Vitamin Deficiency Syndromes
Medicine · Haematology · lean revision notes
Vitamin Deficiency Syndromes
Vitamins are organic micronutrients required in minute amounts that cannot be synthesised in sufficient quantity by the body. Their deficiencies produce highly examinable, pattern-based syndromes — from the haematological storm of B12/folate deficiency to the dermatological and neurological signatures of pellagra, beri-beri and scurvy. These notes integrate the haematology core (megaloblastic anaemia, subacute combined degeneration) with the wider water- and fat-soluble vitamin map.
Classification
Vitamins are divided by solubility, which dictates storage, toxicity risk and deficiency onset.
| Feature | Water-soluble (B-complex, C) | Fat-soluble (A, D, E, K) |
|---|---|---|
| Storage | Minimal (except B12, ~3–5 yr liver store) | Stored in liver/adipose |
| Toxicity | Rare (except B6, niacin) | Common (A, D especially) |
| Deficiency onset | Rapid (weeks–months) | Slow (months–years) |
| Excretion | Renal | Biliary/faecal |
| Absorption needs | Generally simple | Need bile salts + intact fat absorption |
High-yield: B12 is the exception among water-soluble vitamins — large hepatic stores mean deficiency takes 3–5 years to manifest even after total absorption stops (e.g., post-gastrectomy).
The B-vitamins of greatest exam weight: B1 (thiamine), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B7 (biotin), B9 (folate), B12 (cobalamin).
Vitamin B12 (Cobalamin) Deficiency
Biochemistry & absorption
Dietary B12 (animal sources only) binds R-protein (haptocorrin) in saliva → in the duodenum pancreatic proteases release it → it binds intrinsic factor (IF) secreted by gastric parietal cells → the B12–IF complex is absorbed in the terminal ileum via cubam receptor (cubilin).
B12 is a cofactor for two reactions:
- Methylmalonyl-CoA → succinyl-CoA (enzyme: methylmalonyl-CoA mutase). Block → methylmalonic acid (MMA) accumulates → abnormal odd-chain fatty acids incorporated into neuronal myelin → demyelination.
- Homocysteine → methionine (enzyme: methionine synthase, also needs methyl-folate). Block → homocysteine rises and the methyl-folate trap develops (folate stuck as methyltetrahydrofolate, unavailable for DNA synthesis) → megaloblastic anaemia.
High-yield: The neurological damage of B12 deficiency is attributed to the MMA pathway (myelin), while the megaloblastic anaemia is due to the methyl-folate trap. This is why folate corrects the anaemia but worsens/unmasks the neurology.
Causes
Stepwise approach: Dietary lack → Gastric IF loss → Ileal absorption failure → Competition.
- Pernicious anaemia — autoimmune atrophic gastritis with anti-parietal cell and anti-IF antibodies; commonest cause in the West; associated with other autoimmune disease, vitiligo, and gastric carcinoma risk.
- Vegans / pure vegetarians (dietary) — relevant in India.
- Gastrectomy / atrophic gastritis — loss of IF.
- Terminal ileal disease/resection — Crohn disease, ileal TB, tropical sprue.
- Fish tapeworm — Diphyllobothrium latum (competes for B12).
- Blind loop syndrome (bacterial overgrowth consumes B12).
- Drugs: metformin (ileal absorption), proton-pump inhibitors, nitrous oxide (irreversibly oxidises cobalamin → classic exam trap).
Clinical features
- Megaloblastic anaemia — fatigue, pallor, mild jaundice (ineffective erythropoiesis → indirect hyperbilirubinaemia), lemon-yellow tint.
- Glossitis (beefy red tongue), angular stomatitis, anorexia.
- Subacute combined degeneration (SACD) of the cord — see below.
- Neuropsychiatric: paraesthesiae, peripheral neuropathy, dementia, depression ("megaloblastic madness").
