• Clinical science

Vitamins

Abstract

Vitamins are a group of chemically diverse organic compounds that an organism requires for normal metabolism. Apart from a few exceptions (e.g., vitamin D), the human body cannot synthesize vitamins on its own in sufficient amounts and must, therefore, ensure a steady supply through the diet. Vitamins are micronutrients that do not provide energy (like macronutrients) but instead have very specific biochemical roles: They are coenzymes in various reactions (B vitamins, vitamins A and K) and antioxidants that protect the cell and its membranes from free radicals (vitamins C and E), enable cell signaling (vitamin A) and gene transcription (vitamins A and E), and serve hormone-like functions (e.g., vitamin D). Vitamins are classified as fat-soluble vitamins, which the body can store, and water-soluble vitamins, which, with the exception of vitamins B9 (folate) and B12, cannot be stored in the body over significant lengths of time and therefore require continuous intake. A balanced diet typically supplies the body with all the vitamins it requires, and deficiencies occur mainly due to malnutrition, malabsorption disorders, or restrictive diets (e.g., vitamin B12 in a vegan diet).

Overview of vitamins

Fat-soluble vitamins

Fat-soluble vitamins are nonpolar molecules that require lipids for resorption. Since the body can store them for long periods of time, mainly in the liver and adipose tissue, excess accumulation is possible and may cause toxicity. While toxicity occurs mainly in industrialized countries due to oversupplementation, most deficiencies are a health concern mainly in developing countries (vitamin D being the notable exception). Treatment of deficiency involves oral supplementation, dietary adjustment (e.g., if due to restricted diet), or causal treatment of the underlying disease (esp. malabsorption disorders). For further information on etiology, diagnostics, and differential diagnoses, see the learning card on “Malabsorption.”

The fat cat is in the ADEK (pronounced “attic”).

Name

Active forms Action Symptoms of deficiency Excess
Vitamin A (retinol)
  • Retinal
  • Retinoic acid
Vitamin D (calciferol)
  • Bone calcification
  • Ca2+ homeostasis
  • ↑ Resorption of calcium and phosphate in the intestine
  • ↑ Bone resorption
Vitamin E (tocopherol)
  • Antioxidant
  • Very rare
Vitamin K (phytomenadione)
  • Vitamin K hydroquinone
  • Very rare

Vitamin A

Chemistry

  • Fat-soluble vitamin
  • Synonyms: retinol
  • Substance class: retinoids
  • Chemical structure: isoprenoid
  • Inactive precursors (provitamins): carotenoids (esp., alpha-carotene, beta-carotene, gamma-carotene)
  • Active forms
    • Vitamin A
    • Retinol (alcohol)
    • Retinal (aldehyde)
    • Retinoic acid (carboxylic acid)
    • Retinyl esters

Physiology

  • Sources
    • Plant sources; : as inactive provitamin (esp. beta-carotene) in yellow and leafy vegetables (e.g., spinach, kale, carrots)
    • Animal sources: in storage form; (esp. retinyl ester), e.g., in liver, fish, eggs, butter
  • Activation: The carotinoid is cleaved into two retinal molecules. Retinal can be reversibly reduced to retinol and reversibly oxidized to retinoic acid.
  • Transport:
  • Storage: : in hepatic stellate cells
    • Storage form: retinyl ester (e.g., retinyl palmitate)
  • Excretion: via bile and urine

Functions

Retinal plays a major role in vision, while retinoic acid and retinol are involved mainly in gene transcription and tissue maintenance!

Deficiency [1]

Excess

  • Causes: Oversupplementation
  • Symptoms
    • Acute
      • Nausea
      • Vertigo
      • Fatigue
      • Headache
      • Blurry vision
    • Chronic
    • Teratogenic (e.g., microcephaly, cleft palate, skeletal, neurologic, and cardiac abnormalities, fetal death)

Therapeutic uses

Isotretinoin is a strong teratogenic agent. A negative pregnancy test and two forms of contraception are required before prescription in women.

Vitamin A should be given to patients with measles to boost their immune system, especially in countries where vitamin A deficiency is endemic.

References:[3][4][5]

Vitamin D

Chemistry

Physiology

Vitamin D is the only vitamin that the human body can produce entirely on its own!

