What is the approach to assessing anemia, including its definition, classification, differential diagnosis, history, physical examination, investigations, empiric treatment, and indications for referral?

Approach to Assessment of Anemia

Definition

Anemia is defined as hemoglobin concentration below 130 g/L in men over 15 years and below 120 g/L in non-pregnant women over 15 years. 1

Severity Classification

• Mild anemia: Hb ≤11.9 g/dL and ≥10 g/dL 1
• Moderate anemia: Hb ≤9.9 g/dL and ≥8.0 g/dL 1
• Severe anemia: Hb <8.0 g/dL 1

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Classification

By Red Cell Indices (MCV)

• Microcytic (low MCV): Iron deficiency, thalassemia, anemia of chronic disease, sideroblastic anemia 1
• Normocytic (normal MCV): Acute blood loss, anemia of chronic disease, chronic kidney disease, hemolysis 1
• Macrocytic (high MCV): Vitamin B12/folate deficiency, thiopurine therapy, alcohol abuse, hypothyroidism, reticulocytosis 1

By Reticulocyte Count

• Low/normal reticulocytes: Deficiencies causing inappropriate erythropoiesis or primary bone marrow disease 1
• Elevated reticulocytes: Hemolysis or acute blood loss with appropriate marrow response 1

By Etiology

• Blood loss: GI bleeding, menstrual bleeding, trauma 1
• Decreased production: Nutritional deficiencies (iron, B12, folate), chronic kidney disease, bone marrow infiltration, anemia of chronic disease 1
• Increased destruction: Hemolysis (immune or non-immune), hemoglobinopathies 1
• Mixed causes: Combination of above mechanisms 1

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Differential Diagnosis

Common Causes

• Iron deficiency anemia: Most common; GI blood loss, menstrual bleeding, malabsorption 1, 2
• Anemia of chronic disease: Inflammatory conditions, malignancy, chronic infections 1
• Chronic kidney disease: Erythropoietin deficiency 1
• Vitamin B12/folate deficiency: Pernicious anemia, malabsorption, dietary insufficiency 1
• Hemolysis: Autoimmune, drug-induced, hereditary hemoglobinopathies 1
• Bone marrow disorders: Myelodysplasia, aplastic anemia, infiltrative disease 1
• Hemoglobinopathies: Thalassemia, sickle cell disease 1

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History

Character of Symptoms

• Fatigue and weakness: Reduced exercise capacity and energy levels 2, 3
• Dyspnea: Particularly with exertion 2, 3
• Syncope, vertigo, headache: Reduced oxygen delivery to brain 2
• Chest pain: High-output cardiac state in severe anemia 2, 3
• Palpitations: Compensatory tachycardia 3

Red Flags (Require Urgent Investigation)

• Hb <110 g/L in men or <100 g/L in non-menstruating women: Warrants fast-track referral for suspected GI malignancy 1
• Abnormalities in two or more cell lines: Suggests bone marrow pathology requiring hematology consultation 1
• Neurologic symptoms: Suggests B12 deficiency or other serious pathology 2, 3
• Jaundice: Suggests hemolysis 2, 3
• Petechiae: Suggests platelet abnormalities or vasculitis 2, 3

Risk Factors to Elicit

• Medication exposure: Chemotherapy, NSAIDs, anticoagulants, thiopurines 1
• Dietary history: Vegetarian diet, alcohol abuse 1
• GI symptoms: Melena, hematochezia, dyspepsia, change in bowel habits 1
• Menstrual history: Heavy or prolonged bleeding in women 1
• Family history: Hemoglobinopathies, hereditary hemorrhagic telangiectasia 2
• Chronic diseases: Inflammatory bowel disease, chronic kidney disease, malignancy, autoimmune disease 1
• Previous surgery: Gastrectomy, small bowel resection 1

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Physical Examination (Focused)

General Inspection

• Pallor: Conjunctival, palmar, nail bed 2, 3
• Jaundice: Suggests hemolysis 2, 3
• Tachycardia and systolic flow murmurs: Compensatory cardiovascular response 3

Specific Signs of Iron Deficiency

• Angular stomatitis: Cracking at corners of mouth 3
• Glossitis: Smooth, red, painful tongue 3
• Koilonychia: Spoon-shaped nails 3
• Blue sclerae: Bluish discoloration of whites of eyes 3

Signs Suggesting Underlying Causes

• Splenomegaly: Hemolysis, hematologic malignancy, portal hypertension 2, 3
• Telangiectasias: Hereditary hemorrhagic telangiectasia 2, 3
• Neurologic abnormalities: Peripheral neuropathy, posterior column signs in B12 deficiency 2, 3
• Petechiae or purpura: Platelet abnormalities 2, 3
• Lymphadenopathy: Malignancy or chronic infection 2

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Investigations

Minimum Initial Workup

• Complete blood count (CBC) with differential: Hemoglobin, MCV, MCH, RDW, white blood cells, platelets 1, 2
• Reticulocyte count: Assess bone marrow response 1
• Serum ferritin: Most specific test for iron deficiency; <15 μg/L diagnostic, <30 μg/L suggests low stores 1, 2
• Transferrin saturation (TfS): Helps diagnose iron deficiency, especially with inflammation 1
• C-reactive protein (CRP): Identifies inflammation that may elevate ferritin falsely 1

Extended Workup (When Indicated)

