Intracellular iron regulation, infections and the effect of LPS endotoxins

pamojja

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The daily calcium intake recommended is 1200-1500 mg

So if you take 2 x 400 UI vit D3 daily with 2 x 500 mg calcium, you can't harm yourself.
I would be very wary of that high calcium intake recommendation without having labs showing deficiency. For supplementing I would rather choose a Mg to Ca ratio of at least 2 :1


The higher doses are not always the best ones, especially for the D vitamin that can produce overdose (vitamin D and A are the ones that can be toxic if taken too much!)
Not my experience either. It took my 8.800 daily IUs to just stay above a 25(OH)D serum level of 60 ng/dl during the last nine years. 20.000 IUs of preformed vitamin A didn't raise my low normal serum retinol and retinol binding protein at all. And vitamin A together with vitamin D3 and K2 are known to mitigate potential toxicities of each other.

With a wide online search one couldn't find any case reports of overdoses from either Vitamin A or D3, taken together with no or little supplemented calcium. Even the few case studies showing overdoses, by taking one of them in isolation, intakes required are quite astronomical.
 

pattismith

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@pamojja ,

of course magnesium is very important too.

I know this vit D/calcium thread is quite complicated and full of controversy, so I won't go too far in it.(yet your experience of it is very interesting!)

The recommended vit D and Calcium daily doses (from either food or supplements) by specialists from Switzerland are below

upload_2017-8-28_12-45-32.jpeg


"Beyond 50 years, the dietary calcium requirements are 1200 to 1500 mg / d. As a quick rule, it can be considered that to consume 1200 mg / d, you need: 2 dl of milk, yogurt and a portion of hard cheese (Tables 8 and 9)."

(So if you doesn't eat dairies, best to take calcium supplements)

https://www.revmed.ch/RMS/2011/RMS-319/Vitamine-D-actualite-et-recommandations

The advise to take calcium with vitamin D in order to upregulate calcidiol and lower calcitriol is not my own! It's from a doctor here, it seems that it worked for this woman:

"A few months ago, I got a letter from a woman who mistakenly had her calcitriol levels measured. Her calcitriol levels were high even though her 25(OH)D levels were low. I recommended that she take extra calcium in her diet and also take a supplement that contained calcium, magnesium, K2, and zinc. I also recommended that she take 5,000 IU/day of vitamin D even though her activated vitamin D levels were high. Below is her follow up letter."

https://www.vitamindcouncil.org/activated-vitamin-d-vs-25ohd-levels-what-should-you-measure/
 
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pamojja

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I know this vit D/calcium thread is quite complicated and full of controversy, so I won't go too far in it.
Well, with extensive lab testing of nutrient levels I had to put this serious warning about additional calcium intake out there. I wouldn't ignore it without lab testing and checking sources on account of mere faith in authorities.. But each is responsible for one's decisions oneself.
 

pattismith

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@pamojja ,

I understand your concern, I guess what one experiences may not be Ok for others.

But what I quoted are recommendations from Swiss specialists.
I do not know swiss people to be kamikaze :)

Your experience with very high vitamin D and A and no calcium intake doesn't seem classical, maybe it will be so one day.

in my case, I can only report that I need calcium supplement to functionnate (maybe because of my low calcidiol/calcitriol?)...But who knows, maybe I will be able to lower my dose when my vit D levels will be better. I will put attention on it, thank to you!
 

Learner1

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I have no idea how to treat high iron storage (as opposed to free iron in the blood) when the cause is not known. There is a rare form of haemochromatosis in which this occurs and I presume there are treatments but I do not recall them. My guess is most doctors will fall back on venesection or in some cases drugs.

Measuring hepcidin might provide a clue but it seems to be elevated in a number of states. It does not directly tell you the cause.

One of the problems with ME and haemochromatosis is the risk of collapse from venesection. I recall this happening to a patient some years ago. If we have low blood volume then removing blood is a bad idea, though you can replace it with saline to restore blood pressure ... but this will not restore oxygen carrying capacity. A typical ME patient will have excessive glycolytic energy production, decreasing oxygen supply might make this worse.
I had to look up venisection, which doctors here call phlebotomy.

I schedule phlebotomies just before getting mitochondrial cocktail/B vitamin/glutathione IVs and do hyperbaric oxygen therapy a couple of times a week, so I really haven't noticed any ill effects from the phlebotomies beyond changes in my iron labs, so one can compensate.
 

alex3619

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Phlebotomies and venesection are very different. Phlebotomists do venesections but need special training and equipment. Venesection involves the direct removal, via a large needle, of a large amount of blood. This is usually under a local anaesthetic, because that needle goes deep. You could do hundreds of blood tests with that blood. Its why they schedule them weeks apart, so you have time to recover.

