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This is a Physiology exam paper on Megaloblastic Anemia (Vitamin B12/Folate deficiency). Here are concise answers to all 10 sub-questions plus Q2 and Q3:
Q1 Case: 45-year-old male with macrocytic normochromic anemia
Q.1 What is this patient suffering from?
Megaloblastic anemia - specifically Vitamin B12 deficiency anemia (pernicious anemia). Evidence: macrocytic normochromic RBCs, MCV 100fL (raised), hypersegmented neutrophils, peripheral neuropathy, angular stomatitis, glossitis.
Q.2 What are the causes of this type of anemia?
- Vitamin B12 deficiency: pernicious anemia (lack of intrinsic factor), strict vegetarian diet, gastrectomy, gastric atrophy, terminal ileum disease (Crohn's)
- Folate deficiency: poor diet, malabsorption, increased demand (pregnancy), anti-folate drugs (methotrexate, phenytoin)
Q.3 What is the cause of peripheral neuropathy in this type of anemia?
Demyelination of posterior and lateral columns of spinal cord. Vitamin B12 is required for myelin synthesis via methylmalonyl-CoA metabolism. Its deficiency leads to accumulation of methylmalonyl-CoA, causing abnormal fatty acid incorporation into myelin sheath, resulting in subacute combined degeneration of the spinal cord.
Q.4 What do you understand by macrocytic and normochromic RBCs?
- Macrocytic: RBCs larger than normal (MCV > 100fL). Occurs because DNA synthesis is impaired (B12/folate needed for thymidine synthesis), so cells grow in size but cannot divide.
- Normochromic: normal hemoglobin content per cell (MCH and MCHC normal) - iron metabolism is unaffected, so hemoglobin synthesis proceeds normally.
Q.5 Why are large nucleated RBCs (megaloblasts) seen in PBF?
B12/folate deficiency impairs DNA synthesis (blocked conversion of deoxyuridine to thymidine monophosphate). RNA synthesis continues normally, so cytoplasm grows but nuclear division is arrested - nuclear-cytoplasmic dissociation. Cells remain large with immature nuclei (megaloblasts) and are released prematurely into blood.
Q.6 How is the deficient nutrient (Vitamin B12) absorbed and utilized?
- Absorption: Dietary B12 binds to R-protein in stomach, then transferred to Intrinsic Factor (IF) secreted by gastric parietal cells. IF-B12 complex is absorbed at the terminal ileum via specific receptors (cubilin).
- Transport: Carried in blood by transcobalamin II to tissues.
- Utilization: Acts as coenzyme for (1) conversion of methylmalonyl-CoA to succinyl-CoA (myelin synthesis), and (2) conversion of homocysteine to methionine (regenerates THF for DNA synthesis).
Q.7 Why is this anemia seen in gastric atrophy?
Gastric atrophy destroys parietal cells, which produce Intrinsic Factor (IF). Without IF, dietary B12 cannot be absorbed in the terminal ileum, leading to B12 deficiency over time (body stores last ~3-5 years). This is classic pernicious anemia.
Q.8 How will you manage this patient?
- Vitamin B12 (cyanocobalamin/hydroxocobalamin): 1000 mcg IM daily for 1 week, then weekly for 4 weeks, then monthly for life (if pernicious anemia)
- Oral B12 1000 mcg/day if dietary cause
- Treat underlying cause
- Folic acid supplementation if folate deficient (only AFTER confirming B12 is not the sole cause)
Q.9 What will happen if you give only folic acid in pernicious anemia?
Folic acid will correct the hematological manifestations (anemia improves, megaloblasts disappear), but neurological damage (subacute combined degeneration) will progress and worsen. This is because folic acid does not correct the B12-dependent myelin synthesis pathway. This is why B12 must always be given alongside or before folic acid when B12 deficiency is suspected.
Q.10 Mode of action of Vitamin B12 and folic acid in erythropoiesis?
- Folic acid (as THF - tetrahydrofolate): donates single carbon units for synthesis of thymidine monophosphate (TMP) from dUMP, enabling DNA synthesis for RBC maturation and division.
- Vitamin B12: regenerates THF from 5-methyl THF (the "folate trap" reaction) via methionine synthase. Also required for DNA synthesis indirectly. Both are essential for normal nuclear maturation of erythroblasts.
Q2. Types of Cell Junctions
| Type | Function | Location |
|---|---|---|
| Tight junctions (Zonula occludens) | Seal between cells; prevent paracellular passage | Intestinal epithelium, blood-brain barrier |
| Adherens junctions (Zonula adherens) | Mechanical attachment via cadherins + actin | Below tight junctions in epithelia |
| Desmosomes (Macula adherens) | Strong mechanical anchoring via intermediate filaments | Skin, cardiac muscle |
| Gap junctions | Electrical/chemical communication via connexons | Cardiac muscle, smooth muscle, neurons |
| Hemidesmosomes | Attach epithelial cells to basement membrane | Basal epithelial cells |
(Draw a labeled diagram showing zonula occludens, zonula adherens, and desmosome in the junctional complex)
Q3. Resting Membrane Potential (RMP) and Gibbs-Donnan Equilibrium
RMP = -70 mV (inside negative relative to outside) in neurons.
Genesis of RMP:
- Selective permeability: At rest, membrane is mainly permeable to K+ (via leak channels). K+ diffuses out down concentration gradient, leaving negative charges inside.
- Na+/K+ ATPase pump: Pumps 3 Na+ out and 2 K+ in per cycle - electrogenic, contributes -5 to -10 mV directly.
- Large intracellular anions: Negatively charged proteins (A-) are trapped inside, contributing to interior negativity.
Gibbs-Donnan Equilibrium:
When a membrane is permeable to small ions but impermeable to large charged molecules (like proteins), the diffusible ions distribute unequally to maintain electrical neutrality on each side. Result:
- At equilibrium: [K+]in × [Cl-]in = [K+]out × [Cl-]out
- The side with impermeant anions (intracellular) has higher osmotic pressure and more total ions
- This creates a Donnan potential (inside negative) that contributes to RMP
- The cell must use active transport (Na+/K+ pump) to counteract the osmotic imbalance, otherwise the cell would swell due to excess intracellular ions
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