Vitamins

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 can be coenzymes in various reactions (B vitamins, vitamins A and K) and/or antioxidants that protect the cell and its membrane from free radicals (vitamins C and E). They can also enable cell signaling (vitamin A) and gene transcription (vitamins A and E) or function as hormones (e.g., vitamin D). Vitamins are classified into fat-soluble vitamins, which the body can store, and water-soluble vitamins, which, with the exception of vitamins B₉ (folate) and B₁₂ (cobalamin), the body cannot store over significant periods of time and, therefore, require continuous intake. A balanced diet typically supplies the body with all vitamins it requires. Deficiencies occur mainly due to malnutrition, malabsorption disorders, or restrictive diets (e.g., vitamin B₁₂ deficiency in a vegan diet).

Accumulation and toxicity occur almost exclusively with fat-soluble vitamins.

Fat-soluble vitamins: The fat cat is in the attic (= “ADEK”).

Characteristics

• Synonyms: retinol
• Substance class: retinoids
• Chemical structure: isoprenoid
• Inactive precursors (provitamins): carotenoids (esp., alpha-carotene, beta-carotene, gamma-carotene)
• Activation: carotinoid is cleaved into two retinal molecules; it can be reversibly reduced to retinol and reversibly oxidized to retinoic acid
• Active forms
  • Retinal
  • Retinoic acid
• Sources
  • Plant sources; : as inactive provitamin (esp. beta-carotene) in yellow and leafy vegetables (e.g., spinach, kale, carrots)
  • Animal sources: in storage form; (e.g., in liver, kidney, fish, eggs, butter)
• Transport: via transport proteins (in the form of retinol)
  • Cellular retinoic acid-binding (CRAB) protein: selectively binds retinoic acid
  • Retinol-binding protein: retinol transport vehicle in serum
• Storage
  • In hepatic cells; (Ito cells) within the perisinusoidal space (of Disse)
  • Storage form: retinyl ester (e.g., retinyl palmitate)
• Excretion: via bile and urine

Functions

• Vision: component of rhodopsin as 11-cis-retinal
• Gene transcription
  • All-trans retinoic acid (ATRA) binds to its nuclear receptors; (retinoic acid receptors, RAR; retinoid X receptors, RXR) → receptor dimerization → binding to DNA; → uncoiling of chromatin → exposure of promoter regions of genes → binding of transcription factors to promoter → initiation of transcription and cell differentiation
  • Regulation of various genes responsible for cell growth, cell differentiation, apoptosis, reproduction (e.g., spermatogenesis), and embryonic development
  • Vitamin A production in the intestine is controlled by a homeobox transcription factor. ^[1]
• Tissue maintenance and cell differentiation
  • Mainly retinoic acid
  • Promotes differentiation of epithelium into specialized tissue (e.g., pancreatic cells and goblet cells)
  • Prevents metaplasia of squamous cells
• Antioxidant

Retinal is a major component of the retinal pigment rhodopsin in rods, which is necessary for vision, while retinoic acid and retinol are involved mainly in gene transcription and tissue maintenance.

Retinol (vitamin A) nurtures the retinA, acts as an Antioxidant, and can be used for Acne treatment.

Vitamin A deficiency ^[2]

• Causes
  • Disorders associated with fat malabsorption: inflammatory bowel disease (e.g., Crohn disease), celiac disease, cystic fibrosis, pancreatic insufficiency, cholestasis^[3]
  • Malnutrition: most common cause of vitamin A deficiency in developing countries
• Clinical features
  • Ocular manifestations
    • Night blindness (nyctalopia)
    • Retinopathy
    • Xerophthalmia
    • Keratomalacia
    • Bitot spots: gray, triangular, dry patches on the bulbar conjunctiva, covered by a layer with a foamy appearance
      • Typical sign of vitamin A deficiency
      • Caused by squamous cell metaplasia and keratinization of the conjunctiva
  • Keratinizing squamous metaplasia of the bladder (pearl-like plaques on cystoscopy)
  • Xerosis cutis
  • Immunosuppression: Vitamin A deficiency increases the risk of a measles infection taking a severe course.
  • Poor growth

Vitamin A toxicity

• Causes: increased intake via supplements or drugs
• Clinical features
  • Acute toxicity
    • Nausea, vomiting
    • Vertigo
    • Fatigue
    • Headache
    • Blurred vision
  • Chronic toxicity
    • Alopecia
    • Arthralgias
    • Dry skin, scaling
    • Hepatosplenomegaly, hepatic toxicity
    • Pseudotumor cerebri
  • Teratogenic effects
    • Facial anomalies: microcephaly, microphthalmia; , and cleft palate
    • Thymic agenesis
    • Cardiovascular abnormalities
    • Neurodevelopmental disability
    • Fetal death

Isotretinoin is highly teratogenic. A negative pregnancy test and two forms of contraception are required before prescribing isoretinoin to women.

