Iron Deficiency Anemia

At a Glance

In many instances, iron deficiency anemia is an unexpected finding, resulting from routine office visits in which a complete blood count (CBC) is requested. This is especially the case in toddlers and adolescent females. Excessive intake of cow milk in young toddlers is a common cause of iron deficiency, which can be easily identified during routine visits. Fatigue and other constitutional symptoms are often the first clue of iron deficiency anemia, especially in women before menopause.

Iron deficiency anemia should also be suspected in any patient either experiencing chronic blood loss or recovering from acute blood loss. Patients affected by inherited diseases with chronic blood loss, such as hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) and Peutz-Jeghers syndrome, are at particularly high risk of developing iron deficiency anemia. Patients with chronic inflammatory bowel disease are also likely to develop iron deficiency anemia. In patients treated with erythropoietic stimulating agents (ESAs), like erythropoietin and other recombinant products, the increased functional requirements of the stimulated erythropoietic tissue may not be met by the available iron, resulting in production of iron deficient erythrocytes, despite normal baseline iron availability. This state is defined as iron restricted erythropoiesis or functional iron deficiency, an important factor that limits the effectiveness of ESAs.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

CBC

The presence of anemia (reduced Hb/Hct below the age-adjusted reference range) with reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) already provides a high degree of suspicion for diagnosis, especially if previous laboratory results on the patient are normal. World Health Organization (WHO) guidelines provide different Hb thresholds for anemia identification based on age and other conditions. In children, values of 11.0, 11.5, and 12.0 g/dL have been selected based on age (6 months to younger than 5 years of age, 5 to 12 years of age, and 12 to younger than 15 years of age, respectively). For women and men older than 15 years of age, Hb thresholds are 12.0 and 13.0 g/Dl, respectively, whereas 11.0 g/dL is the anemia threshold for pregnant women.

Iron deficiency has no effect on white blood cell (WBC) counts. Platelet (PLT) count increases above baseline values in iron deficiency and returns to normal with successful iron supplementation therapy. PLT counts are highest, at times greater than 1 million PLT/µL, in patients with iron deficiency and active bleeding.

Red cell/reticulocyte indices may provide additional clues regarding the inadequate supply of iron to the bone marrow, at times even before Hb falling below the normal range. Values of MCV and MCH below the normal range or at the lower end of the normal range with increased red cell distribution width (RDW) indicate there is not enough iron available to sustain the production of normal red cells. However, a clear-cut fall of MCV below the normal range may not be present until Hb drops below 10-1 g/dL. A decreased reticulocyte Hb content (CHr or RetHb, for Siemens and Sysmex analyzers) is another indicator of the presence of iron deficient erythropoiesis.

Red Cell Morphology

In the peripheral smear, erythrocytes show various degrees of anysocytosis, poikilocytosis, microcytosis, and hypochromia, with occasional target cells, whereas platelets appear overabundant.

If this is the first encounter with a particular patient, it is important to collect a careful history regarding the presence of congenital anemias and to ascertain the ethnic background of the patient. This will help in rule out thalassemias, which are frequently encountered in patients of Mediterranean (beta-thalassemia) or Asian descent (alpha-thalassemia). Thalassemias are also commonly found in patients originating from Africa, the Middle East, and India.

In young patients, an Hb electrophoresis should be ordered to r/o thalassemic traits. In adult patients with no prior family or past medical history of anemia, this is unnecessary.

Confirmatory/follow-up tests are geared toward the determination of an insufficient iron supply to the bone marrow and are mostly biochemical, including serum iron, serum transferrin, transferrin saturation, and ferritin.

Serum Iron

Serum iron levels are sensitive to diurnal variations and to dietary intake, resulting in higher serum iron values late in the day or following ingestion of iron-rich food or dietary supplements. Measurements are best performed in the morning, after more than 8 hours fasting, to avoid transient increases in serum iron due to the intake of food or multivitamin supplements containing iron. Serum iron values below the normal range are supportive of, but are not an obligatory requirement for, the diagnosis of iron deficiency anaemia.

Serum transferrin and transferrin saturation

Under normal conditions, only 30% of transferrin is saturated with iron. Transferrin saturation values lower than 16% are insufficient to meet the iron requirements of the bone marrow and are uniformly associated with iron deficient erythropoiesis. Transferrin saturation values are affected by factors affecting serum iron as previously described.

Serum ferritin

The normal range of serum ferritin varies between 20 and 300 ng/mL (or microg/L). It has no circadian variation and is quite stable over time in the same subject. Feritin values are higher at birth, decrease during childhood, and increase with age in adults. There are ethnic variations in the normal range of serum ferritin, with mean values 69 ng/mL higher in Asian versus Caucasian males and 23 ng/mL higher in Asian versus Caucasian females. Ferritin values below 12 ng/mL are generally considered diagnostic of a complete depletion of iron stores. However, there is evidence that a threshold of 30 ng/mL has better sensitivity, yielding positive predictive values of 92% versus 75% for the lower threshold.

Other tests have shown promise, but they are either not routinely used or not available through reference laboratories. They include serum soluble transferrin receptor, urinary, and serum hepcidin.

A test that should not be requested is a bone marrow biopsy for iron stain; although regarded by some as the gold standard to assess iron stores, this procedure is no better than transferrin saturation (TSAT) or ferritin in identifying patients likely to respond to iron therapy and has shown great variability due to the subjective nature of the test interpretation.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Hematological indices (MCV, MCH, reticulocyte hemoglobin content)

Hematological indices may be decreased to values similar to those of iron deficiency because of the presence of genetic disorders of Hb production, such as alpha- and beta-thalassemias.

Serum Iron

Serum iron values decrease with infection and inflammation, whereas they increase following the ingestion of iron-rich food or dietary supplements. Some laboratory assays will provide falsely elevated serum iron values in the sample has significant hemolysis.

Serum transferrin and transferrin saturation

Transferrin synthesis and levels in plasma are increased by iron deficiency and by augmented iron needs, such as those of pregnancy. Serum transferrin increases with the use of oral contraceptives and decreases with inflammation/infection. Serum transferrin is also elevated in the presence of parenchymal liver damage and in pregnancy.

Serum ferritin

Rarely, ferritin values are lowered by the presence of either hypothyroidism or vitamin C deficiency. Serum ferritin is an acute phase reactant, and its values are elevated and do not reflect iron availability in the presence of inflammatory diseases, both acute and/or chronic. Presence of acute or chronic inflammation is usually confirmed by an elevated C-reactive protein (CRP >0.5 mg/dL). Hyperthyroidism; liver disease, especially due to hepatitis C virus; alcohol consumption; and use of oral contraceptives are known to elevate serum ferritin independently of iron status. Increased serum ferritin may also reflect cellular damage of ferritin-rich tissues. This is seen in liver disease, leukaemias, pancreatic and bronchial cancer, and neuroblastoma.

What Lab Results Are Absolutely Confirmatory?

A hematological response to oral or intravenous (IV) iron therapy provides the ultimate confirmation of diagnosis. It is generally accepted that an increase of 2 grams of Hb/dL over 3 weeks is indicative of response. Increases in reticulocyte counts and/or reticulpocyte Hb content can be indicative of response after 1 week of therapy. Ferritin is one of the last parameters to normalize, because it reaches and remains in the normal range only after anemia has been corrected.

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