6th February 2024

Vitamins

Vitamins

Vitamins are organic molecules that function in various body capacities, including cofactors in many enzymatic reactions. They typically cannot be synthesised by mammalian cells and, as such, are supplied from dietary sources. They are separated as water-soluble (Vitamins B1-12 and Vitamin C) and fat Soluble (Vitamin A, D, E and K) 

Vitamin B Complexes

Vitamin B1 

Thiamine is derived from pyrimidine and a thiazole, coupled by a methylene bridge. It is absorbed in the small intestine. Vitamin B1 is involved in the TCA cycle as a critical cofactor for pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. It is also crucial for the branched-chain amino acid metabolism, leucine, isoleucine and valine.

Image Source: Wikimedia Commons (2007). Thiamine pyrophosphate V2, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/a/aa/Thiamine_pyrophosphate_V2.svg  (Accessed: 4 January 2023).

Dietary requirements of thiamine are proportional to calorific intake due to its role in metabolism. The primary sources include whole-grain cereals, navy beans, kidney beans, wheat germ, pork, and fish. 

Thiamine deficiency can lead to constipation, appetite suppression, and nausea. Chronic deficiency can lead to neuropathy, fatigue and lethargy, and with time, central neurological symptoms such as ataxia, confusion, and nystagmus.

Dietary deficiency is known as beriberi. It is further distinguished as dry versus wet beriberi. Dry beriberi is associated with chronic alcohol consumption. Alcohol impairs the uptake of thiamine from the small bowel. It is characterised by Confusion, Ataxia and Nystagmus (CAN). 

Wet beriberi is when there is prolonged deficiency leading to cardiovascular manifestations. In prolonged deficiency, there is four-chamber cardiac dilatation due to the loss of aerobic metabolic processes, leading to fluid retention and symptoms of left and right heart failure.

When thiamine deficiency is prolonged and left untreated, there is a risk of a condition called Wernicke-Korsakoff Syndrome, a combination of Wernicke’s Syndrome and confabulation and hallucinations. The features of Korsakoff are not reversible with treatment with thiamine.

Vitamin B2 

Riboflavin is a precursor for the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). It is also absorbed in the small intestine and involved in multiple dehydrogenase cascades. Riboflavin is found in eggs, milk and cereals, and due to its wide availability, B2 deficiency is rare. Symptoms include itching and burning eyes, angular stomatitis and cheilosis. Several congenital deficiencies secondary to gene mutation cause reduced uptake, leading to neurological disorders characterised by progressive pontobulbar palsy associated with sensorineural deafness – Brown-Vialetto-Van Laere Syndrome (BVVL).

Vitamin B3 

Nicotinic Acid and nicotinamide are the dietary sources for the active forms of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). It is also absorbed in the small intestine, and unlike the vitamins mentioned earlier, a small quantity can be synthesised within the body through the amino acid tryptophan. There needs to be more to achieve the daily recommended requirements, and as such, dietary sources found in meats, liver, peanuts and whole grains are needed. Pellagra is caused by niacin deficiency. It is characterised by the three D’s -dermatitis, diarrhoea and depression.

Other causes of niacin deficiency include isoniazid, a common anti-tuberculosis drug. Conditions which affect tryptophan metabolism, including carcinoid syndrome and Hartnup disorder, in which tryptophan absorption is impaired, can lead to niacin deficiency. 

Vitamin B5 

Pantothenic acid is synthesised in the large bowel from pantoic acid and β-alanine. It is involved in synthesising coenzyme A. Whilst it is vital for a diverse range of metabolic processes. Regarding clinical significance, deficiency is extremely rare, and symptoms are non-specific, including sensory change, dizziness, digestive disturbance, vomiting, and restlessness. 

Vitamin B6

The bioactive form of Vitamin B6 is pyridoxal phosphate (PLP). It is synthesised from pyridoxine, pyridoxamine and pyridoxal. PLP is a cofactor for the catabolism of amino acids. It synthesises several neurotransmitters, including serotonin and the catecholamines dopamine, noradrenaline, adrenaline, and γ-aminobutyric acid. It also has a role in heme synthesis.

B6 deficiency is rare and is seen in chronic malnutrition states similar to the other B vitamins. It is also seen in isoniazid use and penicillamine use.

Due to its role in heme synthesis, it can lead to microcytic hypochromic anaemia. Due to reduced heme production, there are increased iron deposits in erythroblast mitochondria, forming ringed sideroblasts and increased concentration of serum iron and ferritin.

Vitamin B7 

Biotin is required as a cofactor for carboxylation, decarboxylation or transcarboxylation reactions. In humans, it is involved in fatty acid synthesis gluconeogenesis. Deficiency is only seen in prolonged antibiotic use, which depletes the intestinal commensal bacteria, or following excessive raw egg consumption, in which white egg protein prevents intestinal biotin absorption or in biotinidase deficiency, which is a rare autosomal recessive inherited disorder.

Vitamin B9

Folic acid and folate are sometimes used interchangeably. However, they are different terms. Folate is a generic descriptor for a family of structurally related compounds with a pteroylglutamic acid core (folic acid). Folic acid is rarely found in nature and is available as a commercially synthesised product.

