Hepatitis:

HBV- o 32nm virus o 350 mil chronically infected o 1 mil deaths/yr o Most prevalent in northern south America, Africa and Asia, and least prevalent in southern south America, UK and Australia – however due to increasing UK immigration, rates in the UK are rising

Outcome of HBV infection  <1%

infection, 90% self-limiting infection and 10%

HCV-

Most prevalent in

Highly stigmatized – as associated with

Outcome of HCV infection: 20% self-limiting infection  80% persistent infection – with 20% progressive and 80% of cases being non-progressive

Dyspepsia- i.e.

 Common reason for primary/secondary consultations  High risk for complications  40% prevalence in adults, with 26% experiencing symptoms on a weekly basis but only 2% consulting their GP

Related to GORD (gastro-esophageal reflux disease) o associated with

GORD may potentially lead to the development of complications such as strictures (4-20%), oesophageal ulceration, bleeding + perforation

2-7% of GORD patients will go on to develop an

leading to chronic oesophigitis

Chronic oesophagitis is generally regarded as the primary cause of

and the epithelial changes that occur have been linked to a substantially increased risk of oesophageal carcinoma

Barrett’s oesophagus occurs in 10-15%, and results in epithelial changes in which the squamous-cell epithelium of the oesophageal mucosa is replaced by metatastic

cell.

o There is also an association between symptomatic GORD and oesophageal adenocarcinoma, independent of Barrett’s oesophagus  The development of oesophageal adenocarcinoma instead of oesophageal carcinoma is linked to an increased frequency, severity and duration of GORD symptoms  However the absolute risk of developing adenocarcinoma is still very low (1/2 mil)

Helicobacter pylori related-

gram-

spiral bacterium which colonises the gastric mucosa

Infection persists for life unless treated

Helicobacter related disease –

o 85% no long-term effects o 14% peptic ulceration o 1% gastric adenocarcinoma/lymphoma

Duodenal ulcer – caused by helicobacter pylori + NSAIDs o Affects up to 10% of the population o Estimated to cause up to 2000 UK deaths o Main complication = perforation + bleeding

Cancer in the GI tract

Prevalent in the UK: colorectal, oesophageal, pancreatic, stomach + liver

Liver cancer o May be primary or secondary o Primary liver cancer arise in liver cells, e.g. hepatocellular + cholangio carcinomas – more prevalent in association with cirrhosis o Secondary liver cancer is metastatic cancer from other primary locations; is more common in the UK but results in later detection o Primary liver cancer can be detected at an early stage by

Pancreatic cancer-

95% adenocarcinoma of the

Inflammatory conditions:

Ulceratic colitis + Crohn’s disease o UK prevalence 150,000 people o 8,500 new diagnosed cases/yr o Ulceratic colitis only affectsthe colon and rectum, and may have an acute presentation; ulcerative cholitis with associated toxic megacolon (rapid dilation of the colon) o Crohn’s disease results in transmural inflammation, structures and fissures at any part of the GI tract

Coeliac disease o Common in the west o Prevalence of 1/1000 o Caused by gluten sensitivity, with an HLA related aetiology o Results in subtotal villi atrophi, with associated malabsorption

Pancreatic diseases

Acute pancreatitis o Mid to life-threatening o Blockage of the pancreatic duct results in a back-up of pancreatic enzymes causing severe

Ethanol accumulation + gallstones also present in 80% cases

Chronic pancreatitis o Results in permanent damage to the pancreas, which may greatly impair quality of life o Main cause alcoholism

Intestinal diseases  Diarrhoea prevalence worldwide = 200 mil  Water + foodborne infections caused by viruses, bacteria + parasites – clean water supply essential!

Large bowel diseases  Irritable bowel syndrome (IBS)  Affects 1/3 population  Only about 1 in 10 people seek GP

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

Conduit from getting 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. This is under

Where the phaynx becomes the oesophagus is

and ends at

The oesophagus passes very close to the recurrent laryngeal nerves + the pericardium. These may be damaged in excessive oesophagus extension.

