Fat-Soluble Vitamins

Vitamin A—Retinoids

• Vitamin A (eg, retinol, retinaldehyde, retinoic acid) is found in fish

oils, meats, dairy products, and eggs.
• β-Carotene, a precursor of vitamin A, which is metabolized by
intestinal mucosal cells into retinaldehyde, is found in green
vegetables. Vitamin A in the form of retinol is absorbed into the
intestinal mucosal cells and is transported to the liver via
chylomicrons. Vitamin A is delivered to the rest of the body via
prealbumin and retinol-binding protein.
• In the liver, vitamin A is stored in Ito cells, which are located in the
space of Disse. Ito cells contribute to cirrhosis by secreting
transforming growth factor beta (TGF-β) and promoting fibrosis.
 Functions of Vitamin A—Retinoids
• Vitamin A combines with opsin in the eye to form rhodopsin in the rod cells of
the retina. A similar reaction produces iodopsin in cone cells. These proteins
play a crucial role in sensing light in the retina and are essential for vision.
• Vitamin A also has a role in the differentiation and proliferation of epithelial
cells in the respiratory tract, skin, cornea, conjunctiva, and other tissues.
• Deficiency of vitamin A, therefore, causes vision problems, disorders of
epithelial cell differentiation and proliferation, and impaired immune response.
Visual symptoms are usually the first sign of vitamin A deficiency, which
include loss of green light sensitivity, poor adaptation to dim light, and night
blindness (loss of retinol in rod cells). Xerophthalmia (squamous epithelial
thickening), Bitot spots (squamous metaplasia), and keratomalacia also occur
in vitamin A deficiency.
 Vitamin A—Retinoids

• Keratomalacia is metaplasia of the conjunctival lining, which leads to a change

from a thin squamous lining to a keratinized, stratified squamous epithelium.
Metaplasia of respiratory epithelia is seen (often common in cystic fibrosis due to
failure of fat-soluble vitamin absorption), as well as frequent respiratory
infections (secondary to respiratory epithelial defects).
• Because vitamin A is stored in the liver and is lipophilic, the body can store
large amounts of the vitamin. Toxicity can occur acutely, chronically, or as a
teratogenic effect. Acute toxicity can be caused from a large, single dose of
vitamin A and results in nausea, vertigo, and blurry vision.
• Chronic toxicity can manifest as ataxia, alopecia, hyperlipidemia, edema, or
hepatotoxicity. Excess vitamin A also can turn the skin yellow, but this can be
distinguished from jaundice because the sclera remain white.
Eye Signs of vitamin A
deficiency
 Clinical Correlation
• Vitamin A derivitives such as isotretinoin are commonly used to treat Acne a
dermatological condition commonly affecting the sebacious glands on the face.
• Their use during pregnancy have been linked to birth defects such as facial
abnormalities , as such common practice requires simultaneous use of two forms
of contraceptive while taking these medication.n
 Vitamin D—Cholecalciferol

• Vitamin D plays an important role in bone metabolism by regulating plasma calcium

concentrations. Vitamin D is absorbed from dietary sources (saltwater fish and egg
yolks) and is also synthesized in the skin. Vitamin D absorption is regulated by serum
calcium concentrations.
• In the presence of UV light, 7-dehydrocholesterol present in the skin is converted to
previtamin D. Once previtamin D is formed, it is converted to cholecalciferol, which
enters the circulation. Activation of cholecalciferol takes place in the liver and the
kidney.
• The liver converts cholecalciferol to 25-hydroxycholecalciferol. The kidney converts
25-hydroxycholecalciferol into 1,25-hydroxycholecalciferol (1,25 OHD, cal- citriol),
its active metabolite. The kidney also converts 25-hydroxycholecalciferol into 24,25-
hydroxycholecalciferol, an inactive metabolite (Figure 2-80). Vitamin D–binding
globulin stores vitamin D and is also responsible for its transport in the circulation.
 Vitamin D—Cholecalciferol
• Vitamin D maintains the plasma calcium concentration by increasing intestinal
absorp- tion of calcium, minimizing calcium excretion in the distal renal tubules, and
mobiliz- ing bone mineral in bones. It also stimulates osteoblasts and improves
calcification of bone matrix (and, hence, bone formation).
• Activated vitamin D binds to a nuclear receptor in cells (intestinal cells, renal cells,
and osteoblasts) and induces gene expression. It is regulated by a series of feedback
mechanisms involving parathyroid hormone (PTH), calcium, and phosphate. Low
levels of calcium stimulate PTH synthesis and secretion, which in turn prompt the
conversion of 25-hydroxy- cholecalciferol to 1,25-hydroxycholecalciferol.
• In turn, 1,25-hydroxycholecalciferol has a negative feedback effect on its own
production and PTH production. In excess, 1,25-hydroxycholecalciferol also
promotes the production of 24,25-dihydroxyvitamin D.
 Vitamin D—Cholecalciferol
• In the presence of excess calcitriol and thus calcium from either bone or intestinal
absorption, high levels of calcium act to decrease PTH production, and high levels of
phosphate act to decrease conversion of 25-hydroxycholecalciferol to 1,25-hydroxycho-
lecalciferol by blocking the 1α-hydroxylase enzyme (found in the kidney) involved in
the activation of the 25-hydroxy derivative (Figures 2-81 and 2-82).
• Deficiency of vitamin D leads to rickets in children and osteomalacia in adults, with
the differences being open (in children) and closed (in adults) epiphyseal plates. Rickets
results from not receiving enough calcium and phosphate at the sites where bone min-
eralization is taking place.
• Clinically, children with rickets show signs of hypocalcemia, bowing of the lower
extremities, and poor dentition. Other signs include pigeon breast deformity, frontal
bossing, rachitic rosary (knobs of bone at costochondral joints), and bowing of the legs.
The treatment for vitamin D–deficient rickets and osteomalacia is vitamin D therapy.
 Vitamin D—Cholecalciferol
• In vitamin D–resistant rickets, vitamin D repletion does not treat the syndrome,
and a genetic abnormality may be present.
• Type I vitamin D–resistant rickets occurs when there is a genetic mutation of
1α-hydroxylase. This can be treated with 1,25-hydroxycholecalciferol bypassing
the conversion of 25-hydroxycholecalciferol in the kidney. If supplementation of
1,25-hydroxycholecalciferol does not treat the underlying problem, then the
patient has type II vitamin D–resistant rickets.
• Type II vitamin D–resistant rickets occurs when the 1,25-hydroxycholecalciferol
receptor is mutated and therefore unresponsive to both vitamin D and calcitriol.
 Vitamin D—Cholecalciferol
• X-linked rickets is entirely due to renal phosphate wasting. In this condition,
1,25-hydroxycholecalciferol levels are normal or low.
• Excess vitamin D leads to hypercalcemia and all of the sequelae associated with it
(eg, kidney stones, dementia, constipation, abdominal pain, depression).
• Sarcoidosis can lead to excess vitamin D, because there is increased production of
1α-hydroxylase by macrophages, which completes the production of vitamin D.
Similarly, lymphoma can produce calcitriol.
 Vitamin E—α-Tocopherol

