Liver Function PDF

FUNCTIONS OF LIVER AND GALLBLADDER: (Dr. Hızır Kurtel) A- STRUCTURE OF LIVER Each liver lobule is organized around a central vein. At the periphery of the lobule blood enters the sinusoids from branches of the portal vein and the hepatic artery. In the sinusoids, blood flows towar...

FUNCTIONS OF LIVER AND GALLBLADDER: (Dr. Hızır Kurtel) A- STRUCTURE OF LIVER Each liver lobule is organized around a central vein. At the periphery of the lobule blood enters the sinusoids from branches of the portal vein and the hepatic artery. In the sinusoids, blood flows toward the center of the lobule between plates of hepatic cells that are one or two hepatocytes thick.  Each hepatocyte is thus in direct contact with sinusoidal blood because of the large fenestration between the endothelial cells that line the sinusoids. Because of these large gaps or pores between endothelial cells of sinusoids the normal Starling equilibrium does not operate in the liver and proteins tend to remain inside the skeletal muscle capillary they are not fluid readily leaks out into the extracellular fluid. leaky proteins cannot escape so they create colloidal osmotic pressure These are drained by large numbers of lymphatic vessels, which return fluid from the liver through thoracic duct to the subclavian vein. The liver produces between 1/3 and 1/2 of all the lymph in the body.  Biliary canaliculi lie between adjacent hepatocytes, and the canaliculi drain into bile ducts at the periphery of the lobule.  The sinusoids are lined by endothelial cells, some of which are Kupffer cells (macrophages), capable of phagocytosis of foreign material. Kupffer cells express a specialized pathogen receptor, the Complement Receptor of the Immunoglobulin superfamily (CRIg), which has evolved to catch circulating pathogens (opsonized particles) under shear conditions. The number of Kupffer cells in the sinusoids increases markedly when increased quantities of particulate matter or other debris are present in the blood. The Kupffer cells represent the largest population of fixed macrophages in the body. The functions of the Kupffer cells include: Phagocytosis and clearance of: Micro-organisms, including bacteria and viruses Endotoxins Immune complexes Tumour cells Lipid assemblies Fibrin degradation products Other particulate matter Modulation of the synthesis of acute phase proteins and lipoproteins; Cytokine secretion; Antigen processing; Catabolism of glycoproteins and lipids. 1- The Hepatic Circulation: The liver acinus can be divided into the three circulatory zones specifically the oxidative which surround the portal axis as layers. metabolism of bile acids, refers to the chemical modification of bile acids through oxidation reactions, Zone 1 encompasses the hepatocytes situated close to the which alters their structure, activity, and toxicity. This portal axis and the origin of sinusoid, therefore they are bathed process is part of a larger set of reactions the liver by blood rich in nutrients and oxygen. These cells are most performs to modify various compounds for easier active for both oxidative metabolism and the uptake of bile excretion or functional use in the body. acids.  The cells in Zone 3 are situated at the periphery of the acinus, near the central vein. Hepatocytes in Zone 3 receive blood that has already exchanged nutrients and oxygen with cells in Zones I and 2 (the arbitrary intermediate zone). Conversely, the cells in Zone 3 are more geared for anaerobic metabolism, and the rate of bile acid uptake is low. Zone 3 cells are also most sensitive to damage due to ischemia, nutritional deficiency, and toxic substances.  Total hepatic blood flow accounts for approximately 25% of cardiac output, i.e., 1250 to 1500 mllmin. The portal vein supplies the liver with 70 to 75 % of its blood; the hepatic artery provides the remaining 25 to 30 %.  Why do you expect to see heptomegaly in pateints The liver is probably the most important blood reservoir in man. The suffering from haemorrhages? liver contains 25 to 30 ml of blood per 100 grams of tissue mass, accounting for 10 to 15 per cent of total blood volume. Hepatic blood volume can expand to as much as 60 mI/grams of liver with cardiac failure. The capacitance function of the liver also plays an important role during hemorrhage. The space of Disse of the liver harbours an intriguing cell which is known under a variety of names: Ito cell, fat-storing cell, lipocyte, perisinusoidal cell, parasinusoidal cell, or, as was recently proposed, hepatic stellate cell. The changes in the stellate cells which are observed in human liver diseases indicate that they play a central role in extracellular matrix remodelling after recovery from acute liver injury, in chronic liver disease and in fibrous capsule formation around liver tumours.  