Human Nutrition PDF

3. NUTRITION AND METABOLISM 3.1. HUMAN NUTRITION 3.1.1. OVERVIEW NUTRITION AND METABOLISM - Nutrition: - Using food and drink to provide nutrients which are then metabolised to provide energy and converted to different biochemical molecules to sustain li...

3. NUTRITION AND METABOLISM 3.1. HUMAN NUTRITION 3.1.1. OVERVIEW NUTRITION AND METABOLISM - Nutrition: - Using food and drink to provide nutrients which are then metabolised to provide energy and converted to different biochemical molecules to sustain life - The types of nutrients needed and how they are obtained are different for different organisms - Metabolism: - The chemical reactions that occur throughout the body within each cell - Includes processes of varied nature - Purpose of metabolism: 1. Degradation of compounds (nutrients) absorbed into the intestines into simpler products a. can be used as precursors (building blocks) for the synthesis of new biomolecules b. To be disposed of via the waste disposal pathway if they have no value to our body or even toxic to our body 2. Generation of energy required for the synthesis of molecules and different functions of the body [The energy obtained from the chemical reactions are trapped in the form of ATP (GTP is also viable)] 43 - Pathways: - Carbohydrate metabolism - Lipid metabolism - Amino acid metabolism - Energy metabolism - Nucleotide metabolism - Metabolism of cofactors and vitamins - Biosynthesis of secondary metabolites - Neurotransmitters - Porphyrins - Nucleotides - Biodegradation of xenobiotics 3.1.2. INTRODUCTION TO NUTRIENTS - Nutrition is important for: - Prevention of disease - Progression of disease - Management of disease - Major purpose of nutrients: - To supply the energy needed for the body to perform work - To provide the building blocks for the synthesis of other important molecules - To support the function of metabolic pathways - Nutrition science is the study of: - The components of food - Where and how energy and nutrients are derived from food - Factors influencing dietary intakes and patterns - The actions, interactions and balance of these in relation to health and disease - Nutrition is related to IAXM: - Ingestion and digestion – mouth to stomach - Absorption (assimilation and transport) – along GI tract, to liver and body cells - Excretion – through urine, faeces, sweat and exhalation - Metabolism – catabolism and anabolism - Factors affecting nutritional status: 44  1. Biological factors: - Genetic background: - Individual response to nutrients is determined by genetics - Genes affect digestion, absorption, metabolism, excretion, taste and satiety - Nutrigenomics: consequences for nutritional guidelines; as the gene pool varies between populations, nutrition guidelines should be population-specific - Digestion, absorption and excretion: - According to IAXM, if there is no ingestion and absorption, metabolism cannot take place; if there is no excretion, there is no release of toxic waste products - Age and phase of lifecycle - In pregnancy, there is increased demand for nutrients - After delivery, there is a transition from feeding through the placenta to breastfeeding (and then gradually adapting to free diet) - After breastfeeding stage, infant is entirely dependent on mother for nutrition - Growth hormones assume a major role in directing development - At school age, new eating and activity patterns emerge as the child becomes more independent - At adolescent stage, sex hormones begin to play a prominent developmental role - In adulthood, muscle mass increases between 20-30 years of age (level of physical activity stabilises - Thereafter, muscle mass starts to decline and fat mass starts to increase - This accelerates after the age of 60 (bone mass also declines with age) 2. Psychological factors: - Satiety: - Appetite - Palatability of food 3. Social factors: - Availability of food: - Poorer countries may have food shortage, leading to malnutrition - Cultural customs - Certain types of food may be prohibited – alternative foods need to be taken to compensation for nutrition 4. Energy expenditure (elaborated below) 5. Presence of disease: - Disease can affect the nutrition that is absorbed or metabolised in our body - Example of prevention of disease by nutrition: 45  - Living with excess weight is a risk factor for: - Type 2 diabetes - Cardiovascular diseases - Cancers - Liver diseases and respiratory diseases - Excess weight is linked to higher prevalence of COVID-19 complications: - Increased risk for positive test, hospitalisation, advanced level treatment (mechanical ventilation and ICU), death - Increases exponentially with BMI - Mechanism: - Excess fat tissue and deposition around the upper airway → reduce respiratory function → affect circulating levels of oxygen - Fat tissue have high levels of ACE2 enzyme – COVID viruses latches on to ACE2 to gain access to body cells - Excess fat tissue enhances inflammatory and immune response → affect antiviral treatments - Higher risk of thrombosis (blood clot blocking arteries and veins) in COVID - Example of progression and management of disease: - E.g. Chronic diseases – renal diseases, diabetes, etc. - Dietary requirements for treatment - E.g. Surgical and anaesthetic conditions - Affected by nutrition - Emergency treatment (clinical): - To survive, we need oxygen, water, and nutrients: - Without oxygen, the survival time is minutes - Without water, the survival time is days - With these two supplied, a human can survive without food for between 60 and 90 days - These considerations determine the urgency of treatment in critical situations 1. Re-establishment of oxygen supply and circulating volume is the first priority 2. Repletion of lost fluids and electrolytes is also necessary within hours to days, depending on the state of the patient 3. Provision of other nutrients becomes important as soon as the life-saving measures have been taken - The rule of thumb is that patients unable to eat would need nutritional support if they have been (or will be) unable to take food for more than 7 days - This period is shorter in hypercatabolic patients, such as those with severe burns or sepsis 3.1.3. CLASSIFICATION OF NUTRIENTS 46  1. Carbohydrates (macronutrient): - Main energy source (along with fats) - Some carbohydrates tend to create a sense of satiety over a longer period of time – may be helpful in weight control and diabetes treatment - Some carbohydrates are digested rapidly and stimulate craving – these carbohydrates can promote fat deposition in tissues - Fibre is an indigestible carbohydrate – its main role is to regulate gut motility and transit. It is not used as an energy source 2. Fats (macronutrient): - Main energy source (along with carbohydrates) - Most important nutrient used for energy storage - Strongly linked to heart disease 3. Proteins (macronutrient): - Provide cell structure - Responsible for cell functions, communications, signalling - ‘Last resort’ energy substrate – releasing amino acids from muscle, and thus muscle wasting 4. Essential fatty acids - Linoleic acid and α-linoleic acid 5. Essential amino acids - 10 amino acids (out of 20) considered essential – PVT TIM HALL - Phenylalanine, Valine, Tryptophan - Threonine, Isoleucine, Methionine - Histidine, Arginine, Leucine, Lysine [*Arginine included as it is essential in growing children] - Proteins from animal sources contain all essential amino acids - Proteins from plant sources contain some essential amino acids 6. Vitamins and Minerals - Essential nutrients that act as coenzymes, form functionally important prosthetic groups of enzymes, involve in critical development and function of the body - Micronutrients - Others – ethanol is an energy source but not a macronutrient 3.1.4. TOTAL DAILY ENERGY EXPENDITURE (TEE) 47 - Forming fuel and energy: - As we eat, foodstuffs are digested and absorbed - Products of digestion are taken up by cells and oxidised to produce energy - Any dietary fuel that exceeds the body’s immediate