• Vitamin E is a lipid-soluble antioxidant found in sunflower oil, corn oil, soybeans,

meats, fruits, and vegetables. It can be found in cell membranes and serves as an
antioxidant like glutathione and vitamin C. It is used to react to the radicals
formed by peroxida- tion of fatty acids. Like other fat-soluble vitamins, vitamin E
is absorbed in the intestine and travels to the liver via chylomicrons.
• Fat malabsorption diseases (cystic fibrosis, liver disease) decrease the amount of
vitamin E available. Deficiency of vitamin E is uncommon, but can cause
hemolytic anemia, peripheral neuropathy and ataxia due to degeneration of the
spinocerebellar tract, and ophthalmoplegia.
• In excess, vitamin E can interfere with vitamin K metabolism, which can lead to
hemorrhagic stroke in adults and necrotizing enterocolitis in infants.
 Vitamin K—Phylloquinone

• Vitamin K is found in either vegetable or animal sources (phylloquinone) or through

bacterial flora (menaquinone). It is used by the liver in the carboxylation of glutamate
residues during post-translational modification of coagulation factors.
• Prothrombin and coagulation factors II, VII, IX, and X, and the antithrombotic proteins
C and S all require γ-carboxylation of glutamate residues for function (Figure 2-83). γ-
carboxyglutamate acts as a chelator, trapping calcium ions and thereby allowing the
clotting proteins to bind to negatively charged phospholipids at the surface of platelets
and to function at these membranes.
• The reduced form of vitamin K is oxidized by γ-glutamyl carboxylase (and epoxidase)
to form the γ-carboxyglutamate (Gla) in the postsynthetic modification. The oxidized
form of vitamin K, or vitamin K epoxide, is converted back to its reduced form by
2,3-epox- ide reductase. Warfarin inhibits this enzyme, thereby preventing adequate
recycling of vitamin K and the γ-carboxylation of coagulation factors.
 Vitamin K—Phylloquinone
• Vitamin K deficiency is rare in otherwise healthy adults, but can be present when
broad-spectrum antibiotics are taken, as they kill gut bacteria.
• Vitamin K deficiency can predispose patients to GI bleeding, intracranial
bleeding, ecchymoses, epistaxis, and hematuria. Laboratory signs include
prolonged prothrombin time (PT/INR) and partial thromboplastin time (PTT).
Clinical Correlations
Trace elements
 Zinc

• Zinc is found in foods such as beef, crab, and cashews. One of the most notable
uses of zinc is structural stabilization of zinc finger proteins, which have diverse
functions includIng DNA sequence recognition, transcriptional regulation, and
protein folding.
• A common cause of zinc deficiency is consumption of food grown in soil lacking
zinc. Common manifestations include delayed wound healing, hypogonadism,
anosmia, and acrodermatitis enteropathica (characterized by well-demarcated,
scaly plaques in the intertriginous area).
• Oral zinc supplements can reduce the symptoms of diarrhea in children with low
levels of zinc, such as from malnutrition. There isn't enough evidence to
recommend use of oral zinc for children with diarrhea who have a healthy, varied
diet.
 References
1. Textbook Of Medical Biochemistry by Chatterjea Shinde 8th edition.
2. Biochemistry by U. Satyanarayana and U. Chakrapani 4th edition
3. First Aid for the basic science general principles latest edition
4. NICE ( National institute of health and care excellence )
5. Medscape
6. Clinical Biochemistry an illustrated color text book 5th edition