The bioactive form of folic acid includes dihydrofolate (DHF) and tetrahydrofolate (THF) and their derivatives. It is absorbed in the jejunal mucosa. It is crucial for synthesising all purines and thymidine used for DNA and RNA synthesis. 

Folic acid is directly correlated to neural tube defects and is recommended as a supplement in pregnancy. Due to its role in DNA synthesis, it is a state of amplified cell division, such as in the developing foetus in pregnancy.

During DNA synthesis, folic acid deficiency leads to impaired dTMP synthesis, leading to cell cycle arrest. As such, haemopoiesis is impaired, resulting in megaloblastic anaemia. Additionally, without DHF, there is no conversion of homocysteine to methionine, resulting in elevated serum levels associated with cardiovascular diseases such as atherosclerosis and venous thromboembolic disease. 

Vitamin B12 

Cobalamin is synthesised exclusively in micro-organisms. It is found in animal liver, cows, milk and soybeans. It is bound to methylcobalamin and 5′-deoxyadenosylcobalamin. For it to be biologically active, pepsin, a gastric protease released in the stomach, causes the release of cobalamin, which then binds to an endogenous protein called haptocorrin. 

Haptocorrin is a small glycoprotein produced in the oral salivary glands in response to food intake. Within the small intestine, trypsin hydrolyses the haptocorrin-cobalamin complexes. Cobalamin then binds to another protein called intrinsic factor (IF), produced in the stomach but requires the alkaline pH of the distal jejunum and proximal ileum to bind. B12 is then further transported in plasma through transcobalamin II. 

Its function in the body is in the catabolism of fatty acids with odd numbers of carbon atoms and the amino acids valine, isoleucine, methionine and threonine. Through its role in the conversion of homocysteine to methionine via methionine synthase, This reaction results in the transfer of methyl group from N5-methyltetrahydrofolate (5-methylTHF) to cobalamin generating THF and methylcobalamin. Without the presence of cobalamin, folate becomes trapped as 5-methylTHF. As a result, B12 deficiency causes a functional folate deficiency, resulting in all the adverse effects seen in folate deficiency. 

Vitamin B12 deficiencies are rare as it is stored in the liver for up to 5 years. Deficiencies are seen in chronic alcoholics and malnutrition states. Pernicious anaemia is a megaloblastic anaemia resulting from a lack of intrinsic factor released from the stomach’s parietal cells, primarily through antibody-mediated autoimmune destruction. Gastrectomy is also a cause of pernicious anaemia due to the loss of parietal cells. 

Vitamin C

Ascorbic acid is required as a reducing agent for several reactions, including collagen processing enzymes and catecholamine synthesis. It is involved in non-heme iron absorption in the small intestine and the overall regulation of iron homeostasis. Vitamin C is vital for wound healing and bone remodelling. Sources include fruits and vegetables such as oranges, citrus, strawberries, raspberries, bell peppers, broccoli, spinach and tomatoes. 

Deficiency in vitamin C leads to the disease scurvy. Scurvy is characterised by easily bruised skin, muscle fatigue, soft swollen gums, decreased wound healing, increased bleeding tendency, osteoporosis and anaemia. The bleeding dysfunction results from dysfunctional collagen synthesis, leading to reduced ability of platelets to adhere to the exposed collagen matrix. As such, there is a prolonged bleeding time, but the prothrombin time is not altered. 

The primary cause of vitamin C deficiency is poor diet or increased requirements. In heightened physiological states such as severe stress/ sepsis/ trauma, vitamin C stores are rapidly depleted. This is believed to be due to rapid utilisation in the adrenal glands due to increased ACTH production or redistribution due to increased demand systemically. 

Vitamin A

Vitamin A consists of retinoic acid, retinol, and retinal (all-trans-retinaldehyde and 11-cis-retinaldehyde). It is derived from the plant precursor, β-carotene. Dietary retinol is derived from animal products and released from fatty esters through pancreatic lipases. The uptake of chylomicron remnants by the liver results in the delivery of retinol to this organ for storage as a lipid ester within lipid droplets in hepatocytes. 

Retinol and retinoic acid are required to grow, differentiate, and maintain epithelial cells. When retinal is first made, it is in the ‘all-trans’ form. It is converted to the active form cis-retinal in the pigment epithelium cells of the eye. The cis-retinal is then transferred to opsin in the rod cells, forming the light receptor. 

Deficiencies only occur after prolonged periods of reduced dietary intake or malnutrition states as it is stored in the liver. Patients with cystic fibrosis are particularly prone to vitamin A deficiency and pancreatic exocrine dysfunction. The earliest symptoms of vitamin A deficiency are night blindness. Early symptoms include follicular hyperkeratosis, increased susceptibility to infection, cancer, and anaemia. This increases cancer risk and is suspected to be due to the depletion of β-carotene, an excellent anti-oxidant thought to reduce the risk of cancers known to be initiated by free radicals. 