energy needs is stored (primarily in fat tissues, muscles, liver and other cells) [When we are fasting, fuel is drawn from these stores and is oxidised to provide energy] - Energy is stored in the form of ATP (adenosine triphosphate) - Energy content of macronutrients: - Carbohydrates = 4.1 kcal/g - Proteins = 4.1 kcal/g - Fat = 9.3 kcal/g - Units abbreviated to calories - With this information, we can calculate an approximate amount of the total energy intake based on the macronutrients we eat - Total daily energy expenditure (TEE): - A sum of: 1. The basal metabolic rate (resting metabolic rate)/ BMR - Energy required to maintain normal physiological functions when the body is at rest (60 to 70% of total energy expenditure) - Equivalent to the caloric requirement of our major organs and resting muscle - Affected by multiple factors: 2. The energy used up during physical activity - Energy required to support certain levels of physical exertion (variable amount) - Most important changeable component of energy expenditure in health 3. The thermic effect of food (i.e. the amount of energy needed to meet the body’s demands) - Energy expended during digestion, absorption, and metabolism of nutrients - ~10% of total energy expenditure - Fat (in adipose tissue): 48  - A major fuel store - 3 distinct depots in body: 1. Subcutaneous fat under the skin - Generally benign - Source of energy - Hips and thighs 2. Visceral fat within abdominal cavity - Produces mediator molecules that promote atherosclerosis, cardiovascular diseases, type 2 diabetes - Rounded abdomens 3. Ectopic fat (e.g. cardiac and pharyngeal fat pads) - Obstruct heart (impair cardiac function) - Obstruct pharynx (respiratory difficulties) - Energy balance - If we consume more food than required for the energy we expend, the body’s fuel stores enlarge and we gain weight - If we do not consume enough food each day to supply that much energy, the body’s fuel stores supply the remainder and we lose weight - Obesity: - High intake of high-calorie food (more energy intake, more fuel stored than needed) - Decrease in physical activity both at work and during leisure time (less energy expenditure) - Losing weight: - Generally, a combination of diet and exercise plus behavioural interventions (e.g. goal-setting and relapse avoidance) is more effective in inducing weight loss than diet alone - Be careful of attempting weight loss through diet alone – possibility of undernutrition - Limited evidence-based interventions that can induce a weight loss greater than 5% of body weight and maintain this long term (except for surgical interventions like bariatric surgery) 49  3.1.5. NUTRITIONAL RECOMMENDATIONS AND ASSESSMENT - Dietary Reference Intake (DRIs): - Developed by the Food and Nutrition Board of the National Academies in the US - Estimates nutrition recommendation - Consists of 4 dietary reference standards for the intake of nutrients: 1. Estimated average requirement (EAR) – level estimated to meet the requirement of 50% of the healthy individuals in a particular life stage and gender group 2. Recommended dietary allowance (RDA) – level sufficient to meet the nutrient requirements of nearly all (97–98%) individuals in a life stage and gender group [not a minimal requirement, intentionally set within the margin of safety for most individuals] 3. Adequate Intake (AI) – (if EAR or RDA not available) estimates of nutrient intake by a group (or groups) of apparently healthy people that are assumed to be adequate 4. Tolerable Upper Intake Level (UL) – highest level likely to pose no risk of adverse health effects to almost all individuals in a particular life stage and gender group [not intended to be recommended level of intake] - Most nutrients have corresponding RDA - Intakes between UL and RDA are considered to have no risk of adverse effects - Dietary guidelines are recommendations for food choices, which can help reduce the risk of developing chronic disease while maintaining an adequate intake of nutrients - MyPlate: - Set up by the US Department of Agriculture - Eatwell Guide used by NHS in the UK - Recommended servings per food group - Customised for individuals - Superseded the well-known food pyramid - Malnutrition Universal Screening Tool (MUST): 50  - Introduced by British Association for Parenteral and Enteral Nutrition (BAPEN) - Enable fast assessment of nutritional state in adults - 5-step screening tool to identify adults who are malnourished, at risk of undernutrition or obesity – simplified assessment of nutritional status - Management guidelines to develop care plan – hospitals, community, or other care settings - Steps: 1. Measure height and weight to get a BMI score using chart provided 2. Note the percentage unplanned weight loss score using table provided 3. Establish if patient is acutely ill, and whether there has been or is likely to be no nutritional intake for >5 days 4. Add scores from Steps 1 to 3 to obtain overall score of malnutrition 5. According to score, use management guidelines or local policy to develop a care plan - Other forms of assessment: - Anthropometric measurements (e.g. BMI) - Weight in kg/ height in m2 - Between age 2 and 20, BMI is interpreted in relation to age and gender - Advantages: easy, portable, non-invasive, cheap - Limitations: athletes, lean deformity, adults with age related loss of skeletal mass; more detailed analysis through different means - Others: - Waist-to-hip ratio, measure amount visceral fat to determine risk of metabolic syndromes - Mid-arm circumference - Skinfold thickness - Biochemical data (e.g. biomarkers) - Blood (plasma proteins – albumin, haemoglobin – iron) - Urine (urinary nitrogen, i.e. urea assesses nitrogen balance relating to body protein requirements) - Faeces - Advantage: objective, qualitative indicators - Limitations: not exclusively determined by the state of nutrition, but also medication and presence of disease - Dietary data (e.g. dietary habits) - Dietary habits include meal patterns, amount and composition of food - Biological factors (state of the systems responsible for ‘IAXM’) - Psychological factors (eating disorders) - Sociological factors (availability and price of food, societal measures to improve diets) - Cultural factors (eating patterns and food preference) - Food frequency questionnaires, 24h dietary recalls, food records, direct analysis of foods, metabolic balance studies 3.2. VITAMINS 51  3.2.1. OVERVIEW OF MICRONUTRIENTS - Background: - In the late 19th century, it was believed that to ensure a good nutritional status, a complete diet needed proteins, carbohydrates, lipids, inorganic salts and water - By combining all of these, a balanced diet could be obtained - Studies in animals showed that this was not the case, and such a diet resulted in severe alterations that even led to death - Other unknown factors needed in small amounts known as dietary accessory factors – vitamins and minerals - Purpose of micronutrients: 1. Form prosthetic groups of enzymes or serve as their cofactors 2. Hormones 3. Cell growth, proliferation and differentiation - Vitamins: - An essential non-caloric organic nutrient needed in very small amounts (μg-mg) in the body - Minerals: - An essential non-caloric inorganic nutrient needed in very small amounts (μg-mg) in the body - Fat-soluble vs water-soluble vitamins: - Fat-soluble vitamins are packaged into micelles with other diet-derived lipids (fats) for absorption within the intestines. They are transported by carrier proteins and stored in both the liver and adipose tissue. - Water-soluble vitamins are absorbed into the blood within the intestines. They generally travel freely in the body without the need of carrier proteins and are not stored in the body. Instead, they are excreted in urine. 