Alimentary System Flashcards
What is digestion?
Break down of macromolecules to allow absorption (physical or enzymatic)
What is absorption?
Moving nutrient and water across a membrane
What are the components of the GI tract?
Mouth Oesophagus Stomach Liver (gall bladder) Duodenum Jejunum Ileum Colon Appendix Anus
What are the names of the salivary glands?
Sublingual gland
Parotid gland
Submandibular gland
What are the general symptoms of GI disease?
Anorexia
Weight loss
Anaemia
What is koilnychia?
Spooning of the nails
What is leuconychia?
Whitening of the nails
What is the biggest cause of disease in UK from a GI disease?
Liver cirrhosis
What proportion of hospital admissions are due to GI disease?
1/8
What are the major GI diseases worldwide?
1) Malnutrition
2) Enteric infections
3) Viral hepatitis and consequences
4) Gastric cancer
What are the major GI diseases in the UK?
1) Dyspepsia (indigestion)
2) Liver disease (due to alcohol and obesity)
3) Colon cancer
What are the main causes of abnormal liver function tests in the UK?
1) Chronic Hep B
2) Chronic Hep C
3) Alcohol-related steato-hepatitis
4) Obesity-related steato-hepatitis
What is Barrett’s oesophagus?
Where the squamous-cell epithelium of the oesophagus mucosa is replaced by metastatic columnar cells
What is the prevalence of gall stones? Who is most likely to suffer?
1/10
Middle-ages overweight women
What is the main cause of chronic pancreatitis?
Alcoholism
What is normally present in acute pancreatitis?
Ethanol accumulation and gallstones
How many people are affected by IBS?
1/3
What is the basic structure of the gut wall?
- Epithelium
- Lamina propria
- Muscularis mucosae
- Submucosa
- Muscularis
- Serosa / Adventitia
What is the lamina propria and what is contained in this layer?
Connective tissue containing capillaries, nerve endings etc
What are the submucosa and muscularis and what is contained in these layers?
Submucosa: Connective tissue
Muscularis: Smooth muscle
Both contain nerve plexus
What spinal levels does the oesophagus start and pass through the diaphragm?
Starts C5
End T10
What nerves are at risk during oesophageal surgery?
Recurrent laryngeal nerve
What epithelia make up the oesophagus lining?
Stratified squamous epithelia
What sphincters are present in the oesophagus and where are they? When are they open?
Upper oesophageal sphincter at the top
Lower oesophageal sphincter near the stomach
Permanently closed. Opened by the brain by active swallowing.
Upper closes as soon as food passes
Lower open for the whole duration of swallowing
What type of muscle is the upper oesophageal sphincter
Skeletal
What type of muscle is the lower oesophageal sphincter
Skeletal and smooth muscle
How does the peristalsis wave move food down the oesophagus?
Muscle above the food bolus is contracting and the muscle below is relaxing which pushes the food down the oesophagus.
Can have secondary wave if food does not pass down the first time
GRAVITY HAS NO IMPACT!
What is the gastro-oesophageal junction? How is acid reflux prevented at this point
The point where the oesophagus joins the stomach. Once swallowing reflex has passed the skeletal muscle of the diaphragm, the circular muscle of the lower oesophagus closes so food can’t pass back into the oesophagus. This is helped by the fact that the stomach is below the diaphragm so the pressure either side of the sphincter is equal. Less likely to get reflux
(Negative pressure above the diaphragm)
Why do you get bad acid reflux when pregnant?
Pushes stomach up so oesophagus only above the diaphragm where there is negative pressure. Pressure difference either side of the sphincter means acid reflux is more likely
What is the epithelial transition in the oesophagus? At what point does the transition occur>
Oesophagus has stratified squamous (abrasion)
Stomach has simple columnar (secretory)
Transition occurs at the zigzag line (Z) line
What are the folds of the stomach called? What is their purpose?
Rugae
Allows stomach volume to change drastically
Allows it to expand and contract
How does the process of belching occur?
You initiate a swallowing reflex which allows the air to escape
What is the function of the stomach?
Break down food into smaller particles stored (due to acid and pepsin); hold food and release at a controlled steady rate into duodenum; kill parasites and certain bacteria.
Where does mucus secretion occur in the stomach?
In the fundus, cardia, body and pyloric region
Other than mucus secretion, what occurs in the body and the fundus of the stomach?
HCl and pepsinogen secretion
What occurs in the antrum of the stomach?
Gastrin secretion
How does the stomach maintain a highly acidic concentration without it burning through the stomach lining?
Cells produce mucus which acts as a gel coating. They produce HCO3- which gets trapped in the mucus and neutralises acid
How much acid does the stomach produce?
2L/day
What is the pH of the epithelial lining and the stomach lumen?
Epithelial lining= 6-7
Stomach lumen= 1-2
What is the gastric chief cell? What does it produce?
