Alimentary system Flashcards
Define Digestion
Process of breaking down macro-molecules to allow absorption
Define Absorption
Process of moving nutrients and water across a membrane
Describe the different pathways after ingestion.
- Digestion -> Excretion
- Digestion -> Absorption
- Excretion
List the components of the GI system.
(Salivary glands - Parotid, sublingual and sub-mandibular)
- Oesophagus
- Stomach
- Liver
- Gallbladder
- Pancrease
- Duodenum
- Jejenum
- Ileum
- Appendix
- Ascending colon
- Transverse colon
- Descending colon
- Sigmoid colon
- Rectum
- Anus
List the main diseases of the Upper, mid and lower GI tract.
- Oesophageal cancer
- Barret’s oesophagus
- Gastro-oesophageal reflux disease
- Stomach cancer
- Gastric ulcers
- Liver sclerosis
- Hepatitis
- Jaundice
- Cholangiti
- Liver failure
- Diabetes
- Pancreatitis
- Pancreatic cancer
- Duodenal ulcers
- Obesity
- Coeliac disease
- Crohn’s disease
- Irritable bowel syndrome
- Appendicitis
- Colon cancer
What are the general symptoms related to GI tract disease?
- Anorexia
- Weight loss
- Anaemia
What are the symptoms related to upper GI tract disease?
- Haematemesis (vomiting blood)
- Melaena (dark faeces)
- Nausea and vomiting
- Dysphagia
- Odynophagia (painful swallowing)
- Heartburn
- Acid regurgitation
- Belching
- Chest pain
- Epigastric pain
What are the symptoms related to hepatobilary GI tract disease?
- Right upper quadrant pain
- Biliary colic (pain related to gallbladder)
- Jaundice
- Dark urine
- Pale stool
- Abdominal distension (Ascites)
What are the symptoms related to mid GI tract disease?
- Abdominal pain
- Steatorrhoea
- Diarrhoea
- Abdominal distension
What are the symptoms related to lower GI tract disease?
- Abdominal pain
- Bleeding
- Constipation
- Diarrhoea
- Incontinence
List the general signs and symptoms seen in GI tract disease.
- Cachexia (weakness, and wasting of body)
- Obesity
- Lymphadenopathy
- Anaemia
- Jaundice
List the signs and symptoms seen in the hands in GI tract disease.
- Koilinychia (spoon shaped nails)
- Leuconychia (white spots on nails)
- Clubbing
- Dupytrens contracture (fixed forward curvature of finger/s)
- tachycardia
- tremor
List the signs and symptoms seen in the abdomen in GI tract disease.
- Organ enlargement
- Mass
- Tenderness
- Distension
List the signs and symptoms seen in the anus and rectum in GI tract disease.
- Haemorrhoids
- Fistula (abnormal passage)
- Fissure (tear/open sore)
- Rectal masses
- Proctitis (inflammation)
What basic investigations can be done for the GI system?
- History: presenting symptoms, dietary habits, family history, ethnicity, environmental factors, travel
- Physical examination: hands, skin, palpable abdominal organs, digital rectal exam, rigid sigmoidoscopy
What further investigations/procedures can be done for the GI system?
Haematology, biochemistry and microbiology:
- Blood tests: blood sugar (glucose, fasting glucose, glucose intolerance, HbA1C)
- Tumour markers (CA19-9 - pancreatic and other GI cancers)
- Erythrocyte sedimentation rate (Crohn’s disease)
- Urea and electrolytes (absorption disorders)
- Liver function tests
- Antibodies
- Microbiology - Hep B, Hep C, faecal occult blood)
Procedures:
- Endoscopy
- Colonoscopy
- Ultrasound
- CT, MRI, X-ray
What GI tract diseases have the highest mortality rates?
- GI tract cancers (cumulatively) have the largest proportion of deaths from cancer
- Liver cirrhosis is the largest cause of death out of all GI tract diseases (and increasing)
What is the prevalence of ulcerative colitis? What is the treatment?
1 in 500
Treatment - colectomy
What is the prevalence of Crohn’s disease?
1 in 1000
What is Coeliac disease? What is the prevalence?
- Gluten insensitivity
- 1 in 87
Outline pancreatic conditions.
Acute pancreatitis:
- mild to life-threatening
- blockage of pancreatic duct causing back-up of pancreatic enzymes causing severe inflammation
- ethanol and gallstones in 80%
Chronic pancreatitis:
- permanent damage to pancreas
- alcohol excess main cause
- can greatly impair quality of life
What infections are common in the GI tract?
Bacterial:
- Helicobacter Pylori:(commonly found) nausea, bloating, weight loss
- Escherichia coli: nausea, diarrhoea, cramps
Viral:
- Norovirus: nausea, vomiting, diarrhoea
Describe the consequences of H. pylori infection.
- 85% no long term effects
- 14% peptic ulceration
- 1% gastric adenocarcinoma or lymphoma
What environmental factors affect the susceptibility to GI disease across the world?
- Energy intake
- Staple foods
- Changes in food through time
What is QALY and DALY?
QALY - quality adjusted life year
DALY - disability adjusted life years
Describe the economic burden of GI disease.
- Mortality and lost years
- Absence from work
- Morbidity
- NHS prescription
Outline the basic plan of the gut wall.
Mucosa:
- Epithelium
- Lamina Propria: loose connective tissue, contains capillaries, nerve endings, lymphatic capillaries
- Muscularis mucosae
Submucosa: connective tissue, containing nerve plexus (including enteric nervous system) and larger vessels.
Muscularis: smooth muscle (containing nerve plexus)
Serosa/Adventitia:
- connective tissue, outer lining keeping it suspended
- epithelium
Outline the anatomy of the oesophagus.