Design specifically for function; the lining needs to be designed for “wear and tear” existence =

epithelium

o Non-keratinising – therefore moist o Lubricated by mucus secreting gland o Many layers act as protective layer if surface layer damaged o 2 sphincters – most of the pressure within the oesophagus is <atm (which means food wants to backtrack up) so these prevent this

The swallowing centre within the medulla opens the upper oesophageal sphincter under parasympathetic control via

There is a fair amount of skeletal muscle in the upper oesophagus, but this decreases as it descends – this leaves an element of voluntary control within the upper half

When food has entered and the upper oesophagus sphincter is

the bolus of food is moved down the oesophagus by peristalisis (purely under muscular control, gravity has no effect)

Circular muscle is major driver of the movement. The muscle just superior to the bolus contract, whereas the one in front/inferior relaxesrhythmic contraction down the oesophagus

If food gets stuck half way down, the swallowing centre can start

Gastro-oesophageal junction:

At the

stratified squamous lining of the oesophagus gives way to the simple columnar epithelium of the stomach

Lower sphincter resides here – the sphincter isn’t really one as such; there are 3 contributing mechanisms which lead to the sphincter action o The pressure difference between the abdominal oesophagus + stomach o Contraction of the diaphragm o As the stomach expands, it compresses the Z-line

The acidic content being ejected into the oesophagus-

When the stomach is empty, there are gastric folds =

As the stomach distends, there is not great change in pressure but the rugae expand. This is important in preventing reflux

Main function is to

The small intestine is approximately

long and 3.5 cm in diameter. The duodenum is

The jejunum is 2.5m long and the ileum is

Mesentery is fan shaped and throws the small intestine into folds and supports blood supply

The circular folds become progressively less prominent from proximal to distal

Digestive epithelium:

External wall has longitudinal and circular muscles- important for

Internal mucosa is arranged in circular folds. The mucosa are covered in villi and the invaginations are known as

Cell types:

Mucosa are lined with

They are the most abundant cells in the small intestine. They're tall columnar with microvilli and a

nucleus. It's specialised for absorption and transport, they have a

lifespan of 1-6 days

Tight junctions whose permeability changes as you move down the alimentary tract

Scattered goblet cells:

Second most epithelial cell type

Mucous containing granules accumulate at the

end of the cell causing a

Mucous is a large

that facilitates the passage of material through the bowel.

Abundance of goblet cells along the entire length of the bowel increases i.e few in

but many in the colon

Enteroendocrine cells:

Columnar epithelial cells scattered among the absorptive cells. In the intestine they are found in the lower part of the

Hormone secreting cells which influence gut motility

They sense what is going on in the gut and release hormones from their basal side into the bloodstream

They're known as

Microvilli:

Glycocalyx is a carbohydrate layer on top of the villi that attracts a layer of water and mucous known as the

The carbohydrate layer on the apical membrane also serves as protection from the digestional lumen

Makes up the brush border.

In crypts of Lieberkuhn-

Paneth cells:

Found only in the

of crypts

Contain very large acidophilic granules which contain:

Antibacterial enzyme lysozyme and glycoproteins and zinc

They're also able to engulf some bacteria and protozoa and have a role in regulating gut flora

Stem cells:

Epithelial cells are essential in the GI tract to continually repair the surface epithelium

They continually divide by mitosis and migrate to the

of the villus replacing older cells that die by apoptosis

At villus tips, cells become senescent (aged), sloughed into the

of the intestine and are digested and reabsorbed

Motility:

Digestion and absorption- Villi occur only in

Motile have a rich blood supply and lymph drainage for absorption of digested nutrients. They have good innervation from the

They have simple epithelium and dominated by enterocytes

Function = break down

of food, hold food and release it at a controlled rate into the

+ kill parasites/certain bacteria

Structure – several regions: cardia, fundus, body, antrum + pyloris

The sphincters of the stomach remain closed post-eating for about

before it is released into the duodenum. During this period the bolus is churned steadily

Secretions:

Cardia + pyloric –

Body + fundus –

Antrum – gastrin

The slightly different secretory functions of the different regions of the stomach – the epithelium may be slightly different

All regions have mucus producing cells – mucin “mops up” excess acid

HCl produced by

cells. Endocrine cells produce

Acid production – 2L/day, 150mM [H+] o Epithelial surface pH=6-7 (neutralised by bicarbonate ions trapped in mucus) o Lumen pH

Chief cell- Cell that produces

Well designed for

-large amounts of RER, golgi + secretion granules o Pepsinogen passes through gastric pit into stomach

Parietal cells – acid producing cell o Seen in the resting state, many mitochondria (requires vast ATP to conc H ions by 3mil X than blood – very active process)  ATP used predominantly by H/K ATPase within cytoplasmic tubulovesicles  Important structure = internal canaliculi – internal reservoirs

