11.3 - Hepatobiliary System Flashcards
What are the upper and lower limits of the liver?
- upper - right nipple
- lower - right subcostal margin (ribcage)
- it lives within the chest - ribs are there to protect it
What are the right and left lobes of the liver divided by?
The middle hepatic vein which goes down the right lobe (meaning part of the right lobe is actually part of the left lobe)
What is the ligamentum teres?
Remnants of the umbilical vein of foetus that would have come from umbilicus to falciform ligament (which is a fold of the peritoneum) and joined with the left portal vein.
Describe the inflow (blood supply) of the liver.
- hepatic artery (25% of blood) - supplies oxygenated blood to the liver
- portal vein (75% of blood) - supplies the liver with metabolic substrates (first organ to do so) and processes any ingested substances (detoxifies toxins)
Describe the outflow of the liver.
- bile that liver produces that comes out of the common bile duct
- 3x hepatic veins take blood out to inferior vena cava which goes straight into the heart
How many segments does the liver have?
8 segments that go clockwise, on left and right side
What makes up the micro-morphology of the liver?
- lobules - portal lobule and hepatic lobule
- portal triads (tracts)
Describe hepatic lobules.
- hexagonal structural unit of liver tissue
- each corner consists of a portal triad - links with 3 adjacent lobules
- centre of liver lobule is a central vein which collects blood from hepatic sinusoids –> hepatic veins –> systemic venous system –> IVC
- within lobules are rows of hepatocytes - each has a sinusoid-facing side to pick up things from blood & bile canaliculi-facing side to put nutrients into bile
What makes up a portal triad?
- branch of hepatic artery - brings O2-rich blood into liver to support hepatocytes increased energy demands
- branch of portal vein - mixed venous blood from GI tract (carrying nutrients, bacteria and toxins) and spleen (waste products) - hepatocytes process nutrients, detoxify blood and excrete waste
- bile duct - bile produced by hepatocytes drains into bile canaliculi which join with cholangiocyte-lined bile ducts around lobule perimeter
Describe the venous circulation of the liver.
Portal vein (formed by joining of superior mesenteric vein and splenic vein) –> liver sinusoids –> liver central veins –> intralobular vein –> interlobular vein –> etc until hepatic veins (right, middle and left) –> IVC
What are sinusoids formed from?
- hepatic artery and portal vein (blood from both mix)
- bile flows in opposite direction to blood in sinusoids
What is the micro-function of the liver?
- acinus
- blood flow
- bile flow
What is the hepatic acinus?
- functional unit of the liver which is hard to define anatomically
- diamond shaped, consisting of 1/6 of two adjacent hepatic lobules and is the area between two triads and two central veins (= diamond)
- share 2 portal triads
- extend into hepatic lobules as far as central vein
Describe the three zone model of the acinus.
- blood comes into hepatic acinus via portal triad (point A on diagram)
- blood drains out of hepatic acinus via central vein (point B)
- hepatocytes near outer hepatic lobule (zone 1) receive early exposure to blood contents - both good like O2 and bad like toxins
- acinus split into 3 regions:
- zone 1 - high O2, high toxin risk
- zone 2 - intermediate O2, intermediate toxin risk
- zone 3 - low O2, low toxin risk (this is where we see liver damage if liver ischaemia occurs)
What are sinusoidal endothelial cells?
- no basement membrane
- fenestrated (discontinuous endothelium)
- allow lipids and large molecule movement to and from hepatocytes
- line sinusoids
What are Kupffer cells?
- sinusoidal macrophage cells
- attached to endothelial cells
- they do phagocytosis to eliminate and detoxify substances arriving in liver from portal circulation
- within sinusoids
What are hepatic stellate AKA ito AKA perisinusoidal cells?
- within space of disse
- exist in dormant state
- store vitamin A in liver cytosolic droplets
- activated (fibroblasts) in response to liver damage
- proliferate, chemotactic and deposit collagen in ECM
What are hepatocytes?
- 80% of liver mass and are cubical
- synthesis e.g. albumin, clotting factors and bile salts
- drug metabolism
- receive nutrients and building blocks from sinusoids
What are cholangiocytes?
Secrete HCO3- and H2O in bile
What are the functions of hepatocytes?
- metabolic and catabolic functions - synthesis and utilisation of carbohydrates, lipids and proteins
- secretory and excretory functions - synthesis and secretion of proteins, bile and waste products
- detoxification and immunological functions - breakdown of ingested pathogens and processing of drugs
What is glycolysis?
- anaerobic conversion of glucose to lactate (RBCs, renal medulla, skeletal muscle)
- aerobic oxidation of glucose (CNS, heart, skeletal muscle, most organs)
What is glycogenesis?
