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Vitamins - Complete In-Depth Overview

Sources: Guyton & Hall Medical Physiology, Harper's Illustrated Biochemistry (32nd Ed.), Henry's Clinical Diagnosis & Management by Laboratory Methods

Definition & Classification

A vitamin is an organic compound needed in small (microgram to milligram) quantities for health, growth, and reproduction that cannot be synthesized in adequate amounts by the body. With the exception of vitamin D, the body depends completely on dietary intake (some enteric bacterial synthesis of K, niacin, riboflavin, biotin, B12, and folate occurs in the colon but is nutritionally insignificant due to poor absorption).

Vitamins are classified into two major groups based on solubility:

Group	Members	Absorption	Storage
Water-soluble	B1, B2, B3, B5, B6, B7, B9, B12, C	Easily absorbed	Minimal - deficiencies develop quickly (weeks)
Fat-soluble	A, D, E, K	Require bile salts, pancreatic lipase, micellar solubilization	Stored extensively (liver, adipose)

Daily Requirements (Adult Men / Women)

Vitamin	Men	Women
A (Retinol)	900 µg (3000 IU)	700 µg (2333 IU)
B1 (Thiamine)	1.2 mg	1.0 mg
B2 (Riboflavin)	1.3 mg	1.0 mg
B3 (Niacin)	16 mg	14 mg
B5 (Pantothenic acid)	5 mg	5 mg
B6 (Pyridoxine)	1.3 mg	1.3 mg
B9 (Folic acid)	0.4 mg	0.4 mg
B12 (Cobalamin)	2.4 µg	2.4 µg
C (Ascorbic acid)	90 mg	75 mg
D (Calciferol)	15 µg (600 IU)	15 µg (600 IU)
E (Alpha-tocopherol)	15 mg (22.4 IU)	15 mg (22.4 IU)
K	120 µg	90 µg

(- Guyton and Hall Textbook of Medical Physiology, Table 72.3)

FAT-SOLUBLE VITAMINS

Vitamin A (Retinol)

Sources: Animal tissues (as retinol); provitamins (beta-carotene and other carotenoids) from vegetables, converted to retinol in the liver.

Functions:

Forms retinal pigments (rhodopsin) - essential for vision, especially night vision
Maintains normal growth and proliferation of epithelial cells throughout the body
Required for normal reproductive function (germinal epithelium)
Supports immune function ("anti-infection vitamin")

Deficiency:

Feature	Details
Night blindness	Earliest and most specific sign
Xerophthalmia	Keratinization of cornea → corneal opacity → blindness
Skin changes	Scaliness, acne, follicular hyperkeratosis
Growth failure	Cessation of skeletal growth in children
Reproductive failure	Testicular atrophy, interruption of female sexual cycle
Recurrent infections	Keratinization of mucosal surfaces (conjunctiva, urinary tract, respiratory passages)

Storage: Liver stores sufficient for 5-10 months without dietary intake.

Toxicity: Hypervitaminosis A - headache, raised intracranial pressure (pseudotumor cerebri), hepatotoxicity, bone/joint pain, teratogenicity.

Vitamin D (Calciferol)

Sources: Skin synthesis (UV irradiation of 7-dehydrocholesterol → D3), dietary fish oils, fortified foods.

Functions:

Increases calcium absorption from the GI tract (promotes active transport via calcium-binding protein in ileal epithelium)
Controls calcium deposition in bone
Acts as a steroid hormone; receptors in almost every cell

Metabolism: Liver (25-hydroxylation) → Kidney (1-alpha hydroxylation → active 1,25-dihydroxyvitamin D = calcitriol)

Deficiency:

Children: Rickets - failure of bone mineralization, soft bones, bowing of weight-bearing limbs, rachitic rosary, Harrison's sulcus
Adults: Osteomalacia - bone pain, muscle weakness, proximal myopathy, pseudofractures
Hypocalcemia - tetany, carpopedal spasm

Toxicity: Hypercalcemia, hypercalciuria, metastatic calcification, renal stones (D is the most toxic fat-soluble vitamin in excess).

Storage: Liver stores sufficient for 2-4 months.

Vitamin E (Alpha-Tocopherol)

Sources: Vegetable oils, nuts, green leafy vegetables.