Active state – tubular vesicles fuse with

which also fuse to form large open reservoir extending to the apical surface; H+ then diffuses out through the stomach

On basolateral membrane, there is a Na/K pump which pumps K into cell; this passively diffuses into lumen.  H+ ions generated by

from the readily available CO2 + H2O

The H+ ions are actively secreted into the reservoir in exchange for

All of the bicarbonate ions are exchanged out of the cell for Cl entry, which also diffuses into the reservoir  The H+ and Cl- ions then bond to form HCl

Protein concentrations –

H/K ATPase + carbonic anhydrase

Pepsinogen – interacts with HCL to form

via autocatalytic process.

The pepsinogen on its own has conformation with internal active site which is protected, the

environment exposes the active site. Pepsin itself then further catalyses its own production once the active site is exposed (positive feedback) o Pepsin is a

Gastrin- endocrine product of the stomach

Produced predominantly in the

One of its major action is to stimulate

release from

cells within the lamina propria

Together, these then increase acid production in the stomach o There is a sort of negative feedback system, as the stomach gets more acidic – gastrin secretion is inhibited

The pancreas derives as part of the

arising at the foregut-midgut junction

Composed of both a dorsal and ventral bud with the ventral bud being part of the hepatobiliary bud

Ventral and dorsal pancreatic buds fuse with what was originally the ventral bud now being called the

The development also explains why there is an accessory pancreatic duct because the pancreas originally was two separate structures. Ventral bud becomes main

Look at structure

Endocrine function is more concentrated in the

Portal vein forms behind the head of the pancreas and gets trapped between uncinate process and neck region

Portal vein formed from SMV and splenic vein

Lies mainly on posterior abdominal wall extending from C-shaped duodenum to hilum of

Pancreatic juice reaches duodenum via main and accessory pancreatic

Main posterior relation are IVC, abdominal aorta and left kidney with the pancreas also having close relations with coeliac and superior

- Secretion into blood stream to have effect on distant target organ

Secretion into a duct to have direct local effect

Insulin- Anabolic hormone, promotes glucose transport into cells and storage as glycogen, reduces blood glucose, promotes protein synthesis and lipogenesis

Glucagon- Increases gluconeogenesis and glycogenolysis

Somatostatin- Endocrine cyanide- brutal

Endocrine-

of the gland - Islets of Langerhans, secretes hormones into blood

Exocrine-

of the gland- Secretes pancreatic juice into duodenum via pancreatic duct/common bile duct

Duct system of the pancreas:

Exocrine: Ducts, acini are grape-like clusters of secretory units, acinar cells secrete pro-enzymes into ducts

Endocrine: Derived from branching duct system, differentiate into alpha and beta cells secreting into the blood, more endocrine function from

Pancreatic acinus- Small sac like cavity in the pancreas containing

cells that secrete low volume high viscous enzyme rich fluid, there are also duct and centrocinar cells that secrete high volume watery

into the lumen

Components of pancreatic secretion (exocrine):

bicarbonate- Duct and centroacinar cell, juice is rich in bicarbonate

Neutralises

This prevents damage to the

It raises pH to an optimum range for pancreatic enzymes to work

It washes low volume enzyme secretion out of the pancreas into the

Mechanism for bicarbonate secretion:

H2O + CO2 <-> H2CO3 <-> H+ + HCO3-

Blood coming away from the stomach is quite alkali-

Blood coming away from the pancreas is relatively acidic-

Look at diagram for duct cells

CFTR chlorine channels are important for chlorine to pass into the

so they can be exchanged for bicarbonate

Some of the main enzymes that the pancreas releases are:

a precursor of a powerful protease which is converted to trypsin by

an enzyme present on the brush border of the small intestine

Chymotrypsinogen which can be activated by trypsin

Zymogen means pro-enzyme

Proteases are secreted as inactive pro-enzymes which protects acini against

Pancreatic juice contains a

inhibitor to prevent activation

Enzymes only just become active in the

The problem is that blockage of the pancreatic duct may overload protection mechanisms and result in auto-digestion =

Pancreatic secretions adapt to diet e.g. high protein low carbs lead to increased secretion of proteases and decreased secretion of amylases

Pancreatic enzymes are essential for normal digestion of a meal, lack of these can lead to

