Fat-Soluble Vitamins: Complete Study Guide

VITAMIN A (Retinol)

Forms & Sources

• Retinol (animal sources: liver, dairy, eggs) and provitamin A carotenoids (plant sources: β-carotene in orange/yellow vegetables)
• Absorbed in the proximal small bowel; stored extensively in the liver
• Circulates bound to retinol-binding proteins (RBP)

Functions

Deficiency - Clinical Features

• Night blindness (nyctalopia) - earliest sign
• Xerophthalmia - xerosis (dryness) of conjunctiva and cornea
• Bitot's spots - foamy white plaques on conjunctiva (pathognomonic)
• Keratomalacia - corneal ulceration and softening → blindness
• Follicular hyperkeratosis (phrynoderma) - keratotic papules on skin
• Increased susceptibility to infections (measles can precipitate acute deficiency)

Treatment (Harrison's 2025)

• Any stage of xerophthalmia: 200,000 IU (60 mg) orally, repeated at day 1 and day 14
• For infants 6-11 months: half dose (100,000 IU)
• Children hospitalized with measles: two 60 mg doses on 2 consecutive days
• Prevention in at-risk children 6-59 months: supplementation every 4-6 months

Toxicity (Hypervitaminosis A)

• Acute (>150 mg adults / >100 mg children): increased intracranial pressure, vertigo, diplopia, bulging fontanels (infants), seizures, exfoliative dermatitis
• Chronic: hepatotoxicity, bone pain, alopecia, dry skin, teratogenicity (most important - causes neural tube defects)
• Carotenemia: yellowing of skin (palms/soles) but NOT sclerae - from excess carotenoid intake >30 mg/day; benign, resolves in 30-60 days
• Note: Smokers should avoid high-dose β-carotene supplements (increased lung cancer risk)

Clinical Applications

• Retinoic acid (ATRA) - treatment of acute promyelocytic leukemia (APL)
• Isotretinoin (13-cis-retinoic acid) - treatment of cystic acne (inhibits keratinization, reduces sebum)
• Differentiate carotenemia (no scleral icterus) from jaundice (sclerae are yellow)

VITAMIN D (Calciferol)

Forms & Activation (the 2-step hydroxylation)

Skin (UV-B 290-320 nm)
  → Cholecalciferol (D₃, inactive)
    → LIVER (25-hydroxylase)
      → 25(OH)D₃ [main circulating form, used for assessment]
        → KIDNEY proximal tubule (1α-hydroxylase)
          → 1,25(OH)₂D₃ = Calcitriol (ACTIVE)

• Vitamin D₂ (ergocalciferol) = plant source (fungi, yeast)
• Vitamin D₃ (cholecalciferol) = animal source + skin synthesis
• PTH stimulates renal 1α-hydroxylase; hypophosphatemia also stimulates it
• 25(OH)D is used to assess vitamin D status (optimal >20 ng/mL; some experts >30 ng/mL)

Functions

• Primary: promotes Ca²⁺ and phosphate absorption from the small intestine by inducing synthesis of calbindin D-28K (calcium-binding protein)
• Acts on bone, kidney, and intestine to maintain calcium homeostasis
• VDR (Vitamin D Receptor) is present in >200 gene regulatory sites; expressed in immune cells, brain, breast, colon, prostate, heart muscle

Deficiency

• Symptoms also include muscle soreness, weakness, fatigue

Special Forms of Rickets

• Vitamin D-dependent rickets (VDDR type 1): defect in renal 1α-hydroxylase → low calcitriol; treat with calcitriol
• Vitamin D-resistant rickets (X-linked hypophosphatemia): defect in phosphate reabsorption in kidney (PHEX gene mutation)
• Glucocorticoid-induced osteoporosis: prevent with calcium 1000 mg/day + vitamin D 800 IU/day

Treatment

• Deficiency: Vitamin D₃ 1500-2000 IU/day or intermittent high-dose supplementation
• Renal failure (cannot convert 25→1,25): give calcitriol directly
• Chronic renal failure leads to secondary hyperparathyroidism via this mechanism

Toxicity (Hypervitaminosis D)

• Hypercalcemia, hypercalciuria → nephrocalcinosis, kidney stones, soft tissue calcification
• Symptoms: nausea, vomiting, polyuria, polydipsia, confusion, weakness
• Note: Sunlight exposure does NOT cause vitamin D toxicity (cutaneous photodegradation)

VITAMIN E (Tocopherol)

Forms & Sources

• α-Tocopherol is the biologically active form in humans
• Sources: vegetable oils (soybean, corn, cottonseed, safflower), leafy greens, nuts
• RDA: 15 mg/day for adults
• Transported in chylomicrons; the liver incorporates it into lipoproteins via α-tocopherol transfer protein (α-TTP)

Function

• Primary role: antioxidant - protects cell membranes from lipid peroxidation by free radicals
• Particularly important for protecting red blood cell membranes and neural tissue

