The Liver Flashcards
THE HEALTHY LIVER
oSynthesis and secretion of _.
oMetabolism
oPlasma proteins– major source of plasma proteins including albumin and _ factors (see blood lectures)
oEndocrine function
oExcretory and degradative functions
oIron storage
Bile
Clotting
SUMMARY OF LIVER FUNCTIONS
Exocrine (digestive) Functions- synthesis and the secretion of bile for the adequate digestion and absorption of _.
Secretes _ into a bicarbonate rich solution that helps to neutralize acid in the duodenum
Endocrine functions– e.g. Secretes insulin-like growth factor 1 (IGF-1) in response to growth hormone. This promotes cell division in a number of tissues including bones.
Clotting factors- Produces many of the plasma clotting factors including prothrombin an fibrinogen.
Bile salts – essential for the absorption of fat soluble vitamin K that is required for the formation of _ factors in the liver.
Plasma proteins- Synthesizes and secretes proteins including plasma _, acute phase proteins, binding proteins for a variety of hormones and lipoproteins
Metabolism-
- Coverts plasma glucose to _ and triglycerides
- Converts plasma amino acids to fatty acids
- Synthesizes triglycerides and secretes them as lipoproteins
- Produces glucose from glycogen (_)
- Converts fatty acids to _ during fasting
- Produces urea – major end product of amino acid (protein) catabolism and releases into the blood
Cholesterol metabolism-
- Synthesizes cholesterol and releases into the blood
- Secretes cholesterol into bile
- Covers plasma cholesterol into bile salts
Iron and vitamin B12 storage
Fats
Bile
Clotting
Albumin
Glycogen
Glyconeogenesis
Ketones
ANATOMY

WHAT IS THE LIVER COMPOSED OF?
Four incompletely separated lobes that are supported by two ligaments
GROSS LIVER ANATOMY
oApprox 1.5 kg (2 % body weight in adults)
oAnatomically four lobes: left, right, caudate and quadrate
oFunctionally considered as two lobes - left and right
oDiaphragmatic surface is the superior upper surface of the liver
oVisceral surface faces adjacent abdominal organs (faces downwards); the porta hepatis and gallbladder are located on this surface.
WHAT ARE THE FOUR LOBES OF THE LIVER CALLED?
Left
Right
Caudate
Quadrate
ANATOMY 2
- Caudate (cauda = tail)
- Quadrate (quadratus = squre)
The Caudate lobe is next to the _ vena cava
The Quadrate lobe is next to the _ bladder

Inferior
Gall
WHERE IS THE CAUDATE LOBE OF THE LIVER?
Next to the inferior vena cava
WHERE IS THE QUADRATE LOBE OF THE LIVER?
Next to the gall bladder
LIVER STRUCTURE
oFalciform ligament: separates the major right and left lobes and attaches the liver to the _ and anterior abdominal wall
oRound Ligament: Found at the lower edge of the falciform ligament.
oGall bladder – accessory organ – pear shaped sac 7-10 cm long
-Rests in a recess on the inferior, visceral surface of the liver
FACIFORM LIGAMENT – secures the liver to the anterior abdominal wall
Round ligament – remnant of the _ _.
Diaphragm
Umbilical cord
LIVER LOBES FROM VISCERAL SURFACE

HEPATIC BLOOD CIRCULATION
oThe liver receives blood from two sources; the _ and GI tract.
oHepatic portal vein delivers poorly _ blood from the GI tract.
oHepatic artery delivers oxygenated blood from the heart.
oHepatic portal vein and artery divide into two to supply the left and right side of the liver
Heart
Oxygenated
WHAT TWO SOURCES DOES THE LIVER RECEIVE BLOOD FROM?
Heart
GI Tract
HEART STRUCTURE

