Intracellular iron regulation, infections and the effect of LPS endotoxins

pattismith

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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
 
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Horizon

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This is fascinating. I have been wondering if this is partially my problem. I am always anemic, yet even with intravenous iron most of it goes to my liver and spleen and I have iron toxicity in my organs yet stay anemic.

I wonder if my body is protecting me from iron as a way to fight a pathogen(s), the problem is I can't have iron overloading in my organs and I keep needing infusions because I get severely anemic.

I think I would need to kill off whatever the pathogen(s) are to have a hope at reversing this cycle except I don't know what they are or how to get rid of them. Instead they keep pumping me full of iron!
 

NotThisGuy

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same problem here. anemic with low free iron and low ferritin but high intracellular iron.
ferroportin gets upregulated with vitamin d.
anemia fixed through vitamin d lasted for about 2 days and stopped working after that.
 

Horizon

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same problem here. anemic with low free iron and low ferritin but high intracellular iron.
ferroportin gets upregulated with vitamin d.
anemia fixed through vitamin d lasted for about 2 days and stopped working after that.
How do you measure intracellular iron?
 

pattismith

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same problem here. anemic with low free iron and low ferritin but high intracellular iron.
ferroportin gets upregulated with vitamin d.
anemia fixed through vitamin d lasted for about 2 days and stopped working after that.
Very interesting! I am also low for Calcidiol and Calcitriol so I feel concerned!

According to my understanding, Vitamine D (calcitriol) decreases Hepcidin hormon, which is a Ferroportin inhibitor.

So when calcitriol is low, Hepticidin is high and Ferroportin is inhibited, leading to more iron in macrophages!

Do you actually know if your calcidiol (vit 25 OH D) is well converted to calcitriol (1.25 OH D) by your body?
I mean when you take vitamin D3, does your calcitriol level increases well ?

"Hepcidin-25 (hepcidin), the key iron regulating hormone, prevents iron egress from macrophages and thus prevents normal recycling of the iron needed to support erythropoiesis."
"1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the hormonally active form of vitamin D, is associated with decreased hepcidin and increased ferroportin expression"
 

NotThisGuy

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my 1.25 OH D are between normal and high in reference.
So yes it gets converted.
my 25 OH D is always on the low side, but increases with supplementation. If I'm able to tolerate them.
 

Chocolove

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Withholding iron from potential pathogens is a host defense strategy.
Anemia of Chronic Disease (ACD) or anemia of inflammatory disease, ...is in fact a protective and natural phenomenon the human body employs to limit the amount of iron a person absorbs when potentially harmful agents such as bacteria have invaded the body. ...the human body will regulate how much iron it absorbs based on the needs and the presence of any potential threat to life. ....The Iron Withholding Defense System is activated as part of the inflammatory response....

Differentiating between anemia of chronic disease and iron-deficiency anemia
Patients of anemia of chronic disease do not generally have hemoglobin values below 9.5 g/dl, although on rare occasions levels can go much lower. ...Transferrin, a protein that transports iron, is elevated in iron-deficiency anemia, indicating that the body needs more iron. The total iron-binding capacity (TIBC), an indirect measure of transferrin, is low in anemia of chronic disease because there is ample iron, but it is not easily available....

In nearly two-thirds of the patients, the serum ferritin is one test that can be used to distinguish between anemia of chronic disease and iron-deficiency anemia.....

The greatest risk for harm is mistaking anemia of chronic disease for iron-deficiency and allowing the patient to take iron pills.
This excerpt is from a very helpful, readable and inexpensive book from the Iron Disorders Institute, "Guide to Anemia" second edition. This book goes on to help decipher some complex causes of anemia. It is a book I found helpful to share with doctors.

https://smile.amazon.com/Iron-Disor...id=1503859628&sr=8-1&keywords=Guide+to+anemia
 

pattismith

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my 1.25 OH D are between normal and high in reference.
So yes it gets converted.
my 25 OH D is always on the low side, but increases with supplementation. If I'm able to tolerate them.

High Calcitriol + low Calcidiol may be correlated with an insufficiency of calcium intake...did you checked that?
 

pattismith

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calcium in serum was ok
calcium corrected was a little low. But I dont know what that means
I meant did you checked your dayly calcium intake? You have to take Calcium together with vitamine D3 ( in food or as a supplement). (The proportion shall be 500 mg Calcium for 400 UI vitamine D)

If you don't, you may experience vitamine D intolerance and your Calcitriol will stay high.
 

alex3619

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I am a haemochromatosis carrier with very high ferritin but I always have borderline anaemic levels of iron. However my RBC count is adequate. Its not easy to demonstrate iron sequestration though, and basically would require a liver biopsy etc. In a patient with leaky gut it might well be the case that there is some level of gastrointestinal bleeding as well.
 