Functions:

Major lipid-soluble antioxidant - protects polyunsaturated fatty acids (PUFAs) in cell membranes from oxidative damage
Prevents peroxidation of membrane unsaturated fats - protects mitochondria, lysosomes, and cell membranes
Works synergistically with vitamin C (ascorbate regenerates vitamin E from tocopherol radical)

Deficiency (rare in adults, mainly in premature neonates or fat malabsorption):

Hemolytic anemia in newborns (PUFAs in RBC membranes vulnerable to oxidation)
Spinocerebellar ataxia - degeneration of posterior columns and spinocerebellar tracts
Peripheral neuropathy
Retinopathy
In animals: infertility, fetal resorption ("anti-sterility vitamin")

Toxicity: Low; may antagonize vitamin K function at very high doses.

Vitamin K

Sources: Green leafy vegetables (K1 = phylloquinone); synthesized by gut bacteria (K2 = menaquinone); synthetic K3 = menadione.

Functions:

Essential cofactor for gamma-carboxylation by liver enzyme that carboxylates glutamate residues on:
- Clotting factors: II (prothrombin), VII, IX, X (the "1972" factors)
- Anticoagulant proteins: Protein C, Protein S
- Bone protein: Osteocalcin
Without carboxylation, these proteins are inactive

Deficiency:

Bleeding tendency - prolonged PT, raised INR
Hemorrhagic disease of the newborn (neonates lack gut bacteria + poor placental transfer)
Fat malabsorption (steatorrhea, obstructive jaundice, celiac disease) causes K deficiency
Antibiotics that kill gut flora can reduce K2 production

Drug interaction: Warfarin (and dicumarol) work by antagonizing vitamin K - blocking carboxylation of clotting factors.

Toxicity: K1 and K2 are non-toxic even at high doses. K3 (menadione) can cause hemolytic anemia and neonatal jaundice.

WATER-SOLUBLE VITAMINS

Vitamin B1 - Thiamine

Active form: Thiamine pyrophosphate (TPP) / Thiamine diphosphate (TDP)

Coenzyme roles:

Pyruvate dehydrogenase complex (pyruvate → acetyl-CoA)
Alpha-ketoglutarate dehydrogenase (citric acid cycle)
Branched-chain keto acid dehydrogenase (leucine, isoleucine, valine catabolism)
Transketolase (pentose phosphate pathway)
Thiamine triphosphate activates a chloride channel in nerve membranes (nerve conduction)

Sources: Yeast, legumes, pork, enriched grains. All US breads and flour are enriched with thiamine.

Deficiency - Beriberi and Wernicke-Korsakoff:

Syndrome	Features
Dry beriberi	Peripheral polyneuropathy - depressed reflexes, paresthesias, weakness, muscle atrophy
Wet beriberi	High-output cardiac failure, edema (cardiomegaly, tachycardia)
Shoshin beriberi	Acute fulminating cardiac failure without neuritis
Wernicke encephalopathy	Ataxia, ophthalmoplegia (nystagmus, lateral rectus palsy), confusion (triad)
Korsakoff psychosis	Anterograde amnesia + confabulation; mammillary body lesions
Infantile beriberi	Aphonia/weak cry → sudden cardiac failure

Associated with alcoholism (alcohol impairs thiamine intestinal absorption)
Deficiency leads to elevated lactate and pyruvate (impaired PDH) - lactic acidosis risk in high-carbohydrate diet

Lab assessment: Erythrocyte transketolase activation test (gold standard)

Toxicity: None described from high oral doses.

Vitamin B2 - Riboflavin

Active forms: Flavin Mononucleotide (FMN) and Flavin Adenine Dinucleotide (FAD)

Functions:

Electron carriers in oxidoreduction reactions
Mitochondrial respiratory chain
Fatty acid and amino acid oxidation
Citric acid cycle enzymes
Contributes to oxidant stress via generation of superoxide/H2O2

Sources: Milk, dairy, meat, fish, green vegetables, fortified cereals.

Deficiency:

Widespread globally but not fatal (very efficient tissue conservation)
Cheilosis (cracking/swelling of lips)
Angular stomatitis (cracking at mouth corners)
Magenta tongue / glossitis (deep red, smooth tongue)
Seborrheic dermatitis (greasy scaling of cheeks, behind ears)
Interstitial keratitis (most serious: corneal opacification and ulceration)
Normocytic anemia
Impairs growth in children

Lab assessment: Erythrocyte glutathione reductase activation by FAD added in vitro.

