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