Prolonged deficiency leads to deterioration of ophthalmic tissue, progressive keratinisation of the cornea leads to abnormal dryness of the conjunctiva and cornea and lack of ability to produce tears, a condition called xeropthalmia. 

Vitamin D

Vitamin D is a member of a superfamily of lipophilic hormones consisting of steroid and thyroid hormones. It functions to regular specific gene expression through interaction with its intracellular receptor, the vitamin D receptor (VDR). The hormonally active form is 1,25-dihydroxyvitamin3 (more commonly called calcitriol)

Active calcitriol is derived from ergosterol (produced by plants) and from 7-dehydrocholesterol, which is an intermediate in the synthesis of cholesterol that accumulates in the skin. Upon exposure to sun ultraviolet B(UVB) light, through thermal isomerisation, 7-dehydrocholesterol is converted to pre-vitamin D3 and then to vitamin D3. Ergocalciferol (Vitamin D2) is formed by UVB irradiation of ergosterol. Vitamin D2 and D3 are both then transported to the liver, where they go through the first of two hydroxylation reactions and become D2-calcitriol and D3-calcitriol.

Dietary vitamin D3 supplements (cholecalciferol) and D2(ergocalciferol) are absorbed from the intestines and are similarly transported to the liver for the first hydroxylation reaction. In the case of cholecalciferol, this forms  25-hydroxy-D3 (calcidiol). Conversion of calcidiol to its biologically active form, calcitriol, occurs through hydroxylation by 1-α-hydroxylase in the inner mitochondrial membrane of cells of the proximal convoluted tubule of the kidneys, and several extra-renal sites such as keratinocytes, macrophages and placenta. 

Calcitriol regulates calcium and phosphorus homeostasis with parathyroid hormone (PTH). PTH is released from the parathyroid gland in response to low serum calcium and induces the production of calcitriol by activating the expression of the renal CYP27B1 gene. Circulating calcium levels activate the parathyroid gland’s calcium-sensing receptor (CaSR). Activation of the CaSR, when there are normal serum calcium levels, results in increased proteolysis of PTH, resulting in reduced secretion. 

In children, vitamin D deficiency produces rickets, a constellation of skeletal abnormalities most strikingly seen as deformities of the legs, but many other developing bones are affected. Muscle weakness is also common. Vitamin D deficiency after epiphyseal fusion causes osteomalacia, which is characterised by demineralisation of previously forming bone, leading to increased softness and susceptibility. The resultant decrease in calcium uptake leads to hypocalcaemia, causing an increase in serum PTH as a compensatory mechanism (secondary hyperparathyroidism). 

Vitamin D toxicity results in hypercalcaemia. As a lipophilic vitamin, it can be stored in tissue, primarily in the liver. The direct effect of excessive vitamin D on bone is resorption, as seen similarly in vitamin D deficiency. Hypercalcaemia can cause symptoms such as polyuria, polydipsia and nocturia. Prolonged hypercalcaemia can lead to deposition in soft tissue, notably the kidney, producing irreversible damage. 

Vitamin E

Vitamin E is a mixture of related compounds known as tocopherols and tocotrienols. The primary function of vitamin E is to act as a natural anti-oxidant by scavenging free radicals and molecular oxygen. In particular, vitamin E is essential for preventing peroxidation of polyunsaturated membrane fatty acids. It is found in nuts, seeds and vegetable oils. Vitamin E deficiency is very rare. Conditions that result from vitamin E deficiency are related to disturbances in nerve cell membrane lipid homeostasis. These conditions include cerebellar ataxias, myopathies, retinopathy, loss of deep tendon reflexes and dysarthria. 

Additionally, increased red cell fragility is also seen in deficiency due to increased erythrocyte membrane peroxidation in the absence of tocopherols. Since vitamin E is absorbed from the intestines in chylomicrons, any fat absorption disorder can lead to deficiencies in vitamin E intake. 

Increased vitamin E intake is recommended in premature infants fed formulas that are low in the vitamin and persons consuming a diet high in polyunsaturated fatty acids. Polyunsaturated fatty acids form free radicals upon exposure to oxygen, which may lead to an increased risk of certain cancers. 

Vitamin K

Vitamin K exists naturally as K1 (phylloquinone) in green vegetables, K2 (menaquinone) is produced by intestinal bacteria, and K3 is synthetic vitamin K. When administered, K3 is alkylated to K2. 

The primary function of vitamin K is maintaining normal blood clotting protein levels (Factors 2,7,9,10, protein C and S). These proteins are synthesised in the liver as inactive precursor proteins. Conversion from inactive clotting factors requires a posttranslational modification of specific glutamate residues. The enzyme vitamin K epoxide reductase (VKORC1) involved a two-step reaction, allowing for the conversion of prothrombin to thrombin. 

Vitamin K deficiencies are seen in malabsorption states, such as in chronic biliary pathology, and prolonged treatment with antibiotics, which cause the elimination of intestinal bacteria that supply vitamin K. Vitamin K is used as a reversal agent for warfarin, which is a vitamin K epoxide reductase inhibitor. 

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