Vitamins - Biochemistry MBBS 1st Year: Functions, Deficiencies & Toxicity

Vitamins are essential organic micronutrients required in small amounts to maintain normal metabolism, growth, and physiological functions. Most vitamins act as coenzymes or regulatory molecules in key biochemical reactions, making them indispensable for energy production, DNA synthesis, hematopoiesis, nervous system function, and tissue integrity. 

In biochemistry, the study of vitamins forms a strong bridge between basic metabolic pathways and clinical medicine, as deficiencies, excess intake, and drug interactions produce well-defined disease states. A thorough understanding of vitamin classification, biochemical functions, dietary sources, deficiency manifestations, and toxicities is therefore crucial not only for MBBS 1st-year examinations but also for clinical correlation and future medical practice.

Important Clinical Aspects & Exam Preparation

1. Exam Question Formats

This topic yields both Long Answer Questions (LQs) and Short Answer Questions (SQs).

• Important LQs include:

• Folic Acid and Vitamin B12 (a must-read question)

• Vitamin A

• Vitamin D

• Vitamin C

• Important SQs include:

• Pyridoxine (B6)

• Beriberi (B1 deficiency)

• Folate Trap

• Pellagra (B3 deficiency)

• Megaloblastic Anemia

• Wernicke-Korsakoff Syndrome

• Wald's Visual Cycle

• Other LQs can group vitamins by function:

• Antioxidant Vitamins (Vitamin A/Beta-carotene, Vitamin E, Vitamin C)

• Hematopoietic Vitamins (Vitamin B12, Folic Acid, Pyridoxine)

• Energy-Releasing B-Complex Vitamins (B1, B2, B3, B5, B6, B7)

2. How to Study and Answer Questions

For each vitamin, focus on four key areas:

1. RDA (Recommended Dietary Allowance)

2. Dietary Sources (mention specific rich sources)

3. Biochemical Functions

4. Deficiency Manifestations

Specific Rich Sources Examples:

• Vitamin E: Vegetable oils

• Folic Acid: Green leafy vegetables (folium means leaf)

• Vitamin B12: Exclusively food of animal origin

• Vitamin A: Cod liver oil, shark liver oil, orange-colored fruits, green leafy vegetables

3. Vitamin Toxicity

Toxicity is important for four specific vitamins:

1. Vitamin A: Chronic toxicity from self-medication (e.g., for acne).

2. Vitamin D: Toxicity from excessive supplementation.

3. Pyridoxine (B6): Toxicity when co-administered with Isoniazid (INH).

4. Niacin (B3): Nicotinic acid used to reduce lipid levels can cause toxicity.

Overview of Vitamin Deficiency Disorders

Here are key deficiency disorders and their associated vitamins:

• Night Blindness (Nyctalopia): Vitamin A

• Rickets & Osteomalacia: Vitamin D

• Bleeding Manifestations: Vitamin K (Memory Tip: K for Koagulation)

• Beriberi: Thiamine (B1)

• Ariboflavinosis: Riboflavin (B2)

• Pellagra: Niacin (B3) (Classical 3Ds: Diarrhea, Dementia, Dermatitis)

• Scurvy: Vitamin C (petechial hemorrhages, bleeding gums)

• Biotin (B7) Deficiency: Dermatitis, Alopecia, Dementia (DAD)

• Burning Feet Syndrome: Pantothenic acid (B5)

• Neurological Manifestations & Anemia: Pyridoxine (B6)

• Subacute Combined Degeneration of the Spinal Cord: Vitamin B12

• Megaloblastic Anemia: Folic Acid or Vitamin B12

Fat-Soluble Vitamins (A, D, E, K)

Vitamins are classified into fat-soluble (A, D, E, K) and water-soluble types.

Vitamin A

1. Vitamers and Forms

Retinoids possess Vitamin A activity:

• Retinol (alcohol form)

• Retinal (aldehyde form)

• Retinoic Acid (acid form)

• Beta-carotene: A pro-vitamin yielding two retinal molecules; provides antioxidant function.