- Starts at C5
- Passes through the thorax, and diaphragm to connect to the stomach
- Ends at T10
- Passes close to the trachea and aorta (if ruptures can be fatal)
- Divided into thirds: Cervical (narrow), middle and lower
- More smooth muscle as you go down
What is the function of the oesophagus?
Conduit for food, drink and swallowed secretions from pharynx to stomach
Describe the epithelium of the oesophagus.
- Non-keratinising
- Stratified squamous
- ‘Wear and tear’ lining (extremes of temp and textures)
- Lubrication: mucus secreting glands (and also saliva)
Describe the sphincters in the oesophagus.
- Upper and lower oesophageal sphincters
- Tonically active: permanently closed unless swallowing
- Due to pressure differences without the sphincters there would be a tendency of contents of the stomach to be drawn up or air to be drawn in
- Initiation of swallowing cause nerve impulses to travel to the brain and back to open the sphincters, then once food passes the upper oesophageal sphincter it closes (to be able to breathe) whereas the lower remains open till the food enters the stomach
- Structure: Mix of skeletal and smooth. Upper - skeletal, mid - mix, lower - smooth.
- Involuntary control by swallowing centre in brain, though initiation is voluntary
How is a bolus of food moved through the oesophagus?
- Circular muscle is particularly important
- Peristaltic wave:
Circular muscle above food contracts, and circular muscle below the food relaxes - Assisted by longitudinal muscle
- Oesophagus detects presence of food and so can initiate a secondary peristaltic wave
Describe the features of the gasto-oesophageal junction.
- Lower oesophageal sphincter = skeletal muscle of diaphragm assisting the circular muscle of oesophagus to constrict and close it
- As the lower part of the oesophagus is in the abdomen there is no pressure difference between it and the stomach so less likely to have stomach contents moving up
- Pregnancy or a very large meal can lead to reflux
- Epithelial transition from stratified squamous to simple columnar (stomach) at the zigzag (Z) line
- Gastric folds (rugae) in the stomach for increased surface area to expand or contract as required
Describe the mechanism of belching.
Initiation of a swallowing reflex to open both sphincter and allowing release (due to the pressure) of gas from the stomach
What is the function of the stomach?
Breaks food down into smaller particles stored (due to acid and pepsin), hold food and release at a controlled steady state into duodenum, kill parasites and certain bacteria
Describe the features of the stomach.
- Simple columnar epithelium
- Made up of the fundus and body (secreting mucus, HCl and pepsinogen), Cardia and pylori region (secreting mucus only) and the antrum (secretes gastrin)
- Acid produced about 2L/day, can reach 150mM H+
Describe the different cell types in the stomach.
- Epithelial cells secreting mucus with large amount of bicarbonate, found all over the stomach. Protects the lining of the stomach by neutralising acid at the surface
- Chief cell - Protein-secreting (pepsinogen) epithelial cell, abundant RER and Golgi for packaging and modifying for export, masses of apical secretion granules.
- Parietal cell - Many mitochondria to actively transport H+, cytoplasmic tubovesicles contain H+/K+ ATPase, internal canuliculi near apical surface. When active the tubular vesicle fuse with the membrane and project into the cannaliculi.
Outline the production of H+ by parietal cells.
- Carbonic anhydrase converts CO2 and H2O to H+ and HCO3-
- HCO3- is exchanged for Cl- which enters the cell
- H+ ions are actively transported into the lumen in exchange for K+ ions
- Cl- moves with H+ out of the cell
- K+ is taken up into the cell (via Na+/K+ pump) and then exits into the lumen
- Fusion of the tubular vesicles and the canaliculi mean increase no. of H+/K+ ATPase
NET = secretion of HCL into the lumen
How does the chief and parietal cell interact?
- Chief cells secrete pepsinogen which is an inactive precursor
- The acidic environment created by the parietal cells causes a conformation change leading to enzymatic activity within the pepsinogen and cleavage of other pepsinogen molecules
- This leads to production of pepsin (protease)
Describe the features of gastrin.
- Produced in the Pyloric antrum
- Stimulates acid secretion
- At very high pH gastrin secretion is supressed (i.e. empty stomach)
- After meal protein content changes pH to 3/4 -> there is no inhibition of gastrin -> gastrin secretion -> increase in acid
- (OR) Gastrin stimulates histamine release from chromaffin cells in the lamina propria -> acid production
Outline the phases of gastric secretion.
- Cephalic phase: Thought, sight, smell and taste of food causes impulses from brain through vagus nerve to stomach. Acetyl choline stimulates acid production by stimulating parietal cells or histamine release from chromaffin cells.
- Gastric phase: When there is food in the stomach, the distension detected by stretch receptors signals brain through vagus, and in turn efferent impulses stimulate more acid production. Enteric nervous system also acts in response to stretch. Chemoreceptors detect to chemical changes and respond with gastrin secretion.
- Intestinal phase: Mostly inhibitory. As stomach contents passes into the small intestine (particularly if pH
Describe the enterogastric reflex
- Low pH of chyme stimulates secretion of enterogastrones from the small intestine.
- Enterogastrones: gastric inhibitory peptidem cholecystokinin, secretin
- Secreted into the blood and switch off acid production in the stomach
What drugs are used to decrease acid secretion?
- Omeprazole: Proton pump inhibitor that prevents the release of H+ into the lumen
- Ranitidine: Histamine receptor antagonist to prevent stimulation of acid production by acetyl choline or gastrin
What is the function of the small intestine?
To absorb nutrients, salt and water
Describe the structure of the small intestine.
- Approx. 6m long, 3.5 cm in diametre
- Duodenum - 25cm
- Jejenum - 2.5m
- Ileum - 3.75m
- All have same basic histology with some differences- no sudden transition between them
- Mesentery: fan-shaped connective tissue which throws the small intestine into folds and supports the blood supply
- External wall - longitudinal and circular muscles (motilit)
- Internal mucosa - arranged into circular folds. Covered in villi (about 1mm tall) with invaginations known as crypts of Lieberkuhn
What are the features of the villi?