Orlistat-

Increased faecal fat- occurs when pancreatic lipase secretion significantly reduced. Social anus can't tell different between oil and air

Regulation of pancreatic juice release:

Gut is stimulated by the

Control of secretion:

Cephalic phase-

Mediated by cholinergic vagus nerve, the juice secreted in this phase is mainly enzyme rich containing very little

In response to vagal stimulation, the acinar cells secrete

which catalyse the production of bradykinin, a vasodilator. This results in increased blood flow to the pancreas and increased volume of secretion

Gastric phase-

The presence of food in the stomach simulates secretion of pancreatic juice via a hormonal mechanism

Activation of chemoreceptors in the walls of the stomach by

and the activation of mechanoreceptors causes the release of the hormone

from G cells and the local circulation. Stimulation of cholinergic is also involved in this phase of control. During the gastric phase, the secretion of both the enzyme-rich and the alkaline components of pancreatic juice is

Intestinal phase- 70-80% of pancreatic secretion

Food material in the

stimulates both secretion of alkaline and enzymatic components of pancreatic juice

Acid stimulates the release of

in the walls of the intestine and this hormone stimulates the duct cell to secrete the

Note this is a feedback control of pH

Enzyme rich juice is released during the intestinal phase in response to fat and peptides in the food. The fats and peptides causes release of

(CKK) from the walls of duodenum into blood, it also stimulates

to secrete enzymes. Trypsin in the duodenum inhibits the release of enzymes via inhibition of

Secretin exerts a permissive effect on the secretion of enzymes, it doesn't stimulate enzyme secretion on its own but enhances CCK effect

CCK exerts a permissive effect on secretion of alkaline fluid by

Vagus stimulation causes mainly release of enzyme rich secretion but if vague are sectioned, alkali secretion elicited in response to secretin is reduced by 50% indicating a functional overlap. Vagal mechanism may

effect of secretin

Extra information:

Bicarbonate rich component is controlled by release of

Enzyme rich component secretion is controlled by vagal reflex and by

CCK stimulates secretion of

Switching off CCK:

Cephalic phase ends when meal eaten, absorption of fats and peptides removes local luminal stimulus for CCK release from mucosa

CCK alone has

on bicarbonate secretion, it can markedly increase bicarbonate secretion that has been stimulated by

Vagus nerve has similar effect to CCK

Enterocytes and goblet cells of the small intestine have a short life span, a huge energy resource is required to constantly renew cells

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 and metabolic rate will be diminished

Any lesion will be short-lived.

Cholera:

Cholera enterotoxin results in prolonged opening of

in the

allowing uncontrolled secretion of water. Bodily fluid moves freely into the lumen and hence out through the intestine, leading to massive

Treatment is

Duodenum:

Distinguished by

Submucosal coiled tubular mucous glands secreting

fluid

Open into the base of the crypts and the alkaline secretions neutralise acidic

and help optimise pH for action of pancreatic digestive enzymes

Jejunum:

Characterised by presence of many large folds in the submucosa called

These are also present in the duodenum and ileum but plicae in the jejunum tend to be taller, thinner and more frequent

Ileum:

Shares some features with the

The ileum has lots of Peyer's patches- large clusters of lymph nodules

This is the prime immune response against intestinal

Functions of small intestine motility:

a. To mix ingested food with

b. To facilitate contact between intestinal contents and intestinal

c. To propel intestinal contents along alimentary tract

Segmentation:

Mixes contents of lumen, it occurs by

contraction of circular muscles at intervals

More frequent contractions in duodenum compared to ileum and allows pancreatic enzymes and bile to mix with

Although moves in both directions, net effect is downwards.

Peristalsis:

Involves sequential contraction of adjacent

of smooth muscle

Propels chyme towards colon, most waves of peristalsis travel about

CNS is needed to be involved

Mitigating motor complex:

Cycles of smooth muscle contraction that mainly occurs in

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

Prevents migration of small bacteria into the

and may clean the ileum of food residues

Duodenum:

In the small intestine digestion occurs in an

environment, digestive enzymes and bile enter the duodenum from the pancreatic duct and bile duct. Usually enzymes are associated with the

Carbohydrates:

of ingested food in Western diet

Digestion begins in the mouth by

but is destroyed in the small intestine

Most of the digestion of carbohydrates occurs in

Digestion of carbohydrates:

Pancreatic alpha amylase-

Secreted into

in response to a meal, continues digestion of starch and glycogen which is started by salivary amylase.

