Liver Function Flashcards
What are the features of sinusoidal capillaries?
DAN
→ large intracellular gaps
→ allowing movement of proteins and cells across endothelial lining
→ which allows transport between blood and hepatocytes (via space of Disse)
How are hepatocytes specialised to to exchange solute between space of Disse and bile canaliculi?
DAN
→ Hepatocytes contain microvilli to increase SA for exhange from blood
→ they have special transporters that uptake, metabolise and excrete range of solutes:
NTCP → bile acid transporter
OST → organic solute transporter
MATE1 → organic cation transporter
BSEP → bile salt export pump
BCRP → drug transporter
How are lipids transported in body?
DAN
→ dietry fats and lipids get put into chylomicrons
→ which are hydrolyzed by lipoprotein lipase (LPL) to triglyerides when they touch endothelial walls
→ to release FA and glycerol to be stored in adipocytes of skeletal muscle
→ the remaining chylomicron remnants bind to endothelial cells in liver sinusoids
→ the apolipoprotein-E on surface of chylomicron remnants, which trigger clearance of plasma liproteins.
How is cholesterol metabolised?
DAN
→ liver secretes very-low density lipids (VLDL) into blood - which are converted to IDL
→ IDL can then be taken up by liver to make more VLDL or stays in circulation where it is converted to cholesterol-rich LDL
→ LDL is taken up by LDL-R on hepatocytes via internalisation un clathrin-coated pits
→ into endosome where vesicles fuse with lysosomes
→ in the lysosomes, HMG-CoA reductase degrades LDL to mevalonate - which then converted to free cholesterol in cytoplasm.
→ Statins will inhbit HMG-CoA
How is protein metabolism?
DAN
Transamination:
→ AA converted to keto acids by aminotransferase (ALT,AST)
→ and in a side reaction the NH2(amine group) is removed from AA
→ and incorparted into α-ketogutaric acid to form glutamate
Deamination:
→ Glutamate dehydrogenase
→ will convert glutamate back into α-ketogutaric acid and ammonia
Urea Cycle:
→ occurs in liver mitochondria
→ where ammonia is converted to carbamyle phosphatase
→ via carbomyl phosphatase synthase (require ATP).
Carbamyle phosphatase + orthinine = Citrilline
Citrilline → Aspartate → Arginine.
Arginine is then converted back into Orthinine but as a by-product. Urea is formed and excreted into blood.
How can ketoacidosis occur?
DAN
→ during starving/fasting states, lack of insulin or unresponsiveness insulin-dependent cells to insulin
→ means only glucagon dominates causing lots of reactions including lipolysis → as a result of lipolysis reactions
→ lots of Acely-CoA is made, which undergoes ketogenesis to form ketone bodies such as acetate and β-hydroxybutyrate
→ these then go into blood stream, increase H+ ion concentration of plasma → causing decrease pH
→ causing metabolic acidosis, which causes vomitting, increase urine output (dehydration) and fall into coma
What is bilirubin metabolism?
