GIT Transport & Metabolic Functions of the Liver PDF

Physiology Gastrointestinal System Chapter 28 | Transport & Metabolic Functions of the Liver Gastrointestinal System | Functions of the Liver Contents : Introduction 4 Functional Anatomy of Liver 6 Hepatic Circulation 21 Functions Of The Liver 32 Metabolism & Detoxification 36 Synthesis Of Plasma Pr...

Physiology Gastrointestinal System Chapter 28 | Transport & Metabolic Functions of the Liver Gastrointestinal System | Functions of the Liver Contents : Introduction 4 Functional Anatomy of Liver 6 Hepatic Circulation 21 Functions Of The Liver 32 Metabolism & Detoxification 36 Synthesis Of Plasma Proteins 42 Gastrointestinal System | Functions of the Liver Contents : Bile 44 Bilirubin Metabolism & Excretion 49 Jaundice 54 The Biliary System Bile Formation 59 Functions Of The Gallbladder 62 Regulation Of Biliary Secretion 66 Chapter Summary 68 Gastrointestinal System | Functions of the Liver 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, including ridding the body of substances that would otherwise be injurious if allowed to accumulate, and excreting drug metabolites. Gastrointestinal System | Functions of the Liver It is also the first port of call for most nutrients absorbed across the gut wall, supplies most of the plasma proteins, and synthesizes the bile that optimizes the absorption of fats as well as 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. Gastrointestinal System | Functions of the Liver Functional Anatomy of liver: 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 in sinusoids between plates of hepatic cells and eventually drains into the hepatic veins, which enter the inferior vena cava. Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver During its passage through the hepatic plates, it is extensively modified chemically. Bile is formed on the other side at each plate. The bile passes to the intestine via the hepatic duct (Figure). Hepatic artery blood also enters the sinusoids. Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver The central veins coalesce to form the hepatic veins, which drain into the inferior vena cava. The average transit time for blood across the liver lobule from the portal venule to the central hepatic vein is about 8.4 s. Additional details of the features of the hepatic microcirculation and macrocirculation, which are critical to organ function, are provided below. Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver 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 common hepatic duct. The cystic duct drains the gallbladder. Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver The hepatic duct unites with the cystic duct to form the common bile duct (Figure). 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. Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver The walls of the extrahepatic biliary ducts and the gall-bladder contain fibrous tissue and smooth muscle. They are lined by a layer of columnar cells with scattered mucous glands. 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. Gastrointestinal System | Functions of the Liver Hepatic Circulation Gastrointestinal System | Functions of the Liver 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. Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver 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. Gastrointestinal System | Functions of the Liver 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. The hepatic veins drain into the inferior vena cava. The acini have been likened to grapes or berries, each on a vascular stem. The human liver contains about 100,000 acini. Gastrointestinal System | Functions of the Liver Portal venous pressure is normally about 10 mm Hg in humans, and hepatic venous pressure is approximately 5 mm Hg. The mean 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. This pressure drop is adjusted so that there is an inverse relationship between hepatic arterial and portal venous blood flow. Gastrointestinal System | Functions of the Liver 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. When portal flow is reduced, it is washed away more slowly, and the local accumulation of adenosine dilates the terminal arterioles. Gastrointestinal System | Functions of the Liver In the period between meals, moreover, many of the sinusoids are collapsed. 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. Gastrointestinal System | Functions of the Liver 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. 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. Gastrointestinal System | Functions of the Liver No known vasodilator fibers reach the liver. 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. Gastrointestinal System | Functions of the Liver 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 brisk, 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. Functions Of The Liver Gastrointestinal System | Functions of the Liver Functions Of The Liver: The liver has many complex functions that are summarized in Table 28–1. Several will be touched upon briefly here. Gastrointestinal System | Functions of the Liver Table : Principal functions of the liver Principal functions of the liver 1. Formation and secretion of bile Glucose and other sugars Amino acids 2. Nutrient and vitamin metabolism Lipids (Fatty acids, Cholesterol, Lipoproteins) Fat-soluble vitamins Water-soluble vitamins Gastrointestinal System | Functions of the Liver Principal functions of the liver Toxins 3. Inactivation of various substances Steroids Other hormones Acute-phase proteins Albumin 4. Synthesis of plasma proteins Clotting factors Steroid-binding and other hormonebinding proteins 5. Immunity Kupffer cells Gastrointestinal System | Functions of the Liver Metabolism & Detoxification: It is beyond the scope of this volume to touch upon all of the metabolic functions of the liver. Instead, this chapter will focus on those aspects most closely aligned to gastrointestinal physiology. First, the liver plays key roles in carbohydrate metabolism, including glycogen storage, conversion of galactose and fructose to glucose, and gluconeogenesis. Gastrointestinal System | Functions of the Liver 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. Gastrointestinal System | Functions of the Liver In liver failure, hypoglycemia is commonly seen. Similarly, 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. Amino acids and two carbon fragments derived from carbohydrates are also converted in the liver to fats for storage. 