate. I take TMG, trimethylglycine, and various things that use the glycine. It appears to be no problem at all. My usual order from them is 4x90 15mg caps and 1 bottle of their Quatrefolic product. I think both of them are quite excellent. Either one works for about 3 months for me and then suddenly it doesn't and I have to switch to the other for a day or two and then the effectiveness of returns of the original. I take 15mg 3 times daily, one on wakeup, one at bedtime and one with my late afternoon medications. I don't take it with food and and the stack of everything else becasue I have some things blocking other things and I didn't know whether the mfolate was being blocked by anything else. Then I switch to the MethylPro Quatrefolic. It's more expensive so I and my partner both use it as our 1-2 day refresh mfolate that gives back the effectiveness of the original product used. She has quite a different problem than I do but has the same thing happening with the mfolate.

The CblC disease is my trigger into the 4-way deadlock of MeCbl, AdoCbl, L-methylfolate and L-carnitine (best personal typer and it can change; fumarate is most often the one to start with). However folate related polymorphisms can be a trigger. For some people like me glutathione is a trigger. It ties up the MeCbl/AdoCbl and excretes it promptly causing methyltrap when a cell needs MeCbl and doesn't get it, then the methylfolate is kicked out of the cell and the symptoms of the cell failure are paradoxical folate deficiency symptoms. It quickly casues various types of lesions in epithelial tissues very rapidly.

I'm in the USA. I checked out the phosphate situation in the USA and it was rarely a problem, the writer saying becasue the usual diet has high amounts of phosphorus becasue of dough conditioners, phosphoric acid in soft drinks, and so on. I don't eat those but I take lecithin with phosphatidylcholine and/or phosphatidylserine and such.

One time a person posting mentioned she had ended up in the ER with hypokalemia. They tested and it showed 4.2, about midrange. However, her symptoms worsened and they tested every hour an in 3 hours it was down to 3.5. In me, the CblC has problems with electrolytes. It seems that for me the potassium can't get pulled from the tissue and I need to keep a relatively level serum level by drinking water with potassium gluconate.

I do subcutaneous MeCbl injections. The overlapping series keeps my serum level pretty constant.

600pg/ml of serum cobalamin is actually quite low. I need to maintain > 220,000 pg/ml to keep my nerves from demyelinating and/or keep up with the repairs.


"I ended up in ICU with hypokalemia (I had warned them to look out for this) and hypophosphatemia (low phosphorous). It was an African visiting doctor who recognised the Refeeding Syndrome and we had a great discussion about B12 replacement etc." - You were fortunate to see a doctor who had seen the aftermath of starvation, refeeding syndrome, and recognize the "slow" version of it rather than the acute form gotten with starvation.

The high MMA and HCY are functional proof of deficiencies affecting the methylation-ATP process. There is also a methylation process inside the mitochondria based on AdoCbl withTMG instead of the MeCbl with methylfolate methylation. The one internal to the mitochondria and the external process can happen at different rates and can affect the balance. TMG with the carnitine works in the mitochondria and and reduces the energized-edginess of the MeCbl-methylfolate pathway. They are both needed. The important thing to remember with these things is on the first day of adding or increasing something with symptoms shows what is being positively affected and the refeeding symptoms typically start on the 3rd day for the clues to what is next. The microminerals are the most difficult. The deficiency symptoms can be diminishing the next couple of days (benefits) and on day 5 or 6 the next induced deficiency symptoms start popping up, some very slowly. Most of these things happen in a 5-6 day cyclke if you can spot them with the first symptom up from the usual group. My first folate deficiency symptom is putting on 2-3 pounds of water in a day (edema). Increasing folate (or switching methylfolate form) starts the water pouring out and that takes potassium with it. Watch out for that.

Do you have copies of the refeeding symptoms list as it currently is? Can you specify the phosphate deficiency symptoms that come on fast and then slow, and how much phosphate the doctor prescribed?

One thing I have found is that things keep on going, getting more subtle and fewer symptoms that are affected by anything I have found. Some of the changes are not noticeable in less than some months or a year. And changes keep on going. While some things get better. You can't count on anybody being able to say "Oh, that looks like deficiency symptoms". That unfortunately goes for almost anything and especially trace minerals.
@Freddd Yes, thanks I have the latest Refeeding list. I want to check my CblC genes at some stage. I had bouts of mysterious crashes ('viruses' 'growing pains') since childhood and as an infant was given the last rites after being diagnosed with 'failure to thrive'. I only really 'thrived' for a few years (with intermittent crashes) until about age 24.

