Fat-Soluble Vitamins
Biochemistry · Vitamins · lean revision notes
Fat-Soluble Vitamins
Vitamins A, D, E and K dissolve in lipids, are absorbed with dietary fat through the lymphatic route, stored in the liver and adipose tissue, and—unlike water-soluble vitamins—accumulate to produce toxicity (hypervitaminosis). For NEET PG this is a high-frequency, easily-scored cluster: learn one absorption story, four function-deficiency-toxicity blocks, and a handful of cut-offs.
Overview and shared properties
All four (A, D, E, K) are absorbed in the proximal small intestine, packaged into chylomicrons, and enter the lymphatics (not portal blood). Their absorption therefore depends on:
- Normal bile salts and pancreatic lipase (fat digestion)
- Intact intestinal mucosa
- A means of fat transport
Consequently, any fat-malabsorption state—chronic pancreatitis, cystic fibrosis, cholestasis/biliary obstruction, coeliac disease, Crohn disease, short-bowel syndrome, abetalipoproteinaemia, or prolonged use of orlistat / cholestyramine / mineral oil—causes a combined deficiency of A, D, E and K.
High-yield: Fat-soluble vitamins are absorbed via chylomicrons into lymph; water-soluble vitamins (except B12) enter portal blood. Fat malabsorption (e.g. cystic fibrosis, cholestasis) → deficiency of all four (ADEK) simultaneously.
| Property | Fat-soluble (A, D, E, K) | Water-soluble (B, C) |
|---|---|---|
| Absorption | With dietary fat, via lymph/chylomicrons | Portal blood (B12 needs IF) |
| Storage | Liver & adipose (large stores) | Minimal (except B12 in liver) |
| Excretion | Bile / faeces (slow) | Urine (rapid) |
| Toxicity | Common (A, D especially) | Rare |
| Deficiency onset | Slow (months–years) | Faster (weeks) |
Mnemonic — "All Dogs Eat Kibble" = the four fat-soluble vitamins A, D, E, K.
Vitamin A (Retinoids and Carotenoids)
Forms and metabolism
- Preformed vitamin A (retinoids): retinol, retinal, retinoic acid — from animal sources (liver, fish-liver oils, egg, dairy).
- Provitamin A (carotenoids): β-carotene from plants (carrots, green leafy vegetables) — cleaved in enterocytes to retinal.
- Stored as retinyl esters in hepatic stellate (Ito) cells; transported in blood bound to Retinol-Binding Protein (RBP) + transthyretin.
Functions (by active form)
- 11-cis-retinal → vision. In rods, 11-cis-retinal binds opsin → rhodopsin. Light isomerises it to all-trans-retinal, triggering the phototransduction cascade. Essential for scotopic (night/dim-light) vision.
- Retinoic acid → gene transcription. Binds nuclear RAR/RXR receptors → controls epithelial differentiation, growth, and embryogenesis. (Analogous to steroid/thyroid hormone action.)
- Retinol/retinal → reproduction and maintenance of mucosal/epithelial integrity, immune function.
High-yield: Wald's visual cycle — 11-cis-retinal + opsin → rhodopsin; the first symptom of vitamin A deficiency is night blindness (nyctalopia).
Deficiency
Vitamin A deficiency (VAD) is the leading cause of preventable childhood blindness globally and a WHO public-health priority.
Stepwise ocular progression (xerophthalmia): Night blindness (nyctalopia) → Conjunctival xerosis → Bitot's spots → Corneal xerosis → Keratomalacia (corneal melting/perforation) → irreversible blindness
- Bitot's spots = foamy, triangular grey plaques of keratinised debris on the bulbar conjunctiva (temporal side) — pathognomonic.
- Follicular hyperkeratosis (phrynoderma, "toad skin") — keratin plugs in hair follicles.
- Increased susceptibility to measles, diarrhoea and respiratory infection (impaired immunity).
WHO prophylaxis (National Programme, India): mega-dose oral vitamin A:
- <6 months: 50,000 IU
- 6–12 months: 100,000 IU
- >12 months: 200,000 IU (repeated 6-monthly)
High-yield: Measles + vitamin A deficiency is a deadly combination; WHO recommends vitamin A for all children with measles. Treatment of xerophthalmia = 200,000 IU on day 1, day 2 and after 2 weeks.