It needs

for optimum activity and neutral/slightly alkaline pH

Acts mainly in the lumen, breaks down large carbohydrates

Disaccharides and oligosaccharides are broken down to monosaccharides by enzymes on the

Absorption of carbohydrates:

Absorption of glucose and galactose is by 2degree active transport (Carrier protein and electrochemical gradient) Carrier protein is

on the apical membrane

Absorption of fructose is by

Carrier protein=

This facilitates exit at the basolateral membrane

The human small intestine can absorb

of simple sugars per day

Digestion of proteins:

Protein digestion begins in the stomach by

but it is inactivated by the alkaline duodenum

Trypsin is activated by

an enzyme located on the duodenal brush border, trypsin then activates other proteases by

Brush border peptidases break down the largest peptides prior to absorption. Amino acids are absorbed by facilitated diffusion and secondary active transport.

Di and tri peptides are absorbed using carrier proteins distance from single amino acids. Cytoplasmic peptidases break most of them down before they cross the

Digestion of lipids:

Lipids are poorly soluble in water which makes them complicated to digest.

4 stage process in the small intestine: 1) Secretion of

and lipases

2) Emulsification

3) Enzymatic

and ester linkages

4) Solubilisation of lipolytic products in bile salt micelles

Emulsification of lipids:

Bile and lipase are secreted into the

Bile salts facilitate the emulsification of fat into a suspension of lipid droplets

The function of emulsification is to increase the

for digestion. Allows pancreatic lipase to split triglycerides

Bile salt molecule:

Steroid nucleus planar- two faces amphipathic

Hydrophobic nucleus and a methyl face dissolves in

Hydrophilic hydroxyl and carboxyl face dissolves in

Collapse prevents bile salts form displacing lipase form the fat droplet

Absorption of lipids:

are important in absorption as they are absorbed much quicker than the emulsion

Micelles allow transport across the

and present the fatty acids and monoglycerides to the brush border

Lipid metabolism:

Monoglycerides and free fatty acids absorbed by enterocytes are resynthesises into triglycerides via 2 different pathways:

1. Monoglyceride

(major)

2. Phosphatidic acid pathway (minor)

Monoglyceride acylation:

Fatty acids bind to the apical membrane, fatty acid binding proteins facilitate transfer of fatty acids from apical membrane to the

Then the fatty acids are esterified into diglycerides and triglycerides

Phosphatidic acid: Triglycerides are synthesised from CoA fatty acid and

Chylomicrons:

These are lipoprotein particles synthesised in enterocytes as an

80-90% triglycerides, 8-9% phospholipids, 2% cholesterol, 2% protein, trace carbohydrates

Chylomicrons are transported to the Golgi and secreted across the basement membrane by exocytosis

They are too big to enter blood capillaries of the villi so instead enter the lacteals

Consists of the colon, cecum, appendix, rectum and

The cecum is a blind pouch just distal to the ileocaecal valve- larger in herbivore for the breakdown of food with bacteria

The appendix is a thin finger-like extension of the cecum- not physiologically relevant in humans

Colon- Principal function of colon is

and the elimination of undigested food and waste.

long and 6cm in diameter

The ascending colon is on the right side of the abdomen, runs from the cecum to the

(the turn of the colon by the liver)

The transverse colon runs from hepatic flexure to

Descending colon runs from splenic flexure to

(s-shaped) which runs from descending colon to the rectum

Taeniea coli- Bands of

muscle that leads to pouched appearance. It contains fatty tags-

suggested to have a protective function against intra-abodminla infection but still relatively unsure about function

Taeniea coli is

than small intestine. They cause the formation of pouched ovoid segments called

Rectum:

Dilated distal portion of the alimentary canal, histologically similar to the colon but distinguished by

in it submucosa and the absence of taenia coli. Terminal position is the

Comparison of large and small intestine:

Like the small intestine, enterocytes and goblet cells are abundant

There are abundant crypts and

are found in the crypts

Large intestine- Mucosa appears

because it has no

Enterocytes have short, irregular microvilli and primarily concerned with reabsorption of salts

Water is absorbed as it passively follows electrolytes

number of goblet cells than small intestine. More prevalent in crypts than surface and number

distally towards the rectum

The mucus facilitates the passage of the increasingly solid colonic contents and covers bacteria and particulate matter.