You mention lecithin. Funnily enough I use sunflower lecithin powder (tablespoon daily) too and as you say it contains phosphorous, and I eat meat or poultry daily, sometimes twice daily, also yoghurt or kefir most days so plenty of phosphorous containing foods (I don't drink soft drinks or eat that dough you mentioned).

To answer your question re symptoms:
the acute low phosphorous symptoms after the operation were shortly after I arrived home. My husband went to the shops and I was lying on the couch resting when suddenly I went completely flaccid in all my muscles and very quickly began to lose sense of myself or where I was. Just before he came home (about 20 minutes later) I felt I was floating above the couch and when he tried to talk me I couldn’t talk and I wasn’t sure who he was. Then I blacked out. Next thing I knew I was in and out of consciousness in an ambulance on the way back to ICU where I had already been a few days earlier with hypokalemia. (By the way I didn’t have nitrous oxide. I had some form of ether instead after discussing with anaesthetist my worry about nitrous oxide). There were no other complications apart from hypokalemia & later the hypophosphatemia for which they had given me 500mg once or twice daily in the hospital (not enough) - I think the nurses forgot the dose a few times, hence the low phosphorous crash when I arrived home, with no prescription yet filled.

Surprisingly I’m still just outside range for Inorganic phosphate on CBC (result back today). 0.75 (0.81-1.45). My prescription is for Phospate Sandoz https://www.medicines.org.uk/emc/product/958/smpc
6 tablets daily (500mg each) dissolved in water. Bloody expensive here! I take two at a time x 3 daily. Doing this for three weeks now and the usual high phosphorous foods. Getting lots of vitamin D from current heatwave and magnesium is coming up nicely again after temporary dip post op. Am I missing something else? I have Boron 3mg daily. Calcium 300mg.

More symptoms:
When I’m due another phosphorous dose I get very suddenly weak and breathless (much like potassium but an awful lot quicker, with no warning) and not able to concentrate well (even some slight confusion), and very irritable (again like potassium when it goes low, but again very immediate with no warning like muscle aches or heart thumping). About an hour after I take my dose I’m up and doing things, usually house work that’s been left undone.

Over the past two months I have found a tiny flake/chip of tooth from my bottom front teeth, twice. I just filed them down gently with a cardboard nail file and tried not to worry about it. Now it seems it was low phosphorous. It isn't noticeable (back surface of teeth) and it hasn't happened again, thankfully.

Yesterday I had a violent crash – I call it the Carnitine Crash. It was four days after I raised my LCF dose from 1/5 th of capsule of Dr’s Best to ¼ daily. I had barely been tolerating 1/5 th since restarting the LCF after the operation so it might have been a bit foolish and over ambitious of me to increase 4 days ago. Yesterday's crash caused all over body aches and my trademark itchy scalp and hair shedding (my low folate signs) and gradual muscle aches (my low potassium signs) then sudden complete weakness (which I get from low potassium or was it low phosphorous? Though I wasn’t due a phosphorous dose). This has happened before from both Adocbl and LCF.

The worst symptom was the really violent headache (happened before last year from a crash after over exercising) and when folate goes low. This was similar but even more frighteningly intense. It went from back of neck below skull, through to top of skull, front of skull, jaw bones and cheek bones. Top of skull and forehead throbbed even worse if I lay down or bent forward. Every nerve in my teeth throbbed in my jaws too. The pain built and got so bad I was moaning, then vomited after which the pain very gradually eased over half an hour or more. I had unexpected rage as well, over the tiniest thing. The episode lasted an hour leaving me completely weak. I slept for six hours after a big dose of potassium and folate about ¾ of an hour later and I felt fine, no pains, falling asleep, and today I feel fine and just did the washing up (now feel a bit achy and tired again but getting better since resting).

@Freddd You mentioned ‘cherries’ before re subcut injections. I noticed over last three days of LCF increase that the ‘cherries’ – those subcutaneous injection pools under the skin, were not absorbing so that 6 hours later when next injection due the ‘cherry’ was only a bit diminished, whereas usually it’s gone or almost gone. Why would it not be absorbing?

