Structure and function of liver and gallbladder

1. Structure and function of liver and gallbladder Romana Šlamberová, M.D. Ph.D. Department of Physiology, 3rd Faculty of Medicine

2. Liver • Largest organ in the body • Contributing about 1/50 of the total body weight (about 1.5 kg in adults) • Basic functional unit of the liver is the liver lobule (0.8 -2 mm in diameter; 50-100 thousands in the liver) • High blood flow - 1350 ml/min to liver sinusoids (1050 ml from the portal vein, 300 ml from hepatic artery) = functional and nutritive blood circulation • Physiologically – low vascular resistance (small difference between pressures in the portal vein and hepatic vein) - in case of pathological changes (steatosis or cirrhosis), the vascular resistance increases, blood flow decreases (portal hypertension, ascites) Department of Physiology, 3rd Faculty of Medicine

3. Function of the liver • Liver is the largest gland in the body 1.Formation and secretion of bile 2.Detoxication of various substances • Metabolic products of intestine microbes • Exogenous toxins (medicaments, alcohol, poisons) • Hormones (thyroxine, estrogen, cortisol, aldosterone) 3.Synthesis of plasma proteins • Acute-phase proteins • Albumin • Clotting factors • Steroid-binding and other hormone-binding proteins Department of Physiology, 3rd Faculty of Medicine

4. Function of the liver (2) 4. Coagulation (synthesis of most of the coagulating factors). Vitamin K is required for the formation of Factors II (prothrombin), VII (proconvertin), IX (Christmas factor), X (Stuart factor). 5. Blood reservoir– filtration and storage of blood (450 ml = almost 10 % of the body’s total blood volume). In cardiac failure it can be stored there up to 1 l of blood. 6. Immunity (Kupffer cells = macrophages) 7. Vitamins- metabolism and storage of vitamins A, D and B12 8. Relation to blood formation • storage of vitamin B12 • metabolism of iron and its storage as ferritin(hepatic cell contains apoferritin and when excess of iron in the blood it forms ferritin) = blood iron buffer • participation on production of erythropoietin Department of Physiology, 3rd Faculty of Medicine

5. Function protein metabolism • Deamination of amino acids • Formation of urea for removal of ammonia from the body fluids • Formation of plasma proteins (90% of all plasma proteins, up to 50 g of plasma proteins daily) – not gamma globulins (cirrhosis = very low albumins = ascites and edema) • Interconversions of the various amino acids and synthesis of other compound from amino acids Department of Physiology, 3rd Faculty of Medicine

6. Functionprotein metabolism (2) Protein metabolism disorder in hepatic diseases • Ammonia detoxication disorder and failure of urea formation(ammonia comes from bacterial degradation of nitrogen substances in intestines, from intestine mucosa during glutamin degradation, from degradation of aminoacids in kidneys and muscles ) • Hyperamonemia = increase of ammonia blood concentration (>50 μmol/l) • Hepatic encephalopathy = toxic effect of ammonia in the brain (?Binding of ammonia to glutamate = glutamine) • Mental changes (capriciousness, disorientation, sleeping disorders, chaotic speech, personality changes) • Motoric changes (increased in muscle reactivity, hyperreflexion, tremor) • Hepatic coma to death • Endogenous = viral hepatitis and poisoning (hepatic cells desintegration) • Exogenous = final status of chronic cirrhosis (ammonia and other toxic substances bypass the liver through the extrahepatic anastomoses) Department of Physiology, 3rd Faculty of Medicine

7. Function carbohydrate metabolism Maintaining a normal blood glucose concentration • Storage of glycogen (1-4 %) – removing excess of glucose from blood, storage, fast return when the blood concentration decreases = Glucose buffer function • Conversion of galactose and fructose to glucose • Gluconeogenesis • Formation of many chemical compounds from intermediate products of carbohydrate metabolism • Pentose phosphate pathway is source of the NADPH (reduction synthesis) and ribose (synthesis of nucleotides) Department of Physiology, 3rd Faculty of Medicine

8. Function carbohydrate metabolism (2) Carbohydrate metabolism disorder in hepatic diseases • Hyperglycemia in patients with cirrhosis after carbohydrate rich meal (50% has glucose tolerance, 10% has hepatic diabetes mellitus) • Combination of pathological glucose tolerance test, hyperinsulinemia, and increased insulintolerance (liver insuficience  decrease of glucose utilization  hyperglycemia  hyperinsulinemia  down-regulation of insulin receptors  insulin rezistence) • Hypoglycemia in alcohol abusers – alcohol suppresses citrate cycle and thereby impairs gluconeogenesis from aminoacids. After depletion of glycogen storages comes hypoglycemia that threatens the patient’s life. Department of Physiology, 3rd Faculty of Medicine

9. Function fat metabolism • Oxidation of fatty acids to supply energy for other body function • Synthesis of large quantities of cholesterol (80% of cholesterol synthesized in the liver is converted into bile salts), phospholipids, and most lipoproteins • Inactivation of steroids and their excretion of the body • Synthesis of fat from proteins and carbohydrates Department of Physiology, 3rd Faculty of Medicine

10. Function fat metabolism (2) Fat metabolism disorder in hepatic diseases • Dyslipoproteinemia • Hypertriacylglycerolemia - ↑ LDL – from decreased activity of hepatic lipase • ↑ IDL (intermediate density lipoprotein) and↓HDL – from decreased production of LCAT (lecitincholesterolacyltransferase) = transformation of VLDL to LDL = cirrhosis • ↓ cholesterol – decreased esterification of cholesterol when decreased activity of LCAT • ↑ cholesterol – decreased excretion of cholesterol in bile due tocholestasisor increased synthesis due to decreased intestinal resorption of lipids = causes steatosis of the liver • Hepatic steatosis– accumulation of TAG minimaly in ½ of the hepatocytes (if less = steatosis of hepatic cells) • Toxic substancesincluding alcohol and medicaments • Nutrition(obesity, malnutrition, kwashiorkor) • Metabolic disorder (DM, hyperlipoproteinemia, pregnancyí) • Inflammation of intestines Department of Physiology, 3rd Faculty of Medicine

