Topics to Cover Metabolism Including: - Nutrition Obesity Surgical Stress Response Thermoregulation GI Physiology The Liver METABOLISM Basically its all about energy = all the biochemical pathways that are involved in providing energy and materials for life Sources Requirements Acquisition Storage Usage METABOLISM Energy Sources come from Macronutrients Carbohydrates and Fats Needed for energy 1/3 rd for External work 2/3rds for metabolism Non protein calories are provided as a ratio of 70:30 (carb:fats) Protein Needed for growth and repair - Metabolic Machinery Formed from Amino Acids 20 essential Nitrogen is used as a marker of protein intake 1g Nitrogen = 6.25g of protein Requirements Daily requirements Calories = 30kcal/kg/day 1 Calorie = energy (J) needed to raise 1g of H2O by 1C = 4.184J Water = 30ml/kg/day Glucose = 2g/kg/day Fat = 2g/kg/day Protein = 0.3g N2/kg/day (0.5g in burns) Sodium = 1.2mmol/kg/day Potassium = 0.8mmol/kg/day Other requirements Arginine, glutamine, insulin, folic acid and various branch chain amino acids Energy Carriers Chemical bonds store energy Energy is released with these bonds are broken 60% of this energy causes heat 40% is used to perform work e.g. skeletal muscle movement ATP Adenosine Triphosphate Energy from hydrolysis to ADP is used for the majority of bodily reactions ATP is continuously produced everyday (40kg) ATP Phosphorylation Other Energy Carriers Two: - Nicotinamide Adenine Dinucleotide (NAD+) Flavin Adenine Dinucleutide (FADH) Both trap energy from the Glucose Carbon skeleton as it passes through the Krebs cycle Oxidative Phosphorylation uses these carriers to generate ATP Putting Metabolism Together Carbohydrate Metabolism C n (H 2 O) n
Ingested as simple or complex carbohydrates, absorbed as monosaccharides and passed to liver or muscle for further metabolism Aerobic Metabolism of per molecule of glucose ! net gain of 38 moles ATP Glycolysis = 2 ATP Krebs Cycle = 2 ATP Oxidative Phosphorylation 2 NADH (from glycolysis) = 6 ATP 2 NADH (from pyruvate oxidation) = 6 ATP 6 NADH (from Krebs Cycle) = 18 ATP 2 FADH2 (from Krebs Cycle) = 4 ATP = Grand Total of 38 ATP Pathways Glycolysis Gluconeogenesis Glycogenolysis and glycogenesis PPP or HMP shunt Carbohydrate Metabolism Glycolysis A.k.a. Embden-Meyerhof pathway Glucose must first be activated to glucose-6-phosphate (in this form it can also be used to make glycogen). Uses 2 ATP per glucose molecule Generates 4 ATP and 2 NADH per glucose molecule Net Gain of 2 ATP and 2 NADH Aerobic conditions ! oxidation phosphorylation and 2NADH form more ATP Anaerobic conditions ! Net gain is ONLY 2 ATP and lactate (which accumulates as part of the oxygen debt) Glycogen = branched polymer of glucose (phosphorylated ! combined with Uridine Triphosphate ! added to glycogen chain by Glycogen Synthase) Efficient storage form energy cost of storage + retrieval is -3% of total available energy Total bodily reserves = 325g stored in a 3:1 ratio between skeletal muscle and the liver Glycogenolysis = process when a phosphorylase activates and splits the terminal glucose from a glycogen chain Gluconeogenesis= generation of glucose from substrates e.g. pyruvate or lactate De-amination of amino acids easily produces such substrates (hence muscle mass is a large potential glucose source) Occurs mostly in the liver BUT ALSO some occurs in the renal Allows plasma glucose to be maintained for tissues that use glucose preferentially as their energy source. Net cost = 6 ATP PPP or MHP Shunt Pentose Phosphate Pathway or Hexose Monophosphate Shunt Alternative pathway for glucose-6-phosphate Important in tissues that need reductive power for anabolic processes E.g. cell membrane repair, amino acid/fatty acid/steroid synthesis A cyclic pathway occurring in activated glucose units involves tranfers of a C2 fragment between pentoses (C5) Produces CO2, ribose-5-Phosphate (needed for formation of nucleic acids) and 2 NADPH (a reducing agent) Oxidation of Pyruvate