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Iron Therapy and Oxidative Free Radicals – Part III

Iron Therapy and Oxidative Free Radicals – Part III

We talked about the essentials of iron metabolism, iron uptake and iron control in part 1 and 2.  Now let’s try to unravel the mystery of iron therapy.  But first we take a side trip into oxygenation, reactive oxygen species (ROS) and free radicals.

In reading through the literature it is obvious this is a very complex subject. Far more complex than is usually admitted. And I have alluded to many controversies where another binary choice is offered. Either you are leery of iron therapy because it is dangerous and unhealthy or you are an advocate of the multiple benefits of iron.

It’s not an easy choice.  I am showing you why iron is so important and beneficial.  So let’s delve into the reactive aspects of iron.  Then we can come to a happy and more beneficial  conclusion.

Free Radicals and Reactive Oxygen Species (ROS)

There is a major and ongoing controversy.  Oxidative versus antioxidant therapies.  The literature and current belief is replete with references to iron promoting free radicals or ROS (reactive oxygen species). In other words, iron would be considered unhealthy because of its pro-oxidative properties.  Consider the “Fenton reaction.  Adding Ferric Iron + Hydrogen Peroxide to form Ferrous Iron + Free Radical Oxidative Species.

iron participates in the Fenton reaction generating free radicals

Figure 2

Now I have always maintained the action of antioxidants is overly simplified. There are structures that should be protected from reactive oxygen species. Namely cell wall structures, mitochondria and DNA. On the other hand, white blood cells depend upon highly reactive oxidative zones to kill bacteria or to have anticancer properties.

Oxidative Therapies vs. Anti-Oxidant Therapies

The debate rages on. I have many colleagues who are strenuously pro-oxidative advocates. They treat cancer and other infectious processes with hydrogen peroxide and/or ozone (triple oxygen) therapies.

One of the prevailing theories of aging is oxidation. It is one of the four pillars of aging in my book Life Extension Revolution.   That is, oxidation hastens aging.  Much like metallic iron oxidizes and rusts.  I have always postulated that over-oxidation is unhealthy.

There is newer thinking that is evolving. It is possible that a small amount of free radicals or reactive oxidative species actually engages and causes a protective and homeostatic reaction.  There is a process called hormesis. A small amount of poison introduced in a system stimulates a protective response.

So that a small amount of oxidative free radicals actually induces a beneficial reaction. But the system can become overwhelmed with too many reactive species in which case there is a negative and pathologic effect.

Chemotherapy and Radiation Therapy

Chemotherapy and radiation therapy are examples of highly reactive oxidative reactions that kill cancer cells. That is how they work. So here we have the ultimate example of oxidative therapy.  But it is not specifically targeted. So that there is collateral damage.  Killing normal cells as well as cancer cells.

And there is a prevailing caution in the oncology community that antioxidants should not be used during chemotherapy or radiation therapy. It might cancel effects of these cancer therapies. This has never been proven to be true.  It is only an unproven presumption.

Iron as a Pro-oxidative element

Now why this discussion? Because it assumed that free iron is so highly reactive and potentially oncogenic (causes cancer).  Or it promotes and feeds cancer. But within the context of the above discussion, I contend that this has never been definitively proven. It is simply the prevailing theory.  This is the genesis of iron causing cancer.

There is definitive no proof that free radicals de novo (by themselves) cause cancer.  There is no proof that iron by itself causes cancer.  Just like my highly controversial assertion that cholesterol does not cause cardiovascular disease and hormones do not cause cancer.  Over time these assertions are gathering more merit and acceptance.

Iron Deficiency and Therapy Next

This was originally going to be a 3 part series.  Now maybe 4 or 5 parts.  So you can easily digest what is important to you.  So you can understand all aspects of iron deficiency and therapy.  And why this is such a vital topic which needs a new and refreshing view.