Synthesis of glycogen from glucose (liver and muscle)
What is glycogenolysis?
Breakdown of glycogen to glucose
What is gluconeogenesis?
- production of glucose from non-sugar molecules:
- amino acids (glutamine) in liver and renal cortex
- lactate (from anaerobic glycolysis in RBCs and muscles)
- glycerol (from lipolysis)
What is lipolysis?
Breakdown of triacylglycerols –> glycerol + FFAs
What is lipogenesis?
Synthesis of triacylglycerols (storage in fat depots)
How does carbohydrate metabolism happen in the liver and muscle cells together?
- Cori cycle is when lactate (pyruvate –> lactate in anaerobic conditions) is reconverted into glucose in liver then sent back to muscle cell to be used
- lactate is reconverted to pyruvate by lactate dehydrogenase which undergoes gluconeogenesis in the liver –> glucose, which is then transported to muscle cell
- if O2 in muscle cell, then pyruvate –> ATP in aerobic respiration
How does protein synthesis happen in the liver and muscle cells together?
- AA (from diet in fed state, from muscle cells in fasted state) –> liver
- AA –> secreted proteins
- e.g. plasma proteins, clotting factors, lipoproteins
How are non-essential amino acids made by the liver?
- through transamination - different keto acids can be converted into multiple amino acids depending on the transaminase enzyme (vital for production of non-essential amino acids)
- eg alanine + a-ketoglutarate –> pyruvate + glutamate
- alpha-ketoglutarate –> glutamate, proline, arginine
- pyruvate –> alanine, valine, leucine
- oxaloacetate –> aspartate, methionine, lysine
What problem does the glucose-alanine cycle solve?
Muscle can potentially utilise amino acids to produce glucose for energy but:
- to convert pyruvate to glucose requires energy
- to remove nitrogen as urea requires energy
- glucose-alanine cycle - deamination in the liver, which has energy to do this (not muscle)
What four amino acids are in higher concentrations in cells than the other 16?
- alanine, aspartate, glutamate, glutamine
- glutamate is most important as it is related to alpha-ketoglutarate (key intermediate in Krebs)
What amino acid is principally released from muscle during starvation and how?
- alanine
- glutamate is released from AA breakdown and the NH2 is transaminated onto pyruvate to form alanine
- transamination: alanine + alpha-ketoglutarate –> pyruvate + glutamate
What does fat do?
- main energy store in body (100x more than glycogen)
- stored in adipose and liver
- when glycogen stores full, liver converts excess glucose and AA to fat for storage
Describe triglyceride breakdown in adipose tissue cells and liver cells.
- triglyceride broken down into FFAs (adipose tissue cell) which are shuttled into the liver
- FFA converted to acetyl CoA (beta oxidation) which can enter TCA cycle –> ATP
How can acetyl CoA be used as an alternate fuel source? (Ketone bodies)
2 acetyl CoA –> acetoacetyl CoA then add another acetyl CoA –> HMG-CoA which can be cleaved –> acetoacetate + acetyl CoA
How can glucose entering the liver be converted into components of lipoproteins?
- directly into glycerol
- into pyruvate –> acetyl CoA which can form cholesterol (HMG-CoA reductase) and fatty acids (malonyl CoA)
- glycerol and FFAs –> triacylglycerols
- apoproteins, phospholipids and cholesterol get added to make lipoproteins
What two lipoproteins are made by the liver?
- VLDL - transport fatty acids to tissues, this forms LDL once fatty acids delivered, which are high in cholesterol to deliver to tissues for cell membrane integrity and to make hormones - excess cholesterol returned to liver and excreted as bile
- HDL - high protein and low fat content - picks up excess cholesterol in circulation to return to liver
What does the liver store?
- fat soluble vitamins (A, D, E, K) and B12 - stores sufficient for 6-12 months except vitamin K (essential for blood clotting) where store is small
- iron as ferritin - available for erythropoiesis
- copper
What enzyme performs detoxification?
P450 enzymes
What are the two phases of detoxification?
- modification - making substance more hydrophilic
- conjugation - attach water soluble side chain to make the substance less reactive
What is the composition of bile?
- water - 97%
- bile salts - 0.7%
- inorganic salts - 0.7%
- bile pigments (bilirubin, biliverdin) - 0.2%
- fatty acids - 0.15%
- lecithin - 0.1%
- fat - 0.1%
- cholesterol - 0.06%
- alkaline phosphatase - varies
- drug metabolites - higher mw > urine
- trace metals - Fe, Zn, Mn, Pb, Cu
What are the uses of bile?