to Acetyl-CoA Occurs within mitochondria Irreversibly funnels pyruvate into the Citric Acid Cycle Net Reaction Pyruvate + CoA + NAD + = Acetyl-CoA + CO 2 + NADH Requires co-factors and pyruvate dehydrogenase (which itself is made up of 3 different enzymes) High levels of energy (as NADH, ATP and Acetyl-CoA) act as negative feedback and switch off pyruvate dehydrogenase Net energy gain of NADH ! can be converted to ATP by oxidative phosphorylation Krebs/Citric/Tricarboxylic Acid Cycle Takes place in the Mitochondria Common end pathway (with oxidative phosphorylation) for carbohydrates, lipids and proteins Carbohydrate and Lipid metabolism feed Acetyl-CoA into the cycle Protein metabolism can feed the cycle at several points Oxaloacetate, Alpha-ketoglutarate or Fumarate Energy produced from each cycle 3 NADH 1 ATP 1 FADH 2
REMEMBER A MOLECULE OF GLUCOSE RESULTS IN 2 TURNS OF THE CYCLE THEREFORE A MOLECULE OF GLUCOSE CAUSES THE KREBS CYCLE TO PRODUCE 6 NADH 2 FADH2 2 ATP 4 CO2 Oxidative Phosphorylation occurs in mitochonria process by which ATP is generated by high potential electrons carried by NADH and FADH 2
High Potential tendency to transfer electrons to low potential carriers in the mitochondrial membrane Which act as proton pumps (activated by electron flow through them) ! pumping H+ out of inner mitochondrion ! creates H+ gradient ! ATP synthesis is catalysed by driving H+ back across the inner membrane through ATP synthase channels Anaerobic Metabolism Four steps Glucose is still converted to pyruvate (requiring 2 ATP) Glucose can not be further metabolised to acetyl CoA ! hence does NOT enter the Krebs Cycle Pyruvate is instead converted to Lactate (producing a net of only 2 ATP) Once aerobic conditions are restored ! lactate is transported bacl to the liver where it is converted to glucose as the Cori Cycle Protein Metabolism Bodily proteins are being constantly broken down into / resynthesized from an amino acid pool Excess amino acids are deaminated !Carbon skeletons can enter other pathways, whilst Amino groups excreted as urea / creatinine Transamination = transfer of an NH2 group to another molecule, usually a keto acid allows excess amino acids to be degraded to intermediates that can be metabolised to give energy Deamination= removal of the amino group from an amino acid to leave a carbon skeleton that can be metabolised Urea Cycle A.k.a. Ornithine cycle Excess amino acids are deaminated to release NH4+ Occurs mostly in 2 tissues Kidneys NH4+ dissociated into NH3 and H+ for excretion in urine Liver NH4+ converted to carbamyl phosphate which contributes to formation of urea Urea is formed in a cyclic process in the mitochondria (approx 30g daily) synthesis of one molecule of urea requires energy from 3ATP Essential Amino Acids main carbon atom is asymmetrical and has four different chemical groups attached COOH (carboxyl group = acidic) NH2 (amino group = basic) H (hydrogen atom) R (residue varies depending on particular amino acid) Essential Amino Acids = amino acids that cannot be synthesizd by the organism from other available resources Therefore muse come from diet 8 amino acids are regarded as essential for humans (2 others are essential for children Histidine and Arginine) Threonine These Tryptophan Ten Valine Valuable Arginine Amino Acids Histidine Have Lysine Long Phenylalanine Preserved Leucine Life Isoleucine In Methionine Man Lipid Types Fatty Acids = Main energy store of the body (9kcal/g, compared to 4kcal/g for carbohydrates/protein) Also Component of phospholipids, glycolipids, hormones and intracellular messengers Synthesized in cytoplasm and stored as triglycerides Triglycerides 3 fatty acid chains attached to glycerol (C3) by ester bonds Transported as lipoproteins in chylomicra Plasma Lipoproteins Phospholipids and Glycolipids Building blocks for plasma membranes and tissues Cholesterol Precursor of steroid hormones and component of membranes Essential Fatty acids Cannot be synthesized by