In a pateimt with liver fibrosis the Matrix and cellular alterations in liver function is hepatic fibrosis. deteriorating why ? In liver disease stellate cell activation leads to accumulation of scar (fibril- forming) matrix. This in turn contributes to the loss of hepatocyte microvilli and sinusoidal endothelial fenestrae, which result in deterioration of hepatic function. Kupffer cell (macrophage) activation accompanies liver injury and contributes to paracrine activation of stellate cells. B- FUNCTIONS OF LIVER: 1- Vascular functions for storage and filtration of blood. 2- Secretory functions for secreting bile into the gastrointestinal tract. 3- Metabolic Functions Metabolic functions: Liver and skeletal muscles are two major sites of glycogen storage Liver is also the major site of glycogenolysis, glyconeogenesis Liver is involved in lipid metabolism by taking up chylomicron remnants rich in cholesterol. Hepatocytes syntheses and secrete very-low-density lipoproteins (VLDL). VLDL then converted to the other types of serum lipoproteins. Hepotocytes are a principal source of cholesterol in the body and the major site of excretion of cholesterol (in bile). Liver dissipates ammonia (NH3) by conversion to urea, mainly in the liver. Liver synthesizes all the major plasma proteins Liver serves as a storage site for certain vitamins and iron, degrading certain hormones. inactivating and excreting certain drugs and toxins. Triglyceride pathway. The gut produces chylomicrons following the absorption of fat. The triglyceride (TG) component of chylomicrons is removed by lipoprotein lipase located on the vascular endothelium of muscle, myocardium and adipose tissue. The resulting chylomicron remnants are cleared from the circulation by hepatic receptors that recognize apolipoprotein E (apo E). The liver exports triglycerides into the circulation in the core of very- low-density lipoprotein (VLDL) particles. CMAJ NOV. 26, 2002; 167 (11)  Major normal lipoprotein metabolic pathways. ABCA1, ATP binding cassette transporter 1; CE, cholesterol ester; CETP, cholesteryl ester transfer protein; FFA, free fatty acid; HTGL, hepatic triglyceride lipase; IDL, intermediate-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL-R, LDL receptor; Lp(a), lipoprotein(a); LPL, lipoprotein lipase; LRP, LDL-R–related protein; SR B1, scavenger receptor B1; TG, triglyceride. Bonnie C.H. Kwan et al. JASN 2007;18:1246-1261 ©2007 by American Society of Nephrology Plasma proteins synthesised by the liver include: Albumin Vitamin K-dependent blood coagulation factors: II, VII, IX, X; proteins C and S Fibrinolysis proteins Protease inhibitors: Alpha 1-antitrypsin, alpha 2-antiplasmin, antithrombin III Caeruloplasmin (cooper carrying protein) Alpha-fetoprotein (fetal form of serum albumin, tumor marker) Iron storage and binding proteins Acute phase proteins B- BILE 1- Anatomy of the biliary tree: The extra hepatic biiary system in man consists of the 1- hepatic bile ducts (right and left), 2- cystic duct, 3- common bile duct, and 4- gallbladder.  At the entrance of the bile duct into the duodenum there is a thickening of the circular muscle of the duct which is called the sphincter of Oddi. The sphincter governs the diameter of the bile duct orifice in the ampulla and, thereby controls the rate of bile flow into the gut lumen Bile Secretion: Bile, elaborated by hepatocytes, contains bile acids, cholesterol, lecithin, and bile pigments. These constituents are all synthesized and secreted by hepatocytes into the bile canaliculi along with an isotonic fluid that resembles plasma in its concentrations of Na+, K-, C-, and HC03.  What is the difference between bile duct secretion The epithelial cells that line the and plasma ? bile ducts secrete a watery fluid that rich in bicarbonate and contributes to the volume of bile that leaves the liver. The secretion of the bile duct epithelium is isotonic and contains Na+ and K+ at levels similar to plasma. However, the concentration of HCO3 is greater - and the concentration of Cl is less than in plasma.  Which statement about bile acid is correct? Secretin leads to The secretory activity of the bile duct epithelium is gallbladder contraction and emptying. Flase specifically stimulated by secretin alone the volume flow of Secreterin changes the contact of bile aicds. Fals the bile and its bicarbonate concentration increase, but e Secretein increased content of bile acids does not increase. bicarbonate conectration. True  In periods between meals, bile is diverted into the gallbladder. The gallbladder epithelium extracts salts and water from the stored bile, and the bile acids are thereby concentrated five to twentyfold.  