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. Gastrointestinal System | Functions of the Liver Part of this function is physical in nature—bacteria and other particulates are trapped in and broken down by the strategically located Kupffer cells. 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. Gastrointestinal System | Functions of the Liver Detoxification reactions are divided into phase I (oxidation, hydroxylation, and other reactions mediated by cytochrome P450s) and 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. Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver 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. Gastrointestinal System | Functions of the Liver 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. Bile Gastrointestinal System | Functions of the Liver Bile : Bile is made up of the bile acids, bile pigments, and other substances dissolved in an alkaline electrolyte solution that resembles pancreatic juice (Table 28–2). Gastrointestinal System | Functions of the Liver Table: Composition of human hepatic duct bile. Composition of human hepatic duct bile. Water 97.0% Fatty acids 0.15% Bile salts 0.7% Phosphatidylcholine 0.2% Bile pigments 0.2% Fat 0.1% Cholesterol 0.06% Alkaline phosphatase … Inorganic salts 0.7% Gastrointestinal System | Functions of the Liver 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 lipid-soluble waste products. The glucuronides of the bile pigments, bilirubin and biliverdin, are responsible for the golden yellow color of bile. Gastrointestinal System | Functions of the Liver Gastrointestinal System | Functions of the Liver 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. Gastrointestinal System | Functions of the Liver It is next conjugated to glucuronic acid in a reaction catalyzed by the enzyme glucuronyl transferase (UDPglucuronosyl-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. Gastrointestinal System | Functions of the Liver 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. 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. Gastrointestinal System | Functions of the Liver 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. Gastrointestinal System | Functions of the Liver 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. Jaundice Gastrointestinal System | Functions of the Liver 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). Gastrointestinal System | Functions of the Liver 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, or 5. Intrahepatic or extrahepatic bile duct obstruction. Gastrointestinal System | Functions of the Liver 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. The Biliary System Gastrointestinal System | Functions of the Liver 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. Gastrointestinal System | Functions of the Liver 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. Gastrointestinal System | Functions of the Liver 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. Gastrointestinal System | Functions of the Liver 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). Gastrointestinal System | Functions of the Liver Table: Comparison of human hepatic duct bile and gallbladder bile. Hepatic Duct Bile Gallbladder Bile Percentage of solids 2–4 10–12 Bile acids (mmol/L) 10–20 50–200 pH 7.8–8.6 7.0–7.4 Gastrointestinal System | Functions of the Liver 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. However, bile becomes less alkaline as sodium ions are exchanged for protons (although the overall concentration of sodium ions rises with a concomitant loss of chloride and bicarbonate as the bile is concentrated). Gastrointestinal System | Functions of the Liver 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. Gastrointestinal System | Functions of the Liver Regulation Of Biliary Secretion : When food enters the mouth, the resistance of the sphincter of Oddi decreases under both neural and hormonal influences (Figure). Gastrointestinal System | Functions of the Liver 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 and by 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. Chapter Summary Gastrointestinal System | Functions of the Liver Chapter Summary: The liver conducts a huge number of metabolic reactions and serves to detoxify and dispose of many exogenous substances, as well as metabolites endogenous to the body that would be harmful if allowed to accumulate. The structure of the liver is such that it can filter large volumes of blood and remove even hydrophobic substances that are protein-bound. This function is provided for by a fenestrated endothelium. The liver also receives essentially all venous blood from the intestine prior to its delivery to the remainder of the body. Gastrointestinal System | Functions of the Liver The liver serves to buffer blood glucose, synthesize the majority of plasma proteins, contribute to lipid metabolism, and preserve cholesterol homeostasis. Bilirubin is an end product of heme metabolism that is glucuronidated by the hepatocyte to permit its excretion in bile. Bilirubin and its metabolites impart color to the bile and stools. Gastrointestinal System | Functions of the Liver The liver removes ammonia from the blood and converts it to urea for excretion by the kidneys. An accumulation of ammonia as well as other toxins causes hepatic encephalopathy in the setting of liver failure. Bile contains substances actively secreted across the canalicular membrane by hepatocytes, and notably bile acids, phosphatidylcholine, and cholesterol. The composition of bile is modified as it passes through the bile ducts and is stored in the gallbladder. Gallbladder contraction is regulated to coordinate bile availability with the timing of meals.