body from other fatty acids, therefore must come from food Originally called Vitamin F until realized that they are best classified with the fats Arachodonic acid, Linoleic acid and Linolenic acid Support the cardiovascular, reproductive, immune and nervous systems Required to manufacture and repair cell membranes, to produce prostaglandins and for adequate neural development in children Beta-Oxidation of Fats = Breaks down fatty acids to produce energy Cyclic process occurring in mitochondrial matrix Acetyl-CoA esterificates free fatty acids in the cytoplasm Complex loaded onto Carnitine carrier protein ! transported into inner mitochondria Complex recombines with Acetyl CoA (is unloaded) by Carnitine Acyl- transferase (carnitine then returns to outer membrane) This is the so-called Carnitine shuttle C2 fragments split off fatty acids ! producing Acetyl CoA for citric acid cycle and a ketoacid (which can also enter the Krebs Cycle) Ketones = acetoacetate and gamma-hydroxybutyric acid formed from excessive levels of acetyl-CoA accumulation of ketone bodies ! ketosis / ketoacidosis Acetyl CoA can be obtained from two routes Under normal conditions by glycolysis By Beta-oxidation as in starvation or uncontrolled diabetes Basal Metabolic Rate Metabolic Rate (kcal/hr) = continuous energy expenditure per unit time that is supplied by metabolism Basal Metabolic Rate = metabolic rate under standardised conditions of mental and physical rest, in a comfortable environmental temperature and fasted for 12 hours = approx 70-100kcal/H NOT the minimum metabolic rate (may occur when patient is asleep) Two methods of measurement: - Directly measured with a whole body calorimeter = temperature rise of a steady flow of water through the calorimeter (no external work is done at rest, therefore energy expenditure = heat produced) Indirectly measured with a modified spirometer with oxygen and a CO2 absorber = measure oxygen consumption per hour at rest, and multiply by 4.8kcal/H of heat produced per L of Oxygen Influenced by: - Age, Gender, BSA, physiological stress level, Muscle Activity, Level of Consciousness, Body Temperature, Thyroid level, Pregnancy and Feeding Malnutrition = state of nutrition in which a deficiency, excess, or imbalance of energy, protein and other nutrients causes measurable adverse effects on tissue and body structure, function and clinical outcome. Nutrition may be: - Under-nutrition what we tend to mean by malnutrition Over-nutrition Unbalanced nutrition e.g. alcoholism Incidence = 40% in hospital patients (MacWhirter and Pennington 1994) Early nutrition in critical illness associated with: - 32% reduction in mortality 24% reduction in infections Importance of Malnutrition If left untreated will lead to death When coupled with an acute physiological insult, death occurs more quickly Impaired organ function Poor healing / increased tissue breakdown Weakened immune response 3 x post-op complications 4 x mortality Effects of Malnutrition CVS Decreased heart rate, cardiac output and CVP RS Decreased inspiratory force and FVC Increased difficult of respiratory weaning GI Decreased gut motility ! Atony / Ileus Villous atrophy / Oedema Loss of barrier function ! Increased gut permeability to intestinal bacteria Exocrine failure Malabsorption Other Decreased metabolic rate Immunosuppression Muscle weakness Poor wound healing Impaired organ function Increased morbidity and mortality Fasting Vs. Starvation Fasting = lack of nutritional intake for up to 48hours NOT associated with maladaptation Starvation = lack of nutritional intake for over 48hours associated with maladaptation which will lead to death within 60days if untreated Stage 1 (lasts 24hours) Low insulin and High Glucagon concentrations Hepatic Glycogenolysis (body stores exhausted within 24hours) All result in a maintained plasma glucose concentration Stage 2 (lasts 24hours to 4days) Lipolysis (mobilisation of fat stores) Hepatic Gluconeogenesis (beta-oxidation of