Iron Deficiency

What happens when the supply of iron in the body is inadequate to meet the demands of erythropoiesis? When this condition—iron deficiency—leads to anemia, iron replacement therapy may be indicated to restore effective erythropoiesis. Click on a link below for more information:

• Causes of iron deficiency
• Diagnosis of anemia
• Clinical presentation of iron deficiency
• Iron deficiency anemia in chronic renal failure
• Functional iron deficiency and epoetin (recombinant human erythropoietin)
• Tests used to assess iron status
• Shortcomings of Iron Status Measures
• Differentiating iron deficiency anemia from other anemias
• Criteria for diagnosing anemia and iron deficiency

Causes of Iron Deficiency
Iron deficiency is the depletion of iron stores to the point that red blood cell (RBC) production is impaired. It can have various causes—the most prevalent of which is insufficient iron intake as the result of inadequate nutrition or an imbalanced diet in a population that has increased iron requirements (eg, women of childbearing age, children and adolescents during periods of rapid growth) (see Table 1).^1,2 Even when dietary iron intake is adequate, a deficiency can result from insufficient iron absorption. The amount of iron absorbed is affected by the composition of the diet. In a diet containing meat, an individual can absorb up to 20% of the iron in the diet, but in a vegetarian diet, an individual can absorb only 5% to 10% of the available iron.¹

The second most common cause of iron deficiency is blood loss.¹ Blood loss may be due to blood donation; surgery; gastrointestinal blood loss associated with hemorrhage, hookworm infestation, or inflammatory bowel disease (which includes Crohn's disease and ulcerative colitis); or dialysis.^3-5 Any significant chronic blood loss will deplete iron stores and increase iron needs beyond what diet can supply.⁴

Malabsorption syndromes, conditions in which the absorptive capacity of the gastrointestinal tract is reduced or altered, can also lead to iron deficiency despite adequate dietary iron intake.^4,6

Table 1: Causes of Iron Deficiency⁶

Iron deficiency anemia
Anemia is a condition in which the number of RBCs, the amount of hemoglobin (Hb), and the volume of packed RBCs in the blood are below normal levels. When tissue demands for oxygen increase, levels of erythropoietin (produced by the kidney) rise, thereby stimulating erythroid cells in the bone marrow to step up RBC production.^4,7 If iron supplies are inadequate, blood levels of Hb and RBCs ultimately decrease, and iron deficiency anemia results.

Other causes of anemia
It is important to note that while iron deficiency is the main cause of anemia, anemia may have other causes (see Table 2).² Anemia can be caused by: chronic infection, eg, tuberculosis; genetic conditions, eg, thalassemia and sickle cell anemia; nutritional deficiencies, eg, folate deficiency, vitamin B₁₂ deficiency; or an enzyme disorder, eg, sideroblastic anemia. Malaria, a parasitic infection, can cause anemia through the destruction of RBCs (hemolytic anemia). Nutritional deficiencies of folate and vitamin B₁₂ can lead to anemia by interrupting the production and maturation of RBCs.² In patients with chronic diseases, including malignancies, inflammatory disorders, and chronic renal failure, anemia develops as a result of suppressed Hb production. This condition is known as anemia of chronic disease.^2,8

Table 2: Causes of Anemia^2,8

Diagnosis of Anemia
Anemia is diagnosed through laboratory determinations of Hb and hematocrit (HCT).² Hemoglobin is a measure of the mass of RBCs per fixed volume of blood. Hematocrit is a measure of RBCs as a percentage of the total blood volume.

Anemia is diagnosed when either Hb or HCT is below the fifth percentile for healthy individuals of the same gender and age.² Table 3 presents the mean normal values of Hb and HCT in healthy individuals.⁹ Hemoglobin and HCT levels alone are insufficient to diagnose iron deficiency anemia. Additional laboratory tests that are needed to diagnose and to differentiate among the various forms of anemia will be discussed later in this section.

Table 3: Mean Normal Values of Hemoglobin and Hematocrit⁹

Clinical Presentation of Iron Deficiency
Patients at the earliest stage of iron depletion may fail to exhibit any physiologic impairment.¹⁰ When iron deficiency progresses, causing anemia, the symptoms and signs generally parallel the severity of anemia.⁴ Fatigue, pallor, and decreased exercise capacity may be evident. Anemia of sudden onset or severe anemia may be accompanied by cardiovascular and respiratory symptoms, such as increased heart rate, lightheadedness, and breathlessness.⁶ When iron deficiency itself is severe, patients may complain of mouth soreness, difficulty swallowing, and spooning (softening and curling of the nails).⁴ Some patients with chronic iron deficiency report pica, a craving to ingest substances such as clay, ice, or cornstarch.⁶

