GI/Liver Flashcards
What are the functions of the stomach?
Store and mix food
Dissolve and continue digestion
Regulate emptying into duodenum
Kill microbes
Secrete proteases and intrinsic factor
Activate proteases
Lubrication
Mucosal protection
How much HCl is produced each day in stomach?
Approx 2 litres
How is gastric acid secreted from parietal cells?
CO2 + H2O from cell resp combine with parietal cell cytoplasm catalysed by (carbonic anhydrase) to form H2C03
H2CO3 split into H+ and HCO3-
H+/K+ ATPase (proton pump) pumps H+ out into stomach lumen, K+ into parietal cell
HCO3- goes into blood, Cl- enters parietal cell from blood (exchange)
K+ and Cl- passively flow into gastric lumen across gradient
H+ and Cl- both in lumen and combine to form HCl
How is gastric acid secretion increased (cephalic phase)? (on phase)
Sight of food or chewing
Vagus nerve parasympathetic fibres release acetycholine
ACh acts directly on parietal cells
ACh triggers release of gastrin and histamine (both then act of parietal)
Increased gastric acid
How is gastric acid secretion increased (gastric on phase)?
Stomach distends during eating, presence of peptides/proteins, vagal stimulation
G cells stimulated to release gastrin
Gastrin travels in blood to parietal cells
Binds to CCK receptors on parietal
Increased gastric acid production
How do proteins in the stomach increase gastric acid secretion?
Act as a buffer, takes H+ ions
pH rises
Decreased secretion of somatostatin
More parietal cell activity
How is gastric acid secretion decreased (gastric phase)? (off phase)
Low luminal pH (can reach pH of 2)
Directly inhibits gastric secretion
Inhibits histamine release
Stimulates somatostatin release from D cells which inhibits parietal cell activity
How is gastric acid secretion decreased (intestinal phase)?
Duodenum distends
Low pH from acidic chyme is hypertonic
Duodenum sends signal via enterogastones (secretin and CCK)
Secretion of somatostatin promoted
Signals also go to brain to stop ACh release
Turns stomach off
What are two enterogastrones?
CCK - Cholecystokinin
Secretin (function is to inhibit gastrin and promote somatostatin)
What is an ulcer?
A breach in a mucosal surface
What can cause peptic ulcers?
NSAIDs
Helicobacter pylori (H.pylori) infection
Chemical irritants (alcohol, bile salts etc…)
Gastrinoma
How does the gastric mucosa defend itself?
Tight junctions between epithelial cells to prevent liquid contents getting into underlying tissues
Rapidly replaces damaged cells
Negative feedback loops to regulate acid
Alkaline mucus resists acid attack
How does H.pylori cause peptic ulcers?
It lives in gastric mucus
Secretes urease to make ammonia
Ammonia beomes ammonium which is toxic
Ammonium plus other substances attack
Inflammatory response
Reduced defence
How do NSAIDs cause peptic ulcers?
Inhibit cyclo-oxygenase 1
cox 1 needed to produce prostglandins
Mucus secretion stimulated by prostaglandins
Reduced mucosal defence
How do bile salts cause peptic ulcers?
Regurgitated bile strips away mucus layer
Reduced mucosal defence
How are peptic ulcers treated?
Antibiotics and PPIs for H.pylori
Misoprostol stimulates mucus production for NSAIDs
H2 receptor antagonists, e.g. ranitidine
What are some PPIs?
Omeprazole
Lansoprazole
Esomeprazole
What do chief cells produce?
Pepsinogen
Describe positive feedback loop for pepsin
Chief cell makes pepsinogen
Parietal makes HCl
HCl cleaves pepsinogen into pepsin
Pepsin digests pepsinogen into more pepsin
Conversion of pepsinogen to pepsin must occur at low pH (2)
What is the role of pepsin?
Break down proteins into peptides in gastric lumen with aid of HCl
How is pepsin inhibited?
Raise pH
HCO3-
What is the role of pepsin in protein digestion?
Accelerates but not essential (e.g. if stomach removed)
Breaks down collagen in meat, chemically shred into smaller pieces
Accounts for 20% of protein digestion
What is receptive relaxation in stomach?
Mediated via vagus (parasympathetic nervous system)
Smooth muscle relaxes
Increase stomach volume without pressure in stomach rising
How does gastric motility occur?
Coordinated contractions start in fundus (peristalsis)
Contractions increase in strength as head towards pylorus
Pylorus closes, gastric content forced backwards, mixing it
Little chyme enters duodenum
What determines peristalsis?
Pacemaker cells, interstitial cells of cajal
3 contractions per minute
Slowly depolarising and repolarising
No significant contraction on empty stomach
What can increase peristalsis strength?
Gastrin increases gastric peristalsis (gastrin triggered by stretch and vagus)
What can decrease peristalsis strength?
Increase in luminal fat
Increase in osmolarity
Decreased luminal pH
Increased sympathetic NS/ decreased parasympathetic
What can overfilling of the duodenum by a hypertonic solution cause?
Dumping syndrome (vomiting, bloating, cramps, weakness, dizziness etc…)
Can happen in diabetes mellitus/ surgery
How is gastric emptying regulated?
Enterogastrones
Neural receptors
Same as acid secretion
What is gastroparesis?
Delayed gastric emptying
Has many causes (female, MS, Parkinson’s, abdominal surgery, neuropathy)
What are the functions of saliva?
Lubricant for mastication, swallowing and speech
Oral hygiene (wash, immunity, buffer)
Digestive enzyme
Remineralisation ( through calcium and phosphate)
What is the normal pH for saliva?
