Water-soluble vitamins

Why these vitamins matter

• Water-soluble vitamins are mostly coenzymes that are not stored for long and are lost in urine, so deficiency appears within weeks to months. B12 is the exception: liver stores last 3–5 years.
• Each deficiency syndrome makes sense once you know which reaction stops: tissues with high turnover (marrow, gut, skin) or high energy use (nerve, heart) fail first.

• Pyruvate dehydrogenase (and α-ketoglutarate dehydrogenase) needs five cofactors: thiamine (B1), lipoic acid, CoA (B5), FAD (B2) and NAD (B3). Biotin is not one of them: biotin serves carboxylases, which add CO₂ (acetyl-CoA to malonyl-CoA; pyruvate to oxaloacetate).

Remember Decarboxylating dehydrogenases use thiamine; carboxylases use biotin; transaminases use B6.

Thiamine (B1)

• TPP is needed to feed glucose carbon into the Krebs cycle (PDH, α-KGDH) and for the pentose phosphate pathway (transketolase). Without it, glucose-dependent brain and heart cannot make enough ATP, and lactate rises.
• Causes: alcoholism (poor intake and absorption), diets of polished rice, hyperemesis gravidarum, prolonged vomiting, bariatric surgery, refeeding. Raw fish and shellfish contain thiaminase, which destroys thiamine; tea and betel nut contain anti-thiamine factors.
• Dry beriberi: symmetrical sensorimotor neuropathy, burning feet, wasting. Wet beriberi: vasodilatation causing high-output heart failure and oedema (a cause of dilated cardiomyopathy).
• Wernicke encephalopathy: confusion, ophthalmoplegia (nystagmus, lateral rectus palsy) and ataxia; lesions in the mammillary bodies, medial thalamus and periaqueductal grey. Give IV thiamine before glucose, because glucose drives the remaining thiamine into use and can precipitate it.
• Korsakoff syndrome: anterograde and retrograde amnesia with confabulation; often permanent.
• Thiamine status is best assessed by red cell transketolase activity (and its rise when TPP is added).

Exam trap A fisherman on raw fish and polished rice with neuropathy and oedema has thiamine deficiency from thiaminase, not B12 deficiency.

Riboflavin (B2) and niacin (B3)

• Riboflavin deficiency affects rapidly turning-over surfaces: angular stomatitis, cheilosis, glossitis, corneal vascularisation, seborrhoeic dermatitis, normocytic anaemia.
• Niacin can be made from tryptophan (60 mg tryptophan gives 1 mg niacin; needs B2 and B6).
• Pellagra: dermatitis in sun-exposed skin (Casal necklace), diarrhoea, dementia, and death.
• Causes: maize diets (niacin bound, low tryptophan), Hartnup disease (defective neutral amino acid transport, including tryptophan), carcinoid syndrome (tryptophan diverted to serotonin), isoniazid (blocks B6, needed to make niacin), alcoholism.
• Pharmacological niacin is the most effective drug for raising HDL and lowers triglycerides and LDL; it causes flushing (prostaglandin-mediated, reduced by aspirin), hyperglycaemia and hyperuricaemia.

Pyridoxine (B6)

• Pyridoxal phosphate is the cofactor for transamination, decarboxylation to neurotransmitters (GABA, serotonin, dopamine, histamine), ALA synthase (first step of haem) and cystathionine β-synthase.
• Deficiency from isoniazid (give pyridoxine prophylaxis), penicillamine, hydralazine, alcohol: peripheral neuropathy, seizures (low GABA; pyridoxine-dependent seizures in neonates), sideroblastic anaemia, glossitis.
• Very high doses cause sensory neuropathy.

