Vitamins A, D, C, and B12 - A Comprehensive Overview

Vitamin A (Retinol)

Functions

• Vision: Retinal is the functional form in photoreceptors. It combines with opsin to form rhodopsin in rod cells, which is essential for dim-light vision.
• Immunity: Maintains epithelial integrity; critical for mucosal immune defenses.
• Gene regulation: Retinoic acid acts as a ligand for nuclear receptors (RAR/RXR), regulating cell growth, differentiation, and embryogenesis.
• Skin and epithelium: Maintains the turnover of keratinized and mucus-secreting epithelial cells.

Dietary Sources

Deficiency

• Night blindness (nyctalopia) - earliest sign; impaired rhodopsin regeneration reduces vision in dim light.
• Xerophthalmia - progressive corneal dryness and softening (keratomalacia) leading to blindness.
• Bitot's spots - white keratinized lesions on the conjunctiva.
• Increased susceptibility to infections; impaired bone growth in children.
• Leading cause of preventable blindness in the developing world.

Toxicity (Hypervitaminosis A)

• Activation and hyperplasia of hepatic stellate cells (primary storage site), causing sinusoidal obstruction.
• Perisinusoidal fibrosis -> portal hypertension.
• Liver biopsy: characteristic greenish autofluorescence under UV light; "Swiss cheese" appearance from hypertrophied stellate cells compressing sinusoids.
• Water-soluble/emulsified preparations are up to 10x more toxic than oil-based forms.
• Because the liver half-life is 50 days to 1 year, fibrosis may progress even after stopping supplementation.

Vitamin D (Calciferol)

Synthesis and Metabolism

• Skin: Cholesterol -> 7-dehydrocholesterol -> Vitamin D3 (requires UVB sunlight). Melanin, sunscreen (SPF ≥8), and high latitude reduce this conversion.
• Liver: D2/D3 + Vitamin D-binding protein (DBP) -> 25(OH)D (calcidiol) via CYP27A1. This step is largely unregulated.
• Kidney: Calcidiol -> 1,25(OH)₂D (calcitriol) via CYP27B1. This is the active form and is tightly regulated by PTH, calcium, and phosphate.

Functions

• Promotes intestinal calcium and phosphate absorption.
• Regulates osteoclast activity (bone resorption/remodeling).
• Suppresses PTH secretion from the parathyroid glands.
• Acts on the kidney to enhance calcium reabsorption.
• Immune modulation, muscle function, cell differentiation (extrarenal synthesis).

Deficiency

• Children: Rickets (bowed legs, craniotabes, rachitic rosary).
• Adults: Osteomalacia (bone pain, proximal muscle weakness, fractures), hypocalcemia, tetany, seizures, low bone mineral density, osteoporosis.

Toxicity

Vitamin C (Ascorbic Acid)

Functions

• Antioxidant - scavenges reactive oxygen species; regenerates vitamin E.
• Collagen synthesis - hydroxylates proline and lysine residues (essential for cross-linking); without it, collagen is unstable.
• Promotes non-heme iron absorption in the gut.
• Required for carnitine biosynthesis, dopamine -> norepinephrine conversion (dopamine-beta-hydroxylase), tyrosine catabolism, and peptide hormone synthesis.
• Histone and DNA demethylation (epigenetic role).
• Component of mixed-function oxidase drug-metabolizing systems.

Dietary Sources

Deficiency - Scurvy

• Perifollicular hemorrhages, petechiae, ecchymoses
• Inflamed and bleeding gums (gingivitis)
• Hemorrhage into joints, peritoneal cavity, pericardium, adrenal glands
• Impaired bone growth in children
• Generalized fatigue

Other Uses

• High-dose supplementation may modestly reduce duration of upper respiratory infections.
• Useful in Chediak-Higashi syndrome and osteogenesis imperfecta.
• IV pharmacologic doses (up to 1 g/kg body weight) are under investigation for cancer treatment (metastatic pancreatic, ovarian, glioblastoma, NSCLC) - the mechanism is pro-oxidative, synergistic with gemcitabine and PD-1 inhibitors.

Toxicity

• 2 g in single dose: abdominal pain, diarrhea, nausea.

• Theoretical risk of oxalate kidney stones with chronic high-dose use; avoid in patients with history of oxalate stones or renal insufficiency.
• Possible risk of promoting iron overload in predisposed patients.

Vitamin B12 (Cobalamin)

Functions

• DNA synthesis - cofactor for thymidylate synthesis; deficiency causes megaloblastic anemia.
• Methylation reactions - methylcobalamin is a cofactor for methionine synthase (homocysteine -> methionine). Deficiency raises homocysteine.
• Fatty acid/odd-chain amino acid metabolism - adenosylcobalamin is a cofactor for methylmalonyl-CoA mutase; deficiency raises methylmalonic acid (MMA).
• Nerve myelination - B12 deficiency causes subacute combined degeneration of the spinal cord (posterior and lateral columns).

Absorption

Causes of Deficiency

Clinical Features of Deficiency

• Megaloblastic anemia (macrocytosis, hypersegmented neutrophils)
• Subacute combined degeneration (SCD) - demyelination of dorsal columns (loss of proprioception/vibration) and corticospinal tracts (spasticity, Babinski sign)
• Glossitis, angular stomatitis
• Elevated homocysteine AND methylmalonic acid (both elevated = B12 deficiency; only homocysteine elevated = folate deficiency)
• Neurological symptoms can occur without anemia in B12 deficiency - important clinical pearl.

Treatment

• IM hydroxocobalamin 1 mg/day for severe deficiency or pernicious anemia (since absorption requires IF which is absent).
• Oral high-dose cyanocobalamin (1000-2000 mcg/day) can be effective even without IF via passive diffusion, but IM is standard for pernicious anemia.
• Lifelong treatment required for pernicious anemia and post-total gastrectomy.

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