Transport & Metabolic Functions of the Liver PDF

Chapter 28 Transport & Metabolic Functions of the Liver 1 Introduction The liver is the largest gland in the body. It is essential for life because it conducts a vast array of biochemical and metabolic functions 1. ridding the body of substances that would otherwise be injurious if allowed to accumu...

Chapter 28 Transport & Metabolic Functions of the Liver 1 Introduction The liver is the largest gland in the body. It is essential for life because it conducts a vast array of biochemical and metabolic functions 1. ridding the body of substances that would otherwise be injurious if allowed to accumulate 2. excreting drug metabolites 3. the first port of call for most nutrients absorbed across the gut wall, supplies most of the plasma proteins 4. synthesizes the bile that optimizes the absorption of fats 5. serving as an excretory fluid. The liver and associated biliary system have therefore evolved an array of structural and physiologic features that underpin this broad range of critical functions. 2 The Liver Functional Anatomy An important function of the liver is to serve as a filter between the blood coming from the gastrointestinal tract and the blood in the rest of the body. Blood from the intestines and other viscera reach the liver via the portal vein. This blood percolates (leak) in sinusoids between plates of hepatic cells and eventually drains into the hepatic veins, which enter the inferior vena cava. During its passage through the hepatic Bile plates, it is extensively modified chemically. is formed on the other side at each plate. The bile passes to the intestine via the hepatic duct (Figure 28–1). 3 4 Hepatic artery blood also enters the sinusoids. The central The veins coalesce to form the hepatic veins, which drain into the inferior vena cava. average transit time for blood across the liver lobule from the portal venule to the central hepatic vein is about 8.4 s. Numerous macrophages (Kupffer cells) are anchored to the endothelium of the sinusoids and project into the lumen. Each liver cell is also opposed to several bile canaliculi. The canaliculi drain into intralobular bile ducts, and these coalesce via interlobular bile ducts to form the right and left hepatic ducts. These ducts join outside the liver to form the hepatic duct. common 5 The cystic duct drains the gallbladder. The common bile duct enters the duodenum at the duodenal papilla. Its orifice is surrounded by the sphincter of Oddi, and it usually unites with the main pancreatic duct just before entering the duodenum. The sphincter is usually closed, but when the gastric contents enter the duodenum, cholecystokinin (CCK) is released and the gastrointestinal hormone relaxes the sphincter and makes the gallbladder contract. 6 The walls of the extrahepatic biliary ducts and the gall-bladder contain fibrous tissue and smooth muscle. In the gallbladder, the surface is extensively folded; this increases its surface area and gives the interior of the gall-bladder a honeycombed appearance. The cystic duct is also folded to form the so-called spiral valves. This arrangement is believed to increase the turbulence of bile as it flows out of the gallbladder, thereby reducing the risk that it will precipitate and form gallstones. 7 8 9 Hepatic Circulation Large gaps occur between endothelial cells in the walls of hepatic sinusoids, and the sinusoids are highly permeable. The way the intrahepatic branches of the hepatic artery and portal vein converge on the sinusoids and drain into the central lobular veins of the liver The functional unit of the liver is the acinus. Each acinus is at the end of a vascular stalk containing terminal branches of portal veins, hepatic arteries, and bile ducts. Blood flows from the center of this functional unit to the terminal branches of the hepatic veins at the periphery. This is why the central portion of the acinus, sometimes called zone 1, is well oxygenated, the intermediate zone (zone 2) is moderately well oxygenated, and the peripheral zone (zone 3) is least well oxygenated and most susceptible to anoxic injury 10 11 12 13 The hepatic veins drain into the inferior vena cava. The human liver contains about 100,000 acini. Portal venous pressure is normally about 10 mm Hg in humans hepatic venous pressure is approximately 5 mm Hg. pressure in the hepatic artery branches that converge on the sinusoids is about 90 mm Hg, but the pressure in the sinusoids is lower than the portal venous pressure, so a marked pressure drop occurs along the hepatic arterioles. 