Toxicity: Essentially none - excess rapidly excreted in urine (turns urine bright yellow).

Vitamin B3 - Niacin (Nicotinic acid)

Not strictly a vitamin - can be synthesized from the essential amino acid tryptophan (60 mg tryptophan = 1 mg dietary niacin equivalent).

Active forms: NAD (Nicotinamide Adenine Dinucleotide) and NADP - central to oxidation/reduction reactions in virtually all metabolic pathways.

Additional functions of NAD:

Source of ADP-ribose for ADP-ribosylation of proteins (DNA repair)
Cyclic ADP-ribose acts as intracellular calcium signal

Sources: Meat, fish, poultry, enriched grains. Most niacin in cereals is biologically unavailable.

Deficiency - Pellagra (the "3 Ds" + 1 D):

Dermatitis: photosensitive, symmetrical, in sun-exposed areas (Casal's collar around neck)
Diarrhea
Dementia (depressive psychosis)
(Death) - untreated pellagra is fatal

Pellagra despite adequate intake (secondary):

Hartnup disease: defective membrane transport of tryptophan (intestinal malabsorption + renal loss)
Carcinoid syndrome: tryptophan diverted to serotonin synthesis
Riboflavin or B6 deficiency (both required for tryptophan → niacin conversion)
Women affected twice as often as men (estrogen metabolites inhibit tryptophan metabolism)

Toxicity: Nicotinic acid (not nicotinamide) causes:

Flushing (vasodilation) - prostaglandin-mediated
Hepatotoxicity at pharmacological doses
Used therapeutically to raise HDL and lower triglycerides

Vitamin B5 - Pantothenic Acid

Active form: Component of Coenzyme A (CoA) and Acyl Carrier Protein (ACP)

Functions:

Acetyl-CoA: central role in TCA cycle, fatty acid oxidation and synthesis, cholesterol synthesis
CoA and ACP carry acyl groups in lipid metabolism

Sources: Ubiquitous ("pan-" = everywhere) - liver, adrenals, meat, dairy, eggs, legumes.

Deficiency: Extremely rare - only in severe malnutrition.

"Burning feet syndrome" (seen in malnourished WWII prisoners of war; responded to pantothenate)

Toxicity: None known at dietary levels.

Vitamin B6 - Pyridoxine

Active form: Pyridoxal phosphate (PLP)

Functions:

Coenzyme for transaminases and decarboxylases in amino acid metabolism
Required for synthesis of: heme (delta-aminolevulinic acid synthase), niacin from tryptophan, neurotransmitters (serotonin, dopamine, GABA, norepinephrine)
Glycogen phosphorylase (muscle glycogen metabolism)

Sources: Meat, fish, poultry, potatoes, bananas.

Deficiency:

Sideroblastic anemia (impaired heme synthesis - ringed sideroblasts in bone marrow)
Peripheral neuropathy
Seborrheic dermatitis, cheilosis, glossitis
Convulsions (especially in neonates - reduced GABA synthesis)
Drug-induced deficiency: isoniazid (INH) chelates PLP - give B6 prophylactically with INH

Toxicity: Sensory neuropathy at doses of 2-7 g/day; residual damage even after withdrawal. Neurotoxic at >100-200 mg/day.

Vitamin B7 - Biotin

Active form: Biotin (covalently bound to carboxylase enzymes via lysine)

Functions: Coenzyme for carboxylase enzymes:

Pyruvate carboxylase (pyruvate → oxaloacetate; anaplerosis for TCA cycle)
Acetyl-CoA carboxylase (acetyl-CoA → malonyl-CoA; fatty acid synthesis)
Propionyl-CoA carboxylase (propionate → succinyl-CoA)
Beta-methylcrotonyl-CoA carboxylase (leucine catabolism)

Sources: Widespread in foods; gut bacteria synthesize biotin in colon.

Deficiency (rare):

Absent from TPN formulations
Avidin in raw egg whites binds biotin irreversibly → prevents absorption ("egg white injury")
Symptoms: scaly dermatitis, alopecia (hair loss), glossitis, anorexia, depression, hypercholesterolemia

Toxicity: None known.

