Alimentary System Flashcards
What is digestion?
The process of breaking down macromolecules to allow absorption
What is absorption?
The process of moving nutrients and water across a membrane
What are the possible routes from ingestion to excretion or absorption?
Ingestion-> digestion-> excretion
Ingestion-> digestion-> absorption
Ingestion-> excretion
Ingestion -> absorption
What are the main parts of the GI system?
Mouth and oesophagus
Stomach
Small intestine (duodenum, jejunum and ileum)
Liver
Biliary system (gall bladder)
Pancreas
Large intestine (colon, rectum and anus)
Colon= caecum, appendix, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon
Outline the route from swallowing to evacuation?
Swallow-> back of throat (epiglottis stops it falling into trachea)-> oesphagus-> stomach (highly acidic)-> duodenum (pancreas secretes into, bile in)-> digested products -> jejjenum and ileum-> colon-> evacuation
What are some possible diseases of the GI system?
Oesophageal cancer Gastro-oesophageal reflux disease Barrett's oesophagus Stomach cancer Gastric ulcers Duodenal ulcers Liver sclerosis Hepatitis Jaundice Cholangitis Liver failure Diabetes Pancreatitis Pancreatic cancer Obesity Coeliac disease IBS Crohn's disease Appendicitis Colon cancer
What does the disease burden of GI disease affect?
The patient
The economy
The population
Society
What are typical signs and symptoms of GI tract diseases
GENERAL
Anorexia
Weight loss
Anaemia
UPPER GI Haematemesis Melaena (bleeding high in GI tract-> dark colour, like tar) Nausea and vomiting Dysphagia Odynophagia Heartburn Acid regurgitation Belching (excess gas) Chest pain Epigastric pain
HEPATOBILIARY RUQ pain (right upper quadrant) Biliary colic (when biliary tree is obstructed by gallstone) Jaundice (icterus) Dark urine (pruritus) Pale stool (cholestasis) Abominal distension (ascites)
MID GI AND PANCREAS Abdominal pain Steatorrhoea Diarrhoea Abdominal distension
LOWER GI Abdominal pain Bleeding Constipation Diarrhoea Incontinence
What signs are doctors looking for with GI basis? (General, hands, abdomen, anus and rectum)
GENERAL Cachexia Obesity Lymphadenopathy Anaemia Jaundice
HANDS
Koilinychia (spooning-> concave)
Leuconychia
Clubbing (especially distalling)
Dupytrens contractures (can’t hold hand out flat)
Tachycardia (hold radial pulse or detect tremor)
Tremor
ABDOMEN Organ enlargement Mass Tenderness Distension
ANUS AND RECTUM Haemorrhoids Fistula Fissure Rectal masses Prolapse
What investigations are carried out for the GI system?
HISTORY Symptoms Dietary habits Family history Ethnicity Environmental Travel
BASIC PHYSICAL EXAM Hands Skin Palpable abdominal organs Digital rectal exam Sigmoidoscopy
HAEMATOLOGY, BIOCHEMISTRY AND MICROBIOLOGY
Blood tests
- Blood sugar (glucose, fasting glucose, glucose tolerance test, HbA1C)
- Tumour markers (CA19-9 – pacreatic and other GI cancers)
- Eythrocyte sedimentation rate (Crohn’s disease)
- Urea & electrolytes (absorption disorders)
Liver function tests
Antibodies
Microbiology (HBV, HCV, faecal occult blood)
PROCEDURES Endoscopy Colonoscopy Ultrasound CT MRI X-ray
Outline the national and global burden of GI disease to the population?
5% UK adults suffer chronic illness e.g. pancreatic, liver, inflammatory bowel disease
Drug prescriptions >£4 billion
Responsible for 12% UK deaths
1/8 hospital admissions
1/4 main operations
GI increasing especially in middle-aged adults (but heart and lung disease more common)
WORLDWIDE
Malnutrition, enteric infections, viral hepatitis and consequences, gastric cancer
UK
Dyspepsia, liver disease (due to alcohol and obesity), colon cancer
Why are liver deaths significant?
The only top 5 cause of mortality that is rising
Prevalence growing
Burden of alcoholic liver disease-> younger people, more males
Liver cancer more likely later in life, slightly more males
How can neural tube defects in infants/fetuses?
Vitamin B12 and folate (folic acid)
Now routinely screened in UK
What are the main causes of abnormal liver function tests?
Chronic HepB
Chronic HepC
Alcohol-related steato-hepatitis (this is hugely increasing due to increasing alcohol consumption)
Obesity-related steato-hepatitis
What is ulcerative colitis?
IBD
Colon only, superficial
Prevalence: 1 in 500
Incidence: 10-16 per 100,000
Cause: Thought to be autoimmune
Poorly understood
Symptoms: pain, bloody stool, weight loss, bloating
Treatment: Colectomy
What is Crohn’s disease?
IBD
Entire GI tract, deeper
Prevalence: 1 in 1000
What is gastro-oesophageal reflux disease (GORD)?
Acid escapes from stomach into oesophagus
Oesophagus cant handle this very low pH
Can lead to chronic oesophagitis
Chronic oesophagitis is generally regarded as the primary cause of Barrett’s oesophagus, and the
epithelial changes that occur have been linked to a substantially increased risk of oesophageal
carcinoma
What are the common biliary conditions?
ACUTE PANCREATITIS Mild to life-threatening Blockage of pancreatic duct Back-up of pancreatic enzymes (-> severe inflammation ethanol and gallstones in 80%)
CHRONIC PANCREATITIS
Permanent damage to pancreas
Alcohol excess main cause
can greatly impair quality of life
What are common GI infections?
BACTERIAL
Helicobacter pylori (
Gram negative, spiral bacterium) = nausea, bloating, weight loss
Escheria coli= nausea, diarrhoea, cramps
VIRAL
Norovirus= nausea, vomiting, diarrhoea
Outline the possible effects of h. pylori
85%= no long term effects
14%= peptic ulceration
1% gastric adenocarcinoma or lymphoma
-> Duodenal ulcer (main complication is perforation and bleeding) Massively based on environment - Energy intake - Staple foods - Foods in last 5 decades
What ranking (in terms of common cancer) is bowel cancer?
2nd most common UK cancer
What are the most common GI diseases globally?
GORD (gastro-oesophageal reflux disease)
Non-ulcerative dyspepsia (indigestion)
Functional bowel disease (which most people will self-treat during their life time)
What are QALY and DALY?
QALY= quality-adjusted life year DALY= disability-adjusted life years
What are the main types of GI cancer?
LIVER
May be primary or secondary
Primary liver cancer arise in liver cells, e.g. hepatocellular and cholangio carcinomas – more prevalentin association with cirrhosis
(If detected at an early stage by ultrasound scanning, with an associated 50% 5 yr survival)
Cholangiocarcinoma – no treatment
Secondary liver cancer is metastatic cancer from other primary locations; is more common in the UK
but results in later detection
PANCREATIC CANCER
95% adenocarcinoma of the pancreatic duct
Difficult to diagnose early there has one of the poorest survival rates (2% at 5yrs)
What is the most common large bowel disease?
IBS
1/3 population
What are anal diseases?
Faecal incontinence (soiling) may affect 1/20 people
By age 50, about 1/2 population have haemorrhoids
Over half of the >70yr old population have diverticula of the large intestine
What are the main economic burdens of GI disease?
HEALTHCARE COSTS In-patients 6.1% GI Out-patients 6.9% GI Primary care 3.9% GI Community health and social care 3% GI
COSTS
Not-working= early death, short-term sick, long-term sick
NHS costs= healthcare and drugs >3 billion
What is the cost of dyspepsia?
