Fat Soluble Vitamins

Overview Examples

Characteristics

precursors for coenzymes

pancreatic enzymes required for absorption in the ileum

malabsorption syndromes can cause fat-soluble vitamin deficiencies

e.g. steatorrhea, cystic fibrosis, and sprue

stored in fat making toxicity possible (unlike water soluble vitamins)

Vitamin A (Retinol)

Function
- antioxidant
  - neutralize free radicals
- constituent of visual pigments (retinal)
  - β-carotene from diet enzymatically converted to cis-retinal, which undergoes photoisomerization to trans-retinal when light is absorbed
  - co-factor for protein rhodopsin
- essential for normal differentiation of epithelial cells into specialized tissue
  - pancreatic and mucus-secreting cells
  - binds intracellular receptors that regulate transcription at the retinoic acid response elements
- immune system stimulation
  - stimulates T-cell differentiation and proliferation
  - vitamin A supplementation recommended for measles treatment
- retinitis pigmentosa
  - vitamin A supplementation used as a treatment in retinitis pigmentosa (usually autosomal dominant)
Source
- found in liver and green/yellow vegetables
- β-carotene also a source
  - dimer of retinal that must be cleaved and converted to trans-retinol for intestinal absorption
- isotretinoin
  - form of retinoic acid used in treatment of acne
Deficiency
- causes
  - deficiency in dietary intake
    - due to storage in fat must occur over several months
  - malabsorption
  - fat-free diets
- symptoms
  - night blindness
  - xerophthalmia
  - squamous metaplasia of corneal epithelium
    - spots are known as Bitot spots
  - follicular hyperkeratosis
    - dry skin due to loss of sebaceous gland function
  - frequent infections
Excess
- causes
  - over supplementation
    - regular intake > 15 x RDA
  - consumption of wild game liver
  - isotretinoin treatment
- symptoms
  - arthralgias
    - periosteal proliferation
  - alopecia
  - papilledema and seizures
    - result of intracranial swelling
  - skin changes
    - yellow pigment with excess β-carotene but sclera remain white
      - contrasted with jaundice which sclera and skin turn yellow
- teratogenic
  - cleft palate and cardiac abnormalities
a pregnancy test must be done before isotretinoin is prescribed for severe acne

Vitamin D

Function
- raise low blood calcium concentrations
  - ↑ duodenal absorption of calcium and phosphate
  - ↑ reabsorption of calcium from distal renal tubules
  - ↑ bone resorption via activation of osteoclasts
    - bisphosphonates inhibit activation of osteoclasts and ↓ bone resorption
      - e.g., ibandronate, risedronate, and alendronate
- remodeling of bone
  - osteoblasts have receptors for vitamin D
  - binding stimulates release of alkaline phosphatase (alk-phos)
  - alk-phos dephosphorylates pyrophosphate
    - pyrophosphate normally inhibits bone mineralization
- matures macrophage stem cells into osteoclasts
Source
- pre-formed ingestion in diet
  - D₂ = ergocalciferol
    - ingested from plants
    - used as pharmacologic agent
  - D₃ = cholecalciferol
    - consumed in milk and fish
- formed in sun-exposed skin
  - 7-dehydrocholesterol → cholecalciferol (D₃) in skin catalyzed by UV light
    - step insufficient in climates where low temperatures do not allow for sun exposure
  - cholecalciferol (D₃) → 25-hydroxycholecalciferol (25-OH D₃) in liver catalyzed by 25-hydroxylase
    - decrease in hepatic function may result in vitamin D deficiency
      - must supplement with 25-OH D₃
    - occurs in the P450 system
  - 25-OH D₃→ 1,25-dihydroxycholecalciferol (1,25-(OH)₂ D₃) in kidney catalyzed by 1α-hydroxylase
    - 1α-hydroxylase upregulated by PTH in response to hypocalcemia
    - decrease in renal function may result in vitamin D deficiency
      - pseudo-vitamin D deficiency rickets
        hereditary deficiency in 1α-hydroxylase
      - must supplement with 1,25-(OH)₂ D₃ equivalent
- 25-OH D₃ = storage form
- 1,25-(OH)₂ D₃ (calcitriol) = active form
Deficiency
- causes
  - low sunlight exposures
  - hepatic or renal function decrease
  - fat malabsorption
  - induction of P450 which degrades active vitamin D precursors
  - exclusive breastfeeding
- symptoms
  - rickets in children (bending bones)
  - osteomalacia in adults (soft bones)
  - hypocalcemic tetany
Excess
- causes
  - supplementation > 10x RDA
  - seen in sarcoidosis
    - ↑ activation of vitamin D by epithelioid macrophages
- symptoms
  - polyuria, polydipsia, and nocturia
  - hypercalcemia and hypercalciuria
    - high blood calcium concentration promotes metastatic calcification
  - loss of appetite and stupor
high levels of vitamin D promote bone resorption

Vitamin E (α-tocopherol)

Function
- antioxidant
- prevents peroxidation of fatty acids allowing membranes to maintain normal fluidity
- prevents oxidation of LDL
- protects against arteriosclerosis
Deficiency
- rare
- causes
  - fat malabsorption
    - abetaliproteinemia
- symptoms
  - ↑ fragility of erythrocytes (hemolytic anemia)
  - muscle weakness
  - neurodysfunction
    - poor joint sensation and ataxia
Excess
- synergistic ↓ in vitamin K dependent clotting factors with warfarin
potential hemorrhage in warfarin patients

Vitamin K

Function
- catalyzes γ-carboxylation of glutamic acid residues on blood clotting proteins
  - cofactor for γ-glutamyl carboxylase
  - allows Ca²⁺ binding site
  - co-translational modification in RER
  - necessary for the synthesis of clotting factors II (prothrombin), VII, IX, X, and protein C and S
- must be activated by epoxide reductase enzymes
  - inhibited by warfarin, which is a vitamin K antagonist
  - an anticoagulant in vivo (not in vitro)
  - 2-3 days required to achieve anticoagulation
    - heparin given for immediate results
Source
- normal gut bacterial flora
- green vegetables
- breast milk does NOT contain vitamin K
Deficiency
- causes
  - fat malabsorption
  - neonates have sterile intestines and are unable to synthesize vitamin K
    - aggravated by mothers who took anticonvulsants during pregnancy
    - neonates are given vitamin K injection at birth to prevent hemorrhage
  - can also occur after prolonged use of broad-spectrum antibiotics
    - destruction of normal gut flora
  - ↓ in hepatic function can ↓ vitamin K activation
- symptoms
  - ↑ PT and normal aPTT, but normal bleeding time (can also see increased aPTT, but as factor VII has the shortest half-life, PT increases before aPTT)
    - easy bruising and bleeding
    - hemorrhagic disease of the newborn
Excess
- rare
- symptoms
hemolytic anemia and liver damage

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