2. Recommended Dietary Allowance (RDA)

• Adult Male & Female: 600 micrograms/day

• Pregnancy: 800 micrograms/day

• Lactation: 950 micrograms/day

3. Dietary Sources

• Richest Sources: Cod liver oil, fish liver oil.

• Pro-vitamin A (Beta-carotene): Orange-colored fruits and green leafy vegetables.

4. Biochemical Functions

• Vision: Retinal is part of rhodopsin in the visual cycle.

• Epithelial Maintenance: Retinol maintains epithelia, especially germinal epithelium, and aids mucus production.

• Growth and Differentiation: Retinoic acid regulates gene expression via intranuclear receptors.

• Antioxidant Function: Beta-carotene has a significant antioxidant role.

• Skin Health: Prevents hyperkeratinization.

5. Deficiency Manifestations

This is the most common cause of preventable blindness.

Ocular Manifestations (WHO Classification):

• XN: Night Blindness (Nyctalopia) - earliest sign.

• X1A: Conjunctival Xerosis (dry conjunctiva).

• X1B: Bitot's Spots (keratin deposition on conjunctiva).

• X2: Corneal Xerosis (dry cornea).

• X3A/B: Corneal ulceration.

• XS: Corneal Scarring.

Skin Manifestations:

• Phrynoderma ("toad skin"): Hyperkeratinization, giving a rough appearance. It's a multi-deficiency disorder, primarily Vitamin A and essential fatty acid deficiency.

6. Toxicity (Hypervitaminosis A)

• Acute Toxicity: From highly concentrated sources (e.g., polar bear liver).

• Chronic Toxicity: From long-term, high-dose supplementation.
  Key Toxic Effects:

• Raised Intracranial Tension (Pseudotumor Cerebri): Mimics brain tumors, causing headache and papilledema.

• Bone Damage: Osteoclastic lesions, frequent fractures.

• Teratogenicity: Contraindicated in pregnancy due to birth defect risk.

7. Wald's Visual Cycle

Crucial for dim light vision. Rhodopsin, made of 11-cis-retinal and Opsin, absorbs light. Light isomerizes 11-cis-retinal to all-trans-retinal, activating a G-protein (transducin) and triggering a nerve impulse. Regeneration: All-trans-retinal converts back to 11-cis-retinal. (Memory Tip: For the diagram, Left Side is 11-cis, Right Side is all-trans; Above the line is Retinal, Below is Retinol).

Vitamin D (The Sunshine Vitamin)

Vitamin D is also a hormone due to its endogenous synthesis and steroid hormone-like action on gene expression (e.g., Calbindin synthesis).

1. Synthesis and Activation

1. Skin: 7-dehydrocholesterol converts to Cholecalciferol (Vitamin D3) with UV light.

2. Liver: D3 becomes 25-hydroxycholecalciferol (storage/transport form).

3. Kidney: 25-hydroxycholecalciferol becomes 1,25-dihydroxycholecalciferol (Calcitriol), the active form.

2. Recommended Dietary Allowance (RDA)

• Children: 400 IU/day

• Adults: 200 IU/day

3. Dietary Sources

• Mainly sunlight exposure.

• Dietary sources: Egg yolk, liver, liver oils, meat.

4. Functions & Mechanism of Action

Essential for calcium and phosphorus homeostasis, increasing serum calcium by acting on:

1. Intestine: Increases calcium/phosphorus absorption (via calbindin).

2. Kidney: Increases calcium reabsorption.

3. Bone: Promotes mineralization. Can also increase bone resorption with PTH.

5. Deficiency Manifestations

Leads to defective bone mineralization.

• Rickets (in Children): Soft bones, Craniotabes, Rachitic rosary, Harrison's sulcus, bowing of legs.