HEPATIC CIRCULATION
- The hepatic portal vein carries blood form the GI tract, _ and pancreas,
- Rich in nutrients but poor in _.
- Hepatic artery – branches from _ and eventually splits into right and left hepatic arteries
- Hepatic vein –at the centre of each lobule is the central vein that drains into the hepatic vein
oAorta supplies oxygenated blood via the hepatic artery
oBlood supplied to the liver via the hepatic portal vein and hepatic artery
oHepatic portal vein drains blood from the capillary beds of the GI tract including spleen and pancreas.
oHepatic vein carries blood away from the liver back to the _.
Spleen
Oxygen
Aorta
Heart
WHERE DOES THE HEPATIC PORTAL VEIN CARRY BLOOD FROM?
Carries blood from the spleen, GI tract and pancreas
HOW IS BLOOD SUPPLIED TO THE LIVER?
Via the hepatic portal vein and hepatic artery
WHAT DOES THE HEPATIC VEIN DO?
Carries blood away from the liver back to the heart
LIVER HISTOLOGY
o50,000 – 100,000 functional units called _. Hepatic lobules have a small polyhedral shape; these are the functional units of the liver.
oWithin each lobule are cells called _.
oAt the edge of each lobule are portal triads – these are formed by the hepatic portal vein, the hepatic artery and the bile duct
oCentral Vein empties into the hepatic veins and then the vena cava.
Lobules
Hepatocytes
WHAT ARE PORTAL TRIADS FORMED BY?
Formed by the hepatic portal vein, the hepatic artery and the bile duct
WHAT ARE THE CELLS INSIDE LIVER LOBULES CALLED?
Hepatocytes
CLASSIC LIVER LOBULES
Blood flows from the portal triad (contains the portal vein and hepatic artery) towards the central _.
Bile flows in the opposite direction towards the portal triad (contains the bile _)
Vein
Duct
LIVER LOBULE STRUCTURE

The numerous projections of the wheel spokes are the hepatic sinusoids – thin walled leaky _ where venous and arterial blood mix as they slowly flow through the hepatic lobe towards the central vein.
Hepatocytes absorb nutrients from blood and produce bile that collects in the small bile caniculus.
Capillaries
WHAT ARE HEPATIC SINUSOIDS?
Thin walled leaky capillaries where venous and arterial blood mix as they slowly flow through the hepatic lobe towards the central vein.
LIVER LOBULE STRUCTURE 2

HEPATOCYTES
oLiver cells that separate sinusoidal blood from the canalicular bile.
oPolarized cells
oBasal membrane faces the liver sinusoidal endothelial cells
oApical membrane contributes to bile canaliculi jointly with the directly opposing hepatocytes.
WHAT ARE HEPATOCYTES?
Liver cells that separate sinusoidal blood from the canalicular bile
BILE
oExocrine secretory product of the liver
oBile contains HCO3-, cholesterol, lecithin (a phospholipid), bile pigments and bile salts.
oBile salts are important for the absorption of water insoluble _.
oStored and concentrated in the gall _.
oReleased during _.
Fats
Bladder
Meals
WHAT DOES BILE CONTAIN?
HCO3-, cholesterol, lecithin (a phospholipid), bile pigments and bile salts.
WHY ARE BILE SALTS IMPORTANT?
For the absorption of water insoluble fats
LIVER LOBULES
oCounter current flow of _ and bile (opposite directions)
oBile ducts lined by _.
oBlood sinusoid lined by single layer of fenestrated endothelial cells.
oPortal field (portal triad) composed of portal hepatic vein, portal artery and bile duct.
oCentral vein drains to the vena cava.
Blood
Hepatocytes
WHAT IS THE PORTAL FIELD/PORTAL TRIAD COMPOSED OF?
Portal hepatic vein
Portal artery
Bile duct
LIVER SINUSOIDAL ENDOTHELIAL CELLS
oFilter between the lumen of the hepatic sinusoid and hepatocytes.
oMinimize any barrier for the bi-directional transfer of small or soluble substrates between blood and the extracellular space of Disse
oFenestrations are approximately 50–150 nm in diameter and most are aggregated into groups of 10–100, so-called liver sieve plates
KUPFFER CELLS
o80 – 90% tissue macrophages in the liver
oAlso known as stellate macrophages
oDiscovered by pathologist C von Kupffer
oReside in the lumen of the sinusoids of the liver, adherent to endothelial cells
oImportant role in host _.
Defence
WHAT DO KUPFFER CELLS HAVE AN IMPORTANT ROLE IN?
Host defence
STELLATE CELLS
oStellate cells are found in the subendothelial space between the basolateral surface of hepatocytes and anti-luminal side of the sinusoidal endothelial cells.
oSpindle-shaped cell bodies with oval or elongated _.
oSingle stellate cell usually surrounds more than two nearby sinusoids.
oThought to be involved in _ formation.
Nuclei
Fibrosis
WHERE ARE STELLATE CELLS FOUND?
Found in the subendothelial space between the basolateral surface of hepatocytes and anti-luminal side of the sinusoidal endothelial cells
CYSTIC DUCT
oApprox 4 cm long
oConnects the neck of the gall _ to the common hepatic duct.
oCholangiocytes are epithelial cells that line the intra- and extra-hepatic ducts of the biliary tree
oModifies bile to generate ductal bile.
Bladder
BILE DUCT CIRCULATION
- Bile is transported down Bile canaliculi in the liver.
- The bile canaliculi empty into bile ductules and then bile ducts.
- Empties into the _ ducts.
- Bile then directly enters the _ or diverted to the cystic duct into the gall bladder.
- The gall bladder concentrates and stores bile ready for use.
Hepatic
Duodenum
GALL BLADDER
oPear shaped, 7 -10 cm long
oFundus: wide end of gall bladder and projects from the inferior border of the liver
oBody: contacts the visceral surface of the liver
oNeck: narrow and tappered; makes an S bend into the cystic duct. Internally the mucosa spirals into the spiral fold that keeps the cystic duct open.
INTRAHEPATIC BILE DUCT ANATOMY

