Fat-soluble vitamins

Shared features

• Absorbed with dietary fat in micelles, which need bile salts and pancreatic lipase; packed into chylomicrons and carried in lymph.
• Stored in liver and fat, so deficiency develops slowly and excess (especially A and D) is toxic; water-soluble vitamins, in contrast, are mostly excreted.
• All four fall together in fat malabsorption: cystic fibrosis, coeliac disease, cholestasis and biliary atresia, chronic pancreatitis, short bowel, orlistat, colestyramine.

Vitamin A (retinol)

• Sources: liver, dairy, egg, fish oils (preformed retinol); β-carotene in yellow, orange and dark-green vegetables, split into retinol in the gut wall.
• Vision: 11-cis retinal combines with opsin to form rhodopsin in rods. Light isomerises it to all-trans retinal, triggering the signal. The retinal pigment epithelium takes up retinol from blood, stores it and regenerates 11-cis retinal, and phagocytoses shed outer segments.
• Epithelium and immunity: retinoic acid acts on nuclear receptors to keep mucous epithelia differentiated; without it they become keratinised (squamous metaplasia), and barrier and immune defences fail.
• Deficiency: night blindness (earliest symptom, as rods need most rhodopsin), then xerophthalmia: conjunctival xerosis, Bitot spots (foamy triangular conjunctival plaques), corneal xerosis, keratomalacia and blindness. Also follicular hyperkeratosis, growth failure and more severe infections. It is the leading preventable cause of childhood blindness.
• Measles: the virus lowers vitamin A levels and deficiency makes measles worse. WHO advises vitamin A to every child with measles (two doses 24 hours apart) because it reduces complications (pneumonia, diarrhoea, corneal damage) and deaths.
• Toxicity: acute headache, vomiting and idiopathic intracranial hypertension; chronic liver damage, bone pain, alopecia, dry skin; strongly teratogenic (isotretinoin causes craniofacial, heart and CNS defects, so contraception is essential). Excess carotene gives yellow skin with white sclerae (harmless carotenaemia).
• Therapeutic use: all-trans retinoic acid in acute promyelocytic leukaemia; retinoids in acne and psoriasis.
• Night blindness in two brothers since childhood suggests an inherited retinal dystrophy such as retinitis pigmentosa, confirmed by electroretinography, rather than diet.

Exam trap Night blindness comes first; Bitot spots and keratomalacia come later.

Vitamin D: synthesis and action

• Cholecalciferol (D3) forms in skin from 7-dehydrocholesterol under UVB; ergocalciferol (D2) comes from plants and fungi.
• Step 1: 25-hydroxylation in the liver gives 25-hydroxyvitamin D, the main circulating and storage form, with a long half-life. This is the form measured to assess vitamin D status.
• Step 2: 1α-hydroxylation in the kidney (proximal tubule) gives calcitriol (1,25-dihydroxyvitamin D), the active hormone. It is stimulated by PTH, low phosphate and low calcium, and inhibited by FGF23 and calcitriol itself.
• Actions: raises intestinal absorption of calcium and phosphate, so both serum calcium and phosphate rise; helps mineralise bone; increases renal calcium reabsorption; suppresses PTH. Calcium and phosphate balance is controlled by PTH, vitamin D and calcitonin together.

Remember Measure 25(OH)D to judge stores; calcitriol is the active form but is short-lived and kept normal by PTH until late.

Rickets and osteomalacia

• Rickets (children, before growth plates fuse): bowed legs or knock knees, rachitic rosary (swollen costochondral junctions), Harrison sulcus, craniotabes, frontal bossing, widened wrists, delayed fontanelle closure and dentition; X-ray shows cupped, frayed, widened metaphyses.
• Osteomalacia (adults): bone pain, proximal myopathy (waddling gait), Looser zones (pseudofractures).
• Biochemistry of nutritional deficiency: calcium low or normal, phosphate low, ALP high, PTH high, 25(OH)D low.
• Causes: little sunlight (covered or dark skin, housebound), poor diet, exclusive breastfeeding without supplements, malabsorption, liver disease, enzyme-inducing anticonvulsants, chronic kidney disease (no 1α-hydroxylation, so give alfacalcidol or calcitriol), and inherited forms.

