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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 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

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