Protein secreting epithelial cell with an abundant RER
Golgi packaging and modified for export
Masses of apical secretion granules
Secretes pepsinogen
What is the gastric parietal cell? What components contribute to H+ production? What is it’s structure?
Main acid producing cell in the body
Has many mitochondria which requires a lot of ATP, cytoplasmic tubulovesicles which contain H+/K+ ATPase and internal canaliculi which extend to the apical surface
When it switches to the active secreting state tubulovesicles fuse with membrane and microvilli project into canaliculi leading out into the lumen of the stomach.
How does a parietal cell produce H+?
1) Carbonic anhydrase converts H2O+CO2 to HCO3- and H+
2) Na+/K+ exchange in interstitial fluid/capillaries and then in stomach lumen (K+ into cell, into lumen)
3) HCO3- is exchanged for Cl- (Cl- into cell into lumen)
4) Mitochondria produce lots of ATP
5) H+/K+ ATPase exchange = lots of H+ in lumen)
How would inhibition of carbonic anhydrase influence acid secretion in the stomach?
It would decrease acid secretion
What is pepsinogen? How is it activated?
A inactive precursor.
An acidic environment causes a conformational change causing enzymatic activity within pepsinogen molecules, cleaving themselves to produce peptin
What does peptin digest?
Protein
The hardest thing to digest
What is gastrin? What does it do?
At very high pH gastrin secretion is suppressed (when stomach is empty)
When you eat protein stomach acid concentration drops which stimulates gastrin release. Gastrin stimulates acid secretion which in turn activates pepsin.
It can also stimulate histamine release from chromaffin cells (lamina propia) and histamine is also a powerful stimulus for acid secretion
What are the three phases of gastric secretion?
1) Cephalic phase
2) Gastric phase
3) Intestinal phase
What is the cephalic phase of gastric secretion?
The thought, sight, smell and taste of food activates the brain to have an effect on the stomach.
The vagus nerve (parasympathetic) is activated. Acetylcholine acts on chromaffin cells to stimulate secretion of histamine or acts directly on parietal cells.
What is the gastric phase of gastric secretion?
When food is in the stomach stretch (stretch receptors) stimulates the brain to initiate gastric secretion (production of more acid) via the vagus nerve (parasympathetic nerve)
The stretch is also detected by the enteric nervous system which also responds by initiating gastric secretions.
Chemoreceptors detect the chemical change in the gut have an effect (trigger) on gastrin secretion
What is the intestinal phase of gastric secretion?
Largely inhibitory
If pH is low or nutrients present signals sent to brian to switch off gastrin secretion
Enterogastric reflex: Low pH in chyme causes hormone production:
- Gastric inhibitory peptide
- Cholecystokinin
- Secretin
which pass via the blood back to stomach to switch off acid production
If there is undigested protein STIMULATION of gastrin
What are the enterogastrones?
Gastric inhibitory peptide
Cholecystokinin
Secretin
What is the excitatory component of the intestinal phase of gastric secretion?
Depends on the protein concentration in the duodenum.
If your stomach hasn’t effectively broken down the protein (high [protein] entering the SI) there is a stimulation of gastrin to increase acid production
What are two types of drug that would decrease acid secretion in the stomach?
1) Omeprazole: proton pump inhibitor, block H+/K+ ATPase pump
2) Ranitidine: Histamine receptor antagonist- blocks histamine receptor and prevents stimulation of acid secretion
What is the size of the SI and the size of each of the parts?
Approximately 6m long and 3.5cm in diamter
Duodenum: 25cm
Jejunum: 2.5m
Ileum: 3.75m
What is the mesentery?
Throws the SI into folds and supports the blood supply to the SI
What is the basic structure of the small intestine?
External wall has longitudinal and circular muscles (important for motility
Internal mucosa arranged in circular folds and is covered in villi (∼1mm tall)
Has invaginations known as Crypts of Lieberkuhn
What are villi? Where are they found? What is their structure?
Only occur in the small intestine. They are motile and have a rich blood supply and lymph drainage for absorption or digested nutrients. They also have a good innervation from the submucosal plexus.
Villi have simple epithelium (1 cell thick), dominated by enterocytes (columnar absorptive cells)
What cell type makes up the mucosa in the SI?
1) Primarily enterocytes (absorptive cells)
2) Scattered goblet cells
3) Enteroendocrine cells
What cells are found in the Crypts of Lieberkuhn?
1) Paneth cells
2) Stem cells
What are enterocytes? What is their function? What is their lifespan?
The most abundant cells in the SI. Tall columnar cells with microvilli and a basal nucleus
Specialised for absorption and transport of substances.
Short lifespan of 1-6 days
What are the functions of tight junctions in enterocytes?
Stops things moving between gaps in between cells. Also stops proteins in the phospholipid bilayer moving to different parts of the cell
What are microvilli? How many are there per cell? What if found on the surface of microvilli?
