Folic Acid and Reticulocytosis Quiz

Hematology Lecture Notes

• Course: Hematology
• Lecturer: Dr. Sura Al Shamma
• Department: Pathology
• Year: 2024

Macrocytic Anemias

• These anemias feature red blood cells (RBCs) with mean corpuscular volume (MCV) greater than 98 fl.
• Two types of macrocytic anemias exist:
  • Megaloblastic anemia
  • Non-megaloblastic macrocytic anemia

Non-Megaloblastic Macrocytic Anemias

• These conditions result from factors other than vitamin B12 or folic acid deficiency.
• Red blood cells (RBCs) in these conditions are round.
• Conditions leading to round macrocytes:
  • Reticulocytosis
  • Hypothyroidism/myxedema
  • Myelodysplastic syndrome
  • Scurvy (vitamin C deficiency)
  • Liver disorders
  • Alcohol excess (with MCV not exceeding 110)
  • Congenital dyserythropoietic anemia (CDA I and III)
  • Erythroleukemia
  • Neonates

Megaloblastic Anemia

• This anemia group is characterized by abnormal erythroblasts in bone marrow.
• Maturation of the nucleus is delayed relative to the cytoplasm in erythroblasts.
• Caused by vitamin B12 or folic acid deficiency.
• The underlying defect relates to DNA synthesis errors during cell maturation.
• Macrocytes in this condition are usually oval, hence termed macro-ovalocytes.

Causes of Megaloblastic Anemia

• Vitamin B12 deficiency
• Folate deficiency
• Abnormalities in vitamin B12 or folate metabolism (e.g. transcobalamin deficiency, nitrous oxide, or antifolate drugs)
• Other defects in DNA synthesis
• Congenital enzyme deficiencies (e.g., orotic aciduria)
• Acquired enzyme deficiencies (e.g., alcohol, therapy with hydroxyurea, or cytosine arabinoside)

Vitamin B12

• Dietary sources: Primarily meats, fish, eggs, and dairy products.
• Daily requirement: Approximately 1-2 µg in adults.
• Body stores: 2-3 mg stored in the liver (sufficient for 2-4 years).
• Absorption: B12 binds to proteins in foods, released in the stomach by acid and pepsin, and then binds to intrinsic factor (IF) and absorbed in the terminal ileum.
• Deficiency Causes: Autoimmune gastric atrophy (leading to decreased IF production), gastrectomy, ileal resection, ileitis, Zollinger-Ellison syndrome, blind loop syndrome, fish tapeworm infestation, and pancreatic insufficiency.

Vitamin B12 Absorption (Mechanism)

• B12 binds to proteins in foods.
• Stomach acid and pepsin release B12 from proteins.
• Stomach lining cells release intrinsic factor (IF).
• IF binds to B12 in the small intestine.
• B12-IF complex binds to receptors in the ileum, allowing absorption.
• Some un-bound B12 may be absorbed by passive diffusion.

Folate

• Dietary source: Present in green vegetables, fruits, meat, and liver.
• Daily adult needs: 100-150 µg
• Body stores: 10-12 mg stored in the liver (sufficient for 3-4 months).
• Absorption: Primarily absorbed in the jejunum.
• Factors affecting folate availability : Decreased intake, increased demand (pregnancy, hemolysis, hemodialysis, malabsorption, and disorders interfering with folate metabolism).

Clinical Features of Megaloblastic Anemia

• Gradual onset of anemia symptoms.
• The hallmark is defective DNA synthesis in rapidly dividing cells in bone marrow and other tissues.
• Macrocytic cells appear on blood count.
• Potential symptoms include shortness of breath, muscle weakness, pale skin, loss of appetite/weight loss, diarrhea, nausea, fast heartbeat.

Clinical Features of Megaloblastic Anemia (Specific Signs)

• Glossitis (swollen, beefy tongue).
• Jaundice and splenomegaly (due to excess breakdown of hemoglobin from ineffective erythropoiesis).
• Peripheral neuropathy/paresthesia.
• Dementia.
• Loss of vibratory and positional sense/ataxia.
• Neural tube defects in neonates (folate related).
• Purpura (less frequent).

