Liver Functional unit: Hepatocyte Hexagonal lobules Vascular sinusoids Dr Jaria Fatahia 11/17/2018

Dr Jaria Fatahia 11/17/2018

Liver lobules Liver lobules – hexagonal structures . Hepatocytes radiate outward from a central vein At each of the six corners of a lobule is a portal triad Liver sinusoids Liver lobules – hexagonal structures consisting of hepatocytes Hepatocytes radiate outward from a central vein At each of the six corners of a lobule is a portal triad Liver sinusoids Sinusoids are low pressure vascular channels that receive blood from terminal branches of the hepatic artery and portal vein at the periphery of lobules and deliver it into central veins. Sinusoids are lined with endothelial cells and flanked by plates of hepatocytes 11/17/2018 Dr Jaria Fatahia

Hepatocytes produce bile Bile flows through canals called bile canaliculi to a bile duct Bile ducts leave the liver via the common hepatic duct 11/17/2018 Dr Jaria Fatahia

Bile BILE – bile salts, bile pigments, cholesterol, neutral fats, phospholipids and electrolytes Liver produces 0.5-1 l of bile daily Dr Jaria Fatahia 11/17/2018

Dr Jaria Fatahia 11/17/2018

Functions Metabolic Synthesis Breakdown Other functions – storage of vitamin A,D,B12,F… Excretion of waste products from bloodstream into bile Vascular – storage of blood Dr Jaria Fatahia 11/17/2018

Protein metabolism Synthesis of amino acids Formation of plasma proteins Albumins, globulins Clotting factors Transamination & transpeptidation Deamination Urea ccle Formation of nitrogen containing compounds N containing compounds :Porphyrins,Creatine,Neurtransmitters,Purines,Pyrimidine Dr Jaria Fatahia 11/17/2018

Protein metabolism Produces albumin the major osmolar component of blood serum Synthesizes angiotensinogen, the hormone responsible for raising blood pressure when activated by renin (enzyme released when the kidney senses low blood pressure) Dr Jaria Fatahia 11/17/2018

Carbohydrate Metabolism Formation & storage of glycogen Conversion of glycogen to glucose Gluconeogenesis Conversion of fructose & galactose to glucose Dr Jaria Fatahia 11/17/2018

Lipid Metabolism Formation of ketone bodies Formation of TG & VLDL Cholesterol Saturation & desaturation of FA Uptake of plasma LDL Bile, Bile salts, bile acids Bile pigment metabolism Dr Jaria Fatahia 11/17/2018

Breakdown Breaks down insulin and other hormones Breaks down hemoglobin Breaks down or modifies toxic substances (methylation) → sometimes results in toxication Converts ammonia to urea Dr Jaria Fatahia 11/17/2018

Breakdown Hb: Globin Iron Porphyrin part 11/17/2018 Dr Jaria Fatahia

11/17/2018 Dr Jaria Fatahia

The catabolism of hemoglobin is outlined in the graphic on the left The catabolism of hemoglobin is outlined in the graphic on the left. Red blood cells are continuously undergoing a hemolysis (breaking apart) process. The average life-time of a red blood cell is 120 days. As the red blood cells disintegrate, the hemoglobin is degraded or broken into globin, the protein part, iron (conserved for latter use), and heme (see middle graphic). The heme initially breaks apart into biliverdin, a green pigment which is rapidly reduced to bilirubin, an orange-yellow pigment (see bottom graphic). These processes all occur in the reticuloendothelial cells of the liver, spleen, and bone marrow. The bilirubin is then transported to the liver where it reacts with a solubilizing sugar called glucuronic acid. This more soluble form of bilirubin (conjugated) is excreted into the bile. The bile goes through the gall bladder Dr Jaria Fatahia 11/17/2018

In the human body approx In the human body approx. 100 – 200 million ery are broken down every hour. Degradation of Hb begins in ER of reticuloendothelial cells (RES) of the liver, spleen, bone marrow and skin. Hb is degraded to: ● globins → AAs → metabolism ● heme → bilirubin ● Fe2+ → transported with transferrin and used in the next heme biosynthesis Not only Hb but other hemoproteins also contain heme groups which are degraded by the same pathway Dr Jaria Fatahia 11/17/2018

Extravascular Pathway for RBC Destruction (Liver, Bone marrow, & Spleen) Phagocytosis & Lysis Hemoglobin Globin Heme Bilirubin Amino acids Fe2+ Amino acid pool Excreted 11/17/2018 Dr Jaria Fatahia

Heme Degradation  75% is derived from RBCs In normal adults this results in a daily load of 250-300 mg of bilirubin Normal plasma concentrations are less then 1 mg/dL Hydrophobic – transported by albumin to the liver for further metabolism prior to its excretion Dr Jaria Fatahia 11/17/2018

Uptake of bilirubin by the liver is mediated by a carrier protein (receptor) Uptake may be competitively inhibited by other organic anions On the smooth ER, bilirubin is conjugated with glucoronic acid, xylose, or ribose Glucoronic acid is the major conjugate - catalyzed by UDP glucuronyl tranferase “Conjugated” bilirubin is water soluble and is secreted by the hepatocytes into the biliary canaliculi Converted to stercobilinogen (urobilinogen) (colorless) by bacteria in the gut Oxidized to stercobilin which is colored Excreted in feces Some stercobilin may be re-adsorbed by the gut and re-excreted by either the liver or kidney Dr Jaria Fatahia 11/17/2018

Hemoglobin dissociates into Heme & globin Porphyrin ring is cleaved Oxidation of alpha methylene bridges Heme loses one molecule of CO & one atom of iron in ferric form Biliverdin ( biliverdin reductase) Bilirubin Dr Jaria Fatahia 11/17/2018

Biliverdin Dr Jaria Fatahia 11/17/2018

Bilirubin (Bil) is released from RES into the blood. BUT Bilirubin (Bil) is released from RES into the blood. BUT! Bil is only poorly soluble in plasma, and therefore during transport it is bound to albumin („nonconjugated Bil“). ↓ LIVER In the hepatocytes, Bil is conjugated by 2 molecules of glucuronic acid → bilirubin diglucuronide (soluble in water, „conjugated Bil“) BILE INTESTINE Bil is reduced to urobilinogen and stercobilinogen Dr Jaria Fatahia 11/17/2018

Conjugation bilirubin-diglucuronide = conjugated bilirubin is soluble in water → „direct bilirubin“ Urobilinogen and stercobilinogen can be: reabsorbed and returned to the liver (= enterohepatic circulation) b) oxidized (in the presence of O2) to pigments urobilin (orange) and stercobilin (yellow) → they are excreted in the stool Urobilinogen also appears in the urine. Dr Jaria Fatahia 11/17/2018

Bile pigments: bilirubin urobilin stercobilin Blood tests Bil reacts directly when reagents are added to the blood sample → conjugated bilirubin = direct Bil (up to 3.4 µmol/L) free Bil does not react to the reagents until alcohol (methanol) or caffeine is added to the solution. Therefore, the measurement of this type of bilirubin is indirect → unconjugated bilirubin = indirect Bil (up to 13.6 µmol/L) total bilirubin measures both unconjugated and conjugated Bil (normal value up to 17 µmol/L). Dr Jaria Fatahia 11/17/2018

Liver Function Tests Dr Jaria Fatahia 11/17/2018