7.2
ranges 6.2-7.4
bicarbonate/carbonate buffer for acid neutralisation
What is the flow rate and daily amount of saliva produced?
0.3-7ml per minute- flow
800-1500ml a day in adults
What do the parotid glands produce?
Serous saliva
What do the submandibular and sublingual glands produce?
Both serous and mucus saliva
What is serous secretion in saliva?
More watery
Contains alpha amylase
Digestion of starch
What is mucus secretion in saliva?
Mucins for lubrication of mucosal surfaces
What do the minor glands produce?
Mucus saliva (mainly)
What can affect the composition and amount of saliva produced?
Flow rate
Circadian rhythms
Type and size of gland
Duration and type of stimulus
Diet
Pharmaceutical drugs
Age
Gender
What is saliva?
Secretion of proteins and glycoproteins in a buffered electrolyte solution
How is the oral cavity defended?
Mucosa (physical barrier)
Palatine tonsils
Salivary glands (washes away food particles bacteria or viruses may use for metabolic support)
What are the different salivary glands
Submandibular
Sublingual
Minor
Parotid - only one that’s not continuously active, only when stimulated
What makes up unstimulated saliva?
Submandibular (and others, not parotid) components
What makes up stimulate saliva?
Parotid secretions
What is the structure of salivary glands?
Acinar cells make saliva
Ducts carry salvia out of glands into mouth
Channels and transporters in apical and basolateral membrane
Describe histology of serous acini
Dark staining, tightly packed
Nucleus in base third of cell
Small central duct
Secrete water and alpha amylase
In parotid gland
Describe the histology of mucus acini?
Pale staining
Nucleus at base of cell
Large central duct
Secrete mucus (water and glycoproteins)
Describe the structure of the ducts in salivary glands
Intralobular ducts (intercalated and striated)
- intercalated: short, narrow duct with cuboidal cells connect acini to striated
- striated: major site for reabsorption of NaCl, appear at basal end
Main excretory duct
What is primary saliva like?
NaCl rich
Isotonic
Secreted by acini
What do ducts in salivary glands secrete and reabsorb?
Secrete K+ and HCO3-
Reabsorb Na+ and Cl-
Doesn’t allow water movement so final saliva hypotonic
Why is the final saliva produced hypotonic?
Epithelium of ducts don’t allow any water movement so final saliva becomes hypotonic
Ions still absorbed
How is saliva production distributed?
Minor glands produce 20%
SMG, SLG and parotid produce 80%
What does xerostomia mean?
Dry mouth
Describe briefly the pathway glucose takes from intestine to where it is needed
Glucose absorbed from intestine into bloodstream
Travels in bloodstream to liver
Distributed to muscles, RBCs, brain, adipocytes
How is glucose stored in the liver?
Glucose molecules joined together to form glycogen
Facilitated by insulin
Glucose also feeds into acetyl CoA which goes on to Krebs (if excess, acetyl CoA can also produced triglycerides, which then become VLDLs)
What is glycogen?
Storage form of glucose in the liver
Role of insulin
Promotes the uptake of glucose from bloodstream to cells
Facilitates glucose to glycogen
What happens to glucose in muscles?
Glucose from bloodstream is stored in muscle as glycogen
Facilitated by insulin
What happens to glucose in the brain?
Glucose from bloodstream goes to acetyl CoA in the brain
Enters Krebs and ATP is formed
What happens to glucose in the RBCs?
Glucose converted into pyruvate (no Krebs because no mitochondria in RBCs)
Pyruvate can become source of energy or lactate
What happens to glucose at adipocytes?
Glucose stored in triglycerides or used to produce ATP
Promoted by insulin
What can happen to amino acids after being absorbed into bloodstream?
Form protein
Can form other compounds, e.g. peptide hormones, carrier proteins
Can feed into Krebs
What can happen to triglycerides after digestion?
Join with proteins (form chylomicrons, VLDLs etc…) to be transported in bloodstream
Chylomicrons enter lymphatic system
Where is excess energy stored?
Triglycerides stored in adipose tissue
Glycogen stored in liver and muscle
What happens during a short fast (e.g. overnight)
Glycogen broken back into glucose
Liver releases glucose back into bloodstream (promoted by glucagon)
This is called glycogenolysis
What happens during a long fast? (e.g. days)
Glycogen stores used up by now
Break down AAs from muscles
RBCs release lactate which can be used as energy
Triglycerides broken down into glycerol
All go to liver and gluconeogenesis takes place
What is gluconeogenesis?
Making glucose from the body’s own breakdown products or from the breakdown products of lipids or proteins
When glucose not available from eating
What happens to stored fats during fasting?
Triglycerides broken down into glycerol and fatty acids
Glycerol goes to liver and can be used to make glucose
FAs used as energy source by kidneys and muscle
FAs can also become ketones in the liver (lipolysis, promoted by glucagon)
What happens to stored fats during fasting?
Triglycerides broken down into glycerol and fatty acids
Glycerol goes to liver and can be used to make glucose
FAs used as energy source by kidneys and muscle
FAs can also become ketones in the liver (lipolysis, promoted by glucagon)
What does glucagon promote?
Breakdown of glycogen to glucose
Breakdown of fatty acids to ketones
What happens during prolonged fasting?
Muscles use fatty acids as form of energy
Ketogenesis
Ketones released into bloodstream and can be used by the brain for energy
Decreased use of glucose as ketones used instead means more glucose available for RBCs
What is ketogenesis?
Producing ketone bodies by breaking down fatty acids and ketogenic amino acids.
How is the pancreas endocrine and exocrine?
Releases hormones (insulin and glucagon) and digestive enzymes
What does insulin promote?