I have tried the tartrate form of carnitine and it crashed me too. I tried acetylcarnitine and same effect. Sudden loss of folate and potassium. Same happens if I try to raise Adocbl but I’m going to go to 10mg weekly as per your advice on that. The monthly 50mg crashed me badly for several days before so I’m dreading trying that again.

Would it help do you think, if I were to cut the ¼ LCF into two doses about 5 or 6 hours apart? Or should I just go back to the 1/5th capsule for now? I really want to get moving on the Ado & LCF. I’ve been trying to increase for 3 yrs now and want so much to get on your gradual walking rehab regimen. Would the low phosphorous be holding me back with the LCF? I have problems digesting fat, even in eggs, since I began the protocol properly two years ago.

My mother ended up with dementia and Parkinsons after years of hypothyroidism, so probably low B12 too, another reason I want to crack this Adocbl and LCF problem…
 
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Athene*

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@Freddd Just to say that immediately after the violent headache faded away my legs were both jerking briefly, and then again a few minutes later, briefly. Then I was fine and walked upstairs to bed. I never had restless legs or anything like that before. Today they're fine. In fact I had a lot of energy today (just took 1/8th of LCF today) and walked around shops (very slowly) for about 30 minutes. A bit hot & cold and slightly achy now, but feel I will have a good sleep.
Today I notice my nails are soft again, got one caught on a thread and it just peeled away, no break. They had hardened up last year so maybe this is from phosphorous dropping too. Another symptom to add to the list!
 

Freddd

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@Freddd Just to say that immediately after the violent headache faded away my legs were both jerking briefly, and then again a few minutes later, briefly. Then I was fine and walked upstairs to bed. I never had restless legs or anything like that before. Today they're fine. In fact I had a lot of energy today (just took 1/8th of LCF today) and walked around shops (very slowly) for about 30 minutes. A bit hot & cold and slightly achy now, but feel I will have a good sleep.
Today I notice my nails are soft again, got one caught on a thread and it just peeled away, no break. They had hardened up last year so maybe this is from phosphorous dropping too. Another symptom to add to the list!
Hi Athene,

I have a theory, from 16 years of injection experience. A problem with cobalamins is that they form hydrate crystals. Back before I used foil wrap on all syringes and bottles, I could see a very find sludge, microcrystals that fit through a 30 gauge needle unless they get to clogging level. Then I have to warm in a cup of hot from the faucet water. The same vial that hasn't caused a cherry suddenly does for a couple days or until I warm to dissolve the microcrystals.. However, my serum half life l varies each 2 weeks for unknown reasons from puberty or so. That caused a 2 week cycle to increased folate deficiency symptoms , edema first, I would put on 2-3 pounds of water a day until increasing mfolate, then it would dump potassium in the urine. If you take a diuretic it might be causing part of your potassium problem. TOO MUCH b1, b2, b3 or inositol can cause a huge demand in potassium and no obvious increased signs of healing. Watch out for folic acid. MeCbl ruined by cumulative light exposure (become contaminated with HyCbl-H2oCbl by photolytic deterioration) and can cause methyltrap folate deficiency symptoms, fast and hard.

Intense folate deficiency symptoms and hypokalemia, needs more folate, or maybe divide into more frequent doses. Same with potassium. I appear to have a problem getting potassium into serum as fast as I need it. I do best with potassium gluconate powder dissolved in water and basically drink it all day. I find that multiple overlapping MeCbl injections maintain a high even serum level. The microcrystals just take a little longer to dissolve.

I found that I had more potassium required after I added each set of trace minerals. Copper deficiency can cause nasty neurological problems fast, and mood changes, hard and nasty. I also take selenium, chromium GTF, vanadium (vanadyl sulfate), lithium orotate (non ionic trace mineral micro quantity, affects B12 in tissue, molybdenum, manganese, iodine (kelp), boron, copper.

With the carnitine, it is causing more cell formation that increases the deficiency of mfolate symptoms and the hypokalemia. I found that 45mg (3x15) daily worked wonders. Cutting the dose of carnitine into 2 or 3, each time on an empty stomach, will absorb it well. Also will smooth down the effects. Take TMG and usually it will smooth things out. Perhaps you can get the Jarrow liquid freebase carnitine in a pint bottle. It can be measured out in drops giving you more control, or even fractions of drops. Try to find a dose that doesn't drive you so hard, and then increase it a little each few days. The TNG increased by "balance" a lot.

