After studying this chapter, you should be able to:
Describe the major functions of the liver with respect to metabolism, detoxification, and excretion of hydrophobic substances.
Understand the functional anatomy of the liver and the relative arrangements of hepatocytes, cholangiocytes, endothelial cells, and Kupffer cells.
Define the characteristics of the hepatic circulation and its role in subserving the liver’s functions.
Identify the plasma proteins that are synthesized by the liver.
Describe the formation of bile, its constituents, and its role in the excretion of cholesterol and bilirubin.
Outline the mechanisms by which the liver contributes to whole body ammonia homeostasis and the consequences of the failure of these mechanisms, particularly for brain function.
Identify the mechanisms that permit normal functioning of the gallbladder and the basis of gallstone disease.
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. 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.
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. 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 28–1).
FIGURE 28–1 Schematic anatomy of the liver. Top: Organization of the liver. CV, central vein. PS, portal space containing branches of bile duct (green), portal vein (blue), and hepatic artery (red). Bottom: Arrangement of plates of liver cells, sinusoids, and bile ducts in a liver lobule, showing centripetal flow of blood in sinusoids to central vein and centrifugal flow of bile in bile canaliculi to bile ducts. (Redrawn and modified from Ham AW: Textbook of Histology, 5th ed. Philadelphia: JB Lippincott Co., 1965.)
In each hepatic lobule, the plates of hepatic cells are usually only one cell thick. Large gaps occur between the endothelial cells, and plasma is in intimate contact with the cells (Figure 28–2). Hepatic artery blood also enters the sinusoids. 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 micro- and macrocirculation, which are critical to organ function, are provided below. Numerous macrophages (Kupffer cells) are anchored to the endothelium of the sinusoids and project into the lumen. The functions of these phagocytic cells are discussed in Chapter 3.
FIGURE 28–2 Hepatocyte. Note the relation of the cell to bile canaliculi and sinusoids. Note also the wide openings (fenestrations) between the endothelial cells next to the hepatocyte. (Drawing by Sylvia Colard Keene.)
Each liver cell is also apposed to several bile canaliculi (Figure 28–2). 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. The hepatic duct unites with the cystic duct to form the common bile duct (Figure 28–1). 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.
The walls of the extrahepatic biliary ducts and the gallbladder 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 gallbladder 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.
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 is shown in Figure 28–1. 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 (Figure 28–3). 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.
FIGURE 28–3 Concept of the acinus as the functional unit of the liver. In each acinus, blood in the portal venule and hepatic arteriole enters the center of the acinus and flows outward to the hepatic venule. (Based on the acinar concept of Rappaport AM: The microcirculatory hepatic unit. Microvasc Res 1973 Sep;6(2):212–228.)
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. 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. 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. 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 via the 3rd to 11th thoracic ventral roots and the splanchnic nerves. The vasoconstrictor innervation of the hepatic artery comes from the hepatic sympathetic plexus. 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 congestive 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 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
The liver has many complex functions that are summarized in Table 28–1. Several will be touched upon briefly here.
TABLE 28–1 Principal 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, we will describe here 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, as well as many of the reactions covered in Chapter 1. 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. 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.
The liver also detoxifies the blood of substances originating from the gut or elsewhere in the body (Clinical Box 28–1). 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. 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.
CLINICAL BOX 28–1
The clinical importance of hepatic ammonia metabolism is seen in liver failure, when increased levels of circulating ammonia cause the condition of hepatic encephalopathy. Initially, patients may seem merely confused, but if untreated, the condition can progress to coma and irreversible changes in cognition. The disease results not only from the loss of functional hepatocytes, but also shunting of portal blood around the hardened liver, meaning that less ammonia is removed from the blood by the remaining hepatic mass. Additional substances that are normally detoxified by the liver likely also contribute to the mental status changes.
The congnitive symptoms of advanced liver disease can be minimized by reducing the load of ammonia coming to the liver from the colon (eg, by feeding the nonabsorbable carbohydrate, lactulose, which is converted into short-chain fatty acids in the colonic lumen and thereby traps luminal ammonia in its ionized form). However, in severe disease, the only truly effective treatment is to perform a liver transplant, although the paucity of available organs means that there is great interest in artificial liver assist devices that could clean the blood.