Glycogen storage
Fat storage
Protein synthesis
Which out of glucagon and insulin are anabolic/catabolic?
Insulin is anabolic
Glucagon is catabolic
What is leptin and what does it cause?
Peptide hormone
Released by adipocytes
Stimulates the inhibitory neurones and inhibits the excitatory neurones in the arcuate nucleus to cause suppression of appetite
What is ghrelin and what does it cause?
Ghrelin is a peptide hormone
Produced in the pancreas and released from the stomach wall when the stomach is empty
Stimulates the excitatory primary neurones stimulates appetite
When stomach is full, ghrelin release is inhibited, appetite stimulus is also inhibited.
How can iron be lost?
Menstruation/ other blood loss
Desquamation
Sloughed mucosal cells
(about 1-2mg lost per day)
Describe the pathway iron takes from diet
1-2mg per day in diet
Absorbed into plasma and transported via transferrin
Deposited in muscle to create myoglobin, bone marrow to make RBCs, stored in liver and reticuloendothelia cells
Describe the structure of ferritin
Large spherical protein consisting of 24 noncovalently linked subunits.
Subunits form a shell surrounding a central core.
Core contains up to 5000 atoms of iron.
Where is ferritin found?
Cytoplasm (particularly of liver and reticuloendothelial cells)
Serum
What is the concentration of ferritin in serum directly proportional to?
Total iron stores in body
What can cause excess ferritin due to excess iron storage?
Hereditary haemochromatosis
Haemolytic anaemia
Sideroblastic anaemia
Multiple blood transfusions
Iron replacement therapy
What can cause excess ferritin (not from excess iron)?
Liver disease
Some malignancies
Significant tissue destruction
Acute phase response:
- Inflammation
- Infection
- Autoimmune disorders
What can cause ferritin deficiency and what are the levels?
The only known cause of a low ferritin is iron deficiency
Ferritin less than 20 µg/L indicates depletion
Ferritin less than 12 µg/L suggests a complete absence of stored iron
What are some of the roles of vitamins?
Gene activation
Free radical scavenging
Coenzymes/cofactors in metabolic reactions
List the water soluble vitamins
Vitamins B and C
List the fat soluble vitamins
Vitamins A, D, E and K
What is the function of vitamin A (retinoids) and where does it come from?
Used to form rhodopsin in the rod cells in the retina.
Reproduction: Spermatogenesis in males, prevention of foetal resorption of female
Growth
Stabilisation of cellular membranes
Ingested directly from meat, dairy, egg or produced from carotene in fruit and veg
What is the recommended daily requirement for vit A?
0.6 mg/day in men, 0.7 mg/day in women
What can cause vitamin A deficiency and how does it clinically present?
Drop only when liver stores are very depleted, rare in Western countries
Deficiency may occur due to fat malabsorption
Clinical Features:
- Night blindness
- Xeropthalmia
- Blindness
Clinical features of acute vit A excess
Abdominal pain, nausea and vomiting
Severe headaches, dizziness, sluggishness and irritability
Desquamation of the skin
Clinical features of chronic vit A excess
Joint and bone pain
Hair loss, dryness of the lips
Anorexia
Weight loss and hepatomegaly
What are the functions of vit D and how is it obtained?
Absorption of calcium from intestines
Resorption and formation of bone
Reduced renal excretion of calcium
From sunlight: 7-dehydrocholesterol created and converted into vit D3
Vit D3 from meat and fish, D2 from supplements
What can vit D deficiency cause?
Demineralisation of bone:
Rickets in children
Osteomalacia in adults
How does vitamin D become active?
Vitamin D3 and D2 obtained and travel to liver
Liver converts to 25-hydroxyvitamin D3
Kidneys then convert to 1,25-dihydroxyvitamin d3 which is active form
Where is vitamin E stored and what is its role?
Liver
Plasma
Adipose cells (fixed pool, only used in extreme circumstances)
Role as an antioxidant
What food is vit E in?
Nuts and seeds
Wheatgerm
Plant oils
What is recommended vit E requirements per day?
4 mg/day in men
3 mg/day in women
What can cause vitamin E deficiency?
Fat malabsorption (e.g. cystic fibrosis)
Premature infants
Rare congenital defects in fat metabolism e.g. abetalipoproteinaemia.
What are the clinical manifestations of vit E deficiency?
Haemolytic anaemia
Myopathy
Retinopathy
Ataxia
Neuropathy
Where is vitamin K in the body?
Rapidly taken up by the liver
Then is transferred to VLDL and LDLs which carry it into the plasma
What is the function of vitamin K?
Responsible for the activation of some blood clotting factors
Necessary for liver synthesis of plasma clotting factors II, VII, IX and X.
Can be assessed by measuring prothrombin time
What are some sources of vitamin K?
Vitamin K1 (phylloquinone): Synthesized by plants and present in food
Vitamin K2 (menaquinone): Synthesized in humans by intestinal bacteria
Synthetic vitamin K’s:
- K3 (menadione)
- K4 (menadiol)
What can vitamin K deficiency lead to?
Haemorrhagic disease of the newborn: Vitamin K injection given to newborn babies to prevent
Rare in adults, unless on warfarin.
What can vitamin K excess lead to?
K1 is relatively safe
Synthetic forms are more toxic
Can result in oxidative damage, red cell fragility and formation of methaemoglobin.
What is the recommended daily intake of vitamin C?
Adults need 40 mg/day
What are the functions of vitamin C and where can it be found?
Collagen synthesis
Antioxidant
Iron absorption
Found in fresh fruit and veg
What can vitamin C deficiency cause?