40% adults suffer with dyspepsia, of which 2% consult their GP
£600 million for endoscopies and prescribed drugs
£100 million for OTC drugs
What NHS prescriptions are commonly given for GI disease (and cost)?
Antacids Antispasmodics Ulcer-healing Chronic diarrhoeal agents Laxatives Haemorrhoid treatment Stoma care Intestinal secretion drugs
Total cost to NHS in 1995/6 was £0.83 billion
What screening programme is available in the UK for GI diseases?
NHS bowel cancer screening (BCSP) programme
What are the social problems of GI disease?
DIETARY LIMITATION
Lactose intolerance, diabetes, cholecystitis, coeliac, alcohol
FLATULENCE
Sound and smell
INCONTINENCE AND SOILING
TREATMENT
Smell and sight
E.g. stoma bag
What percentage of British adults suffer long-standing illness of the GI tract?
5%
What 4 layers can the gut wall be divided into?
Mucosa= epithelium, lamina propria, LCT and muscularis mucosae
Submucosa= connective tissue, nerve plexuses
Muscularis= smooth muscle, nerve plexuses
Serous/adventitia= connective tissue +/- more epithelium
What parts of the gut wall are made up of mucosa?
Colonic epithelium
Stomach epithelium
Small intestinal epithelium
What parts of the gut wall are made up of submucosa?
Submucosa
Ganglion cells and nerves (also muscularis)
Submucosal gland
What parts of the gut wall are made up of muscularis?
Longitudinal muscle
Circular muscle
Ganglion cells and nerves (also submucosa)
What parts of the gut wall are made up of serosa/adventitia?
Seroa (external)
Where does the oesophagus start and end?
C5 (where pharynx becomes oesophagus)
T10 (pierces into the diaphragm)
What does the oesophagus do?
Gets food from the mouth to the stomach
Important in control of swallowing
Food comes in through the mouth-> the tongue forces food posteriorly to the pharynx (soft palette raised to
close nasal cavity) into the pharynx (under neural control)
The oesophagus passes very close to the recurrent laryngeal nerves and the pericardium
These may be
damaged in excessive oesophagus extension
Why is the oesophageal lining important for function?
Designed for ‘wear and tear’
Stratified squamous epithelium
Non-keratinising-> moist
Lubricated by mucus secreting gland
Many layers act as protective layer if surface layer damaged
2 sphincters (prevent backflow of food)
Tonically active
How is the upper oesophageal sphincter opened?
Swallowing centre within the medulla
Under parasympathetic control via vagus
How does the amount of skeletal muscle in the oesophagus change?
Lots in upper oesophagus (some voluntary control in upper half)
Decreases as it descends
(Smooth muscle increases as it descends)
What happens when food has entered and the upper oesophagus sphincter is closed?
Bolus of food moved down by peristalsis (purely under muscular control, gravity has no effect)
How does peristalsis lead to rhythmic contraction down the oesophagus?
Circular muscle is major driver
Assisted by longitudinal muscle
Muscle just superior to bolus contracts
One in front/inferior relaxes
If food gets stuck, swallowing centre can start a wave of 2nd peristalsis
How long does it take for food to move 30cm along the oesophagus?
9 seconds
What is the difference in the structure of the upper and lower oesophageal sphincters?
Upper= skeletal muscle Lower= skeletal and smooth
Why does the oesophagus have a tendency to draw stuff up from the stomach?
Negative pressure
But sphincter prevents this (sealed off)
How does swallowing and breathing rely on sphincters?
Upper= only open to let food in, can't breathe when it's open Lower= open until food passes down
What is the gastro-oesophageal junction?
Where the oesophagus and stomach are joined
At the Z-line, stratified squamous lining of the oesophagus gives way to the simple columnar epithelium of the stomach
Where is the lower sphincter?
At the gastro-oesophageal junction
What are the 3 contributing mechanisms which lead to the lower sphincter action?
The pressure difference between the abdominal oesophagus and stomach
Contraction of the diaphragm
As the stomach expands, it compresses the Z-line
What do the lower sphincter and diaphragm aim to prevent?
Acid reflux
What causes heartburn?
Acidic content is ejected into the oesophagus
Lower sphincter not working properly
Common in pregnancy because stomach is forced upwards so lower oesophagus is forced back into thorax
-> Loss of pressure difference and contractile element of diaphragm
Also after large meal
What are rugae and what do they allow?
Gastric folds (present when stomach is empty) As stomach distends-> rugae expand
Allow for huge changes in surface area
Allows stomach to expand after meal
What is the role of the stomach?
Break food down into smaller particles stored (due to acid & pepsin)
Hold food and release at a controlled steady rate into duodenum
Kill parasites and certain bacteria
What is the structure of the stomach?
Cardia Fundus Body Antrum Pyloris
When is the stomach content released into the duodenum?
Sphincters of the stomach are closed post-eating for about 4 hours before release into duodenum
Bolus churned steadily during this time
What are the secretions (by part of stomach)?
Cardia and pyloric region= mucus only
Body and fundus= mucus, HCl, pepsinogen
Antrum= gastrin
How does the epithelium vary within the stomach?
Slight variation due to different secretory functions
Simple columnar
Invaginates into mucosa- tubular glands
Where are mucus producing cells in the stomach and what is their role?
All regions
Mucin ‘mops up’ excess acid
Where is HCL produced?
Parietal cells
Where is gastric produced?
Endocrine cells
How much acid is produced by the stomach per day?
2L per day
150mM [H+]
What is the epithelial surface and lumen pH in the stomach?
Epithelial surface= pH 6-7
Neutralised by bicarbonate ions trapped in mucus gel (mucins= gel coating)
Lumen= pH 1-2
What is the chief cell?
Pepsinogen secreting cell
Protein-secreting epithelial cell
Abundant RER
Golgi packaging and modifying for export
Masses of apical secretion granules
(Pepsinogen passes through gastric pit into stomach)
What is a parietal cell?
RESTING Many mitochondria (requires lots of ATP) Cytoplasmic tubulovesicles (contain H+/K+ ATPase) Internal canaliculi (extend to apical surface)
SECRETING (active state)
Tubovesicles fuse with membrane and microvilli project into canaliculi (which also fuse to form large open reservoir extending to apical surface-> H+ diffuse out through stomach lumen)
How do parietal cells cause H+ to diffuse out through the stomach lumen and HCL production?
On BL membrane= Na/K pump (K in, passive diffusion into lumen)
H+ ions generated by carbonic anhydrase (and bicarbonate ions) from CO2 and H2O
H+ ions are acively secreted into the reservoir in exchange for K
All bicarbonate ions are exchanged out of the cell for Cl entry (also diffuses into reservoir)
H+ and Cl- ions bond-> HCl
(Need high H/K ATPase and carbonic anhydrase)
What does pepsinogen do?
Interacts with HCl-> pepsin (via autocatalytic process)
The pepsinogen on its own has conformation with internal active site which is protected
Acidic environment of the stomach exposes the active site
Pepsin itself then further catalyses its own production once the active site is exposed (positive
feedback)
Pepsin is a protease
What is gastrin?
Endocrine product of the stomach (predominant)
Produced predominantly in the pyloric antrum
One of its major actions is to stimulate histamine release from the chromafin cells within the lamina propria
Together, these then increase acid production in the stomach
There is a sort of negative feedback system, as the stomach gets more acidic – gastrin secretion is inhibited
A protein rich meal acts against this, as proteins make very good buffers for acid
What effect do histamine and gastrin have on stomach acid production?
Together-> increase acid production
List the phases of gastric secretion
Cephalic phase
Gastric phase
Intestinal phase
What happens in the cephalic phase of gastric secretion?