Vitamin B9 - Folate (Folic Acid)

Active form: Tetrahydrofolate (THF) - accepts and donates one-carbon units

Functions:

DNA synthesis - provides one-carbon units for purine synthesis and dTMP synthesis (thymidylate synthase)
Amino acid metabolism - serine ↔ glycine interconversion; homocysteine → methionine (with B12)
Neural tube development in early embryogenesis

Sources: Green leafy vegetables (folium = leaf), legumes, fortified grains, liver. Sensitive to cooking and storage.

Deficiency:

Megaloblastic anemia (impaired DNA synthesis in rapidly dividing cells → large, immature RBCs with hypersegmented neutrophils)
Neural tube defects (spina bifida, anencephaly) - if deficient in early pregnancy
Elevated homocysteine (cardiovascular risk)
Unlike B12 deficiency, no neurological symptoms with folate deficiency alone

Key clinical point: Folate supplementation in B12 deficiency can mask megaloblastic anemia while neurological damage from B12 deficiency continues - always check B12 first.

RDA in pregnancy: 0.4 mg/day preconception; 0.6 mg/day during pregnancy; 5 mg/day in high-risk women.

Toxicity: No adverse effects at high oral doses; possible teratogenic effect in rodent model.

Vitamin B12 - Cobalamin

Structure: Cobalt-containing compound with corrin ring. Forms: cyanocobalamin (supplement), hydroxocobalamin, methylcobalamin, adenosylcobalamin.

Only synthesized by microorganisms - found only in foods of animal origin. Strict vegans are at risk.

Absorption (complex process requiring two binding proteins):

Gastric acid + pepsin releases B12 from food proteins
B12 binds haptocorrin (cobalophilin) in saliva
Pancreatic proteases in duodenum release B12 from cobalophilin
B12 binds Intrinsic Factor (IF) secreted by gastric parietal cells
IF-B12 complex absorbed via specific receptors in distal ileum
Significant enterohepatic circulation - liver stores ~2-5 mg (lasts 2-3 years)

Functions - Two B12-dependent enzymes:

Methylmalonyl-CoA mutase (methylmalonyl-CoA → succinyl-CoA; requires adenosylcobalamin)
- Deficiency → elevated methylmalonic acid (MMA) in blood/urine
Methionine synthase (homocysteine → methionine; requires methylcobalamin; regenerates THF from methyl-THF)
- The "methyl trap" hypothesis: B12 deficiency traps folate as methyl-THF → functional folate deficiency → megaloblastic anemia

Deficiency causes:

Cause	Mechanism
Pernicious anemia	Autoimmune destruction of parietal cells → no intrinsic factor
Strict veganism	No dietary B12
Gastrectomy	No IF secreted
Ileal disease/resection	No absorption site
Pancreatic insufficiency	Cobalophilin not cleaved → B12 not released to bind IF
Metformin use	Reduces B12 absorption
Fish tapeworm (Diphyllobothrium)	Competes for B12

Deficiency effects:

Megaloblastic anemia (macro-ovalocytes, hypersegmented neutrophils)
Subacute combined degeneration of spinal cord (SACD) - demyelination of posterior columns and corticospinal tracts → loss of vibration/proprioception, spastic paraparesis
Peripheral neuropathy
Glossitis (smooth "beefy red" tongue - Hunter's glossitis)
Elevated MMA and homocysteine (distinguishes from folate deficiency, which has only elevated homocysteine)

Toxicity: None appreciable.

Vitamin C - Ascorbic Acid

Functions:

Essential cofactor for alpha-ketoglutarate-dependent dioxygenases, especially:
- Prolyl hydroxylase and lysyl hydroxylase - collagen crosslinking and stability
- Dopamine beta-hydroxylase (dopamine → norepinephrine)
- HIF-1 alpha regulation (tumor, energy metabolism)
Antioxidant - free radical scavenging; regenerates vitamin E (reduces tocopherol radical)
Enhances non-heme iron absorption (reduces Fe3+ → Fe2+ in gut)
Immune function and wound healing

Sources: Citrus fruits, berries, kiwi, tomatoes, peppers, vegetables. Destroyed by prolonged storage and overcooking.