Scurvy
- Easy bruising and bleeding
- Teeth and gum disease
- Hair loss
Easily treated by giving vitamin C
What are the 2 active forms of B12?
Methylcobalamin
5-deoxyadenosylcobalamin
What happens to B12 in the body?
Released from food by acid and enzymes in the stomach
Binds to R protein to protect it from stomach acid
Released from R proteins by pancreatic polypeptide.
Intrinsic factor (IF) produced by the stomach needed for absorption.
IF-B12 complex absorbed in the terminal ileum.
B12 is stored in the liver.
What food does B12 come from?
Meat
Fish
Dairy
Eggs
What can cause B12 deficiency?
Pernicious anaemia – autoimmune destruction of IF-producing cells in stomach.
Malabsorption – lack of stomach acid, pancreatic disease, small bowel disease.
Veganism
What are the clinical manifestations of B12 deficiency?
Macrocytic anaemia
Peripheral neuropathy in prolonged deficiency
What are the functions of folate?
Functions as a coenzyme in methylation reactions, DNA synthesis, synthesis of methionine from homocysteine
What is folate found in?
foods fortified with folic acid
When would someone need more folate?
Pregnancy
What can cause folate deficiency?
Malabsorption
Drugs that interfere with folic acid metabolism (anticonvulsants, methotrexate)
Disease states that increase cell turnover (e.g. leukaemia, haemolytic anaemia, psoriasis
Clinical manifestations of folate deficiency
High homocysteine levels
Macrocytic anaemia
Foetal development abnormalities (neural tube defects)
How is the extrinsic clotting pathway activated?
FVII coming in contact with tissue factor.
How is the intrinsic clotting pathway activated?
Exposed endothelial collagen
Which clotting factors are produced in the liver?
I (fibrinogen)
II (prothrobim)
IV
V
VI
VII
How can performance of clotting pathways be measured?
Prothrombin time (PT) (extrinsic pathway)
International normalised ratio (INR)
Activated partial thromboplastin time (aPTT) (intrinsic pathway)
What may a prolonged PT suggest?
deficiency in the synthetic capacity of the liver
can have other causes, e.g. warfarin, vit K, GI bleeding
What are the functions of the colon?
Absorption of water and electrolytes (osmosis)
Excretion of waste (motility)
Production of vitamins (microbiome)
What is the histology of the colon?
Simple columnar epithelial cells
Goblet cells, secrete mucus for lubrication
Describe the enteric nerve supply to colon
2 dense networks of neurones (plexus)
- Myenteric plexus (between circular and longitudinal muscle layers)
- Submucosal plexus (between mucus and submucus layer)
What is the function of the rectum?
Temporary reservoir for faecal contents before elimination
What is the function of the anal canal and what two muscles are there?
Maintaining continence and evacuation of stool
Made up of external and internal sphincter muscles
Describe the internal anal sphincter muscle
Continuation and thickening of rectal smooth muscle wall
involuntary muscle under control of parasymp pelvic nerve and local enteric
generates 85% of resting tone of anal canal
Describe the external anal sphincter muscle
Voluntary muscle
Controlled by somatic
Contracts to keep faecal matter inside if not near a toilet
What happens during the basal phase of defaecation?
Colon has segmental contractions
Random bursts of contractile activity in rectum to keep it empty (braking mechanism)
Anal sphincters remain contracted
Puborectalis - contracted (90o anorectal angle)
What are the 4 phases of defaecation?
Basal
Pre-expulsive
Expulsive
Termination
What is the puborectalis’ location and function?
Sling like muscle that loops round posterior aspect of external anal sphincter
When contracted creates 90 degree angle at junction between rectum and anus (anorectal angle) important for continence
What happens during the pre-expulsive phase of defaecation?
Colon motility: circular muscle helps produce high amplitude propagating contractions, propels content along towards rectum (mass movement of stool ~8 times day, in response to eating when stomach wall stretched, called gastro-colic reflex)
Rectum fills causing distension
Rectal compliance (adaptive relaxation), accommodate increasing faecal matter without changes in pressure
Internal anal sphincter relaxes, small amount of contents enters the canal, detected as gas, liquid or solid, then moves back into rectum (called sampling), external sphincter remains contracted
Puborectalis remains contracted to preserve anal rectal angle
What happens during the expulsive phase of defaecation?
Critical volume of 200ml
Rectum begins to contract and propels stool into anal canal
All muscles relax
Anorectal angle more obtuse to allow for stool exit
Valsalva manoeuvre and posture aid emptying
What happens during the termination phase of defaecation?
External anal sphincter snaps shut (closing mechanism) due to traction loss
Posture changes, valsalva ceases
What is the parasympathetic defecation reflex?
Extrinsic and intrinsic nerve fibres work together
Rectal wall stretches as stool enters rectum
Signals via afferent nerves to sacral part of SC
Messages via efferent nerves to rectum (contracts) and internal sphincter (relaxes)
Continuous downward signals via pudendal nerve to keep external sphinctercontracted unless acceptable to go to toilet
What counts as constipation?
Less than 3 bowel movements a week
What can influence stool consistency?
Diet- not enough fibre causes hard stool
Fluid intake- lack causes hard stool
Medication use- opiod use, e.g. codeine
In bowel for longer- more water absorbed, hard stool
What can slow down bowel movements?
Endocrine and metabolic disorders
Underactive thyroid
Hyperkalaemia
Diabetes
Parkinsons
What can cause obstructive defecation?
Anatomical causes- rectal prolapse
Functional- dyssynergia
What is diarrhoea?
3 or more time a day, loose stool
What can cause diarrhoea?