Toxicity (Hypervitaminosis A)
- Acute: nausea, vomiting, raised intracranial pressure (pseudotumour cerebri, bulging fontanelle in infants), headache; classically from eating polar bear liver.
- Chronic: alopecia, dry/peeling skin, hepatotoxicity/cirrhosis, bone/joint pain, hypercalcaemia.
- Teratogenicity: retinoids (isotretinoin, etretinate) cause craniofacial, cardiac and CNS malformations — contraindicated in pregnancy.
- β-carotene is non-toxic (causes only harmless yellow-orange skin = carotenoderma, sparing sclera — distinguishes it from jaundice).
High-yield: Isotretinoin (oral retinoid for acne) is a potent teratogen → mandatory contraception. Excess β-carotene = carotenoderma (skin yellow, sclera/conjunctiva spared), not toxic.
Vitamin D (Calciferol)
Sources and synthesis
- D3 (cholecalciferol) — synthesised in skin when 7-dehydrocholesterol is converted by UV-B light; also from animal foods/fish oils.
- D2 (ergocalciferol) — from plants/fungi.
Activation pathway (two hydroxylations): 7-dehydrocholesterol —(UV-B, skin)→ Cholecalciferol (D3) —(25-hydroxylase, LIVER)→ 25-OH-D₃ (calcidiol) —(1α-hydroxylase, KIDNEY/PCT)→ 1,25-(OH)₂-D₃ (calcitriol = active hormone)
- Renal 1α-hydroxylase is the rate-limiting, regulated step; stimulated by PTH, low phosphate, low calcium; inhibited by FGF-23 and calcitriol itself.
- Best indicator of body vitamin D status = serum 25-OH-D (long half-life). Calcitriol is not used to assess status.
High-yield: Liver does 25-hydroxylation; kidney does 1α-hydroxylation (rate-limiting, PTH-driven). Storage/circulating form = 25-OH-D; active form = 1,25-(OH)₂-D (calcitriol).
Functions
- ↑ Intestinal absorption of calcium and phosphate (via calbindin) — the main action.
- ↑ Bone mineralisation; permits PTH-mediated bone resorption.
- ↑ Renal reabsorption of calcium and phosphate.
- Net effect: raises serum Ca²⁺ and PO₄³⁻ (unlike PTH, which lowers phosphate).
Deficiency
- Children → Rickets: defective mineralisation of growing bone → bowing of legs (genu varum), rachitic rosary, Harrison's sulcus, widened wrists, frontal bossing, craniotabes, delayed fontanelle closure, "double malleoli".
- Adults → Osteomalacia: undermineralised bone → bone pain, proximal myopathy, pseudofractures (Looser's zones / Milkman lines).
- Biochemistry: ↓Ca, ↓PO₄, ↑ALP, ↑PTH (secondary hyperparathyroidism), low 25-OH-D.
| Status | Serum 25-OH-D (ng/mL) |
|---|---|
| Deficiency | < 20 |
| Insufficiency | 20–30 |
| Sufficiency | 30–100 |
| Toxicity | > 100 (often >150) |
High-yield: In nutritional rickets/osteomalacia: low Ca, low phosphate, HIGH alkaline phosphatase. ALP is the earliest and most sensitive marker.
Toxicity (Hypervitaminosis D)
- Hypercalcaemia, hypercalciuria → stones, nephrocalcinosis, polyuria, constipation, "moans, groans, stones, bones", metastatic calcification.
- Caused by excess supplementation, or granulomatous disease (sarcoidosis, TB) and lymphoma where macrophages express unregulated 1α-hydroxylase → high calcitriol.
High-yield: Sarcoidosis causes hypercalcaemia via macrophage 1α-hydroxylase producing extrarenal calcitriol — independent of PTH (which is suppressed).
Vitamin E (Tocopherols)
Form and function
- Most active = α-tocopherol. Found in vegetable oils, nuts, seeds, green leafy vegetables.
- Principal role: lipid-soluble antioxidant — scavenges free radicals/peroxyl radicals in cell membranes and lipoproteins, protecting polyunsaturated fatty acids (PUFA) from peroxidation. Protects RBC membranes.
