Pathology
Haematology
Regarding folate requirements, which of the following statements is CORRECT:
Answer:
Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the growth stage to the mitosis stage. This leads to continuing cell growth without division, which presents as macrocytosis. The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency. Folate is an essential vitamin found in most foods, especially liver, green vegetables and yeast. The normal daily diet contains 200 - 250 μg, of which about 50% is absorbed. Daily adult requirements are about 100 μg. Absorption of folate is principally from the duodenum and jejunum. Stores of folate are normally only adequate for 4 months and so features of deficiency may be apparent after this time.Megaloblastic Anaemia
Pathology / Haematology / Anaemia
Last Updated: 4th August 2019
Megaloblastic anaemia is characterised by an abnormal appearance of the bone marrow erythroblasts in which nuclear development is delayed and nuclear chromatin has a lacy open appearance.
Pathophysiology
Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the growth stage to the mitosis stage. This leads to continuing cell growth without division, which presents as macrocytosis. The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency.
Vitamin B12 and Folate Requirements
Vitamin B12 is found exclusively in food of animal origin. Dietary vitamin B12 is cleaved from food proteins by gastric acid and bound to R protein found in saliva and in gastric secretions which protects it from digestion in the stomach. Vitamin B12 is cleaved from R protein by the action of pancreatic proteases, and subsequently binds to intrinsic factor secreted by gastric parietal cells. Receptors for the intrinsic factor-B12 complex are present in the membrane of epithelial cells of the terminal ileum, which bind the complex and allow uptake of vitamin B12. Vitamin B12 is then transported across the basal membrane of the epithelial cells into the plasma, where it is bound to transcobalamin II and taken up by the tissues. Normal body stores are largely in the liver with an enterohepatic circulation. Stores of vitamin B12 are normally adequate for 2 - 4 years and so features of deficiency take years to appear.
Folate is an essential vitamin found in most foods, especially liver, green vegetables and yeast. The normal daily diet contains 200 - 250 μg, of which about 50% is absorbed. Daily adult requirements are about 100 μg. Absorption of folate is principally from the duodenum and jejunum. Stores of folate are normally only adequate for 4 months and so features of deficiency may be apparent after this time.
Causes of Vitamin B12 and Folate Deficiency
Causes of vitamin B12 deficiency:
- Inadequate intake e.g. vegan diet
- Malabsorption
- Gastric causes
- Pernicious anaemia
- Gastrectomy
- Congenital intrinsic factor deficiency
- Atrophic gastritis
- H.pylori infection
- Intestinal causes
- Fish tapeworm infestation
- Overgrowth of intestinal flora
- Ileal resection
- Crohn's disease
- Coeliac disease
Causes of folate deficiency:
- Inadequate intake
- Old age, alcoholism, institutions, poverty
- Excessive requirement
- Physiological
- Pregnancy, lactation, prematurity
- Pathological
- Haemolytic anaemia, myelofibrosis, malignancy, inflammatory disease
- Physiological
- Malabsorption
- Coeliac disease, Crohn's disease, jejunal resection, tropical sprue
- Excessive urinary loss
- Congestive heart failure, chronic dialysis
- Drugs
- Anticonvulsants, sulfasalazine
- Mixed
- Liver disease, alcoholism
Clinical Features
- General features of anaemia
- Increased incidence of foetal neural tube defects in pregnancy
- Megaloblastic anaemia:
- Lemon yellow tinge (combination of pallor and jaundice) caused by ineffective erythropoiesis
- Glossitis
- Angular cheilitis
- B12 deficiency:
- Symmetrical neuropathy affecting the pyramidal tracts and posterior columns of the spinal cord (subacute combined degeneration of the cord) and the peripheral nerves (patients present with tingling in feet, difficulty in gait, visual or psychiatric disorders)
Laboratory Features
Megaloblastic anaemia is characterised by:
- Macrocytic anaemia with oval macrocytes and hypersegmented neutrophils
- Moderate reduction in leucocyte and platelet counts
- Raised serum bilirubin (indirect) and lactate dehydrogenase (LDH) (due to haemolysis of defective red cells)
- Low B12 +/- folate
- Hypercellular bone marrow, increased proportion of early cells, megaloblastic erythropoiesis and giant metamyelocytes
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