They make up the brush border (∼0.5-1.5μm high) (1/1000 a size of villi)
Several thousand microvilli per cell
Surface of microvilli is covered with glycocalyx
What is glycocalyx?
A rich carbohydrate layer on apical membrane that serves as protection from digestional lumen, yet it allows for absorption. It traps a layer of water and mucous known as the unstirred layer, which regulates the rate of absorption from the intestinal lumen
How big is the surface area of the small intestine?
Cylindrical internal surface area is 0.4m²
The volli and microvilli increase the surface area to ∼200m²
500 fold increase
What is the second most abundant cell type in the SI?
Goblet cells
What are enteroendocrine cells in the SI? What cell type are they? What is their role?
Columnar epithelial cells, scattered among the absorptive cells. Mostly found in the lower part of the crypts.
Hormone secreting (e.g. to influence gut motility)
a.k.a. Chromaffin cells
What are Paneth cells? What do they secrete? What are their roles?
Found only in the bases of the crypts. Contan large acidophilic granules containing:
- antibacterial enzyme lysozyme (protects stem cells)
- glycoproteins, and zinc (essential trace metal for a number of enzymes)
Also engulf some bacteria and protozoa
May have a role in regulating intestinal flora
What is the life span of cells in the epithelium of the SI?
Enterocytes and goblet cells have a short life span (about 36 hours)
Continually replaced by dividing stem cells in the crypts
Migrate up the villi and shed
What are the stem cells in the SI
Undifferentiated cells which remain capable of cell division to replace cells which die.
They are ESSENTIAL to continually replenish the GI surface epithelium
Continually divide by mitosis
Migrate up to top of villus, replacing older cells that die by apoptosis. At villus tips cells become senescent, sloughed into lumen and are digested and reabsorbed
Differentiate into various cell types (pluripotent)
Why is the lifespan of epithelial cells in the SI so short in comparison to other tissues?
Enterocytes are the first line of defence against GI pathogens and may be directly affected by 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
How does cholera infect a host?
The cholera enterotoxin results in prolonged opening of the chloride channels in the SI allowing uncontrolled secretion of water
Bodily fluid moves freely into the lumen and out, leading to rapid, massive dehydration and death
Treatment is rehydration. Cholera bacteria will clear as epithelium is replaced.
What characteristics are unique to the duodenum?
Distinguished by the presence of Brunner’s glands
- Submucosal coiled tubular mucous glands secreting alkaline fluid
- Open into the base of the crypts
Alkaline secretions:
- Neutralises acidic chyme from the stomach, protecting the proximal SI
- Help optimise pH for action of pancreatic digestive enzymes
What characteristic are unique to the jejunum?
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 jejunum tend to be taller, thinner and more frequent
What characteristics are unique to the ileum?
Shares some of the features with the large intestine
Has lots of Peyer’s patches (large clusters of lymph nodules in the submucosa)
Prime immune system against intestinal bacteria (bactericidal Paneth cells, rapid cell turnover)
Well positioned to prevent bacteria from colon migrating up to small intestine
What are the different cell types in the SI and their brief function?
Enterocytes - Absorption (most abundant) Goblet cells - mucous secreting Enteroendocrine cells - hormone secreting Paneth cells - antibacterial, protect stem cells Stem cells - cell turnover, pluripotent
What are the three functions of motility in the SI?
1) To mix ingested food with digestive secretions and enzymes
2) To facilitate contact between contents of intestine and the intestinal mucose
3) To propel intestinal contents along alimentary tract
What is segmentation?
MIXES the contents of the lumen
Segmentation occurs by stationary contraction of circular muscles at intervals
More frequent contractions in duodenum compared to ileum- allow pancreatic enzymes and bile to mix with chyme
Although chyme moves in both directions, net effect is movement towards the colon
What is peristalsis?
Involved sequential contraction of adjacent rings of smooth muslce
Propels chyme towards the colon
Most waves of peristalsis travel about 10cm (not the full length of the intestine)
Segmentation and peristalsis result in chyme being segmented, mixed and propelled towards the colon
What is the migrating motor complex?
In fasting = cycles of smooth muscle contractions
Each cycle = 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 the fed state- but less ordered and less frequent
What sphincter lies between the stomach and the duodenum?
Pyloric sphincter
What sphincter lies between the bile/ pancreatic duct and the duodenum?
Sphincter of Oddi
Hepatopancreatic sphincter
How do digestive enzymes and bile enter the duodenum?
Through the bile duct and pancreatic duct
How does digestion occur in the duodenum?
1) Bile and digestive enzymes enter the duodenum
2) Duodenal epithelium also produces its own digestive enzymes
Digestion occurs both in the lumen and in contact with the membrane
What type of absorption doesn’t use carrier proteins?
Passive diffusion
What type of absorption does require carrier proteins but does not require energy?
Facilitated diffusion
What type of absorption uses hydrolysis of ATP to move substances against the concentration gradient using a carrier protein?