Therapeutic uses ^[4]

Vitamin A is contraindicated in pregnancy (teratogenic): A negative pregnancy test and two forms of contraception must be provided before isotretinoin can be prescribed to women.

• Measles; : Treatment with vitamin A is recommended for all individuals with vitamin A deficiency,; since it reduces complications and mortality. ^[5][6]
• Skin conditions
  • Severe cystic acne (e.g., nodulocystic) and rosacea: isotretinoin (13-cis-retinoic acid) PO
  • Mild acne: topical vitamin A
• Acute promyelocytic leukemia: all-trans retinoic acid (ATRA)

Vitamin A should be given to measles patients with vitamin A deficiency to boost their immune system and reduce the risk of complications and mortality, especially in countries where vitamin A deficiency is endemic.

Characteristics

• Substance class: steroid hormones, calciferols
• Active form: 1,25-dihydroxyvitamin D (1,25-(OH)2 D₃, calcitriol)
• Sources:
  • Ergocalciferol (vitamin D₂): mushrooms, fortified foods; (e.g., milk, breakfast cereals, formula), yeast (from ergosterol)
  • Cholecalciferol (vitamin D₃)
    • Synthesized in the skin (stratum basale) when exposed to UV light
    • Fortified foods; (e.g., milk; , breakfast cereals, formula), fatty fish; (liver), egg yolks, plants
• Vitamin D synthesis
  1. Liver: cholesterol → 7-dehydrocholesterol (provitamin D₃)
     • Enzyme: cholesterol dehydrogenase
  2. Skin
     • Storage of 7-dehydrocholesterol
     • Cleavage of 7-dehydrocholesterol via irradiation with UV light → cholecalciferol (in the stratum basale)
  3. Liver: hydroxylation of cholecalciferol to 25-hydroxyvitamin D (25-OH D3, calcidiol)
  4. Kidneys: 1α-hydroxylase hydroxylates 25-hydroxyvitamin D → 1,25-dihydroxyvitamin D
• Transport to target cells: vitamin D-binding protein (DBP)
• Storage: as 25-hydroxycholecalciferol, mainly in adipose tissue; (25-OH D₃)
• Regulation of vitamin D synthesis: via regulation of 1α-hydroxylase activity in proximal convoluted tubule
  • ↓ Calcium, ↓ phosphate, and ↑ PTH → ↑ 1α-hydroxylase activity → ↑ 1,25-dihydroxyvitamin D biosynthesis
  • ↑ Calcium, ↑ phosphate, and ↑ 1,25-dihydroxyvitamin D (feedback inhibition) → ↓ 1α-hydroxylase activity → ↓ 1,25-dihydroxyvitamin D biosynthesis

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

Functions

• Calcium and phosphate metabolism (see “Calcium homeostasis.”)
  • ↑ Absorption of calcium and phosphate in the intestine
  • ↑ Reabsorption of calcium in the kidneys
• Stimulation of bone mineralization and remodeling (at low vitamin D levels)
  • Indirectly: through maintenance of serum calcium and phosphate levels
  • Directly: through activation of osteoblasts and promotion of osteoclast differentiation
• Bone resorption (at high vitamin D levels)

Deficiency ^[7]

• Most commonly because of a lack of sun exposure; (particularly high risk of deficiency in heavily pigmented skin and use of sunscreen due to inhibition of vitamin D synthesis) )
• May cause:
  • In adults: osteomalacia
  • In children: rickets
  • Symptoms of hypocalcemia; (e.g., tetany)
• For more information see “Vitamin D deficiency.”

