Vitamins: Water & Fat Soluble
Cofactors, deficiency syndromes, and toxicities
Water-soluble vs fat-soluble
Water-soluble (B complex and C). B1, B2, B3, B5, B6, B7, B9 (folate), B12, and C are poorly stored and wash out in urine, so deficiencies are common and toxicity is rare. The exceptions to washout are B12 and folate, which are stored in the liver (B12 stores last years; folate stores only months).
Fat-soluble (A, D, E, K). Absorption requires bile and intact fat digestion, and these vitamins accumulate in fat, so toxicity is more common. Deficiencies accompany fat malabsorption such as cystic fibrosis and celiac disease.
B vitamins and vitamin C
| Vitamin | Active form / role | Deficiency | Classic causes / notes |
|---|---|---|---|
| B1 thiamine | TPP: PDH, α-KG dehydrogenase, transketolase, branched-chain ketoacid dehydrogenase | Wernicke-Korsakoff, beriberi | Alcoholism, malnutrition; give before glucose |
| B2 riboflavin | FAD, FMN (redox reactions) | Cheilosis, corneal vascularization (the 2 C's) | Malnutrition |
| B3 niacin | NAD+, NADP+; can be made from tryptophan (needs B6) | Pellagra: diarrhea, dermatitis (Casal necklace), dementia | Hartnup disease, carcinoid syndrome, isoniazid; excess causes flushing |
| B5 pantothenate | Coenzyme A | Dermatitis, enteritis, alopecia (rare) | Rarely deficient |
| B6 pyridoxine | PLP: transamination, decarboxylation, ALA synthase (heme), neurotransmitter synthesis | Peripheral neuropathy, convulsions, sideroblastic anemia | Isoniazid, oral contraceptives |
| B7 biotin | Carboxylases (pyruvate, acetyl-CoA, propionyl-CoA) | Dermatitis, alopecia, enteritis (rare) | Large amounts of raw egg white (avidin), antibiotics |
| C ascorbic acid | Hydroxylates proline and lysine in collagen; reduces Fe3+ to Fe2+ for absorption; dopamine → norepinephrine | Scurvy | Poor diet (tea-and-toast) |
Thiamine and the alcoholic patient. Deficiency causes Wernicke encephalopathy — confusion, ophthalmoplegia, and ataxia, with damage to the mammillary bodies — which can progress to Korsakoff syndrome, adding confabulation and memory loss. Beriberi comes in a dry form (symmetric peripheral neuropathy with muscle wasting) and a wet form (dilated cardiomyopathy with high-output heart failure and edema).
Give thiamine BEFORE glucose: a glucose load consumes the remaining thiamine and can precipitate acute Wernicke encephalopathy.
Niacin. Carcinoid syndrome diverts tryptophan into serotonin, Hartnup disease blocks tryptophan absorption, and isoniazid depletes the B6 needed to convert tryptophan into niacin — all three can cause pellagra. High-dose niacin used for dyslipidemia causes facial flushing.
Scurvy. Without vitamin C, prolyl and lysyl hydroxylases cannot stabilize the collagen triple helix: swollen, bleeding gums, perifollicular hemorrhages, corkscrew hairs, poor wound healing, and easy bruising.
Folate vs B12
A shared pathway. Folate (as tetrahydrofolate, THF) carries one-carbon units for DNA synthesis. B12 (cobalamin) is the cofactor for methionine synthase, which moves a methyl group from methyl-THF to homocysteine, regenerating THF and methionine. B12 also serves methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA. Either deficiency stalls DNA synthesis and causes megaloblastic anemia, but only B12 deficiency raises methylmalonic acid (MMA) and damages myelin.
| Feature | Folate deficiency | B12 deficiency |
|---|---|---|
| Common causes | Alcoholism, pregnancy, methotrexate, phenytoin, trimethoprim | Pernicious anemia, ileal disease, Diphyllobothrium latum, vegan diet |
| Blood | Macrocytic megaloblastic anemia, hypersegmented neutrophils | Same |
| Neurologic | None | Subacute combined degeneration: dorsal columns, lateral corticospinal and spinocerebellar tracts |
| Homocysteine | ↑ | ↑ |
| Methylmalonic acid | Normal | ↑ |
Periconceptional folate prevents fetal neural tube defects. Folate given alone to a B12-deficient patient can correct the anemia while the neurologic damage progresses.
Fat-soluble vitamins
| Vitamin | Key roles | Deficiency | Excess / clinical use |
|---|---|---|---|
| A (retinol/retinal) | Vision, epithelial differentiation, immunity | Night blindness, dry eyes, Bitot spots | Teratogen (isotretinoin), pseudotumor cerebri; used for measles and APL |
| D (calcitriol) | ↑ intestinal Ca and phosphate absorption; bone mineralization | Rickets (children), osteomalacia (adults) | Hypercalcemia; excess production in sarcoidosis |
| E (tocopherol) | Antioxidant protecting RBC membranes and neurons | Hemolytic anemia; posterior column and spinocerebellar syndrome | Potentiates warfarin |
| K | γ-Carboxylation of factors II, VII, IX, X and proteins C and S | Bleeding, including neonatal hemorrhage | Given to reverse warfarin |
Vitamin A. All-trans retinoic acid (ATRA) is the treatment for acute promyelocytic leukemia (APL; AML M3, t(15;17)).
Vitamin D activation. Serum 25-OH D, the storage form, is what is measured to judge vitamin D status. In sarcoidosis and other granulomatous diseases, macrophages carry out the 1α-hydroxylation themselves, producing excess calcitriol and hypercalcemia.
- Skin: 7-dehydrocholesterol → D3Requires UV light
- Diet: D2 or D3Absorbed in the gut
- Liver: 25-hydroxylase25-OH D, the storage form
- Kidney: 1α-hydroxylase1,25-(OH)2 D (calcitriol), the active form; stimulated by PTH
Vitamin E. Deficiency mimics B12 deficiency neurologically (posterior columns, spinocerebellar tracts) but WITHOUT megaloblastic anemia or a raised MMA — and it adds hemolysis.
Vitamin K. It is the cofactor for γ-glutamyl carboxylase; epoxide reductase recycles it and is warfarin's target. Newborns have sterile guts and low vitamin K stores, so without prophylaxis they can bleed (intracranial, umbilical) with both PT and PTT prolonged — hence IM vitamin K at birth. Long courses of broad-spectrum antibiotics can also cause deficiency.