• Iron panel: Serum iron, total iron-binding capacity (TIBC) 2
• Vitamin B12 and folate levels: If macrocytic or neurologic symptoms 1
• Peripheral blood smear: Assess red cell morphology 1
• Hemoglobin electrophoresis: If microcytosis with normal iron studies, especially in appropriate ethnic background 1
• Coombs test: If suspected hemolysis, particularly in CLL, NHL, or autoimmune disease 1
• Haptoglobin, lactate dehydrogenase (LDH), bilirubin: If hemolysis suspected 1
• Renal function (creatinine, urea): Assess for chronic kidney disease 1
• Stool and urine for occult blood: Assess for GI or urinary blood loss 1
• Bone marrow examination: If diagnosis unclear or cytopenias present 1

Expected Findings by Anemia Type

Iron Deficiency:

• Low MCV, low MCH, low ferritin (<30 μg/L), low transferrin saturation (<20%), elevated TIBC 1, 2

Anemia of Chronic Disease:

• Normal or low MCV, normal or elevated ferritin, low transferrin saturation, elevated CRP 1

B12/Folate Deficiency:

• Elevated MCV, hypersegmented neutrophils on smear, low B12 (<200 pg/mL) or folate 1

Hemolysis:

• Elevated reticulocytes, low haptoglobin, elevated LDH, elevated indirect bilirubin, positive Coombs if immune-mediated 1

Chronic Kidney Disease:

• Normocytic, normochromic, low reticulocytes, elevated creatinine 1

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Empiric Treatment

Iron Deficiency Anemia

• Identify and treat underlying cause, especially GI sources of blood loss 1, 2
• Oral iron supplementation: First-line for mild-moderate anemia with tolerance 1, 2
• Parenteral iron: For severe anemia, intolerance to oral iron, malabsorption, or ongoing blood loss 1, 2
• Expected response: Hb rise ≥10 g/L within 2 weeks confirms iron deficiency 1

Anemia of Chronic Disease

• Treat underlying inflammatory condition 1
• Correct iron deficiency if present before considering other therapies 1

Chronic Kidney Disease

• Correct nutritional deficiencies first (iron, B12, folate) 1
• Erythropoiesis-stimulating agents (ESAs): Only after excluding other causes 1

Vitamin B12/Folate Deficiency

• Vitamin B12 replacement: Intramuscular or high-dose oral 1
• Folate supplementation: Oral replacement 1

Important Treatment Principles

• All causes of anemia should be corrected before using ESAs 1
• Good response to iron therapy (Hb rise ≥10 g/L in 2 weeks) is highly suggestive of absolute iron deficiency, even if iron studies are equivocal 1

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Indications to Refer

Urgent Hematology Referral

• Abnormalities in two or more cell lines: Suggests bone marrow pathology 1
• Severe anemia (Hb <8.0 g/dL) without obvious cause 1
• Suspected hemolysis with unclear etiology 1
• Anemia remains unexplained after extended workup 1

Fast-Track GI Referral

• Iron deficiency anemia with Hb <110 g/L in men or <100 g/L in non-menstruating women: Suspected colorectal cancer 1
• Any iron deficiency anemia in adults unless significant non-GI blood loss identified 1, 2
• Upper GI endoscopy and lower GI examination should be considered in all confirmed iron deficiency anemia 2

Nephrology Referral

• Anemia with chronic kidney disease requiring ESA therapy or advanced management 1

When to Consider Specialist Input

• Microcytosis with normal iron studies: Consider hemoglobin electrophoresis; may need hematology input 1
• Macrocytic anemia unresponsive to B12/folate replacement 1
• Suspected bone marrow disorder 1

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Critical Pitfalls

Diagnostic Pitfalls

• Assuming ferritin is normal in the presence of inflammation: Ferritin is an acute phase reactant; levels <45 μg/L may still indicate iron deficiency in inflammatory states 1
• Missing iron deficiency in patients with higher Hb levels: Investigation should be considered at any level of anemia with iron deficiency, not just severe anemia 1
• Failing to perform GI investigation in iron deficiency anemia: All patients with confirmed iron deficiency anemia require GI evaluation unless significant non-GI blood loss is identified 1, 2
• Overlooking microcytosis disproportionate to anemia: Suggests thalassemia; requires hemoglobin electrophoresis 1
• Not recognizing functional iron deficiency: MCH may be more reliable than MCV in chronic disease; transferrin saturation helps identify functional deficiency 1
• Relying solely on physical examination: Clinical manifestations are neither sensitive nor specific to anemia type 3

Treatment Pitfalls

• Using ESAs before correcting all reversible causes of anemia: All nutritional deficiencies and treatable causes must be addressed first 1
• Using ESAs in patients not receiving chemotherapy: Increased risk of death when ESAs target Hb 12-14 g/dL in non-chemotherapy patients 1
• Treating anemia without identifying the underlying cause: May delay diagnosis of serious conditions like GI malignancy 1, 2
• Inadequate monitoring frequency: CKD patients require at least yearly screening; more frequent in diabetics 1

Investigation Pitfalls

• Not checking B12/folate in patients on thiopurines or with extensive small bowel disease: These patients require more frequent monitoring 1
• Failing to assess for hemolysis in appropriate clinical contexts: Check haptoglobin, LDH, and Coombs test in CLL, NHL, or autoimmune disease 1
• Missing subtle nutritional deficiency signs: Angular stomatitis, glossitis, koilonychia may be overlooked 3
• Not considering bone marrow examination when diagnosis unclear: Essential when cytopenias or unexplained anemia persists 1