Vitamin D toxicity

• Causes
  • Oversupplementation
  • Granulomatous disorders (e.g., sarcoidosis): due to increased 1α-hydroxylase activation in epithelioid macrophages → increased 1,25-dihydroxyvitamin D synthesis
• Clinical features
  • Hypercalcemia, hypercalciuria (see also laboratory evaluation of bone disease)
  • Loss of appetite
  • Stupor

Therapeutic uses

• Osteoporosis (prevention and treatment)
• Paget disease
• Prenatal supplementation for vegetarian mothers (400 IU per day)

Characteristics

• Synonyms: : tocopherol, tocotrienol
• Substance class: tocopherols
• Chemical structure: chromane with isoprenoid side chain
• Inactive precursors (provitamins): none
• Active form: tocopherol
• Sources: meat, eggs, vegetable oils, leafy vegetables ^[8]
• Transport: alpha-tocopherol transfer protein (α-TTP)
• Storage: adipose tissue, parenchymal cells of the liver
• Excretion: via bile

Functions

• Antioxidant
  • Prevents free radical damage, especially in RBCs and at cell membranes
  • Interrupts free radical chains and oxidizes itself as a result
• Other functions
  • Inhibition of platelet aggregation, cell proliferation, and monocyte adhesion
  • Enzyme inhibition (e.g., protein kinase C, phospholipase A2)
  • Inhibition of gene transcription (e.g., for α-TTP, tropomyosin alpha-1 chain)

Vitamin E deficiency

• Deficiency is very rare.
• Causes ^[8]
  • Fat malabsorption disorders (e.g., cystic fibrosis)
  • Defects in genes that code for α-TTP
• Clinical features
  • Neurologic dysfunction
    • Demyelination of the posterior column and spinocerebellar tract → ↓ proprioception and vibration sensation; ataxia (mimics Friedreich ataxia)
    • Neurologic symptoms are similar to vitamin B₁₂ deficiency, except that vitamin E deficiency does not lead to hypersegmented neutrophils, megaloblastic anemia, and increased methylmalonic acid levels. ^[9]
  • Hemolytic anemia; : deficiency results in increased fragility of erythrocytes and membrane breakdown ^[8]
  • Acanthocytosis
  • Muscle weakness

Vitamin E toxicity

• Toxicity is very rare.
• Causes: oversupplementation
• Clinical features
  • In infants: increased risk of necrotizing enterocolitis (NEC)
  • High-dose supplementation: alteration of vitamin K metabolism → ↑ anticoagulatory effects of warfarin → ↑ risk of bleeding
  • Increased incidence of heart failure, subarachnoid hemorrhage, and increased mortality ^[10]

Therapeutic uses

• Nonalcoholic steatohepatitis: consider vitamin E for antioxidant effect

Characteristics

• Synonyms
  • Vitamin K₁ (phytomenadione, phytonadione, or phylloquinone)
  • Vitamin K₂ (menaquinone)
• Substance class: naphthoquinones
• Chemical structure:
  • Vitamin K1
  • Vitamin K2
• Inactive precursors (provitamins): none
• Active form: vitamin K hydroquinone
  • Activation occurs via enzyme epoxide reductase.
  • Mutations in the VKORC1 (Vitamin K epOxide Reductase Complex subunit 1) gene impair the reduction of vitamin K epoxide, resulting in deficiencies in vitamin K-dependent clotting factors.
• Sources
  • Leafy green vegetables (vitamin K₁)
  • Eggs, dairy, and meat (vitamin K₂)
  • Synthesized in small amounts by intestinal bacteria
• Transport: via lipoproteins; no specific protein
• Storage: liver
• Excretion: bile and urine

Functions

• Cofactor for γ-carboxylation of glutamate residues on vitamin-K-dependent proteins involved in:
  • Coagulation: maturation of factors II (prothrombin), VII, IX, and X, protein C, protein S
  • Bone formation: osteocalcin (bone Gla protein), matrix Gla protein

Koagulation requires Vitamin K.

Vitamin K deficiency ^[11]

• Causes
  • Liver failure (e.g., cirrhosis)
  • Fat malabsorption
  • Prolonged broad-spectrum antibiotic therapy
  • Vitamin K antagonists (e.g., warfarin)
  • Neonatal deficiency
    • The neonatal intestine is sterile (no flora to synthesize vitamin K).
    • Vitamin K does not cross the placenta.
    • Breast milk does not contain vitamin K.
    • The neonatal liver is incapable of synthesizing the active form of vitamin K.
• Clinical features
  • Hemorrhage (e.g., petechiae, ecchymoses)
  • Vitamin K deficiency bleeding (VKDB)
    • ↑ PT and aPTT, normal bleeding time
    • Postnatal prophylaxis: vitamin K injection at birth

Warfarin inhibits the vitamin K-dependent synthesis of clotting factors and proteins.