11. Amount of abused alcohol and its level in the blood Drunk up at once on an empty stomach = 0,4 ‰ in blood Department of Physiology, 3rd Faculty of Medicine

12. Acute intoxication with alcohol Stage 1: Signs of drunkenness are not necessary evident Basic symptom is euphoria. Patient is talkative or in contrast silent more than usually and has subjective feeling of increased mental activity. Objectively = decreased reflex reactions and working performance Stage 2: Selfcontrol disorders Inattention and talking problems Unsteady walking Increased self-confident Loss of emotions control – increased aggressiveness or tearfulness Increased libido, decreased capability. Decreased reflex reaction Dangerous for car driving! Department of Physiology, 3rd Faculty of Medicine

13. Acute intoxication with alcohol(2) Stage 3:High muzziness • Unsteady walking or unable to walk • Unclear talking • Often nausea and vomiting • Falling a sleep Stage 4: Deep sleep followed by coma • Cold skin • Bradypnoa a tachycardia • Coma • Death due to failure of breeding and vasomotor centers. Department of Physiology, 3rd Faculty of Medicine

14. Bile • secreted by cells of the liver into the bile duct, which drains into the duodenum. • Between meals the duodenal orifice (m. sfincter Oddi) is closed and bile flows into the gallbladder, where it is stored (50 – 80 ml). • The bile is concentrated in the gallbladder from 97% to 89% of the water (osmotic gradient) • m. sfincter Oddi opens by food intake within 30 minutes, the presence of aminoacids and fatty acids in duodenum activates the cholecystokinin, which causes gallbladder contractions and excretion of bile • production of 500-1000 ml of bile daily • pH = 7,1-7,3 Department of Physiology, 3rd Faculty of Medicine

15. Composition of bile • Water= 97 % • Bile salts (0.7%) = primary bile acids are transported to the bile as sodium and potassium salts • Cholic acid (converted by colon bacteria to Deoxycholic acid) • Chenodeoxycholic acid (converted by colon bacteria to Lithocholic acid) Function: • reduction of surface tension • responsible for the emulsification of fat preparatory to its digestion and absorption in small intestine • tend to form micelles, because of their amphipathic character (have both hydrophilic and hydrophobic domains) Department of Physiology, 3rd Faculty of Medicine

16. Composition of bile (2) • Bile pigment(0,2%)= glucuronides bilirubin and biliverdin (golden-yellow color of bile) • Cholesterol(0,06%) – raises in patients with obstructive icterus • Inorganic salts(0,7%) • Fatty acids(0,15%) • Lecithin(0,1%) = the main phospholipide of bile • Fat(0,01%) • Alcaline phosphatase Department of Physiology, 3rd Faculty of Medicine

17. Enterohepatic circulation of bile salts Daily synthesis of bile salt to replaced the lost = 0.2 – 0.4 g/day The total bile salt pool = 3.5 g Recycling: the entire pool recycles 6-8 times / day (2 times / meal) Micelles = cylindrical discs formed by bile salt Function: Keeping fat in solution and transporting fat to the brush boarder of the intestinal epithelial cells, where they are absorbed. Hydrophilic surface and hydrophobic interior with fat inside (fat acids and cholesterol). Department of Physiology, 3rd Faculty of Medicine

18. Enterohepatic circulation of bile salts (2) • 90-95 % of the bile salt are absorbed from the small intestine some by nonionic diffusion, most by Na+ - salt cotransport in the terminal ileum). • 5-10% of the bile salt enter the colon and are converted to deoxycholic acid (from Cholic acid) or lithocholic acid (from Chenodeoxycholic acid). • Deoxycholic acidis absorbed back and transported back to portal vein of the liver. • Lithocholic acid is insoluble and is mostly excreted. Department of Physiology, 3rd Faculty of Medicine

19. Bilirubin – Metabolism & Excretion • Formed in the tissues by the breakdown of hemoglobin. • In the circulation bound to albumin. • In the liver bilirubin dissociates and free bilirubin enters liver cells, where it is bound to cytoplasmic proteins. • Bilirubin diglucuronide is more water-soluble and is mostly transported to the bile canaliculi and to the intestines and changes to Stercobilinogen and after oxidation to Stercobilin. Only small amount escapes into the blood and is excreted by the urine as Urobilin (oxidized form of Urobilinogen). Department of Physiology, 3rd Faculty of Medicine

20. Icterus (Jaundice) • Detectable when the total plasma bilirubin > 2mg/dl (34 mol/l) • Reasons: • excess production of bilirubin (hameolytic anemia) • decreased uptake of bilirubin into hepatic cells • disturbed intracellular protein binding or conjugation • disturbed secretion of conjugated bilirubin into the bile canaliculi • intrahepatic or extrahepatic bile duct obstruction Department of Physiology, 3rd Faculty of Medicine

21. Icterus (2) • Non-conjugated icterus (hemolytic) due to reasons 1-3 = the free bilirubin rises • Conjugated icterus (obstructive) due to reasons 4 or 5 = bilirubin glucuronide regurgitase into the blood • Differentiation • van den Bergh reaction (rate conjugated/non-conjugated bilirubin in the blood) • From urine (non-conjugated bilirubin is not present in urine, conjugated bilirubin turns urine foam when shaking to intense yellow) Department of Physiology, 3rd Faculty of Medicine