14 This pressure drop is adjusted so that there is an inverse relationship between hepatic arterial and portal venous blood flow. This inverse relationship may be maintained in part by the rate at which adenosine is removed from the region around the arterioles. According to this hypothesis, adenosine is produced by metabolism at a constant rate. Adenosine has a direct vasodilator effect on the hepatic artery but not on the portal vein. When portal flow is reduced, it is washed away more slowly, and the local accumulation of adenosine dilates the terminal arterioles. In the period between meals, moreover, many of the sinusoids are collapsed 15 Following a meal, on the other hand, when portal flow to the liver from the intestine increases considerably, these “reserve” sinusoids are recruited. This arrangement means that portal pressures do not increase linearly with portal flow until all sinusoids have been recruited. This may be important to prevent fluid loss from the highly permeable liver under normal conditions. Indeed, if hepatic pressures are increased in disease states (such as the hardening of the liver that is seen in cirrhosis), many liters of fluid can accumulate in the peritoneal cavity as ascites. 16 The intrahepatic portal vein radicles have smooth muscle in their walls that is innervated by noradrenergic vasoconstrictor nerve fibers reaching the liver. The vasoconstrictor innervation of the hepatic artery comes from the hepatic sympathetic plexus. No known vasodilator fibers reach the liver. 17 When systemic venous pressure rises, the portal vein radicles are dilated passively and the amount of blood in the liver increases. In heart failure, this hepatic venous congestion may be extreme. Conversely, when diffuse noradrenergic discharge occurs in response to a drop in systemic blood pressure, the intrahepatic portal radicles constrict, portal pressure rises, and blood flow through the liver is active , bypassing most of the organ. Most of the blood in the liver enters the systemic circulation. Constriction of the hepatic arterioles diverts blood from the liver, and constriction of the mesenteric arterioles reduces portal inflow. In severe shock, hepatic blood flow may be reduced to such a degree that patchy necrosis of the liver takes place. 18 FUNCTIONS OF THE LIVER 19 METABOLISM & DETOXIFICATION First, the liver plays key roles in carbohydrate metabolism, including glycogen storage, conversion of galactose and fructose to glucose, and gluconeogenesis. The substrates for these reactions derive from the products of carbohydrate digestion and absorption that are transported from the intestine to the liver in the portal blood. The liver also plays a major role in maintaining the stability of blood glucose levels in the postprandial period, removing excess glucose from the blood and returning it as needed— the so-called glucose buffer function of the liver. In liver failure, hypoglycemia is commonly seen. 20 Second : the liver contributes to fat metabolism. It supports a high rate of fatty acid oxidation for energy supply to the liver itself and other organs. Third: Amino acids and two carbon fragments derived from carbohydrates are also converted in the liver to fats for storage. Forth : The liver also synthesizes most of the lipoproteins required by the body and preserves cholesterol homeostasis by synthesizing this molecule and also converting excess cholesterol to bile acids. 21 Fifth : Part of this function is physical in nature—bacteria and other particulates are trapped in and broken down by the strategically located Kupffer cells. Sixth: The remaining reactions are biochemical, and mediated in their first stages by the large number of cytochrome P450 enzymes expressed in hepatocytes. These convert xenobiotics and other toxins to inactive, less lipophilic metabolites. Detoxification reactions are divided into phase I (oxidation, hydroxylation, and other reactions mediated by cytochrome P450s) phase II (esterification). Ultimately, metabolites are secreted into the bile for elimination via the gastrointestinal tract. In this regard, in addition to disposing of drugs, the liver is responsible for metabolism of essentially all steroid hormones. Liver disease can therefore result in the apparent overactivity of the relevant hormone systems. 22 SYNTHESIS OF PLASMA PROTEINS Albumin is quantitatively the most significant, and accounts for the majority of plasma oncotic pressure. Many of the products are acute-phase proteins, proteins synthesized and secreted into the plasma on exposure to stressful stimuli. Others are proteins that transport steroids and other hormones in the plasma, and still others are clotting factors. Following blood loss, the liver replaces the plasma proteins in days to weeks. The only major class of plasma proteins not synthesized by the liver is the immunoglobulins. 23 BILE 24 About 500 mL is secreted per day. Some of the components of the bile are reabsorbed in the intestine and then excreted again by the liver (enterohepatic circulation). In addition to its role in digestion and absorption of fats, bile (and subsequently the feces) is the major excretory route for lipidsoluble waste products. The glucuronides of the bile pigments, bilirubin and biliverdin, are responsible for the golden yellow color of bile. 25 BILIRUBIN METABOLISM & EXCRETION Most of the bilirubin in the body is formed in the tissues by the breakdown of hemoglobin. The bilirubin is bound to albumin in the circulation. Most of it is tightly bound, but some of it can dissociate in the liver, and free bilirubin enters liver cells via a member of the organic anion transporting polypeptide (OATP) family, and then becomes bound to cytoplasmic proteins (Figure 28–5). 