High-yield: Vitamin E is the body's major membrane antioxidant; vitamin C regenerates oxidised vitamin E. Selenium (glutathione peroxidase) works synergistically.
Deficiency
Rare (large stores); seen in severe fat malabsorption and abetalipoproteinaemia and in premature/low-birth-weight infants.
- Neurological: spinocerebellar ataxia, loss of proprioception/vibration (posterior column), areflexia, peripheral neuropathy, ophthalmoplegia — mimics Friedreich's ataxia.
- Haematological: haemolytic anaemia (RBC membrane fragility), especially in neonates.
- Retinopathy.
High-yield: Vitamin E deficiency → posterior-column/spinocerebellar degeneration + haemolytic anaemia of the newborn. AVED (ataxia with isolated vitamin E deficiency) is due to a mutation in the α-tocopherol transfer protein (α-TTP).
Toxicity
Least toxic fat-soluble vitamin, but high doses antagonise vitamin K → potentiate warfarin → bleeding; high-dose supplements linked to increased haemorrhagic stroke / mortality.
Vitamin K (Phylloquinone & Menaquinone)
Forms
- K1 (phylloquinone) — green leafy vegetables.
- K2 (menaquinone) — synthesised by gut bacteria.
- K3 (menadione) — synthetic, water-soluble; can cause haemolysis in neonates (avoid).
Function — γ-carboxylation
Vitamin K is the cofactor for γ-glutamyl carboxylase, which adds carboxyl groups to glutamate residues (→ Gla residues) on:
- Clotting factors II, VII, IX, X (and proteins C and S)
- Osteocalcin and matrix Gla protein (bone)
The Gla residues chelate Ca²⁺, allowing factors to bind phospholipid membranes. In the reaction, vitamin K is oxidised to its epoxide and recycled by vitamin K epoxide reductase (VKORC1) — the enzyme inhibited by warfarin.
High-yield: Vitamin K–dependent factors = 2, 7, 9, 10 + Protein C & S ("1972 ⇒ 2,7,9,10"). Warfarin inhibits VKOR (epoxide reductase); factor VII has the shortest half-life → PT/INR prolongs first.
Deficiency
- Adults: rare; from malabsorption, prolonged broad-spectrum antibiotics (kill gut flora), warfarin, or liver disease.
- Newborn → Haemorrhagic Disease of the Newborn / Vitamin K Deficiency Bleeding (VKDB): because of low placental transfer, sterile gut and low breast-milk vitamin K → intracranial/GI bleeding.
- Lab: prolonged PT (then aPTT), normal platelets/bleeding time; PIVKA-II (des-γ-carboxy prothrombin) raised.
Prophylaxis: single IM injection of vitamin K1 (phytomenadione) 1 mg to every newborn at birth (0.5 mg if <1500 g).
High-yield: Every newborn gets IM vitamin K1 0.5–1 mg at birth to prevent VKDB. Warfarin (vitamin K antagonist) is teratogenic ("warfarin embryopathy" — nasal hypoplasia, stippled epiphyses) → use heparin in pregnancy.
Reversal / treatment
- Vitamin K (oral/IV) reverses warfarin over hours; for major bleeding give 4-factor PCC (prothrombin complex concentrate) ± vitamin K for immediate correction (FFP if PCC unavailable).
| Vitamin | Active form / cofactor role | Deficiency hallmark | Toxicity hallmark |
|---|---|---|---|
| A | 11-cis-retinal (vision); retinoic acid (RAR/RXR) | Night blindness, Bitot's spots, keratomalacia | Pseudotumour cerebri, teratogenic, hepatotoxic |
| D | 1,25-(OH)₂-D (calcitriol) | Rickets / osteomalacia (↑ALP) | Hypercalcaemia, nephrocalcinosis |
| E | α-tocopherol (antioxidant) | Haemolysis, spinocerebellar ataxia | Bleeding (warfarin potentiation) |
| K | γ-carboxylase cofactor | Bleeding, ↑PT/INR (VKDB in newborn) | Haemolysis (menadione, neonate) |
Diagnosis & investigations of choice
- Vitamin A: serum retinol; dark-adaptation test; conjunctival impression cytology. Bitot's spots = clinical clue.