fatty-acids ! "Acetyl-CoA ! saturates Krebs Cycle ! ketosis Protein and Nitrogen sparing initially to maintain basal plasma glucose concentration Stage 3 (day 4 onwards) Adaptive Ketogenesis = use of ketoacids (from free fatty acid metabolism) to drive Citric Acid Cycle (instead of glucose). Process driven by hormones (GH and cortisol) Fall in Energy Requirements to approx 15kcal / kg / day Lipid supply is being used up ! Reduced Ketones and Increased Protein Catabolism ! leading to increased plasma and urinary Nitrogen Maladaption = uncontrolled loss of nitrogen ! Loss of organ lean mass (heart and kidney) leads to irreversible damage ! Death Hormones in Starvation Insulin initially increases and then decreases leading to increased fatty acid levels Glucagon levels are high ! beta-oxidation Growth hormones increase leading to lipolysis Levels of Catecholamines are initially high, but decrease in the long-term Cortisol is increased (stress response) Thyroxine increased in 1 st three days and then declines Obesity Condition where natural energy reserve, stored in the fatty tissues of humans and mammals is increased to the point where it may impair health Often defined in terms of BMI Healthy = 18.5 24.9 Overweight = 25 29.9 Obese = 30-34.9 Morbidly Obese = 35 39.9 Super Morbidly Obese= >40 Obesity increases morbidity and mortality Effects of Obesity RS Increased VO2, CO2 production and Work of breathing Increased V/Q mismatch ! hypoxaemia Decreased Compliance and FRC (which may be less than Closing Capacity) Hypoxic pulmonary vasoconstriction increases RVs work and may ! pulmonary hypertension and RV failure Obstructive sleep apnoea / Obesity Hypoventilation Syndrome CVS Increased cardiac output and Blood Volume Hypertension common ! increases LV work, can ! LV hypertrophy and LV failure GI Increase intra-abdominal pressure may ! hiatus hernia Other co-morbidities Type 2 diabetes, Hypercholesterolaemia, Gout, Arthritis, Gallbladder disease, Hepatic impairment, Cerebrovascular accident, Certain malignancies, etc Surgical Stress Response = a local and systemic neuro-hormonal and inflammatory response to physiological upheaval Aim of which, is to maximise survival magnitude depends on: - a) severity of insult and b) duration of insult The changes seen usually return to normal without serious sequelae especially in fit and well patients In patients with serious co-morbidities, however, such changes can have a serious impact on morbidity and mortality Two phases Shock phase Short hypodynamic state (reduced metabolic rate & physiological depression) Flow phase - Longer lasting hyperdynamic compensatory state (increased metabolic rate, glucose production and restoration of circulating volume and tissue normalcy) Stimuli include: - Surgery, Pain, Hypotension, Oxygen, CO2, H+, Emotions, Temperature, Drugs and Anaesthesia Neuroendocrine Response Cortisol = the key hormone in the stress response Stress ! increase in ACTH ! increased (+ possibly prolonged cortisol) causing changes in: - Glucose metabolism ! Increased glycogenesis (the primary glucose source) and gluconeogenesis, but reduced glucose utilization Protein metabolism ! increased peripheral catabolism, increased hepatic plasma protein production, but otherwise decreased protein synthesis Fat metabolism ! increased lipolysis and beta-oxidation of fatty acids Catecholamine Surge leading to: - Cardiorespiratory = tachycardia, +ve inotropy, hypertension and tachypnoea Metabolic = glycogenolysis, gluconeogenesis, lipolysis, ketogenesis and insulin resistance Glucagon Release ! Prolongs hepatic glycogenesis Biphasic Insulin Response ! Initial a phase of physiological insulin resistance (i.e. suppressed) ! Normalisation Growth Hormone Release ! Increased protein synthesis, lypolysis and glycogenolysis Vasopressin Release ! increased water and Na+ retention ! reduced urine volume Reduced Thyroid hormone conversion Increased Renin-Angiotensin-Aldosterone Acitivity Inflammatory Response