26 27 It is next conjugated to glucuronic acid in a reaction catalyzed by the enzyme glucuronyl transferase (UDP-glucuronosyl-transferase). This enzyme is located primarily in the smooth endoplasmic reticulum. Each bilirubin molecule reacts with two uridine diphosphoglucuronic acid (UDPGA) molecules to form bilirubin diglucuronide. This glucuronide, which is more water-soluble than the free bilirubin, is then transported against a concentration gradient most likely by an active transporter known as multidrug resistance protein-2 (MRP-2) into the bile canaliculi. 28 A small amount of the bilirubin glucuronide escapes into the blood, where it is bound less tightly to albumin than is free bilirubin, and is excreted in the urine. Thus, the total plasma bilirubin normally includes free bilirubin plus a small amount of conjugated bilirubin. Most of the bilirubin glucuronide passes via the bile ducts to the intestine. The intestinal mucosa is relatively impermeable to conjugated bilirubin but is permeable to unconjugated bilirubin and to urobilinogens, a series of colorless derivatives of bilirubin formed by the action of bacteria in the intestine. Consequently, some of the bile pigments and urobilinogens are reabsorbed in the portal circulation. Some of the reabsorbed substances are again excreted by the liver (enterohepatic circulation), but small amounts of urobilinogens enter the general circulation and are excreted in the urine. 29 JAUNDICE When free or conjugated bilirubin accumulates in the blood, the skin, scleras, and mucous membranes turn yellow. This yellowness is known as jaundice (icterus) and is usually detectable when the total plasma bilirubin is greater than 2 mg/dL (34 μmol/L). Hyperbilirubinemia may be due to (1) excess production of bilirubin (hemolytic anemia) (2) decreased uptake of bilirubin into hepatic cells (3) disturbed intracellular protein binding or conjugation (4) disturbed secretion of conjugated bilirubin into the bile canaliculi (5) intrahepatic or extrahepatic bile duct obstruction. When it is due to one of the first three processes, the free bilirubin rises. When it is due to disturbed secretion of conjugated bilirubin or bile duct obstruction, bilirubin glucuronide regurgitates into the blood, and it is predominantly the conjugated bilirubin in the plasma that is elevated. 30 THE BILIARY SYSTEM BILE FORMATION Bile contains substances that are actively secreted into it across the canalicular membrane, such as bile acids, phosphatidylcholine, conjugated bilirubin, cholesterol, and xenobiotics. Each of these enters the bile by means of a specific canalicular transporter. It is the active secretion of bile acids, however, that is believed to be the primary driving force for the initial formation of canalicular bile. Because they are osmotically active, the canalicular bile is transiently hypertonic. However, the tight junctions that join adjacent hepatocytes are relatively permeable and thus a number of additional substances passively enter the bile from the plasma by diffusion. These substances include water, glucose, calcium, glutathione, amino acids, and urea. 31 Phosphatidylcholine that enters the bile forms mixed micelles with the bile acids and cholesterol. The ratio of bile acids: phosphatidylcholine: cholesterol in canalicular bile is approximately 10:3:1. Deviations from this ratio may cause cholesterol to precipitate, leading to one type of gallstones. Functions of the Gallbladder In normal individuals, bile flows into the gallbladder when the sphincter of Oddi is closed (ie, the period in between meals). In the gallbladder, the bile is concentrated by absorption of water. The degree of this concentration is shown by the increase in the concentration of solids (Table 28–3) 32 33 hepatic bile is 97% water, whereas the average water content of gallbladder bile is 89%. However, because the bile acids are a micellar solution, the micelles simply become larger, and since osmolarity is a colligative property, bile remains isotonic. When the bile duct and cystic duct are clamped, the intra- biliary pressure rises to about 320 mm of bile in 30 min, and bile secretion stops. However, when the bile duct is clamped and the cystic duct is left open, water is reabsorbed in the gallbladder, and the intra-biliary pressure rises only to about 100 mm of bile in several hours. 34 35 REGULATION OF BILIARY SECRETION 36 Fatty acids and amino acids in the duodenum release CCK, which causes gallbladder contraction. The production of bile is increased by stimulation of the vagus nerves the hormone secretin, which increases the water and HCO3 − content of bile. Substances that increase the secretion of bile are known as choleretics. Bile acids themselves are among the most important physiologic choleretics. 37