Primary active transport
What type of absorption uses the electrochemical gradient to move substances against the concentration gradient using a carrier protein?
Secondary active transport
How and where does digestion of carbohydrates occur?
Digestion begins in the mouth by salivary α-amylase, but α-amylase is destroyed in the stomach (acid pH)
Most of the digestion of carbohydrates occurs in the small intestine
After being broken down by salivary and pancreatic α-amylase the products and simple carbohydrate digestion occurs at the membrane
Monosaccharides are absorbed into enterocytes
What is pancreatic α-amylase? When is it secreted?
Secreted in the duodenum in response to a meal
Continues digestion of starch and glycogen in the SI (started by salivary amylase)
Needs Cl- for optimum activity and neutral/slightly alkaline pH (Brunner’s glands in duodenum= alkaline secretion)
Acts mainly in the lumen (some also absorbed into brush border)
How are glucose and galactose absorbed? What is the carrier protein?
By secondary active transport (carrier protein and electrochemical gradient)
Carrier protein= SGLT-1 on apical membrane
How is fructose absorbed? What is the carrier protein?
Facilitated diffusion (carrier protein, no energy required) Carrier protein= GLUT-5 on apical membrane
What is better absorped? Glucose or fructose? Why?
Glucose? Uses energy for absorption unlike fructose which uses facilitated diffusion
What carrier protein facilitates movement of glucose across the basolateral membrane in the SI?
GLUT-2
How are proteins digested?
Begins in the stomach by pepsin, but this is inactivated by the alkaline duodenum
Pancreatic proteases are secreted as precursors
Trypsinogen is activated by enterokinase (duodenum) to trypsin, an enzyme located on the duodenal brush border
Trypsin then activates the other proteases (e.g. chymotrypsin, elastase)
Where is enterokinase found? What does it do?
In the duodenum
Activates trypsinogen to form trypsin
How are proteins absorbed?
Brush border peptidases break down the larger peptides prior to absorption.
Amino acids 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?
Lipids are poorly soluble in water. Four stage process in the SI:
1) Secretion of bile and lipases
2) Emulsification
3) Enzymatic hydrolysis of ester linkages
4) Solubization of lipolytic products in bile salt micelles
How does bile emulsification occur?
Bile and lipase are secreted into the duodenum. Bile salts facilitate the emulsification of fat inot suspension of lipid droplet (∼1μm diameter)
The function of emulsification is to increase the surface area for digestion. Allows pancreatic lipase to split triglycerides (into two fatty acids and a monoglyceride at fat/water interface)
What is the structure of a bile acid?
Amphipathic
Steroid nucleus planar- two faces
- Hydrophobic (nucleus and methyl) face dissolves in fat
- Hydrophobic (hydroxyl and carboxyl) face dissolves in water
What are bile salt micelles? What is their function?
Hydrophilic “head” regions in contact with surrounding solvent, sequestering the hydrophobic tail regoins in the micelles centre
Mixed micelles in small intestine = water insoluble monoglycerides from lipolysis are solubised by forming a core, stabilised by bile salts
What is the function of lipase? How does it work?
Lipase breaks down triglycerides into monoglycerides and free fatty acids.
It need to form a complex with colipase to work.
Colipase prevents bile salts from displacing lipase from the fat droplet
What are the lipid digestion enzymes?
1) Lipase (colipase)
2) Phospholipase A2
3) Pancreatic cholesterol esterase
What is the function of phospholipase A2?
Hydrolyses fatty acids at the 2 position in many phospholipids, resulting in lysophospholipids and free fatty acids
What is the function of pancreatic cholesterol esterase?
Hydrolyses cholesterol ester to free cholesterol and fatty acid
How are lipids absorbed in the SI?
Micelles are important in absorption- they are absorbed much quicker than an 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, but lipid absorption is usually complete by the middle of the jejunum
Bile salts are transported back to the liver for recycling (enterohepatic circulation)
What happens to lipids once they have been absorbed by enterocytes?
They are resynthesised into triglycerides
What are the two different pathways that resynthesise triglycerides in enterocytes after they have been absorbed?
1) Monoglyceride acylation pathway (MAJOR)
2) Phosphatidic acid pathway (minor)
What is the monoglyceride acylation 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 are esterified into diglycerides and triglycerides
What is the phosphatidic acid pathway?
Triglycerides are synthesised from CoA fatty acid and α-glycerophosphate
How are lipoproteins transported in the body?
In chylomicrons
How are chylomicrons produced? Where are they transported?
Lipoprotein particles are synthesised in enterocytes as an emulsion
80-90% triglycerides, 8-9% phospholipids, 2% cholesterol, 2% protein, trace carbohydrate
Chylomicrons are transported to the Golgi and secreted across the basement membrane by exocytosis
Too big to enter blood capillaries of villi so enter lacteals (lymph channels)
What is the function of the ileocaecal sphincter?
