Vitamins — Fat-Soluble

Vitamin A (Retinol)

• Functions as 11-cis retinal in visual pigment rhodopsin; required for photon absorption in retinal photoreceptors and conversion to electrical impulses
• Acts as a retinoic acid ligand for nuclear receptors (RAR, RXR) regulating gene transcription for epithelial cell differentiation, immune function, and spermatogenesis
• Absorption requires dietary fat and micelle formation; stored primarily in hepatic stellate cells; deficiency impairs dark adaptation before overt blindness occurs
• Excessive intake causes hypervitaminosis A with teratogenic effects (cleft palate, cardiac defects, CNS malformations); accumulates in liver causing cirrhosis

Vitamin D (Calciferol)

• Synthesized in skin from 7-dehydrocholesterol upon UVB exposure OR obtained from diet (cholecalciferol, ergocalciferol); undergoes sequential 25-hydroxylation in liver and 1-alpha hydroxylation in kidney to form active 1,25-dihydroxyvitamin D
• Functions as a steroid hormone via vitamin D receptor (VDR) in intestine, bone, kidney, parathyroid, and immune cells to regulate calcium and phosphate homeostasis
• Increases intestinal calcium/phosphate absorption; enhances osteoclast resorption; suppresses PTH secretion; modulates immune tolerance and innate immunity
• Deficiency results in secondary hyperparathyroidism, impaired mineralization, and systemic complications

Vitamin E (Tocopherol)

• Acts as a lipophilic antioxidant within cell membranes, protecting polyunsaturated fatty acids from free radical oxidation and lipid peroxidation
• Regenerated by vitamin C and coenzyme Q10; plays roles in immune function, endothelial function, and neurologic protection
• Absorption enhanced by fat; stored in adipose tissue and cell membranes; deficiency rare except in severe malabsorption or abetalipoproteinemia
• Excessive supplementation increases bleeding risk and may impair bone health; no established toxicity threshold unlike other fat-soluble vitamins

Vitamin K (Phylloquinone/Menaquinone)

• Functions as an electron acceptor in gamma-carboxylation of glutamic acid residues on vitamin K-dependent clotting factors (II, VII, IX, X) and proteins C and S
• Gamma-carboxylation allows these proteins to bind calcium and membrane phospholipids, essential for coagulation cascade assembly on activated platelet surfaces
• Cycle: reduced vitamin K (hydroquinone) → oxidized form (epoxide) → regeneration by epoxide reductase (warfarin's target); dietary sources (leafy greens, plant oils) supplement gut bacterial synthesis
• Deficiency causes impaired prothrombin time (PT), increased bleeding, and can manifest as hemorrhagic disease of the newborn (HDNB)

Vitamin A Deficiency

• Night blindness (nyctalopia) — earliest sign; impaired dark adaptation due to insufficient 11-cis retinal; reversible with supplementation
• Xerophthalmia — drying of conjunctiva and cornea; progresses to Bitot's spots (foamy, triangular patches on conjunctiva), corneal scarring, and irreversible blindness
• Follicular hyperkeratosis — goose-skin appearance; impaired epithelial cell differentiation affecting skin, respiratory, and urinary tract integrity
• Increased susceptibility to infections — especially respiratory and measles; impaired immune response and epithelial barrier function
• Clinical pearl: Night blindness is reversible and occurs first; corneal involvement represents advanced disease with risk of permanent blindness

Vitamin A Toxicity (Hypervitaminosis A)

• Acute toxicity: headache, vomiting, abdominal pain, dizziness, visual blurring occurring within hours of massive dose ingestion
• Chronic toxicity: alopecia, dry skin/mucous membranes, bone pain, hepatosplenomegaly, cirrhosis, elevated intracranial pressure (pseudotumor cerebri)
• Teratogenicity — absolute contraindication in pregnancy; associated with cleft palate, cardiac defects, CNS malformations, thymic hypoplasia
• Clinical pearl: Isotretinoin (13-cis retinoic acid) is a potent teratogen requiring iPLEDGE program with strict contraception

Vitamin D Deficiency (Rickets and Osteomalacia)

• Rickets (in children): impaired mineralization of growth plate; presents with skeletal deformities (bow legs, Harrison's groove), frontal bossing, delayed fontanelle closure, dental enamel hypoplasia, rachitic rosary (costochondral beading)
• Osteomalacia (in adults): bone pain, muscle weakness, proximal myopathy; increased fracture risk; radiographic Looser's zones (pseudofractures)
• Biochemical abnormalities: ↓ calcium, ↓ phosphate, ↑↑ PTH (secondary hyperparathyroidism), ↑ alkaline phosphatase; 25-OH vitamin D < 20 ng/mL diagnostic
• Extraskeletal manifestations: fatigue, depression, increased infection risk, immune dysfunction; possible association with autoimmune diseases
• Clinical pearl: Hypocalcemia causes tetany, paresthesias, and seizures; Looser's zones are pathognomonic radiographic finding

