Liver, GI and Metabolism
Tom Lawson July 2013
Topics to Cover ! Metabolism
! Including: - ! Nutrition ! Obesity ! Surgical Stress Response ! Thermoregulation
! GI Physiology
! The Liver
METABOLISM
! Basically it’s 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
! 1/3rd 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 Kreb’s cycle
! Oxidative Phosphorylation uses these carriers to generate ATP
Putting Metabolism Together
Carbohydrate Metabolism ! Cn(H2O)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 ! Kreb’s Cycle = 2 ATP ! Oxidative Phosphorylation
! 2 NADH (from glycolysis) = 6 ATP ! 2 NADH (from pyruvate oxidation) = 6 ATP ! 6 NADH (from Kreb’s Cycle) = 18 ATP ! 2 FADH2 (from Kreb’s 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 + CO2 + 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
Kreb’s/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 FADH2
! REMEMBER – A MOLECULE OF GLUCOSE RESULTS IN 2 TURNS OF THE CYCLE
! THEREFORE A MOLECULE OF GLUCOSE CAUSES THE KREB’S 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 FADH2
! 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 Kreb’s 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 Kreb’s 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 Kreb’s
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 1st 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 RV’s 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
o Cholinergic inhibition
o Dopaminergic stimulation
o Oestrogen
o Alpha adrenergic inhibition
o Beta adrenergic stimulation
o CCK
o Secretin
o Prostaglandin 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 (Auerbach’s) = Motility = Moving Along
! Submucosal (Meissner’s) = Secretions = Sloppy Mess
! Myenteric plexus (Auerbach’s)
! 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 2nd 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 (Glisson’s 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