What is the recommended workup and treatment for anemia, covering iron‑deficiency, vitamin B12 deficiency, folate deficiency, anemia of chronic disease, and severe anemia?

Treatment for Anaemia

Initial Diagnostic Workup

All patients with suspected anaemia require a complete blood count with red cell indices (MCV, MCH, RDW), reticulocyte count, serum ferritin, transferrin saturation (TSAT), and C-reactive protein (CRP) to classify the type of anaemia and guide treatment. 1, 2, 3

Essential Laboratory Tests

• Measure haemoglobin against WHO thresholds: men <13 g/dL, non-pregnant women <12 g/dL, pregnant women <11 g/dL, children 11–12 g/dL depending on age. 1, 2, 4
• Obtain red cell distribution width (RDW) because an elevated RDW (>14%) is an early and sensitive indicator of iron deficiency even when MCV is normal. 1, 2
• Calculate transferrin saturation as (serum iron × 100) ÷ total iron-binding capacity; TSAT <20% confirms iron deficiency requiring treatment. 1, 2
• Measure vitamin B12 and folate levels in all anaemic patients, especially when MCV >100 fL or when macrocytosis may be masked by concurrent microcytosis. 1, 2, 3
• Check serum creatinine and estimated glomerular filtration rate to identify chronic kidney disease as a contributor. 2, 3

Interpreting Ferritin in Context

• Without inflammation (normal CRP): Ferritin <30 µg/L confirms iron deficiency; ferritin <15 µg/L has 99% specificity for absolute iron deficiency; ferritin >100 µg/L essentially rules out iron deficiency. 1, 2, 4
• With inflammation (elevated CRP/ESR): Ferritin values up to 100 µg/L may still represent true iron deficiency because ferritin is an acute-phase reactant. 1, 2
• Ferritin 30–100 µg/L with elevated CRP indicates a mixed picture of true iron deficiency plus anaemia of chronic disease. 1, 2
• Ferritin >100 µg/L combined with TSAT <20% and elevated CRP defines anaemia of chronic disease with functional iron deficiency. 1, 2

Reticulocyte Count Interpretation

• Low or normal reticulocyte count indicates inadequate bone marrow response due to nutrient deficiencies (iron, B12, folate) or primary bone marrow disease. 1, 2, 4
• Elevated reticulocytes suggest increased red cell production, which excludes deficiency states and points toward haemolysis; order haptoglobin, lactate dehydrogenase, and bilirubin. 1, 2

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Iron-Deficiency Anaemia Treatment

Oral iron supplementation at 100–200 mg elemental iron daily is the first-line treatment for iron deficiency anaemia and should be started immediately while diagnostic work-up proceeds. 1, 2, 3

Oral Iron Therapy

• Prescribe ferrous sulphate, ferrous gluconate, or ferrous fumarate providing 100–200 mg elemental iron per day. 1, 2, 3
• Continue therapy for at least 3–6 months after haemoglobin normalisation to fully replenish iron stores, targeting ferritin >50 µg/L. 2
• Patients with mild anaemia (Hb >10 g/dL) can be adequately treated with 100 mg/day iron sulphate. 1
• Monitor haemoglobin at one month; if there is not a 1–2 g/dL increase, consider malabsorption, continued bleeding, or an undiagnosed lesion. 5

Intravenous Iron Therapy

• Intravenous iron is preferred when oral iron is poorly tolerated, malabsorption is documented, haemoglobin fails to improve despite adherence, or active inflammation is present. 1, 2, 3
• Several randomised studies demonstrate that IV iron is at least as effective as oral iron and is safe in inflammatory bowel disease. 1
• Typical IV iron regimens include ferric carboxymaltose or iron sucrose; a common protocol is 500 mg initially, followed by a second 500 mg dose four weeks later. 2
• Intramuscular iron should be avoided because there is no clear evidence it is less toxic or more effective than oral or IV iron. 1

Common Pitfalls

• Do not attribute severe iron deficiency in perimenopausal adults solely to menstrual blood loss; gastrointestinal pathology must still be investigated. 2
• Do not discontinue iron supplementation once haemoglobin normalises; iron stores must be restored (target ferritin >50 µg/L) to prevent rapid recurrence. 2
• Oral iron preparations frequently cause gastrointestinal adverse effects (nausea, flatulence, diarrhoea, gastric erosion), and non-absorbed iron can potentially exacerbate inflammatory bowel disease. 1

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Anaemia of Chronic Disease Management

Aggressive treatment of the underlying inflammatory condition is the primary intervention for anaemia of chronic disease; iron supplementation is not the first-line therapy when ferritin >100 µg/L with TSAT <20% in the setting of active inflammation. 1, 2