Vitamin K toxicity

• Toxicity is very rare.
• Cause: oversupplementation
• Clinical features
  • Hemolytic anemia
  • Hyperbilirubinemia
  • Jaundice
  • Kernicterus in infants

Therapeutic uses

• Postnatal vitamin K injection to prevent VKDB
• Coagulopathy: disorders of the extrinsic pathway of coagulation.

Characteristics

• Synonyms: thiamine
• Inactive precursor (provitamin): none
• Active form: thiamine pyrophosphate (TPP); activation via intracellular phosphorylation of thiamine
• Sources: whole-grain cereals (e.g., whole wheat, brown rice), yeast, pork, legumes ^[13]
• Resorption: via thiamine transporter-2 (ThTR2)
• Transport in blood: mainly via blood cells; only ∼10% is free or bound to albumin

Functions

• Cofactor for several enzymes involved in carbohydrate and amino acid metabolism:
  • Pyruvate dehydrogenase (connects glycolysis to citric acid cycle): pyruvate → acetyl-CoA
  • Alpha-ketoglutaric acid dehydrogenase (citric acid cycle): α-Ketoglutarate → succinyl-CoA
  • Transketolase (HMP shunt)
    • D-xylulose-5-P ⇄ D-ribose-5-P
    • Glyceraldehyde-3-P ⇄ D-xylulose-5-P
  • Branched-chain ketoacid dehydrogenase
    • Valine/isoleucine → Propionyl-CoA
    • Leucine → Acetyl-CoA

Enzymes thiamine is a cofactor for: Thiamine PATs your Back! (Pyruvate dehydrogenase, Alpha-ketoglutaric acid dehydrogenase, Transketolase, Branched-chain ketoacid dehydrogenase).

Vitamin B₁ deficiency ^[14]

• Causes
  • Heavy drinking
  • Malnutrition, starvation
  • Malabsorption
  • Malignancy
  • Diarrhea, prolonged vomiting
  • Diuretics, hemodialysis
  • Bariatric surgery
• Pathophysiology
  • Thiamine deficiency → impaired glucose breakdown → ATP depletion → tissue damage that primarily affects highly aerobic tissues (e.g., brain, heart)
  • High-dose glucose infusions lead to increased ATP depletion, which can trigger Wernicke encephalopathy.
    • In malnourished individuals and chronic alcohol users/heavy drinkers, thiamine should be administered before glucose infusions.
• Clinical features
  • Beriberi: inadequate thiamine uptake due to malnutrition, heavy drinking, or increased demand (e.g., hyperthyroidism, pregnancy)
    • Dry beriberi
      • Symmetrical peripheral neuropathy (sensory and motor)
      • Progressive muscle wasting
      • Paralysis
      • Confusion
    • Wet beriberi
      • High-output cardiac failure (due to systemic vasodilation)
      • Dilated cardiomyopathy
      • Cardiomegaly
      • Edema
    • Infantile beriberi: cardiomegaly, tachycardia, cyanosis, aseptic meningitis (vomiting and seizures)
  • Wernicke encephalopathy
  • Leigh syndrome
• Diagnostics: vitamin B₁ administration → ↑ RBC transketolase activity

In malnourished or alcohol-dependent patients, always administer thiamine before giving dextrose to decrease the risk of precipitating or exacerbating Wernicke encephalopathy.

Vitamin B1 deficiency causes Ber1Ber1.

Characteristics

• Synonyms: riboflavin
• Substance class: flavins
• Inactive precursor (provitamin): none
• Active forms: : flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD)
• Sources: meat, fish, eggs, milk, green vegetables, yeast^[13]
• Resorption: flavoproteins are cleaved into riboflavin in the intestine
• Transport in blood: via albumin and immunoglobulins

Active forms of riboFlavin are FMN and FAD.

Functions

• FAD and FMN are cofactors for enzymes that are involved in redox reactions (chemical reactions in which electrons are transferred from one substance to another), including:
  • Succinate dehydrogenase (TCA cycle)
  • FAD is part of glutathione reductase (GR) in erythrocytes: NADPH binds to GR → reduction of FAD to FADH^- → FADH^- breaks disulfide bond in GSSG → GSR can be reduced

Vitamin B₂ deficiency ^[15][16]

• Causes
  • Malnutrition
  • Restricted diet (e.g., vegan, lactose-free)
  • ↑ Demand: pregnancy, lactation
• Clinical features
  • Corneal vascularization
  • Cheilitis, glossitis, stomatitis, pharyngitis
  • Normocytic normochromic anemia
  • Seborrheic dermatitis
• Diagnosis
  • Erythrocyte glutathione reductase assay: identifies subtle deficiencies
  • Erythrocyte glutathione reductase activity coefficient: the activity coefficient (AC) of glutathione reductase is measured in the presence and absence of FAD

The 2 C's of Vitamin B2 deficiency: Corneal vascularization and Cheilitis!