After an individual has eaten, the gallbladder contracts and empties its concentrated bile into the duodenum. The most potent stimulus for emptying of the gallbladder is the hormone CCK, which is released by the duodenal mucosa primarily in response to the presence of fats and their digestion products.  From 250 to 1500 ml of bile enters the duodenum each day. Bile salts emulsiIfy lipids, thereby increasing the surface area available to lipolytic enzymes. Bile salts then form mixed micelles with the products of lipid digestion. This process increases the transport of lipid digestion products to the brush border surface and in this way enhances absorption of lipids by the epithelial cells.  Bile acids are actively absorbed, chiefly in the terminal part of the ileum. A small fraction of bile acids escapes absorption and is excreted. The returning bile acids are avidly taken up by the liver and are rapidly re-secreted during the course of digestion. The entire bile acid pool is recirculated twice in response to typical meal. The recirculation of the bile is known as the enterohepatic circulation.   About 10-20 % of the bile acid pool is excreted in the feces each day and is replenished by hepatic synthesis of new bile acids. Bile acids lost into the feces are a significant mechanism of excretion of cholesterol. Treatment with drugs that inhibit the reabsorption of bile acids in the ileum promotes the synthesis of new bile acids from cholesterol. Such drugs have been used to lower the level of cholesterol in the blood. Drugs that lower cholesterol levels in blood actually increase the amount of cholesterol secreted in bile. This in turn can increase the risk of gallstones The Bile Acids: Bile acids comprise about 50 % of the dry weight of bile. Other important compounds secreted by the hepatocytes into the bile include lecithin, cholesterol, bile pigments, and proteins.  Bile acids have a steroid nucleus and are synthesized by the hepatocytes from cholesterol. The major bile acids synthesized by the liver are called primary bile acids. The cholic acid (3-hydroxyl groups) and chenodeoxycholic acid (2-hydroxyl groups).  The presence of the carboxyl and hydroxyl groups makes the bile acids much more water soluble than the cholesterol from which they are synthesized. Bacteria in the digestive tract dehydroxylate bile acids to form secondary bile acids. Bile contains both primary and secondary bile acids  What is the difference Bile acids are usually secreted between bile salts and bile acids? conjugated with glycine and taurine. At the near-neutral pH of the gastrointestinal tract the conjugated bile acids are more complexly ionized, and more water soluble, than the unconjugated bile acids. Conjugated bile acids therefore exist almost entirely as salts of various cations (mostly Na+) and hence often are called bile salts.  Bile acids tend to form molecular aggregates (due to having both hydrophilic and hydrophobic domains) called micelles, by turning their hydrophobic faces inside and away from water and their hydrophilic faces surfaces toward to water.  Whenever bile acids are present above a certain concentration, called the critical micelle concentration, bile acid micelles will form. Above this concentration any additional bile acid will go into the micelle exclusively and not into molecular solution. In the bile, the bile acids are normally present at a concentration well above the critical micelle concentration. Phospholipids in Bile: Hepatocytes also secrete phospholipids into the bile, the most prominent class being lecithins. Cholesterol being apolar, dissolve into the center of the micelle. Lecithin, because it is amphipathic, buries its fatty acyl chains in the micelle interior and leaves its polar head group near the micelle surface. The lecithin increases the amount of cholesterol that can be solubilized in the micelles.  If more cholesterol is present in the bile than can be solubilized in the micelies, crystals of cholesterol will form in the bile. These crystals are important in formation of cholesterol gallstones (the most common kind of gallstones) in the duct system of the liver or more commonly in the gallbladder. Bile Pigments: When red blood cells are degraded in reticuloendothelial cells, the porphyrin moiety of hemoglobin is converted to bilirubin. Bilirubin is released into the plasma, where it bounds to albumin. Hepatocytes efficiently remove bilirubin from blood in the sinusoids via a protein-mediated transport mechanism in the hepatocyte plasma membrane that faces the sinusoids. Haptoglobin is the protein that A decrease in HAPTOGLOBIN can binds to free hemoglobin, and support a diagnosis of hemolytic anemia thereby inhibits its deleterious oxidative activity. The haptoglobin/hemoglobin complex will then be removed by the reticuloendothelial system (mostly the spleen). In the hepatocytes bilirubin is conjugated with one or two glucuronic acid molecules (glucuronyl transferase), and the bilirubin glucuronides are secreted into the bile, probably by an active transport mechanism. Unconjugated bilirubin is not secreted into the bile.  