Histology_Ross

Histology_Ross. The liver stores and converts several vitamins and iron. Several vitamins are taken up from the bloodstream and are then stored or biochemically modified by the liver. They include  vitamin A (retinol), an important vitamin in vision. Vitamin A is the precursor of retinal, which is required for the synthesis of rhodopsin in the eye. The liver plays a major role in the uptake, storage, and maintenance of circulating levels of vitamin A. When the vitamin A levels in the blood decrease, the liver mobilizes its storage sites in the hepatic stellate cells (see page 637). Vitamin A is then released into the circulation in the form of retinol bound to retinolbinding protein (RBP). The liver also synthesizes RBP; RBP synthesis is regulated by plasma levels of vitamin A. Night blindness and multiple skin disorders are related to vitamin A deficiency.


Histology_Ross

Histology_Ross.  vitamin D (cholecalciferol), an important vitamin in calcium and phosphate metabolism. Vitamin D is acquired from dietary vitamin D3 and is also produced in the skin during exposure to ultraviolet light by conversion of 7-dehydrocholesterol. Unlike vitamin A, vitamin D is not stored in the liver but is distributed to skeletal muscles and adipose tissue. The liver plays an important role in vitamin D metabolism by converting vitamin D3 to 25-hydroxycholecalciferol, the predominant form of circulating vitamin D. Further chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas LIVE R 629


Histology_Ross

Histology_Ross. Lipoproteins are multicomponent complexes of proteins and lipids that are involved in the transport of cholesterol and triglycerides in the blood. Cholesterol and triglyc-erides do not circulate freely in the plasma because lipids, on their own, would be unable to remain in suspension. The association of the protein with the lipid-containing core makes the complex sufficiently hydrophilic to remain suspended in the plasma. Lipoproteins serve a variety of functions in cellular mem-branes and in the transport and metabolism of lipids. Lipoprotein precursors are produced in the liver. The lipid component is produced in the sER; the protein component is produced in the rER of the hepatocytes. The lipoprotein complexes pass to the Golgi, where secretory vesicles containing electron-dense lipoprotein particles bud off and are then released at the cell surface bordering the perisinu-soidal space to reach the bloodstream. Several hormones, such as estrogen and thyroid hormones, regulate the


Histology_Ross

Histology_Ross. particles bud off and are then released at the cell surface bordering the perisinu-soidal space to reach the bloodstream. Several hormones, such as estrogen and thyroid hormones, regulate the se-cretion of lipoproteins. In general, four classes of lipoproteins have been de-fined by their characteristic density, molecular weight, size, and chemical composition: chylomicrons, VLDLs, LDLs, and HDLs. These lipoproteins differ in chemical composi-tion and can be isolated from plasma according to their flotation properties, from largest and least dense to small-est and most dense. Chylomicrons, the lightest of all lipoproteins, are made only in the small intestine. Their main function is to transport the large amount of absorbed fat to the bloodstream. VLDLs are denser and smaller than chylomicrons; they are synthesized predominately in the liver and to a lesser extent in the small intestine. VLDLs are rich in triglycerides. Their function is to transport most of the triglycerides from the


Histology_Ross

Histology_Ross. they are synthesized predominately in the liver and to a lesser extent in the small intestine. VLDLs are rich in triglycerides. Their function is to transport most of the triglycerides from the liver to other organs. Liver VLDLs are associated with circulating apolipoprotein B-100, also synthesized in the liver, which aids in secretion of VLDLs. In congenital liver disease, such as abetalipoproteinemia, and to a lesser degree in acute and chronic disorders, the liver is unable to produce apolipoprotein B-100, leading to blockage in the secretion of VLDLs. In liver biopsy specimens from these individuals, large lipid droplets occupy most of the hepato-cyte cytoplasm. LDLs and HDLs are produced in the plasma; however, small amounts of these fractions are produced by the liver. LDLs are denser than VLDLs, and HDLs are denser than LDLs. The function of LDLs is to transport cholesterol es-ters from the liver to the peripheral organs. The HDLs are involved in the transport of cholesterol


Histology_Ross

Histology_Ross. than VLDLs, and HDLs are denser than LDLs. The function of LDLs is to transport cholesterol es-ters from the liver to the peripheral organs. The HDLs are involved in the transport of cholesterol from the peripheral tissues to the liver. High levels of LDL are directly corre-lated with increased risk of cardiovascular disease; high levels of HDL or low levels of LDL are associated with decreased risk.