Cytokines, Interleukins, TNF, Eicosanoids, Serotonin, Histamine, Kallikreins-Kinins, etc Myriad effects, including: - Vasoconstriction / vasodilation, Increased VO2, Increased BMR, Increased platelet aggregation, Increased capillary permeability, Bronchospasm, Pain, etc Hormones Involved in Metabolism Insulin - From beta cells in islets of Langerhans Increases Glycolysis, Glycogen synthesis, Protein synthesis, Triacylglycerol synthesis and Fatty acid synthesis Decreases Glycogenolysis, Ketone formation and Breakdown of triglycerides Glucagon - From alpha cells in islets of Langerhans Increases Glycogenolysis, Gluconeogenesis and Ketone formation Adrenaline - From Adrenal Medulla Increases Glycogenolysis, Gluconeogenesis and Lipolysis Cortisol - From Adrenal Cortex Increases Gluconeogenesis, Lipolysis and Protein Catabolism Decreases DNA synthesis Growth Hormone - From Anterior Pituitary Increases Gluconeogenesis and Lipolysis Thyroid Hormone - From Thyroid Gland Normal Concentrations increase RNA and Protein Synthesis High Concentrations increases Basal Metabolic Rate, Decreases Protein Synthesis and Uncouples oxidative phosphorylation Thermoregulation Body Temperature = Tightly regulated to ensure enzyme systems work efficiently Normal body temp = 37degrees C with Circadian variation of up to +/- 0.7C Affected by many things including: - menstrual cycle (temp increases with ovulation), exercise, feeding, thyroid disease, infection and drugs Physiology Hypothalamus processes temperature information transmitted by fibres in the Spinothalamic tract Cold signals via A fibres and Warm signals via C fibres Heat loss responses Behaviour modification (the MAJOR regulator) e.g. taking off clothes Cutaneous vasodilation Sweating (can increase heat loss by a factor of 10) Panting Thermogenic responses Behavioural (e.g. putting on more clothes) Exercise Cutaneous vasoconstriction Piloerection Lack of Sweating Shivering Non-shivering thermogenesis (specialised brown fat in children increase metabolic output by fat oxidation much less effective in adults) GI - Oesophagus = 30cm long muscular tube than transmits food from mouth to stomach and prevents reflux upper 6cm = striated skeletal muscle under voluntary control Remainder = smooth muscle NO voluntary control Two sphincters Upper at Level of C5 / C6 = cricopharyngeal and pharyngeal constrictor muscles supplied by vagus usually tonically contracted prevents air entrainment Lower = zone of increased luminal pressure (15-25mmHg) indistinguishable from rest of oesophagus usually closed to prevent reflux Barrier pressure = pressure difference between intragastric pressure and that exterted by LOS Decreased LOS pressure / increased intragastric pressure ! reduces Barrier pressure ! increased likelihood of reflux LOS tone Factors Increasing LOS tone Cholinergic stimulation Dopaminergic stimulation Histamine Alpha adrenergic stimulation Beta adrenergic blockade Gastrin Motilin Prostaglandin F2 Factors decreasing LOS tone oCholinergic inhibition oDopaminergic stimulation oOestrogen oAlpha adrenergic inhibition oBeta adrenergic stimulation oCCK oSecretin oProstaglandin E1 Swallowing = motor reflex (cannot be interrupted / terminated once initiated) afferent limbs = trigeminal and vagus to tractus solitarius efferent limbs = via vagus, trigeminal, facial and spinal accessory controlled by deglutination centre in reticular formation Oral preparatory (voluntary) Food bolus formed by squeezing against the hard palate Initiates reflex arc at pharyngeal stage Pharyngeal (involuntary) Soft palate rises against posterior pharyngeal wall and pharyngeal constrictors move bolus Larynx raises (closes glottis) and epiglottis covers ! temporary halt in respiration Takes 1-2 seconds Begins a peristaltic wave (=primary peristalsis) Oesophageal (involuntary) Upper oesophageal sphincter relaxes Peristalsis propels bolus to stomach If primary peristalsis fails oesophageal stretch receptors initial secondary