Functions

  • Calcium and phosphate metabolism (see also calcium homeostasis)
    • Increases resorption of calcium and phosphate in the intestine
    • Increases reabsorption of calcium in the kidney
  • Stimulation of bone mineralization and remodeling
    • Indirectly: through maintenance of serum calcium and phosphate levels
    • Directly: through activation of osteoblasts and promotion of osteoclast differentiation

Deficiency [6]

Excess

Vitamin E

Chemistry

  • Fat-soluble vitamin
  • Synonyms: tocopherol, tocotrienols
  • Substance class: tocopherols
  • Chemical structure: chromane with isoprenoid side chain
  • Inactive precursors (provitamins): none
  • Active form: tocopherol

Physiology

Functions

  • Antioxidant: protects sensitive substances, esp. erythrocytes and cell membranes, from free radicals
    • Tocopherol interrupts free radical chains caused by oxidative damage and becomes oxidized itself in the process.
  • Other functions

Deficiency

Excess

  • Toxicity is very rare.
  • Causes: Oversupplementation
  • Symptoms
    • In children: increased risk of enterocolitis
    • Can alter the metabolism of warfarin → enhanced anticoagulant effect → increased risk of bleeding
    • Studies have linked long-term high-dose supplementation to increased incidence of heart failure and increased risk of fatal subarachnoid hemorrhage and mortality.

References:[9]

Vitamin K

Chemistry

  • Fat-soluble vitamin
  • Synonyms: phytomenadione, phylloquinone, phytonadione
  • Substance class: naphthoquinones
  • Chemical structure:
    • Vitamin K1 (phytomenadione)
    • Vitamin K2 (menaquinone)
  • Inactive precursors (provitamins): none
  • Active form: vitamin K hydroquinone

Physiology

  • Sources: leafy green vegetables ; synthesized in small amounts by intestinal flora
  • Transport: via lipoproteins; no specific protein
  • Storage: liver
  • Excretion: bile and urine
  • Activated by the enzyme epoxide reductasecofactor for γ-carboxylation of glutamic acid residues on clotting factors → adequate hemostasis

Functions

In 1972 vitamin K Killed CSf

Deficiency[10]

Excess

Water-soluble vitamins

Water-soluble vitamins are polar molecules that function primarily as coenzymes in various chemical reactions. They are not stored in the body except vitamins B9 and B12, which are stored in the liver. Accumulation and consequent toxicity are exceedingly rare, even with vitamins B9 and B12. Treatment of deficiency involves oral supplementation, dietary adjustment (e.g., if due to restricted diet), and causal treatment of underlying disease (esp. malabsorption disorders). For more information on etiology, diagnostics, and differential diagnoses, see the learning card on “Malabsorption.” Deficiency of B-complex often causes glossitis, dermatitis, and diarrhea.

  • Resorption and transport
    1. Resorption in the intestine: active transport and passive diffusion
    2. Transport in the blood: active, via various transport proteins
Name Active forms Function Deficiency
Vitamin B1 (thiamine)
Vitamin B2 (riboflavin)
  • Coenzyme in redox reactions
Vitamin B3 (niacin)
  • Coenzyme in redox reactions
Vitamin B5 (pantothenate)
Vitamin B6 (pyridoxine)

Vitamin B7 (biotin)

  • Coenzyme for carboxylases, transcarboxylases, and decarboxylases
Vitamin B9 (folate)
  • Coenzyme for 1-carbon transfer methylation reactions

Vitamin B12 (cobalamin)

  • Cobamamide
  • Methylcobalamin
  • Coenzyme for methylmalonyl-CoA (cobamamide) and homocysteine methyltransferase (methylcobalamin)
  • Macrocytic, megaloblastic anemia
  • Neurologic symptoms
  • Hypersegmented polymorphonuclear cells
Vitamin C (ascorbic acid)
  • Hydrophilic antioxidant
  • Coenzyme in important redox and hydroxylation reactions
  • Facilitates iron resorption by preventing oxidation and keeping iron in Fe2+ reduced state

Vitamin B₁

Chemistry

Physiology

  • Sources: whole grain cereals (e.g., whole wheat, brown rice), yeast, pork, legumes[11]
  • Resorption: via thiamine transporter-2 (ThTR2)
  • Activation: intracellular phosphorylation of thiamine to thiamine pyrophosphate
  • Transport in blood: mainly via blood cells; only approx. 10% free or bound by albumin

Functions

Deficiency[12]

In alcoholic or malnourished patients, always administer thiamine before giving dextrose to decrease the risk of worsening or precipitating Wernicke encephalopathy.

References:[14]

Vitamin B₂

Chemistry

Physiology

  • Sources: meat, fish, eggs, milk, green vegetables, yeast[11]
  • Resorption
    • Flavoproteins in food are cleaved to riboflavin in the intestine (sole resorbable form).
  • Transport in blood: via albumin and immunoglobulins, esp. as FAD

Functions

  • FAD and FMN are used as coenzymes for redox reactions
    • Example: glutathione reductase in erythrocytes (prevents damage of RBCs due to oxidative stress)NADPH binds to glutathione reductase → reduction of FAD to FADH (electrons from NADPH) → NADP+ + FADH-

Deficiency[15]

  • Causes
    • Malnutrition from restricted diet (e.g., vegan, lactose-free)
    • ↑ Demand: pregnancy, lactation
  • Symptoms
  • Diagnosis: : In developing countries, riboflavin deficiency rarely presents with overt manifestations. So use of an assay, such as erythrocyte glutathione reductase assay, helps in identifying subtle deficiencies.
    • Erythrocyte glutathione reductase activity coefficient: in this assay, the activity coefficient (AC) of glutathione reductase is measured in the presence or absence of FAD. Riboflavin is the precursor for FAD, which is a coenzyme for different oxidation-reduction reactions, including the pentose phosphate pathway. With riboflavin deficiency, the AC of glutathione reductase is higher (> 1.4) with the addition of FAD due to the presence of unsaturated enzyme.