Vitamin D Toxicity (Hypervitaminosis D)

• Hypercalcemia — primary manifestation causing polyuria, polydipsia, nephrogenic diabetes insipidus, renal insufficiency, nephrolithiasis
• Anorexia, nausea, vomiting, constipation, lethargy, confusion, arrhythmias from severe hypercalcemia
• Band keratopathy, metastatic calcification (kidney, heart, vessels) with chronic toxicity

Vitamin E Deficiency

• Rare; primarily seen in severe malabsorption (cystic fibrosis, celiac disease) or abetalipoproteinemia (no apoB-containing lipoproteins)
• Neurologic manifestations: progressive spinocerebellar degeneration, peripheral neuropathy, ataxia, ophthalmoplegia, loss of proprioception and vibration sense
• Hemolytic anemia from RBC membrane oxidative damage (especially in premature infants)
• Clinical pearl: Abetalipoproteinemia presents with fat malabsorption + neurologic symptoms + acanthocytosis

Vitamin K Deficiency

• Bleeding diathesis: spontaneous bleeding (epistaxis, GI bleeding, hematuria), easy bruising, ecchymosis; bleeding from trivial trauma
• Hemorrhagic disease of the newborn (HDNB): presents day 1–7 (classic) or day 1–3 months (late form) with intracranial hemorrhage, GI bleeding, skin bleeding
• Causes: malabsorption, broad-spectrum antibiotics (eliminate gut flora), warfarin use, dietary deficiency (TPN without K), liver disease
• Clinical pearl: Late HDNB (week 2–3 months) associated with exclusive breastfeeding (breast milk low in vitamin K) and absence of prophylaxis

Vitamin A

• **Serum retinol < 20 μ

Buzzwords that give away the answer

• **Night blindness + *Bitot's spots***: vitamin A deficiency; nyctalopia precedes corneal damage because 11-*cis* retinal is depleted before epithelial keratinization occurs. The AAP and WHO recommend vitamin A supplementation for children with measles, where deficiency drives mortality.
• Ataxia + loss of proprioception/vibration with a normal B12 level: vitamin E deficiency. It mimics subacute combined degeneration but there is no megaloblastic anemia and methylmalonic acid/homocysteine are normal — the classic distractor. Think abetalipoproteinemia if acanthocytes plus fat malabsorption are also present.
• Isolated prolonged PT that corrects on mixing study: vitamin K deficiency or warfarin effect. PT rises first because factor VII has the shortest half-life; severe deficiency later prolongs aPTT as well.

Single best next step

• Order 25-hydroxyvitamin D, not 1,25-dihydroxyvitamin D, to assess vitamin D status — 25-OH-D reflects total stores, while 1,25-(OH)₂D is PTH-driven and may be normal or high in deficiency. The Endocrine Society reserves 1,25-(OH)₂D testing for granulomatous disease, lymphoma, and hereditary rickets.
• All newborns receive intramuscular vitamin K₁ (phytonadione) 1 mg at birth (AAP). Parental refusal is the setup for late hemorrhagic disease of the newborn with intracranial hemorrhage in an exclusively breastfed infant at 2 weeks–3 months.
• Major warfarin-associated bleeding: give IV vitamin K plus four-factor prothrombin complex concentrate (ACC expert consensus / CHEST antithrombotic guidance). Vitamin K alone works too slowly because carboxylated factors must be resynthesized.

The association examiners love

• **All-*trans* retinoic acid** in acute promyelocytic leukemia (t(15;17), PML-RARα) — watch for differentiation syndrome.
• Hypervitaminosis A: pseudotumor cerebri, alopecia, hepatotoxicity, and teratogenicity; isotretinoin requires iPLEDGE contraception.

Distractors to avoid

• In advanced CKD, renal 1-α-hydroxylase fails, so ergocalciferol will not correct hypocalcemia — an active analog such as calcitriol is required (KDIGO CKD-MBD).
• Vitamin D toxicity causes hypercalcemia with suppressed PTH; deficiency causes hypocalcemia with elevated PTH.
• USPSTF found evidence insufficient to screen asymptomatic adults for vitamin D deficiency.