Acetyl choline stimulates

There

Paneth cells in the large intestine because we want to keep commensal bacteria

Reminder- The function of Paneth cells is to release acidophilic granules contains bacterial lysozyme, glycoproteins and zinc to engulf bacteria

Microvilli- Make up brush border and surface of microvilli is covered with

which is a rich carbohydrate layer on apical membrane and is protection from digestion lumen in apical membrane. It traps a layer of water and mucous known as the

Motility of large intestine:

Like the small intestine muscular externa consists of an inner circular and outer longitudinal layer. Circular muscles are segmentally thickened.

Longitudinal bands concentrated in 3 bands known as the

Between the bands, the longitudinal layer is thin

bundles of taenia coli penetrate the circular layer.

Taenia coli is

than the circular muscle layer, ovoid segments called haustra can contract individually

Apart from rectum and anal canal, muscle layers are substantial and continuous

Large intestine motility-

5-10cm per hour moving along the large intestine. Kneading process designed for

Try to keep it up in the top of the large intestine due to the top being able to absorb more

Haustral contraction - thickened

muscle causes back and forth mixing

Short propulsive movements every 30 mins which increase in frequency following a meal.

Mass movement: 1-3 times a day

Control:

Most of large intestine is controlled by parasympathetic

External anal sphincter is controlled by somatic motor fibres in the

nerves.

Afferent sensory neutrons detect pressure

Hirschsprung's disease- No enteric intramural

Myenteric plexus ganglia concentrated below taenia coli

Control of defaecation:

Rectum filled with faeces by mass movement in the sigmoid colon, stores until convenient to void, the reflex is mainly controlled by the

-both reflex and voluntary actions

Reflex-

reflex to sudden distention of walls of rectum, pressure receptors see signals via

to initiate peristaltic waves in descending sigmoid colon and rectum. The internal and sphincter is

Weak intrinsic signals are augmented by autonomic reflex. External anal sphincter under voluntary control

Social rectum- Can distinguish between solid, liquid and gas but can't tell the difference between

Faeces:

150g/day per adult

is water.

Solids: Cellulose, bacteria, cell debris, bile pigments, salts

Colour of poo is due to

Odour is due to

Main functions of large intestine:

Reabsorption-

Colon absorbs electrolytes and water, more is absorbed into the

Na and Cl absorbed by exchange mechanisms and ion channels. Water follows by osmosis.

K+ moves passively into the gut. Large intestine can reabsorb approx

of water . Above this you have diarrhoea

Large intestine flora:

All mammals have symbiotic relationships with their gut microbial community, stomach and small intestine have

bacteria than large intestine

Roles:

Synthesis and excretion of

- germ free animals can have clotting problems

Prevalent colonisation by pathogens by competing for attachment sites or for essential nutrients

Antagonise other bacteria

Stimulate production of cross-reactive

Antibodies produced against components of normal flora can cross react with certain pathogens and prevent infection or invasion

Species:

Bactericides- Gram negative, anaerobic, non-sporeforming bacteria

Bifidobacteria- Gram

non spore-forming

bacteria. Thought to stop colonisation by pathogens

Main functions:

Secretes bile into

Phagocytoses and breaks down over-dated

Excretes bile pigments into bile

Metabolises many natural and synthetic molecules to prepare them for excretion

Synthesises and secretes key blood

Key site of insulin dependent glycogen storage

Organisation of the liver:

The liver lies in the

quadrant predominantly and crosses the midline and extends into the superior medial segment of the ULQ

Bare edge of liver is where there is no

because it anastomoses directly with the diaphragm

Lobes of the liver:

Anatomical lobes based on attachment of

Boundary between territories of left and right branches of hepatic artery is important

This put the small lobes (caudate and quadrate) in with the functional left lobe.