peristalsis GI Gastric Motility Two movements: - peristaltic (propulsive) and local constrictive (mixing) 5 layers to gut: - Serosa (outermost), Longitudinal Muscle, Circular Muscle, Submucosa & Mucosa 3 smooth muscle layers: - Longitudinal, Circular and Inner submucosal layer (muscularis mucosa) Motility is controlled by nervous and endocrine systems which are all integrated Systemic = ANS Parasympathetic = largely by Vagus nerve Vagus to proximal GI tract and sacral fibres to distal GI tract) increase motility Sympathetic from T5 L1 Preganglionic fibres pass via paravertebral ganglia without synapsing to form the splanchnic nerves ! synapse at superior, middle and inferior prevertebral mesenteric plexuses. Postganglionic fibres run with mesenteric vessels supplying all gut areas ! terminate in enteric nervous system stimulates sphincter contraction and relaxes non-sphincteric muscles Local = Enteric nervous system (complicated lattice of neurones in bowel wall) Enteric Nervous System Two plexuses Myenteric (Auerbachs) = Motility = Moving Along Submucosal (Meissners) = Secretions = Sloppy Mess Myenteric plexus (Auerbachs) Lies between longitudinal and circular muscle layers Neurones classified as Cholinergic (stimulatory) Adrenergic (inhibitory) Neurotransmitters include: - Substance P Vasoactive Intestinal polypeptide (VIP) Nitric Oxide (NO) Integrates neural information from autonomic nervous system and other plexuses Provides second-by-second control of contractile gut activity GI - Bowel Small Intestine = 5m long in adults Mixing contractions - presence of chyme encourages alternating contraction and relaxation Propulsive movements - Peristalsis slows from proximal to distal intestine; mean transit time is 3-5hours; Increased by: - chyme in duodenum, Gastroenteric reflex and hormones e.g. cholecystokinin and gastrin Decreased by: - Secretin and Glucagon, fasting initiates peristaltic waves (migrating motor complex) to prevent accumulation of secretions and ileocaecal valve slows flow from ileum to caecum and prevents backflow Colon Slow proximal movements promote reabsorption of fluid and electrolytes Transit time = 33hours Colon important for: - absorption of water and electrolytes from chyme, fermentation of complex carbohydrates by colonic bacteria and storage of faeces prior to defaecation GI Secretions Saliva 3 Pairs Salivary Glands produce 0.5 1.5L saliva per day Constituents vary with flow rates: - water, mucus, digestive enzymes, NaCl, KCl (x20 plasma levels), Bicarb (higher at higher flow rates) Rate of production is controlled by autonomic nervous system PNS and SNS both increase salivation (PNS = watery, SNS = viscous) Functions of saliva: - lubrication for speech/swallowing, buffering, antimicrobial and digestion Mucus secreted throughout GI tract by mucus cells - cover the entire mucosa in a 0.2 0.6mm layer Consists of: - 70% water, electrolytes, sloughed cells and Mucins complex glycoproteins Functions coats/lubricates food, protects mucosa from HCL, buffering, formation of solid faeces, etc Secretion increased by: - Cholinergic stimulation and Prostaglandin E2 Bicarbonate Secretion Secretion is active and passive Is exchanged for intraluminal Cl- Intrinsic Factor = mucoprotein secreted by parietal cells in stomach essential for absorption of vitamin B12 - forms complex with vitamin ! actively absorbed in distal ileum GI Secretions II Pancreatic Juice 500ml of alkaline (pH 8.0) pancreatic juice formed daily Consists of: - digestive enzymes (secreted by acina) and Bicarb (from ductal epithelial cells) Pancreatic enzymes synthesized as inactive proenzymes Secretion fluctuates throughout the day (Increases following food, Decreases during fasting) Main secretory stimulus = intestinal fat and protein Two hormones responsible for pancreatic juice secretion Secretin - Released from S cells in upper small intestine in response to duodenal pH<4.5 Main effect = production of large volumes of bicarb rich fluid