Separates the ileum and the colon
Relaxation and contraction controls the passage of material into the colon
Also prevents the back flow of bacteria into the ileum
Paneth cells
1) Are found at the villus tip
2) Secrete mucous
3) Contain acidophilic granules
4) Are pluripotent
5) Secrete enterokinase
3) Contain acidophilic granules
What ligament runs down the middle of the liver?
Falciform ligament
What are the four lobes of the liver?
Right lobe
Caudate lobe
Quadrate lobe
Left lobe
During liver development what parts of the embryo form the respective cells of the liver?
Endoderm: parenchymal cells
Mesoderm: connective tissue
What is the process of development of the liver?
∼29 days: Hepatic diverticulum of liver bud development (diverticulum invades septum transversum). Cell differentiation
∼30 days: Septum transversum forming liver stroma. Hepatic diverticulum forming hepatic trabeculae
∼32 days: Epithelial cord proliferation enmeshing stromal capillaries
∼33 days: Enlargement of the liver bud. Haematopoietic function appears
∼44 days: Bile ducts become reorganised (continuity between liver cells and gut)
∼44-56 days: Biliary ductules developed in periportal connective tissue and ductal plates form that receive biliary canaliculi
How many days into development is the liver bud first apparent? What Carnegie stage?
∼29 days
Carnagie stage 11
After how many weeks of development has the pancreas migrated to the posterior, left portion of the abdominal cavity/ coelom?
8 weeks
After how many weeks of development has the liver rotated round towards the right?
10 weeks
How much of cardiac output goes to the liver?
25%
What type of blood supply does the liver have? Wha vessels supply and drain it?
Dual blood supply
20% arterial blood from the hepatic arteries (left and right branches)
80% venous blood draining from the gut through the hepatic portal vein
Blood drains into the inferior vena cava via the hepatic vein
How many segments make up the liver?
8 segments
What is the Couinaud classification?
The dividing of the liver into 8 segments
What is the significance of the liver segments?
They each have their own blood supply. They can be resected without damaging those remaining
What liver segment is the caudate lobe?
Segment 1
What segments are on the far left side of the liver? Which is superior and which is inferior?
Superior 2
Inferior 3
What segments are next to segments 2 and 3 in the liver (superior and inferior)?
Superior 4a
Inferior b
What lobes are on the far right of the liver? Which is superior and which is inferior?
Superior 7
Inferior 6
What segments are next to segments 6 and 7 in the liver (superior and inferior)?
Superior 8
Inferior 5
What are the different cell types in the liver? What is their brief function?
1) Hepatocytes 80% 2) Endothelial cells Lining blood vessels and sinusoids 3) Cholangiocytes (bile duct epithelial cells) Lining biliary structures 4) Kupffer cells Fixed phagocytes (liver macrophages) 5) Hepatic stellate cells Vitamin A storage cells (Ito cells) may be activated to a fibrogenic myofibroblastic phenotype
What cell would have a flattened, dense cell nuclei that appears to be in the sinusoids?
Kupffer cell (in hepatic sinusoid) OR Hepatic stellate cell (next to hepatocytes)
What do hepatic cells radiate around?
A central vein
What is the function of hepatic stellate cells in the liver?
Vitamin A storage
Activation=ECM production (fibrogenesis)
What is the function of sinusoidal endothelial cells in the liver?
Fenestrated- allows lipid and other large molecule movement to and from hepatocytes
What is the function of Kupffer cells in the liver?
Phagocytosis (including RBC break down)
Secretion of cytokines that promote HSC activation- proliferation, contraction and fibrogenesis
What is a liver lobule comprised of?
6 portal triad - Bile duct - Branch of hepatic portal vein - Branch of hepatic artery Flowing to the central canal which leaves the liver forming a hexagonal structure
Where are the portal tracts in the liver?
Around the adjoining lobules
What are portal tracts comprised of?
1) An arteriole
2) A branch of the portal vein
3) A bile duct
What vessels supply the liver and where does the blood flow?
Deoxygenated nutrient rich blood from the portal vein
Oxygenated blood from the hepatic artery
Flows towards the central vein
What is an acinus in the liver?
A functional unit between two central veins and two portal triads.
Divided into zones dependent on proximity to arterial blood supply
3- Closest to central vein
2- In between 1 and 3
1- In between the two portal triad
Which zone in an acinus is most susceptible to ischaemia?
Zone 3
Which zone in an acinus is most susceptible to viral hepatitis?
Zone 1
What cells produce bile, how do they get to the bile duct and in what direction?
Hepatocytes produce bile
Flows along the canaliculus to the bile duct in the opposite direction to blood flow
What are the functions of the liver?
1) Protein metabolism
2) Carbohydrate metabolism
3) Lipid metabolism
4) Detoxification
How is the liver involved in protein synthesis and metabolism?