Subacute combined degeneration (SACD)
High-yield: SACD affects the posterior (dorsal) columns AND the lateral corticospinal tracts — "combined." It is symmetrical, begins in the legs, and spares the spinothalamic (pain/temperature) initially.
- Posterior column loss → impaired vibration & proprioception, sensory ataxia, positive Romberg.
- Lateral corticospinal loss → spastic paraparesis, extensor plantars (upgoing toes).
- Mixed sign combination: absent ankle jerks (neuropathy) with extensor plantars — a classic exam clue (also seen in Friedreich ataxia, taboparesis, conus lesions).
Differential of posterior column disease
Mnemonic — causes of dorsal column degeneration: "Friedreich's Disease Spreads To Many" → Friedreich ataxia, Diabetes, SACD (B12), Tabes dorsalis, Multiple sclerosis.
Folate (Vitamin B9) Deficiency
Biochemistry & absorption
Dietary folate (green leafy vegetables, "foliage") is absorbed in the jejunum (proximal small bowel). Folate, as tetrahydrofolate, donates one-carbon units for purine and thymidylate (DNA) synthesis. Body stores are small → deficiency develops in months (compare B12's years).
Causes
- Poor diet / alcoholism (commonest; alcohol also impairs folate metabolism).
- Increased demand — pregnancy, haemolysis, exfoliative skin disease, malignancy.
- Malabsorption — coeliac disease, tropical sprue (jejunal).
- Drugs: anti-epileptics (phenytoin, phenobarbitone), methotrexate, trimethoprim, pyrimethamine (dihydrofolate reductase inhibitors), sulfasalazine.
High-yield: Folate deficiency causes megaloblastic anaemia WITHOUT neurological features. Neurology = think B12, not folate. (The fetal exception: maternal folate deficiency → neural tube defects.)
B12 vs Folate — the master comparison
| Parameter | B12 deficiency | Folate deficiency |
|---|---|---|
| Body store / time to deplete | 3–5 years | Weeks–months |
| Source | Animal products only | Green vegetables, liver |
| Absorption site | Terminal ileum (needs IF) | Jejunum |
| Neurological features | Yes — SACD, neuropathy | No (except fetal NTD) |
| Serum methylmalonic acid | Elevated | Normal |
| Serum homocysteine | Elevated | Elevated |
| Schilling test | Abnormal | Normal |
| Effect of giving folate alone | Corrects anaemia, worsens neurology | Corrects fully |
High-yield: MMA distinguishes the two — raised in B12 deficiency, normal in folate deficiency. Homocysteine is raised in both, so it cannot differentiate.
Megaloblastic Anaemia — Diagnosis & Investigation
Both B12 and folate deficiency converge on impaired DNA synthesis with preserved RNA/cytoplasmic maturation → nuclear–cytoplasmic asynchrony → large cells.
Peripheral smear / counts:
- Macrocytic anaemia, MCV > 100 fL (often >110–120).
- Hypersegmented neutrophils — neutrophil with ≥6 lobes, or >5% of neutrophils with ≥5 lobes. An early and sensitive sign.
- Macro-ovalocytes, anisopoikilocytosis.
- Pancytopenia in severe cases (megaloblastic process affects all lineages).
High-yield: Hypersegmented neutrophils are among the earliest peripheral findings of megaloblastic anaemia and may persist after treatment for ~2 weeks.
Bone marrow: hypercellular, megaloblasts, "giant metamyelocytes/band forms," nuclear–cytoplasmic dissociation.
Biochemistry — ineffective erythropoiesis pattern:
- Raised LDH (markedly), raised indirect bilirubin, low haptoglobin, low reticulocyte count (intramedullary destruction).
- Serum B12 low; serum/RBC folate low. RBC folate reflects tissue stores better than serum folate.
- Raised MMA and homocysteine confirm functional B12 deficiency when serum B12 is borderline.
