Bilirubim Meatbolism

BILIRUBIM MEAT BOLISM Structure and function of hepatic circulation: The blood supply to the liver has two sources. The portal vein (portal) contributes ∼75% of the total circulation to the liver; hepatic artery (systemic) contributes the other 25%. Blood from portal venules and hepatic arterioles combines in a complex network of hepatic sinusoids. Blood from these sinusoids converges on terminal hepatic venules (or central veins), which, in turn, join to form the hepatic vein. Branches of the portal vein, hepatic artery, and a bile duct (i.e. the triad), as well as lymphatics and nerves, travel together as a portal tract Apical: Tight junctions Desmosomes – contains bile Basolateral: Sinusoid lumen – contains blood Hepatocytes form an epithelium, one cell thick, which constitutes a functional barrier between two fluid compartments with differing ionic compositions: the tiny canalicular lumen containing bile and the much larger sinusoid containing blood. Microvilli increase surface area of the baso-lateral membrane and sinusoid is fenestrated to allow movement. Hepatocytes can significantly alter the composition of fluids by vectorial transport of solutes across the hepatocyte. This depends critically on the polarised distribution of specific transport mechanisms and receptors that are localised to the apical membrane facing canalicular lumen and the basolateral membrane that faces the pericellular space between hepatocytes and the blood-filled sinusoid. The complement of transporters and receptor differs along biliary tree → Change in composition of bile to Iso-osmotic with plasma Bile is secreted into canaliculi → Terminal Bile ductules (canals of Hering) → Perilobular Bile ducts → Interlobular Bile ducts (luminal surface lined by microvilli) → Septal → Lobar → Hepatic → Common hepatic duct Bile production: Bile formation by hepatocytes requires the active, energy-dependent secretion (ATP dependent) of the inorganic and organic solute into canalicular lumen, followed by passive movement of water. This should also create a transmembrane potential. This movement of water through the tight junctions between the hepatocytes carrie other solutes by solvent drag (Canalicular bile is an isosmotic fluid; thus, the intercellular junctions allow the passage of water and smal ions). Further down the biliary tree (i.e. ducts and gallbladder), pore size of paracellular junctions is significantly smaller, solvent drag i not as important. Organic solutes do not readil enter bile distal to the canaliculi. An organic anion-transporting polypeptide (OATP) is a membrane transport protein that mediates the transport of organic anions across the cell membrane. Organic anion transporters may carry bile acids as well as bilirubin over the basolateral membrane (facing sinusoids) in hepatocytes, as well as other anions for excretion in bile. Some bilirubin may reflux back into plasma before it is enzymatically changed. Multidrug resistance-associated protein 2 (MRP2) is expressed in the canalicular (apical) part of hepatocyte and functions in biliary transport. Biliriubin is conjugated (glucose added) and transported into canaliculus, effectively trapped in bile. MRP2 is also expressed in on the apical membrane of proximal renal tubule endothelial cells where they are involved in the excretion of small organic anions. Bile: Changes in Ductules Secretin, glucagon, VIP, and the gastrin-releasing peptide (GRP) either enhance fluid absorption or inhibit secretion. Apical membrane: − Cl--HCO3- exchanger − Cl- channels Basolateral membrane: (power source) − − − − Na+/K+ ATPase Na+/H+ exchanger Na+/ HCO3- symporter K+ Channel Na+/H2O move passively via tight junctions / paracellular pathway → Solvent drag This process is stimulated hormones such as secretin as shown in the diagram. Bile: Changes in Gall Bladder Concentration: 10-20 Fold, by dragging water BACK into epithelial cell and interstitial space Basolateral membrane: − Na+/K+ ATPase − K+ Channel − Cl- channels Apical membrane: − Parallel Na+/H+ and Cl--HCO3- exchanger The H+ secreted by the gallbladder protonates intraluminal contents (neutralises HCO3-). This increases the solubility of calcium salts in bile and reduces the likelihood of calcium salt precipitation and gallstone formation. Storage & Discharge: Vagal (Ach) activity − Smooth-muscle contraction / evacuation of the gallbladder Duodenal lipid → CCK Secretion − Smooth-muscle contraction / evacuation of the gallbladder − Relaxation of the sphincter of Oddi − ↑ Bile flow into the duodenum Origin of Bilirubin Bilirubin is the pigment produced by metabolism of haemoglobin released during the destruction of red blood cells at end of their life span (~120 days) – in spleen, liver + bone marrow (macrophages called the Kupffer cells residing in the hepatic sinusoidal vascular space removes particulate matter such as old RBCs from the circulation) Jaundice & buildup of bilirubin levels: Potential causes: − Excessive production of bilirubin − ↓ Hepatocyte uptake − ↓ Conjugation (Gilbert’s disease ↓UDP gluconyl transferase) − ↓ Hepatocellular excretion (The rate limiting step) − ↓ Bile flow (intrahepatic and extrahepatic) Last 2 are conjugated hyperbilirubinemia