- Only occur in the small intestine (where most absorption takes place)
- Increase surface area
- Motile, have a rich blood supply and lymph drainage for absorption of digested nutrients
- Have good innervation from the submucosal plexus
- Have simple epithelium (1 cell thick) dominated by enterocytes (columnar absorptive cells)
Describe the cell types found in the small intestine.
Mucosa lined with simple columnar epithelium consisting of: - Primary enterocytes (absorptive cells) - Scattered goblet cells - Enteroendocrine cells Crypts of Lieberkuhn epithelium include: - Paneth cells - Stem cells
Describe the features of enterocytes.
- Most abundant type in small intestine
- Tall columnar cells with microvilli and a basal nucleus
- Specialised for absorption and transport of substances
- Short lifespan of about 1-6 days (average 30hrs)
- Tight junctions between cells prevent paracellular movement and allow polarity of proteins
Describe the features of the microvilli.
- About 0.5-1.5μm high
- Make up the brush border
- Several thousand per cell
- Surface covered with glycocalyx, a rich carbohydrate later which protects from digestion and allows absorption. It traps a layer of water and mucous (unstirred layer) which regulated the rate of absorption from intestinal lumen
What is the important of villi, microvilli and folds?
Increase the surface are from 0.4m^2 to around 200m^2 (500 fold)
Describe the features of goblet cells.
- 2nd most abundant epithelial cell type
- Mucous containing granules accumulate at the apical end -> goblet shape
- Mucous = large glycoprotein that facilitates passage os material through the bowel
- Abundance increases along the length of the bowel (as more water in absorbed it becomes harder to move)
Describe the features of the enteroendocrine cells.
(Chromaffin cells)
- Columnar epithelial cells, scattered among the absorptive cells
- In intestine most often found in the lower parts of the crypts
- Hormone secreting, e.g. to influence gut motility
Describe the features of paneth cells.
- Found only in bases of the crypts
- Contain large acidophilic granules which contain antibacterial enzyme lysozyme (protect stem cells) and glycoproteins (protect from the enzymes) and zinc (co-factor of enzymes)
- Engulf some bacteria and protozoa
- May have a role in regulating intestinal flora
Describe the lifespan of the epithelium.
- Cell proliferation, differentiation and death are continuous processes in the gut epithelium
- Enterocytes and goblet cells of the small intestine have a short life span (about 36hrs)
- Continually replaced by dividing stem cells in the crypts
Outline the stem cells found in the small intestine and their role.
- Undifferentiated cells which remain capable of cell division to replace cells which die
- Epithelial stem cells are essential in the GI tract to continually replenish the surface epithelium
- Continually divide by mitosis
- Migrate up to the tip of villus, replacing older cells that die by apoptosis (‘escalator’ of migration)
- At villus tips cells become senescent and sloughed (shed) into the lumen of the intestine to be digested and reabsorbed
- Differentiate into various cell types (pluripotent)
Why does the small intestine have a rapid turnover of cells?
- Enterocytes are first line of defense against GI pathogens and may be affected directly by toxic substances in the diet
- Effect of agents which interfere with cell function, metabolic rate etc will be diminished
- Any lesions with be short-lived
- If there’s impaired production of new cells (e.g. radiation) there will be severe intestinal dysfunction
Describe the how cholera affects the small intestine.
- Cholera enterotoxin results in prolonged opening of the chloride channels in the small intestine allowing uncontrolled secretion of water
- Bodily fluid moves freely into the lumen and hence out through the intestine, leading to rapid, massive dehydration and death
- Treatment is rehydration. Cholera bacteria will clear when the epithelium will be replaced
Outline the distinguishing features of the duodenum.
- Distinguished by presence of Brunner’s glands: submucosal coiled tubular mucous glands secreting alkaline fluid, open into the base of the crypts
- Alkaline secretion of Brunner’s glands: neutralises acidic chyme from the stomach, protecting proximal small intestine, help optimise pH for the action of pancreatic digestive enzymes
Outline the distinguishing features of the Jejenum.
- Characterised by the presence of numerous, large folds in the submucosa, called plicae circulares (or valves of Kerckring)
- Also present in the duodenum and ileum but plicae in the jejenum tend to be taller, thinner and more frequent
Outline the distinguishing features of the Ileum.
- Shares some features with large intestine
- Has a lot of Peyer’s patches: large clusters of lymph nodules in the submucosa
- Prime immune system against intestinal bacteria (other mechanisms = bactericidal paneth cells, rapid cell turnover)
- Well positioned to prevent bacteria from colon migrating up into the small intestine
What is the function of the small intestine’s motility?
- Mix ingested food with digestive secretions and enzymes
- Facilitate contact between contents of intestine and intestinal mucosa
- Propel intestinal contents along the alimentary tract
What are the three types of movement in the small intestine?
- Segmentation (mixing)
- Peristalsis (propelling)
- Migratory motor complex (sweeps through gut, preventing accumulation of residue)
Outline segmentation of the small intestine.
- Mixes contents of the lumen
- Segmentation occurs by stationary contraction of circular muscles at intervals
- More frequent contractions in duodenum compared to ileum to allow pancreatic enzymes and bile to mix with chyme
- Although chyme moves in both directions the net effect is movement towards the colon
Outline peristalsis in the small intestine.
- Involves sequential contraction of adjacent rings of smooth muscle
- Propels chyme towards the colon
- Most waves of peristalsis travel about 10 cm (not full length)
- Segmentation and peristalsis result in chyme being segmented, mixed and propelled towards the colon
Outline migrating motor complex in the small intestine.
- In fasting there’s cycles of smooth muscle contraction
- Each cycle there’s contraction of adjacent segments of small intestine
- Begin in stomach, migrate through small intestine towards colon. On reaching terminal ileum, next contraction starts in the duodenum
- Prevents migration of colonic bacteria into the ileum and may ‘clean’ the intestine of residual food
- Also occurs in fed state, but less ordered and less frequent
Describe digestion in the small intestine.