• Osteomalacia (in Adults): Softening of bones, fractures, bone pain.
  Both show increased serum alkaline phosphatase.

6. Toxicity

Causes hypercalcemia, leading to calcinosis (soft tissue calcium deposition) and elevated blood pressure.

Vitamin E (Tocopherol)

1. Forms and Activity

Tocopherols and tocotrienols are active forms. Alpha-tocopherol is most active. It's a powerful antioxidant due to its 6-hydroxychroman ring. Also known as the anti-sterility vitamin.

2. Recommended Dietary Allowance (RDA)

• Male: 10 mg/day

• Female: 8 mg/day

3. Dietary Sources

Most important sources are vegetable oils (sunflower, safflower, soybean oil).

4. Functions: Antioxidant Activity

Vitamin E is a chain-breaking antioxidant preventing lipid peroxidation. It donates a hydrogen atom to peroxyl radicals, neutralizing them. Vitamin C regenerates active Vitamin E. Selenium works synergistically as a cofactor for glutathione peroxidase, which detoxifies formed lipid peroxides.

Benefits: Maintains RBC membrane integrity, prevents LDL oxidation (protects against atherosclerosis), and may protect against cataract formation.

5. Deficiency and Toxicity

• Deficiency: Can cause sterility and mild hemolytic anemia.

• Toxicity: Least toxic of fat-soluble vitamins.

Vitamin K

Vitamin K is the only fat-soluble vitamin with a confirmed coenzyme function. (Memory Tip: K for Koagulation).

1. Forms

Naphthoquinone derivatives:

• K1 (Phylloquinone): Green leafy vegetables.

• K2 (Menaquinone): Synthesized by intestinal microflora.

• K3 (Menadione): Synthetic, water-soluble form.

2. Recommended Dietary Allowance (RDA)

• 30 to 100 micrograms/day.

3. Dietary Sources

• K1: Green leafy vegetables (e.g., spinach).

• K2: Animal products.

4. Function: Post-Translational Modification

Vitamin K is a coenzyme for gamma-glutamyl carboxylase, enabling gamma-carboxylation of glutamate residues in proteins. This adds a second carboxyl group, creating a gamma-carboxyglutamate (Gla) residue that binds calcium ions (Ca²⁺). This is crucial for:

• Blood Clotting Factors: Factors II (Prothrombin), VII, IX, and X.

• Other Proteins: Osteocalcin, Protein C, Protein S.

5. Deficiency

• Symptom: Bleeding tendency due to inactive clotting factors.

• Hemorrhagic Disease of the Newborn: High risk in newborns due to poor placental transfer, sterile gut, and immature liver. Prophylactic Vitamin K (1 mg IM) is routinely given.

Recap of Fat-Soluble Vitamins (A, D, E, K)

• RDA Values:

• Vitamin A: 600 µg

• Vitamin D: 200 IU

• Vitamin E: 10 mg

• Vitamin K: 30-100 µg

• Key Points for Vitamin K:

• K3 (Menadione) is a synthetic, water-soluble form (important for MCQs).

• K2 (Menaquinone) is produced endogenously by intestinal microflora.

• Coenzyme Activity: Vitamin K is crucial for post-translational gamma-carboxylation of glutamic acid residues in clotting factors II, VII, IX, and X, enabling calcium binding for blood clotting.

• Mechanism & Inhibition: Vitamin K epoxide reductase regenerates active Vitamin K. Warfarin and Dicoumarol are competitive inhibitors of this enzyme (important for MCQs).

• Deficiency: Causes hemorrhagic tendencies in neonates.

Water-Soluble Vitamins (B-Complex and C)

Vitamin B1 (Thiamine)

• Coenzyme Form: Thiamine Pyrophosphate (TPP)

• RDA: 1.0–1.5 mg/day (increases with carbohydrate intake).

Biochemical Functions

Thiamine is an energy-releasing vitamin vital for carbohydrate metabolism.