Schilling test (historical but examinable): distinguishes pernicious anaemia from ileal/dietary causes using radiolabelled oral B12 ± IF, measuring urinary excretion.
| Schilling stage | What is given | Pernicious anaemia | Ileal disease |
|---|---|---|---|
| Part 1 | Oral radio-B12 alone | Low urinary B12 | Low |
| Part 2 | + Intrinsic factor | Corrects | Still low |
| Part 3 | + Antibiotics | No change | — (improves in bacterial overgrowth) |
Management
B12 deficiency: Intramuscular hydroxocobalamin (1000 µg) — typically daily/alternate-day loading then maintenance; lifelong if pernicious anaemia or post-gastrectomy. Oral high-dose B12 works in dietary deficiency.
Folate deficiency: Oral folic acid 5 mg/day.
High-yield: ALWAYS exclude/correct B12 before giving folate in megaloblastic anaemia of uncertain cause — folate alone can precipitate/worsen SACD.
Treatment response monitoring:
- Reticulocytosis peaks at day 5–7.
- Watch for hypokalaemia (cellular uptake during brisk haematopoiesis) — exam favourite complication.
- Coexisting iron deficiency may be unmasked as erythropoiesis accelerates.
Pregnancy: periconceptional folic acid 400 µg/day (5 mg if prior NTD, diabetes, or on anti-epileptics) to prevent neural tube defects — start before conception, continue through first trimester.
Other High-Yield Vitamin Deficiencies
Thiamine (B1)
- Dry beri-beri — symmetrical peripheral neuropathy.
- Wet beri-beri — high-output cardiac failure, oedema.
- Wernicke encephalopathy — triad of ophthalmoplegia + ataxia + confusion; give IV thiamine BEFORE glucose in alcoholics (glucose first precipitates Wernicke).
- Korsakoff psychosis — irreversible anterograde amnesia, confabulation. Lesion: mammillary bodies and dorsomedial thalamus.
High-yield: In a malnourished/alcoholic patient, thiamine precedes dextrose, always.
Niacin (B3) — Pellagra
"3 Ds → 4th D": Dermatitis (photosensitive, Casal's necklace), Diarrhoea, Dementia, Death. Causes: maize-based diet, Hartnup disease (tryptophan malabsorption), carcinoid syndrome (tryptophan diverted to serotonin), isoniazid (depletes B6, a niacin precursor cofactor).
Pyridoxine (B6)
- Deficiency: peripheral neuropathy, sideroblastic anaemia, seizures (esp. INH-induced — give prophylactic B6).
- Toxicity also causes a sensory neuropathy — B6 is the rare water-soluble vitamin with a toxic syndrome.
Vitamin C (Ascorbic acid) — Scurvy
Defective collagen hydroxylation (proline/lysine hydroxylase needs vitamin C).
- Perifollicular haemorrhages, corkscrew hairs, swollen bleeding gums, poor wound healing, subperiosteal haemorrhage (painful in children), woody oedema.
High-yield: Scurvy = bleeding gums + perifollicular haemorrhage + corkscrew hair + normal platelet count.
Vitamin A (Retinol)
- Night blindness (nyctalopia) — earliest sign, Bitot's spots, xerophthalmia → keratomalacia (commonest cause of preventable childhood blindness), follicular hyperkeratosis.
- Toxicity: pseudotumour cerebri, teratogenic (avoid in pregnancy).
Vitamin D
- Children: rickets (genu varum, rachitic rosary, widened epiphyses). Adults: osteomalacia (Looser's zones/pseudofractures). Low Ca/PO₄, raised ALP and PTH.
Vitamin E — neurological: ataxia, areflexia, haemolysis (RBC fragility) in neonates.