Thought/sight/smell and taste of food- central effect
Central effect mediated by efferent vagus nerve-> ACh production
ACh acts directly of parietal cells (to increase acid) or indirectly on chromaffin cells (increase histamine)
Prepares for arrival of food
HCl pepsin and gastrin present
What happens in the gastric phase of gastric secretion?
Distension when food enters stomach-> activates stretch receptors
Contents activatate chemoreceptors (local enteric phase)
ACh and gastrin release (more than during cephalic)
HCl pepsin present
What happens in the intestinal phase of gastric secretion?
Largely inhibitory effect on acid secretion
Food leaves stomach and enters small intestine (pH must be increased, acid secretion reduced)
= Chyme (
Protein concentration in duodenum stimulates gastrin secretion
Gastric inhibitory peptide
Cholecystokinin
Secretin
Enterogastrones-> enterogastric effect
How can stomach acid secretion be decreased pharmacologically?
Affect H/K ATPase (omeprazole)
Affect histamine receptor (-> cAMP and Ca) (ranitidine)
What stimuli is best to decrease stomach acid secretion?
Protein (high content in meal)
What is chyme?
Semifluid mass of partly digested food that is expelled by the stomach into the duodenum via pyloric sphincter
What is the function of the small intestine?
To absorb nutrients, salt and water (from the lumen to the blood)
How long is the small intestine (and its parts)?
6m long, 3.5cm diameter
Duodenum= 25cm Jejunum= 2.5m Ileum= 3.75m
Describe the mesentery surrounding the small intestine
Fan shaped mesentery
Throws the small intestine into folds
Large blood supply to support the metabolic functions of the cells and aid absorption
Outline the histological organisation of the small intensine
No suddentransition between duodenum, jejunum and ileum
All have same basic histological organisation (differences are slight)
External wall has longitudinal and circular muscles (important for motility)
Internal mucosa arranged in circular folds and covered in villi (1mm tall)
Invaginations known as Crypts of Lieberkühn
What is the structure and function of intestinal villi?
1mm tall
Simple epithelium= 1 cell thick (like rest of intestine), dominated by enterocytes
Have good innervation from the submucosal plexus
Motile, have a rich blood supply and lymph drainage for absorption of digested nutrients
Increase surface area for absorption (most nutrients absorbed in small intestine)
Villi only occur in the small intestine
What are between the villi?
Crypts of lieberkuhn
Epithelium which include paneth cells and stem cells
What are the cell types in the epithelium?
LINE MUCOSA (simple columnar epithelium consisting of:) Enterocytes= absorptive Goblet cells= mucous secreting Enteroendocrine cells= hormone secreting
IN CRYPTS OF LIEBERKUHN (epithelium includes:)
Paneth cells= antibacterial, protect stem cells
Stem cells= migrate up villus ‘escalator’, pluripotent
How much is the surface area increased by mucosal folds, villi and microvilli?
Cylindrical internal surface area of the small intestine increased by 500x
0.4-> 200m2
Maximum opportunity for nutrient absorption
What are enterocytes?
Columnar absorptive cells with microvilli and a basal nucleus
Cells of intestinal lining
Most abundant cells in small intestine
Specialised for absorption and transport of substances
Lifespan 1-6 days
Tight junctions between cells are important for intercellular communication and to maintain polarity (stop proteins moving between surfaces)
What are microvilli?
0.5-1.5um high
Make up brush border
Several thousand microvilli per cell-> increased surface area
Surface covered with glycocalyx
What is glycocalyx?
Rich carbohydrate layer on apical membrane that serves as protection from the digestional lumen
But allows for absorption
Traps a layer of water and mucous known as the “unstirred layer” -> regulates rate of absorption from intestinal lumen
What are goblet cells?
2nd most abundant epithelial cell type (between enterocytes)
Goblet shape because mucous containing granules accumulate at the apical end of the cell (where brush border is)
Increasing goblet cells along the entire length of the bowel (few in duodenum, many in colon)
What is mucous?
Large glycoprotein that facilitates passage of material through the bowel
What are enteroendocrine cells (chromaffin cells)?
Columnar epithelial cells scattered among absorptive cells
Mostly in lower part of crypts in intestine
Hormone secreting (influence gut motility
What are paneth cells?
Found only in bases of the crypts
Contain large, acidophilic granules containing:
- Lysozyme (antibacterial enzyme, protects stem cells)
- Glycoproteins and zinc (essential trace metal for number of enzymes)
Engulf some bacteria and protozoa
May have a role in regulating intestinal flora
How long do epithelial cells survive?
Most cells are constantly proliferating
Enterocytes and goblet cells of the small intestine have a short life span (36 hours)
Continually replaced by dividing stem cells in the crypts
What are stem cells (small intestine)?
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 tip of villus, replacing older cells that die by apoptosis
Differentiate into various cell types (pluripotent)
Describe the cells in the crypt from bottom to top
Paneth cells
Stem cells
Crypt enterocytes
Escalator of epithelial migration
How does the ‘escalator of epithelial migration’ work?
Dividing stem cells in the crypts -> surface and tips of villi
At villus tips, cells become senescent -> sloughed into the lumen of the intestin-> digested and reabsorbed
For rapid turnover of enteroctyes
Why is there such a rapid turnover of enterocytes?
Rapid turnover (compared with lifespan of weeks/months for other epithelial cell types e.g. lung, blood vessels)
Because enterocytes are are the first line of defence against GI pathogens/toxic substances in the diet
Effects of agents which interfere with cell function, metabolic rate etc will be diminished
Any lesions will be short-lived
If escalator-like transit of enterocytes is interrupted through impaired production of new cells (e.g. radiation) severe intestinal dysfunction will occur
What did John Snow do?
London physician
Proved water bourne transmission of cholera in 1849
What does cholera enterotoxin do?
Causes prolonged opening of the chloride channels in the small intestine-> uncontrolled secretion of water
Causes rapid, massive dehydration-> death (unless treated with rehydration, cholera bacteria will clear and epithelium will be replaced)
Describe the histological organisation of the duodenum?
Brunner’s glands
Submucosal coiled tubular mucous glands secreting alkaline fluid
Open into base of crypts
Alkaline secretions of Brunner’s glands-> neutralises acidic chyme from stomach (protects proximal small intestine) and helps optimise pH for pancreatic digestive enzymes)
Describe the histological organisation of the jejunum?
Plicae circulares (valves of Kerchring) Numerous, large fold in the submucosa
Present in duodenum and ileum too but in jejunum= taller, thinner and more frequent
Frilling interior (formed of circular folds in mucosa)
Describe the histological organisation of the ileum?
Some features shared with large intestine
Lots of Peyer’s patches (large clusters of lymph nodules in submucosa)
Prime immune system against intestinal bacteria (other mechanisms for defence= bactericidal Paneth cells, rapid cell turnover)
Well positioned to prevent bacteria from colon migrating up into small intestine
What are the functions of small intestine motility?
To mix ingested food with digestive secretions and enzymes
To facilitate contact between contents of intestine and the intestinal mucosa
To propel intestinal contents along alimentary tract
What is segmentation?
Mixes the contents of the lumen
Segmentation by stationary contraction of circular muscles at intervals (breaks big bolus into smaller segments)
More frequent contractions in duodenum compared to ileum-> allow pancreatic enzymes and bile to mix with chyme
General movement DOWN
What is peristalsis?
Sequential contraction of adjacent rings of smooth muscle
Propels chyme towards the colon
Most waves travel about 10cm
What do segmentation and peristalsis result in?
Chyme being segmented, mixed and propelled towards the colon
What is the migrating motor complex?