- Digestion and absorption of carbohydrates, proteins and lipids
- Occurs in alkaline environment
- Digestive enzymes and bile enter the duodenum from pancreatic duct and bile duct
- Duodenal epithelium also produces its own enzymes
- Digestion occurs both in the lumen and in contact with the membrane
Outline the mechanisms of absorption in the small intestine.
- Passive diffusion: no carrier protiens, with the concentration gradient, no energy required
- Facilitated diffusion: carrier proteins, with the concentration gradient, no energy required
- Primary active transport: carrier proteins, against concentration gradient, energy required from hydrolysis of ATP
- Secondary active transport: carrier proteins, against concentration gradient, energy required from electrochemical gradient
Outline the digestion of carbohydrates.
- Begins by salivary α-amylase, but it’s destroyed by acidic pH in stomach
- Most digestion occurs in the small intestine
- Pancreatic α-amylase secreted into duodenum by pancreas in response to a meal. Continues digestion of starch and glycogen in small intestine.
- Acts mainly in lumen, and some adsorbs to brush border.
- Digestion of amylase products and simple carbohydrates occurs at the membrane (e.g. by maltase, lactase, sucrase)
What are the requirements of pancreatic α-amylase?
- Cl-
- slightly alkaline pH (Brunner’s glands in duodenum=alkaline secretion)
Outline the different types of carbohydrates and their break down.
- Simple carbohydrates, e.g. monosaccharides - glucose and fructose, diasaccharides - sucrose and maltose. Broken down at membrane.
- Complex carbohydrates, e.g. starch, cellulose, pectins. Sugars bonded together to form a chain. Broken down in lumen
Outline the absorption of carbohydrates in the small intestine.
Apical:
- Absorption of glucose and galactose is by secondary active transport. Carrier protein = SGLT-1 (sodium-glucose transport protein) on apical membrane.
- Absorption of fructose is by facilitated diffusion. Carrier protein = GLUT-5 on apical membrane
Basal:
- GLUT-2 facilitates exit at the basolateral membrane
- Can absorb 10kg of simple sugars per day
Outline the digestion of protein in the small intestine.
- Begins in the stomach by pepsin, but pepsin is inactivated in the alkaline duodenum
- Pancreatic proteases are secreted as precursors
- Trypsin is activated by enterokinase, an enzyme located on duodenal brush border
- Trypsin then activated the other proteases
Outline the absorption of proteins in the small intestine.
- Brush border peptidases break down the larger peptides prior to absorption
- Amino acids are absorbed by facilitated diffusion and secondary active transport
- Di- and tri-peptides are absorbed using carrier proteins distinct from single amino acids
- Cytoplasmic peptidases break down most of the di- and tri- peptides before they cross the basolateral membrane
Summarise the process of digestion of lipids in the small intestine.
- Lipids are poorly soluble in water
- Four stage process in the small intestine:
1. Secretion of bile and lipases
2. Emulsification (bile)
3. Enzymatic hydrolysis of ester linkages
4. Solubilization of lipolytic products in bile salt micelles
Outline the emulsification of lipids in the small intestine.
- Fat is hydrophobic
- Bile and lipases are secreted into the duodenum
- Bile salts facilitate the emulsification of fat into the suspension of lipid droplets ( about 1μm diametre)
- Function of emulsification is to increase the surface area for digestion
- Allows pancreatic lipase to split triglycerides
- A triglyceride is broken down into two free fatty acids and a monoglyceride at the fat/water interface
What is a bile salt molecule?
- Steroid nucleus planar with two faces (amphipathic)
- Hydrophobic (nucleus and methyl) face dissolves fat
- Hydrophilic (hydroxul and carboxyl) face dissolves in water
- Emulsify lipids and allow diffusion of micelles into enterocytes via microvilli
Outline the structure of bile salt micelles.
- Micelles = hydrophilic head regions in contact with the surrounding solvent, sequestering the hydrophobic tail regions in the micelle centre
- Mixed micelles in small intestine = water insoluble monoglycerides from lipolysis are solubilised by forming a lipid core, stabilised by bile salts.
How are lipids digested?
- Lipase breaks down triglycerides into free fatty acids and monoglycerides.
- Pancreatic lipase complexes with colipase
- Colipase prevents bile salts from displacing lipase from the fat droplet
What other enzymes are involved in lipid digestion?
- Phopsholipase A2: hydrolyses fatty acids at the 2 position in many phospholipids, resulting in lysophospholipids and free fatty acids
- Pancreatic cholesterol esterase: hydrolyses cholesterol ester to free cholesterol and fatty acid
Outline the absorption of lipids in the small intestine.
- Bile salt micelles are important as they are absorbed much quicker than emulsion
- Micelles allow the transport across the unstirred layer and present the fatty acids and monoglycerides to the brush border
- The whole micelle is not absorbed together: bile salts are absorbed in the ileum (transported back to liver for recycling - enterohepatic circulation), but lipid absorption is completes by the middle of the jejunum
Outline the metabolism of lipids in enterocytes.
Monoglycerides and free fatty acids are absorbes by enterocytes and resynthesised into tri-glycerides by to pathways:
- Monoglyceride acylation (major)
- Phosphatidic acid pathway (minor)
Describe monoglyceride acylation.
- Fatty acids bind to the apical membrane
- Fatty acid binding proteins (FABP) facilitate transfer of fatty acids from apical membrane to the smooth ER
- In the smooth ER fatty acids are esterified into diglycerides and triglycerides
Describe the phosphatidic acid pathway.
Tri-glycerides are synthesised from CoA fatty acid and α-glycerophosphate
What are the features of chylomicrons?