52 - Possible causes of micronutrient deficiency: - Inadequate intake - Increased demand – pregnancy, lactation, adolescent growth spurt - Poor absorption of gastrointestinal tract – old age (less efficient absorption) - Inefficient utilisation by the body - Increased loss from the body through excretion 3.2.2. FAT-SOLUBLE VITAMINS – VITAMIN A 53 - 4As: 1. Antioxidant properties 2. Aura: - Vitamin A forms component of eye retina and epithelial lining of cornea - Vitamin A produces visual pigment rhodopsin, found in the rod cells of the retina - Rhodopsin is exposed to light → leads to conformational change and elicits nerve impulse perceived by the brain as light - Rod cells responsible for vision in poor light - Vitamin A deficiency leads to night blindness 3. Activation: - Epithelial cell differentiation (in the cornea) - Retinoic acid is a nuclear hormone that binds to transcription factors (DNA-binding receptors) - Influence the transcription of specific genes - Growth, differentiation, and proliferation of cells; in embryonic development and organogenesis; and in the maintenance of epithelia 4. Abnormal pregnancy: - Result of Vitamin A deficiency or excess - Attributed to its provitamin form β-carotene and its various derivatives, which include retinol, retinal, retinoic acid, and synthetic forms (drugs) - Function as follows: - β-Carotene functions as an antioxidant - Retinal is used to produce the visual pigment rhodopsin - Retinoic acid contributes to the proper differentiation of epithelial cells - Oral isotretinoin (synthetic) used to treat severe acne but is teratogenic – disrupt development of embryo or foetus during pregnancy - Hypovitaminosis A: - Deficiencies occur due to inadequate dietary intake or absorption - Night blindness - Keratomalacia – As vitamin A affects the growth and differentiation of epithelial cells, its deficiency produces defective epithelialisation and corneal softening and opacity - Permanent blindness - Growth impediment, impaired wound healing, etc. 54  - Hypervitaminosis A: - Results from the excessive intake of Vitamin A supplements - Liver toxicity - Infants exposed to excess vitamin A or isotretinoin may have birth defects e.g. cleft palates and heart abnormalities - Abnormal pregnancy may be a result of too much Vitamin A or too little 3.2.3. FAT-SOLUBLE VITAMINS – VITAMIN D - Precursors obtained from sunlight (UV) and diet - Cholecalciferol is used to synthesise 25-OH-D3 in the liver - 25-OH-D3 is used to synthesise 1,25-(OH)2-D3 in kidneys (active form of Vitamin D) Hypovitaminosis D: - Deficiencies occur due to: - Inadequate dietary intake - Disruption of lipid absorption - Poor functioning of the liver and kidneys - Hypoparathyroidism [Bowing of the knees] Hypervitaminosis D: - Elevated levels of Ca2+ in blood (hypercalcemia) - Deposition of calcium in many organs, particularly arteries and kidneys - Elevated levels of Ca2+ in urine (hypercalciuria), formation of kidney stones 55  3.2.4. FAT-SOLUBLE VITAMINS – VITAMIN E - Serves as an antioxidant to protect cells from the harmful effects of reactive oxygen species (ROS) generated from free radicals reacting with oxygen - Free radicals are extremely reactive and unstable – may damage biological molecules (nucleic acids, proteins, lipids) - Hypovitaminosis E: - Deficiency is almost entirely restricted to premature infants. In adults, usually associated with defective lipid absorption or transport (e.g. cystic fibrosis, abetalipoproteinemia) - Haemolytic anaemia (erythrocytes susceptible to rupture – haemolysis) – related to antioxidant properties - Impaired vision (retinal degeneration) - Muscle weakness (myopathy) - Peripheral neuropathy - Ataxia (poor muscle coordination with tremors) - Areflexia (loss of reflexes in limb) - Poor proprioception (sensation of one’s position and movement) - Decreased vibratory sensation - Hypervitaminosis E: - Rare, but can be caused by excessive intake of Vitamin E supplements - Vitamin E supplementation does not prevent chronic diseases (e.g. cardiovascular diseases), but increased the incidence of stroke 3.2.5. FAT-SOLUBLE VITAMINS – VITAMIN K - Used to make clotting factors - Warfarin inhibits the synthesis of clotting factors and gets “crushed” - Co-factor of gamma-carboxylation - Cannot be found in newborn infants - Blood clotting: 56 [Glutamic acid residues in prothrombin → thrombin, fibrinogen → fibrin] [Warfarin – good for treating thrombosis, reduce clotting] Hypovitaminosis K: - Deficiency occur when: - Absorption of lipids is disrupted - Gut bacteria that synthesise Vitamin K is absent - Anticoagulation drugs (e.g. warfarin) taken - Susceptible to bleeding and bruising - Anaemic, weak, present with nose bleeds, bleeding gums, heavy menstrual bleeding, gastrointestinal bleeding - Newborn infant – Gut is sterile. There is no source of Vitamin K - Normalises when absorption of food starts, but this is delayed in preterm infants - Preterm infants are at particular risk of bleeding disorders Hypervitaminosis K: - No clear toxicity associated with Vitamin K (phylloquinone and menaquinone). So, no tolerable upper intake level (UL) has been set. - Excessive, prolonged intake of synthetic Vitamin K (menadione) causes liver toxicity and haemolytic anaemia (due to toxic effects on the membrane of red blood cells). This is no longer used to treat Vitamin K deficiency. 57  3.2.6. WATER-SOLUBLE VITAMINS – VITAMIN B - Essential for normal metabolism - Serve as coenzymes in many reactions in carbohydrate, fat, and protein metabolism - The greater the caloric intake, the greater the requirement of dietary intake of Vitamin B - High protein intake increases the demand for pyridoxine - Excreted in urine so rarely reach toxic levels - Inadequate uptake is more common and leads to potential health consequences [A coenzyme is an organic compound that binds with an enzyme to catalyse a reaction. They are often vitamins, or derivatives of vitamins.] - Vitamin B1 – THIAMINE: - Essential for carbohydrate metabolism - Coenzyme of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase - In thiamine deficiency, the activity of these two dehydrogenase-catalysed reactions is decreased → decreased ATP production → impaired cellular function - Thiamine deficiency: - Results in beriberi (occurs where polished rice is major diet component) - Seen in association with chronic alcoholism (alcoholics develop Wernicke-Korsakoff syndrome) - Alcohol may inhibit absorption of Vitamin B1 - Vitamin B2 – RIBOFLAVIN: - Riboflavin forms part of FMN (flavin mononucleotide) and FAD (flavin adenine dinucleotide) - FAD is coenzyme of succinate dehydrogenase/complex II; acyl-CoA dehydrogenase; retinal dehydrogenase; NADH dehydrogenase/complex I - Succinate dehydrogenase: in the TCA cycle; Complex II in the electron transport chain - NADH dehydrogenase/ Complex I in the electron transport chain - FAD and FMN are coenzymes for vitamin-activating enzymes 58  - Vitamin B3 – NIACIN: - Niacin forms part of NAD+ (nicotinamide adenine dinucleotide) - NAD+ serves as an electron carrier: NADH transfers electrons from the TCA cycle to complex I of the electron transport chain - Deficiency results in pellagra, involving the GI tract and CNS – symptoms progress through 3Ds: dermatitis, diarrhoea, dementia - Vitamin B5 – PANTOTHENIC ACID: - Component of coenzyme A (CoA) - Deficiency not well-established - Vitamin B6 – PYRIDOXINE: - Coenzyme for a variety of enzymes (especially amino acid metabolism) - Deficiency causes neurological symptoms and anaemia - Vitamin B7 – BIOTIN: - Coenzyme for synthesis of fat, glycogen, amino acid - Deficiency can be caused by eating raw eggs – a protein called avidin in egg white combines with biotin and prevents absorption by the body - Vitamine B9 – FOLIC ACID (FOLATE): - Folic acid plays a key role in one-carbon metabolism; essential for biosynthesis of several compounds - Tetrahydrofolate (reduced folate) receives one-carbon fragments from donors (e.g. serine, glycine, histidine) and transfers them to intermediates in the synthesis of amino acids, purines and TMP – a pyrimidine found in DNA - Folate deficiency can result in megaloblastic anaemia caused by diminished synthesis of purines and TMP → Cells are unable to make DNA → Cells