Diagnostic Criteria

• Anaemia of chronic disease is diagnosed when ferritin >100 µg/L and TSAT <20% in the presence of biochemical or clinical inflammation. 1, 2
• Inflammatory cytokines (especially IL-6) stimulate hepatic hepcidin production, which blocks iron release from macrophages and enterocytes, leading to functional iron deficiency despite adequate total body iron stores. 2

Treatment Approach

• Treat the underlying inflammatory disease (e.g., inflammatory bowel disease, rheumatoid arthritis, chronic infection) to permit mobilisation of sequestered iron stores. 1, 2
• After successful treatment of inflammation, re-measure complete blood count, iron studies, and inflammatory markers (CRP, ESR). 2
• If ferritin falls to 30–100 µg/L while TSAT remains <20% after inflammation resolves, true iron deficiency is present and iron supplementation should be initiated. 2

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Vitamin B12 Deficiency Treatment

Treat confirmed vitamin B12 deficiency immediately with hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, then maintenance 1 mg IM every 2 months for life. 3

Diagnosis

• Measure serum vitamin B12 levels in any patient with macrocytic anaemia (MCV >100 fL) or when iron studies are inconclusive. 1, 2, 3
• Vitamin B12 deficiency can mask iron deficiency by increasing MCV and mean cell haemoglobin, so concurrent deficiencies must be considered. 6
• In patients with extensive small bowel resection, extensive ileal Crohn's disease, or ileal-anal pouch, vitamin B12 should be monitored more frequently than annually. 1, 2

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Folate Deficiency Treatment

Folate deficiency should be treated with oral folic acid 5 mg daily for 2 weeks, then 5 mg weekly for an additional 6 weeks, but only after excluding vitamin B12 deficiency. 2, 3

Critical Caveat

• Never initiate folate therapy before excluding B12 deficiency, because folate can partially correct the anaemia of B12 deficiency while allowing irreversible neurological damage to progress. 3
• Macrocytosis may arise from thiopurine treatment (azathioprine, 6-mercaptopurine), other medications, alcohol abuse, hypothyroidism, or reticulocytosis, not only from vitamin deficiency. 1

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Severe Anaemia Management

Treatment should be considered for all patients with haemoglobin below normal; the approach depends on symptoms, severity of anaemia, and aetiology. 1

Transfusion Indications

• Red blood cell transfusion is usually not necessary for iron deficiency anaemia and should be reserved for severe symptomatic anaemia with haemodynamic compromise. 7
• Chronic inflammation is frequently a key issue leading to anaemia, and the likelihood of anaemia increases with disease severity. 1

Monitoring

• Patients in remission should be monitored every 12 months; those with mild disease every 6 months; and those with active disease at least every 3 months. 1, 3
• Recurrence of anaemia is common (>50% after 1 year) and is often indicative of ongoing intestinal inflammation. 1

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Special Population Considerations

Inflammatory Bowel Disease

• In IBD patients in remission, ferritin <30 µg/L reliably indicates iron deficiency. 1, 2
• During active IBD inflammation, use ferritin <100 µg/L as a screening threshold and confirm iron deficiency with TSAT <20%. 1, 2
• Vitamin B12 and folate levels should be checked at least annually, or if macrocytosis is present. 1, 3

Chronic Kidney Disease

• For non-dialysis CKD patients with anaemia not receiving erythropoiesis-stimulating agents (ESAs), consider IV iron if TSAT ≤30% and ferritin ≤500 ng/mL to achieve haemoglobin rise without initiating ESA therapy. 2
• Initiate ESA therapy only after iron deficiency has been corrected and other reversible causes (vitamin B12/folate deficiency, blood loss, inflammation, malignancy) have been excluded. 2

Chronic Heart Failure

• Evaluate all patients with chronic heart failure (NYHA class II–IV) for iron deficiency using serum iron, total iron-binding capacity, and ferritin, irrespective of anaemia status. 2
• Iron-deficiency criteria in heart failure are either ferritin <100 ng/mL or ferritin 100–300 ng/mL together with TSAT <20%. 2
• Intravenous iron (ferric carboxymaltose or iron sucrose) improves functional capacity, quality of life, and NYHA class in iron-deficient heart failure patients. 2

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Critical Diagnostic Pitfalls to Avoid

• Do not rely on ferritin alone when inflammation is present; always calculate TSAT because functional iron deficiency can exist with high ferritin but low TSAT. 1, 2
• Do not interpret an elevated ferritin (>100 µg/L) during acute infection as evidence of adequate iron stores; it reflects inflammation. 2
• Do not assume mild anaemia is less indicative of serious underlying disease; no evidence supports down-ranking its clinical significance. 2
• Do not postpone endoscopic investigation while awaiting response to iron therapy in adults; gastrointestinal malignancy work-up should proceed in parallel. 2
• Relying solely on MCV, MCH, and RDW can be misleading, as these parameters may be normal in early iron deficiency or mixed deficiency states. 4