RER: synthesis of non-essential amino acids, albumin, clotting factors etc
Golgi apparatus: packaging for secretion
Deamination of amino acids: amino group to urea cycle (cycle enzymes situated in cytoplas of hepatocyte. Carbon skeleton reused (glucose and lipid metabolism
How is the liver involved in carbohydrate metabolism?
Has SER, mitochondria and cytoplasmic enzymes
- Glycolysis: glucose oxidation to form ATP and pyruvate (pyruvate→Kreb’s 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 lipid metabolism?
Has SER, peroxisomes and mitochondria
- Triglyceride metabolism: synthesis of fatty acids converted to triglycerides and lipoproteins for transport to cells requireing energy (FA β-oxidation). Digested triglyceride chylomicron remnants processed into lipoproteins (including cholersterol)
- Bile acid (+Na=salt) production
How is the liver involved in detoxification?
Has lysosomes and SER
Metabolises, modifies/ detoxifies endogenous compounds e.g. drugs
How does the gall bladder and cystic duct develop? How far into embryogenesis does this occur?
∼4 weeks: The hepatic bud (diverticulum) divides in the pars hepatica and pars cystica.
∼8 weeks: The pars cystica develops into the gall bladder and cystic duct
From hepatocytes what vessels does bile travel through to reach the gall bladder?
Hepatocytes Bile canaliculi Interlobular bile ducts Right/left hepatic ducts Common hepatic duct Cystic ducts Gallbladder
From the gall bladder what is bile transported through to reach the small intestine?
Gallbladder
Common bile duct
Ampulla vater
Small intestine
What functions does the liver have a key role in?
Digestion
Biosynthesis
Energy metabolism
Degradation / Detoxification
Where is glucose stored as glycogen?
In the liver and in muscles
How long can liver glycogen stores last? How much is there?
24 hours (fasting) 80g
What is the Cori cycle?
Method of recycling lactate from muscle (to the liver) and made into glucose (then back to muscle) Muscle: Glucose→2Pyruvate (2ATP) 2 Pyruvate⇌2Lactate Liver: 2Lactate⇌2Pyruvate 2Pyruvate (+6ATP)→Glucose
What reactions occur during gluconeogenesis?
The Cori cycle
Deamination of amino acids
How does deamination of amino acids produce glucose?
Alanine→Pyruvate→Glucose
or from triglycerides:
Triglycerides→Glycerol→Glucose
How many calories are produced from carbohydrate and fat?
Carbohydrate: 120kcal per mole oxygen
Fat: 100kcal per mole oxygen
How much protein is synthesised by the liver per day?
90% of plasma proteins
15-50g/day
What proteins does the liver synthesise?
Plasma proteins- binding/carrier proteins, plasma COP- oedema
Blood clotting factors
Dietary “non-essential” amino acids by transamination
What occurs in a transamination reaction?
The exchange of an amine group from an amino acid to a keto-acid
Why is gluatamic acid important?
It is an important intermediate for essential amino acids which do not have appropriate keto acid precursors
It is the end product of many transamination reactions
Where and how does deamination occur?
Muscle: Glucose→2Pyruvate (2ATP) 2Pyruvate→2Alanine (transamination) (α-amino acid→α-keto acid) 2Alanine transported to liver: 2Alanine→2Pyruvate (deamination) NH₃ (+4ATP) →Urea 2Pyruvate (+6ATP)→Glucose
What happens to the NH₃ produced in the deamination reaction?
NH₃ is highly toxic (particularly to the CNS) so it is converted to urea
2NH₃ + CO₂ (+4ATP) → Urea + H₂O
Urea is very water soluble, metabolically inert, non-toxic. It is excreted in the urine
How does the liver metabolise fat?
Fat main energy store in the body (100xglycogen). When glycogen stores are full the liver can convert glucose and amino acids to fat for storage
1) Converts FAs to acetyl CoA (TCA cycle)
2) Converts acetyl coA to acetoacetate for transport in the blood to other tissues where it can produce energy
3) Synthesises lipoproteins, cholesterol and phospholipids
Where is fat stored in the body?
In adipose tissue and the liver
What is the process of fat metabolism?
Fat is stored as triglyceride, broken down to fatty acids and transported to the liver.
In mitochondria they undergo β-oxidation to produce Acetyl-CoA and then enter the TCA cycle or produce ketone bodies
What hormones stimulate break down of triglycerides into fatty acids!
Glucagon
Adrenaline
Glucocorticoids
How are fatty acids transported to the liver?
Bound to albumin
Why are ketone bodies produced during fat metabolism?
To provide energy for the brain and extrahepatic tissue
What ketone bodies are produced to provide energy for tissues?
Acetoacetate
3HMG-CoA
What enzyme converts ketone bodies to a usable source? Where is this NOT found?
Thiophorase
Not found in the liver
Why are lipids converted into lipoproteins?
To allow them to be transported in the blood as they are normally hydrophobic
How can triglyceride reach the liver? (From what sources?)