Bilirubin is yellow and contributes to the yellow color of bile. In the intestine, about one half of the bilirubin is converted into highly soluble substance called urobilinogen by the intestinal flora.  Urobilinogen is absorbed into portal circulation or excreted in the feces. Most of the urobilinogen that is absorbed is returned to the liver to be re-secreted into the bile.  A small amount of urobilinogen about 5% is absorbed into general circulation and is then excreted by the kidneys.  Usually only a small amount of bilirubin is found in the blood; the normal level of total serum bilirubiN is 0.1 to 1.2 mg/dl.  Laboratory measurements of bilirubin usually measure free and conjugated bilirubin and the total bilirubin. These are reported as the direct or conjugated bilirubin and indirect or free bilirubin.  Jaundice (or icterus) describes the yellow coloration that appears whenever either free or conjugated biluribin reaches a level high enough to stain tissue. Usually it is visible in the skin mucous membranes and conjunctiva when plasma bilirubin rises above 2 mg/dl  Causes include: 1- Excess production, as occurs in hemolytic anemias 2- Hepatic disease associated with decreased hepatocellular uptake of bilirubin, failure of intracellular protein binding, or impaired secretion of bilirubin into new canaliculi 3- Intra or extra-hepatic obstruction of the biliary tree.  Bile Pigment Gallstones are the other major class of gallstones; their major constituent is the calcium salt of unconjugated bilirubin. Conjugated is quite soluble and does not form insoluble calcium salts in bile. In liver disease, bile may contain elevated levels of unconjugated bilirubin because hepatocytes are deficient in forming the glucuronides of bilirubin. Individuals with liver disease have an increased likelihood of forming bile pigment stones. 5- Bile Concentration and Storage in the Gallbladder: Between meals the tone of the sphincter of Oddi, which guards the entrance of the common bile duct into the duodenum, is high. Thus most bile flow is diverted into the gallbladder. The gallbladder is a small organ, having a capacity of 15 to 60 ml (average about 35 ml) in humans. Many times this volume of bile may be secreted by the liver between meals. The gallbladder concentrates the bile by absorbing Na+, Cl-, HCO3- and water from the bile so that the bile acids can be concentrated from 5 to 20 times in the gallbladder.  The epithelial cells of the distal part of the ileum actively take up bile acids against a large concentration gradient. The active transport system has a higher affinity for conjugated bile acids.  Bile acids also have fair degree of lipid solubility. Thus they also can be taken up by simple diffusion. Bile acids, whether absorbed by active transport or simple diffusion, are transported away from the intestine in the portal blood, mostly bound to plasma proteins. In the liver, hepatocytes avidly extract the bile acids from the portal blood.  In a single pass through the liver the portal blood is essentially cleared of bile acids. Bile acids in all forms, primary and secondary, both conjugated and deconjugated are taken up by the hepatocytes. The hepatocytes reconjugate almost all the deconjugated bile acids and rehydroxylate some of the secondary bile acids. These bile acids are secreted into the bile along with newly synthesized bile acids.  The rate of return of bile acids to the liver is a major influence on the rate of synthesis and secretion of bile acids. Bile acids in the portal blood stimulate the secretion of bile acids by the hepatocytes but inhibit the synthesis of bile acids. This is called the choleretic effect of bile acids. Substances that act to enhance bile acid secretion are known as choleretics Liver and Biliary Pain: Pain arises from the liver only as a result of stretching the liver capsule and is experienced in a diffuse area over the right hypochondrium. Distention of either the common bile duct or the gallbladder results in pain experienced in the mid-epigastrium or the right subcostal region. Occasionally, pain from the biliary tract is experienced in the area below the scapula.