Diet- too much fibre, dairy, caffeine, processed food
Natural intolerance to lactose or gluten
Inflammatory bowel disorder, e.g. crohns
What can affect frequency of bowel movements?
Inflamed colon: crohn’s, gut infection
Anxiety
Shortened bowel, e.g. resection from cancer
What is the function of the digestive system?
Take relatively large solids and digest them into smaller molecules that can be absorbed as nutrients, while still serving as a barrier to toxins, bacteria, parasites, etc
Where can fluid come from to get into the gut and how much?
Daily 9 litres in from
- Ingesting
- Saliva
- Gastric secretions
- Pancreatic juices
- Intestinal secretions
- Bile
How is fluid lost from the gut and how much?
Small intestine absorbs 7.5 litres a day
200ml lost in urine
Colon absorbs under 1.5 litres
Where do secretion and absorption take place within the small intestine?
Villi increase surface area of small bowel
Most of absorption of fluids of nutrients happen in villi
Secretion occurs in crypts (bottom, below villi)
How does the transcellular transport of water work?
Transporters on enterocytes, transport Na into cell
Basolateral side of cell has sodium/potassium ATPase transport, shifts sodium from cell into interstitial space
Water always follows sodium
How does intestinal secretion work?
cAMP shifts Cl- into lumen
Na+ attracted from basolateral side to lumen where Cl- is
Water follows sodium
What factors can affect absorption in GI?
Number and structure of enterocytes
Blood and lymph flows
Nutrient intake
GI motility
How does cholera lead to diarrhoea?
Cholera toxin released from bacteria in infected intestine
Binds to Intestinal cells
Stimulates adenylate cyclase to produce cAMP
Dramatic efflux of ions and water
Watery Diarrhoea
What is digestion?
Breakdown of large, complex organic molecules that can be used by the body.
What are the 2 types of digestion?
Mechanical (eg. chewing, churning of food)
Chemical (eg. enzymes)
What role does the small intestine play in digestion?
primary site for digestion and absorption of food
Where does digestion occur?
occurs in the GI lumen by secreted enzymes and on
surface of enterocytes by membrane-bound enzymes.
How are carbs digested?
Glucose polymers breakdown into disaccharrides which breakdown into monosaccharides
Enterocytes absorb glucose and galactose through an Na dependent secondary active transport process, while fructose is absorbed by facilitated transport
How is fat digested?
Fat doesn’t mix with water
Bile has affinity for fat and water so emulsifies fat
Fat is mixed into water where enzymes are so digestion can take place
Where do bile acids come from?
Gall bladder releases bile acids into small intestine which are recycled back round to liver when used
How are lipids absorbed?
Large fatty molecule broken down by lipase
Bile salts break fatty acids down and take into cells
Become triglycerides and end up in lymph system
Which enzymes are found in the salivary glands?
Amylase - starch
Lipase - triglycerides
Which enzymes are found in the stomach?
Pepsin - protein
Lipase - triglycerides
Which enzymes are found in the pancreas?
Amylase - protein
Lipase and Colipase - triglycerides
Phospholipase - phospholipids
Trypsin - peptides
Chymotrypsin - peptides
Which enzymes are found in the intestine?
Enterokinase - Activates trypsin
Disaccharidases - Complex sugars
Peptidases - peptides
What are the functions of saliva?
1.Lubricates, cleans oral cavity
2.Dissolves chemicals
3.Suppresses bacterial growth
4.Digest starch by amylase
What is the function of G cells?
Produce gastrin which stimulates gastric acid secretion
What is the function of D cells?
Produce somatostatin which inhibits gastric acid secretion
What is the function of chief cells?
Produce pepsin and pepsinogen and gastric lipase
What is the function of parietal cells?
Produce gastric acid which activates pepsin and kills bacteria
Produce intrinsic factor which complexes with B12 for absorption
What is the function of enterochromaffin-like cells?
Produce histamine which stimulates gastric acid secretion
What is the function of mucous neck cells?
Produce mucus as a physical barrier
Produce bicarbonate as a buffer for gastric acid to prevent damage to epithelium
What is the function of the liver?
Metabolic regulation
* Store absorbed nutrients, vitamins
* Release nutrients as needed
Haematological regulation
* Plasma protein production
* Remove old RBCs
Production of bile
* Required for fat digestion and absorption
What cells in the pancreas secrete enzymes?
Acinar cells
What are the functions of the pancreas?
Secretes bicarbonate (1 litre a day)
Endocrine (hormonal)
Exocrine (digestive)
How does bicarbonate secretion work in the pancreas?
H20 + CO2 -> H2CO3 -> H+ + HCO3-
H+ is exchanged for Na+ in the blood by H+/Na+ antiporter
Na+ removed by Na+/H+ ATPase
HCO3- transported into intercalated ducts of pancreas in exchange for Cl- (returned to lumen)
Bicarbonate ions, sodium and water move through intercalated ducts to main pancreatic for secretion
When does the pancreas secrete bicarbonate?
Continually secreting bicarb but also stimulated by food entering the stomach
What do acinar cells secrete? (pancreas)
enzymes and water
What do ductal cells secrete? (pancreas)
water and bicarbonate
How does the pancreas store proteases so that it doesn’t digest itself?
Pancreatic proteases packaged into secretory vesicles as stored as trypsinogen and chymotrypsinogen)
Vesicles also contain a trypsin inhibitor
What are the 2 main pancreatic proteases?
trypsin and chymotrypsin
What activates trypsinogen to become trypsin?
enterokinase
How does protein digestion work?
