Iron Deficiency Signs and Symptoms -Part IV

Symptoms of Iron Deficiency Anemia:

Iron is essential for oxygen carrying capacity.  Iron deficiency and anemia decreases oxygen delivery to all major organs of the body. Most especially the brain, heart and muscles.   Iron deficiency manifests with easily identified symptoms and conditions.  Here is a quick overview followed by a more detailed description.


common symptoms of iron deficiency anemia

Mental Fatigue and Cognitive Impairment.

Iron is an essential cofactor for neurotransmitter and myelin synthesis.  Brain neuronal cells require iron for DNA synthesis, mitochondrial respiration, and other vital processes.  As with each of these conditions, iron deficiency anemia reduces tissue oxygenation.  The brain is vitally dependent on O2 and glucose.

Pale (pallid) or Yellow (sallow) Skin.

Here is a comparison of a well perfused (red blooded) iron sufficient hand with an anemic iron deficient hand.  This is simply a visual sign of arterial oxygenation saturation.  Well oxygenated and perfused blood is red.   Technically, we can measure arterial pO2, pCO2 and pH.   The pO2 is the partial pressure of oxygen.

Pulling the lower eyelid revealing the conjunctival inner surface.  This reveals a lack of normal capillary perfusion.  While I was an Emergency Physician we also used another rapid test.  Pressing a fingernail watching for rapid reperfusion or capillary refilling.

anemia with (pallid) poor conjunctival perfusion pallor of anemia compared to normally perfused hand

Unexplained Fatigue or Lack of Energy

physical and mental fatigue

Heart Failure in Susceptible Individuals with Heart Disease

In individuals with a weak or failing heart, iron deficiency anemia stresses heart function.  Diminished oxygen saturation requires more rapid blood flow to keep up with oxygen requirements.  This increases heart rate.  We call this tachycardia.  This tachycardia in turn stresses an already weakened heart.   The heart is, after all, a large muscular organ.  Lack of oxygen leads to myoglobin deficit.   It is a circular set of reactions as seen in figure 5

iron and heart failure
figure 5

Pagophagia – Craving for Ice or Clay

This is an interesting phenomenon.  And it is not well scientifically explained.  It is possible this increase in alertness is a response to the fatigue of iron deficiency anemia.

pica or pagopahgia is a symptom or iron deficiency

Sore or smooth tongue and cheilitis

A smooth tongue.  The “angles” of the mouth show signs of angular cheilitis.  This appears to be an inflammatory condition.  In the past I thought this was a vitamin deficiency.

glossitis (re tongue) and angular cheilitis are symptoms of iron deficiency

Brittle nails or hair loss

Another interesting phenomenon  indicating the need for iron in hard connective tissue synthesis.  A poorly explained phenomenon.  We think this may be related to injury to the nail plate – the origin of nail growth.  Somehow this may be more susceptible to damage or injury with iron deficiency anemia.

brittle nails are a symptom of iron deficiency

Restless Legs Syndrome

Restless legs is an annoying condition that disturbs healthy and regenerative sleep.  It is nearly synonymous with “periodic limb movement.”  This is an important  observation during a thorough sleep study.  Iron deficiency as a cause is becoming more recognized.  Iron infusions are quite dramatic in their ability to completely resolve this condition.   In the past we have treated this condition with Mirapex, a dopamine agonist, more commonly used to treat Parkinson’s Disease.

restless leg syndrome at night (periodic limb movement)

Additional Symptoms:

Here are further manifestations mostly related to more rapid arterial blood flow in response to diminished oxygen availability:

  • Shortness of breath or chest pain, especially with activity (dyspnea)
  • Unexplained generalized weakness (asthenia)
  • Rapid heartbeat (tachycardia)
  • Pounding or “whooshing” in the ears (pulsatile tinnitis)
  • Headache, especially with activity (exertional headache)

So let’s move on to the final episode: treatment of iron deficiency and anemia.

Previous Pages

 Part I, Part II, 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

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

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