- Lipoprotein particles synthesised in enterocytes as an emulsion
- 80-90% triglycerides, 8-9% phospholipids, 2% cholesterol, 2% protein and a trace of carbohydrate.
- Chylomicrons are transportef to the golgi and secreted across the basement membrane by exocytosis
- Too big to enter blood capillaries
- Enter lacteals (lymph channels) instead
Describe the joining of the small and large intestine.
- Ileocaecal sphincter joins the ileum of the small intestine and the caecum of the large intestine
- Relaxation and contraction controls the passage of material into the colon
- Also prevents the back flow of bacteria into the ileum
Describe the gross anatomy of the liver.
- 4 lobes: left, right, caudate and quadrate
- Falciform ligament divides right (bigger) and left lobe then
- The inferior free edge of the falciform ligament contains the ligamentum teres
- Gall bladder is posterior in junction of segments 4 and 5
- Calot’s triangle = bound by cystic duct, bile duct and cystic artery. Tringular space which is dissected in a cholecystectomy to find safe window to expose gallbladder
- Superiorly: coronary ligament (right lobe), left triangular ligament
- Posteriorly: Hilis (common bile duct, hepatic portal vein and hepatic portal artery), Inferior vena cava
What is the origin of the liver in embryology?
Liver and biliary system have common origin with ventral part of pancreas, at the distal foregut/proximal midgut
What are the developing layers in liver embryology?
- Endoderm (parencymal cells (secretory cells) originate from this): one of three germ layers in very early embryo (innermost layer). Consists of flattened cells which subsequently become columnar and the epithelial lining of multiple systems.
- Mesoderm (connective tissue originates from this): middle layer. Differentiates from the rest of embryo through intracellular signally leading to polarisation by an organising centre
- Somites: form skin and muscoskeletal parts of the body.
- Ectoderm: outside layer
Outline the stages of liver development.
- Stage 11 (-29 days): Liver bud develops (hepatic diverticulum), invades septum transversum (mesoderm/connective tissue)
Cell differentiation - Stage 12 (-30 days): Septum transversum (connective tissue) develops into liver stroma. Hepatic diverticulum forms hepatic trabeculae
- Stage 13 (-32 days): Epithelial cord proliferation enmeshing stromal capillaries (Parenchyma entangles with connective tissue)
- Stage 14 (-33 days): Enlargement of the liver bud, Haematopoietic function appears.
- Stage 18 (-44 days): Bile ducts become reorganised (continuity between liver cells and gut)
- Stage 18-23 (-44-56 days): Structure of the liver develops e.g. ductal plates form that receive biliary canaliculi. Begins migrating to right side.
- 70 days: Liver mostly in right side
Describe the blood supply to the liver.
- 25% of resting cardiac output
- Dual: 20% arterial blood from hepatic artery (left and right branches), 80% venous blood draining from gut through hepatic portal vein.
- Blood from liver drains into inferior vena cava via hepatic vein
- Arterial blood for oxygen supply to tissues, venous blood from gut supplies deoxygenated blood full of nutrients (for metabolic activity)
What is Couinaud Classification?
- 8 functionally independent segments of the liver each with their own vascular inflow, outflow and biliary drainage.
- The portal vein, hepatic artery and bole duct drains centrally
- The hepatic vein drains peripherally
- Each segment can be resected without damaging those remaining
What are the positions of the segments in the liver? (clockwise)
- Caudate lobe
- Lateral to falciform ligament and superior to portal venous supply
- Lateral to falciform ligament and inferior to portal venous supply
- Medial to falciform ligament
- Medial and inferior right hemisphere
- Posterior portion of right hemisphere
- Above 6
- Above 5 (medial and superior right hemisphere)
Summarise the cells in the liver and their functions.
- Hepatocytes: 80% of cells
- Endothelial cells: Lining blood vessels and sinusoids
- Cholangiocytes (bile duct epithelial cells): Lining biliary structures
- Kupffer cells: Fixed (liver) macrophages
- Hepatic stellate cells: Vit A storage cells (Ito cells), may be activated to a fibrogenic myofibroblastic phenotype
Describe the histological appearance of the cells in the liver.
- Hepatocytes: large cells with pale and rounded nuclei. Cords (sheets) radiating from the central vein. 80% of liver mass
- Kupffer or Hepatic stellate cells: Flattened, dense cell nuclei that appear to be in the sinusoids
Outline the function of hepatic stellate cells.
- Vitamin A storage
- Activation -> ECM production (fibrogenesis)
Outline the function of Sinusoidal endothelial cells.
Fenestrated to allow lipid and other large molecule movement to and from hepatocytes
Outline the function of Kipffer cells.
- Phagocytosis, including RBC breakdown
- Secretion of cytokines that promote hepatic stellate cell activation (-> proliferation, contraction and fibrogenesis)
What are the micro-anatomy structures in the liver?
- Lobules: Morphological. Classically hexagonal, divided into At the corners of the lobule (hexagon) there are portal tracts/triad (hepatic artery, vein and bile duct)
- Acinis: Functional unit. Elliptical or diamond shaped, hepatocytes divided into zones dependent on proximity to arterial blood supply.
What are portal tracts in the liver?
- Around edges of adjoining lobules
- Composed of: an arteriole, branch of the portal vein and bile duct
Outline the structure of acini.
- Less clearly defined
- Divided into zones, dependent on distance to vascular supply (Zone 1 = periportal, 2 = Transition zone, 3 = Pericentral)
- Zone 1 (closest) receives most oxygenated blood therefore is least susceptible to ischaemic injury, but most susceptible to viral hepatitis or hemosderin deposition (iron overload)
What are the divisions of the lobules in the liver?
- Centrilobular
- Midzonal
- Periportal
Outline the functions of the acini.
- Zone 1 is involved in gluconeogenesis, fatty acid oxidation and cholesterol synthesis
- Zone 3 involved in glycolysis, lipogenesis and P450 based drug detoxification.