cannot divide [Cells in the bone marrow are enlarged and have fragile membranes, with a tendency to lyse, leading to low red blood cell count and anaemia] - Folate deficiency can result in neural tube defects (spina bifida and anencephaly) – especially before conception and during the first trimester → Related to the importance of folic acid in nucleic acid synthesis → Rapid cell growth during neural tube development 59 - Vitamin B12 – COBALAMIN: - Required in two essential reactions: - Effects of Vitamin B12 are prominent in rapidly dividing cells (e.g. erythropoietic tissue of bone marrow) - These tissues need N5-methyl form of THF for nucleotide synthesis - Vitamin B12 helps to convert N5-methyl- tetrahydrofolate to tetrahydrofolate - Folic acid is recycled to make various other compounds - Participates in nucleic acid synthesis, production of erythrocytes, recycling of folates - Deficiency results in symptoms of megaloblastic anaemia 3.2.7. WATER-SOLUBLE VITAMINS – VITAMIN C - Antioxidant: - Like Vitamin E, Vitamin C protects cells from the harmful effects of ROS generated from free radicals reacting with oxygen - Reducing agent: - Vitamin C keeps iron in its reduced state (Fe3+→Fe2+), which facilitates collagen folding and stability (via hydroxylation) – which helps maintain the integrity of body structures like bone, teeth, bones and cartilage - Hypovitaminosis C: - Scurvy, characterised by sore and spongy gums, loose teeth, fragile blood vessels, swollen joints, anaemia - Symptoms explained by deficiency in the hydroxylation of collagen, resulting in defective connective tissue - Scurvy common among sailors in the past, since there were no fresh fruit or vegetables during long sea voyages, and Vitamin C was destroyed by the methods used to preserve food at sea (SEE P. 19, 1.3.6. PROTEIN-RELATED PATHOLOGIES) 60  - Hypervitaminosis C: - Low toxic effects - Theoretically, as it is metabolised to oxalate, there is risk of developing renal oxalate stones in patients undergoing dialysis - Claims that Vitamin C can prevent common cold and cancer have no basis - Vitamin C has antioxidant properties and hence prevent the development of chronic diseases - Vitamin supplements: - Supplement of some vitamins have clear health benefit: - Folic acid during pregnancy - Vitamin D for people living in areas of low sunlight - Supplement of some vitamins have uncertain health benefit: - Controversial results as to whether Vitamins A, B6, B12, C, and E could prevent cardiovascular diseases and cancer - Supplement of some vitamins are harmful: - High doses of Vitamin A can lead to liver toxicity, teratogenicity, reduction of bone - Supplementation of β-carotene in smokers can result in an increase in lung cancer mortality - Fruits and vegetables are the best source of vitamins 3.3. MINERALS 3.3.1. OVERVIEW OF MINERALS 61 - Macroelements: - Required in quantities over 100 mg/day - Sodium, chloride, potassium, calcium, magnesium, phosphate - Microelements: - Required in quantities less than 100 mg/day - Iron, zinc, copper 3.3.2. SODIUM, CHLORIDE, POTASSIUM - Purposes: - Maintain osmotic pressure - Maintain acid-base balance (pH) - Maintain nerve and muscle excitability - Regulated by kidneys: - Water, nutrients and minerals absorbed, waste products excreted - Regulated the electrolytes and body fluids - Increase in renal excretion, vomiting and diarrhoea may lead to mineral deficiencies - Excesses have more specific causes 3.3.3. CALCIUM, MAGNESIUM, PHOSPHATE - Stored in the matrix of bone and teeth - Bone serves as reservoir – degradation mobilises ions to perform other body functions - Calcium (Ca2+) and (Mg2+): - Contraction of skeletal, cardiac and smooth muscle - Propagation of nerve impulses - Mg2+: - Important cofactor for many enzymes (those utilising ATP) - ATP readily forms a complex with magnesium ion - This complex is required in ALL reactions in which ATP participates - Deficiency impairs virtually all of metabolism because ATP can neither be made nor utilised in adequate amounts 62 - Ca2+: - Blood clotting, hormonal signalling 3- - PO4 : - Component of DNA and RNA – Component of ATP - Phosphorylation - Blood levels of Ca2+ and PO43- are regulated by three key hormones: - Calcitriol (1,25-OH2-D3, active form of Vitamin D) – produced by kidneys [cholecalciferol: inactive form] - Parathyroid hormone (PTH) – produced by parathyroid gland - Calcitonin – produced by thyroid gland 3.3.4. IRON, ZINC, COPPER - Iron: - Important component of heme (serves to bind oxygen or participate in redox reactions) - Heme-containing proteins include: - Haemoglobin and myoglobin – iron binds to oxygen - Redox enzymes – Include proteins that function in the electron transport chain (e.g. cytochromes) - Present in non-heme form, complexed to sulphur in proteins. Iron-sulphur proteins – components of complex I of electron transport chain 63  - Regulation: - Facilitated by hepcidin, the levels of which affect absorption of iron - High [Iron] = ↑Hepcidin = ↓Ferroportin = ↓Iron absorption - Low [Iron] = ↓Hepcidin = ↑Ferroportin = ↑Iron absorption (Ferroportin – iron-transporting protein channel) - Deficiency: - Iron-deficiency anaemia is a common nutritional problem (especially common in menstruating and pregnant women) - Men require about 1 mg iron/day, menstruating women about 2 mg/day, and pregnant women about 3 mg/day - Iron is required to maintain normal amounts of haemoglobin and the cytochromes and iron–sulphur complexes that are central to oxygen transport and energy metabolism - Iron deficiency impairs all these processes - Excess – haemochromatosis : - An inherited disorder resulting from the increased absorption of iron - Most common inherited disorder in persons of Northern European ancestry - Iron accumulates in heart, liver, and pancreas and can cause liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis, and heart failure - Zinc: - Trace element - Contained in approximately 100 enzymes associated with carbohydrate and energy metabolism, protein synthesis and degradation, and nucleic acid synthesis - Not stored in body - Deficiency is common - Occurs in patients with major burns and renal damage – lost during dialysis - Develops during intravenous feeding - Affects growth, skin integrity, wound healing 64  - Deficiency: - Patients with major catabolic illness and increased gastrointestinal losses have markedly increased zinc requirements - The zinc-depleted state could aggravate his illness by preventing healing of his gastrointestinal lesions and by making him more susceptible to infection - Patients receiving intravenous feeding need to have their micronutrient status checked regularly - Copper: - Scavenges superoxide and other reactive oxygen species (scavenging ability) - Associated with oxygenase enzymes like cytochrome c oxidase – complex in the electron transport chain - Rare deficiency leads to anaemia - Excess causes liver cirrhosis – scar tissue prevents liver from working properly - More on deficiency: - Copper deficiency can impair ATP production (failure to synthesise adequate amounts of cytochrome c oxidase, inhibiting the terminal reaction of the electron transport chain) - This can lead to pathology in the heart, where energy demand is high - Dietary formulas for premature infants must contain adequate copper; cow's milk alone is unsuitable because it is low in copper - Summary: 3.4. NUTRITION-RELATED PATHOLOGIES 65  3.4.1. OVERVIEW OF UNDERNUTRITION - 2 types of undernutrition: 1. Protein-energy malnutrition (PEM): - Poor nutritional status due to inadequate nutrient intake that can lead to decrease in nutrient stores, changes in body composition, and more efficient use of fuels (e.g. use of ketone bodies by the brain) 2. Other specific deficiencies: - Deficiency in specific nutrients, such as vitamin(s) and mineral(s) - Undernutrition in global countries: - Developed countries: - Frequently seen in patients with medical conditions that decrease appetite or alter how nutrients are digested/absorbed - Frequently