- Protein enters stomach, pepsin starts to digest
- Majority of digestion starts in the small intestine
- Pancreatic enzymes released and arrive into 2nd part of dudoenum
- activated by enterokinase, secreted by small intestinal epithelia cells
- presence of trypsin activates chymotrypsin and additional trypsinogen
- trypsin inhibitor diluted and stops working
What does trypsin activate?
chymotrypsin and additional trypsinogen
What is the function of lipases?
hydrolyse triglycerides to monoglyceridees and free fatty acids, so that they can then be absorbed by small intestinal cells
What do bile salts help with?
aid triglyceride digestion and absorption of monoglycerides and free fatty acids
What does fat absorption rely on?
pancreatic and hepatic secretion
What are bile salts and what do they do?
They are the product of conjugation of bile acids with taurine or glycine.
facilitate the formation of micelles for fat absorption
What is bile made up of?
bile acids, cholesterol, phospholipids, bile pigments (such as bilirubin and biliverdin), electrolytes and water.
What is bile?
Complex lipid-rich micellar solution (water, inorganic electrolytes, and organic solutes – bile acids, phospholipids, cholesterol, bile pigments)
Isosmotic with plasma
What does amylase do?
Hydrolyses starch to maltose (glucose- glucose disaccharide) and maltotriose (trisaccharide) and limit dextrins
Where does amylase come from?
Majority from pancreas
Also from saliva
What are the 2 stages of enzyme secretion?
Cephalic stage: vagus nerve anticipates food, low level stimulation, gastrin
Intestinal stage: cholecystokinin and gastrin secreted
Where are cck and secretin synthesized?
enteroendocrine cells in the mucosal lining of the small intestine (mostly duodenum)
What stimulates secretin release and what does it do?
Stimulated by low duodenal pH
Caues pancreatic water and bicarb secretion
What is the role cholecystokinin?
Delays gastric emptying for sufficient digestion
Gallbladder contraction
Pancreatic enzyme and bicarb secretion
Inhibits gastric acid secretion
What stimulates gastrin release and what does it do?
Stimulated by gastric distention and irritation
Causes acid secretion from parietal cells and enzyme release
How is enzyme secretion controlled?
- Pancreatic secretions contain enzymes to digest protein, starch and triglyceride
- Gastrin and CCK stimulate enzyme secretion and neutralise gastric acid entering small intestine
- As proteins and fats are digested and absorbed, pH rises and stimuli for CCK an secretin disappear and pancreatic secretion reduces
How much bile is expelled a day from the gall bladder?
500-600ml per day
Where are bile acids formed and secreted?
Formed in the liver (hepatocytes)
Secreted into the cannilicular
What makes up fecal bile acids?
These are deconjugated and form deoxycholic
What is the function of bile?
Lipid digestion and absorption
Cholesterol homeostasis
Excretion of lipid soluble xenobiotics / drug metabolites / heavy metals
How are the primary bile acids formed and what are they?
synthesised from cholesterol in the hepatocytes
cholesterol broken down into cholic acid and chenodeoxycholic acid (water soluble)
change from lipophilic to hydrophilic
What does conjugation of primary bile acids achieve?
Enhances hydrophilicity and acidity of side chain
Decreases passive diffusion of bile acids across cell membranes (keeps intraluminal)
How do secondary bile acids form from primary?
Bile moves towards colon
Dehydroxylation by intestinal bacteria forming deoxycholic acid and lithocholic acid
Why are bile acids good for emulsification?
Hydrophilic and hydrophobic (amphipathic)
Why is fat emulsification important?
Breaks fat into micelles, increasing SA for lipolysis
Lipases act at surface of emulsified droplets and liberate fatty acid from the glycerol backbone of triglyceride
What is the process of lipolysis?
- In gut lumen, Colipase allows lipase to break down triglyceride into monoglyceride and FA
- Amphipathic bile acids allow aqueous diffusion into enterocyte
- Reassembled within enterocyte
- exocytosed into chylomicrons into bloodstream
What are the functions of bile acids?
Induce bile flow (osmotic effect) & secretion of biliary lipids
Important in digestion and absorption of dietary fats
Important in cholesterol homeostasis
Antimicrobial
How does enterohepatic circulation work?
- Bile acids travel down biliary tract to gall bladder where they are concentrated x10
- CCK released and causes GB to contract, opening sphincter of Oddi
- Bile flows into duodenum and mixes with food
- Bile acids absorbed in terminal ileum and transported back into blood via ASBT (apical sodium bile acid tranporter)
- Reenters liver via portal circulation (HPV) and taken up into hepatocytes
How regularly does bile circulate round?
2-3 times per meal
What do hepatocytes do?
Detoxify harmful substances
Help maintain blood glucose level
Store vitamins A,D,E,K,B12 and minerals (Fe,Cu)
Removes amine group from AA for metabolising into ATP
Synthesises proteins (albumin, coag factors)
Regulates lipid metabolism (break down FA)
Synthesise VLDLs and HDLs
Convert cholesterol into bile salts
What are Kupffer cells?
In liver sinusoid
Modified macrophages
Destroy RBC, WBCs, bacteria and foreign substances
What makes up bile?
Bile acids
Cholesterol
Phospholipids
Bile pigments
Electrolytes
Water
What are the 2 main bile acids?
Cholic acid
Chenodeoxycholic acid
What are the hepatic lobules?
Functional units of liver
Hexagon shape
Consist of hepatocytes
Drained by central vein
Have portal triad at periphery
What is in the portal triad in hepatic lobules?
branch of the hepatic artery entering the liver
branch of the hepatic portal vein entering the liver
branch of the bile duct leaving the liver
Vagus fibres
Lymphatics
What is the blood supply to the liver?