WHAT ARE CHOLANGIOCYTES?
Epithelial cells that line the intra-hepatic and extra-hepatic ducts of the biliary tree
WHAT DOES THE CYSTIC DUCT DO?
Connects the neck of the gall bladder to the common hepatic duct
EXTRAHEPATIC BILE DUCT ANATOMY

THE IMPORTANCE OF CHOLESTEROL
oSynthesis of cell membranes and contributes to the fluidity of membranes (lipid rafts)
oPrecursor for the synthesis of several molecules including vitamin D, cortisol, aldosterone, progesterone, estrogen, testosterone, bile salts.
WHY IS CHOLESTEROL IMPORTANT?
oSynthesis of cell membranes and contributes to the fluidity of membranes (lipid rafts)
oPrecursor for the synthesis of several molecules including vitamin D, cortisol, aldosterone, progesterone, estrogen, testosterone, bile salts
CHOLESTEROL SYNTHESIS
o80 % total daily cholesterol production is found in the liver
oSynthesized from Acetyl Co-A
oMulti-step pathway to form cholesterol from AcCoA that can be divided into 3 major steps.
WHAT IS CHOLESTEROL SYNTHESISED FROM?
Acetyl Co-A
CHOLESTEROL SYNTHESIS: STEP 1

CHOLESTEROL SYNTHESIS: STEP 1 (CONTINUED)

CHOLESTEROL SYNTHESIS: STEPS 2/3
oSqualene is synthesized from isopentenyl pyrophosphate
oCyclization of squalene to form lanosterol
oLanosterol goes through several steps to eventually form cholesterol.
CHOLESTEROL TRANSPORT IN THE BODY
o_ molecule and does not dissolve well in aqueous environment
oPackaged with phospholipids and apolipoproteins to form a series of different lipoproteins
oLipoproteins contain a lipid core (contain cholesterol esters and triglyercides) and a hydrophilic outer surface containing phospholipids, free cholesterol and apolipoproteins
oMain cholesterol carrying lipoproteins are low _ and high density lipoproteins (LDL and HDLs)
Lipophilic
Density
LIVER CHOLESTEROL METABOLISM
oAtherosclerosis is a progressive disease of large arteries and a leading cause of cardiovascular diseases and stroke.
oElevated levels of circulating _ associated with the development of atherosclerosis.
oInhibitors of cholesterol _ used to treat atherosclerosis
oStatins inhibit HMG CoA Reductase in the cholesterol synthesis pathway
o Newer drugs target LDL levels in the body (PCSK9 inhibitors)
LDL
Synthesis
WHAT IS A COMMON TREATMENT OPTION FOR ATHEROSCLEROSIS?
Cholesterol synthesis inhibitors
WHAT IS ATHEROSCLEROSIS?
A progressive disease of the large arteries, and a leading cause of cardiovascular diseases and stroke
BILE SALT PRODUCTION