Chronic iron deficiency in children is associated with developmental delays and behavioral disturbances. In pregnant women, iron deficiency increases the risk for preterm delivery and low-birth-weight infants.⁶

Iron Deficiency Anemia in Chronic Kidney Disease
In chronic kidney disease, the anemia that develops is frequently complex. Its primary cause is inadequate production of erythropoietin by the diseased kidney.¹¹ In patients undergoing dialysis, blood loss, which can also contribute to anemia, occurs due to blood retention in the dialyzer and blood lines, frequent blood sampling, and vascular access complications.^11,12 One study showed an average monthly blood loss of 167 to 226 mL and a monthly iron loss of 57 to 78 mg among patients on hemodialysis. Blood drawing for laboratory testing resulted in average monthly losses of 127 mL in a group of hemodialysis patients hospitalized for more than 2 days per month.

Patients with chronic kidney disease may have a decreased dietary intake of iron that can contribute to the development of anemia.¹² This occurs when patients are encouraged to lower their intake of protein because of declining renal function. Decreasing protein (eg, meat) intake reduces iron intake and depletes iron stores. Absorption of iron from the gastrointestinal tract may also be decreased.³

Thus, multiple factors can contribute to inadequate total body iron stores in patients with chronic kidney disease, a condition known as absolute iron deficiency.³ Notably, one fifth of patients starting dialysis have absolute iron deficiency.¹² This condition is commonly detected through 2 laboratory tests: measures of serum ferritin and transferrin saturation (TSAT). A serum ferritin <100 ng/mL and a TSAT <20% indicate absolute iron deficiency.^11,12

Functional Iron Deficiency and Epoetin
Functional iron deficiency may develop in chronic kidney disease patients who are undergoing treatment with epoetin. It is not only caused by epoetin usage; dialysis patients may also have coexisting occult infections or other conditions that affect the body's ability to mobilize iron rapidly.³

Epoetin was first introduced to the US marketplace in 1989 as a treatment for anemia associated with renal failure. It is a 165 amino acid glycoprotein that is manufactured by recombinant DNA technology. It is produced by mammalian cells into which the human erythropoietin gene has been introduced. Epoetin contains the identical amino acid sequence of natural erythropoietin and has the same biological effects, ie, it stimulates the process of RBC production by erythroid cells in bone marrow.¹³

Administration of epoetin to patients with anemia of chronic kidney disease, who have a deficiency of natural erythropoietin, produces increases in Hb and HCT, leading to many benefits, including¹⁴:

• Improved quality of life
• Increased energy and exercise tolerance
• Reduced fatigue
• Increased appetite
• Decreased need for blood transfusions as treatment for anemia in chronic renal failure

The use of blood transfusions as treatment for patients with anemia of chronic kidney disease warrants a brief mention here. Before the availability of epoetin, RBC transfusions were commonly given to patients with chronic kidney disease in an attempt to raise HCT.¹¹ These transfusions frequently resulted in iron overload. If allowed to progress, iron overload can cause hepatic or cardiovascular dysfunction and hemosiderosis and may increase the risk for bacterial infections.^8,15

How does epoetin treatment lead to the development of functional iron deficiency?¹²

• It causes dramatic increases in RBC production, Hb, and HCT
• Iron uptake by erythroid cells is increased to meet the demand of increased RBC production
• Reticuloendothelial cells are unable to release stores of iron fast enough to meet demand
• Despite adequate levels of stored iron (ferritin), insufficient iron is available for epoetin-stimulated RBC production
• Iron deficiency erythropoiesis develops. The RBCs produced are small and have low Hb content and a high concentration of protoporphyrin
• In time, functional iron deficiency limits the response to epoetin therapy, and higher doses of epoetin are required to reach target Hb and HCT levels¹⁵

Eventually, absolute iron deficiency occurs (serum ferritin levels fall) and Hb and HCT levels fall despite high epoetin doses.

Tests Used to Assess Iron Status
The diagnosis of iron deficiency is based on laboratory studies.¹⁶ The 2 tests most commonly used in the diagnosis are serum ferritin and TSAT.