Iron Regulation Part II: Transport Signaling

Iron Regulation Part II: Transport Signaling

All these years I was trying to understand the relationship between serum free iron, bound transferrin iron, storage as ferritin iron and anemia. What is the control mechanism?   What is the cause of iron deficiency?   How is this related to chronic anemia?  How much lab data do we need to determine true iron status?  OK. So let’s review iron cycling through each body compartment.

Bivalent Iron

You want lab data that measures all these forms of iron transport and storage for a complete and accurate assessment.

Iron exists in two states (bivalent).  Ferrous Fe² iron is a reduced state which is more easily absorbed.  Ferric Fe³ iron is the more reactive oxidized state.  It is less easily absorbed.  Ferric iron generates free radicals which can damage tissues and DNA.   I will show you later why the more reactive form of iron generates so much controversy.

transport and reversible conversions of ferrous and ferric iron
fig 5

Figure 6 shows the traversal of iron into various key compartments.    Here is what is important.

Iron Transport

Dietary iron in the ferrous form is transported across the gut (enterocytes) into the blood stream.   Intra-vascular ferrous iron is enzymatically converted to the more reactive ferric iron by ferroxidase.  It is then bound to Transferrin.   This carrier binding protein transports iron throughout the blood to various tissue sites.

Iron then enters the cells of the liver, spleen, muscle and bone marrow.   Inside each cell, iron is bound to Ferritin.   This storage protein is capable of binding large quantities of ferric iron.  By encapsulating ferric iron, it protects cellular components from reactive free radical damage.

Ferritin is key.  I stressed this in part I.  Remember, ferritin can also represent inflammation.

The most important compartment is entrance into the bone marrow.  That is where red blood cells are manufactured.   It is the incorporation of iron into erthryocyte (red blood cell) hemoglobin that is critical for oxygen carrying capacity.   Remember, anemia results in oxygen deficit at the cellular level.

Myoglobin is essential for muscle oxygenation.  Most especially the muscles of your heart. Hemosiderin is denatured ferritin.

Iron transport from ingest iron to cellular storage
fig 6

Here is the take home message.  You want lab data that measures all these forms of iron transport and storage for a complete and accurate picture.

Hepcidin — Master Controller of Iron Regulation

Now here is my recent discovery and “aha” moment. Hepcidin (1) is the x-factor that I had been missing. It is a liver derived protein that has pro-homonal signaling activity. It is a key regulator of iron absorption. [From the latin hep = liver and cidin = killing.]

Hepcidin, a peptide hormone which is mainly synthesized in the liver, was discovered in 2000. It reduces extracellular iron in the body by several mechanisms: 1) It lowers dietary iron absorption by reducing iron transport across gut mucosal cells (enterocytes); 2) It reduces iron exit from macrophages, the main site of iron storage; and 3) it reduces iron exit from the liver. In all three instances this is accomplished by reducing the transmembrane iron transporter ferroportin.   — Wikipedia


Hepcidin protein regulates iron absorption
fig 7

How Hepcidin Controls Iron Absorption

Any signal that increases hepcidin levels decreases iron absorption. Contrariwise, any signal that decreases hepcidin will increase iron absorption

I know.  It’s complex picture. But simply put, hepcidin determines efficiency of iron absorption. Any signal that increases hepcidin levels from the liver decrease iron absorption. Contrariwise, any signal that decreases hepcidin will increase iron absorption. You can see in fig 7 that the genetic abnormality hemochromatosis is characterized by a deficiency of hepcidin activity.   This causes an accumulation of abnormally toxic iron levels.  Inflammation is a major signal for increased hepcidin activity thereby causing anemia.

Hepcidin is a regulator of iron metabolism. Hepcidin inhibits iron transport by binding to the iron export channel ferroportin which is located on the basolateral surface of gut enterocytes and the plasma membrane of reticuloendothelial cells (macrophages)…

Inhibiting ferroportin prevents iron from being exported and the iron is sequestered in the cells.[9][10] By inhibiting ferroportin, hepcidin prevents enterocytes from allowing iron into the hepatic portal system, thereby reducing dietary iron absorption …

Increased hepcidin activity is partially responsible for reduced iron availability seen in anemia of chronic inflammation, such as renal failure.[11]     Wikipedia

That’s a quick overview and background of the complexity of iron transport and control.   So how do we correct these deficiencies and improve your iron status?   There is a rich array of opinions, guidelines and approaches.  That is the subject of the next part III.   So stay with me.