1. Oxidative Decarboxylation: TPP is a coenzyme for:

• Pyruvate Dehydrogenase (PDH) Complex

• α-Ketoglutarate Dehydrogenase Complex

• Branched-Chain α-Ketoacid Dehydrogenase Complex
  These complexes require five coenzymes: TPP (B1), Lipoic Acid, Coenzyme A (B5), FAD (B2), NAD (B3).

2. Transketolase Activity: TPP is a coenzyme for transketolase in the Hexose Monophosphate (HMP) Shunt. RBC transketolase activity assesses thiamine status (important for MCQs).

3. Nerve Function: Important for nerve conduction and acetylcholine synthesis.

Deficiency Manifestations: Beriberi

Means "weakness."

Wernicke-Korsakoff Syndrome

• Occurs in chronic alcoholics, impairing thiamine absorption and TPP conversion.

• Wernicke's Encephalopathy: Characterized by the triad: (Memory Tip: GOA - **G**lobal **C**onfusion, **O**phthalmoplegia, **A**taxia).

• Korsakoff's Psychosis: Memory loss and psychosis.

Vitamin B2 (Riboflavin)

• Coenzyme Forms: Flavin Mononucleotide (FMN) and Flavin Adenine Dinucleotide (FAD).

• RDA: 1.5 mg/day.

• Function: Crucial for oxidation-reduction (dehydrogenation) reactions. FADH₂ yields 1.5 ATP. Examples include Succinate Dehydrogenase (FAD-dependent) and NADH Dehydrogenase (FMN-dependent).

Deficiency Manifestations (Ariboflavinosis)

Presents with circumoral and ocular signs:

• Cheilosis (lip inflammation).

• Angular Stomatitis (fissures at mouth corners).

• Glossitis (tongue inflammation, magenta-red color).

• Seborrheic Dermatitis.

• "Pink eye" (circumcorneal vascularization).

Vitamin B3 (Niacin)

• Coenzyme Forms: Nicotinamide Adenine Dinucleotide (NAD⁺) and Nicotinamide Adenine Dinucleotide Phosphate (NADP⁺).

• RDA: 20 mg/day.

• Endogenous Synthesis: From Tryptophan (60 mg Tryptophan yields 1 mg Niacin).

Biochemical Functions

• NAD⁺-linked Reactions (Catabolic): Oxidizing agent in energy pathways (Glycolysis, PDH Complex, TCA Cycle).

• NADPH-linked Reactions (Anabolic): Reducing agent in reductive biosynthesis (fatty acid, cholesterol, steroid synthesis). HMP shunt is the major source of NADPH.

Deficiency: Pellagra

Characterized by the "3 Ds":

1. Dermatitis: Photosensitive, forming Casal's necklace.

2. Diarrhea

3. Dementia
   Untreated, can lead to a fourth D: Death.

Causes of Pellagra

1. Dietary Deficiency: Low Niacin/Tryptophan intake.

2. Hartnup's Disease: Defective Tryptophan absorption.

3. Vitamin B6 Deficiency: Blocks tryptophan-to-niacin pathway.

4. Jowar (Sorghum) Staple: High leucine inhibits niacin synthesis.

5. Maize (Corn) Staple: Niacin in maize is non-bioavailable.

6. Carcinoid Syndrome: Tryptophan diverted to serotonin synthesis.

Vitamin B6 (Pyridoxine)

• Forms: Pyridoxine, Pyridoxamine, Pyridoxal.

• Active Coenzyme Form: Pyridoxal Phosphate (PLP).

• RDA: 2 mg/day.

Biochemical Functions

PLP is a versatile coenzyme in amino acid metabolism.