Hepatic artery proper (25%)
Hepatic portal vein (75%)
How does hep artery proper supply liver?
Derived from coeliac trunk
supplies the non-parenchymal structures of the liver with arterial blood
How does hep portal vein supply liver?
Supplies the liver with partially deoxygenated blood, carrying nutrients absorbed from the small intestine.
The dominant blood supply to the liver parenchyma
Allows the liver to perform its gut-related functions e.g. detoxification.
What is the venous drainage of the liver?
central veins of the hepatic lobule form collecting veins
combine to form multiple hepatic veins
hepatic veins then open into IVC
What do VLDLs do?
Transport triglycerides, fatty acids and cholesterol to cells that need it or adipocytes
What do HDLs do?
Transport cholesterol back to liver to be broken down
How do O2 and nutrients get to hepatocytes?
Through pores in sinusoids
What are sinusoids?
low pressure vascular channels that receive blood from terminal branches of the hepatic artery and portal vein at the periphery of lobules and deliver it into central veins
porous
How does bile get from lobules to gallbladder?
Secreted into bile canaliculi
Bile ductule then duct
Hepatic duct (R or L)
Common hepatic duct
Cystic duct
GB
Where do the hep artery and portal veins drain from lobules?
Into sinusoids
Central vein
Hepatic veins
IVC
What is the liver’s role in digestion?
Bile production for fat digestion
Energy storage and release
Detoxification
Protein production (primarily plasma)
Reception and metabolisation of absorbed products
What is the role of the large intestine?
Reabsorb water from faecal matter to form semi-solid faeces
What is the function of the small intestine?
assists in the digestion and absorption of ingested food
approx 6.5m long
What is bilirubin?
a yellow bile pigment produced through the breakdown of red blood cells
Features of unconjugated bilirubin
Insoluble
Bound to albumin in bloodstream
Cannot be directly excreted from body
Features of conjugated bilirubin
Water soluble
Can be excreted
Travels in bloodstream
Steps of bilirubin metabolism
- Reticuloendothelial cells take up RBCs and metabolise haemoglobin into haem and globin
- Globin recycled into AAs
- Haem broken down by haem oxygenase into iron (recycled) and biliverdin
- Biliverdin forms unconjugated bilirubin which binds to albumin to move to liver
- Conjugated bilirubin moved into colon
- Deconjugated into urobilinogen
- 80% converted into stercobilin which is excreted in faeces
20% reabsorbed and either used in bile or excreted in urine
What enzyme breaks haem into biliverdin and iron?
Haem oxygenase
What is added to unconjugated bilirubin to conjugate it?
Glucoronic acid by glucuronyl transferase in liver
What happens to urobilinogen?
80% becomes stercobilin which is excreted through faeces
20% reabsorbed to either become bile in the liver or urobilin in kidneys and leave in urine
What does the liver store?
Excess glucose as glycogen
Vitamins A,D,E,K,B12
Iron and copper minerals
What causes pre-hepatic jaundice?
Increased haemolysis
e.g. sickle cell, gilberts, malaria
What causes hepatic jaundice?
liver impairment
e.g. hepatitis, toxins
What causes post-hepatic jaundice?
Blockage of bile ducts
e.g. gallstones, tumours
Why is the liver important in protein metabolism?
It stores more proteins than other tissues
Can rapidly synthesise or degrade proteins.
Can quickly synthesise and degrade AA
What is needed for transamination?
precursor alpha-keto acid
donor of amino group
aminotransferase
What catalyses the formation of H2CO3 from CO2 and H2O?
carbonic anhydrase
What do parietal cells produce?
HCl and intrinsic factor
What do G cells in the stomach secrete?
Gastrin
What can activated G cells in the stomach?
Vagus
Gastrin related peptides
Peptides from digestion
When do enterochromaffin cells secrete histamine?
In response to gastrin or ACh
What does histamine bind to in stomach?
H2 receptors on parietal cells
What produces somatostatin?
D cells
When is secretin produced?
From S cells in duodenum in response to excessive acid production in stomach
What do chief cells secrete?
Pepsinogen
What is gastric mucus?
a gel-mucous barrier secreted by epithelial cells and glandular cells in the stomach wall
part of a barrier that protects the stomach wall from the acid and digestive enzymes within the stomach lumen
Why is bicarbonate in the stomach mucus important?
allows an increased pH local to the epithelial cells, protecting them from the highly acidic stomach environment
What increases mucus production in the stomach?
Vagus stimulation
What mediates mucus production in the stomach?
Prostaglandins
What are the functions of somatostatin?
Decrease gastrin release leading to reduced gastric acid
Increase fluid absorption
Increase smooth muscle contraction
Paracrine inhibition of insulin and glucagon secretion from α and β-cells of the Islets of Langerhans
Decrease bile flow
Decrease blood glucose concentration
What 3 carbohydrate products are absorbed by the small intestine?
glucose, galactose and fructose
How are glucose and galactose absorbed?
In small intestine
Active transport via SGLT1
out of cell into blood via GLUT2
How is fructose absorbed in the small intestine?
Enters cells via facilitated diffusion via GLUT5
Exits into blood via GLUT2
What does the small intestine absorb?
Water and digested nutrients, electrolytes
What does absorption mean in the SI?
Absorption refers to the movement of nutrients, water and electrolytes from the lumen of the small intestine into the cell, then into the blood
What are the 4 histological layers in the small intestine?
Mucosa (innermost)
Submucosa
Muscularis externa
Adventitia
What secretes CCK?
