What is the best approach to diagnose and treat anemia in a patient?

Approach to Anemia

Begin with a complete blood count with reticulocyte count and iron studies to classify anemia by mean corpuscular volume (MCV), then pursue targeted investigation based on whether the anemia is microcytic, normocytic, or macrocytic. 1

Initial Laboratory Workup

• Obtain a complete blood count (CBC) with red cell indices, reticulocyte count, and peripheral blood smear examination 2
• Measure serum ferritin and transferrin saturation to assess iron stores and availability for erythropoiesis 1
• Check vitamin B12 and folate levels to rule out nutritional deficiencies 1
• A reticulocyte count distinguishes inadequate bone marrow production (low count) from hemolysis or blood loss (elevated count) 1

Classification-Based Diagnostic Algorithm

Microcytic Anemia (MCV <80 fL)

If ferritin is <45 ng/mL (or <30 μg/L), diagnose iron deficiency anemia and proceed with gastrointestinal evaluation. 1, 2

• Test for H. pylori and celiac disease non-invasively before endoscopy 1
• Perform bidirectional endoscopy in all men and postmenopausal women with iron deficiency anemia to evaluate for gastrointestinal malignancy 1, 3
• If ferritin is normal or elevated, consider thalassemia, anemia of chronic disease, or sideroblastic anemia 2
• Critical pitfall: Ferritin is an acute phase reactant and may be falsely elevated in inflammatory states despite true iron deficiency—check CRP and consider iron deficiency even with ferritin 30-100 μg/L if inflammation is present 1, 2

Normocytic Anemia (MCV 80-100 fL)

• Evaluate for anemia of chronic disease, renal failure, or endocrine disorders by assessing kidney function and checking for chronic inflammatory conditions 1
• Consider hemolysis workup if clinically suggested: direct Coombs test, lactate dehydrogenase (LDH), haptoglobin, indirect bilirubin, and peripheral blood smear 1, 2
• Elevated reticulocyte count with elevated LDH, decreased haptoglobin, and elevated indirect bilirubin indicates hemolytic anemia 2

Macrocytic Anemia (MCV >100 fL)

• Measure vitamin B12 and folate levels to identify deficiencies 1
• Never start folic acid before excluding B12 deficiency to prevent irreversible neurological complications 1, 2
• Elevated methylmalonic acid and homocysteine confirm B12 deficiency 2
• Consider hypothyroidism, myelodysplastic syndrome, or medication effects (especially in elderly patients) 2, 4

Treatment Based on Etiology

Iron Deficiency Anemia

Initiate oral iron supplementation as first-line therapy while treating the underlying cause. 1, 4

• Lower-dose oral iron formulations (e.g., 15-50 mg elemental iron daily) may be as effective as higher doses with fewer adverse effects 3
• Normalization of hemoglobin typically occurs by 8 weeks after treatment in most patients 3
• Confirm iron stores are restored after hemoglobin normalizes by rechecking ferritin 1
• Use intravenous iron for patients with intolerance to oral iron, chronic kidney disease with poor oral response, or inflammatory bowel disease 1, 4

Vitamin B12 Deficiency

Treat immediately with hydroxocobalamin 1 mg intramuscularly. 1

• For neurological involvement, give on alternate days until no further improvement, then every 2 months 1
• For pernicious anemia, parenteral vitamin B12 is required for life: 100 mcg daily for 6-7 days intramuscularly, then alternate days for seven doses, then every 3-4 days for 2-3 weeks, followed by 100 mcg monthly for life 5
• The oral route is not dependable for pernicious anemia—avoid using the intravenous route as almost all vitamin will be lost in urine 5

Anemia of Chronic Disease

Treat the underlying inflammatory, infectious, or neoplastic condition as the primary strategy. 1

• Consider erythropoiesis-stimulating agents (ESAs) only in severe symptomatic anemia, particularly in chronic kidney disease 4
• Normal or elevated serum ferritin with low serum iron and transferrin saturation, plus elevated inflammatory markers (CRP, ESR), support this diagnosis 2

Genetic Microcytic Anemias

For X-linked sideroblastic anemia (XLSA) due to ALAS2 defects:

• Initial treatment with pharmacologic doses of pyridoxine (50 mg or higher) should be attempted 6
• Management involves both treatment of anemia and prevention/treatment of iron overload 6

For severe microcytic sideroblastic anemia due to SLC25A38 defects in children:

• Hematopoietic stem cell transplantation (HSCT) is recommended as the only curative option 6

Transfusion Considerations

Reserve blood transfusions for hemoglobin ≤5.1 g/dL with hemodynamic instability or severe symptoms, or for symptomatic patients with hemoglobin ≤8 g/dL. 1

Population-Specific Adjustments

Adjust anemia definitions for pregnant women, elderly patients (≥70 years), high altitude residents, smokers, and non-Caucasian populations. 1, 2, 4

• WHO defines anemia as hemoglobin <13.0 g/dL in adult men and <12.0 g/dL in non-pregnant adult women 2
• In children, thresholds vary: 11.0 g/dL for ages 6 months to 5 years, 11.5 g/dL for ages 5-11 years, and 12.0 g/dL for ages 12-13 years 2

Common Pitfalls to Avoid

• Mixed anemias can present with normal MCV when microcytosis and macrocytosis coexist—examine the red cell distribution width (RDW) and peripheral smear 2
• In elderly patients presenting with myelodysplastic syndrome with ring sideroblasts, consider ALAS2 defects, especially if anemia is microcytic 6
• Anemia in older adults is associated with increased morbidity and mortality and warrants thorough investigation even when asymptomatic 3