seen in hospitalised patients with major trauma or infections - Also seen in children or elderly who are malnourished - Associated with increased morbidity and mortality, longer hospital stays, increased complications - Underdeveloped/ Developing countries: - Primary cause of PEM: Inadequate intake of protein and/or energy - Maternal and child malnutrition is responsible for ~1/3 of deaths in young children (below 5 years) - Effects of maternal and child malnutrition include intrauterine growth restriction, stunting and wasting - Other symptoms – depressed immune system → prone to infections - Two extreme forms of PEM: kwashiorkor and marasmus - It is an issue among disadvantaged social groups and hospitalised individuals 3.4.2. TYPES OF PEM - 2 types of PEM: 1. Kwashiorkor: - Protein deprivation is relatively greater than reduction in total calories - Frequently seen in children (~1 year old) when diet is predominantly carbohydrates - Typical symptoms: - Stunted growth, oedema, skin lesions, depigmented hair, anorexia, enlarged fatty liver, decreased plasma albumin concentration - Oedema (hallmark) – results from lack of adequate plasma proteins to maintain distribution of water between blood and tissues. May mask muscle/weight loss 66  2. Marasmus: - Calorie deprivation is relatively greater than the reduction in protein - Usually occurs in children younger than 1 year old, when breast milk is supplemented with diet that are usually deficient in protein and calories - Typical symptoms: - Arrested growth, extreme muscle wasting (emaciation), weakness, anaemia - Emaciation: no carbohydrates to be used as energy source → proteins are broken down in muscles as the last energy reserve - Do not show oedema, clear loss of weight [Marasmus and kwashiorkor are terms rarely used in hospital practice in developed countries] [Malnutrition and complicated malnutrition are probably more appropriate terms (severity measured by anthropometric measurements, presence of oedema)] 3.4.3. SYNDROME AND EFFECTS OF UNDERNUTRITION - Syndromes related to undernutrition: 1. Refeeding syndrome - A consequence of inappropriate feeding of a malnourished person - Too quick a replacement may be dangerous → major shift of fluid and electrolytes between intracellular and extracellular compartments a. Famine areas: - Standard preparations such as Formula 100 therapeutic milk (F100) – liquid diet which includes dried skimmed milk, oil, sugar, mix of vitamins and minerals (without iron) - Life-sustaining general rations containing grains, legumes, vegetable oil + adequate water, sanitation, basic health care - Frequent simple meals at short intervals recommended b. Hospital setting: - Gradual introduction of nutritional support and close monitoring recommended 2. Frailty - Multisystem deterioration associated with age – affects the nervous, endocrine, musculoskeletal, and immune systems - Characterised by muscle wasting (after age of 50, there is 1-2% loss of muscle per year) - Others are anorexia, weight loss, exhaustion, slowness of gait, low daily energy expenditure, muscular weakness 3. Cachexia - Weight loss predominantly related to diseases – particularly linked with cancer/ sepsis - Causes predominant loss of muscle (can be life-threatening) - Characterised by anorexia and muscle protein breakdown 67 - Effect of undernutrition: - On clinical outcomes via mechanisms including: - Muscle function and strength: - Body draws on functional reserves in tissues e.g. muscle, adipose tissue, and bone - Leads to changes in body composition - Results in loss of functional capacity in tissues - Cardio-respiratory function: - Reduction in cardiac muscle impacts renal function - Poor respiratory muscle function delays recovery from respiratory tract infection - Immunity and wound healing: - Lowered immunity increases risk of infection - Results in appetite loss, nutrient loss, malabsorption, altered metabolism (undernutrition) - Delayed wound healing in malnourished surgical patients - Increase comorbidity risks: - Malnourished surgical patients have complication and mortality rates 3-4 times higher than normally nourished patients - Positive outcomes for surgery depend heavily on adequate immune defence and wound healing – relying on enhanced synthesis of new proteins - Affect fertility and childbearing matters 3.4.4. OVERNUTRITION AND OBESITY - Obesity: - World obesity has increased by >70% since 1980 - Energy imbalance: - High intake of high-calorie food – More energy intake, more fuel store than needed - Decrease in physical activity both at work and during leisure time – Less energy expenditure 68  - Genetic regulation of food intake and energy expenditure: - Large population studies on relationship between changes in genes and body weight: - There is a close relationship between the body mass of members of the same family, especially identical twins - ~40–70% of the differences in the predisposition to obesity can be explained by genetics 3.4.5. EFFECTS OF OVERNUTRITION - Effects of overnutrition: - On comorbidity risk, fertility, pregnancy challenges: - Cardiovascular system (hypertension, coronary artery disease, heart failure, atrial fibrillation, stroke, venous thromboembolism) - Respiratory system (obstructive sleep apnoea) - Endocrinology (type 2 diabetes mellitus, dyslipidemia, metabolic syndrome, vitamin D deficiency) - Musculoskeletal system (osteoarthritis) - Gastrointestinal tract (non-alcoholic fatty liver disease, gallstones) - Urinary tract (chronic kidney disease) - Reproductive system (irregular menstrual cycle, infertility, increased risk of miscarriage, endometrial hyperplasia and malignancy, sexual dysfunction) - Infection (COVID-19) - Neoplasm (cancer) - On surgical associated risks: 69  3.4.6. SPECIFIC DIETARY REQUIREMENTS - These include: - Gluten-free - Lactose-free - Low fibre - Low fat - Ketogenic diets - Low phenylalanine/protein diets - Vegetarian diets (including vegan diet in which it is important to know medicines/feeds that are free of animal products) - Religious/cultural diets (kosher, halal, etc) - Food allergies & common diagnosed intolerances (nuts, milk, soya etc) - Foods to be avoided or restricted during pregnancy 1. Gluten-free diet for coeliac disease: - Pathophysiology: - A peptide derived from gluten (gliadin) causes damage to the small intestine. Local inflammation > destruction of the small intestinal villi > decreased functionality of the intestinal surface and malabsorption - The lack of nutrient absorption impacts directly on the digestive system but also indirectly on all the systems of the body - Symptoms: - Lethargy, diarrhoea/constipation, abdominal discomfort, etc. 2. Ketogenic diet for childhood epilepsy: - Involve a high fat and very low carbohydrate diet > body will mainly burn fat rather than carbohydrate and protein for energy > ketone production > ketones used as alternative energy source - High ketone state decreases seizure activity (by mechanisms poorly understood) 3. Low phenylalanine/protein diet for phenylketonuria: - Pathophysiology: - Deficiency of the enzyme phenylalanine hydroxylase which converts phenylalanine to tyrosine - Deficiency of this enzyme causes accumulation of phenylalanine - Results in high phenylalanine levels in the blood and brain - Symptoms: - Delayed developmental milestones (intellectual disability), microcephaly, hypopigmentation, hyperactivity/behaviour problems, seizures, and a musty odour to skin and urine - Incurable, reliant on protein substitutes with low phenylalanine, and amino acid supplements 70  3.4.6. PERSONALISED NUTRITION - Personalised nutrition is an approach that uses information on individual characteristics to assist individuals in achieving lasting dietary behaviour change that is beneficial to health A. Nutrigenetics (Genes → Diet): - E.g. genetic variant in the glucose transporters type 2 is associated with higher intakes of sugars in two distinct populations - E.g. genetic variation in TAS1R2 (Ile191Val) is associated with consumption