Serum ferritin
A soluble form of ferritin is released into circulation during ferritin synthesis.^1,4 The amount of ferritin in the circulation (measured as serum ferritin) has been shown to correlate with total body iron stores.⁴ In subjects with chronic renal failure, absolute iron deficiency is defined as serum ferritin levels <100 ng/mL and TSAT levels <20%.⁹

Transferrin saturation
Transferrin saturation represents the amount of protein-bound iron in circulation, ie, the amount readily available for erythropoiesis.^9,16 Transferrin saturation is calculated by dividing serum iron by total iron-binding capacity (TIBC) and then multiplying the result by 100.⁹ (Total iron-binding capacity is a measure of the total binding capacity of transferrin.) Normal TSAT is 30% to 50%.⁴ A TSAT value <20% indicates iron deficiency, while a level of 50% or greater indicates iron overload.⁴

Why not just measure serum iron? Serum iron alone has limited value when diagnosing iron deficiency; it is subject to considerable variation between laboratories and also to diurnal variation (variation over the course of a day).¹⁶

Shortcomings of Iron Status Measures
Serum ferritin and TSAT are practical tools for the diagnosis of iron deficiency.⁴ Although widely used, these tests present problems in diagnosing iron deficiency in patients with chronic kidney disease.⁹ Serum ferritin reflects stored iron and not the iron readily available for RBC production. (Remember that patients with functional iron deficiency may have adequate iron stores.) For this reason, even bone marrow studies, commonly accepted as the gold standard for diagnosing iron deficiency, are not helpful in diagnosing functional iron deficiency.¹⁶ In addition, increases in serum ferritin without actual changes in iron storage commonly occur in patients with inflammatory conditions, infections, liver disease, and cancer.¹⁷ Transferrin saturation may not be a valid indicator of iron deficiency, since factors other than iron deficiency, eg, nutrition, can affect transferrin concentrations in patients with chronic kidney disease.¹⁶ Reliance on serum ferritin and TSAT can fail to detect functional iron deficiency; in this case, TSAT may decrease to levels consistent with iron deficiency yet serum ferritin may be normal or even elevated.⁹

Other tests of iron status are less widely available and appear to offer no increase in diagnostic sensitivity or specificity over serum ferritin and TSAT.⁹ (One test, the percentage of hypochromic [pole] red cells, does appear to be a sensitive and reliable indicator for iron deficiency. Normally, less than 2.5% of RBCs have Hb concentrations below 28 mg/dL.¹⁶ A percentage of hypochromic RBCs greater than 10% indicates iron deficiency.)

Differentiating Iron Deficiency Anemia From Other Anemias
Additional laboratory studies that may be helpful in differentiating iron deficiency anemia from other forms of anemia include mean corpuscular volume (MCV), also referred to as mean cell volume, and RBC distribution width.^4,10

Mean corpuscular volume is a measure of the average volume of RBCs.¹⁰ In iron deficiency, RBC morphology is altered.⁶ RBCs are hypochromic and microcytic (reduced in size). A low MCV indicates microcytic anemia.

Red blood cell distribution width reflects the variation in blood cell size.¹⁰ Iron deficiency usually causes a greater variation in RBC size. A low MCV and an RBC distribution width above 14% indicate iron deficiency anemia.

Criteria for Diagnosing Anemia and Iron Deficiency
In 1995, the National Kidney Foundation (NKF) established the Dialysis Outcomes Quality Initiative (DOQI).¹⁸ DOQI initially involved the work of 70 professionals who reviewed clinical literature and developed clinical practice guidelines for the care of dialysis patients in specific areas.¹⁸ These templates for clinical care of dialysis patients, first published in 1997, are updated and expanded by NKF on a continuing basis.¹⁹ In 2001, they became part of the K/DOQI.

The current K/DOQI Anemia of Chronic Kidney Disease guideline recommends an anemia workup for patients with chronic renal failure when⁹:

• HCT is <33% and/or Hb <11 g/dL in premenopausal women and patients before puberty
• HCT is <37% and/or Hb <12 g/dL in adult males and postmenopausal females

Recognizing the important role of iron in the development of anemia in chronic kidney disease, particularly during therapy with epoetin, the guideline also recommends assessing iron status. The recommended measures are TSAT and serum ferritin. Target iron levels established by K/DOQI are⁹:

• TSAT ≥20%
• Serum ferritin ≥100 ng/mL

The target for Hb is 11 to 12 g/dL and the target for HCT is 33% to 36%. Treatment with epoetin and supplemental iron is recommended to achieve these target ranges.⁹

Some controversy currently exists about the optimal target Hb level for epoetin treatment in patients with chronic kidney disease.²⁰ Some pilot studies show greater clinical improvements in patients in whom Hb is returned toward normal levels (12 to 14 g/dL). Further studies are needed to determine if a higher target Hb²⁰:

• Decreases morbidity and mortality
• Improves quality of life
• Increases side effects

A TSAT <20% and serum ferritin <100 ng/mL indicate absolute iron deficiency.^11,12 In functional iron deficiency, serum ferritin may be >100 ng/mL, but TSAT is <20%.

References

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