Characteristics

• Synonyms: niacin, nicotinic acid
• Inactive precursor (provitamin): none
• Active forms
  • Nicotinamide adenine dinucleotide (NAD⁺/NADH)
    • NAD⁺ serves as an electron carrier in redox reactions, especially in catabolic cellular processes.
    • Reduced form is NADH; oxidized form is NAD⁺.
    Nicotinamide adenine dinucleotide phosphate (NADP⁺/ NADPH)
    • NADPH provides electrons for anabolic reactions (e.g., synthesis of fatty acids and steroids) and oxidation-reduction reactions. Also used in the respiratory burst, the cytochrome P450 system, and glutathione reductase.
    • Reduced form is NADPH; oxidized form is NADP⁺.
• Sources: meat (liver), cereals, seeds, legumes
• Synthesis: : derived from tryptophan; ; requires vitamins B₂ and B₆
• Resorption: passive resorption in the intestine
• Transport in blood: as nicotinate

Active forms of Niacin are NAD+ and NADP+.

Functions

• Cofactor for redox reactions (e.g., alcohol dehydrogenase, isocitrate dehydrogenase, G6PD)

Vitamin B₃ deficiency ^[13]

• Causes
  • Malnutrition
  • Heavy drinking
  • Conditions associated with tryptophan deficiency
    • Hartnup disease: decreased renal and intestinal tryptophan absorption
    • Carcinoid syndrome (if metabolically active): increased tryptophan metabolism
  • Vitamin B₆ deficiency (e.g., due to treatment with isoniazid): decreased niacin synthesis from tryptophan
  • Chronic consumption of grains (e.g., corn) that have not been processed by nixtamalization (common cause in developing countries)
• Clinical features
  • Glossitis
  • Pellagra (caused by severe deficiency)
    • Characteristic dermatitis
      • Circular broad collar rash on the neck (Casal necklace); affects dermatomes C3 and C4
      • Hyperpigmented skin lesions in sun-exposed areas (especially on the limbs)
    • Diarrhea and vomiting
    • Neurologic symptoms; (e.g, dementia, hallucinations, anxiety, insomnia, encephalopathy)

3 typical features of severe vitamin B3 Deficiency: Dermatitis, Diarrhea, and Dementia.

Vitamin B₃ toxicity

• Facial flushing: due to prostaglandin release and NOT due to histamine; (typically seen when niacin therapy is started, can be avoided by coadministration of aspirin) ^[17]
• Hyperuricemia, podagra
• Hyperglycemia
• Possibly: nausea, vomiting, pruritus, hives ^[12]

Therapeutic use

• Dyslipidemia: Niacin lowers VLDL and increases HDL serum levels (see “Second-line lipid-lowering agents”).

Characteristics

• Synonyms: pantothenic acid, pantothenate
• Substance class: carboxylic acid
• Inactive precursor (provitamin): none
• Active forms: pantothenic acid
• Sources: liver, kidney, egg yolks, broccoli, milk
• Transport in blood: bound to proteins

Functions

• Essential component of coenzyme A (pantothenic acid + ADP + cysteine)
  • Cofactor for the transfer of acyl groups → activation of carboxylic acids (e.g., pyruvate dehydrogenase, α-ketoglutarate dehydrogenase)
  • Cofactor for fatty acid, cholesterol, and acetylcholine synthesis

Vitamin B₅ deficiency ^[13]

Deficiency is rare.

• Causes: malnutrition
• Clinical features
  • Adrenal insufficiency; may lead to distal paresthesias and dysesthesias (burning sensation of the feet)
  • Alopecia
  • Dermatitis
  • Enteritis

Vitamin B5 is pentothenic acid, as in “pente,” the Greek word for “five.”