Outline the flow of bile in the liver.
- Produced by hepatocytes
- Flows along bile canaliculus to interlobular bile ducts
- Into right/left hepatic ducts -> Common hepatic duct (-> Cystic duct gallbladder) -> Common bile duct -> Ampulla vater (joining of common bile duct and pancreatic duct) -> small intestine
- Opposite direction to blood flow
What are some functions of hepatocytes? What is necessary for their action?
- Protein metabolism: Synthesis, packaging, deamination of amino acids produce urea and reuse carbon skeleton (RER and golgi)
- Carbohydrate metabolism: e.g. glycolysis, glycogenesis, glycogenolysis, glucogenesis (SER, mitochondria, cytoplasmic enzymes)
- Lipid metabolism: Triglyceride metabolism - synthesis of fatty acids -> triglycerides and lipoproteins for transport to cells, and digested triglyceride chylomicron remnants processed into lipoproteins. Bile acid production (and salt e.g. Na+) (SER, peroxisomes, mitochondria)
- Detoxification: Metabolise, modify/detoxifiy exogenous compounds e.g. drugs. (Lysosomes, SER)
Outline the embryology of the biliary structures.
- Hepatic diverticulum/bud divides in the pars hepatica and pars cystica around 4 weeks
- The pars cystica develops into the gallbladder and cystic duct by around 8 weeks
Outline the gross anatomy of the biliary system.
- Gallbladder lies on ventral surface of the right lobule of the median lobe
- Left and right hepatic ducts join to form the common hepatic duct
- Cystic (from gallbladder) and common hepatic duct unite to form the common bile duct
- Common bile duct enters the duodenum
- Lower end of common bile duct is surrounded by muscle proximally known as the Sphincter of Oddi which controls release of bile
What are the functions of the liver?
Large, multifunctional organ
- Digestion
- Biosynthesis (glucose, protein, fat, bile)
- Energy metabolism
- Degradation and detoxifaction
Outline the role of the liver as a glucose buffer.
- After a meal, blood glucose increases and is taken up by the tissues
- Stored as glycogen mainly in the muscle and liver
- Breakdown of liver glycogen maintains blood glucose concentration between meals (muscle cannot release glucose back into the blood)
- 24hr fast will exhaust liver glycogen (80g)
Outline the role of the liver after exhaustion of glycogen.
Gluconeogenesis: synthesis of glucose from non-carbohydrate sources
- From lactate -> pyruvate –(6 ATP)–> glucose (through Cori cycle)
- From amino acids via deamination (removal of amino group) e.g. Alanine -> Pyruvation -> Glucose
- From triglycerides -> glycerol -> glucose
Outline the role of liver in protein synthesis.
- Synthesises 90% of plasma proteins (remainder are γ-globulins) Makes 15-50g/day
- Importance: binding/carrier function, plasma -> colloid osmotic pressure (decrease can lead to oedema)
- Synthesis of blood clotting factors
- Synthesis of dietary ‘non-essential’ amino acids by transamination
Give an example of transamination.
General: amino acid + keto acid -> new amino acid + new keto acid
E.g. Alanine + α-oxoglutaric acid -> Glutamic acid + pyruvic acid
What is the process of synthesis of dietary ‘non-essential’ amino acids?
- Transamination
- ‘Non-essential’ amino acids are ones which cannot be obtained from diet
- Start with appropriate α-keto acid precursor
- Exchange of an amino acid group from an amino acid to a keto-acid
- Essential amino acids (Lys, Leu, Ile, Met, Thr, Tyr, Val, Phe) don’t have appropriate keto acid precursors.
- Glutamic acid is the most common intermediate in transamination reactions
What is deamination and why is the liver important in the process?
- Deamination is the conversion of an amino acid into the corresponding keto acid by the removal of the amine group as ammonia and replacing it with a ketone
- Occurs primarily of glutamic acid because it is the end product of many transamination reactions
- Deaminatio = NH3 production = Highly toxic (especially to the CNS)
- Liver converts NH3 to urea
- Urea is a water soluble, metabolically inert, non-toxic product excreted in urine
Outline the role of the liver in fat (trygylceride) metabolism.
- Fat is main energy store for body - 100x glycogen
- Stored in adipose and liver
- When glycogen store is full, liver can convert excess glucose and amino acids to fat (Lipogenesis)
- Liver metabolises fat as energy store: converts fatty acids to Acetyl CoA (β-oxidation) -> TCA cycle in liver
- OR Liver converts 2 Acetyl CoA -> acetoacetate (ketone body) for transport in blood, travels to other tissues –(by thiophorase)–> Acetyl CoA -> Energy
Note: The liver does not have thiophorase -> cannot use ketone bodies - Ketone bodies produced in liver to be used by other tissues
- Synthesises lipoproteins, cholesterol and phospholipids
How is lipoprotein synthesised in the liver?
- Chylomicrons travel in the blood from the small intestine, and are broken down to release TAGs using lipoprotein lipase
- In hepatocytes TAGs, cholesterol, phospholipid and a protein coat packaged into lipoproteins which stabalises the lipid.
- Synthesis of lipoproteins, cholesterol, and phospholipids allow lipid transport in aqueous medium (blood)
- Allows lipid transport in aqueous medium
Outline cholesterol synthesis in the liver.
- Synthesised from Acetyl CoA connected to a sterol nucleus (also in diet)
- Can be produced in different ways:
- Acetyl CoA –(HMG-CoA)–> melavonate -> cholesterol
- Cholesterol delivered by chylomicrons
- Cholesterol delivered by HDLs from tissues
- Cholesterol is then packaged in lipoproteins with phospholipids and sent around the body
What is enterohepatic recirculation?
- Active reabsorption of bile salts (and other products in bile) mainly in terminal ileum.