Couinaud classification divides the liver into

functionally independent segments

Centrally there is the

, hepatic artery and bile duct

Peripherally there is the

Each segment can be resected without damaging those remaining

Embryological origins of liver:

The liver and billiary system share a common origin with the ventral part of the

at the beginning of the midgut

The septum

is a thick mass of

mesenchyme that gives rise to parts of the thoracic diaphragm and the mesentery of the foregut in a developed human being

It arises at an embryonic junctional site. This is where the ectoderm of the amnion meets the endoderm of the yolk sac and where the foregut meets the midgut

Mesenchymal structure of the septum transversum provides support upon which the liver and blood supply can develop

Microcirculation of liver tissue:

Lobules of the liver consist of cords of

These radiate from a

Round the edges of adjoining lobules are portal triads consisting of: An arteriole, a branch of the

and a bile duct. All of these come from the main triad entering the liver at the

or hilum

of cells in the liver are hepatocytes

Endothelial cells line blood vessels and sinusoids

line biliary structures

cells are fixed phagocytes

Hepatic stellate cells- These are vitamin

storage cells

Hepatocyte sheets near the central vein of a lobule. Flattened, dense cell nuclei belong to phagocytic Kupffer cells. Hepatocyte cells are paler and

Blood supply to the liver:

There is a rich blood supply which is

of the cardiac output. There is a dual blood supply:

20% arterial blood from the

80% venous blood draining from the gut through the

HPB drains the gut which means that the liver is the first organ to have nutrient rich blood which is important for its function

Functional important of main structural features of hepatocytes:

Plasmalemma of adjacent hepatocytes shows irregularities with tight junctions, spot desmosomes and gap junctions. These separate the canaliculus from the rest of the intercellular space

Mitochondria are needed to provide the energy required for endocytosis and membrane

Instead of forming simple sheets or glands facing a lumen on one side and the capillary bed on the other, hepatocytes are arranged as a complex anatomising sheets separated by wide sinusoidal capillaries.

The apical part of the hepatocyte is reduced to a narrow band surrounding the cell within the plane of the sheet of the hepatocytes

These apical domains bound a meshwork of narrow intercellular spaces called

Bile is secreted into the canaliculi; tight junction on each side prevent

The portal vein, hepatic artery and bile ducts that enter the liver together retain their relationship even after multiple branching, these microscopic vascular bundles within the liver are termed

A region of liver parenchyma surrounded by a ring of about 5-6 portal triads is called a

A tributary of the hepatic veins at the centre of each lobule receives the blood draining from the

In other words, the lobule is a unit of vascular supply within the liver.

However the bile canalicular drains towards the bile ductules within the triad and the term

is used for a unit of bile secretion

Bile secreted from the apical surfaces of the hepatocytes drains through the

network of bile ductules in the triads

All other liver secretion products such as albumin, fibrinogen and glucose are released at the non-canalicular surface of the hepatocytes into

space and thus enter the very permeable sinusoidal capillaries

Canaliculus lumen is only 0.75

Microvilli project from the canalicular membrane into the lumen providing a large surface area for

Leaky tight junctions between hepatocytes permit

exchange between the plasma and the canaliculus.

(lack of contraction of bile canaliculus) results in reduced bile flow

One major function of the liver is not attributable to hepatocytes and this is

and

breakdown of old red cells which is handled by fixed macrophages called

that form part of the lining of the sinusoids

Role as glucose buffer:

Breakdown of glycogen maintains glucose conc between meals

24h fast will exhaust liver glycogen- There is around

After that, gluconeogenesis- process of synthesising glucose from

sources. Lactate-->Pyruvate-->Glucose Also amino acids vie

reaction can be used to make glucose via the pathway Alanine-->Pyruvate-->Glucose

Role of liver in protein and fat metabolism:

Protein metabolism-

Synthesises 90% of plasma proteins. Makes 15-50g/day

Importance of plasma proteins- binding/carrier function and plasma colloid osmotic pressure-

Synthesis of blood clotting factors

Synthesis of dietary nonessential

Transamination:

Starts with appropriate alpha keto acid precursor

Essential amino acids (lysine, leucine, isoleucine, methionine, threonine, tyrosine, valine and phenylalanine)

have appropriate keto acid precursors

Glutamic acid is a common intermediate in transamination reactions

Deamination:

De-aminate amino acids prior to use as energy source

Deamination is the conversion of an amino acid into the corresponding keto acid by

of the amine group as ammonia and replacing it with a ketone group

Deamination occurs primarily on

because it's the end product of many transamination reactions.

from water is used to create the ketone group

Urea synthesis:

Metabolism of NH2 leads to formation of NH3. It is toxic particularly to the

Liver converts NH3 to urea which is safe

Fat metabolism:

Main energy store in body. Stored in adipose and liver. When glycogen stores are full, liver can convert excess glucose and amino acids to fat for storage

Metabolises fats as energy store- converts FA's

which is put into TCA

Alternatively liver can convert two acetyl-coA into acetoacetic acid for transport in blood (ketone bodies)

