______________

J Clin Invest 61: 1428-40 (1978)[78194498]

The critical role of iron in host-bacterial interactions.

S. M. Payne & R. A. Finkelstein

The ability of potential pathogens to acquire iron in a host is an important determinant of both their virulence and the nature of the infection produced.

Virulent gram-negative bacteria are capable of acquiring sufficient iron from the host because their virulence (for chick embryos) is unaffected by exogenous iron.

Avirulent mutants which are apparently limited in their ability to acquire iron could be isolated from the virulent strains.

The lethality of these mutants was significantly enhanced by exogenous iron.

Reduction of the relatively high serum iron saturation of chick embryos (to levels more closely approximating those in man) by pretreatment with iron-binding proteins or endotoxin inhibits the lethality of some virulent bacteria.

Those bacteria whose virulence was reduced include the Shigella, Vibrio cholerae and strains of Neisseria gonorrhoeae, all of which are nondisseminating pathogens in the normal human host.

Pathogens which produce septicemic and disseminating infections such as Neisseria meningitidis, Haemophilus influenzae type B, Escherichia coli possessing K-1 antigen, Pseudomonas aeruginosa and Salmonella typhimurium and disseminating strains of N. gonorrhoeae were, in general, unaffected by reduced serum iron saturation.

These disseminating bacteria appeared to produce greater quantities of compounds (siderophores) which stimulated microbial growth in low-iron media than did the nondisseminating pathogens.

Thus, the gram-negative bacteria tested can be divided into four major classes according to their responses to modifications in iron levels in the chick embryo model and these results correlate with the nature of the infections which they typically produce in man.

Subject: storage iron removal


From Dr. Sullivan,  - Mon. March 30 1998 11:02
Subj. - Drop Ferritin below 100?
(in part)
Even when the ferritin is 6 or even zero, there is still the large mass of
iron present in red blood cells. All the other functional iron is also still
present. For people without hemochromatosis, this functioning iron amount is
much greater than typical iron stores. So when you achieve total iron
depletion, there is still that large amount of iron present in the body, in
fact, by definition , exactly just enough.

For a typical adult male, the ratio of functioning iron to stored iron might
be around 2:1. the ratio would vary quite a bit depending on how much stored
iron there is, My working hypothesis is that the ability of your body to
handle the toxicity of iron is proportional to that ratio. So if the stored
iron level falls to zero, your ability to contain the dark side of iron
should rise to a very high value, as the value of the ratio rises,  In
untreated hemochromatosis, the ratio is reversed and may be on the order of
2:20. Much higher in many cases. (obviously the ratio would still be high in
severe anemia and I am of course not advocating severe anemia by this
reasoning.)
Jerome L. Sullivian, MD, PhD

Touching on an important but apparently confusing issue in the treatment of iron overload.

Of course the ferritin should go to zero, and to the extent possible should be kept at zero.

The purpose of measuring ferritin during therapy should not be to reach some arbitrary low target such as 100 or 20.

There is no need whatever to "protect the ferritin".

The goal is to eliminate the ferritin.

The purpose of measuring ferritin during treatment should be to guage the rate of loss as a guide to frequency of phlebotomy. u

Consider the normal blood donor who does not have hemochromatosis.

Neither FDA nor any other accrediting body require a ferritin level for normal blood donors.

Think about what that means.

That means their ferritin level is allowed to fall without limit and without monitoring.

Clearly if normal donors have the benefit of letting their ferritin go into free fall, the same should apply with more emphasis to patients being bled for iron overload.

Normal donors are monitored by hemoglobin level.

As long as the hemoglobin level is within normal limits, the donor is considered to have enough total body iron, even if the ferritin level becomes undetectable.

For an iron overload patient, hemoglobin level becomes the important monitor when ferritin becomes undetectable in serum.

Perhaps surprisingly, the literature is not huge on this very important point.

We need a great deal more work on the effects of iron loss. There are a few studies that focus on removing iron in subjects with "normal" iron status.

These show that there may be benefit not only from de-ironing from massive levels down to "normal" levels, but also from completely unloading even modest "normal" amounts of stored iron.

I would still recommend what Jerome Sullivan recommends, which is to follow your Hemoglobin and Hematocrit for a more true representation of getting to your deep iron stores, as follows:

The serum ferritin level really correlates quite well with tissue iron and liver iron in the majority of cases.

But we don't treat a majority, we treat an individual patient.

What we can be confident of on average may leave major uncertainties when treating the individual patient.

Much of the plasma ferritin can be essentially free of iron. It is the antigen (the ferritin protein) that is detected by the test, not the iron in the ferritin.

The ferritin of 50 ng/mL may consist entirely of iron-free ferritin.

Victor Herbert has devised a new assay that measures the amount of iron in circulating ferritin. I don't think the test is available yet commercially.

Victor believes that the amount of iron present in the plasma ferritin can help to identify hemochromatosis (the patients are thought to have higher iron levels in their ferritin).

Another problem involves pathology that destroys liver cells.

Any such process can cause release of ferritin antigen into plasma.

Presumably this sometimes contains iron and sometimes not, but either way it perturbs the relationship between plasma ferritin and tissue ferritin.

The other extreme, ie having a low ferritin and a higher than expected amount of tissue iron, can be observed clinically. I'm not sure that we know enough about why, but clearly it happens during phlebotomy therapy that a patient hits a plateau for a while.

In other words, units continue to be donated but the ferritin stops going down.

Obviously, a bunch of iron is leaving the body in the form of blood hemoglobin but the ferritin won't budge.

In these cases, there may be iron compartments in the body that cannot be as easily mobilized.

The serum ferritin measurement may fail to detect some of this iron.