BILE SALT SYNTHESIS
Liver receives blood from the gastrointestinal tract via the portal vein and hepatic _.
Blood returns to the system circulation via the hepatic vein into the vena cava.
Liver continuously produces bile into the bile duct that goes to the GI tract or gall _.
Artery
Bladder
WHAT DOES BILE CONTAIN?
- Bile salts
- Lecithin (a phospholipid)
- HCO3-
- Cholesterol
- Bile pigments
- Trace metals
BILE PRODUCTION
oHepatocytes secrete hepatic _ into the bile canaliculi
oHepatic bile also contains bile salts, bile pigments, cholesterol and lecithin (a phospholipid)
oEpithelial cells that line the bile ducts secrete a bicarbonate rich fluid that increases the _ of the bile
oLiver produces 600 – 1000 ml bile per day discharged into the duodenum or stored in gall bladder.
Bile
Volume
CHEMICAL NATURE OF BILE ACIDS
oLiver produces around 500 mg bile salts per day
oPrecursors of bile salts are bile acids and they are synthesized from _.
oPrimary bile acids – cholic acid and chenodeoxycholic acid - are synthesized in the hepatocytes.
oSecondary bile acids – deoxycholic and lithocholic – are formed in the intestine by the dehyroxylating action of bacteria _.
Cholesterol
Flora
WHAT ARE THE TWO PRIMARY BILE ACIDS AND WHERE ARE THEY SYNTHESISED?
Cholic acid
Chenodeoxycholic acid
Synthesised in the hepatocytes
WHAT ARE THE TWO SECONDARY BILE ACIDS AND WHERE ARE THEY SYNTHESISED?
Deoxycholic
Lithocholic
Formed in the intestine by the dehydroxylating action of bacteria flora
BILE SALTS
oPrimary or secondary bile acids are conjugated to _ _ (e.g. glycine) to generate water soluble bile salts.
oExample: cholic acid with glycine forms glycocholate.
oBile salts – hydrophobic and hydrophilic regions that aggregate to form _ at a critical concentration.
oImportant for the emulsification of _.
Amino Acids
Micelles
Fats
ENTEROHEPATIC CIRCULATION
oThe majority of bile salts are re-absorbed by a _-dependent pathway in the ileum (last segment of small intestine)
oApprox 95% bile salts that enter intestine are recycled back to the _ via the portal vein.
oUptake of bile salts form the portal blood into hepatocytes occurs via a active transport pathways.
oRecycling from the GI Tract to the liver is known as the enterohepatic circulation
Sodium
Liver
WHAT IS ENTEROHEPATIC CIRCULATION?
Recycling from the GI tract to the liver
ENTEROHEPATIC CIRCULATION 2
o5% are lost in faeces (but liver makes new bile from cholesterol to replace the lost bile)
oDuring digestion – Bile can be recycled several times via the enterohepatic circulation.
WHAT IS THE SPHINCTER OF ODDI?
A ring of smooth muscle found where the common bile enters the small intestine
CHOLECYSTOKININ (CCK)
oPeptide hormone
oProduced by the small intestine
oStimulus for release = amino acid, fatty acids in the intestine
REGULATION OF BILE SECRETION