Do you have anxiety as a routine symptoms? If so go easy on the carnitine and take it up comfortably. With the liquid I often would suggest starting with 100 mcg with 33mcg increments a couple of times during the day, and then increasing by 33mcg each day.

The sudden body wide pain sounds like HARD methyltrap. That happened to me when I take glutathione or NAC. Beware of the product that is methylfolate with NAC added. Methyltrap like that is caused by not having MeCbl in the cell the moment it is needed, usually becasue something destroyed it, like glutathione or some other things. If you

Keep a daily list of symptom changes and nutrient changes. Look through all the things with multiple ingredients for things that can cause methyltrap. N-acetyl cysteine or other forms of cysteine can be a problem.

These sound like solvable problems. How many years have you been sick?
 

Athene*

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Thanks for those great tips on injections and LCF @Freddd . I will get the liquid LCF and go up slower. Anxiety would certainly have been an issue in my teens and early 20s when I was first experiencing low B12 symptoms starting after two nitrous oxide anaesthetics for dental work as a kid then another nitrous oxide anaesthetic in early 20s.

On B12 I don't have anxiety at all, ecxept during crashes and if too much LCF (more like extreme agitation and irritability becoming really angry about nothing. (This frightens me and reminds me of my mother when she was demented). Afterwards I'm my normal easy-going self. I'm lucky I have an understanding partner but this can't go on, for his sake as well.

If you take a diuretic it might be causing part of your potassium problem. TOO MUCH b1, b2, b3 or inositol can cause a huge demand in potassium and no obvious increased signs of healing. Watch out for folic acid. MeCbl ruined by cumulative light exposure (become contaminated with HyCbl-H2oCbl by photolytic deterioration) and can cause methyltrap folate deficiency symptoms, fast and hard.
Yes, I check carefully for folic acid. I wouldn't touch NAC or Glutathione after reading your experience. No diuretic. I'm obsessive about protecting Meb12 from light (use red light and foil since reading what you do).

I use the low dose B Complex you recommend (Nature Made) so low b3. No extra inositol either.

I do use Allithiamine (b1) 1/2 capsule daily (i.e. 25mg) as we discussed earlier because of coeliac disease/no grains etc...

I use sublingual B2 one tablet (18mg) daily broken into 4 doses which I take after each of my 4 folate doses of 12mg. Every time I try to lower this sublingual B2 (because of your caveat), I get pink urine, becoming red by next day, then I get the Hard methyl trap. Within a day of reintroducing sublingual B2 the red/pink urine goes away and the low folate and b12 symptoms go away.

What do you make of that? Would it suggest methyl trap?

These sound like solvable problems. How many years have you been sick?
Thanks, Freddd. Good to hear 'solvable'.

By age 12 I was having 'collapses', my Granny used to bring me around to doctors because I was jaundiced and very fatigued. She used to feed me with 'Complan' to build me up (yikes, cyanocobalamin!) and egg nogg and lamb chops and lots of good things. She had pernicious anaemia herself and worried I had it. Doctors said I was jaundiced and underweight but 'normal' b12 and 'feed her up'. I also had bad allergies to hay, grass, cats, dust (now all disappeared since folate!). Poor lady died at only 70 of heart failure (her treatment: 3 monthly hydroxocobalamin injections!!).

By 24 I was having periods of crushing fatigue and endocrinological issues with thyroid and ovaries. Both of those organs shut down suddenly in 2000 (no antibodies found, doctors were mystified, no physical evidence of early menopause, everything normal on scans), outcome was a diagnosis of 'possible hypothalmic dysfunction' and 'beyond our level of expertise' 'no unifying diagnosis'. B12 serum was judged 'normal' to 'high normal'. MCV,MCH. low Haematocrit, Low RBC etc ignored ('borderline' anaemia, 'not significant'). I was given Levothyroxine which never worked for me so from then on continuous aches and pains and icy cold with no energy, and depressed mood, but still able to walk around and work, collapsing into bed when I got home.

That was followed by complete adrenal collapse in 2012 and I was prescribed steroids, which kept me moving, but less able, and needing lifts to work and after work, and more and more days in bed, unable to move. Upper arms in particular, got weak, difficulty washing hair in shower.

By 2013 I was sinking to the ground unable to get up. Completely paralysed muscles, then when muscles recovered somewhat, banging heart, vomiting, diarrhoea. I'd crawl to bed and sleep for 12/14 hours. Gradually became bedridden with weakness. Unsteadiness and neuropathy in feet got very bad around this time. Other electrical shock feelings all over. Numbness in some fingers (all now gone).

