What conditions should be ruled out in a patient with mild anemia?

Evaluation of Mild Anemia

In a patient with mild anemia, you must first confirm iron deficiency through serum ferritin (<45 ng/mL) and then systematically rule out gastrointestinal blood loss, celiac disease, and H. pylori infection, as these represent the most common treatable causes with significant morbidity if missed. 1

Initial Laboratory Confirmation

• Measure serum ferritin as the most specific test for iron deficiency, with levels <45 ng/mL providing optimal sensitivity and specificity for iron deficiency in practice 2
• Check complete blood count with mean corpuscular volume (MCV) and red cell distribution width (RDW) 2
• A low MCV with RDW >14.0% suggests iron deficiency anemia, while a low MCV with RDW ≤14.0% suggests thalassemia minor 2
• Evaluate transferrin saturation as a more sensitive test than hemoglobin alone 2
• Note that ferritin is an acute phase reactant and may be falsely elevated in chronic kidney disease or inflammatory states 1

Critical Conditions to Rule Out Based on Patient Demographics

For Men and Post-Menopausal Women:

• Gastrointestinal malignancy (gastric and colonic cancer) is the prime concern and must be excluded 1
• Perform non-invasive testing for H. pylori and celiac disease first 1
• If negative, proceed with bidirectional endoscopy (upper endoscopy and colonoscopy) - this is a strong recommendation with moderate quality evidence 1
• Consider angiodysplasia, NSAID-induced bleeding, and inflammatory bowel disease 1

For Pre-Menopausal Women:

• Menstrual blood loss is the most common cause 3
• Bidirectional endoscopy is a conditional recommendation - younger pre-menopausal women who value avoiding endoscopy risk over detecting rare neoplasia may reasonably choose initial empiric iron supplementation alone 1
• Still perform non-invasive testing for H. pylori and celiac disease 1
• Consider heavy menstrual bleeding as primary etiology before extensive GI workup 2

Additional Causes to Exclude

• Celiac disease - screen with serology in all patients with unexplained iron deficiency 1
• H. pylori infection - perform non-invasive testing 1
• Dietary inadequacy - assess nutritional intake, particularly in elderly patients 4
• Malabsorption disorders - consider if dietary history suggests inadequate intake or if patient fails oral iron therapy 2
• Chronic kidney disease - assess renal function 1
• Thalassemia trait - order hemoglobin electrophoresis if microcytosis with normal iron studies, appropriate ethnic background, or MCV disproportionately low relative to degree of anemia 2
• Anemia of chronic disease - consider in patients with inflammatory conditions, malignancy, or hepatic disease 1

Genetic Disorders (Rare but Important)

• IRIDA (iron-refractory iron deficiency anemia) - consider if ferritin is low-normal with low transferrin saturation and family history of refractory anemia 2
• Sideroblastic anemia - consider in patients with microcytic anemia and iron loading 1
• These conditions typically present in childhood but may be diagnosed later 1

Common Pitfalls to Avoid

• Do not assume all microcytic anemia is iron deficiency - anemia of chronic disease, thalassemia, and sideroblastic anemia must be differentiated to avoid unnecessary iron therapy 2
• Do not overlook combined deficiencies - iron deficiency can coexist with B12 or folate deficiency, which may be masked by a normal MCV 2
• Do not accept ferritin >100 μg/dL as excluding iron deficiency in inflammatory states - use transferrin saturation as an adjunct 1
• Investigation should be considered at any level of anemia with confirmed iron deficiency, especially with more severe degrees 2

Expected Response to Confirm Diagnosis

• Hemoglobin should rise ≥10 g/L (≥1 g/dL) within 2 weeks of starting oral iron therapy if iron deficiency is the cause 2
• If no response occurs, consider non-compliance, ongoing blood loss, malabsorption, or rare genetic disorders 2