1) From adipose tissue- converted to NEFAs then fatty acids then triglycerides
2) Directly from the diet as sugars which can be converted to new fatty acids then triglycerides
3) From the gut, via chylomicrons which can be converted to triglycerides
What does the liver produce from triglycerides to allow easy transport in the blood?
(Lipoprotein synthesis)
VLDLs (Very low denisity lipoproteins)
Converted to VLDL TAG which can be converted to fatty acids
What is the content of VLDLs?
Large amount of triglycerides
What is the content of LDL?
High cholesterol and phospholipid (causes atherosclerosis)
What is the content of HDL?
High protein content
What is the largest lipoprotein? (to smallest?)
VLDL
IDL
LDL
HDL
What is cholesterol used for?
Used in synthesis of various compounds including steroid hormones and bile salts
How much bile is stored in the gall bladder?
15-60ml
What is bile made up of?
Bile salts (50% dry weight) Cholesterol Phospholipids (lecithin) Bile pigments (bilirubin, biliverdin) Bicarbonate ions Water
How is bile produced?
Cholesterol (addition of carboxyl and hydroxyl groups)
(Chenodeoxy) Cholic acid (primary bile acid) (Conjugation with taurine or glycine)
Bile acid conjugates transported to gall bladder
Secreted into duodenum (Bacteria in the ileum deconjugate and dehydroxylate primary bile salts to form secondary bile salts
What is the primary bile acid?
(Chenodeoxy) cholic acid
What is the function of bile?
Digestion/absorption or fats
Excretion variety substances via GI tract
Neutralise acid chyme from stomach
When is bile secreted?
Released into duodenum during digestion. Small amounts during cephalic phase, gastic phases due to vagus nerve and gastrin
Intestinal phase, cholecystikinin causes contraction of gall bladder and relaxation of sphincter of Oddi
How does bile assist in the digestion and absorption of fats?
Lipids are poorly soluble in water which makes them more complicated to digest
1) Secretion of bile and lipases
2) Emulsification (by bile salts)
3) Enzymatic hydrolysis of ester linkages between lipids
4) Solubization of lipolytic products in bile salt micelles
What is the process of enterohepatic recirculation?
Active reabsorption of bile salts in terminal ileum. In addition, deconjugation and de-hydroxylation by bacteria make bile salt lipid soluble.
Recirculate via hepatic portal vein back to the liver. Hepatocytes avidly extract bile salts- one pass clears all
Bile salts are reconjugated and sone rehydroxylated before reuse
How much bile salts are actually lost (not taken into enterohepatic recirculation)?
How many times is the bile salt pool secreted per meal?
Twice
How is bile involved in excretion of substances via the GI tract?
Liver breaks down or inactivated steroid and peptide hormones. They are then 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.
Excretion of bile pigments. Bilirubin from breakdown of haem from old erythrocytes.
Porphyrin group reduced to bilirubin and conjugated to glucoronic acid in liver
What can cause gall stones?
Too much cholesterol
Liver disease- bile pigment gall stones
Where is iron from old erythrocytes removed and conserved?
In the spleen
What is stored in the liver? How long do they last?
Fat soluble vitamins- A, D, E → 6-12 months (K but small store as used constantly for clotting factors)
Storage of iron as ferritin (available for erythropoiesis)
Storage od vitamin B₁₂- pernicious (megaloblastic) anaemia, nerve demyelination
Glycogen and fat stores
What vitamin has very small stores due to frequent use to produce clotting factors?
Vitamin K
How is iron stored in the liver?
As ferratin
What is a deficiency in vitamin B₁₂ associated with?
Pernicious anaemia
Nerve demyelination
How is the liver involved in protection?
Liver sinusoids contain Kupffer cells (macrophages). Bacteria may cross from gut lumen into blood. Kupffer cells destroy these and prevent bacteria entering the rest of the body
How is the liver involved in 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
Where does the first hydroxylation of cholesterol to produce vitamin D occur?
Liver
Where does the second hydroxylation of cholesterol to produce vitamin D occur?
Kidney
What disease affecting the liver present with low calcium?
Rickets
How does the pancreas develop?
A foregut derivative arises at the foregut-midgut junction
Dorsal and ventral buds form. The ventral bud is part of the hepatobiliary bud
The duodenum rotates to form a C shape, the ventral bud swings round to lie adjacent to the dorsal bud, and both buds fuse
The ventral bud becomes the main pancreatic duct
What are the different sections of the pancreas?
Uncinate (hook like) Head Neck Body Tail
Where are islets most abundant in the pancreas?
In the tail
Where is the pancreas located n the body?
Lies mainly on the posterior abdominal wall extending from C-shaped duodenum to hilum of the spleen
Main posterior relations are IVC, abdominal aorta and left kidney
Where does the pancreas get it’s blood supply?
From the coeliac and superior mesenteric arteries
What are the endocrine functions of the pancreas?
Secreting into the blood stream to have an effect on distant target organs
What are the exocrine functions of the pancreas?