Sweeping wave of contraction helps propel down cut
In fasting= cycles of smooth muscle contractions
Each cycle= contraction of adjacent segments of small intestine
Begins in stomach-> through small intestine-> terminal ileum-> duodenum
Prevents migration of colonic bacteria into the ileum (may clean intestine of residual food)
Less ordered and less frequent in fed state
What are the 3 methods that contribute to motility?
Segmentation= mixing
Peristalsis= propelling
Migratory motor complex= sweeps through gut, prevents accumulation of residue
How does digestion in the duodenum occur?
In an alkaline environment
Involves digestive enzymes (from pancreatic duct) and bile (from bile duct)
Duodenal epithelium also produces digestive enzymes (in contact with brush border)
Digestion in lumen and unstirred layer of the membrane
What are the mechanisms of absorption?
PASSIVE DIFFUSION
No carrier proteins
With gradient
No energy required
FACILITATED DIFFUSION Carrier proteins With gradient No energy required Tends to equilibrate substance across the membrane E.g. GLUT-5, GLUT-2
PRIMARY ACTIVE TRANSPORT Carrier proteins Against gradient Energy required (hydrolysis of ATP) E.g. Na+/K+ ATPase, H+/K+ ATPase
SECONDARY ACTIVE TRANSPORT
Carrier proteins
Against gradient
Energy required (electrochemical gradient)
E.g. SGLT-1 co-transport, HCO3-/Cl- counter transport, Na+/H+ counter transport
How are carbohydrates digested?
Digestion begins in the mouth by salivary -amylase, but is destroyed in the stomach (acid pH)
Most of the digestion of carbohydrates occurs in the small intestine
What are simple carbohydrates?
Monosaccharides e.g. glucose and fructose
Disaccharides e.g. maltose and sucrose
What are complex carbohydrates?
Sugars bonded together to form a chain
E.g. starch, cellulose (amylose), pectins (amylopectin)
What is pancreatic a-amylase?
Secreted into duodenum in response to a meal
Continues digestion of starch and glycogen into small intestine (started by salivary amylase)
Needs Cl- for optimum activity and neutral/slightly alkaline pH (Brunner’s glands in duodenum-> alkaline secretion)
Acts mainly in lumen (some absorbs to brush border)
What enzymes in digestion of carbohydrates act in the lumen and in the membrane?
LUMEN= pancreatic a-amylase
MEMBRANE= digestion of amylase products and simple carbohydrates (glucoamylase, sucrase, isomaltase, trehalase, lactase)
What are the products of lactose digestion?
Glucose
Galactose
What are the products of sucrose digestion?
Glucose
Fructose
What are the products of trehalose digestion?
Glucose
Outline how amylase products and simple carbohydrates (lactose, sucrose, trehalose) are digested?
Starch glycogen
- > Amylase
- > a-Dextrins, maltotriose, maltose
- > glucose (with enzymes)
Lactose -> glucose and galactose (with lactase)
Sucrose-> glucose and fructose (with sucrase)
Trehalose-> glucose (with trehalase)
What are brush border enzymes?
Maltase
Lactase
Sucrase
Trehalase
On enterocyte apical membrane
How are carbohydrates absorbed?
SGLT-1
Absorption of glucose and galactose is by secondary active transport
= Carrier protein SGLT-1 on apical membrane
(Effective when glucose levels lower in lumen than enterocytes)
GLUT5
Absorption of fructose is by facilitated diffusion
= Carrier protein GLUT-5 on apical membrane
(Effective at relatively low concs of fructose in lumen as tissue and plasma levels are low)
GLUT-2
Facilitates exit of glucose at the basolateral membrane
= Carrier protein GLUT-2 (high capacity, low affinity facilitative transporter)
(Glucose between plasma and tissue/enterocyte generally equilibrated)
How many simple sugars can be absorbed by human SI per day?
10kg
How are proteins digested?
Protein digestion begins in the stomach by pepsin, but pepsin is inactivated in the alkaline duodenum
Pancreatic proteases are secreted as precursors
Trypsinogen-> (with enterokinase)-> trypsin
Enterokinase= enzyme located on the duodenal brush border
Trypsin then activates the other proteases
What proteases does trypsin activate?
Trypsinogen-> trypsin
Chemyotrrypsinogen-> chymotrypsin
Proelastase-> elastase
Procarboxypeptidase A-> carboxypeptidase A
Procarboxypeptidase B-> carboxypeptidase B
How are proteins absorbed?
Brush border peptidases break down the larger peptides prior to absorption
AAs are absorbed by facilitated diffusion and secondary active transport (similar to sugars)
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
How are lipids digested (4 stage process of bile digesting/absorbing fats)?
Lipids are poorly soluble in water so complicated to digest
- Secretion of bile and lipases
- Emulsification
- Bile salts facilitate the emulsification of a fat into a suspension of lipid droplets, increasing the surface area for digestion - Enzymatic hydrolysis of ester linkages
- Pancreatic lipase then splits the triglycerides into 2 fatty acids and a monoglyceride at a fat/water interface
- Lipases complexes with colipase preventing the bile salts from displacing the lipase from the fat droplet - Solubilization of lipolytic products in bile salt micelles
- Bile salts form micelles with the released fatty acids and glycerol
Why are lipids emulsified?
Water and fat don’t mix
Bile and lipases are secreted into the duodenum
Bile salts facilitate the emulsification of fat into a suspension of lipid droplets (1um diameter)
Increases the surface area for digestion
Allows pancreatic lipase to split triglycerides
A triglyceride is broken down into two fatty acids and a monoglyceride at fat/water interface
Describe a bile salt molecule
Steroid nucleus planar
Two faces= amphipathic
Hydrophobic face (nucleus and methyl) dissolves in fat
Hydrophilic face (hydroxyl and carboxyl) dissolves in water
What are bile salt micelles?
Micelles = hydrophilic “head” regions in contact with surrounding solvent, hydrophobic tail regions in the micelle centre with lipid core (free fatty acids and cholesterol inside bile salts)
Mixed micelles in small intestine= water insoluble monoglycerides from lipolysis are solubilised by forming a core, stabilised by bile salts
- Transported to GI epithelial cells for absorption
HYDROPHILIC DOMAINS FACE OUT
HYDROPHOBIC DOMAINS FACE IN
(i->o, o->i)
How are triglycerides broken down?
Lipase breaks down triglycerides into monoglycerides and free fatty acids
Pancreatic lipase complexes with colipase
Colipase prevents bile salts from displacing lipase from the fat droplet
Also important= phospholipase A1 and pancreatic cholesterol esterase
What does phospholipase a2 do?
Hydrolyses fatty acids at the 2 position in many phospholipids
-> lysophospholipids and free fatty acids
What does pancreatic cholesterol esterase do?
Hydrolyses cholesterol ester to free cholesterol and fatty acid
How are lipids absorbed?
Micelles are important in absorption (absorbed much quicker than emulsion)
Micelles allow 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
- Lipid absorption is usually complete by the middle of the jejunum
Bile salts are transported back to the liver for recycling (enterohepatic circulation)
By what pathways are lipids metabolised?
Monoglyceride acylation (major) Phosphatidic acid pathway (minor)
Describe the monoglyceride acylation (major) pathway?
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 esterified into diglycerides and triglycerides
Describe the phosphatidic acid pathway (minor) pathway?
Triglycerides are synthesised from CoA fatty acid and a-glycerophosphate
What are chylomicrons?
Lipoprotein particles synthesised in enterocytes as an emulsion
Chylomicrons are transported to the Golgi and secreted across the basement membrane by exocytosis
Too big to enter blood capillaries of villi
Enter lacteals (lymph channels) instead
What are chylomicrons comprised of?