DAN
Breakdown of RBC:
→ Globin component broken down into AA
→ Heme component broken down into iron (taken to liver) and protoporphyrin
→ Heme is converted to Unconjugated Bilirubin (Biliverdin) and bound to albumin to be taken to liver
→ Hepatocytes convert Biliverdin to Conjugated Bilirubin via Uridine Glucuronyl Transferase (UGT)
→ UGT is stored in Bile Canaliculi
→ Intestinal bacteria convert Conjugated Bilirubin to Urobilinogen
→ Urobilinogen is then either oxidised to:
Stercobilin (brown colour of faeces) or
Urobilin (yellow of urine)
Alcohol metabolism
DAN
→ ethanol metabolised via alcohol dehydrogenase, cytochrome P-450 (particularly CYP2E1 isoform) isoenzymes or catalase
→ to form acetaldehyde
→ which is converted in mitochondria to ALDH and Acetic acid
Effects of alcohol metabolism
DAN
→ Alcohol dehydrogenase uses up NAD+
→ therefore increases NADH
→ NAD+ is depleted so less hepatic fatty acid oxidation occurs
→ which leads to fat accumulation in liver
Acetaldehyde toxicitiy
→ CYP2E1 produces ROS and lipid peroxidation causing cell damage
What is liver cirrhosis
DAN
→ triggers stellate cells to assume myofibroblast phenotype
→ causing them to deposit collagen in space of Disse
→ causing compression of sinusoidal capillaries
→ causing increase blood flow resistance through sinusoids to hepatic vein
→ causing portal hypertension
→ this then causes build up of pressure in splanchnic circulation
→ triggering NO release
→ vasodilates splanchnic arterioles → causing great blood vol in splanchnic circulation
→ so less blood reaches IVC
→ decrease MAP detected by baroreceptors
→ causing increase SNS activity in kidneys
→ increasing Na+ reabsorbtion and activates RAAS
→ RAAS increases blood vol and thirst
→ this increases blood volume
→ so can handle large scale water loss to peritoneal cavity → ASCITES
→ deposition of collagen blocks fenestrations in sinusoidal capillaries
→ so albumin cannot move into circulation
→ causing hypoalbminemia
→ this increases fluid filtration across hepatic and intestinal cappilaries into peritoneal space
→ causing increase fluid vol
→ this causes decrease blood vol then decrease MAP
→ decrease siusoidal and intestinal pressure
Morphology of cirrhosis
DAN
→ characterized by tansformation of liver
→ into regenrative parenchymal nodules
→ surrounded by fiborus bands
Where does the liver receive blood from and where does it go after?
→ liver is the largest organ and receives blood from the gastrointestinal tract
→ via the hepatic portal vein
→ the liver acts as an interface between the bloodstream and the gastrointestinal tract
Inputs:
→ hepatic artery (O2 rich)
→ hepatic portal vein (nutrient rich)
Outputs:
→ bile duct
→ hepatic vein —> IVC
Key features
→ low blood pressure
→ low vascular resistance
Liver function (4)
→ filters blood
→ stores and releases metabolites
→ production of bile and coagulation factors
→ metabolises vitamins and hormones
Hepatic lobules
Apical side of the hepatocyte
→ faces the Bile Canaliculi
Basolateral side of the hepatocyte
→ faces space of Disse
Consist of:
→ central vein
→ 6x portal triad areas
→ sinusoids
→ hepatocytes
→ bile caniculi
→ Space of Disse
→ cords
Split into zones 1-3:
→ zone 1 is closes to portal triad
→ zone 3 is closest to central vein
Kupffer cells
→ population of fixed macrophages
→ part of reticuloendothelial system
→ help to act as the final component of the gut barrier to pathogens taken up via the gastrointestinal system
→ as well as helping to remove ageing erythrocytes and particulate matter from blood
Hepatic stellate cells
At rest:
→ responsible for storing vitamin A
→ in large lipid droplets inside cell
Upon activation:
→ produce collagen and ECM components
Sinusoidal capillaries
→ large intercellular gaps that allow free movement of proteins and cells across the endothelial lining
→ allowing for effective transport between blood and hepatocytes via the space of Disse
→ liver and spleen have capillaries with incomplete basement membranes and intercellular gaps
→ means a much higher Kf
Hepatocytes
→ Secretory epithelial cells
→ specialised for exchanging solutes between the space of Disse and the bile canaliculi
→ have microvilli to increase SA for exchange from blood
→ able to uptake, metabolise and excrete a wide range of solutes using both multidrug-resistance-associated proteins (MRP) and organic anion transporters (OAT)
Lipid transport
- lipoprotein synthesis, secretion and reuptake
- chylomicron processing
- bile salt production
→ Dietary fats are broken down into fat droplets
→ then broken down into fatty acids, glycerol and cholesterol
→ these are packaged into chylomicrons and travel in the lymphatic system; until they are transformed into VLDL and HDL to travel in systemic circulation
→ travel in the blood to muscle and adipocytes
→ remnant chylomicrons and extra LDL are taken to the liver where they are excreted as bile salts back into the digestive tract
Cholesterol metabolism
Happens in the liver:
→ Acetyl CoA
→ HMG-CoA
→ mevalonate
→ cholesterol
→ VLDL
→ travels in the blood
Or
→ Acetyl CoA
→ HMG-CoA
→ mevalonate
→ cholesterol