Characteristics

• Synonyms: pyridoxine
• Substance class: pyridoxine
• Inactive precursor (provitamin): none
• Active form: pyridoxal phosphate (PLP)
• Sources: nuts, whole grains, vegetables, yeast, meat (esp. liver and poultry) ^[13]
• Resorption: cleavage by phosphorylases and subsequent resorption by the intestine
• Transport in blood: partially free, partially bound to albumin

Functions

• PLP is a coenzyme for the following reactions:
  • Transamination (e.g., AST and ALT)
  • Decarboxylation
  • Amino acid metabolism
  • Glycogenolysis (glycogen phosphorylase)
• Involved in the synthesis of:
  • Heme
  • Histamine
  • Niacin
  • Gluthathione
  • Cystathionine
  • Neurotransmitters, including:
    • Serotonin
    • Dopamine
    • Epinephrine
    • Norepinephrine
    • GABA

Vitamin B₆ deficiency ^[18]

• Causes
  • Malnutrition
  • Heavy drinking
  • Chronic renal failure
  • Chronic hepatitis
  • Drug interactions
    • Isoniazid
    • Oral contraceptives
• Clinical features
  • Cheilosis, glossitis, stomatitis
  • Sideroblastic anemia: Vitamin B₆ deficiency causes heme synthesis dysfunction with impaired transfer of iron to hemoglobin, which ultimately leads to iron accumulation in RBCs.
  • Irritability, seizures, peripheral neuropathy
  • Seborrheic dermatitis

Vitamin B₆ toxicity

• Causes: : oversupplementation
• Clinical features
  • Dizziness
  • Nausea
  • Peripheral neuropathy
  • Dermatosis, photosensitivity ^[12]

Although rare, excess pyridoxine can lead to irreversible sensory neuropathy.

Therapeutic use

• Tuberculosis: administer pyridoxine to prevent INH-induced peripheral neuropathy
• Hyperemesis gravidarum

Characteristics

• Synonyms: biotin
• Inactive precursor (provitamin): none
• Active form: biotin
• Sources
  • Plants (e.g., soy products, nuts), animal products (e.g., liver, egg yolk, dairy products)
  • Small amounts are synthesized by intestinal flora
• Resorption: pancreatic enzyme biotinidase cleaves protein-bound biotin into free biotin → active intestinal resorption
• Transport in blood: mainly free

Functions

• Coenzyme for various carboxylase enzyme complexes, which all add a 1-carbon group
  • Fatty acid synthesis: acetyl-CoA carboxylase
    • Acetyl-CoA (2C) → malonyl-CoA (3C)
  • Gluconeogenesis: pyruvate carboxylase
    • Pyruvate (3C) → oxaloacetate (4C)
  • Fatty acid reduction: propionyl-CoA carboxylase
    • Propionyl-CoA (3C) → methylmalonyl-CoA (4C)

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

Vitamin B₇ deficiency (biotin deficiency)

• Deficiency is rare
• Causes
  • Malnutrition
  • Prolonged use of antibiotics (destruction of intestinal flora)
  • Excessive consumption of raw egg white: contains avidin → binds biotin in the intestinal lumen → inhibition of biotin resorption
• Clinical features
  • Dermatitis
  • Conjunctivitis
  • Enteritis
  • Alopecia
  • Myalgia
  • Neurological symptoms: lethargy, depression, mental status changes, hallucinations, paresthesia

Biotin binds to avidin, which is found in raw egg whites: Biotin loves avidin!

Characteristics

• Synonyms: folic acid, folate
• Substance class: pteridines
• Inactive precursor (provitamin): none
• Active form: tetrahydrofolic acid (THF)
• Sources
  • Leafy green vegetables, fortified foods (e.g., bread, flour, and cereal)
  • Small amounts are synthesized in intestinal flora
• Resorption: jejunum via specific transporters
• Transport in blood: via folate-binding transport proteins
• Storage: small reserve in the liver (enough for approx. 3–4 months)

Foliage (leafy green vegetables) contains Folate.

Function

• See “Folate deficiency” for details.

Vitamin B₉ deficiency ^[19]

• See “Folate deficiency” for details.

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

Therapeutic uses

• Prenatal supplementation (0.4–0.8 mg per day): To reduce the risk of neural tube defects, women should take a folate supplement, starting at least 4 weeks before conception and throughout the first trimester (see “Folic acid supplementation in pregnancy”).