80-90% triglycerides 8-9% phospholipids 2% cholesterol 2% protein Trace carbohydrate
How is the ileum separated from the colon?
Ileocaecal sphincter
How is the passage of material into the colon controlled?
Ileocaecal sphincter
Relaxation and contraction
Also prevents back flow of bacteria into the ileum
Summarise carbohydrate, protein and lipid digestion
CARBOHYDRATE
Pancreatic a-amylase and brush border enzymes
PROTEIN
Trypsin, which activates other proteases
LIPID
Emulsification by bile, hydrolysis and solubilisation into bile salt micelles
Approximately how many people are affected by liver disease?
2 million
Incidence is rising
>1 million hospital admissions a year
1 in 10 deaths of people in their 40s are due to liver disease
Describe the surface anatomy of the liver
Predominantly in right upper quadrant (apex into LUQ)
Superior border at the level of the 5th costal cartilage
Protected mainly by ribcage, superiorly by the diaphragm and interiorly by abdominal muscles and organs
Surface anatomy important in biopsy to avoid damaging other organs
Dull region= liver (percussion)
Large inspiration then expiration prior to insertion of needle
Describe the morphological anatomy of the liver
4 lobes= right, left, caudate, quadrate
Caudate above quadrate and both between L and R (behind falciform ligament)
R and L lobes separated by the falciform ligament
Right lobe is much larger (60% mass)
Coronary ligament (above R lobe) and left triangular ligament (above L lobe) connect the liver to the abdominal wall and diaphragm -> Falciform ligament-> Ligamentum teres (round ligament) connects to front of abdomen
How does the gall bladder link anatomically to the liver?
Gall bladder lies inferiorly in the arch of the liver (under R lobe)
Shouldn’t be palpable unless enlarged
What is Calot’s triangle?
Bound by vystic duct, bile duct and cytic artery
Triangular space (dissected in cholecystectomy to ID window to safely expose gallbladder)
What are the embryological origins of the liver?
Liver and biliary system share a common origin with the ventral part of the pancreas
Secretory cells derived from endoderm (parenchymal cells)
-> Embedded in mesoderm
At junction between foregut and midgut
Arises from the septum transversum- point at which the ectoderm of the amnion meets endoderm of the yolk sac
Mesenchymal structure of the septum provides a framework on which the parenchymal (hepatocyte) cells and bile ducts with associated blood supply can develop
ENDODERM= parenchymal cells, flattened cells become columnar and become epithelial lining
MESODERM= forms connective tissue, differentiates from rest of embryos through IC signalling-> polarisation
Somites form skin and musculoskeletal parts of body
SEE CARNEGIE STAGING
Outline the Carnegie staging of liver development
Carnegie staging= 23 stages, during first 60 days of development
STAGE 1-10
Fertilisation-> blastocyst-> primary yolk sac-> septum traversum (stage 9)
STAGE 11 (29 days)
Hepatic diverticulum or liver bud development
(Diverticulum invades septum transversum)
Cell differentiation
STAGE 12 (30 days)
Septum transversum forming liver stroma
Hepatic diverticulum forming hepatic trabeculae
STAGE 13 (32 days) Epithelial cord proliferation enmeshing stromal capillaries
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)
Cell differentiation
Early structural organisation
Biliary ductules developed in periportal connective tissue and ductal plates form that receive biliary canaliculi
What is the septum traversum?
Thick mass of cranial mesenchyme-> gives rise to parts of throacic diaphragm and ventral mesentry of the foregut in the developed human being
Arises from the mesoderm
What is the liver formed from?
The liver bud (first apparent around 29 days, stage 11)
When does the gall bladder diverticulum arise?
Stage 11
29 days
Grows into transverse septum
What happens to the pancreas by 8 weeks of liver development?
Pancrease migrates to posterior, left portion of the abdominal cavity/coelom
What happens to the liver after 10 weeks of development?
Liver rotates to the right
Describe the blood supply of the liver
25% of resting cardiac output (rich blood supply)
DUAL BLOOD SUPPLY= direct and indirect
- Hepatic artery (L and R branches)
- 20% arterial blood from
- T o bring oxygen - Hepatic portal vein (HPV)
- 80% venous blood draining from the gut
- Brings everything from gut (before it can get into systemic circulation)
Where does blood from the liver drain into?
Inferior vena cava via the hepatic vein
Describe the functional anatomy of the liver
Couinaud classification
8 functionally independent segments (can resect a segment without bleeding and damaging the sounding)
Centrally= portal vein, hepatic artery, bile duct Peripherally= hepatic vein
Determined by blood supply
Each segment can be resected without damaging those remaining
What are the Couinaud segments?
Numbered clockwise from the posterior central caudate lobe
- 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)
What cell types are in the liver?
Hepatocytes (80%)= large cells with pale and rounded nuclei
Endothelial cells= lining blood vessels and sinusoids, fenestrated (allows lipids and other large molecules to move to and from hepatocytes)
Cholangiocytes (aka bile duct epithelial cells)= lining biliary structures
Kupffer cells= fixed phagocytes (liver macrophages), phagocytosis and secretion of cytokines that promote HSC activation (proliferation, contraction and fibrogenesis)
Hepatic stellate cells= Vitamin A storage cells (Ito cells), may be activated to a fibrogenic myofibroblastic phenotype and produce collagen, important in liver disease
Describe the micro-anatomy (histology) of the liver
Units known as lobules
Classical lobule is hexagonal and divided in concentric centrilobular, midzonal and periportal parts
Lobules consist of a central vein (which drains into hepatic veins- IVC) with radiating hepatocyte sheets
Round the edges of adjoining lobules are portal triads
- Hepatic arteriole
- Branch of hepatic portal vein
- Bile duct
Capillary sinusoids eventually drain into central vein
Between sheets of hepatocytes and capillary sinusoids are bile canaliculi (drain bile produced in hepatocytes into ductules which flow outwards into the portal triad)
Whats the difference between a lobule and acinis?
LOBULES
Lobules are HISTOLOGICAL units within the liver
Easily identified and are centred around central
veins which drain into the hepatic veins
ACINI
Acini are FUNCTIONAL units which are aligned around the portal triad, and divided into zones dependent on
their proximity to arterial blood supply
These are less easy to visualise
Unit of hepatocytes divided into zones dependent on proximity to arterial blood supply
What cells are flattened with dense cell nuclei that appear to be in the sinusoids?
Kupffer cells or hepatic stellate cells
What does the portal triad include?
Hepatic arteriole
Branch of hepatic portal vein
Bile duct
How does de-oxygenated, nutrient rich blood reach the liver?
Hepatic portal vein
How does oxygenated blood reach the liver?
Hepatic artery
Where do the hepatic portal vein and hepatic artery flow towards?
The central vein
What is an acinus?
Unit of hepatocytes divided into zones dependent on proximity to arterial blood supply
Cluster of cells like a ‘berry’
Demarcated by zone:
- Periportal
- Transition zone
- Pericentral
The terminal acinus is centred on the the portal tract and each hepatic acinusis centred on the line connecting two portal triads
Which zone of the liver receives the most oxygenated blood and why?
Periportal zone 1 is nearest to the entering vascular supply and receives the most oxygenated blood
Makes it least susceptible to ischaemic injury but most susceptible to viral hepatitis or hemosiderin deposition in haemachromatosis
Involved in gluconeogenesis, oxidation of fatty acids and cholesterol synthesis
Which zone of the liver receives the least oxygenated blood and why?
Zone 3 (pericentral) is least susceptible to ischaemic injury
Furthest from entering vascular supply
Involved in glycolysis, lipogenesis and P450 based drug detoxification
Where do canaliculus interface between?