- Vitamin D: serum 25-OH-D (investigation of choice for status); ALP, Ca, PO₄, PTH; X-ray for rickets (cupping/fraying of metaphysis).
- Vitamin E: plasma α-tocopherol; tocopherol-to-lipid ratio (more accurate); erythrocyte haemolysis test.
- Vitamin K: PT/INR (most sensitive functional test); PIVKA-II.
Management / drug of choice (summary)
- VAD/xerophthalmia → high-dose oral vitamin A (WHO schedule).
- Rickets/osteomalacia → cholecalciferol (replenish) ± calcium; renal failure → calcitriol/alfacalcidol (bypasses defective 1α-hydroxylation); X-linked hypophosphataemic rickets → phosphate + calcitriol (or burosumab, anti-FGF23).
- Vitamin E deficiency → oral/IM α-tocopherol.
- VKDB / warfarin overdose → vitamin K1 (phytomenadione); major bleed → 4-factor PCC.
Complications & key differentials
- Hypervitaminosis A vs pseudotumour cerebri of other causes (tetracyclines, obesity) — both cause raised ICP with papilloedema.
- Carotenoderma vs jaundice — sclera spared in carotenoderma.
- Vitamin D–dependent rickets type I (1α-hydroxylase defect, low calcitriol, responds to calcitriol) vs type II (receptor defect, high calcitriol, alopecia) vs X-linked hypophosphataemic rickets (renal phosphate wasting, normal Ca, high FGF-23).
- Vitamin E deficiency vs Friedreich's ataxia vs B12/copper deficiency (subacute combined degeneration) — overlapping posterior-column signs.
- Vitamin K deficiency vs liver disease — both prolong PT; in liver disease factor V is also low (not vitamin K–dependent) and does not correct with vitamin K, whereas pure vitamin K deficiency corrects.
High-yield: Prolonged PT that corrects with vitamin K = vitamin K deficiency; fails to correct + low factor V = hepatocellular failure.
Recently asked / exam angle
- One-liner image/clinical vignette: child with foamy conjunctival plaques + night blindness → Bitot's spots, vitamin A deficiency.
- Enzyme questions: site of 1α-hydroxylation (kidney/PCT), rate-limiting step of D activation, enzyme inhibited by warfarin (VKOR/epoxide reductase).
- Biochemistry of rickets: classic low Ca, low PO₄, high ALP pattern; identify "Looser's zones".
- "Which vitamin acts via nuclear receptors like a steroid?" → retinoic acid (and vitamin D).
- Vitamin K–dependent factors and the shortest half-life factor VII explaining early PT rise.
- Neonatal MCQ: IM vitamin K at birth dose; menadione causing haemolysis.
- Toxicity pairing: polar bear liver → acute hypervitaminosis A; sarcoid/TB granuloma → vitamin D–mediated hypercalcaemia.
- AVED and α-TTP gene; abetalipoproteinaemia causing E (and A, K) deficiency.
Rapid revision
- ADEK = fat-soluble; absorbed in chylomicrons via lymph; fat malabsorption → all four deficient.
- Vitamin A first symptom = night blindness; pathognomonic sign = Bitot's spots; worst = keratomalacia.
- Retinoic acid & calcitriol act through nuclear (steroid-type) receptors controlling gene transcription.
- Vitamin D: liver = 25-OH, kidney = 1α (rate-limiting, PTH-driven); status marker = serum 25-OH-D.
- Rickets/osteomalacia biochemistry: ↓Ca, ↓PO₄, ↑↑ALP, ↑PTH.
- Sarcoidosis → hypercalcaemia via macrophage extrarenal 1α-hydroxylase.
- Vitamin E = main membrane antioxidant; deficiency → haemolysis + spinocerebellar ataxia (AVED = α-TTP mutation).
- Vitamin K cofactor for γ-carboxylation of factors II, VII, IX, X + protein C, S.
- Warfarin inhibits VKOR; factor VII (shortest t½) → PT/INR rises first; warfarin = teratogen.
- Every neonate gets IM vitamin K1 at birth to prevent VKDB; menadione (K3) avoided (haemolysis).
- β-carotene is non-toxic → carotenoderma with sclera spared (vs jaundice).
- PT corrects with vitamin K = deficiency; doesn't correct + low factor V = liver failure.