Folate (B9)

• Green leafy vegetables, liver, pulses; destroyed by prolonged cooking; absorbed in the jejunum; stores last only about 3–4 months.
• Folate is needed to make thymidine (dTMP), so without it DNA synthesis stalls while RNA and protein synthesis continue: large cells with immature nuclei (megaloblasts).
• Causes: poor diet (elderly, alcohol), increased demand (pregnancy, haemolysis, malignancy), malabsorption (coeliac), and drugs: methotrexate and trimethoprim (dihydrofolate reductase inhibitors), phenytoin, sulfasalazine. Folate deficiency is the commonest cause of megaloblastic anaemia overall.
• Neural tube defects: folic acid 400 µg daily from before conception to 12 weeks; 5 mg for high risk (previous NTD, antiepileptics, diabetes, BMI over 30, sickle cell).

Vitamin B12 (cobalamin)

• Found only in animal foods, so strict vegans are at risk.
• Absorption: acid and pepsin release B12 from food; it binds haptocorrin in the stomach; pancreatic proteases free it in the duodenum; it binds intrinsic factor from parietal cells; the complex is absorbed in the terminal ileum.
• Causes: pernicious anaemia (autoimmune gastritis; anti-intrinsic factor and anti-parietal cell antibodies; raised gastric cancer risk), gastrectomy, terminal ileal resection or Crohn disease, the fish tapeworm *Diphyllobothrium latum*, bacterial overgrowth, metformin, long-term PPIs, nitrous oxide.
• Methionine synthase uses B12 and methyl-THF; when it fails, folate is trapped as methyl-THF (the folate trap), so megaloblastic anaemia develops. Methylmalonyl-CoA mutase failure raises methylmalonic acid and disturbs myelin fatty acids.
• Subacute combined degeneration: dorsal columns (lost vibration and position sense) and lateral corticospinal tracts (weakness, extensor plantars with absent ankle jerks), plus neuropathy, dementia, optic atrophy.
• Folate given alone in B12 deficiency can correct the blood picture while neurological damage advances; give IM hydroxocobalamin first.

Exam trap Both deficiencies raise homocysteine; only B12 deficiency raises methylmalonic acid.

Megaloblastic anaemia not due to B12 or folate

• Hereditary orotic aciduria: defect of UMP synthase in pyrimidine synthesis; megaloblastic anaemia unresponsive to B12 and folate, orotic acid in urine, normal ammonia, poor growth. Treated with uridine, which bypasses the block.
• Ornithine transcarbamylase deficiency also causes orotic aciduria, but with hyperammonaemia and no megaloblastic anaemia.
• Drugs that block DNA synthesis (hydroxycarbamide, azathioprine, zidovudine) also cause macrocytosis.

Vitamin C (ascorbic acid)

• Humans cannot make it (no gulonolactone oxidase).
• Roles: hydroxylation of proline and lysine in collagen (keeps iron in prolyl hydroxylase in the Fe²⁺ state), dopamine β-hydroxylase (dopamine to noradrenaline), carnitine synthesis, iron absorption (reduces ferric to ferrous iron), antioxidant.
• Scurvy: perifollicular haemorrhages, corkscrew hairs, swollen bleeding gums, poor wound healing, bruising, anaemia, subperiosteal bleeding; infants on boiled milk have painful legs. Seen in alcoholics and elderly people who eat no fruit or vegetables.
• High doses increase oxalate stones.
• Biotin deficiency is rare but occurs with excess raw egg white (avidin binds biotin).

How FCPS asks about this

• Cofactor group of thiamine pyrophosphate: PDH, α-ketoglutarate dehydrogenase and transketolase; transketolase activity measures thiamine status.
• Raw fish and polished rice with burning feet and oedema: thiamine deficiency; raw fish contains thiaminase.
• Corneal vascularisation with angular stomatitis: riboflavin deficiency.
• Dermatitis, diarrhoea, dementia: niacin deficiency; think carcinoid, Hartnup, isoniazid, maize.
• Vitamin before conception to prevent neural tube defects: folic acid 400 µg (5 mg if high risk).
• Megaloblastic anaemia with neurology and raised methylmalonic acid: B12 deficiency; folate alone worsens the neurology.
• Megaloblastic anaemia unresponsive to B12 and folate with orotic aciduria and normal ammonia: hereditary orotic aciduria; treat with uridine.