The Liver (FINISH) Flashcards
Liver lobule structure:
Each lobe of the liver is made up of hexagonal lobules which radiate from a central vein which joins the hepatic vein to carry blood away from the liver. Along each of the corners of the lobule is the portal triad consisting of a branch of the hepatic artery which supplies oxygenated blood to the liver, a branch of the hepatic portal vein which carries in venous blood from the GI tract and spleen rich in nutrients and toxins to be detoxified by hepatocytes, and the bile duct which carries bile away from the liver to the gall bladder and duodenum. Blood flows through liver sinusoids, and empties into the central vein of each lobule
bilirubin metabolism:
In a macrophage of the reticuloendothelial system, haem oxygenase catalyses the degradation of Haem to Biliverdin, and Biliverdin reductase converts this to Bilirubin. It is bound to albumin in plasma as the unconjugated bilirubin is insoluble. In the liver, It is conjugated with glucuronic acid by uridyl diphosphatase glucoronyl transferase to make bilirubin diglucoronide in the ER of hepatocytes (conjugated). Much of this makes up bile coming from the liver to join the small intestine via the common hepatic duct. conjugated bilirubin isnt absorbed and enters the colon where colonic bacteria deconjugate the bilirubin to colourless urobilinogen which is oxidised to urobilin and stercobilin which make up the brown faecal colour, Alternatively, some of the urobilinogen is reabsorbed into the enterohepatic circulation to be re-excreted in bile, or processed by the Kidneys to form the yellow urine colour.
Drug-induced liver damage:
The liver is the principal organ of drug metabolism. Drug metabolising enzymes located in the lipophilic membranes of ER (microsomes). These contain enzymes responsible for oxidative drug metabolism such as cytochrome P-450
Principle reactions in drug metabolism
1.) P-450 can oxidate, reduce or hydrolyse lipophilic drugs to phase 1 metabolites which can be conjugated to make water soluble metabolites which are subsequently more polar and more inactive to be transported out of the body as bile.
Pathogenesis of drug-induced liver disease
Drug or drug metabolite can absorb reserve of gluthathione which is a buffering antioxidant required to perform redox reactions on toxic species such as free radicals and reactive oxidative species to neutralise them.
Paracetamol (acetaminophen) toxicity;
If conjugating power of hepatocytes is overwhelmed with excess acetaminophen levels then glucoronidation and sulfation cannot be performed on it and the easily detoxified metabolites are not produced. Instead, the toxic metabolite NAPQI will be present in levels where not all of it is able to be conjugated to gluthathione and will be able to react with nucleophilic groups present on macromolecules to produce cytokines and reactive oxidative species which can lead to hepatic necrosis. N-acetyl cysteine is used as an antidote to replenish levels of gluthathione.
Paracetamol toxicity: pattern of change
Peak serum levels usually 30 mins to 2 hours after ingestion. elimination from body is rapid with half-life of about 2 hours. Peak blood level is usually less than 20mg/L following 1000mg dose. liver injury may occur after a single 15mg dose. Damage depends on level of gluthathione. Administration of NAC within 24hrs can prevent liver failure
Hepatic encephalopathy grading: (4)
- ) Awake, mild confusion, mental clouding.
- ) Disorientation to time and place, decreased level of consciousness.
- ) Sleepy, but rousable to pain and voice, complete disorientation
- ) Comatose, unrousable
Pathogenic factors in Alcoholic liver disease:
Altered methionine metabolism Mitochondrial disfunction Acetaldehyde Hypoxia Oxidative stress Immune
Ethanol Metabolism;
Ethanol is oxidised to Acetaldehyde by hepatic enzyme alcohol dehydrogenase and using NADPH. Acetaldehyde is unstable and forms free radicals which are highly toxic if not neutralised. In mitochondria, it is metabolised to Acetate by aldehyde dehydrogenase and is free to enter the TCA cycle
Oxidative stress In Alcoholic liver Disease
Oxidative stress can arise when the presence of acetaldehyde associated toxic species (through lipid peroxidation which releases ROS) overwhelm the antioxidant capacity of the hepatocytes. The oxidative stress can trigger proinflammatory cytokines which activate stellate cells leading to excess collagen and fibrosis of the liver.. Alcohol increases permeability of endotoxin from gut which stimulates macrophage recruitment, then stellate cells activation..
Altered methionine in Alcoholic Liver Disease;
Methionine is a precursor to gluthathione which enters into the methionine cycle to maintain levels of gluthathione and the ability to deal with toxicity, Methionine adenosyltrasnferase converts methionine to s-adenosylmethionine (responsible for being a methyl donor for decreasing membrane fluidity and cellular ATP). Methionine (up), SAM (down) Homocysteine (up) gluthathione (down) leads to necrosis.
Steatosis (fatty lievr):
Acetate + CoA + ATP –> Acetyl CoA + AMP + PPi
Catalysed by thiokinase
NADH inhibits isocitrate dehydrogenase & alpha-ketoglutarate dehydrogenase + fatty acid oxidation
NADH favours fatty acid synthesis
Excess lipids accumulate in vesicles which displace cytoplasm. Excess levels of NADH due to ethanol metabolism promotoes steatosis by stimulating synthesis of fatty acids, and opposing their oxidation.
Also stimulated by
3 stages of Alcoholic Liver Disease:
Stage 1: Fatty liver, mitochondrial disfunction, reversible.
Stage 2: Alvoholic hepatitis, Necrosis, inflammation, collagen fibres.in around terminal hepatic venule. Precursor for cirrhosis.
Stage 3: Cirrhosis, fibrosis, cell death, end-stage liver failure –> Irreversible
Lab analysis in ALD:
AST > ALT --> AST usually > 2 x ALT. This ratio is suggestive of alcoholic lievr disease, particularly in the setting of raised GGT. Alcoholic fatty liver disease: AST <8 times the Upper limit of reference. both values usually <300 IU/L GGT increased (usually toxin induced damage) ALP increased -> sign of cholestasis, found in liver and bone. ALP increased with Bilirubin indicates source of ALP is the liver. If others are normal, check bone. Albumin decreased (hepatic damage, alcoholic malnourished) Bilirubin usually increased (doesn't clinically show early) Prothrombin time usually prolonged Ascites --> Swollen abdomen due to redistribution of fluid from hypoalbuminaemia