  1. Hepcidin – the Iron Regulatory Hormone, . 2005 Aug; 26(3): 47–49.

To be continued in Part III — How and Why to treat iron deficiency anemia

Iron Metabolism Part I: Sources, Transport, Testing

Iron Metabolism Part I: Sources, Transport, Testing

The Essentiality of Elemental iron

Iron is essential for healthy red blood cell hemoglobin levels. Red blood cell hemoglobin is essential for oxygen transport. Oxygen and glucose are absolutely essential for brain function.  The topic of today’s review.

I think iron metabolism, assimilation and transport is highly misunderstood. And the subject of great controversy.  Here is why. Hemoglobin is the essence of red blood cell function. And you can see in figure 1, iron is the essential core of hemoglobin. Healthy red blood cells transport oxygen.  In plants, magnesium is absolutely essential for chlorophyll function.

Hemoglobin is essential for healthy red blood cells (erythrocytes)

Red blood cells pass through the vasculature of your lungs. Oxygen is inhaled and absorbed by the circulating red blood cells. This is how oxygen is transported to the rest of your body. Your heart, brain and all other vital organs.

red blood cells transport and release oxygen
fig 2

There is a widely held belief that iron supplementation is only essential for younger women especially and not as necessary in postmenopausal women. Similarly iron is believed to be less essential for men as we grow older. This is based on monthly menstrual cycles were iron is shed.   In reality these differences in age are not that significantly different.

Sources of Iron

Iron is ingested in food sources or supplements.   Beef, chicken liver, oysters, sardines, lentils, spinach.

But the plot thickens.

There is an important difference between heme-iron from red meats and seafoods and non-heme sources.  Heme-iron is much more readily and efficiently absorbed.   Non-heme sources are much less efficiently absorbed.  All plant-based sources are non-heme iron.  Additionally many plant based sources contain phytates, polyphenols, or soy that further inhibit efficient iron absorption.

This is why plant based diets so frequently lead to significant iron deficiency anemia.   A source of heated controversy.

Elemental salts are also considered non-heme based.   That would be ferrous sulfate, ferrous gluconate and ferrous fumarate salts.    So simply looking a charts labeling the iron content of each nutrient is not enough.  Chelated iron sources may lie in between.

heme-iron and non-heme-iron sources
fig 5

Now let’s look at the continuum of iron deficiency to iron deficiency anemia.    You can be iron deficient without suffering anemia. But eventually when iron levels are further depleted true iron deficiency anemia occurs.

Lab Testing — Hematology

Iron deficiency anemia is characterized by very small red blood cells – termed microcytosis.  The MCV (the mean corpuscular volume) is a laboratory measure of your red blood cell size. An MCV < 88-90 infers iron deficiency.

Iron deficiency and anemia
fig 3

Figure 3

[The values in the above diagram are Australian values. Divide the hemoglobin values by 10 for American values. ]

Similarly an MCV > 100 (macrocytosis) raises the possibility of B12 or folate deficiency.  .

These are not absolutes. They are general principles. There other conditions that raise the MCV. Alcohol is a major contributor to large (dysfunctional) red blood cells.

In Hematology we measure red blood cells and white blood cells.  In the past a centrifuged (spun down) sample would contain a percentage of red blood cells with a top layer of serum.  The percentage of sampled red blood cells is called the hematocrit (Hct).  Today’s modern labs use flow cytometers so the hematocrit is inferred and not directly measured.

Hematologists have traditionally follow hemoglobin and not hematocrit.  Which is probably more descriptive.  We want to know how much hemoglobin is available.  That is the oxygen carrier or transporter.   In simple terms the hematocrit = 3 x hemoglobin.