Deficiency

1. Fat malabsorption syndromes - biliary/pancreatic disease, cystic fibrosis, celiac, Crohn's, short bowel
2. Abetalipoproteinemia - cannot form chylomicrons → cannot transport vitamin E
3. Ataxia with isolated vitamin E deficiency (AVED) - autosomal recessive defect in α-TTP gene (chromosome 8q12.3) → cannot incorporate vitamin E into liver lipoproteins

Neurological Manifestations (spinocerebellar syndrome)

1. Loss of deep tendon reflexes (earliest neurological sign)
2. Loss of vibration and position sense (dorsal column dysfunction)
3. Sensory ataxia, pseudoathetosis
4. Cerebellar ataxia, wide-based gait
5. Nystagmus, dysconjugate gaze
6. Distal sensory neuropathy
7. Myopathy, rarely cognitive dysfunction
8. Retinopathy - decreased night and color vision → decreased acuity → contraction of visual field → retinal discoloration with angioid streaks

Diagnosis

• Serum vitamin E level: normal 11-37 μM/L in adults
• In hyperlipidemia/cholestasis: use vitamin E:cholesterol ratio (more reliable than absolute level)

Treatment

• Malabsorption: 1000-2000 mg/day (infants), 100 mg/kg/day (adults), 300 mg/day post-bariatric surgery
• Genetic (AVED): 5-10 g/day

Toxicity

• Generally not toxic at normal doses
• Excess: bleeding tendency (antiplatelet effects, hemorrhagic infarcts)
• Myalgia, mild proximal weakness, elevated CK
• In pregnancy: high doses → fetal growth retardation (interferes with oxidation)

VITAMIN K

Forms

• K₁ (phylloquinone) - plant sources (leafy green vegetables); dietary form
• K₂ (menaquinones, MK-n) - synthesized by intestinal bacteria; also found in fermented foods
• K₃ (menadione) - synthetic; can cause hemolysis

Mechanism of Action (the carboxylation cycle)

Glutamate residues on clotting factors
  + CO₂ (carboxylase reaction, requires vitamin KH₂)
  → γ-Carboxyglutamate (Gla) residues [active clotting factors]

Vitamin K cycle:
  Vitamin K (quinone) → Vitamin KH₂ (hydroquinone) [by quinone reductase]
  Vitamin KH₂ → Vitamin K epoxide [used in carboxylation]
  Vitamin K epoxide → Vitamin K → Vitamin KH₂ [by VKOR = vitamin K epoxide reductase]

Vitamin K-Dependent Clotting Factors

• Without Gla residues, these factors cannot bind Ca²⁺ and phospholipid surfaces → cannot form complexes for coagulation

Deficiency - Causes

• Newborns - gut is sterile (no bacterial K₂), breast milk is low in vitamin K → hemorrhagic disease of the newborn → prophylactic vitamin K₁ IM at birth
• Fat malabsorption (bile duct obstruction, cholestasis, short bowel)
• Prolonged antibiotic use (destroys gut flora)
• Warfarin therapy

Deficiency - Clinical Features

• Bleeding: easy bruising, mucosal bleeding, hemarthrosis, intracranial hemorrhage (in neonates)
• Prolonged PT/INR (factor VII has shortest half-life → PT is most sensitive) and prolonged aPTT
• Normal platelet count and bleeding time

Treatment/Reversal

• Vitamin K₁ (phytonadione) orally or IV
• For warfarin reversal: Vitamin K + FFP (fresh frozen plasma) for urgent reversal
• Warfarin antidote: Vitamin K₁

Other Functions

• Bone metabolism: Vitamin K is required to carboxylate osteocalcin and matrix Gla protein (MGP) - important for bone mineralization
• Calcification prevention: MGP inhibits arterial calcification when carboxylated

Quick Comparison Table

Key Exam Points to Remember

1. All fat-soluble vitamins are malabsorbed together in fat malabsorption syndromes
2. Vitamin A: Differentiate carotenemia (palms/soles yellow, sclerae clear) from jaundice
3. Vitamin A: ATRA used in APL treatment; teratogenic (avoid in pregnancy)
4. Vitamin D: 2-step activation: liver (25-OH) → kidney (1α-OH); assess with 25(OH)D levels
5. Vitamin D: Chronic renal failure → cannot activate → give calcitriol directly
6. Vitamin E: Deficiency almost always from malabsorption, not diet, in adults
7. Vitamin E: Spinocerebellar syndrome mimic; loss of DTRs is earliest sign
8. Vitamin K: Warfarin inhibits VKOR; vitamin K₁ is the antidote
9. Vitamin K: Prophylactic IM K₁ given at birth to prevent hemorrhagic disease of newborn
10. Vitamin K also activates osteocalcin and MGP (bone health, anti-calcification)