I cells
How histologically is surface area increased in the SI?
large numbers of folds (or plicae) arranged in a circular fashion in the lumen (therefore called plicae circulares)
Plicae contain microvilli which also increase SA
What do K cells secrete?
Gastric-Inhibitory Peptide
What regulates secretions into the small intestine?
Sphincter of Oddi
What are the 3 main substances that the small intestine receives?
bile, pancreatic enzymes and alkaline juice
Why is bicarbonate secreted by the pancreas important?
Neutralises the stomach acid because the small intestine doesn’t have a thick mucus layer
Digestive enzymes function best at higher pH
What is at the ampulla of vater?
Where the main pancreatic and bile ducts merge to secrete into duodenum
What regulates pancreatic secretion?
Vagal innervation
Secretin
CCK
When does CCK stimulate the pancreas to release digestive enzymes?
Detection of fatty acids in chyme and acidic pH
this also causes bile secretion
What causes alkaline secretion from the pancreas?
Acidic chyme enters duodenum
Stimulates S cells to release secretin
Stimulates alkaline secretion from pancreas
What is the purpose of the urea cycle?
Convert ammonium to urea which is easier to excrete
Why is ammonium bad?
Can cross the blood brain barrier
Neurotoxic
What are the steps of the urea cycle?
NH4+ and co2 in with ornithene
Citrulline
Arginosuccinate
Arginine
Urea out
What catalyses the production of urea?
Arginase during arginine to ornithene
What do transamination reactions do?
Reversible
AA to ketoacids during AA metabolism
Catalysed by aminotransferases
What happens to glutamate after transamination?
Oxidative deamination
Travels to liver mitochondria
Glutamate dehydrogenase turns it into alpha-ketoglutarate and ammonia
What happens to ammonia?
Goes into urea cycle to be removed in liver mitochondria
What catalyses CO2 and NH4+ into carbamoyl phosphate?
Carbamoyl phosphate synthetase 1
What forms citrulline in the urea cycle?
Ornithine and carbamoyl phosphate
What converts citrulline and aspartate into arginosuccinate?
Arginosuccinate synthetase
When is fumarate made in the urea cycle?
Arginosuccinate to arginine via arginosuccinase
What are cytochromes?
cellular proteins containing one or more heme groups that are involved in electron transfer
What happens in liver detox phase 1?
Functionilization
Add or expose functional groups
-OH , -SH , -NH2, -COOH
Small increase in hydrophilicity
What happens in liver detox phase 2?
Conjugation with endogenous molecules: glucuronic acid, sulphate, glutathione.
Covalent bonds formed.
Large increase in hydrophilicity
Biosynthetic
What are xenobiotics?
foreign substances that don’t have nutritional value
serve no purpose so they are excreted, and they may be toxic if not excreted in time
Where are cytochrome P450 enzymes?
sER
Features of c P450
They have a cytochrome reductase subunit which uses NADPH,
They are inducible – enzyme activity may be increased by certain drugs, some dietary components, and some environmental toxins eg smoking,
They generate a reactive free radical compound
What do P450 enzymes do?
oxidise the substrate and reduce oxygen
What are phase 2 reactions in liver detoxification?
conjugation reactions which make the compound more water-soluble
Glucuronyl, sulphate and phosphate groups are polar and make the compound ready for excretion in the urine
Name 2 bile pigemnts
Bilirubin
Biliverdin
What does enterohepatic circulation allow?
allows the liver to recycle and preserve a pool of bile acids
What is the metabolic role of the liver?
maintains a continuous supply of energy for the body by controlling the metabolism of CHO and fats
What regulates the liver?
Endocrine glands e.g pancreas, adrenal, thyroid
Nerves
What are lipids?
Esters of fatty acids and glycerol or other compounds (cholesterol)
naturally occurring organic compounds that are insoluble in water
What makes up triglycerides?
1 glycerol molecule
esterified to 3 fatty acids
(bonded at carboxyl head)
What are the functions of lipids?
Energy reserve
Structural: Part of cell membranes, Integral to form and functions of cells
Inflammatory cascades
Hormone metabolism
How does lipid transport work?
Lipids are often transported as TGs or FAs bound to Albumin or within lipoproteins
TGs cannot diffuse through cell membrane
FA are released through lipases to facilitate transport into the cells
In the cell FA are re-esterified to TG
What is the ratae limiting step of de novo lipogenesis?
Acety-CoA to Malonyl-CoA catalysed by Acetyl-CoA carboxylase
How is cholesterol exported?
Through bile
What is made in one cycle of beta-oxidation?
1 NADH
1 FADH2
1 acetyl-CoA
What does 1 palmitoyl-CoA make in beta oxidation?
7 NADH
7 FADH2
8 Acetyl-CoA
129 ATP (131 but 2 used up)
How does beta-oxidation make energy?
2 carbon segments are progressively released from the fatty acid chain until acetyl co-A is generated.
NADH and FADH2 are generated as byproducts
Acetyl-co-A then binds immediately with oxaloacetate to form citrate and then enters the TCA cycle to release energy in the form of ATP
What do fatty acids bind to to move in blood?
Albumin
What hydrolyses triglycerides into FA and glycerol?
triglyceride lipase
What happens to glycerol when triglycerides are broken down?
Upon entering hepatocytes, glycerol is immediately converted into glycerol-3-phosphate, which then enters the glycolysis pathway
What happens in the muscle part of the glucose-alanine cycle?
Glucose to pyruvate
Lactate produced on side
Pyruvate to alanine in transamination
What happens in the liver part of the glucose-alanine cycle?
Alanine to pyruvate in deamination
NH2 to urea on side
Pyruvate to glucose