Sinusoids (sinusoidal faces) and hepatocytes (lateral faces)
What produces bile?
Hepatocytes
Where does bile flow?
Secreted in bile canaliculi
Drain into ductules-> intralobular bile ducts-> right/left hepatic ducts-> join outside liver to form common hepatic duct
THEN EITHER…
-> Cystic duct drains the gall bladder
OR
-> Common bile duct unites with common hepatic duct-> forms COMMON BILE DUCT (joined by pancreatic duct before entering duodenal papilla)
Opposite direction to blood flow
What are the functions of the liver?
Bile production and excretion
Excretion of bilirubin, cholesterol, hormones, and drugs
Metabolism of fats, proteins, and carbohydrates
Enzyme activation
Storage of glycogen, vitamins, and minerals
Synthesis of plasma proteins, such as albumin, and clotting factors
How is the liver involved in carbohydrate metabolism?
SER
Mitochondria
Cytoplasmic enzymes
Glycolysis
= Glucose oxidation to form ATP and pyruvate
Pyruvate-> Krebs cycle-> more ATP
Glycogenesis
= Storage of excess glucose as glycogen
Glycogenolysis
=Breakdown of glycogen to glucose
Gluconeogenesis
= De novo synthesis of glucose
How is the liver involved in detoxification?
Lysosomes
SER
Metabolise, modify/detoxify exogenous compounds, e.g. drugs
How do biliary structures develop embryonically?
Liver bud gives rise to gall bladder bud
Eventually hepatic diverticulum/bud divides in the pars hepatic and pars cystica around 4 weeks
-> forms liver sites and necessary structures (particularly those that connect liver to gall bladder)
Cystic diverticulum (pars cystica)-> cystic duct and gallbladder by around 8 weeks
Why is the biliary system important?
Important in excretion of toxins and secretion of fats
Bile neutralises chyme and aids digestion of fats
What does the gall bladder do?
STORES
Serves as a reservoir of bile between meals
Stores 50ml-> released after meal for fat digestion
ACIDIFIES BILE
CONCENTRATES BILE
By H2O diffusion following net absorption of Na, Cl, Ca, HCO3
-> decreased intra-cystic pH
-> reduced volume of stored bile by 80-90%
How is the common bile duct formed and what does it do?
Cystic duct fuses gall bladder to the hepatic duct-> common bile duct
The common bile duct has a spiral muscular structure which twists/untwists
-On untwisting of the
duct and sphincter of Oddi, it becomes patent and secretes bile into the ampulla (in the 2nd part of the
duodenum)
At the ampulla, the CBD may also join the pancreatic duct
Why might structural abnormalities of the biliary tree affect digestion?
Bile neutralises chyme and aids digestion of fats
How can a biliary tree be seen?
ERCP (endoscopic retrograde choliographic pancreatography)
- A wire is passed through the spinchter of Oddi (along with a scope), and dye is injected to the see the branches of the bile ducts
- This can be used to see any obstructions, e.g. gall stones or tumours
- Is also good because as it is invasive, provides opportunity to solve problem found, e.g. removing the
obstruction
MRI
- Can also be used to observe the effects of gall stones or tumours on the biliary tree, e.g. dilation due to accumulation of bile, or constriction of the distal end of the bile duct
Describe how the liver has a role as a glucose buffer (i.e. the role of liver in glucose metabolism)
It is important to control blood glucose
After a meal, blood glucose increases and must be taken up into tissues
-> stored mainly as glycogen in muscle and liver
Between meals, liver glycogen breakdown (glycogenolysis) maintains blood glucose concentration
However a 24hr fast will deplete the glycogen store (only 80g), then blood glucose must then be increased by another pathway
What is gluconeogenesis?
The process of synthesising glucose from non-carbohydrate sources
CORI CYCLE
Glucose is broken down anaerobically in muscles into lactate
Lactate can be used by the liver to synthesise glucose (via pyruvate)
Requires 6 ATP and LDH (lactate dehydrogenase)
From lactate (rbc metabolism anaerobic, also muscle) Lactate-> pyruvate -> glucose
VIA DEAMINATION OR FROM TRIGLYCERIDES
Synthesised from AAs via deamination or from triglycerides
Alanine-> pyruvate-> glucose
Triglycerides-> glycerol-> glucose
What is the role of the liver in protein metabolism: synthesis?
Synthesis 90% plasma proteins (remainder are -globulins)
Makes 15-50 g/day
Importance of plasma proteins -binding/carrier function, plasma COP - oedema
Synthesis of blood clotting factors and dietary “non-essential” AAs by transamination
What is the role of the liver in protein metabolism: transamination?
Transamination= synthesis of dietary non-essential AAs from an alpha-keto acid precursor
Involves exchange of amino group (NH2) on an acid with a ketone group (=O) on another acid
E.g. pyruvic acid (keto acid) + glutamic acid (aa)-> alanine (AA) + a-ketoglutaric acid
What AAs don’t have a keto acid precursor?
Essential AAs
What is the role of the liver in protein metabolism: deamination?
Deaminate AAs prior to use as an energy source
Deamination is the conversion of an AA into the corresponding keto acid
= Remove amine group as ammonia
= Replaced with a ketone group
Deamination occurs primarily on glutamic acid because glutamic acid is the end product of many transamination reactions
-> NH3 (needs to be converted)
Why does ammonia need to be converted?
NH3 highly toxic – particularly to CNS
Liver converts NH3 to urea
Urea very water soluble, metabolically inert, non-toxic
Excreted in urine
What is the role of the liver in fat (triglyceride) metabolism?
Fat is the main energy store in body (100x glycogen)
-> Stored in adipose and liver
When glycogen stores full, liver can convert excess glucose and AAs to fat for storage
Metabolises fats as energy source (converts FA’s to AcetylCoA, by Krebs/TCA cycle in liver)
OR
Produces ketone bodies
Synthesise lipoproteins, cholesterol, phospholipids
How do ketone bodies provide energy?
Ketone bodies produced in the liver
Transported to other tissues and used as energy
Water soluble (no need for carriers)
Liver can convert 2 AcetylCoA -> acetoacetatic acid for transport in blood -> other tissues -> acetyl CoA -> energy
Ketone bodies= cetoacetate, beta-hydroxybutyrate and acetone (their spontaneous breakdown product)
How are lipoproteins synthesised by the liver?
Synthesis of lipoproteins required for lipid transport in aqueous environment
Contain triglycerides and
cholesterol core, with a phospholipid and protein coat (stabilising the lipid)
What are the lipoprotein types?
There are various types of lipoproteins depending on their composition:
VLDL = lots of triglycerides (IDL = intermediate density lipoprotein) LDL = high cholesterol and phospholipids (bad cholesterol) HDL = high protein coat (good cholesterol)
In decreasing density= HDL > LDL > IDL > VLDL
The lower the density, the larger the diameter
What is the difference between good and bad cholesterol?
LDL delivers cholesterol to tissues
HDL can transport it back to the liver for re-processing and/or disposal as bile salts
What does cholesteryl ester transfer protein (CETP) do?
Shuttles cholesterol from HDL to LDLs
So inhibiting it-> good for drugs to prevent atherosclerosis (but side effects in current attempts)
How is cholesterol synthesised?
Cholesterol= sterol nucleus synthesised from acetyl CoA (and dietary intake)
What is cholesterol used for?
Used in the synthesis of various compounds including steroid hormones and bile salts
Important in cell/organelle membrane structure
What are phospholipids?
Compound containing fatty acid, phosphoric acid and nitrogen containing base
Important in cell/organelle membrane structure
Where is bile formed and concentrated?
Continually secreted by liver
Stored and concentrated in gall bladder
How much bile can the gall bladder hold?