Key PLP-Dependent Reactions:

1. Transamination: Transfer of amino groups (e.g., AST/SGOT, ALT/SGPT).

2. Decarboxylation: Synthesis of biogenic amines (GABA, histamine, serotonin).

3. Trans-sulfuration: Conversion of homocysteine to cysteine (deficiency causes homocystinuria).

4. Heme Synthesis: First step, catalyzed by ALA synthase.

5. Glycogenolysis: Coenzyme for glycogen phosphorylase (80% of body's PLP is here).

Deficiency Manifestations

• Neurological Symptoms: Neuropathy, seizures (impaired neurotransmitter synthesis).

• Sideroblastic Anaemia: Impaired heme synthesis.

• Homocystinemia/Homocystinuria: Increased thrombosis risk.

• Drug-Induced Deficiency: By Isoniazid (INH).

Vitamin B5 (Pantothenic Acid)

• Coenzyme Forms: Coenzyme A (CoA) and Acyl Carrier Protein (ACP).

• RDA: 10 mg/day.

• Function: Central to metabolism as an acyl group carrier. CoA is in Acetyl-CoA, Succinyl-CoA (TCA cycle, β-oxidation). ACP is essential for fatty acid synthesis.

Deficiency Manifestations

Rare causes Burning Feet Syndrome.

Vitamin B7 (Biotin)

• Coenzyme Form: Biotin or Biocytin.

• RDA: 30–50 µg/day (also synthesized by intestinal microflora).

• Function: Coenzyme for carboxylation reactions (addition of CO₂), requiring A**TP, **B**iotin, and **C**O₂. **Key Biotin-Dependent Carboxylase Enzymes:

1. Acetyl-CoA Carboxylase (rate-limiting in fatty acid synthesis).

2. Pyruvate Carboxylase (gluconeogenesis).

3. Propionyl-CoA Carboxylase (odd-chain fatty acid metabolism).

Deficiency Causes and Manifestations

• Causes:

1. Raw egg whites: Avidin binds biotin.

2. Prolonged antibiotic therapy: Reduces gut flora.

• Symptoms: Dermatitis, Alopecia, Dementia (DAD), mild hemolytic anaemia.

Vitamin B9 (Folic Acid)

• Source: Primarily "foliage" (green leafy vegetables).

• RDA: 200 µg/day (400-500 µg/day in pregnancy).

• Active Coenzyme Form: Tetrahydrofolate (THF), formed by dihydrofolate reductase (inhibited by methotrexate).

Biochemical Function: One-Carbon Metabolism

THF carries one-carbon units.

1. Interconversion of Glycine and Serine.

2. Purine Nucleotide Synthesis: THF donates C2 and C8 atoms.

3. Thymidylate Synthesis: Essential for converting dUMP to dTMP (DNA building block) via thymidylate synthase.

4. Methionine Regeneration: Donates a methyl group to regenerate methionine from homocysteine (requires Vitamin B12).

Deficiency Manifestations

• Megaloblastic Anaemia: Impaired purine/thymidylate synthesis blocks DNA synthesis, causing cell cycle arrest and large cells (macro-ovalocytes, MCV > 100 fL, hypersegmented neutrophils).

• Neural Tube Defects (NTDs) in Pregnancy: Major cause of spina bifida and anencephaly.

• Laboratory Diagnosis: Increased urinary formiminoglutamic acid (FIGLU) excretion after a histidine load.

Vitamin B12 and the Folate Trap

The Folate Trap Hypothesis

A Vitamin B12 deficiency blocks the conversion of homocysteine to methionine (catalyzed by methionine synthase, using methyl-THF). This also blocks the regeneration of active THF from methyl-THF. As methyl-THF has no other metabolic fate, it accumulates, leading to a functional deficiency of folate, known as the "folate trap." This functional deficiency impairs DNA synthesis, causing megaloblastic anemia.