Most labs use these ranges:

  • Hct  (women)  34-46%     <34 is anemic    optimal > 38
  • Hct (men)        39-52%     < 39 is anemic   optimal > 44
  • Hgb (women)   11-15         <11 is anemic     optimal > 13
  • Hgb (men)        12-17         < 12 is anemic   optimal > 14

In practice, I use much tighter ranges.   You are relatively anemic well before you reach these critical cutoff values.   I have denote optimal values vs. strict lab cutoff values.

The third measurement is the actual RBC count.  Your red blood cell mass.

  • Hematocrit

  • Hemoglobin

  • RBC count

  • MCV

Iron Metabolism and Transport

Iron transport in various compartments
fig 4

The movement and transport of iron is complex and subject to various controls.  Figure 4 shows the movement of iron through these various “compartments.”

It is transported in the blood by attaching to transferrin.  A large binding protein complex.  It enters cellular storage through the control of ferroportin.

It is stored intracelluarly in the cellular cytosol as ferritin.   The ferritin complex is a stable protective protein that neutralizes the reactive aspects of free ferrous (Fe³) iron.

Ferritin is the primary measure of stored iron. It is also a acute phase reactant.  A biomarker of inflammation.   This confounds ferritin as a simple measure of iron storage because it can also represent an inflammatory process.

Lab Testing — Iron BioMarkers

Now you can see from diagram 3 that measuring or following simple serum iron levels is inadequate.  It is only a partial measure of iron sufficiency or deficiency.  It is variable.  To obtain a more accurate assessment and picture you must obtain:

  • Serum iron

  • Transferrin Iron saturation

  • Ferritin levels

  • TIBC (total iron binding capacity)

  • Serum transferrin receptor (sTfR) (added for subtle early signs of iron deficiency)

Ferritin is a measure of stored iron. Serum iron measures free floating iron. Because of insurance-based cost containment, ferritin is not routinely included in current laboratory testing. You definitely want ferritin levels.

Now the picture is even richer for the transport of iron. It becomes quite complex. Actually, far more complex than even I had ever imagined. I have often wondered about the relationship between ferritin (stored iron) and serum iron (free floating iron). What is the controlling factor or mechanism?

stay tuned for Part II — signals that control iron absorption

Flu Vaccine 10% Effective

Flu Vaccine 10% Effective

getting your flu vaccineFlu vaccine may only be 10% effective this year?  That means 90% ineffective.  Tell me more.

I am asked frequently by my patients, “do you suggest or advocate the flu vaccine.”   My simple answer is no.  I do not recommend flu vaccines.   I am middle of road on vaccines.  Some vaccines are essential.  No argument.  Tetanus boosters, MMR for measles, mumps and rubella, polio vaccine.  In my day we all had smallpox vaccination.   That is now history.


Sabin oral poio vaccine

I can vividly remember lining up at my high school for the first series of oral polio vaccinations.  It was a new era.  Based on the original Jonas Salk vaccine and later refined as the Sabin Vaccine.   It was the Sabin vaccine that we all eagerly took on sugar cubes.  [many years later Larry Sabin, his son, was one medical school graduating class behind me]

Now the problem with the flu vaccination is quite different.  Every year the current strain mutates or originates in a different vector or region.   It is subject to antigenic drfit.  There is minor antigenic drift and major antigenic drift.

Vaccine Effectiveness by Varies by Year

flu vaccine effectiveness over timeMajor manufacturers of the vaccine only have 6-8 months lead times.  The current stock is always based on last year’s strain.   With the assumption that there are only minor changes.  The minor antigenic drift.  But it is never identical.  In the best of years, the vaccination is 40-60% effective.   Or contrariwise, 40-60% ineffective.

This year, CDC experts are admitting it will only be 10% effective.  90% ineffective or not worth the bother.

So I am greatly puzzled why all hospitals and large institutions mandate the flu vaccination.  “It’s better than nothing.”  10% effective is not “better than nothing.”   It gives rise to a false sense of security.  Staff and patients are protected.  No they are not.  This is where public safety and good epidemiological policy making collides with individual choice.

Here is a news story from 2004.   We have not seen significant change since then.