Its more like donating blood than having a blood test, only even more aggressive. Sometimes they use an IV line to supply saline because of the blood volume drop, but again this will not restore oxygen carrying capacity.

From what I recall the patient I heard of found his doctors too scared to do another, the collapse was that bad, and it took months to recover. I never heard the long term outcome or what he or his doctors decided to do next.
 

alex3619

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I would be very wary of that high calcium intake recommendation without having labs showing deficiency.
All minerals are potentially dangerous. The tolerated range for minerals is much smaller than for nearly all vitamins. Too high or too low can be catastrophic. This is not just calcium, its all of them. If you take a little too much vitamin C its unlikely you will have a severe reaction, but if you take a little too much potassium, zinc, copper, iron, magnesium, calcium etc. then you can die or have very severe symptoms. Medical advice is sometimes necessary with some minerals, backed by blood tests if necessary.
 

msf

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"Withholding iron from potential pathogens is a host defense strategy. There is evidence that iron overload per se compromises the ability of phagocytes to kill microorganisms. Several hypotheses exist to explain the association of hemochromatosis with infection.
....
The list of infectious disease agents whose virulence is enhanced by iron continues to increase (Table 1).5 These pathogens include bacteria (Gram-negative and Gram-positive), fungi, and viruses.

Table 1.
Organisms whose growth in body fluids, cells, tissues, and intact vertebrate hosts is known to be stimulated by excess iron


Fungi Candida, Cryptococcus, Histoplasma, Paracoccidioides, Rhizopus, Trichosporon,
Aspergillus, Pneumocystis

Protozoa Entamoeba, Leishmania, Naegleria, Plasmodium, Toxoplasma, Trypanosoma

Gram-positive and acid-fast bacteria Bacillus, clostridia, corynebacteria, Erysipelothrix, Listeria,
mycobacteria, staphylococci, streptococci, Gemella

Gram-negative bacteria Acinetobacter, Aeromonas, Alcaligenes, Capnocytophaga, Campylobacter,
Chlamydia, Ehrlichia, Enterobacter, Escherichia, Klebsiella, Legionella, Moraxella,
Neisseria, Pasteurella, Proteus, Pseudomonas, Plesiomonas, Shigella, Vibrio, Yersinia

Viruses Hepatitis B and C, cytomegalovirus, parvovirus, HIV"

http://www.sciencedirect.com/science/article/pii/S1201971207000811

"The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens (Yersinia enterocolitica O9) by controlling non-transferrin-bound iron (NTBI) rather than iron-transferrin concentration."

http://www.bloodjournal.org/content/early/2017/05/02/blood-2017-03-772715?sso-checked=true

"As alluded to earlier, iron is essential for the survival and growth of almost all organisms. Furthermore, an important strategy of mammalian antimicrobial defense is based on depriving pathogens of this essential nutrient [21]. One of the best-studied examples of this strategy is Nramp1, the transporter that pumps iron out of the phagosome [22, 23]. Numerous experiments in mouse models and in tissue culture have shown that the ability of Nramp1 to lower phagosomal iron concentrations influences the survival and growth of several intracellular pathogens, including Myocbacterium bovis BCG, Salmonella typhimurium, and Leishmania donovani. Polymorphisms in the NRAMP1 gene have also been linked in some human studies to altered susceptibility to tuberculosis and leprosy [24]. Based on the idea that there may be additional mechanisms that deprive intracellular pathogens of iron, we initiated investigations some years ago to examine the effects of altered FPN expression on the intracellular growth of S. typhimurium.
"(iron is pumped out of the cell by the exporter ferroportin (FPN))"
We found that elevation of FPN levels in either HeLa cells or J774 murine macrophages led to a significant inhibition of intracellular Salmonella growth, whereas hepcidin-induced down-regulation of FPN expression had the opposite effect [25]. Using Salmonella strains transformed with iron-regulated transcriptional reporters, we showed that elevated FPN levels were associated with the increased expression of a bacterial gene that is induced by low iron concentrations, suggesting that FPN-mediated iron efflux led ultimately to depletion of the element in the immediate microenvironment of the pathogen. Since these original observations, several other groups have replicated our findings, both with Salmonella and with several other intracellular bacterial pathogens, including M. tuberculosis, Chlamydia psittaci, C. trachomatis, and Legionella pneumophila [2628]."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085559/

LPS endotoxins have an inhibitory effect on FPN that produces higher iron intracellular levels in macrophages. This may induce higher persistence of some intramacrophage infectious agents.


