Initial Assessment and Diagnosis
Acute and Chronic Symptoms
Patients with non-anemic iron deficiency can experience negative symptoms.
Symptoms vary from fatigue, weakness, irritability to reduced cognitive function, including lower IQ. (4-10)
Symptoms of Iron Deficiency
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Non-Anemic Iron Deficiency (NAID)
Iron Deficiency Anemia (IDA)
Those listed under NAID plus:
(4-12)
Laboratory Tests
Ferritin is the most sensitive and specific marker for iron deficiency in adults and the pediatric population. Ferritin levels should be ordered with a complete blood count (CBC) in patients whose history suggests that they have risk factors for iron deficiency.
Asymptomatic girls and women of reproductive age should have a CBC and ferritin checked at minimum every 3 years. (35) Girls and women with risk factors for iron deficiency such as lower socioeconomic status, minority race/ethnicity, heavy menstrual bleeding and rapid succession pregnancies should be tested yearly. Those who are symptomatic should be tested and retested on treatment every 3 to 6 months.
People with IDA should be monitored more closely and referral to a hematologist and gynecologist should be considered if the hemoglobin is below 100 g/L or if there is refractoriness to menstrual suppression and oral iron therapy. All pregnant women should have a ferritin included in initial antenatal blood work (see flowchart below).
Recommended Screening and Treatment Algorithm for Iron Deficiency in Pregnancy
Most people with iron deficiency anemia have a normal MCV!
Of note, a CBC alone is an inadequate screen for iron deficiency, as low hemoglobin and microcytosis (low MCV) are neither sensitive nor specific for iron deficiency. (36) For example, a recent study of non-pregnant females of reproductive age in Ontario found that the majority (56%) of those with iron deficiency anemia did not have a low MCV. (37)
Laboratory Tests to Order for the Investigation of Iron Deficiency
Quick Reference:
Diagnosis of iron deficiency involves careful history taking and physical examination, which are essential in identifying risk factors and possible etiology, guiding laboratory testing, and identifying the underlying cause of the iron deficiency.
Ferritin Threshold Treatment Suggestions
*If adult patients have concomitant inflammation with Ferritin ≥ 30, order iron studies (serum iron, TIBC, transferrin saturation) IN THE FASTING STATE. For pediatric patients with concomitant inflammation and Ferritin ≥ 20, order iron studies or soluble transferrin receptor IN THE FASTING STATE. If iron studies are required for patients with inflammation, indicate “chronic inflammation” on the Ontario Ministry of Health lab requisition form in the clinical information section.
Adult Patients
Adults with ferritin < 30 mcg/L are considered iron deficient and should have iron therapy initiated. (38–43)
Patients with ferritin levels between 30-50 mcg/L are considered iron insufficient and may benefit from initiation of iron therapy if symptomatic. (4,5,7,43,44)
Patients with ferritin levels > 50 mcg/L without concomitant inflammation are considered iron sufficient.
Patients who have ferritin ≥ 30 mcg/L and concomitant inflammation (see examples below) should have full iron studies ordered (serum iron, TIBC, and transferrin saturation). (28) Iron studies should be ordered in the fasting state, as recent intake of iron-containing foods or supplements can affect serum iron and transferrin saturation. Ferritin concentration is not affected by recent food intake.
Ferritin is a positive acute phase reactant that rises with inflammation even in the presence of iron deficiency. Click here for examples of inflammatory states.
Ferritin ≥ 30mcg/L but transferrin saturation < 20% is consistent with iron deficiency or restriction and should be treated with iron replacement therapy.
(28,30)
Pediatric Patients
In the pediatric population, ferritin levels below 20 mcg/L indicates iron deficiency. Similar to the adult population, ferritin is a positive acute phase reactant and may be elevated in the presence of inflammation. (28) In patients with concomitant inflammation, transferrin saturation < 20% is indicative of iron deficiency. (30)
C-reactive protein levels have been used to detect concomitant inflammation with levels > 5 suggesting possible inflammation in patients with ferritin levels between 20 and 50 mcg/L. (44)
Based on the behaviour of the soluble transferrin receptor (sTfR) to hepcidin ratio, ferritin < 50 may be a sign of early iron deficiency. Soluble transferrin receptor serum values may be used as an alternative to transferrin saturation to assess for iron deficiency in states of inflammation, especially in pediatric patients. (45–47) It is available to order as a separate laboratory test but its access is limited.
Reticulocyte Hemoglobin
Undifferentiated RBC precursor
(Ret He)
Mature RBC
In the adult and pediatric populations, reticulocyte hemoglobin (CHr) is another measure that may identify early states of iron deficiency. (46,47) CHr measures the hemoglobin content of reticulocytes (immature RBCs). (47) CHr is a direct measure of the functional iron that is available to be incorporated into early RBC precursors. This measure is not a positive acute phase reactant and is not affected by concomitant inflammation, infection or malignancy. (48) A CHr level < 28 pg as an indication of iron deficiency with a sensitivity of 100% and specificity of 80%. (47) Serial measures of CHr may be used to monitor response to iron treatment. (47,48) CHr is reported with CBC on some lab analyzers.
Patients with Thalassemia
Iron deficiency in patients with thalassemia should be treated with iron replacement. Thalassemia without iron deficiency should not be treated with iron replacement as it will be of no benefit (i.e. there will not be any improvement in the hemoglobin nor MCV).
Thalassemia minima/minor and iron deficiency anemia can both have low hemoglobin and low MCV (microcytosis). Anemia from thalassemia can be differentiated from iron deficiency anemia by the ferritin test (and/or iron studies in the face of inflammation). Patients with thalassemia alone are not expected to have a low ferritin (i.e. < 30 mcg/L) or low transferrin saturation (i.e. < 20%) in the absence of concomitant iron deficiency. (52)
The physical examination may be normal in patients with iron deficiency (with or without anemia) may be normal, or it may reveal one of more of the following:
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Pallor, dry skin
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Atrophic glossitis, which may be accompanied by dry mouth or tongue pain
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Koilonychia (spoon nails)
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Angular cheilitis
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Alopecia
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Systolic murmur
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Orthostatic hypotension
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Tachycardia
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Hemodynamic instability