SYNTHESIS OF PLASMA PROTEINS
The principal proteins synthesized by the liver are listed in Table 28–1. 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 (see Chapter 3). 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.
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). 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 (Chapter 26), bile (and subsequently the feces) is the major excretory route for lipid-soluble waste products.
TABLE 28–2 Composition of human hepatic duct bile.
The glucuronides of the bile pigments, bilirubin and biliverdin, are responsible for the golden yellow color of bile. The formation of these breakdown products of hemoglobin is discussed in detail in Chapter 31, and their excretion is discussed in the following text.
BILIRUBIN METABOLISM & EXCRETION
Most of the bilirubin in the body is formed in the tissues by the break down of hemoglobin (see Chapter 31 and Figure 28–4). The bilirubin is bound to albumin in the circulation. Some of it is tightly bound, but most 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). It is next conjugated to glucuronic acid in a reaction catalyzed by the enzyme glucuronyl transferase (UDP-glucuronosyltransferase). This enzyme is located primarily in the smooth endoplasmic reticulum. Each bilirubin molecule reacts with two uridine diphosphoglucuronic acid (UDPG) 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. 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.
FIGURE 28–4 Conversion of heme to bilirubin is a two-step reaction catalyzed by heme oxygenase and biliverdin reductase. M, methyl; P, propionate; V, vinyl.
FIGURE 28–5 Handling of bilirubin by hepatocytes. Albumin (Alb)-bound bilirubin (B) enters the space of Disse adjacent to the basolateral membrane of hepatocytes, and bilirubin is selectively transported into the hepatocyte. Here, it is conjugated with glucuronic acid (G). The conjugates are secreted into bile via the multidrug resistance protein 2 (MRP-2). Some unconjugated and conjugated bilirubin also refluxes into the plasma. OATP, organic anion transporting polypeptide.
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.
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, etc; see Chapter 31), (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. 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.
OTHER SUBSTANCES CONJUGATED BY GLUCURONYL TRANSFERASE
The glucuronyl transferase system in the smooth endoplasmic reticulum catalyzes the formation of the glucuronides of a variety of substances in addition to bilirubin. As discussed above, the list includes steroids (see Chapter 20) and various drugs. These other compounds can compete with bilirubin for the enzyme system when they are present in appreciable amounts. In addition, several barbiturates, antihistamines, anticonvulsants, and other compounds cause marked proliferation of the smooth endoplasmic reticulum in the hepatic cells, with a concurrent increase in hepatic glucuronyl transferase activity. Phenobarbital has been used successfully for the treatment of a congenital disease in which there is a relative deficiency of glucuronyl transferase (type 2 UDP-glucuronosyltransferase deficiency).
OTHER SUBSTANCES EXCRETED IN THE BILE
Cholesterol and alkaline phosphatase are excreted in the bile. In patients with jaundice due to intra- or extrahepatic obstruction of the bile duct, the blood levels of these two substances usually rise. A much smaller rise is generally seen when the jaundice is due to nonobstructive hepatocellular disease. Adrenocortical and other steroid hormones and a number of drugs are excreted in the bile and subsequently reabsorbed (enterohepatic circulation).
AMMONIA METABOLISM & EXCRETION
The liver is critical for ammonia handling in the body. Ammonia levels must be carefully controlled because it is toxic to the central nervous system (CNS), and freely permeable across the blood–brain barrier. The liver is the only organ in which the complete urea cycle (also known as the Krebs–Henseleit cycle) is expressed (Figure 28–6). This converts circulating ammonia to urea, which can then be excreted in the urine (Figure 28–7).
FIGURE 28–6 The urea cycle, which converts ammonia to urea, takes place in the mitochondria and cytosol of hepatocytes.
FIGURE 28–7 Whole body ammonia homeostasis in health. The majority of ammonia produced by the body is excreted by the kidneys in the form of urea.