Holds 15-60ml
Concentrates bile salts
What are the major components of bile?
Bile salts (50% dry weight) Cholesterol Phospholipids (lecithin) Bile pigments (bilirubin, biliverdin) Bicarbonate ions and water
Separately, some components would be insoluble, but together, bile is stable solution
How are bile acids/salts made?
IN LIVER
Addition of carboxyl and hydroxyl groups to cholesterol (increases water solubility)
->Primary bile acids (from oxidation of cholesterol into cholic and chenodeoxycholic acids)
Conjugated with taurine or glycine -> bile acid conjugated in liver (->taurocholic and glycocholic acids)
This increases the water solubility further
IN GALL BLADDER
Bile acid conjugates stored/concentrated
Primary bile acids are de-conjugated and de-hydroxylated to form bile salt (ionised) conjugates (secondary bile salts)– involves bacteria in ileum
What is the function of bile?
Digestion/absorption fats (4 stage process)
Excretion variety substances via GI tract
Neutralise acid chyme from stomach
Explain bile secretion
Released into duodenum during digestion
Small amounts during cephalic and gastric phases due to vagal nerve and gastrin
In intestinal phase, CCK causes contraction of the gall bladder and relaxation of sphincter of Oddi
Describe enterohepatic recirculation
Active reabsorption of bile salts in terminal ileum
In addition, de-conjugatation and de-hydroxylation by bacteria make bile salt lipid soluble
(Lose
Why does bile excrete substances via the GI tract?
Liver breaks down/inactivates steroid and peptide hormones
Secreted into bile for excretion
Also performs similar role with variety of “foreign” compounds- usually drugs
Excretory route for excess cholesterol (lecithin allows more cholesterol in micelles)
Too much-> gall stones or lost in salts
EXCRETION OF BILE PIGMENTS
Bilirubin from breakdown of haem from old red blood cells (15% from other proteins)
Iron from haem removed in spleen and conserved
Porphyrin group reduced to bilirubin and conjugated to glucoronic acid in liver.
How can failure to excrete substances with bile lead to liver disease?
Bile pigment gallstones
What is the ‘larder’ function of the liver?
Storage of fat soluble vitamins (A,D,E,K).
- Stores sufficient 6-12 month except Vit K where store is small.
- Vit K is essential for blood clotting
Storage of iron as ferritin - Available for erythropoeisis
Storage Vit B12
- Pernicious (megaloblastic) anaemia, nerve demyelination
Glycogen and fat store
How does the liver have a role in protecting against bacteria?
Liver sinusoids contain tissue macrophages (Kupffer cells)
Bacteria may cross from gut lumen into blood
Kupffer cells destroy these and prevent bacteria entering the rest of the body
What is the liver’s role in calcium metabolism?
UV light converts cholesterol to Vitamin D precursor, which requires a double hydroxylation (to convert it to the active form)
First hydroxylation is in the liver (second in the kidneys)
Can lead to rickets if this fails
How does the pancreas develop embryonically?
A foregut derivative arising at the foregut-midgut junction
Dorsal and ventral buds
Duodenum rotates to form a C shape
- > Ventral bud (part of hepatobiliary bud) swings round to lie adjacent to the dorsal bud
- > Both buds fuse
Ventral bud duct becomes main pancreatic duct
How is the pancreas divided?
Subdivided into head, neck, body, tail and uncinate process
Where in the pancreas is islet tissue most abundant?
Islet tissue most abundant in tail
Describe the structure and location of the pancreas
5 regions
Lies mainly on the posterior abdominal wall extending from the C-shaped duodenum to the hilum of the spleen
Pancreatic juice reaches duodenum via main (and accessory) pancreatic ducts
How does pancreatic juice reach the duodenum?
Via main (and accessory) pancreatic ducts
The branches of the duct system of both the ventral and dorsal buds give rise to both exocrine (acinar) and exocrine (islets) tissue
What are the anatomical relations of the pancreas?
Main posterior relations are IVC, abdominal aorta and left kidney
Spleen lies supralaterally to the left, with left and right kidneys posterolaterally on either side (each associated with their own adrenal gland)
Close relations with (and supply from) coeliac and superior mesenteric arteries
What scans can be used to image the pancreas?
MRI
To image pancreatic tumour
Angiography
For assessing pancreatic disease
Contrast agent into blood supply (tumour needs blood supply to grow)
What are the endocrine roles of the pancreas?
Secretion into the blood stream to have effect on distant target organ
(Autocrine/Paracrine)
Ductless glands
2% of gland
Islets of Langerhans
Secretes insulin and glucagon (and somatostatin and pancreatic polypeptide)
-> Regulates blood glucose, metabolism and growth effects
What are the exocrine roles of the pancreas?
Secretion into a duct to have direct local effect
98% of gland
Secretion of pancreatic juice into duodenum via pancreatic duct/common bile duct
Digestive function
What is insulin?
Anabolic hormone
Promotes glucose transport into cells and storage as glycogen
Reduces blood glucose
Promotes protein synthesis and lipogenesis
What is glucagon?
Increases gluconeogenesis and glycogenolysis
-> increased blood glucose
What is somatostatin?
Hormone that inhibits growth hormone
‘Endocrine cyanide’
What percentage of the pancreatic gland is endocrine and exocrine?
Endocrine= 2% Exocrine= 98%
What kind of function does pancreatic disease affect?
May involve endocrine AND exocrine effects e.g. cystic fibrosis
What is the difference between exocrine and endocrine cells?
EXOCRINE
Ducts
Acini are grape-like clusters of secretory units
Acinar cells secrete pro-enzymes into ducts
ENDOCRINE Derived from the branching duct Lose contact with ducts- become islets Differentiate into alpha and beta cells secreting into blood Tail>head
What is the composition of islets?
IN ENDOCRINE TISSUE
α-cells (A)
Form about 15-20% of islet tissue
Secrete glucagon
β-cells (B)
Form about 60-70% of islet tissue
Secrete insulin
δ-cells (D)
Form about 5-10% of islet tissue
Secrete somatostatin
The islets are highly vascular, ensuring that all endocrine cells have close access to a site for secretion
What is pancreatic juice composed of?
Acinar cells= low volume, viscous, enzyme-rich
Duct and centroacinar cells= high volume, watery, bicarbonate-rich (so quite alkaline)
What is between the exocrine acini and endocrine islets?
Connective tissue with columnar epithelium lining the interspersed minor pancreatic duct (which fuse to form the major pancreatic duct)
Describe pancreatic bicarbonate secretion
Duct and centroacinar cells
Pancreatic juice is rich in bicarbonate
- 120 mM (mmol/L)
- pH 7.5-8.0
Neutralises acid chyme from the stomach
- > Prevents damage to duodenal mucosa
- > Raises pH to optimum range for pancreatic enzymes to work
Washes low volume enzyme secretion out of pancreas into duodenum
What are pancreatic acinar cells?
Large with apical secretory granules
Store inactive precursors in order to protect the tissue from auto-digestion
Describe the pancreatic duct cells
Small, pale with few granules
How does duodenal pH affect bicarbonate secretion rate in the pancreas?
More stomach contents squirted into it-> increased rate of bicarbonate
Pancreas working as much as possible around pH 3
Duodenal pH
Why does bicarbonate secretion stop when the pH is still acid in the pancreas?
Bile also contains bicarbonate and helps neutralise the acid chyme
Brunner’s glands secrete alkaline fluid
How is bicarbonate secreted (pancreas)?