Vitamin K
- Cofactor for factors II, VII, IX, X + protein C & S. Deficiency → prolonged PT (factor VII has shortest half-life), then aPTT. Haemorrhagic disease of the newborn — prevented by IM vitamin K at birth.
| Vitamin | Classic deficiency syndrome | Hallmark sign |
|---|---|---|
| B1 | Beri-beri / Wernicke–Korsakoff | Ophthalmoplegia, high-output failure |
| B3 | Pellagra | Casal's necklace, 3 Ds |
| B6 | Neuropathy, sideroblastic anaemia | INH-related seizures |
| B9/B12 | Megaloblastic anaemia | Hypersegmented neutrophils |
| C | Scurvy | Corkscrew hair, bleeding gums |
| A | Xerophthalmia | Bitot spots, night blindness |
| D | Rickets/osteomalacia | Looser zones, raised ALP |
| K | Coagulopathy | Prolonged PT |
Key Differentials of Macrocytic Anaemia
Not all macrocytosis is megaloblastic. Non-megaloblastic macrocytosis (normal-looking marrow, no hypersegmentation): alcohol, liver disease, hypothyroidism, reticulocytosis (haemolysis/bleeding), myelodysplastic syndrome, drugs (hydroxyurea, azathioprine, zidovudine).
Flow to a megaloblastic diagnosis: Macrocytic anaemia (MCV >100) → smear shows hypersegmented neutrophils + macro-ovalocytes → check B12 and folate → if borderline, check MMA + homocysteine → MMA high = B12; MMA normal/homocysteine high = folate → identify cause (anti-IF antibody, diet, ileal disease) → treat with correct vitamin, never folate alone if B12 unproven.
Recently asked / exam angle
- Image-based: peripheral smear showing a hypersegmented neutrophil — name it and the underlying deficiency category.
- Distinguishing investigation: "Best test to differentiate B12 from folate deficiency" → serum methylmalonic acid (raised only in B12).
- Spinal cord: SACD involves which tracts? → dorsal columns + lateral corticospinal tracts (spinothalamic spared early).
- Pharmacology link: drug causing megaloblastic anaemia via DHFR inhibition → methotrexate/trimethoprim; rescue with folinic acid (leucovorin), not folic acid.
- Nitrous oxide causing acute B12 functional deficiency / myeloneuropathy — a recurrent anaesthesia–medicine crossover.
- Wernicke sequence: order of thiamine vs glucose in an alcoholic with altered sensorium → thiamine first.
- Schilling test interpretation still appears as a single-line MCQ for pernicious anaemia.
- Pellagra triad and its association with Hartnup disease / carcinoid / isoniazid.
- Pregnancy: dose and timing of folic acid for NTD prevention (400 µg, periconceptional; 5 mg if high-risk).
Rapid revision
- B12 is the only water-soluble vitamin with large stores (liver, 3–5 yr); deficiency neurology is its hallmark.
- Folate deficiency = megaloblastic anaemia with NO neurology (except fetal NTD).
- MMA raised in B12 deficiency, normal in folate; homocysteine raised in both.
- SACD = dorsal columns + lateral corticospinal tracts; absent ankle jerks with extensor plantars.
- Hypersegmented neutrophil = neutrophil with ≥6 lobes — earliest megaloblastic clue.
- Never give folate alone in unproven megaloblastic anaemia — may precipitate SACD.
- B12 absorbed in terminal ileum (needs IF); folate in jejunum.
- Metformin, PPIs, nitrous oxide, Diphyllobothrium latum → B12 deficiency.
- Megaloblastic anaemia = raised LDH + indirect bilirubin + low reticulocytes (ineffective erythropoiesis); watch hypokalaemia on treatment.
- Thiamine before glucose in alcoholics to prevent Wernicke; lesion = mammillary bodies.
- Pellagra = 3 Ds (dermatitis-Casal's necklace, diarrhoea, dementia); causes include Hartnup, carcinoid, INH.
- Scurvy = bleeding gums + corkscrew hair + perifollicular haemorrhage; vitamin A night blindness/Bitot spots; vitamin K → prolonged PT.