Ammonia in the circulation comes primarily from the colon and kidneys with lesser amounts deriving from the breakdown of red blood cells and from metabolism in the muscles. As it passes through the liver, the vast majority of ammonia in the circulation is cleared into the hepatocytes. There, it is converted in the mitochondria to carbamoyl phosphate, which in turn reacts with ornithine to generate citrulline. A series of subsequent cytoplasmic reactions eventually produce arginine, and this can be dehydrated to urea and ornithine. The latter returns to the mitochondria to begin another cycle, and urea, as a small molecule, diffuses readily back out into the sinusoidal blood. It is then filtered in the kidneys and lost from the body in the urine.
THE BILIARY SYSTEM
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.
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 (Figure 28–8).
FIGURE 28–8 Cholesterol solubility in bile as a function of the proportions of lecithin, bile salts, and cholesterol. In bile that has a composition described by any point below line ABC (eg, point P), cholesterol is solely in micellar solution; points above line ABC describe bile in which there are cholesterol crystals as well. (Reproduced with permission from Small DM: Gallstones. N Engl J Med 1968;279:588.)
The bile is transferred to progressively larger bile ductules and ducts, where it undergoes modification of its composition. The bile ductules are lined by cholangiocytes, specialized columnar epithelial cells. Their tight junctions are less permeable than those of the hepatocytes, although they remain freely permeable to water and thus bile remains isotonic. The ductules scavenge plasma constituents, such as glucose and amino acids, and return them to the circulation by active transport. Glutathione is also hydrolyzed to its constituent amino acids by an enzyme, gamma glutamyltranspeptidase (GGT), expressed on the apical membrane of the cholangiocytes. Removal of glucose and amino acids is likely important to prevent bacterial overgrowth of the bile, particularly during gallbladder storage (see below). The ductules also secrete bicarbonate in response to secretin in the postprandial period, as well as IgA and mucus for protection.
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); 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 slightly acidic 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).
TABLE 28–3 Comparison of human hepatic duct bile and gallbladder bile.
When the bile duct and cystic duct are clamped, the intrabiliary 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 intrabiliary pressure rises only to about 100 mm of bile in several hours.
REGULATION OF BILIARY SECRETION
When food enters the mouth, the resistance of the sphincter of Oddi decreases under both neural and hormonal influences (Figure 28–9). Fatty acids and amino acids in the duodenum release CCK, which causes gallbladder contraction.
FIGURE 28–9 Neurohumoral control of gallbladder contraction and biliary secretion. Endocrine release of cholecystokinin (CCK) in response to nutrients causes gallbladder contraction. CCK, also activates vagal afferents to trigger a vago-vagal reflex that reinforces gallbladder contraction (via acetylcholine (ACh)) and relaxation of the sphincter of Oddi to permit bile outflow (via NO and vasoactive intestinal polypeptide (VIP)).
The production of bile is increased by stimulation of the vagus nerves and by the hormone secretin, which increases the water and content of bile. Substances that increase the secretion of bile are known as choleretics.Bile acids themselves are among the most important physiologic choleretics.
EFFECTS OF CHOLECYSTECTOMY
The periodic discharge of bile from the gallbladder aids digestion but is not essential for it. Cholecystectomized patients maintain good health and nutrition with a constant slow discharge of bile into the duodenum, although eventually the bile duct becomes somewhat dilated, and more bile tends to enter the duodenum after meals than at other times. Cholecystectomized patients can even tolerate fried foods, although they generally must avoid foods that are particularly high in fat content.
VISUALIZING THE GALLBLADDER
Exploration of the right upper quadrant with an ultrasonic beam (ultrasonography) and computed tomography (CT) have become the most widely used methods for visualizing the gallbladder and detecting gallstones. A third method of diagnosing gallbladder disease is nuclear cholescintigraphy. When administered intravenously, technetium-99m-labeled derivatives of iminodiacetic acid are excreted in the bile and provide excellent gamma camera images of the gallbladder and bile ducts. The response of the gallbladder to CCK can then be observed following intravenous administration of the hormone. The biliary tree can also be visualized by injecting contrast media from an endoscope channel maneuvered into the sphincter of Oddi, in a procedure known as endoscopic retrograde cholangiopancreatography (ERCP). It is even possible to insert small instruments with which to remove gallstone fragments that may be obstructing the flow of bile, the flow of pancreatic juice, or both (Clinical Box 28–2).