Biochemical Functions of Vitamin B12

Vitamin B12 is a coenzyme for only two major reactions:

1. Methionine Synthesis (Homocysteine Methylation): Converts Homocysteine to Methionine (coenzyme: Methyl-B12).

2. Isomerization of Methylmalonyl-CoA: Converts Methylmalonyl-CoA to Succinyl-CoA (coenzyme: Adenosyl-B12).

Clinical Implications of B12 Deficiency

Deficiency in B12 leads to Methylmalonyl-CoA accumulation, causing:

1. Metabolic Markers: Increased methylmalonic acid in blood (methylmalonic acidemia) and urine (methylmalonic aciduria).

2. Neurological Damage: Accumulated methylmalonyl-CoA impairs fatty acid synthesis, leading to defective myelin synthesis and subacute combined degeneration of the spinal cord, causing loss of position and vibration sense.

Vitamin C (Ascorbic Acid)

• Requirement: 60-75 mg/day.

• Sources: Citrus fruits, Amla.

• Historical Context: British Navy used lemons to prevent scurvy (sailors called "Limeys").

Core Function: Collagen Synthesis

Vitamin C is a coenzyme in hydroxylation reactions, essential for prolyl and lysyl hydroxylase. This converts Proline to Hydroxyproline and Lysine to Hydroxylysine, crucial for the proper formation and stabilization of the collagen triple helix.

Deficiency: Scurvy

Impairs collagen synthesis, causing:

• Bleeding gums and loose teeth.

• Delayed wound healing.

• Capillary fragility, leading to petechial hemorrhages.

Comparative Role in Collagen Formation: Vitamin C vs. Copper

Other Functions of Vitamin C

Antioxidant property, metabolism of tyrosine/tryptophan, steroid synthesis, bone and teeth formation.

Clinical Cases and Rapid Review Questions

• Case 1: Patient with fissured tongue, angular stomatitis, and reduced glutathione reductase activity in RBCs.

• Diagnosis: Vitamin B2 (Riboflavin) deficiency.

• Case 2: Alcoholic patient with respiratory distress, edema, and high-output cardiac failure.

• Diagnosis: Vitamin B1 (Thiamine) deficiency (Wet Beriberi).

• Question: Biotin is a coenzyme for all carboxylation reactions EXCEPT the conversion of Glutamate to Gamma-carboxyglutamate.

• Answer: This is a Vitamin K-dependent reaction.

• Question: Vitamin B12 is NOT required for which reaction?

• Answer: Glycogen phosphorylase activity, which requires Pyridoxal Phosphate (Vitamin B6).

• Question: Name the antioxidant vitamins.

• Answer: Beta-carotene (pro-vitamin A), Alpha-tocopherol (Vitamin E), and Ascorbic Acid (Vitamin C).

• Question: Diagnosis for macrocytic anemia with increased urinary excretion of methylmalonic acid?

• Answer: Vitamin B12 deficiency. (If FIGLU excretion increased, it's Folic Acid deficiency).

• Question: What deficiency causes bleeding gums, delayed wound healing, and petechiae?

• Answer: Vitamin C deficiency (Scurvy).

• Image: Casal's necklace (photosensitive dermatitis on neck).

• Diagnosis: Pellagra (Vitamin B3/Niacin deficiency).

• Image: Large, oval RBCs and hypersegmented neutrophils (Megaloblastic Anemia) with increased FIGLU excretion.

• Diagnosis: Folic Acid deficiency.

• Case: Patient with fatigue, tingling in lower limbs, and reduced position/vibration sense, diagnosed with subacute combined degeneration of the spinal cord.

• Diagnosis: Vitamin B12 deficiency.

• Image: Bowing of the legs.

• Diagnosis: Rickets (Vitamin D deficiency).

• Memory Tip: Site of Absorption for Key Micronutrients

• **D**uodenum: **I**ron

• **J**ejunum: **F**olic Acid

• **I**leum: **B**12

• Thus, ileal resection risks Vitamin B12 deficiency.

Comprehensive Vitamin Summary

The important vitamins with their chemical name and coenzymes are:

Memory Tip: A coenzyme is a NOLD: "N"on-protein, "O"rganic, "L"ow-molecular weight, "D"ialyzable substance

Summary Tables