to neutralise stomach acid Cholecystokinin (CCK) - Released from duodenal mucosa in response to duodenal amino acids / fats Main effect - Stimulates pancreatic enzyme release from acina cells Also augments actions of Secretin Others: - Glucagon, Somatostatin and VIP may have a role in inhibition of pancreatic juice secretion Trypsin Trypsinogen converted to trypsin in duodenum by enterokinase (released from duodenal epithelium) Trypsin splits proteins into smaller peptides Also activates most of the other pancreatic proenzymes including: - Chymotrypsinogen converted by Trypsin to Chymotrypsin (similar action to chymotrypsin) Carboxypeptidase cleaves carboxyl groups from peptides to produce free amino acids Ribonuclease + deoxyribonuclease, Pancreatic Lipase, Pancreatic Amylase Bile = complex mixture of water, bile salts, pigments and other organic/inorganic compounds Liver produces 700 1200ml bile daily of which 30-60ml stored in gallbladder green in colour due to presence of pigments (mainly bilirubin) ! responsible for urine & faeces colour Bile salts = synthesized in liver by conversion of cholesterol to cholic and deoxycholic acids (bile acids) ! conjugated with glycine and taurine to form bile salts. They emulsify fatty globulins in small bowel ! break them down into smaller molecules and form micelles fat-soluble vitamins A,D,E and K indirectly require this for absorption Enterohepatic Circulation = distal ileal reabsorption of 94% secreted bile salts ! re-excreted as bile in liver = mechanism in maintaining adequate bile salts for digestion (24g per day) bodily reserve = 6g daily synthesis = 0.5g hence importance of enterohepatic circulation Gastric distension ! stimulates enteric nervous system to stimulate gallbladder contraction Factors affecting Biliary secretion CCK = main hormone controlling biliary secretion release stimulated by presence of intraluminal fat in duodenum causes relaxation of sphincter of Oddi and gallbladder contraction Secretin augments CCK Stomach Acid I Approx 1.2 2.5L gastric juice is produced daily - Stomach stores approx 1.5L Gastric Acid (pH = 1 3.5 ) Aids protein digestion Activates pepsin Has anti-bacterial actions Stimulates biliary and pancreatic secretions in duodenum Phases of gastric secretion Cephalic Phase = Thought, sight, smell, tastes of food ! stimulates stomach via vagus nerve Gastric Phase Food entering stomach elicits long vasovagal reflexes, local enteric reflexes and release of gastrin Mixes food with gastric secretions Slow waves in stomach wall spread towards antrum Constriction of pyloric sphincter encourages further mixing Intestinal Phase A.k.a. Emptying More intense contractions promote antral empyting Rate of fluid emptying influenced strongly by duodenal factors (acidity/osmolality of duodenal juices, proteins, duodenal distension and hormones e.g. cholecystokinin) Food and chyme entering proximal small intestine stimulates gastric secretion via duodenal gastrin release, absorbed amino acids and other hormones Stomach Acid II Two types of secretory glands Oxyntic = tubular mucosal pits (all over gastric mucosa, except lesser curves) 3 different cell types: - Chief cells (secrete pepsinogen), Mucus cells (secrete mucus) and Oxyntic a.k.a. Parietal cells (secrete HCl) Pyloric =in pyloric region Contains G cells (secrete gastrin) and Mucus cells (secrete mucus) Gastric Acid Production Binding to parietal cell receptors -> activates intracellular 2 nd messenger systems Final common pathway ! increased protein phosphorylation and activation of ATP dependent H+/K+ pump Gastric Acid Increasers Ach, Gastrin, Histamine, Amino Acids, Alcohol and Caffeine Gastric Acid Decreasers Prostaglandins, Secretin, Duodenal distension/irritation Prostaglandins produced by the intestinal mucosa ! inhibit gastric acid production Gastric acid converts Pepsinogen to Pepsin Stomach Acid III Digestion I = chemical breakdown of ingested food by GI enzymes for intestinal absorption into