Lipoprotein synthesis:

Problem with transporting lipids in aqueous medium therefore lipoproteins are formed which are cholesterol esters, triglycerides, phospholipid encased in a protein coat

Cholesteryl ester transferase protein (CETP) shuttles cholesterol from

to

Inhibiting of CETP is of interest to drug companies

All developments stopped due to increased SBP, deaths and CVD

Bile:

Secreted by liver and stored in

which holds 15-60ml and concentrates bile salts. The liver uses 2 pathways for absorption and secretion:

1. Secretion of bile through narrow

between adjoining hepatocytes into the biliary system

2.In or out of the blood

Major components are bile salts (50%), cholesterol, phospholipids, bile pigments, bicarbonate ions and water. Separately some components would be insoluble but together bile is a stable solution

Primarily bile acids are made from the oxidation of

to cholic acid and chenodeoxycholic acids leading to addition of carboxyl and hydroxyl groups to make it soluble

Conjugated with taurine or

leads to taurocholic and glycocholic acids increases water solubility

Ratio of glycocholates to taurocholate is usually

Functions of bile are to: digest/absorb

Excrete a variety of substances via

Neutralise acid

from stomach

Bile is released into the duodenum during digestion. Small amounts during cephalic gastric phases due to

nerve and gastrin action

Intestinal phase, cholecystokinin causes contraction of gall bladder and relaxation of

Enterohepatic circulation:

Active reabsorption of bile salts in

in addition, deconjugation and dehydroxylation by bacteria makes bile salts lipid soluble. We lose 5% a day

Recirculate via HPV back to liver. Hepatocytes avidly extract bile salts- one pass clears all

Bile salt pool secreted

per meal

Metabolism/inactivation of steroid and peptide hormones:

Liver breaks down/inactivates steroid and peptide hormones. Secreted into bile for excretion

Don't forget bile is a way of excreting

Also performs similar role with variety of foreign components- usually drugs

Excretory route for excess cholesterol,

allow more cholesterol in micelles. Too much can cause gall stones.

Bilirubin is exerted in bile pigments and is created from breakdown of

form old red blood cells.

In the liver, porphyrin group is reduced to

and conjugated to glucoronic acid

Storage:

The liver stores the fat soluble vitamins (A,D,E,K) Stores are sufficient for

apart from vitamin

where the store is small, it is essential for blood clotting

Storage of iron as

which is necessary for erythropoiesis. Storage of fit b12- pernicious anaemia, nerve demyelination

Glycogen and fat store

Other functions:

Protection- liver sinusoids contain tissue macrophages (Kupffer cells). Bacteria may cross from gut lumen to blood. Kupffer cells destroy these and prevent bacteria entering the rest of the body

Ca2+ metabolism-

converts cholesterol to vitamin D precursor which requires a double hydroxylation at position 25 and 1 to convert it into the active form

Diffusion: Occurs rapidly over microscopic distances but slowly over macroscopic

Cell membranes act as diffusion barrier

Osmosis: Movement of water across a semi-permeable from a hypotonic to a hypertonic solution. Primary active transport uses hydrolysis of ARP. Secondary is coupled to a sodium import

Water:

of H2O presented to GI tract is absorbed

Greatest amount of water is absorbed in the

Paracellular transport is between tight junctions and transcellular is through the cells

Standing gradient osmosis:

Driven by

Transport from lumen into enterocyte complex and varies between species. Becomes

efficient as you travel down the intestine

Counter transport in exchange for

(proximal bowel)

Co-transport with

in the

Co-transport with Cl- in the

Restricted movement through ion channels in the colon

Active transport of Na+ into lateral intercellular spaces by Na+K+ATPase transport in the lateral plasma membrane

Cl and HCO3 are transported into intercellular spaces due to electrical potential created by

High conc of ions in the intercellular spaces causes the fluid there to be

Osmotic flow of water from gut lumen via adjacent cells and tight junctions into the intercellular space

Water distends the intercellular channels and causes

Ions and water move across the basement membrane of the epithelium and are carried away by the

Cl- is co-transported with Na+ in the

and exchanged with HCO3 in the colon. Both are types of

K+ diffuses in via paracellular pathways in the small intestine, leaks out of cells in colon- passive transport

Diarrhoea:

In secretory diarrhoea the secretion of Cl, Na and water into the intestinal lumen by cells in the