- De-conjugation and de-hydroxylation by bacteria make bile salt lipid soluble
- Absorbed by Na+/bile salt co transport -> recirculate via hepatic portal vein back to liver
- Hepatocytes avidly extract bile salts (one pass clears them all)
- Bile salts are re-conjugated and some re-hydroxylated before reuse
- Bile salt pool is secreted twice per meal
- Less than 5% of bile isn’t absorbed in terminal ileum. In colon they’re converted to secondary bile acids
- This can prolong the action of drugs e.g morphine in liver failure
What are the different sources of triglycerides?
- Adipose tissue
- From diet in chylomicrons through lymph system
What are the different types of lipoproteins?
- VLDL: lot of triglycerides (usually what liver produces)
Can be converted to: - LDL: high cholesterol phospholipid. (Bad cholesterol - atherosclerosis) Delivers to tissues
- HDL: high protein content. (Good cholesterol) Removes from tissues
How long can the body survive on fat stores (with water)?
About 2-8 weeks but depends on fat stores
Outline some features of bile production.
- Produced by hepatocytes then drain into canuliculi
- Gall bladder holds 15-60ml
- Major component = bile salts (50% dry weight) , also has cholesterol, phospholipids (lecithin), bile pigments (bilirubin, biliverdin), bicarbonate ions and water
- Some components are insoluble but mostly stable
What is the process of bile formation?
- Addition of carboxyl and hydroxyl of cholesterol
- To form cholic acid (primary bile acids)
- Conjugation with taurine or glycine
- Forms bile acid conjugates
(Each process increases H2O solubility) - Moves to the gall bladder, and released into duodenum when required
- Bacteria in ileum de-conjugate and de-hydroxylate primary bile salts to form secondary bile salts (active form -> increases bile salts)
What is the function of bile?
- Digestion/absorption fats:
- Excretion variety substances via GI tract
- Neutralise acid chyme from stomach
How is bile secreted?
- Released into the duodenum during digestion. Small amounts during cephalic, gastric phases due to vagal nerve and gastrin
- Intestinal phase, cholecystokinin (CCK) causes contraction gall bladder and relaxation of sphincter of Oddi
How does bile aid digestion and absorption of fats?
- Emulsify fat droplets with bile salts, which increases surface area for digestion
- Hydrolysis of triglycerides in emulsified fat droplets into fatty acid and monoglycerides by pancreatic lipase
- Dissolving fatty acids and monoglycerides into micelles to produce mixed micelles
How does bile relate to excretion in the GI tract?
- Liver breaks down/inactivates steriod and peptide hormones which are then secreted into the bile for excretion
- Also performs similar role with variety of foreign compounds - usually drugs e.g. cannabis
- Excretory route for excess cholesterol: lecithin allows more cholesterol in micelles. Too much cholesterol excretion = gall stones. It’s also lost in salts
- Excretion of bile pigments. Bilirubin from break down of haem from old red blood cells (15% from other proteins). Iron from haem group is removed in spleen and conserved. Porphyrin group reduced to bilirubin and conjugated to glucoronic acid in liver. Liver disease - gall stone made from red blood cell (dark red/black)
What other functions does the liver perform?
Larder function: (storage)
- Vitamins (A,D,E,K) stores enough for 6-12 months, except Vit K which has a smaller store and is continuously used in blood clotting.
- Iron as ferritin. Available for erythropoeisis
- Vitamin B12 - Lack can lead to pernicious (megaloblastic) anaemia, nerve demyelination
- Glycogen and fat store
Protection:
- Liver sinusoids contain tissue macraphages (Kupffer cells). Bacteria may cross from gut to blood - Kupffer cells destroy these and prevent them entering the rest of the body
Ca2+ metabolism:
- UV light converts cholesterol to vitamin D precursor, which requires a double hydroxylation to convert it to the active form. First is in the liver, second is in the kidneys. Lack of Vit D -> rickets
Outline the development of the pancreas.
- Arises from the foregut at the foregut-midgut junction
- Dorsal (larger, on left) and ventral buds (smaller, on right)
- Ventral bud is a part of hepatobiliary bud
- In development, as duodenum rotates to form C shape the ventral bud swings round to lie adjacent to the dorsal bud
- Both buds fuse
- Ventral bud ducts becomes main pancreatic duct, and dorsal duct can become accessory pancreatic duct
Describe the regions of the pancreas.
5 main regions
- Body
- Head (duct exits here)
- Neck
- Tail (islet tissue most abundant)
- Uncinate (hook like process at bottom)
Describe the position of the pancreas.
- Lies mainly on posterior abdominal wall extending from C-shaped duodenum to the hilum of the spleen
- Main posterior relations: IVC, abdominal aorta and left kidney
Which vessels supply the pancreas with blood?
- Coeliac artery
- Superior mesenteric artery
What methods can be used to image the pancreas?
- MRI
- Angiography (especially to test for neuroendocrine tumours - blush appears)
Define endocrine and exocrine.
- Endocrine: Secretion into blood stream to have an effect on distant target organ. From ductless glands
- Exocrine: Secretion into a duct to have a direct local effect
What endocrine secretions does the pancreas release?
- Insulin: reduced blood glucose by increasing glucose uptake, lipogenesis and glygogenesis
- Glucagon: increases blood glucose by increasing gluconeogenesis and glycogenolysis
- Somatostatin: ‘endocrine cyanide’ - inhibits other secretions
What is the distribution of functions in the pancreas?
- Endocrine: 2%
Islets of Langerhans secretes insulin and glucagon (also somatostatin and pancreatic polypeptide) which regulates blood glucose, metabolism and growth effects - Exocrine: 98%
Secretes pancreatic juice into the duodenum via pancreatic duct/common bile duct which has digestive function
Note: In pancreatic disease, both are affected e.g. cystic fibrosis
What is the difference structurally between the functionally different parts of the pancreas?
