Treat and Prevent Iron Deficiency Anemia

May 24, 2018 Philip Miller Comments 0 Comment

This is the last in our series on Iron Deficiency and Iron Deficiency Anemia. In parts I, II, III, and IV, I talked about all aspects of the essentiality of iron. How to diagnose iron deficiency anemia. Various controversies surrounding iron supplementation. And the relationship of iron to various inflammatory states including cancer. Let’s recap this series with specific treatment routines. I encourage you to read this final wrap-up containing new and revolutionary medical paradigms.

[If you want the nitty gritty, scroll down to “treatment.”]

Enter Functional Medicine

I want to introduce one more refining and overriding concept. A new paradigm shift in medicine. Functional Medicine. We need to rethink the entire subject of iron deficiency and anemia. How and when do we recognize the condition of iron deficiency and progressive anemia? And then what triggers our decision to treat – or prevent?

Functional Medicine is a systems biology–based approach that focuses on identifying and addressing the root cause of disease. Each symptom or differential diagnosis may be one of many contributing to an individual’s illness. — from the Institute for Functional Medicine

Binary vs. Optimal Choices

In America I see two competing medical paradigms. Structural pathologic medicine based on illness and disease. And functional medicine which is based on dysfunction, suboptimal values with the goal of restoring health and wellness. The goal is not identical. It leads to totally different approaches for you, the patient.

The functional approach to iron therapy realizes various degrees of iron deficiency rather than a binary choice. “In the box” or “out-of-the-box.” You’re either low or you are high. In reality virtually all medical paradigms follow a normalized distribution. A continuum from very low to very high. The goal is always optimal — in the middle — values. This is a concept stressing to all my audiences 20 years.

Fortunately, a new model is proposed and advocated in a major publication in the Austrian literature. This paper lays out guidelines for treating iron deficiency anemia in cancer patients using absolute (AID) and functional (FID) iron deficiency. Seemingly two sets of criteria.

Anemia is common in cancer patients [2]. From a practical viewpoint, two forms of iron deficiency need to be differentiated: absolute iron deficiency (AID) and functional iron deficiency (FID). AID is defined by a TSAT < 20 % and a serum ferritin level < 30 ng/ml in otherwise normal individuals, while in cancer patients a higher cut off level of ferritin levels should be applied (< 100 ng/ml). FID is defined by a TSAT < 20 % and serum ferritin levels of > 30 ng/ml in normal individuals and of > 100 ng/ml in cancer patients.

Great. Here is a clear path. The Austrian literature articulates a major shift in modern medical thought. That is my purpose in writing series for you. Iron therapy is anti-angiogenesis preventing neo-vascularization.

Challenging Standard Definitions

I see so many patients who are relatively anemic and are symptomatic. But they still fall within the “normal range.” And are therefore dismissed. Not falling within the treatment guidelines. Ready for the paradigm shift?

Now remember from the previous blogs that iron deficiency will proceed anemia. So here is the continuum of iron from fully sufficient to deficient that precedes anemia . This is a functional view. We want optimal values.

Anemia appears only after more severe iron deficiency progresses. Once iron falls to more severe levels.

Conventionally, your diagnosis of anemia must meet these standard criteria. Hematocrit values < 35% (women) or <40% (men). Or Hemoglobin values <13 in men or <12 in women. Remembering that hemoglobin is oxygen carrying capacity.

But in reality, you won’t be diagnosed or treated until values fall even much lower. At that point you are really sick.

See figure 2 for “normal values.” You want optimal values.

	Men	Women
RBC Count (million/ug)	4.2 – 5.9	3.6 – 5.5
Hemoglobin gm/dl	13 – 17	11 – 15
Hematocrit %	40-52%	34-46%

Treatment Options

This is a re-cap and wrap-up of the previous blogs. All preceding blogs give you a more in depth look at all the issues of iron therapy.

How do we treat knowing that earlier intervention is essential? The total daily dose for severe cases is 180 mg of elemental iron. I usually use lower doses. You will need increased doses of magnesium to prevent constipation.

Heme vs non-heme iron sources in food.

Heme based sources of iron is the most efficient. Best source is red meat or chicken livers or sardines. Non-heme sources, plant based is a less efficient source of daily iron.

Iron Salts

Ferrous sulfate 325 mg (65 mg elemental iron) three times daily. The preferred form. This may raise hepcidin levels thereby decreasing efficient absorption.³
Ferrous gluconate 325 mg (12 mg elemental iron) three time daily
Ferrous fumarate 325 mg (107 mg of elemental iron) three times daily

Iron chelates

AminoIron – 18 mg elemental iron as bis-glycinate
Reacted Iron – 29 mg elemental iron as ferrous bis-glycinate

Iron Infusions

Ferric carboxymaltose (injectafer) — the most potent and effective for severe cases and those not responsive to oral consumption.
You will need to find a sympathetic and creative hematologist to administer and infuse parenteral (im or iv) iron. A hematologist who is willing to treat early and not late in the process.

Philip Lee Miller, MD
Carmel, CA
May 24, 2018

Iron metabolism and iron supplementation in cancer patients: Wien Klin Wochenschr (2015) 127:907–919 DOI 10.1007/s00508-015-0842-3
Ludwig H, Müldür E, Endler G, et al. Prevalence of iron deficiency across different tumors and its association with poor performance status, disease status and anemia. Ann Oncol. 2013;24:1886–92.
Iron Dosing for Optimal Absorption: NEJM Journal Watch Oct 30 2015.
Iron deficiency Anemia NEJM May 8, 2015

Iron Regulation Part II: Transport Signaling

January 21, 2018 Philip Miller Comments 0 Comment

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.

Hepcidin – the Iron Regulatory Hormone, Clin Biochem Rev. 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

January 11, 2018 Philip Miller Comments 1 comment

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) — fig1

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.

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

Dr. Philip Lee Miller

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Tag: hepcidin