Characteristics

• Synonyms: cobalamin
• Substance class: cobalamin
• Inactive precursor (provitamin): none
• Active forms: methylcobalamin and adenosylcobalamin (activation occurs in the liver)
• Sources
  • Synthesis: Only microorganisms can produce vitamin B₁₂.
    • The colonic flora produces vitamin B₁₂.
    • However, vitamin B₁₂ produced by colonic flora cannot be absorbed by the body because the terminal ileum (absorption site) lies prior to the colon.
  • Found almost exclusively in animal products (except yeast extract)
  • Some dried and fermented plant foods (e.g., tempeh, nori)
• Absorption
  • Stomach: Cobalamin is released from ingested proteins by pepsin and binds to the glycoprotein haptocorrin (R-protein), which protects it from gastric acid. ^[20]
  • Duodenum: Cobalamin is released from haptocorrin by trypsin and binds to intrinsic factor (IF), a protein produced by the parietal cells of the stomach that facilitates cobalamin absorption in the ileum.
  • Terminal ileum: cubilin receptor‐mediated endocytosis of the intrinsic factor-cobalamin complex → breakdown of IF in enterocytes, release of cobalamin, followed by binding to carrier protein transcobalamin II and then enters the plasma → cobalamin is either delivered to metabolically active tissues or stored in the liver
• Transport in blood: via transcobalamin
• Storage: large reserve pool
  • 60% in the liver (enough for approx. 3–4 years)
  • 30% in muscle tissue

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

Functions

• Cofactor for enzymes:
  • Methionine synthase: Methylcobalamin is required for the transfer of methyl groups (e.g., in DNA synthesis).
  • Methylmalonyl-CoA mutase (e.g., in odd-chain fatty acid metabolism)

Vitamin B₁₂ deficiency

• See “Vitamin B₁₂ deficiency.”

Therapeutic uses

• Prenatal supplementation for vegetarians (2 μg per day)

Characteristics

• Synonyms: ascorbic acid, ascorbate
• Substance class: lactones
• Inactive precursor (provitamin): none
• Active form: ascorbate
• Sources: fruits and vegetables
• Resorption
  • Passive resorption via oral mucosa
  • Active resorption in the intestine (especially jejunum)
• Transport in blood: mainly free, 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)

Functions

• Antioxidant: ascorbate and dehydroascorbate form a redox system
  • Can cause false-negative results on stool guaiac test, which is a color-producing oxidant reaction ^[21]
• Promotes intestinal iron resorption
  • As chelating agent: increases iron solubility through chelate complex formation
  • As redox partner: reduces poorly soluble Fe³⁺into highly soluble Fe²⁺ → intestinal absorption
• Coenzyme for important enzymatic reactions
  • Collagen synthesis: hydroxylation of proline and lysine
  • Noradrenaline synthesis: required for dopamine β-hydroxylase (hydroxylation of dopamine to noradrenaline)
  • Carnitine synthesis
  • Peptide hormone synthesis from prehormones (e.g., vasopressin, calcitonin, oxytocin)

Think of vitamin C as “absorbic acid” since it promotes the intestinal absorption of iron.

Vitamin C deficiency ^[13]

• Causes: severe malnutrition (e.g., due to alcoholism, illicit drug use, and/or psychiatric illness)
• Clinical features
  • Scurvy: clinical manifestation of vitamin C deficiency, which leads to impaired collagen synthesis and easily damaged connective tissue
    • Follicular hyperkeratosis, perifollicular hemorrhage, coiled “corkscrew” hair
    • Subperiosteal hemorrhage
    • Gingivitis, swollen gums
    • Mucosal bleeding, easy bruising, petechiae
    • Impaired wound healing
    • Arthralgia, hemarthrosis
    • Signs of anemia (fatigue, paleness) ; ^[22]
      • Normocytic anemia: decreased iron absorption in the small intestine
      • Macrocytic anemia: decreased conversion of folate into its active metabolite
  • Poor immune response
• Diagnosis: established via measurement of plasma or leukocyte vitamin C levels

Vitamin C deficiency results in sCurvy due to impaired Collagen synthesis.

Vitamin C toxicity

• Causes: oversupplementation
• Clinical features
  • Nausea, vomiting
  • Diarrhea, bloating
  • Fatigue
  • ↑ Risk of iron toxicity in transfusion patients and hereditary hemochromatosis due to increased absorption of dietary iron
  • Nephrolithiasis due to ↑ calcium oxalate formation

Therapeutic use

• Supportive treatment for methemoglobinemia: Vitamin C reduces Fe³⁺ to Fe²⁺