- cholesterol homeostasis
- absorption of lipids and lipid-soluble vitamins (A, D, E, K)
- excretion of: xenobiotics/drugs, cholesterol metabolites, adrenocortical and other steroid hormones, alkaline phosphatase
How much bile is produced?
500 ml a day
Why is bile yellow/green?
Due to pigments like bilirubin and biliverdin
How are hepatocytes involved in bile production?
- primary secretion - secrete 60% of total bile
- bile secretions reflect serum concentrations
- secretion of bile salts (acids), lipids and organic ions
How are cholangiocytes involved in bile secretion?
- secrete 40% of total bile
- secondary modification:
- alteration of pH (alkaline electrolyte solution)
- H2O drawn into bile by osmosis via paracellular junctions
- luminal glucose and organic acids reabsorbed
- HCO3- and Cl- actively secreted into bile by CFTR (cystic fibrosis transmembrane regulator)
- IgA exocytosed
What are biliary transporters and what do they do?
- are on apical and basolateral membranes of hepatocytes and cholangiocytes
- perform biliary excretion of bile salts and toxins
What are the main biliary transporters?
Basolateral membrane (importing, portal blood –> hepatocyte):
- organic anion transporting peptide (OATPs) - bile salt uptake
- Na+ taurocholate-cotransporting polypeptide (NTCP) - bile salt uptake
Apical surface (exporting, hepatocyte –> bile):
- bile salt excretory pump (BSEP) - active transport of bile acids into bile
- MDR related proteins (MRP2&MRP3) - negatively charged metabolites
- products of multidrug resistance genes - MDR1 –> excretion of neutral and +ve xenobiotics and cytotoxins, MDR3 –> phosphatidylcholine
What are bile salts (acids) made from?
- synthesised from cholesterol
- Na+ and K+ salts of bile acids conjugated in liver to glycine and taurine
What are the two primary bile salts synthesised in the liver and what secondary acids are produced from them by gut bacteria?
- cholic acid –> deoxycholic acid
- chenodeoxycholic acid –> lithocolic acid
What is the function of bile salts?
- reduce surface tension of fats
- emulsify fat prior to its digestion and absorption
- bile salts form micelles
- they are amphipathic - steroid nucleus planar, have two faces:
- one surface hydrophilic domains (hydroxyl and carboxyl) - faces out –> dissolves in water
- one surface hydrophobic domains (nucleus and methyl) - faces in –> dissolves in fat
- FFAs and cholesterol inside
How is bile flow and secretion regulated?
- between meals the Sphincter of Oddi closed –> bile diverted into gall bladder for storage
- eating = Sphincter of Oddi relaxes - gastric contents with FFAs and AAs enter duodenum causing release of cholecystokinin (CCK) which causes gall bladder to contract
What happens to bile salts once they enter the ileum?
- 95% are reabsorbed from terminal ileum by Na+/bile salt co-transport ATPase system - these go back to liver and re-excreted into bile through biliary transporters (enterohepatic circulation)
- 5% converted to secondary bile acids in colon - all deoxycholic acid is absorbed but 99% of lithocolic acid is excreted into stool
What are the functions of the gallbladder?
- stores bile (50 mls) - concentrates and acidifies bile
- GB contraction triggered by CCK which binds to CCK(A) receptors and neuronal plexus of GB wall (innervated by preganglionic parasympathetic fibres of vagus nerve)
What are the properties of free bilirubin (indirect/unconjugated)?
- H2O insoluble
- yellow pigment
Where does free bilirubin come from?
- 75% from Hb (erythrocytes) breakdown
- 22% from catabolism of other haemoproteins
- 3% from ineffective bone marrow erythropoiesis
What happens to free bilirubin in blood?
- free BR is bound to albumin in blood - high albumin and low bilirubin means liver working properly
- most dissociates in liver and enters hepatocytes
- BR conjugates with 2x molecules of UDP-glucuronate to form bilirubin diglucuronide (direct bilirubin)
- this is secreted across concentration gradient into biliary canaliculi –> GI tract
What happens to bilirubin in gut?
- 200-250mg BR excreted into bile/day
- 85% excreted in faeces - BR –> urobilinogen –> stercobilinogen –> stercobilin (brown compound)
- 15% enters enterohepatic circulation - BR –> deconjugated –> lipophilic form ; urobilinogen ; stercobilinogen
- 1% enters systemic circulation and excreted by kidneys
What are the causes of jaundice?
- pre-hepatic - increased bilirubin, cannot conjugate
- intrahepatic - specific syndromes, acute and chronic liver damage, drug side effects - decreased uptake –> decreased conjugation –> reduced secretion –> reduced outflow = cholestasis
- post-hepatic - gall stones, tumours –> reduced extrahepatic outflow