Secretion into a duct to have a direct local effect
What are the main endocrine secretions of the pancreas?
Insulin
Glucagon
Somatostatin: Endocrine cyanide
What is the function of insulin?
Anabolic hormone, promotes glucose transport into cells and storage as glycogon, reduces blood glucose, promotes protein synthesis and lipogenesis
What is the function of glucagon?
Increases gluconeogenesis and glycogenolysis
What is the function of somatostatin?
Inhibits the action of most hormones and physiological processes
How much of the pancreas is involved in endocrine and exocrine function?
Endocrine: 2%
Exocrine: 98%
Describe the endocrine function of the pancreas
Islets of Langerhans secrete hormones into the blood- insulin and glucagon (also somatostatin and pancreatic polypeptide). Regulates blood glucose, metabolism and growth effects
Describe the exocrine functions of the pancreas
Secretes pancreatic juice into duodenum via pancreatic duct/common bile duct.
Digestive function
If you have pancreatic disease what part of pancreatic function would be affected?
Both endocrine and exocrine
What cells are involved in exocrine function of the pancreas?
Acini: grape like clusters of secretory units (into ducts)
Acinar cells secrete pro-enzymes into ducts
How do the endocrine cells connect to the duct system of the pancreas?
They are derived from the branching duct system but they lose contact with the ducts and become islets.
They differentiate into α- and β-cells secreting into the blood
What is the composition of each cell type in the islets?
β-cells: 60-70% → insulin
α-cells: 15-20% → glucagon
δ-cells: 5-10% → somatostatin
Islets are highly vascular ensuring all endocrine cells have close access to a site for secretion
What are the type cell types involved in the production of pancreatic juice?
1) Acinar cell (blind ends C)
2) Duct cell (ducts =)
C======
What are the two components of pancreatic juice?
Bicarbonate
Enzyme
What component of pancreatic juice do acinar cells produce?
Low volume, viscous, enzyme-rich component
What component of pancreatic juice do duct and centroacinar cells produce?
High volume, watery, HCO₃⁻-rich component
Describe the bicarbonate component of pancreatic juice?
Produced by duct and centroacinar cells.
It is rich in bicarbonate ∼120mM (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 and into duodenum
Why does bicarbonate secretion stop when the pH of chyme is ∼5 (still acidic)?
Bile also contains bicarbonate and help neutralise the acid chyme
Also Brunner’s glands (in small intestine) also secrete alkaline fluid
How is HCO₃⁻ produced in the pancreas?
1) CO₂ diffuses into duct cells and reacts with water (catalysed by carbonic anhydrase) to produce HCO₃⁻ and H⁺
2) HCO₃⁻ is then pumped into the lumen (HCO₃⁻/Cl⁻ exchanger)
3) H⁺ pumped into blood, exchanged with Na⁺
4) Na⁺K⁺ATPase pumps Na⁺ back into the blood and K⁺ into the duct cell
5) K⁺ channel returns K⁺ to blood
6) Cl⁻ returns to the lumen via Cl⁻-channel
7) Na⁺ moves down the gradient via paracellular (“tight” junctions). H₂O follows
How does cystic fibrosis cause pancreatic dysfunction?
Cl⁻-channel is dysfunctional, so you get a concentrated pancreatic juice
How does the production of juice in the stomach and the pancreas relate?
In the stomach: H⁺ goes into gastric juice and HCO₃⁻ into the blood. Gastric venous blood is alkaline
In the pancreas: HCO₃⁻ goes into pancreatic juice and H⁺ into the blood. Pancreatic venous blood is acidic
What enzymes are produced for fat, protein and carbohydrate digestion and where are they stored in the pancreas?
Fat: lipases
Protein: Proteases
Carbohydrate: Amylase
Synthesised and stored in zymogen granules
What are zymogens?
Pro-enzymes
Inactive form of an enzyme
How are pancreatic enzymes released to prevent auto-digestion?
Proteases are released as inactive pro-enzymes to protect acini and ducts.
Pancreas also contains a trypsin inhibitor to prevent trypsin activation
Enzymes are only activated in the duodenum
What problem arises from blockage of pancreatic duct?
May overload protections and result in auto-digestion
Acute pancreatitis
What does enterokinase do? Where is it secreted?
Converts trypsinogen to trypsin
Secreted by duodenal mucosa
What is the function of trypsin?
Activated enzymes in pancreatic juice
Lipase is secreted in it’s active form. What prevents lipase from initiating auto-digestion?
Requires the presence of colipase which is secreted as a precursor
Also requires the presence of bile salts
What causes altered pancreatic enzyme secretion?
Pancreatic secretion adapt to diet (e.g. high protein, low carbs = ↑ proportion of proteases, ↓ proportion of amylases)
What is the mechanism of Orlistat?
Inhibits pancreatic lipases- prevents lipid digestion therefore can’t absorb it and causes steatorrhoea