NotThisGuy

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I meant did you checked your dayly calcium intake? You have to take Calcium together with vitamine D3 ( in food or as a supplement). (The proportion shall be 500 mg Calcium for 400 UI vitamine D)

If you don't, you may experience vitamine D intolerance and your Calcitriol will stay high.
No I dont get enoug calcium.
I have a severe problem with electrolytes.
tiny amounts of any electrolyte gives me overdose symptoms. it always needs to be balanced but I haven't figured the ratio yet... also its pretty dangerous to experiment with this...
 

Horizon

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I am a haemochromatosis carrier with very high ferritin but I always have borderline anaemic levels of iron. However my RBC count is adequate. Its not easy to demonstrate iron sequestration though, and basically would require a liver biopsy etc. In a patient with leaky gut it might well be the case that there is some level of gastrointestinal bleeding as well.
Why would iron sequestration be causing blood loss?
 

Learner1

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@pattismith Thanks for posting this. I'd taken this very article to meet with both a hematologist and a liver doctor, knowing I had several of the listed infections, and looking for an answer to my elevated ferritin (270-605) and odd iron study numbers - TIBC & UIBC low and serum iron and iron saturation high. My hematocrit tends to be at the high end of the range, too.

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 liver doctor said infections aren't in the liver (wrong :bang-head:) and said my ferritin was high due to my nutritional supplements and to stop taking all of them...:bang-head::bang-head:

The hematologist said I had hemachromatosis and should do phlebotomies immediately and often. I asked specifically about my infections and how they might play a role, handing him the article as well as one on chlamydia pneumoniae and iron, and he told me that iron overload was the only cause of my fatigue and brain fog and the infections had nothing to do with it...:ill:

My naturopathic doctor, who's done research on c. pneumoniae thinks the infections are in my liver, and treating the infections dropped my ferritin by 300. Both he and my CFS doctor encouraged me to do phlebotomies to bring my ferritin to between 60 and 100 to reduce the iron that the bugs can use.

Doing 3 phlebotomies lowered my ferritin and normalized my iron study numbers, too. I'm heterozygous for the 2 main HFE SNPs, which is only 10% of hemochromatosis patients, but it does seem to be part of the picture.

Does anyone know about measuring hepcidin? I asked my doctor but haven't gotten a satisfactory answer.

Still working on the bugs, though, and hoping that less iron will their prospects for leaving...

I am a haemochromatosis carrier with very high ferritin but I always have borderline anaemic levels of iron. However my RBC count is adequate. Its not easy to demonstrate iron sequestration though, and basically would require a liver biopsy etc.
@alex3619 What does borderline anemic look like?

What would you do differently if you had a liver biopsy and found iron sequestration?
Early on, one doc suggested a biopsy with my very high ferritin, but no one's suggested one lately. My doctors did send me for a CT scan and they checked every cancer marker they could think of, though.

Would measuring hepcidin help?
 
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alex3619

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Why would iron sequestration be causing blood loss?
It doesn't. Two different issues.

So long as blood volume and RBC count (which is a concentration measure, I think, and so total count is related to blood volume) are normal, then there is not much to worry about. This of course presumes that the haemoglobin chemistry is normal, and pernicious anaemia is a separate concern, but might show up as low RBC count.

What we do not know is how ME metabolism and borderline or full anaemia interact. There is something wrong with energy production, so this might interact with anaemia.

There was something else I wanted to say but my brain is awol at the moment.
 
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alex3619

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@alex3619 What does borderline anemic look like?
I forget the units used here, but 10 is the minimal normal for iron. I am always right on 10. Lower than that is a candidate for anaemia. My RBC count is however within normal though I think it varies through a range. I haven't been back to my doctor for weeks now and there are new results waiting for when I am able to travel.

As I referred to above, while RBC might be normal its actually a concentration measure, so low blood volume and normal RBC count could still mean anaemia as total RBC numbers could be low.
 

alex3619

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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.
 

pattismith

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No I dont get enoug calcium.
I have a severe problem with electrolytes.
tiny amounts of any electrolyte gives me overdose symptoms. it always needs to be balanced but I haven't figured the ratio yet... also its pretty dangerous to experiment with this...
yes it is!

Official recommandations for daily vitamine D3 supplementation ranges from 2 x 400 UI to 2000 UI depending on the level of your deficiency.
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 take myself 3 x 400 UI + 3 x 500 mg until my calcitriol/calcidiol are OK, then I will go back to 2x 400 UI/500 mg)

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!)