Once I got on your regimen my ovaries kicked in again (irregular, but still trying to function). Thyroid meds still needed. Now off all steroids (thanks again!). And able to enjoy drives into the countryside around here with no allergies whatsoever since high dose folate!

I also take selenium, chromium GTF, vanadium (vanadyl sulfate), lithium orotate (non ionic trace mineral micro quantity, affects B12 in tissue, molybdenum, manganese, iodine (kelp), boron, copper.
Freddd, if you get time, can you say what amounts of these minerals you take? I take all of them except for Lithium orotate which I will check out now.

Will we always need high doses of these supplements, for e.g. will I be able to cut down or cut out the phosphorous eventually when it's 're-fed'?? It's bloody hard on the gut! I saw Swanson do a Monosodium Phosphate which I have ordered. Less crap added. The Phosphate Sandoz has saccharin (sulphonamide?) and I've never done well with sulphonamides, but I may be wrong about saccharin and it may too tiny an amount to worry about...

List of excipients
Potassium bicarbonate, sodium bicarbonate, sodium saccharin, orange flavour 52.570 TP, polyethylene glycol 4000, sugar icing CP, citric acid anhydrous, water.

Yeuch!
 

Freddd

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@Athene*

I will list the trace minerals separates. I also get a little more of some of them in a multimineral. I don't take zinc other than the multi (15mg). It competes at the absorption with copper and in the serum. I had enough trouble absorbing copper.

Copper citrate - 2mg copper x 2 per day
Chelated Molybdenum 150 mcg 2 per day
Selenium - 200 mcg x 2 per day
Chelated Manganese 8mg x 2 per day
GTF chromium - 200 mcg x 2 per day
Vanadyl sulphate - 10mg, 2 mg vanadium x 2 per day
Lithium orotate 5mg 1 per day evening, helps sleep
Boron amino acid complex - 9mg (3x3mg caps) x 2 per day
iodine 150 mcg in kelp, x 2 per day


I asked how old you were when you got ill. Since 12 means that you have lots of depth of possibly impaired cells. I didn't start having trouble with trace minerals until after 6 years of healing and a glutathione trial that damaged me seriously. I went directly into copper deficiency trying to heal the glutathione damage. I had potassium signal with each of them I hadn't been taking. all along. or only taking minute amounts in multi mineral.

If all my potassium had accumulated doses I would be taking 8000 mg a day. Instead about 3500 mg keeps me almost balanced.

The copper I would have a couple of targets for reducing. One ios getting my copper level to mid range. The other is if all my deficiency damage heals,then I can reduce it and see if my serum level holds level.

I notice "jaundiced" as well. DId they tell you the cause; liver or rapid red cell breakdown? Different causes and different fixes.

I think getting the deadlock quartet working smoothly and getting rid of all paradoxical folate deficiencies, and getting carnitine going on a smooth titration. The extreme experiences you have had with carnitine appear to be due to CNS demyelinations hypothesized.

AdoCbl rarely has more than 1 CNS startup experience becasue it has a long half life in mitochondria compared to blood..At most 2 or 3 diminishing startup experiences. Then when AboCbl is saturated, the titration of carnitine could go smoother. Ideally, after you reach equilibrium on AdoCbl, you will never feel it directly again and carnitine is the only accelerator. That makes it easier. Also, your thyroid needs a full load of AdoCbl to work correctly. Most of the working B12 in glands and organs is AdoCbl. Lacking that causes local MMA that might not add up to too much in blood stream but a problem for where it is generated. For your thyroid to work right, maybe for the levothyroxin to be converted which requires enzymes and ATP (AdoCbl and carnitine in part). I'm just speculating on this. I have seen some people have their thyroid fully restored to functioning. with this but many no improvement after damage is old enough. If you feel the next 50mg dose, do it at 2 week intervals until it causes no additional response when you take it.. That will simplify getting the carnitine balanced. It can take a year to get the neurological healing to a noticeable degree. And it can heal one part for 9 months and then it starts on something dependent on the first one and that can take another 9 months etc.. And it can be unpleasant. It's like you have hundreds of traumas stashed away to process when able and as the neurology starts healing, you get to see all your issues that are represented in neurological damage that can heal. Further TMG may calm down the carnitine and make it more comfortable.