→ excreted into bile as a primary bile acid (cholic acid and chenodeoxycholic acid)
→ bacteria converts them into secondary bile acids (deoxycholic acid, lithocholic acid)
→ enterohepatic circulation
Statins block mevalonate production
Protein metabolism
Amino acids:
1) deamination to urea
2) Transamination to non-essential fatty acids
3) Gluconeogenesis
4) Protein synthesis - metabolism: albumin, lipoproteins
Inflammation:
→ CRP
→ complement C3
Endocrine:
→ angiotensin
→ albumin
→ plasma binding proteins
Blood coagulation:
→ prothrombin
→ factor VII
→ factor IX
→ factor X
→ fibrinogen
→ plasminogen
Coagulation cascade
→ activated platelets within the thrombus start to express phosphatidylserine on their external face of their plasma membrane
→ circulating tissue factor an other clotting factors bind to the platelet plasma membrane in a calcium-dependent manner. This helps localised all the components of the coagulation cascade to the platelet surface making its catalysis more effective
→ this also helps limit the activation of thrombin to the surface of the platelet aggregate preventing excessive blood clotting
→ thrombin produced cleaves fibrinogen to fibrin
→ fibrin monomers spontaneously polymerise to form a gel
→ cross linking of fibrin by factor XIIIa then creates a strong, insoluble fibrin mesh which prevents the clot from being washed away by the flowing blood
Carbohydrate metabolism - glucose buffer function of liver
1) regulation of blood glucose by glycogen synthesis and breakdown
2) gluconeogenesis
3) conversion of carbohydrate and proteins into fatty acid and triglyceride
Controlled by:
→ insulin
→ glucagon
→ circulating catecholamines
→ sympathetic nervous system
Example:
→ Low blood glucose
→ glucagon glucocorticoids increases glyconeolysis
→ increases gluconeogenesis
→ decrease in glycogen storage as there has been glucose production
High blood glucose
→ insulin increase glycogen store
→ less gluconeogenesis
→ less glycogenolysis as glucose has been uptaken and stored
Insulin
Insulin promotes anabolism and storage
Skeletal muscle:
→ increase glucose uptake (exocytosis insertion of GLUT4)
→ increase glycogen storage (transcription of hexokinase and glycogen synthase)
→ promotes protein production
→ promotes glycolysis
Liver:
→ increase glycogen storage (transcription of hexoinase and glycogen synthase)
→ promotes glycolysis
→ inhibits gluconeogenesis (inhibiting PEPCK, fructose 1,6 biphosphate and glucose-6-phosphate)
→ promotes the synthesis and storage of fats
→ promotes protein production
Adipocytes:
→ increase glucose uptake (exocytotoic insertion on GLUT4)
→ increase glycogen storage (transcription of hexoinase and glycogen synthase)
→ promotes triglyceride production (promotes esterification and inhibits hormone-sensitive lipase)
Glucagon
Skeletal muscle:
→ activates proteolysis - amino acids can be used in hepatic gluconeogenesis
Liver:
→ promotes glyconeolysis (activates glycogen phosphorylase)
→ inhibits glycolysis
→ activates gluconeogenesis (activates PEPCK, fructose 1,6 biphosphate and glucose-6-phosphatase)
→ promotes oxidation of fats and formation of ketone bodies (increasing activity or carnitine acyltransferase
Adipocytes:
→ Accelerates lipolysis - fatty acids can be used in hepatic gluconeogenesis
The Cori cycle / the lactic acid cycle
→ Glucose moves into muscle
→ (glycolysis)
→ 2x pyruvate (+ 2x ATP)
→ 2x lactate
→ 2x lactate moves to the liver
→ converted to 2x pyruvate
→ (gluconeogenesis)
→ glucose (+ 6x ATP)
→ glucose back in circulation
→ (cycle loops)
The liver coordinating the response to fasting
Pre-absorptive phase:
→ the CNS and many other tissues preferentially used glucose, produces from glycogen breakdown
Gluconeogenic phase:
→ protein catabolism is used to feed glucose to the CNS, while other tissues feed on ketones and fat
Protein conservation phase:
→ protein catabolism is decreased to a minimum, fatty acids are used everywhere and ketones instead of glucose fuel the CNS
Lipids that get back into the liver are converted to ketones
Ketoacidosis
→ the liver can produce ketones as an alternative to glucose to fuel metabolism during periods of fasting
→ ketone production usually prevented by insulin. In the absence of insulin and maintained presence of glucagon, the body will release free fatty acids from adipocytes which can be rapidly converted to ketone bodies in the liver
→ these ketones acidify the bloodstream - leading to vomiting, and with concurrent hyperglycaemia triggering an increase in urine output, patients can rapidly become dehydrates and can fall into a coma. Thus diabetic ketoacidosis is a medical emergency
Gluconeogenesis in the liver
Fatty acids can be converted to glucose or in the fasting state ketones as little glucose so the CNS needs to use ketones as an energy source
Liver oxidation of fatty acids can release ketone bodies during fasting
Proteins can be converted to glucose
Bilirubin metabolism
Breakdown of aging red blood cells by the reticuloendothelial system
- Hb → haem + globin
- Haem → (haem oxygenase) → biliverdin → bilirubin
Bilirubin is not very water-soluble and so is usually carried in the bloodstream bound to albumin.