Deficiency - Scurvy (develops after ~20-30 weeks without intake):

Feature	Mechanism
Bleeding gums, loose teeth	Defective collagen → periodontal tissue breakdown
Perifollicular hemorrhages, petechiae, purpura	Defective capillary wall collagen
Poor wound healing	No collagen fibril deposition
Corkscrew hairs	Abnormal hair follicle structure
Swollen, painful joints	Subperiosteal hemorrhage
Bone pain and fractures	Cessation of bone growth, failure to ossify fractures
Anemia	Blood loss + impaired iron absorption
Muscle weakness, fatigue	Muscle cell fragmentation
Cerebral hemorrhage	Vessel wall fragility (can be fatal)

At-risk populations: Elderly with poor diet, alcoholics, infants on unsupplemented formula.

Toxicity:

Chronic megadoses (1-15 g/day) → diarrhea, nausea, abdominal cramps, kidney stones (oxalate)
Abrupt cessation of megadoses → rebound scurvy (metabolism accelerated, stores rapidly depleted)

MASTER SUMMARY TABLE

Vitamin	Key Coenzyme/Function	Classic Deficiency	At-Risk Population	Toxicity
A	Retinal pigments, epithelial growth	Night blindness, xerophthalmia, keratomalacia	Developing nations, fat malabsorption	Pseudotumor cerebri, teratogenicity
D	Calcium/phosphorus homeostasis	Rickets (child), osteomalacia (adult)	Low sun exposure, dark skin, elderly	Hypercalcemia, nephrocalcinosis
E	Antioxidant, protects PUFAs	Hemolytic anemia (neonate), spinocerebellar ataxia	Premature neonates, fat malabsorption	Low; antagonizes vitamin K
K	Carboxylation of clotting factors II, VII, IX, X	Bleeding, prolonged PT	Newborns, antibiotic use, fat malabsorption	K1/K2 safe; K3 hemolytic
B1	TPP - PDH, alpha-KG-DH, transketolase	Beriberi (wet/dry), Wernicke-Korsakoff	Alcoholics, malnutrition	None
B2	FMN, FAD - redox reactions	Cheilosis, glossitis, seborrheic dermatitis, keratitis	Malnutrition, alcoholics	None
B3	NAD, NADP - redox	Pellagra (3 Ds: dermatitis, diarrhea, dementia)	Corn-based diets, Hartnup, carcinoid	Flushing, hepatotoxicity (nicotinic acid)
B5	CoA, ACP - acyl transfer	Burning feet syndrome	Severe malnutrition	None
B6	PLP - transamination, decarboxylation	Sideroblastic anemia, neuropathy, seizures	INH therapy, alcoholics	Sensory neuropathy (>200 mg/d)
B7	Carboxylases	Dermatitis, alopecia, depression	Raw egg whites, TPN without biotin	None
B9	THF - 1-carbon transfer, DNA synthesis	Megaloblastic anemia, neural tube defects	Pregnant women, alcoholics, poor diet	None appreciable
B12	MMA mutase, methionine synthase	Megaloblastic anemia + SACD (subacute combined degeneration)	Vegans, pernicious anemia, elderly	None
C	Hydroxylation reactions, antioxidant	Scurvy	Elderly, alcoholics, food insecurity	Kidney stones, rebound scurvy

Key Clinical Associations to Remember

Fat-soluble vitamins (A, D, E, K): Deficiencies occur together in fat malabsorption states (celiac disease, Crohn's, cystic fibrosis, obstructive jaundice, chronic pancreatitis, bariatric surgery).

B12 vs. Folate differentiation:

Both cause megaloblastic anemia and elevated homocysteine
Only B12 deficiency causes neurological disease (SACD) and elevated methylmalonic acid
Folate supplementation can mask B12 deficiency anemia while neurological damage progresses

Alcoholism: Depletes B1 (Wernicke), B2, B3, B6, folate, and C.

Isoniazid (INH) for TB: Causes B6 deficiency → give pyridoxine 25-50 mg/day.

Newborns: Vitamin K given at birth (prophylaxis for hemorrhagic disease); Vitamin D supplementation for breastfed infants.

Warfarin mechanism: Antagonizes vitamin K-dependent carboxylation of clotting factors.

Pernicious anemia triad: Autoimmune gastritis → anti-parietal cell + anti-intrinsic factor antibodies → B12 deficiency → megaloblastic anemia + SACD.

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