Perhaps some of this iron is embedded within lipofuscin (snarls of degraded membrane and other grunge within cells).

If we put enough pressure on the system by continuing to remove iron in blood, our body's system for getting at this iron finally scrapes the bottom of the barrel and recovers it.

Really knowing where a particular phlebotomy patient is with regard to iron storage level is still an art.

It is usually not useful or justifiable to do every possible test or precedure to achieve exactitude after each phlebotomy.

Jerome L. Sullivan, MD, PhD and:

I don't feel that arbitrary low target values for ferritin are very valuable.

Their main use seems to be to keep ferritin above zero, as if the patient would suddenly collapse if zero ferritin was reached.

I would remind (HOME) the list again that volunteer blood donors are not required to have ferritin measured.

Ever!

That means that, so far as the FDA and the Blood Bank community are concerned, a volunteer donor's serum ferritin can fall straight to zero and stay there as long as the donor continues to donate regularly.

This is not at all an impossibility.

Donors are allowed to donate every 8 weeks and they are not required to take iron.

Remember that most donors do not have HH genes and so are not "protected" from a zero ferritin by the fast iron absorption of hemochromatosis patients.

Thus they are at increased "risk" of having a zero ferritin.

Does this matter?

No!

Volunteer donors do fine, in fact recent studies suggest that they do better that non donors in terms of heart attacks.

Donors are required to have the hemoglobin level checked.

As long as they pass the hemoglobin test they can donate even if their ferritin is unmeasurably low.

A normal hemoglobin assures us that the donor has enough iron for all normal needs even if the donor has a flat zero level of stored iron.

All this stuff about having one iron loaded organ and one iron deficient organ at the same time is just idle speculation.

The totality of evidence says that a normal hemoglobin level means you have enough iron for all normal functions.

Period.

For hemochromatosis patients, there has developed an attitude that serum ferritin should be kept above some lower limit.

In my view, this is nonsense.

Why protect the ferritin level of hemochromatosis patients and let normal blood donors' ferritin fall without limit ?

We must keep the fundamental goal of therapy firmly in mind:

We need to keep the stored iron level DOWN, not up!

If the serum ferritin slams down to flat zero, the patient should be congratulated, not made to worry, so long as hemoglobin remains normal.

For many patients a slightly lower than normal hemoglobin is fine if they tolerate it and if this can be achieved without an excessively burdensome phlebotomy schedule.

These are matters that must be fine tuned by the patient and his/her doctor.

The serum ferritin value should be used to tell you when to keep being bled, not to tell you when to stop being bled.

The hemoglobin is the guide for temporarily stopping, not the ferritin.

You may want to look at the following small collection of papers:

1. Sullivan JL, Till GO, Ward PA. Iron depletion decreases lung injury after systemic complement activation. Fed Proc 1986;45:452. 2. Sullivan JL, Till GO, Ward PA, Newton RB. Nutritional iron restriction diminishes acute complement-dependent lung injury. Nutr Res 1989;9:625-34. 3. Andrews FJ, Morris CJ, Lewis EJ, Blake DR. Effect of nutritional iron deficiency on acute and chronic inflammation. Ann Rheum Dis 1987;46:859-65. 4. Chandler DB, Barton JC, Briggs DD, Butler TW, Kennedy JI, Grizzle WE, Fulmer JD. Effect of iron deficiency on bleomycin-induced lung fibrosis in the hamster. Am Rev Respir Dis 1988;137:85-9. 5. Patt A, Horesh IR, Berger EM, Harken AH, Repine JE. Iron depletion or chelation reduces ischemia/reperfusion-induced edema in gerbil brains. J Pediatr Surg 1990; 25:224-8. 6. Salonen JT, Korpela H, Nyssonen K, Porkkala E, Tuomainen T-P, Belcher JD, Jacobs DR, Salonen R. Lowering of body iron stores by blood letting and oxidation resistance of serum lipoproteins: a randomized cross-over trial in male smokers. J Intern Med 1995;237:161-8.

Subject: cancer/low iron diet

Anticancer Res 1999 Jan-Feb;19(1A):445-50

Inhibitory effect of deferoxamine mesylate and low iron diet on the 13762NF rat mammary adenocarcinoma.

Wang F, Elliott RL, Head JF

Mastology Research Institute, Elliott Mastology Center, Baton Rouge, LA 70806, USA.

The iron chelator deferoxamine mesylate has been shown to inhibit the growth of a variety of human malignant cell lines and the rat 13762NF mammary adenocarcinoma cell line.

In vivo studies in mice have also demonstrated that an iron deficiency induced by either feeding a low iron diet or injecting the iron chelator deferoxamine mesylate decreases tumor growth.

In this study Fisher rats were transplanted with the 13762NF mammary adenocarcinoma and divided into four groups: normal diet, normal diet plus deferoxamine mesylate treatment, low iron diet and low iron diet plus deferoxamine mesylate treatment. The measurements of tumor size and body weight were recorded weekly .

We found that treatment with either deferoxamine mesylate or a low iron diet decreased rat tumor growth, but the greatest inhibitory effect on tumor growth occurred when the rats were treated with deferoxamine mesylate injections plus fed a low iron diet.

These treatments did not significantly inhibit the weight gain of the rats. At the end of the experiments measurement of serum iron proved that these treatments caused iron deficiency, but there was no significant treatment related alteration in blood hematocrit.

We therefore concluded that deferoxamine mesylate may be a useful chemotherapeutic agent in the treatment of breast cancer, when used in combination with standard chemotherapeutic regiments or with other agents that interfere with iron metabolism, and further that the restricting of iron intake should be considered when planning chemotherapy for all cancer patients.

PMID: 10226580, UI: 99243167