systemic circulation (begins in the mouth, most occurs in small intestine) Carbohydrate Small bowel can only absorb Glucose, Fructose or Galactose, therefore, ALL dietary carbohydrates must be broken down to one of these Cellulose = indigestible to humans ! forms dietary fibre Starch = broken down by salivary and pancreatic amylase to oligo/di-sacharrhides Protein = broken down into small peptides / amino acids by stomach Pepsin or small bowl pancreatic peptidases Absorbed by epithelial cells Lipid Lingual and pancreatic lipase hydrolyse triglycerides to free fatty acids and monoglycerides Cholesterol, bile salts, free fatty acids, glycerides and cholesterol form Micelles ! absorbed by intestinal epithelium --> Free fatty acids and monoglyceride reform into triglycerides and then into large lipoproteins called Chylos (enters circulation via lymphatics) Digestion II Vitamin absorption Fat-soluble = A, D, E and K - Absorption depends on Micelle uptake Water-soluble vitamins B1 (thiamine) = Na-dependent active transport in jejunum B12 = combines with glycoprotein in stomach ! digested by duodenal peptidases ! releases free vitamin ! binds to intrinsic factor! absorbed in terminal ileum Folic Acid = actively absorbed through small bowel Vitamin C = absorbed by actively and passively Sodium and Chloride small bowel Water most reabsorbed in small bowel, approx 400ml in colon, leaving about 200ml in faeces Calcium Mainly in duodenum Regulated by 1,25-dihydroxycholecalciferol (synthesized from Vitamin D a.k.a. cholecalciferol) 1,25 dihydroxycholecalciferol stimulates synthesis of calcium binding protein enters cell down concentration gradients via gated channels Iron Gastric / Ascorbic acid (Vitamin C) converts Iron from its Ferric form (Fe3+) to the Ferrous form (Fe2+) The Ferrous form binds to an Integrin receptor on the luminal membrane of the receptor It is then converted to Fe3+ by haemoxygenase in the enterocyte. Binds with apoferritin to form ferritin Apoferritin present in the intestinal mucosal cells prevents iron from gaining access to the circulation by combining with it The Apoferritin production depends on the plasma iron concentration Each ferritin holds 3000-4000 molecules of Fe3+ = major storage form of iron in the body (mostly in the liver) The most immediate source of plasma iron = destroyed red cells Amount absorbed = amount lost Women absorb 2.1mg (due to menstruation) Men absorb 0.6mg Hepatic Physiology largest gland of body Wedge Shaped weighing1200-1600g covered in network of connective tissue (Glissons capsule) divided by fissures into four lobes (Right, Left, Quadrate and Caudate) receives 1800ml/min approx 25-30% of cardiac output has dual blood supply: - hepatic artery (30%) and hepatic portal vein (70%) blood flows to central veins via sinusoids (lined by endothelial and phagocytic cells), separated by hepatocytes Venous drainage via central veins to hepatic veins and into inferior vena cava (IVC) Bile cannuliculi form networks between the hepatocytes towards the biliary tract Two types of cells Parenchymal synthetic and functional Kuppfer cells Macrophages lining sinusoids (part of the reticulo-endothelial system) Hepatic Physiology II Liver Functions Bilirubin metabolism Bilirubin is conjugated with glucuronide to H2O-soluble form Formation of bile acids from cholesterol (reabsorbed via enterohepatic circulation) Detoxification Drugs and Hormones (e.g. steroids, vasopressin & thyroxine) Haematological roles Site of haemopoiesis in fetal/early neonatal life Blood reservoir Kupfer cells phagocytose antigens, bacteria and old RBCs Protein synthesis - Albumin, Globulins and Clotting factors Protein catabolism - Ammonia produced by deamination converted to urea via ornithine cycle Carbohydrate metabolism Glycogenesis, Glycogenolysis and Gluconeogenesis Lipid metabolism Synthesis (e.g. Cholesterol, Prostaglandins), Catabolism (e.g. dietary triglycerides and fatty acids) Vitamin storage A, D, K, B12 and Folate