of sugars in overweight and obese individuals in 2 distinct populations - E.g. Coffee, CYP1A2 genotype and risk of myocardial infarction - Caffeine is metabolised by CYP1A2 - A to C substitution at position 734 in the CYP1A2 gene decreases enzyme inducibility, resulting in impaired caffeine metabolism - Carriers of variant have high risk of myocardial infarction 71 B. Nutrigenomics (Diet → Genes): - Diet can alter the effects of SNPs on disease risk - E.g. Studies on aboriginal populations e.g. Pima Indians of Arizona and indigenous people of Hawaii: - Abandonment of the traditional plant-rich, high-fibre diets - Adoption of a high-sugar, high-fat “Western diet” for the first time - Followed by skyrocketing rates of diabetes, obesity, and later cancer - “In such cases, nutrient availability can provide a selective pressure that drives genotypic shifts in a population,” (Paul Solloway, Nutrition Professor in Cornell University) - E.g. C677T polymorphism of MTHFR gene slows down MTHFR enzyme activity - Reduce capacity to use folate to control gene expression and many other reactions that helps development (develops defective gene expression) - Increase the form of folate that can be used to make thymidine (DNA base) and prevent mutagenic uracil from being incorporated (lower risk of certain cancers) - In low folate environment, carriers of C677T polymorphism may be more prone to developmental defects but at the same time could be protected from certain cancers - Fortifying flour with folic acid: - A move intended to prevent neural tube defects among mothers who eat the flour - May lead to numerous unforeseen health problems - Recent findings show a potential link between supplementation and colorectal cancer (in mothers) - Nutrients can cause epigenetic modifications which can affect someone’s health - E.g. Folic acid and Vitamin B12 are epigenetically active ingredients that play important roles in DNA metabolism and the maintenance of DNA methylation patterns - Nutrients can upregulate or downregulate gene expression, affecting an individual’s predisposition to certain diseases - E.g. Nutrients may directly act as ligands for transcription factors and change gene expression. - Nutrients may be metabolised by different pathways, thereby modifying the concentration of substrates or intermediates that affect gene expression - Alternatively, the substrates or intermediates may act on or alter cell signalling pathways involved in gene expression - Moreover, nutrients may directly alter signal transduction pathways responsible for modifications in gene expression - Finally, the modifications in the signalling pathways, caused by the nutrients, may modulate the metabolism of nutrients affecting gene expression 72 3. Nutrition 3.1. Human nutrition Nutrition Using food and drink to provide nutrients which are then metabolised to provide energy and converted to different biochemical molecules to sustain life The types of nutrients needed and how they are obtained are different for different organisms Purpose of nutrients To supply the energy needed for the body to perform work To provide the building blocks for the synthesis of other important molecules To support the function of metabolic pathways Metabolism The chemical reactions that occur throughout the body within each cell Purpose of metabolism: Degradation of compounds (nutrients) absorbed into the intestines into simpler products ○ Can be used as building blocks for the synthesis of new biomolecules ○ To be disposed via the waste disposal pathway if they have no value to our body or even toxic to our body Generation of energy required for the synthesis of molecules and different functions of the body [Energy obtained from the chemical reactions is trapped in form of ATP (GTP is also viable)] Anabolism Catabolism Synthesise larger molecules from Break large molecules into smaller ones smaller ones Require energy Release energy Metabolic pathways: 3.1.1. Overview Nutrition is important for: Prevention of disease Progression of disease Management of disease Major purpose of nutrients: To supply the energy needed for the body to perform work To provide the building blocks for the synthesis of other important molecules To support the function of metabolic pathways Nutrition science is the study of: The components of food Where and how energy and nutrients are derived from food Factors influencing dietary intakes and patterns The actions, interactions and balance of these in relation to health and disease Nutrition is related to IXM: Ingestion and digestion – mouth to stomach Absorption (assimilation and transport) – along GI tract, to liver and body cells Excretion – through urine, faeces, sweat and exhalation Metabolism – catabolism and anabolism Factors affecting nutritional status: (1) Biological factors: (a) Genetic background Individual response to nutrients is determined by genetics Genes affect digestion, absorption, metabolism, excretion, taste and satiety Nutrigenomics: consequences for nutritional guidelines; as the gene pool varies between populations, nutrition guidelines should be population-specific (b) Digestion, absorption and excretion According to IXM, if there is no ingestion and absorption, metabolism cannot take place; if there is no excretion, there is no release of toxic waste products (c) Age and phase of lifecycle Pregnancy: increased demand for nutrients After delivery: feeding through the placenta → breastfeeding → free diet Growth hormones play major role in directing development At school age: new eating and activity patterns emerge as the child becomes more independent At adolescent stage: sex hormones play prominent developmental role In adulthood: muscle mass increases between 20-30 years of age (level of physical activity stabilises) Later stage: muscle mass decline, fat mass increases, bone mass also declines with age (2) Psychological factors (a) Satiety Appetite Palatability of food (3) Social factors (a) Availability of food:  Poorer countries may have food shortage, leading to malnutrition (b) Cultural customs Certain types of food may be prohibited – alternative foods need to be taken to compensation for nutrition (4) Energy expenditure (elaborated below) (5) Presence of disease Disease can affect the nutrition that is absorbed or metabolised in our body Prevention of diseases by nutrition Living with excess weight is a risk factor for: Type 2 diabetes Cardiovascular diseases Cancers Liver diseases and respiratory diseases Excess weight is linked to higher prevalence of COVID-19 complications: Increased risk for positive test, hospitalisation, advanced level treatment (mechanical ventilation and ICU), death Increases exponentially with BMI Mechanism: Excess fat tissue and deposition around the upper airway → reduce respiratory function → affect circulating levels of oxygen Fat tissue have high levels of ACE2 enzyme – COVID viruses latches on to ACE2 to gain access to body cells Excess fat tissue enhances inflammatory and immune response → affect antiviral treatments Higher risk of thrombosis (blood clot blocking arteries and veins) in COVID 3.1.2. Classification of nutrients (1) Carbohydrates (macronutrient) Main energy source (along with fats) Create a sense of satiety over a longer period of time – may be helpful in weight control and diabetes treatment Being digested rapidly & stimulate craving → promote fat deposition in tissues Fibre: indigestible → regulate gut motility and transit, not used as energy source (2) Fats (macronutrient) Main energy source (along with carbohydrates) Most important nutrient used for energy storage Strongly linked to heart disease (3) Proteins (macronutrient): Provide cell structure Responsible for cell functions, communications, signalling ‘Last resort’ energy substrate – releasing amino acids from muscle → muscle wasting (4) Essential fatty acids Linoleic acid and α-linoleic acid (5) Essential amino acids 10 amino acids (out of 20) considered essential PVT TIM HALL  ○ Phenylalanine, Valine, Tryptophan ○ Threonine, Isoleucine, Methionine ○ Histidine, Arginine, Leucine, Lysine [*Arginine: essential in growing children] Proteins from animal sources contain all essential amino acids Proteins from plant sources contain some essential amino acids (6) Vitamins and Minerals Essential nutrients that act as coenzymes, form functionally important prosthetic groups of enzymes, involve in critical development and function of the body Micronutrients Others: ethanol is an energy source but not a macronutrient 3.1.3. Energy expenditure Energy content of macronutrients Carbohydrates = 4.1 kcal/g Proteins = 4.1 kcal/g Fat = 9.3 kcal/g Total daily energy expenditure (TEE) (1) The basal metabolic rate/ resting metabolic rate (BMR) Energy required to maintain normal physiological functions when the body is at rest (60 to 70% of total energy expenditure) Equivalent to the caloric requirement of our major organs and resting muscle Affected by multiple factors: (2) The energy used up during physical activity Energy required to support certain levels of physical exertion (variable amount) Most important changeable component of energy expenditure in health  (3) The thermic effect of food Energy expended during digestion, absorption, and metabolism of nutrients (~10% of total energy expenditure) Fat (in adipose tissue) A major fuel store 3 distinct depots in body: Subcutaneous fat under Generally benign the skin Source of energy Hips and thighs Visceral fat within Produces mediator molecules that abdominal cavity promote atherosclerosis, cardiovascular diseases, type 2 diabetes Rounded abdomens Ectopic fat (e.g. cardiac Obstruct heart (impair cardiac function) and pharyngeal fat pads) Obstruct pharynx (respiratory difficulties) Energy balance Gain weight: energy intake > energy expenditure ○ Obesity – high intake of high-calorie food → more energy intake, more fuel store than needed ○ Decrease in physical activity → less energy expenditure Lose weight: energy expenditure > energy intake ○ Weight loss through diet alone → possibility of undernutrition 3.1.4. Nutritional recommendation & assessment (1) Dietary Reference Intakes (DRIs) Estimated average requirement (EAR) ○ Level estimated to meet the requirement of 50%of the healthy individuals in a particular life stage and gender group Recommended dietary allowance (RDA) ○ Level sufficient to meet the nutrient requirements of nearly all (97–98%) the individuals in a life stage and gender group Adequate intake (AI) – (if EAR or RDA not available) ○ Estimates of nutrient intake by a group(or groups) of apparently healthy people that are assumed to be adequate Tolerable upper intake level (UL) ○ Highest level likely to pose no risk of adverse health effects to almost all individuals in a particular life stage and gender group (2) MyPlate (US Department of Agriculture) (3) Eatwell Guide(NHS in UK) (4) Malnutrition Universal Screening Tool (MUST) 1) Identify the BMI score 2) Identify the weight loss score 3) Identify the acute disease effect score 4) Identify the overall risk of malnutrition 5) Follow management guidelines (5) Anthropometric measurements  1) BMI 2) Waist-to-hip ratio 3) Mid-arm circumference 4) Skinfold thickness Advantages: easy, portable, non-invasive, cheap Limitations: athletes, lean deformity, adults with age related loss of skeletal mass, require more detailed analysis through different means (6) Biochemical data (e.g. biomarkers) 1) Blood (plasma proteins – albumin, haemoglobin – iron) 2) Urine (urinary nitrogen, i.e. urea assesses nitrogen balance relating to body protein requirements) 3) Faeces Advantage: objective, qualitative indicators Limitations: not exclusively determined by the state of nutrition, but also medication and presence of disease (7) Dietary data (dietary habits: meal patterns, amount and composition of food) 1) Biological factors (state of the systems responsible for ‘IAMX’) 2) Psychological factors (eating disorders) 3) Sociological factors (availability and price of food, societal measures to improve diets) 4) Cultural factors (eating patterns and food preference) 3.1.5. Micronutrients Purpose Form prosthetic groups of enzymes or serve as their cofactors Hormones Cell growth, proliferation and differentiation Vitamins An essential non-caloric organic nutrient needed in very small amounts (μg- mg) in the body Minerals An essential non-caloric inorganic nutrient needed in very small amounts (μg- mg) in the body Classification  Possible causes of micronutrient deficiency Inadequate intake Increased demand – pregnancy, lactation, adolescent growth spurt Poor absorption of gastrointestinal tract – old age (less efficient absorption) Inefficient utilisation by the body Increased loss from the body through excretion 3.2. Vitamins Fat-soluble vitamins Water-soluble vitamins Packaged into micelles with other diet- Absorbed into the blood within the derived lipids (fats) for absorption within intestines the intestines Travel freely in the body without the need of Transported by carrier proteins carrier proteins Stored in liver & adipose tissue Not stored in the body but excreted in urine 3.2.1. Fat soluble vitamin (1) Vitamin A Key forms  β-Carotene: antioxidant Retinal: produce the visual pigment rhodopsin Retinoic acid: contributes to the proper differentiation of epithelial cells Oral isotretinoin (synthetic): treat severe acne but is teratogenic, disrupt development of embryo/ foetus during pregnancy Function (4As) Antioxidant Aura: ability to see light ○ Vit. A forms component of eye retina and epithelial lining of cornea ○ Vit. A produces visual pigment rhodopsin (rod cells of the retina) Rhodopsin: exposed to light → conformational change & elicits nerve impulse perceived by the brain as light ○ Rod cells: responsible for vision in poor light ○ Vit. A deficiency: night blindness Activation: epithelial cell division ○ Retinoic acid: nuclear hormone that binds to transcription factors (DNA-binding receptors) Influence the transcription of specific genes ○ Growth, differentiation, and proliferation of cells; in embryonic development and organogenesis; and in the maintenance of epithelia Abnormal pregnancy ○ Vit. A deficiency/ excess Deficiency: Hypovitaminosis A Cause: inadequate dietary intake or absorption Night blindness Keratomalacia ○ Lack of Vit. A affects the growth and differentiation of epithelial cells → defective epithelialisation → corneal softening and opacity Permanent blindness Growth impediment, impaired wound healing, etc. Excess: Hypervitaminosis A Cause: excessive intake of Vit. A supplements  Liver toxicity Infants exposed to excess Vit. A/ isotretinoin (synthetic) may have birth defects e.g. cleft palates and heart abnormalities Abnormal pregnancy may be a result of too much/ little Vit. A (2) Vitamin D Key forms 7-dehydrocholesterol: found in the skin and a precursor to Vit. D Ergocalciferol: obtained from diet Cholecalciferol: used to synthesise 25-OH-D3 in the liver 25-hydroxyvitamin D (25-OH-D3): form of Vit. D in the bloodstream, produced in the liver from cholecalciferol & ergocalciferol 1,25-dihydroxyvitamin D (1,25-(OH2)-D3): active form of Vit. D produced in kidneys rom 25-hydroxyvitamin D Deficiency: Hypovitaminosis D Cause: inadequate dietary intake, disruption of lipid absorption (affect Vit. D absorption), poor functioning of liver & kidney (impair conversion of Vit D to active forms), hypoparathyroidism (low level of parathyroid hormone affect calcium & Vit. D metabolism) Manifest as brittle bones ○ Rickets in children ○ Osteomalacia in adults Excess: Hypervitaminosis D Elevated levels of Ca2+ in blood → hypercalcemia Deposition of calcium in organs (esp. arteries and kidneys) Elevated levels of Ca2+ in urine → hypercalciuria → formation of kidney stones (3) Vitamin E Properties Antioxidant ○ Protect cells from the harmful effects of reactive oxygen species (ROS) generated from free radicals reacting with oxygen Free radicals: extremely reactive and unstable → damage biological molecules (nucleic