Rickets that does not respond to vitamin D

• X-linked hypophosphataemic rickets (PHEX mutation, X-linked dominant): excess FGF23 makes the kidney waste phosphate and suppresses calcitriol. Picture: normal calcium, very low phosphate, high urinary phosphate, ALP raised, PTH normal or slightly high. A mother with short stature and bowed legs fits X-linked dominant transmission.
• Treatment is oral phosphate with calcitriol, or the anti-FGF23 antibody burosumab; ordinary vitamin D does not work.
• Vitamin D-dependent rickets type 1 (1α-hydroxylase defect) responds to calcitriol; type 2 (receptor defect, often with alopecia) resists even calcitriol.

Vitamin D excess

• Taking very high doses for months causes hypercalcaemia: thirst, polyuria, constipation, nausea, confusion, renal stones, nephrocalcinosis.
• The main biochemical picture is high calcium with suppressed PTH and very high 25(OH)D; phosphate is often high too. This separates it from primary hyperparathyroidism, where PTH is high.
• Granulomas (sarcoidosis, TB) and some lymphomas contain unregulated 1α-hydroxylase and cause the same picture.

Vitamin E (tocopherol)

• The main lipid-soluble antioxidant, protecting membrane lipids and red cells from peroxidation.
• Deficiency (fat malabsorption, abetalipoproteinaemia, premature babies): haemolytic anaemia, spinocerebellar degeneration (ataxia, loss of position and vibration sense, areflexia), neuropathy, retinopathy. It mimics Friedreich ataxia and B12 deficiency but without megaloblastic anaemia.
• High doses may enhance the effect of warfarin.

Vitamin K

• K1 (phylloquinone) from green leafy vegetables; K2 (menaquinone) is made by intestinal bacteria.
• Function: cofactor for γ-glutamyl carboxylase, which adds a carboxyl group to glutamate residues (γ-carboxylation) of factors II, VII, IX, X and proteins C and S, and osteocalcin. The extra carboxyl groups let these proteins bind calcium and attach to phospholipid surfaces.
• During this reaction vitamin K becomes an epoxide; vitamin K epoxide reductase (VKORC1) recycles it, and warfarin blocks this enzyme.
• Deficiency: bleeding with a prolonged PT first (factor VII has the shortest half-life), then APTT; platelets and bleeding time normal.
• Haemorrhagic disease of the newborn: poor placental transfer, sterile gut and little vitamin K in breast milk; classic bleeding at days 2–7, late form up to six months in exclusively breastfed babies or malabsorption. Prevented by intramuscular vitamin K at birth.
• Other causes: malabsorption, long broad-spectrum antibiotic courses, warfarin. In chronic liver disease the problem is failure to synthesise prothrombin and other factors, so vitamin K corrects the PT only partly.

Exam trap In liver disease a prolonged PT that does not correct with vitamin K shows poor synthesis, not deficiency.

How FCPS asks about this

• Earliest sign of vitamin A deficiency: night blindness; Bitot spots and keratomalacia follow.
• Why vitamin A is given in measles: it reduces complications and deaths.
• Vitamin D metabolite measured in blood: 25-hydroxyvitamin D; active form is 1,25-dihydroxyvitamin D made in the kidney.
• Effect of vitamin D on serum: raises both calcium and phosphate.
• Rickets unresponsive to vitamin D with very low phosphate and normal calcium: X-linked hypophosphataemic rickets (FGF23 excess).
• High-dose vitamin D with thirst, stones and confusion: hypercalcaemia with suppressed PTH.
• Reaction needing vitamin K: γ-carboxylation of factors II, VII, IX, X and proteins C and S; warfarin blocks epoxide reductase.