GALL BLADDER
oSphincter of oddi closed -> bile is diverted to the gall bladder.
-Stores bile not required immediately for _ of meals.
oConcentrates the bile by removal of salts and _.
oCan increase concentration of bile salts up to 20 fold.
Digestion
Water
WHAT HAPPENS TO BILE WHEN THE SPHINCTER OF ODDI IS CLOSED?
The bile is directed to the gall bladder, where it is stored
EXCRETORY ROLE OF BILE
oBile pigments are breakdown product of heme portion of _ from erythrocytes broken down in the liver and spleen.
oBile contains approx 0.2 % bile pigments
oResponsible for characteristic colour of bile (greenish yellow)
oMajor pigment is bilirubin; found in bile and secreted into duodenum.
Haemoglobin
WHAT IS THE MAJOR PIGMENT FOUND IN BILE?
Bilirubin
WHAT ARE BILE PIGMENTS?
Breakdown products of heme portion of haemoglobin from erythrocytes broken down in the liver and spleen
SYNTHESIS: PLASMA PROTEINS
oLiver secretes large numbers of proteins.
oAlbumin: plasma protein, transport lipids and steroid hormones
oGlobulins: approx 40% total plasma proteins; alpha and beta- globulins also transport lipids and steriod hormones
oClotting factors: most are produced by liver e.g. fibrinogen and prothromin
WHAT DO ALPHA AND BETA-GLOBULINS DO?
They transport lipids and steroid hormones.
SYNTHESIS: INSULIN-LIKE GROWTH FACTORS
oInsulin like growth factor (IGF) is an important mediator of growth hormone (GH) action.
oLiver synthesizes IGF-1 and -2 in response to growth hormone
oStructurally similar to pro-insulin
oPotent growth promoting effects.
oIGF-1 levels low in infancy, peak in puberty during growth and declines in adult.
oIGF-2 may be more important in fetal and neonatal growth.
DRUG METABOLISM

DRUG METABOLISM: PHASE 1 REACTIONS
oCytochrome P450 enzymes are important
oSuperfamily of related enzymes
oPopulation variation in P450 enzymes are important in terms of therapeutics
oNaturally occurring dietary substances can inhibit (e.g. grapefruit juice) or induce (brussels sprouts) P450 enzymes with impact on drug metabolism
CLOPIDOGREL METABOLISM
oAnti-thrombotic agent that inhibits _ activation (involved in blood clotting)
oPro-drug that requires oxidation.
oA 2-step metabolism using hepatic P450 enzymes to generate the active thiol metabolite that reacts with platelets
oBinds selectively and irreversibly to P2Y12 receptor on _ membranes.
oThe majority of clopidogrel is also inactivated by blood esterases so only 15% metabolised by hepatic P450 enzymes
oA two step metabolism phase leads to a delayed onset of action for clopidogrel
oGenetic mutations in P450 enzymes are associated with a reduced response to clopidogrel treatment
Platelet
Platelet
WHAT IS CLOPIDOGREL?
Anti-thrombotic agent that inhibits platelet activation (involved in blood clotting)
DRUG METABOLISM: PHASE 2 REACTIONS
oPhase 2 is a conjugation step that almost always leads to a pharmacologically inactive or less lipid soluble product that is eliminated in urine or bile.
oGroups most often associated with conjugation are glucuronyl, sulphate, methyl, acetyl, glycyl and glutathione
PARACETAMOL TOXICITY
oParacetamol is commonly used non-narcotic analgesic-antipyretic agent
oOral drug, peak plasma concentration 30-60 mins and inactivated in liver by conjugation to glucuronide or sulphate
oToxic dose (2-3 x max therapeutic dose) causes hepatotoxicity and potentially renal toxicity
oNormal conjugation pathways become saturated and drug metabolised by mixed function oxidases to form N-acetyl-p-benzoquinone imine (NAPBQI) = very toxic to cells
IMMUNE SYSTEM: KUPFFER CELLS
oCritical component of the mononuclear phagocytic system
oResident macrophage of the liver
oFound in the hepatic blood sinosoids
oEfficiently phagocytize pathogens entering from the blood circulation
oFirst line of defence against particulates and immunoreactive material passing from the gastrointestinal tract via the portal circulation and may be considered as a final component in gut barrier function