Bilirubin is metabolised in the liver:
→ bilirubin moves into liver by OATP (Cl- moves out at the same time)
→ bilirubin in the liver is conjugated to improve water solubility and form bilirubin digulcoronide
→ this helps transport bilirubin
→ bilirubin diglucoronide then enters the bile duct and is then converted to bilirubin and then urobilinogen
→ urobilinogen has 3 fates
1) Converted to urobilin and is excreted in urine (yellow colour)
2) Converted to stercobilin and then excreted in faeces (brown colour)
3) Enters hepatic circulation via hepatic portal vein and heads back to the liver to try to be metabolised again
Liver injury
→ loss of microvilli
→ fibrogenesis
→ stellate cells activated
→ Kupffer cells activated
→ loss of fenestrations in the epithelial cells lining the sinusoid → natural killer cell inhibition
→ natural killer T cells activated
Pathophysiology of Ascites
Part 1
- liver cirrhosis triggers the stellate cell to assume a myofibroblast-like phenotype which causes them to deposit collagen in the space of Disse as well as contracting leading to compression of the sinusoidal capillaries - increasing resistance to blood flow through the sinusoids into the hepatic vein
- this deposition of collagen also blocks fenestrations in the sinusoidal capillaries - reducing albumin’s movement from hepatocytes into circulation - leading to hypoalbuminemia
- the increased resistance to flow trigger sinusoidal capillary and portal hypertension
- portal hypertension worsened as the build up of pressure in the splanchnic circulation triggers greater NO production and this elicits vasodilation of the upstream arterioles of the splanchnic arterioles
- increasing blood flow into the splanchnic circulation
- increase in portal hypertension leads to a greater volume of blood becoming stored within the splanchnic veins
- the reduction in plasma albumin content of blood
Pathophysiology of Ascites
Part 2
- therefore to support large-scale filtration into the peritoneum we also need to expand the blood volume to allow fluid to be redistributes from the blood into the peritoneum without affecting arterial blood pressure
- increase in blood volume —> = MAP —> = sinusoidal and intestinal pressure
- the pooling of blood in the splanchnic circulations and the higher resistance of blood flow through the hepatic vein - leads to a reduction in blood reaching the inferior vena cava
- leads to a reduced volume of blood IVC - leading to reduction in blood pressure there. This triggers reduced firing of the cardiopulmonary baroreceptors
- this signal is important in our bloods volume regulation system - when the firing of cardiopulmonary baroreceptors falls here - the body interrupts this as a fall in blood volume and acts to expand the blood volume
- in reality the blood volume isn’t changed, it id just abnormally distributed due to its increased pooling in splanchnic circulation
- the
Pathophysiology of Ascites
Part 3
- angiotensin II and aldosterone increase the blood volume by stimulating an increase in Na+ content of the blood (via increase dietary intake and reducing urine Na+ losses) and increasing our feelings of thirst
- this helps expand our blood volume. This expansion helps endure the body can support large-scale loss of water from the blood into the peritoneal cavity and elicits the onset of the overt symptom of ascites
- by blocking aldosterone function with spironolactone - we reduce the ability of the body to support an expanded blood volume, and so this slow filtration of fluids into the peritoneal cavity and allows lymph to start to redistribute some of the peritoneal fluid back into the blood stream