CLINICAL BOX 28–2
Cholelithiasis, that is, the presence of gallstones, is a common condition. Its incidence increases with age, so that in the United States, for example, 20% of the women and 5% of the men between the ages of 50 and 65 have gallstones. The stones are of two types: calcium bilirubinate stones and cholesterol stones. In the United States and Europe, 85% of the stones are cholesterol stones. Three factors appear to be involved in the formation of cholesterol stones. One is bile stasis; stones form in the bile that is sequestrated in the gallbladder rather than the bile that is flowing in the bile ducts. A second is supersaturation of the bile with cholesterol. Cholesterol is very insoluble in bile, and it is maintained in solution in micelles only at certain concentrations of bile salts and lecithin. At concentrations above line ABC in Figure 28–8, the bile is supersaturated and contains small crystals of cholesterol in addition to micelles. However, many normal individuals who do not develop gallstones also have supersaturated bile. The third factor is a mix of nucleation factors that favors formation of stones from the supersaturated bile. Outside the body, bile from patients with cholelithiasis forms stones in 2–3 days, whereas it takes more than 2 weeks for stones to form in bile from normal individuals. The exact nature of the nucleation factors is unsettled, although glycoproteins in gallbladder mucus have been implicated. In addition, it is unsettled whether stones form as a result of excess production of components that favor nucleation or decreased production of antinucleation components that prevent stones from forming in normal individuals.
Gallstones that obstruct bile outflow from the liver can result in obstructive jaundice. If the flow of bile out of the liver is completely blocked, substances normally excreted in the bile, such as cholesterol, accumulate in the bloodstream. The interruption of the enterohepatic circulation of bile acids also induces the liver to synthesize bile acids at a greater rate. Some of these bile acids can be excreted by the kidney, and thus represent a mechanism for indirect excretion of at least a portion of cholesterol. However, retained biliary constituents may also cause liver toxicity.
The treatment of gallstones depends on their nature, and the severity of any symptoms. Many, particularly if small and retained in the gallbladder, may be asymptomatic. Larger stones that cause obstruction may need to be removed surgically, or via ERCP. Oral dissolution agents may dissolve small stones composed of cholesterol, but the effect is slow and stones often return once therapy is stopped. A definitive cure for patients who suffer from recurrent attacks of symptomatic cholelithiasis is to have the gallbladder removed, which is usually now performed laparoscopically.
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.
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.
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.
For all questions, select the single best answer unless otherwise directed.
1. A patient suffering from severe ulcerative colitis undergoes a total colectomy with formation of a stoma. After a full recovery from surgery, and compared to his condition prior to surgery, which of the following would be expected to be decreased?
A. Ability to absorb lipids
B. Ability to clot the blood
C. Circulating levels of conjugated bile acids
D. Urinary urea
E. Urinary urobilinogen
2. A surgeon is studying new methods of liver transplantation. She performs a complete hepatectomy in an experimental animal. Before the donor liver is grafted, a rise would be expected in the blood level of
D. conjugated bilirubin.
3. Which of the following cell types protects against sepsis secondary to translocation of intestinal bacteria?
A. Hepatic stellate cell
C. Kupffer cell
E. Gallbladder epithelial cell
4. P450s (CYPs) are highly expressed in hepatocytes. In which of the following do they not play an important role?
A. Bile acid formation
C. Steroid hormone formation
D. Detoxification of drugs
E. Glycogen synthesis
5. A 40-year-old woman comes to her primary care physician complaining of severe, episodic abdominal pain that is particularly intense after she ingests a fatty meal. An imaging procedure reveals that her gallbladder is acutely dilated, and a diagnosis of cholelithiasis is made. A gallstone lodged in which location will also increase her risk of pancreatitis?
A. Left hepatic duct
B. Right hepatic duct
C. Cystic duct
D. Common bile duct
E. Sphincter of Oddi
6. Compared to hepatic bile, gallbladder bile contains a reduced concentration of which of the following?
A. Bile acids
B. Sodium ions
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