- SEPARATION OF H+ AND HCO3-
Catalysed by carbonic anhydrase
CO2 diffuses into the duct cell from the blood, reacting with H2O to form H+ and HCO3
CO2 AND H2O HCO3
Simultaneously, Na+ moves down a concentration gradient between tight junctions (paracellular transport)
H2O follows
2. TRANSPORT OF H+ AND HCO3- OUT OF THE DUCT CELL Coupled exchange driven by electrochemical gradients (secondary active transport) The HCO3- is exchanged with Cl-
(Cl has a high lumen concentration compared to IC duct cell concentration so bicarbonate is transported into the lumen with Cl going into the cell)
H+ is exchanged with Na+, which has a higher blood conc compared with the cell conc so flows into the
cell and H+ is transported into the blood
- MAINTENANCE OF NA+ GRADIENT
Primary active transport using ATP
For step 2 (done using the Na/K exchange pump) - RETURNING OF THE K+ TO THE BLOOD AND CL- TO THE DUCT CELL
Via protein channels
K via K channel
Cl via Cl channel (CFTR)
What is the difference in the bicarbonate reaction in the stomach and pancreas?
The same reaction CO2 and H2O H+ and HCO3
Occurs in gastric parietal cells and pancreatic duct cells
In the stomach, the hydrogen goes into gastric juice and the bicarbonate into blood
In the pancreas, the bicarbonate is secreted into the juice and the hydrogen into the blood
What are the enzymes secreted by pancreatic juice?
ACINAR CELL ENZYME SECRETION
Enzymes for digestion of fat (lipases), protein (proteases) and carbohydrates (amylase) are synthesised and stored in zymogen granules
Zymogens= pro-enzymes
How is acinar cell enzyme secretion controlled (pancreas)?
Proteases are released as inactive pro-enzymes-> protects acini and ducts from auto-digestion
Pancreas also contains a trypsin inhibitor to prevent trypsin activation
Enzymes become activated ONLY in duodenum
How can auto-digestion result from pancreatic duct blockage?
Blockage of pancreatic duct may overload protection and result in auto-digestion (= acute pancreatitis)
How does pancreatic enzyme secretion affect protein digestion?
Protein digestion is started in the stomach by pepsin, which acts in acid conditions
When the chyme enters the duodenum, the pepsin is soon inactivated by the alkaline conditions
The pancreas produces a cocktail of proteases, all released as precursors
The duodenal brush border produces enterokinases-> cleaves trypsinogen between a valine and an isoleucine-> active form of trypsin-> can activate other proteases
All the proteases are fairly short lived as they are digested themselves
What is the difference between lipase and proteolytic/ other lipolytic enzymes?
Lipase secreted in active form but requires colipase, which is secreted as precursor
(Lipases require presence of bile salts for effective action)
Trypsin converts all other proteolytic and some lipolytic enzymes
How do pancreatic enzyme functions alter?
Pancreatic secretions adapt to diet e.g. high protein, low carbs, increases proportion of proteases, decreases proportion of amylases
Pancreatic enzymes (and bile) are essential for normal digestion of a meal
Lack of these can lead to malnutrition even if the dietary input is OK (unlike salivary, gastric enzymes)
How does Orlistat work?
Anti-obesity drug
Inhibits pancreatic lipases to limit intestinal fat absorption
-> Steatorrhoea (increased faecal fat) because pancreatic lipase secretion significantly reduced
How is pancreas secretion controlled?
INITIAL CEPHALIC PHASE
Pancreatic secretion begins before food enter the duodenum via a vagal reflex in response to the sight/smell/taste
of food
Involving cholinergic synapses which result in enzyme-rich component only
Low volume- mobilises enzymes
GASTRIC PHASE
When food arrives in the stomach-> stimulates pancreatic secretion
Same mechanisms as the cephalic phase
INTESTINAL PHASE (70-80% of pancreatic secretion) Hormonally mediated when acid chyme enters the duodenum from the stomach Hormones= secretin and CCK: cholecystokinin, into the blood Both components of pancreatic juice stimulated
How are bicarbonate secretion and enzyme secretion controlled?
Bicarbonate secretin is controlled by secretin release (involves cAMP)
Enzyme secretion is controlled by vagal reflex and CCK (cholecystokinin)
- In response to fats/proteins and stimulates enzyme secretion
- Also stimulates bile secretion
- Involves Ca2+ and PLC via vagus reflex
When do the cephalic and intestinal phases end?
Cephalic phase ends when meal is eaten
Intestinal phase ends with absorption of fats and peptides (removes the local luminal stimulus for CCK release)
How do pancreatic stimuli interact?
Synergistic interaction between CCK and secretin i
CCK alone= no effect on bicarbonate secretion
CCK combined with secretin= shows marked increase in bicarbonate secretion compared to secretin alone
Vagus nerve has similar effect to CCK
What effect does secretin have on enzyme secretion?
No effect
Outline the role of the pancreas during a meal?
Food mixed, digested in stomach, pH 2
-> Chyme squirted into duodenum
H+ ions in duodenum
- > Stimulate release of secretin
- > Stimulate release of pancreatic juice (plus bile and Brunner’s gland secretions) to raise pH to neutral/alkaline
Peptides and fat in duodenum
- > Cause sharp rise in CCK and vagal nerve
- > Stimulates pancreatic enzyme release (peaks by 30 mins, continues until stomach empty)
CCK potentiates effects of secretin on aqueous component (necessary because most of duodenum not at low pH)
What does the large intestine consist of?
Colon Cecum Appendix Rectum Anal canal
What is the cecum?
Blind pouch just distal to the ileocecal valve
Larger in herbivores
What is the appendix?
Thin, finger-like extension of the cecum
Not physiologically relevant in humans
Describe the function of the colon
Function= reabsorption of electrolytes and water, elimination of undigested food/waste
What are the dimensions of the colon?
1.5m long
6cm diameter
What are the parts of the colon?
ASCENDING
On the R side of abdomen
Runs from cecum to hepatic flexure
TRANSVERSE
Hangs off the stomach (attached by mesocolon)
Running from hepatic flexure to splenic flexure
DESCENDING
On the L side of abdomen
Runs from splenic flexure to sigmoid colon
SIGMOID
S shaped colon running from descending colon to rectum
What are the structural features of the colon?
Appendices epiploicae
Taeni coli
Haustra
Solitary nodules
What are appendices epiploicae?
Fatty tags of the peritoneum surrounding colon
Structural/functional purpose unknown- possible protective against intra-abdominal infections
What are taeni coli?
3 longitudinal bands running along length of colon
Important for large intestine motility
What are haustra?
Pouchings of the colon wall
Taenia coli are shorter than the length of the colon -> forms pouched avoid segments
What are the solitary nodules in the colon?
Nodules of lymphoid tissue in the wall of the colon
What is the blood supply to the proximal transverse colon?
Middle colic artery
Branch of the superior mesenteric artery
What is the blood supply to the distal third of transverse colon?
Inferior mesenteric artery
What does the different blood supply between the proximal transverse colon and distal third of the transverse colon reflect?
Embryological division between the midgut and hindgut
NB. Region between the two is sensitive to ischaemia
What are Peyer’s patches?
Nodules of lymphoid tissue
Common in the walls of the distal small intestines
(In large intestine= solitary nodules)
How does the colon have a role in (re)absorption?
Colon absorbs electrolytes and water
More in proximal colon
Na+ and Cl- absorbed by exchange mechanisms and ion channels
Water follows by osmosis
K+ moves passively into lumen
Large intestine can reabsorb approx 4.5 litres water (usually 1.5 litres)
Above this threshold = diarrhoea
Ions, vitamins and minerals
How much water can the large intestine reabsorb?
Approx 4.5 litres water (usually 1.5 litres)
What is the rectum?
Dilated distal portion of the alimentary canal
Terminal portion= anal canal