Exocrine: Ducts, acini are grape-like clusters of secretory units, acinar cells secrete pro-enzymes into ducts
Endocrine: Derived from branching duct system but lose contact with ducts and become islets, differentiate into α and β-cells secreting into blood. More in tail than head of pancreas
Outline the composition of cells in the islets.
- α-cells form about 15-20% of islet tissue and secrete glucagon
- β-cells form about 60-70% of islet tissue and secrete insulin
- δ-cells form about 5-10% of islet tissue and secrete somatostatin
- Highly vascular ensuring all endocrine cells have close access to a site for secretion
What is pancreatic juice composed of?
- Low volume, viscous, enzyme-rich secreted by ACINAR CELLS
- High volume, watery, HCO3- rich secreted by DUCT and CENTRIACINAR cells
Describe the appearance of the cells in pancreatic acini.
- Acinar cells: large, with apical secretion granules
- Duct cells: small, pale
What are the features of Bicarbonate secretion in the pancreas?
- Secreted by duct and centriacinar cells
- Juice is rich in bicarbonate, about 120mM (plasma - 25mM). pH 7.5-8.0
- Neutralises acid chyme from the stomach which prevents damage to duodenal mucosa and raises pH to optimum range for pancreatic enzymes to work
- Washes low volume enzyme secretion out of pancreas into duodenum
How is the bicarbonate secretion rate affected by pH in the duodenum? Explain why.
- Duodenal pH
Outline the mechanism of bicarbonate secretion by duct cells.
- CO2 enters cell and carbonic anhydrase catalyses reaction with water (CO2 + H2O -> H+ + HCO3-).
- Na+ moves down concentration gradient paracellularly (tight junctions), and H2O follows
- Cl/HCO3- exchange at lumen allows bicarbonate secretion
- Na+/H+ exchange at basolateral membrane into bloodstream
Exchange is driven by electrochemical gradients (High ec (blood) Na, High Cl in lumen0 - Na+ gradient into cell from blood maintained by Na/K exchange pump (uses ATP - primary transport)
- K+ returns to blood, and Cl- to lumen via K+ and Cl- channel (CFTR)
What are the features of enzyme secretion in the pancreas?
- Enzymes for digestion of fat (lipases), protein (proteases) and carbohydrates (amylase) are synthesised and stored in zymogen granules
- Zymogens = pro-enzymes (precursors)
- Proteases are releases as inactive pro-enzymes -> protects acini and ducts from autodigestion e.g. trypsinogen
- Pancreas also contains a trypsin (protease) inhibitor to prevent its activation
- Enzymes only become active in the duodenum
- Blockage of pancreatic duct may overload protection and result in auto-digestion (acute pancreatitis)
Outline the features of trypsin.
- Secreted by pancreas in inactive form trypsinogen
- Duodenal mucosa secretes enzyme enterokinase (enteropeptidase) that converts trypsinogen to trypsin
- Trypsin then converts all other proteolytic, and some lipolytic enzymes (Note: lipase is secreted in active form but needs colipase which is secreted as a precursor. Also lipases need bile salts for effective action)
What can alter the pancreatic enzyme function?
- Pancreatic secretions adapt to diet e.g. high protein, low carbs, increases proportion of proteases and decreases proportion of amylases
- Pancreatic enzymes (+bile) are essential for normal digestion of a meal. Lack of these can lead to malnutrition even if the dietary input is fine (unlike salivary and gastric enzymes)
- Anti-obesity drug Orlistat inhibits pancreatic lipases -> inhibits intestinal fat absorption -> steatorrhea (increased faecal fat).
Describe generally, the innervation of the gut.
- Vagus
- Cholinergic
- Communicates information from the brain to gut
- Originates from nucleus solitarius in brain stem
Outline the phases of exocrine secretion in the Pancreas.
- Cephalic phase:
Reflex response to sight/smell/taste food. Enzyme-rich component only. Low volume -> mobilises enzymes - Gastric phase:
Stimulation of pancreatic secretion originating from food arriving in stomach. Same mechanisms involved as for cephalic phase - Intestinal: (70-80% of pancreatic secretion)
Hormonally mediated when gastric chyme enters duodenum. Both components of pancreatic juice stimulated (enzymes + HCO3- juice flows into duodenum)
What controls each component of pancreatic exocrine secretion?
- Bicarbonate secretion is controlled by release of hormone SECRETIN which binds and upregulates cAMP intracellularly -> increased transportation across membrane
- Enzyme secretion is controlled by vagal reflex and by hormone CHOLECYSTOKININ (CCK) which binds to acinar cells and change intracellular Ca2+ and Phospholipase C (PLC) -> fusion of zymogen vesicles with membrane
Describe the feedback mechanism of bicarbonate secretion from the pancreas.
- S cells in the duodenum ahve proton receptors and detect the high H+ concentration in acidic chyme
- They produce secretin into the blood and in the pancreas it binds to receptors in duct cells
- Binding leads to secretion of bicarbonate which reacts with chyme and increases pH
- Increase in pH = less H+ so S cells are no longer stimulated
Describe the feedback mechanism of enzyme secretion from the pancreas.
- Presence of peptides and fat in the chyme in the duodenum activate receptors in C cells (or I cells)
Note: also stimulates by vagus nerve (parasympathetic) - CCK secreted into blood and reaches pancreas, where it binds to acinar cells
- Acinar cells stimulates to produce enzyme secretion (pro-enzymes and trypsinogen inhibitor)
- Enzymes break down the peptides and fat -> C cells no longer stimulated
(may be other mechanisms involved)
Describe the effects of stimulation of the exocrine secretion in the pancreas and their interaction.
- CCK alone -> no effect on bicarbonate secretion
- CCK can markedly increase bicarbonate secretion that has been stimulated by secretin
- Vagus nerve has a similar effect to CCK (i.e. enhances production in presence of secretin)
- Secretin has NO EFFECT of enzyme secretion