Pernicious Anemia

• An autoimmune disorder causing vitamin B12 deficiency.
• Common among Northern Europeans, frequently seen in people aged 60-70 years.
• Characterized by chronic gastric inflammation leading to atrophy, diminished or absent intrinsic factor (IF) production.

Laboratory Diagnosis for Macrocytic Anemias

• Blood count: Reduced hemoglobin, MCV above 100-110 fl, presence of ovalocytes
• Serum vitamin B12: Decreased level.
• Serum and erythrocyte folates: Decreased levels.
• Homocysteine and Methylmalonic acid: Increased levels.
• LDH, Bilirubin (unconjugated): Increased levels

Hemolytic Anemias

• Mechanism: Result from increased red blood cell (RBC) destruction. Two mechanisms: intravascular (RBCs broken down directly in circulation) or extravascular (excessive removal by the reticuloendothelial system).
• Causes: Hereditary (defects like membrane or metabolic disorders, hemoglobin abnormalities) or acquired (immune-mediated destruction, infections, drugs, physical injury).

Clinical Features of Hemolytic Anemia

• Jaundice: Result of increased bilirubin production
• Pigment gallstones: Due to excess bilirubin
• Hepatosplenomegaly: Caused by extramedullary hemopoiesis (bone marrow outside of the bone).

Mechanisms of Red Cell Destruction

• Extravascular: Excessive removal of RBCs by cells of the reticuloendothelial system.
• Intravascular: RBC lysis directly within the circulation causing haemoglobinemia and hemoglobinuria.

Laboratory Findings for Hemolytic Anemia

• Features of increased red cell breakdown: Increased serum bilirubin, increased urine urobilinogen, decreased/absent serum haptoglobin.
• Features of increased red cell production: Reticulocytosis, bone marrow erythroid hyperplasia.
• Damaged red cells: Microspherocytes, elliptocytes, fragments, osmotic fragility tests, and specific enzyme, protein, or DNA tests.

Hereditary Hemolytic Anemias

• Membrane defects: Congenital spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis, and others).
• Metabolic defects: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, and Pyruvate kinase (PK) deficiency.
• Hemoglobin defects: Sickle cell anemia and thalassemia.

Specific Hereditary Hemolytic Anemias

• Hereditary Spherocytosis (HS): Common in Northern Europeans and characterized by spheroid red blood cells (RBCs). Related to defects in membrane proteins (e.g., spectrin, ankyrin).
• Hereditary Elliptocytosis: Less severe than HS and features elliptical RBCs.
• Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency: X-linked genetic disorder impairing NADPH production in RBCs, increasing cell susceptibility to oxidant stress (like fava beans).

G6PD Deficiency

• Inheritance: X-linked, primarily affecting males.
• Mechanism: Deficiency of the enzyme G6PD affecting NADPH production.
• Precipitants: Drugs, infections, fava beans, and others.
• Clinical features: Acute hemolytic episodes due to oxidant stress; often asymptomatic.

Pyruvate Kinase Deficiency

• Inheritance: Autosomal recessive.
• Mechanism: Deficiency in the enzyme that generates ATP in RBCs, leading to premature cell death.
• Clinical features: Chronic hemolytic anemia, often with microspherocytes on blood smears; often with increased reticulocytes.

Laboratory Findings for G6PD Deficiency

• Normal blood count between crises.
• Enzyme deficiency detectable by screening tests or direct enzyme assays.
• Abnormal blood film in crisis (e.g., contracted/fragmented cells, bite and blister cells).
• Elevated bilirubin (unconjugated).
• Other laboratory tests might include elevated LDH.

Treatment for Haemolytic Anemias

• General Measures: Treating underlying infections. Discontinuing offending drugs.
• Specific Measures: Blood transfusion for severe cases. Splenectomy (for conditions like HS)