WASHINGTON – The influenza vaccine that many Americans clamored for this year was not very good at protecting people against influenza, colds and similar viruses, a preliminary report published Thursday shows.

The study is the first attempt to show whether the vaccine that many sought after a flu scare this autumn and winter actually worked.

The study of hospital workers in Colorado, a state that was hit early and hard by influenza, showed the vaccine had “no or low effectiveness against influenza-like illness,” the U.S. Centers for Disease Control and Prevention said in its report.

Reporting this year:

What’s more, this year’s flu shot may not be up to the task. It is the same formulation that was used during Australia’s most recent flu season — which typically sets a pattern for what the U.S. will face — and it was only 10 percent effective there.

…  But Sabeti says even though the effectiveness of this year’s vaccine is particularly low, it’s still worthwhile to get a flu shot.

“Even 10 percent effective is better than nothing, and a lot of it has to do with herd immunity — the more people are protected from it, the more other people will also be protected,” she said. “In fact, in a year where it’s low effectiveness, it’s even more important that everybody get it so we can get as much resistance and we don’t allow the virus to thrive and grow and keep changing.”   — CBS news

Searching for the Holy Grail — the Universal Vaccine

Researchers are avidly seeking the “universal vaccine.”  That is the Holy Grail.  An admission that the current crop of vaccines has been admittedly inadequate.

Recent efforts have focused on the development of a new generation of influenza vaccines that could provide broad spectrum, “universal” protection against a wider range of influenza variants including strains with pandemic potential. DNA vaccines possess a number of characteristics that make them particularly well suited for a universal influenza vaccine [36]. In the event of a pandemic threat, DNA vaccines offer an important advantage of accelerated vaccine development and production since the DNA vaccine sequences can be obtained directly from the clinical isolate and rapidly constructed and propagated using well-established molecular techniques without the need for cell culture or eggs. DNA vaccines induce both antibody and T cell responses, and both arms of immunity contribute to cross-protection against different influenza variants [78].  — PLOS One

Anti-Viral Medications and Treatment

As recently as 1990’s the common wisdom offered was, “there is no treatment for the flu.”  That was not true.  And it always puzzled me.  It was quite well known even then that Symmetrel (Amantidine) used for Parkinson’s Disease was effective against the flu.   From empirical observations it was noted that Parkinson’s patients treated with Symmetrel were far less likely to suffer the seasonal influenza.   I began treating patients in walk-in clinics appropriately.

Today we have a new series of anti-viral flu treatments.  The most effective is oseltamivir (Tamiflu).   A second choice is zanamivir (Relenza).  These need to be started in the first 48 hours for maximal effectiveness.

The authoratative and erudite source The Medical Letter concludes:

A neuraminidase inhibitor, either oseltamivir (Tamiflu) or zanamivir (Relenza), remains the drug of choice for treatment of patients with influenza who are at high risk for complications of the disease, and for anyone hospitalized with presumed influenza. Oseltamivir is preferred for treatment of pregnant women. Otherwise healthy persons who are not in a high-risk group generally do not require antiviral prophylaxis or treatment for influenza

A most interesting conundrum.  If anti-viral prophylaxis is not indicated for healthy individuals then why is the flu vaccine indicated for everyone?   And the debate continues.  While there is policy decision-making consensus on flu vaccination, the debate as to the appropriateness of anti-virals continues.   I argue here that anti-viral treatment is far more effective per case than vaccination.

Dr. Miller’s Novel Approach

Which finally leads me to a more novel and less toxic approach that has been effective across a wide variety of viral and flu syndromes:

  1. High dose Vitamin D — 50,000 units daily for 5 days (yes, that is high dose)
  2. Astragalus 1000 mg daily for 5 days.  A most potent Chinese herb known for its potent immune boosting properties
  3. Thymic Protein A — 1-2 packets three times daily for 5 days.   Activates anti-viral t-cell and b-cell immune activity.

thymic protein A -- immune booster

Philip Lee Miller, MD

Jan 09 2018

Carmel, CA



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