acids, proteins, lipids) Deficiency: Hypovitaminosis E Premature infants: entirely restricted Adults: usually associated with defective lipid absorption or transport (e.g. cystic fibrosis, abetalipoproteinemia) Haemolytic anaemia (erythrocytes susceptible to rupture – haemolysis) – related to antioxidant properties Impaired vision (retinal degeneration) Muscle weakness (myopathy) Peripheral neuropathy Ataxia (poor muscle coordination with tremors) Areflexia (loss of reflexes in limb) Poor proprioception (sensation of one’s position and movement) Decreased vibratory sensation Excess: Hypervitaminosis E Cause: rare, but can be caused by excessive intake of Vit. E supplements Vit E supplementation does not prevent chronic diseases (e.g. cardiovascular diseases), but increased the incidence of stroke (4) Vitamin K Key forms Function (4“K”s) Clotting factors ‘Crushed’ by warfarin Co-factor of gamma-carboxylation Cannot be found in newborn infant  Phylloquinone (from diet) → hydroquinone Hydroquinone (reduced & active form of Vit. K) act as a co-factor of gamma- carboxylation Enzymes catalyse gamma-carboxylation to convert glutamic residue to clotting factors Epoxide (intermediate) can be converted to phylloquinone (the cycle repeated before being degenerated) Warfarin: inhibits the synthesis of clotting factors → prevent blood clotting ○ For patients with thrombosis (blood clot in blood vessels) Deficiency: Hypovitaminosis K Cause: absorption of lipids disrupted, lack gut bacteria that synthesise Vit. K, anticoagulation drugs (e.g. warfarin) taken Susceptible to bleeding and bruising Anaemic, weak, present with nose bleeds, bleeding gums, heavy menstrual bleeding, gastrointestinal bleeding Newborn infant – gut is sterile (lack gut bacteria that synthesise Vit. K) → no source of Vit K Excess: Hypervitaminosis K No clear toxicity associated with Vit. K (phylloquinone and menaquinone). → no tolerable upper intake level (UL) has been set Excessive, prolonged intake of synthetic Vit. K(menadione) → liver toxicity/ haemolytic anaemia (due to toxic effects on the membrane of red blood cells) 3.2.2. Water soluble vitamin (1) Vitamin B (B-complex) Key form (a) Vitamin B1: Thiamine Essential for carbohydrate metabolism Coenzyme of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (TCA cycle) Deficiency Beriberi (occurs where polished rice is major diet component) Wernicke-Korsakoff syndrome (associated with alcoholism) (b) Vitamin B2: Riboflavin Forms part of FMN (flavin mononucleotide) Form parts of FAD (flavin adenine dinucleotide) ○ Coenzyme of succinate dehydrogenase/ complex II; acyl CoAdehydrogenase; retinal dehydrogenase; NADH dehydrogenase/ complex Coenzymes for vitamin-activating enzymes (c) Vitamin B3: Niacin Forms part of NAD+(nicotinamide adenine dinucleotide) ○ Electroncarrier: NADH transfers electrons from the TCA cycle to complex I of the electron transport chain Deficiency  Pellagra progressing through 3Ds: dermatitis, diarrhoea, dementia → death (d) Vitamin B5: Pantothenic Acid Component of coenzyme A (CoA) Deficiency: not well-established (e) Vitamin B6: Pyridoxine Coenzyme for a variety of enzymes (especially amino acid metabolism) Deficiency: neurological symptoms & anaemia (f) Vitamin B7: Biotin Coenzyme for synthesis of fat, glycogen, amino acid Deficiency: can be caused by eating raw eggs ○ Glycoprotein in egg whites has a high affinity for biotin → bind tightly → fail to be absorbed in the intestines (g) Vitamin B9: Folic Acid/ Folate Essential for one-carbon metabolism ○ Tetrahydrofolate (reduced folate) receives one-carbon fragments from donors (e.g. serine, glycine, histidine) → transfers to intermediates in the synthesis of amino acids, purines and TMP (pyrimidine in DNA) Deficiency Megaloblastic anaemia (large, immature RBCs in marrow/ blood) ○ Diminished synthesis of purines and TMP → cells unable to make DNA → cells cannot divide Neural tube defects (spina bifida 脊柱裂 & anencephaly 無腦畸形) (h) Vitamin B12: Cobalamin Prominent in rapidly dividing cells (e.g. erythropoietic tissue of bone marrow) Participates in nucleic acid synthesis, production of erythrocytes, recycling of folate Deficiency Megaloblastic anaemia  (2) Vitamin C (non-B-complex) Function Antioxidant ○ Protects cells from harmful effects of reactive oxygen species (ROS) generated from free radicals reacting with oxygen Reducing agent ○ Keeps iron in its reduced state (Fe3+→Fe2+) → facilitate collagen folding and stability (via hydroxylation) Deficiency: Hypovitaminosis C Scurvy, characterised by sore and spongy gums, loose teeth, fragile blood vessels, swollen joints, anaemia ○ Hydroxylation of collagen → defective connective tissue Excess: Hypervitaminosis C Low toxic effects Excess Vit. C metabolised to oxalate → risk of developing renal oxalate stones in patients undergoing dialysis Vitamin supplement Clear health benefit: Folic acid during pregnancy Vitamin D for people living in areas of low sunlight Uncertain health benefit: Controversial results as to whether Vitamins A, B6, B12, C, and E could prevent cardiovascular diseases and cancer Harmful: High doses of Vitamin A can lead to liver toxicity, teratogenicity, reduction of bone Supplementation of β-carotene in smokers can result in an increase in lung cancer mortality Fruits and vegetables are the best source of vitamins  3.3. Minerals Macroelements Microelements (trace elements) Required in quantities over 100 mg/day Required in quantities less than 100 mg/day Include sodium, chloride, potassium, Include iron, zinc, copper, etc calcium,magnesium, phosphate 3.3.1. Sodium, chloride, potassium [Na+, Cl-, K+] Function Maintain osmotic pressure Maintain acid-base balance (pH) Maintain nerve and muscle excitability Regulation (by kidney) Water, nutrients and minerals absorbed, waste products excreted Regulated the electrolytes and body fluids Disorder Increase in renal excretion, vomiting and diarrhoea → deficiency 3.3.2. Calcium, magnesium, phosphate [Ca2+, PO4 3-, Mg2+] Function Stored in the matrix of bone and teeth Bone serves as reservoir – degradation mobilises ions to perform other body functions Calcium & Magnesium: Contraction of skeletal, cardiac and smooth muscle Propagation of nerve impulses Magnesium: Important cofactor for many enzymes (those utilising ATP) ○ ATP readily forms a complex with magnesium ion that is required in ALL reactions in which ATP participates Deficiency: X/ inadequate ATP impairs ALL metabolism Calcium: Blood clotting, hormonal signalling Phosphate:  Component of DNA, RNA, ATP Phosphorylation Regulation of blood level of calcium & phosphate Calcitriol (1,25-OH2-D3): active form of Vitamin D, produced by kidneys) Parathyroid hormone (PTH): produced by parathyroid gland Calcitonin: produced by thyroid gland Disorder 3.3.3. Iron [Fe] Function Iron: Component of haem ○ Haemoglobin & myoglobin: iron binds to oxygen ○ Redox enzymes: include proteins that function in the electron transport chain (e.g. cytochromes) Iron-sulphur proteins (non-haem form): components of complex I of electron transport chain Regulation Facilitated by hepcidin ○ High [Iron] = ↑ Hepcidin = ↓ Ferroportin = ↓ Iron absorption ○ Low [Iron] = ↓ Hepcidin = ↑ Ferroportin = ↑ Iron absorption Disorder  Haemochromatosis ○ Inherited disorder resulting from the increased absorption of iron ○ Iron accumulates in heart, liver, and pancreas and can cause liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis, and heart failure 3.3.4. Zinc [Zn] Function Contained in approximately 100 enzymes associated with carbohydrate & energy metabolism, protein synthesis & degradation, nucleic acid synthesis Not stored in body Disorder Cause of deficiency: patients with major burns/ renal damage, lost during dialysis, develop during intravenous feeding Affects growth, skin integrity, wound healing 3.3.5. Copper [Cu] Function Remove superoxide & ROS Associated with oxygenase enzymes like cytochrome c oxidase (complex in the electron transport chain) Disorder Rare deficiency: anaemia Excess: liver cirrhosis