The Liver Flashcards by Deleted Deleted

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

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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

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ANATOMY

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WHAT IS THE LIVER COMPOSED OF?

Four incompletely separated lobes that are supported by two ligaments

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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.

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WHAT ARE THE FOUR LOBES OF THE LIVER CALLED?

Left

Right

Caudate

Quadrate

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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

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WHERE IS THE CAUDATE LOBE OF THE LIVER?

Next to the inferior vena cava

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WHERE IS THE QUADRATE LOBE OF THE LIVER?

Next to the gall bladder

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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

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LIVER LOBES FROM VISCERAL SURFACE

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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

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WHAT TWO SOURCES DOES THE LIVER RECEIVE BLOOD FROM?

Heart

GI Tract

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HEART STRUCTURE

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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

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WHERE DOES THE HEPATIC PORTAL VEIN CARRY BLOOD FROM?

Carries blood from the spleen, GI tract and pancreas

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HOW IS BLOOD SUPPLIED TO THE LIVER?

Via the hepatic portal vein and hepatic artery

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WHAT DOES THE HEPATIC VEIN DO?

Carries blood away from the liver back to the heart

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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

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WHAT ARE PORTAL TRIADS FORMED BY?

Formed by the hepatic portal vein, the hepatic artery and the bile duct

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WHAT ARE THE CELLS INSIDE LIVER LOBULES CALLED?

Hepatocytes

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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

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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

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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.

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**_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_** ## Footnote 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_** ## Footnote 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_** 1. Bile is transported down Bile canaliculi in the liver. 2. The bile canaliculi empty into bile ductules and then bile ducts. 3. Empties into the _ ducts. 4. Bile then directly enters the _ or diverted to the cystic duct into the gall bladder. 5. 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_** o**Atherosclerosis** 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?

1. Bile salts 2. Lecithin (a phospholipid) 3. HCO3- 4. Cholesterol 5. Bile pigments 6. 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_** ## Footnote 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_** ## Footnote 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)_** ## Footnote 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. o**Albumin**: plasma protein, transport lipids and steroid hormones o**Globulins**: approx 40% total plasma proteins; alpha and beta- globulins also transport lipids and steriod hormones o**Clotting 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_** ## Footnote 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