References:[16]

Vitamin B₃

Chemistry

Physiology

  • Sources: meat (liver), cereals, seeds, legumes
  • Resorption: passive resorption in the intestine
  • Synthesis
    • Derived from tryptophan
    • Requires vitamins B2 and B6.
    • Very small amounts of niacin can be synthesized from tryptophan (1 mg niacin from 60 mg tryptophan).
  • Transport in blood: as nicotinate

Functions

  • Coenzyme for redox reactions

Deficiency[11]

The four D's of Pellagra: Dermatitis, Diarrhea, Dementia, Death

Excess

Therapeutic uses

Vitamin B₅

Chemistry

Physiology

Functions

Deficiency[11]

  • Causes
    • Malnutrition[11]
  • Symptoms

Vitamin B₆

Chemistry

Physiology

  • Sources: nuts, whole grains, vegetables, yeast, meats, (esp. liver and poultry) [11]
  • Resorption: cleavage by phosphorylases in the intestine and subsequent resorption by intestinal lining
  • Transport in blood: partially free, partially bound to albumin

Functions

Deficiency[18]

Vitamin B₇

Chemistry

  • Water-soluble vitamin
  • Synonyms: biotin
  • Inactive precursor (provitamin): none
  • Active form: biotin

Physiology

  • Sources
    • Plants (e.g., soy products, nuts), animal products (e.g., liver, egg yolk, dairy products)
    • Small amounts are synthesized by intestinal flora.
  • Resorption: cleavage of biotin bound to proteins into free biotin with the aid of the pancreatic enzyme biotinidase and subsequent active resorption in the intestine
  • Transport in blood: mainly free

Function

Biotin is a coenzyme in all carboxylase enzyme complexes that are not vitamin K-dependent!

Deficiency

  • Causes (rare)
    • Malnutrition
    • Destruction of intestinal flora
    • Excessive consumption of raw egg whites
      • Egg whites contain the glycoprotein avidin, which binds biotin in the intestinal lumen and thus inhibits resorption
  • Symptoms

Vitamin B₉

Chemistry

Physiology

  • Sources
    • Leafy green vegetables
    • Small amounts are synthesized in intestinal flora
  • Resorption: in jejunum via specific transporters
  • Transport in blood: via folate-binding transport proteins
  • Storage: A small reserve pool is stored in the liver (∼ 3–4 months)

Function

  • Coenzyme for 1-carbon methylation and transfer reactions
  • Involved in the synthesis of purine bases

Deficiency[19]

For more information see folate deficiency.

Unlike vitamin B12 deficiency, folate deficiency is not associated with neurologic symptoms.

Vitamin B₁₂

Chemistry

  • Water-soluble vitamin
  • Synonyms: cobalamin
  • Substance class: cobalamins
  • Inactive precursor (provitamin): none
  • Active forms: methylcobalamin and adenosylcobalamin

Physiology

  • Sources
    • Almost exclusively in animal products, esp. meat (liver), dairy products, eggs
    • Synthesized by the intestinal flora
  • Resorption
  • Activation: in the liver
  • Transport in blood: bound to transcobalamin
  • Storage: 60% in the liver (∼ 3–4 years), 30% in muscle tissue

Vitamin B12 is the only water-soluble vitamin that is stored in the body in significant amounts!

Function

Deficiency[19]

Vitamin C

Chemistry

  • Water-soluble vitamin
  • Synonyms: ascorbic acid, ascorbate
  • Substance class: lactones
  • Inactive precursor (provitamin): none
  • Active form: ascorbate

Physiology

  • Sources: fruit and vegetables
  • Resorption
    • Passive resorption via oral mucosa
    • Active resorption in intestine (esp. jejunum)
  • Transport in blood: especially as free ascorbate, only very small amounts as dehydroascorbate
  • Storage: no specialized vitamin C stores; high concentrations in organs that require vitamin C as a cofactor (e.g., adrenal gland)

Function

  • Hydrophile antioxidant: ascorbate and dehydroascorbate form a redox system
  • Facilitates iron resorption in the intestine
    • As chelating agent: increases iron solubility though chelate complex formation
    • As redox partner: reduces poorly soluble Fe3+ to highly soluble Fe2+ which is easier to absorb
  • Coenzyme for important enzymatic reactions, e.g.:

Deficiency[11]

Excess

Therapeutic use