"Macrophage iron content is further expanded via an inhibitory effect of IFN-γ and LPS on ferroportin transcription thereby reducing cellular iron egress (Yang et al., 2002; Ludwiczek et al., 2003)."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100575/

"Lipopolysaccharide (LPS) is the major molecular component of the outer membrane of Gram-negative bacteria and serves as a physical barrier providing the bacteria protection from its surroundings."

It may be that gut overgrowth of these Gram negative bacteria, and leaky gut may play a role in persistent intrabacterial infections that some of the CFS/ME patient experiments, by increasing iron levels in Macrophages.

@msf
I just thought I would point out that Yersinia is both an extracellular and intracellular pathogen, and also that it loves iron so much (or is so ´siderophilic´) that in patients with haemochromatosis, transfusion-acquired Yersinia infections are often lethal.
 
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Learner1

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Phlebotomies and venesection are very different. Phlebotomists do venesections but need special training and equipment. Venesection involves the direct removal, via a large needle, of a large amount of blood. This is usually under a local anaesthetic, because that needle goes deep. You could do hundreds of blood tests with that blood. Its why they schedule them weeks apart, so you have time to recover.

Its more like donating blood than having a blood test, only even more aggressive. Sometimes they use an IV line to supply saline because of the blood volume drop, but again this will not restore oxygen carrying capacity.

From what I recall the patient I heard of found his doctors too scared to do another, the collapse was that bad, and it took months to recover. I never heard the long term outcome or what he or his doctors decided to do next.
That sounds really invasive.

Apparently, healthy people can do it at a blood bank, having it taken from an arm. As I don't meet the qualifications for the blood bank, I had it done in a chemotherapy clinic at a hospital. I've had 3 done, 3-5 weeks apart, and they took 250ml of blood each time. I was able to use my Porta Cath, which made it easier. The biggest issue was my hypercoagulation problem - twice, the line clogged after 100ml. My doctor says the hypercoagulation is due to the infections I have, so the TPA enzyme was used to unclog it.

Neither my primary doctor nor I were thrilled about my doing it, but from everything I've read about organ damage from hemochromatosis and then the information on the bugs using it, it seemed the sensible thing to do. And, it really wasn't too bad. I'll need them every 5-8 weeks going forward.
 
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Chocolove

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Iron Disorders Institute:: Hemochromatosis
www.irondisorders.org › Iron Disorders
Online Support Group & Forum ... Hemochromatosis (HH) is a disease that results from excessive amounts of iron in the body (iron overload). Hereditary (genetic) ... Individuals with hereditary hemochromatosis absorb too much dietary iron.

American Hemochromatosis Society
www.americanhs.org/
May 2017 is the AHS' national "Hereditary Hemochromatosis Genetic ..... The family would like to thank the staff at UPMC Shadyside for their support and care.

Personal Experiences
haemochromatosis.org.au › ... › General Category › General Discussion
Jul 21, 2016 - 15 posts - ‎10 authors
Many of us felt the same till we discovered this forum. ..... you can be of great assistance to spreading the word about the most ... He also mentioned that, in his many years of treating haemochromatosis, he has not had a ...
 

alex3619

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Most people tolerate venesection very well. My brother is one of them. My comments are to inform, not deter ... if you know there might be issues you can plan around them. Treating high blood iron is essential.

This particular thread is concerned with low blood iron, particularly as a result of pathogenic problems, including LPS. We are forced to speculate because there appears to be a paucity of good research on this specific issue, especially with regard to LPS.
 

pattismith

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I can't find the rs#? For theses Snps ...these appear to be different fromthe 2 HFE Snps?
There is about 35 genes for Iron metabolism, so it is very complicated to study all.

"A total of 35 genes were chosen for examination and genotyping in subjects from the HealthIron study. This selection was based on prior biological evidence for involvement in iron metabolism. Some of these genes have strong historical evidence of involvement in cellular iron uptake and storage (TF, TFRC, FTH1, FTL) whereas others were chosen based on more recent evidence (SLC40A1, SLC11A2, CP, TFR2, CYBRD1, IREB2, HFE2, HEPH, HEPHL1, HAMP, HCP1, DHCR7, HP, HMOX1)."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2289803/

The SLC11A2 gene is coding for the DMT1 protein, a metal ion transporter:

https://en.wikipedia.org/wiki/DMT1

TMPRSS6 is the gene coding for an enzyme involved in hepticidin regulation:

http://onlinelibrary.wiley.com/doi/10.1002/ajh.23929/pdf

conclusion extracts:

"Several TMPRSS6 polymorphisms resulted more frequent in anemic patients than in healthy controls, suggesting their possible contribution in the refractoriness to oral iron, as showed in Table II. This effect would be imputable to reduced ability of TMPRSS6 polymorphisms to down-regulate hepcidin production that persists elevated despite iron deficiency, preventing iron stores refilling. In particular, homozygosity for V736A resulted highly frequent in patients, and absent in controls. This evidence could be related to a possible “protective” TMPRSS6 genotype could be present in the control group, and it could influence the ability to tolerate repeated blood donors without developing iron deficiency.
Considering only anemic patients, no significant differences were observed in hematologic data according to the V736A genotype (Table III). It can probably be related to the impact of previous iron supplementation that inevitably modifies the hematologic parameters, minimizing the differences among the three groups.
In the whole population enrolled in the study, the polymorphism V736A relates to lower hemoglobin, MCV, and MCH values (Table IV). This result is coherent with recent genome-wide association TABLE II.
studies revealing that the this polymorphism is associated with lower transferrin saturation, hemoglobin, and MCV levels in general adult populations, suggesting the role of TMPRSS6 polymorphisms in the erythropoiesis and iron homeostasis [21,30,31].
Compared with patients with “pure” IRIDA, our subjects showed under oral ferrous sulphate therapy a very slow and moderate increase of hemoglobin, MCV and ferritin values (data not shown).
According to the data reported in literature [31], we believe that the TMPRSS6 polymorphisms, and in particular the most common variant—V736A—could play a role in iron homeostasis, influencing negatively the capability of iron store repletion, and as a consequence modifying the degree of anemia and the response to oral iron supplementation.
Association study revealed that in anemic patients, the presence of the V736A polymorphism is variably associated to other polymorphisms reaching the highest agreement percentage for D521D (88.9%) and Y739Y (64.8%)
, as showed in Supporting Information Tables VI and VII, and confirming the data reported in literature by Delbini et al. [30].
Moreover, we found a new mutation, H448R, and two uncommon polymorphisms: A719T and V795I, which may account for impairment in TMPRSS6 function. The patient with the H448R mutation did not show a response to the oral iron supplementation, continuous parenteral iron cycles were scheduled to restore ferritin within the normal range. The two patients with the uncommon polymorphism V795I also required parenteral iron therapy, while the patient with A719T (a 10 years old female) needed oral iron supplementation since the age of 5 years old. Considering these cases, we may assume that both the two polymorphisms cause iron refractoriness.
In thalassemia carriers, the supposed up-regulation of hepcidin due to TMPRSS6 polymorphisms would account for a reduced MCV and hemoglobin values, accentuating their hematologic profile (Supporting Information Table VIII). Hepcidin evaluation in these subjects will better elucidate this point.
Finally, we may suppose that TMPRSS6 polymorphisms could be potential risk factors in those categories of patients who already have a predisposition to iron deficiency, such as celiac patients and fertile
women.
Further studies in larger court of patients are necessary to identify potential haplotypes and polymorphisms responsible for low response to oral iron treatment. Once detected high-risk categories, a short cycle of parenteral iron treatment could be started to spare the patients unsuccessful oral supplementation.
A better knowledge of TMPRSS6 polymorphisms association would allow to evaluate the expected functionality of the entire gene, limiting genetic sequencing to restricted regions of the gene in selected patients."

As you can see, studies of variants effects (differents snp ie rs numbers) are not all done!
I didn't had time to find the rs numbers behind the variants names given so maybe someone could dig into this?

What you can also do is run your datas for these genes in the ENLIS software, and then point missense variants (both common and rare can be interesting as some common variants may be harmful if they are associated with other missense variants of other genes involved in Iron metabolism).
Anyway, you can start with rare variants with bad impact on the protein, and then ENLIS will give you your snp variants (rsnumber), which you can check with current datas available.

Edit 1 = the V736A variant seems to refer to the rs855791
 
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duncan

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I've been trending a little high - but within range - for blood iron, and low for ferritin. My most recent labs, however, had me out-of-range high for blood iron, and right on the border for out-of-range low ferritin. High iron, low ferritin; both trending in opposite directions.

So, unless I had a one-off lab error, or have iron poisoning ( I kinda doubt it as I take no iron suppliments), I'm at a loss.
 

pattismith

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I did a control on my rs855791, I am homozygous mutated (GG), but I never had anemia, nor iron problems (that I am aware of).

My iron level some years ago was 62 to 83 µg/dl (ranges 37-170)
My ferritine level was 12 to 23 µg/l (ranges 10-150)