3.2 Anemia & Hematological Disorders

Anemia & Hematological Disorders

Anemia is a common clinical finding in primary care defined by a decrease in the total red blood cell (RBC) mass or concentration of hemoglobin below normal reference ranges. A systematic diagnostic approach starting with the Complete Blood Count (CBC) is crucial to narrow the differential diagnosis and initiate appropriate therapy.

Interpretation of CBC and Anemia Classification

The evaluation of anemia begins with classifying the red blood cell size using the Mean Corpuscular Volume (MCV):

1. Microcytic Anemia (MCV < 80 fL): Most commonly caused by iron deficiency, thalassemia (alpha or beta), anemia of chronic disease (late stage), and sideroblastic anemia.
2. Normocytic Anemia (MCV 80–100 fL): Frequently due to acute blood loss, hemolysis, early nutritional deficiencies, kidney disease (erythropoietin deficiency), or anemia of chronic disease.
3. Macrocytic Anemia (MCV > 100 fL): Divided into megaloblastic (impaired DNA synthesis due to B12 or folate deficiency, or drugs like methotrexate) and non-megaloblastic (hypothyroidism, liver disease, alcohol use disorder).

Additional CBC parameters help refine the diagnosis:

• Red Cell Distribution Width (RDW): Measures variation in RBC size (anisocytosis). A high RDW is typical of nutritional deficiencies (iron, B12, folate) as new cells are progressively smaller or larger, whereas thalassemia minor characteristically presents with a normal RDW.
• Reticulocyte Count: Reflects the bone marrow's production of new RBCs. An elevated reticulocyte count (> 2%) in the setting of anemia indicates an appropriate bone marrow response, pointing toward hemolysis or acute blood loss. A low or normal reticulocyte count indicates impaired RBC production.

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Iron Deficiency Anemia (IDA)

Iron deficiency anemia is the most common microcytic anemia worldwide. It arises when iron loss or demand exceeds intake, leading to depleted iron stores and impaired hemoglobin synthesis.

Clinical Presentation and Etiology

Patients often report fatigue, weakness, dyspnea on exertion, and cold intolerance. Pathognomonic clinical signs include pica (craving non-food items like dirt or clay) and pagophagia (compulsive ice chewing), as well as physical signs like pallor, koilonychia (spoon-shaped nails), angular cheilitis, and glossitis.

In adult males and postmenopausal females, IDA is considered a sign of gastrointestinal blood loss until proven otherwise, mandating evaluation with upper and lower endoscopy to rule out occult malignancy. In premenopausal females, menorrhagia is the leading cause.

Diagnostic Workup and Iron Studies

A peripheral blood smear demonstrates microcytic, hypochromic red blood cells with variable size (high RDW) and shape, often showing classic "pencil cells" (elongated RBCs). Confirming the diagnosis requires serum iron studies:

Serum ferritin is the most specific marker of total body iron stores; a value below 30 ng/mL is diagnostic of iron deficiency, even in the absence of anemia.

Management

Treatment involves addressing the underlying cause and replacing iron stores. Oral iron supplementation (e.g., Ferrous Sulfate 325 mg, which provides 65 mg of elemental iron) is first-line. Absorption is optimized by administering the dose every other day (which minimizes hepcidin elevation) on an empty stomach with Vitamin C (ascorbic acid). Side effects include metallic taste, nausea, flatulence, constipation, and dark stools.

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Megaloblastic Anemias: Vitamin B12 and Folate Deficiencies

Megaloblastic macrocytic anemias are characterized by impaired DNA synthesis, leading to large, abnormal RBC precursors in the bone marrow.

Pathophysiology and Presentation

• Vitamin B12 (Cobalamin) Deficiency: Caused by pernicious anemia (autoimmune destruction of gastric parietal cells/intrinsic factor), dietary deficiency (strict vegans), malabsorption (Crohn's disease, celiac disease, bariatric surgery, or long-term metformin or PPI use).
  • Neurological Findings: B12 deficiency causes demyelination of the posterior and lateral columns of the spinal cord (subacute combined degeneration), presenting as symmetric paresthesias, loss of vibratory and proprioceptive sensation, ataxia, and dementia.
• Folate (Vitamin B9) Deficiency: Primarily caused by poor dietary intake (lack of green leafy vegetables), chronic alcohol use disorder, malabsorption, or increased demand (pregnancy). It presents with similar hematologic signs but completely lacks neurological symptoms.

Diagnostics

A peripheral smear shows macro-ovalocytes and hypersegmented neutrophils (defined as five or more lobes in ≥ 3% of neutrophils).

• Vitamin B12 Deficiency: Low serum B12 levels. To confirm borderline cases, check Methylmalonic Acid (MMA) and Homocysteine. Both are elevated in B12 deficiency. Pernicious anemia is confirmed by checking anti-intrinsic factor antibodies.
• Folate Deficiency: Low serum or RBC folate. Homocysteine is elevated, but MMA is normal.

Critical Safety Rule: Never treat macrocytic anemia with folic acid alone without ruling out Vitamin B12 deficiency. Folate supplementation can correct the anemia of B12 deficiency but allows the irreversible neurological damage to progress.

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Hemolytic Anemias

Hemolytic anemias are characterized by the premature destruction of red blood cells, which can occur intravascularly or extravascularly (primarily in the spleen).

General Laboratory Markers of Hemolysis:

• Elevated Reticulocyte Count (bone marrow compensation)
• Elevated Lactate Dehydrogenase (LDH) (released from lysed RBCs)
• Elevated Indirect (Unconjugated) Bilirubin (from heme breakdown, causing jaundice)
• Decreased Serum Haptoglobin (free hemoglobin binds to haptoglobin and is cleared by the liver)

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

G6PD deficiency is an X-linked recessive disorder that impairs the hexose monophosphate shunt, leaving RBCs vulnerable to oxidative stress.

• Triggers: Fava beans, infections (most common), and oxidative drugs (e.g., nitrofurantoin, dapsone, primaquine, trimethoprim-sulfamethoxazole).
• Microscopy: Peripheral smear shows Heinz bodies (precipitated oxidized hemoglobin) and bite cells (RBCs after macrophages remove the Heinz bodies in the spleen).
• Testing: G6PD enzyme activity levels can be falsely normal during an acute hemolytic crisis because older, deficient RBCs have already lysed, leaving only young reticulocytes with normal enzyme levels. Testing should be repeated 2–3 months after the acute episode resolves.

Sickle Cell Disorders

Sickle cell disease is an autosomal codominant disorder caused by a point mutation in the beta-globin gene, substituting valine for glutamic acid, resulting in Hemoglobin S (HbS).

• Sickle Cell Trait (HbAS): Carriage of one mutated allele. Patients are generally asymptomatic with normal blood counts, though they have an increased risk of hematuria, renal papillary necrosis, and splenic infarction at high altitudes or under extreme dehydration.
• Sickle Cell Disease (HbSS): Carriage of two mutated alleles. Under hypoxic or acidotic stress, HbS polymerizes, causing RBCs to sickle, leading to microvascular occlusion and chronic hemolytic anemia.
  • Clinical Manifestations: Vaso-occlusive crises (severe bone and joint pain), acute chest syndrome (fever, chest pain, infiltrates on X-ray), splenic sequestration (pooling of blood in the spleen), and functional asplenia due to splenic autoinfarction (increasing risk of infection by encapsulated organisms like Streptococcus pneumoniae).
  • Management: Hydroxyurea (induces production of Hemoglobin F to prevent sickling), folic acid, routine vaccinations, prophylactic penicillin in children under 5, and hydration.