The B12 serum level doesn't say anything at all about what is a sufficient dose for any given person or group. Studies that use symptoms often find that 2/3 or so of people benefitting from MeCbl would not have been accepted into a study becasue their serum level is too high.

Paralysis is how people die from B12 deficiency. Their diaphragm stops working and no more breathing.

If you have epithelial lesions, acne type lesions, canker cores, angular cheilitis, skin cracks by finger nails and the like, getting all those things healing will get most of your body healing. You looked at the symptoms list by nutrients? It is also in order of what things were affected.be the nutrients in the order the nutrients were given. The clustering is such if you can get one of a cluster healing, the others will do so also usually.
 

Freddd

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I don't think that is quite right.

For now, set aside NMN and NR - I think that is a red herring.

What I think is being referred to with TMG and methylation in the mitochondrion is the following series of reactions.

Consider Fig 1 in this paper. On the right hand side of the mitochondrial compartment, you will see that oxidation of choline, where TMG > DMG is an intermediate step, leads to generation of CH2-THF from THF. Reactions with serine and glycine also feed in to this step. CH2-THF then feeds in to a series of transformations which lead to formate production.

The cytoplasmic and mitochondrial compartments are metabolically connected by transport of serine, glycine and formate across mitochondrial membranes in an almost unidirectional flow - clockwise, according to the figure. The flow is from serine, through glycine and then formate to methionine.

Thus the source of the majority of 1C units for cytoplasmic methylation reactions is mitochondrial formate. Dietary serine is an important ultimate source of this formate, but choline oxidation, and hence TMG>DMG, makes an important contribution.

This paper helps to relate this to energy production, as illustrated in Fig 1.



In other words, the generation of CH2-THF is coupled to NADH production and electron transfer that ultimately leads to ATP production, using the mechanism we are familiar with in the Kreb's cycle.

Carnitine and adoB12 are not directly linked to these reactions, but play a related role in energy generation as follows.

Carnitine is essential to carry fatty acids into the mitochondrion where they are broken down by beta oxidation. Even chain fatty acids end up as acetylCoA and are fed directly into the Kreb's cycle to produce energy.

Odd chain fatty acids end up as acetylCoA and propionylCoA. Some amino acids (methionine, valine, isoleucine and threonine), along with cholesterol side chains also end up as propionylCoA. The latter must be processed further before it can be used for energy and this is where adoB12 comes in.

First propionylCoA carboxylase converts it to methylmalonylCoA, then the enzyme MUT which uses adoB12 as cofactor converts methylmalonylCoA to succinylCoA. This molecule feeds directly into the Kreb's cycle where it is first converted to succinate.

If you look at Fig 1 in the second link you will see where succinate feeds in to the ETC, at complex II, or see the Wikipedia entry.

In terms of the overall B12 economy of the cell, the MUT reaction is overwhelmingly favoured since most B12 in the cell ends up in the adoB12 form.

I can't make any sense of the introduction of NMN, NR and methylation to the topic and think this is a mistake.

NADH/NAD+ of course is critically important to electron transfer reactions and ATP production but NMR and NR are merely part of the salvage cycle that ensures that these nucleotides are used efficiently.

Methylation here is a terminal reaction which removes excess niacinamide and is done by the enzyme N niacinamide methyltransferase (NNMT).

This paper shows the clearance pathway and the salvage pathways - 1st and 3rd Fgis in the abstract or Fig 1 and Box 2 in the full paper.

Interesting papers you linked to above, thank you. This is on page 11 near top.

"This may be important as pharmacological doses of NAM riboside (NR), a NAD+ precursor, are being tested in preclinical models and in humans as a treatment for a variety of dysfunctions associated with obesity and aging "

There are thousands of independent individual trials going on with NR. It and related items are being comparatively tested as they produce somewhat different results in various people. It's much more like a pruned Monte Carlo simulation done by all these different ways by lots of different people. Some have excellent results and some have none, for all sorts of reasons. If it has any fast acting symptoms I will know in a few days if it affects me by affecting cell production and causing a burst of hypokalemia. or I may feel it energetically. Some people feel fatigued with it, some feel energized or mood changes and some feel nothing. The people that feel it work have functioning all the way up to the point that NR comes into play. In a computer program this might be called debugging. I am debugging my metabolism along with many others doing theirs.