Histology_Ross

Histology_Ross.  FOLDER 18.1 Clinical Correlation: Lipoproteins conversion takes place in the kidney to 1,25-hydroxycholecalciferol, which is 10 times more active than vitamin D3. Vitamin D is essential for development and growth of the skeletal system and teeth. Deficiency of vitamin D is associated with rickets and disorders of bone mineralization.  vitamin K, which is important in hepatic synthesis of prothrombin and several other clotting factors. Like vitamin D, it is derived from two sources: dietary vitamin K and synthesis in the small intestine by intestinal bacterial flora. Vitamin K is transported to the liver with chylomicrons, where it is rapidly absorbed, partially used, and then partially secreted with the VLDL fraction. Vitamin K deficiency is associated with hypoprothrombinemia and bleeding disorders.


Histology_Ross

Histology_Ross. In addition, the liver functions in the storage, meta bolism, and homeostasis of iron. It synthesizes almost all of the proteins involved in iron transport and metabolism, including transferrin, haptoglobin, and hemopexin. Transferrin is a plasma iron-transport protein. Haptoglobin binds to free hemoglobin in the plasma, from which the entire complex is removed by the liver to preserve iron. Hemopexin is involved in the transport of free heme in the blood. Iron is stored within the hepatocyte cytoplasm in the form of ferritin or may be converted to hemosiderin granules. Recent studies indicate that hepatocytes are the major sites of long-term storage of iron. Iron overload (as in multiple blood transfusions) may lead to hemochromatosis, a form of liver damage characterized by excessive amounts of hemosiderin in hepatocytes. The liver degrades drugs and toxins. Hepatocytes are involved in degradation of drugs, toxins, and other proteins foreign to the body (xenobiotics).


Histology_Ross

Histology_Ross. The liver degrades drugs and toxins. Hepatocytes are involved in degradation of drugs, toxins, and other proteins foreign to the body (xenobiotics). Many drugs and toxins are not hydrophilic; therefore, they cannot be eliminated effectively from the circulation by the kidneys. The liver converts these substances into more soluble forms. This process is performed by the hepatocytes in two phases:  Phase I (oxidation) includes hydroxylation (adding an OOH group) and carboxylation (adding a OCOOH group) to a foreign compound. This phase is performed in the hepatocyte smooth endoplasmic reticulum (sER) and mitochondria. It involves a series of biochemical reactions with proteins collectively named cytochrome P450.  Phase II (conjugation) includes conjugation with glucuronic acid, glycine, or taurine. This process makes the product of phase I even more water soluble so that it can be easily removed by the kidney. The liver is involved in many other important metabolic pathways.


Histology_Ross

Histology_Ross. The liver is important in carbohydrate metabolism as it maintains an adequate supply of nutrients for cell processes. In glucose metabolism, the liver phosphorylates absorbed glucose from the gastrointestinal tract to glucose-6phosphate. Depending on energy requirements, glucose-6-phosphate is either stored in the liver in the form of glycogen or used in the glycolytic pathways. During fasting, glycogen is broken down by the process of glycogenolysis, and glucose is released into the bloodstream. In addition, the liver functions in lipid metabolism. Fatty acids derived from plasma are consumed by hepatocytes using -oxidation to provide energy. The liver also produces ketone bodies that are used as a fuel by other organs (the liver cannot use them as an energy source). The involvement in cholesterol metabolism (synthesis and uptake from the blood) is also an important function of the liver. Cholesterol is used in the formation of bile salts, synthesis of VLDLs, and biosynthesis of


Histology_Ross

Histology_Ross. in cholesterol metabolism (synthesis and uptake from the blood) is also an important function of the liver. Cholesterol is used in the formation of bile salts, synthesis of VLDLs, and biosynthesis of organelles. The liver synthesizes most of the urea in the body from ammonium ions derived from protein and nucleic acid degradation. Finally, the liver is involved in the synthesis and conversion of nonessential amino acids.


Histology_Ross

Histology_Ross. Bile production is an exocrine function of the liver. The liver is engaged in numerous metabolic conversions involving substrates delivered by blood from the digestive tract, pancreas, and spleen. Some of these products are involved in the production of bile, an exocrine secretion of the liver. Bile contains conjugated and degraded waste products that are returned to the intestine for disposal, as well as substances that bind to metabolites in the intestine to aid in absorption (Table 18.1). Bile is carried from the parenchyma of the liver by bile ducts that fuse to form the hepatic duct. The cystic duct then carries the bile into the gallbladder, where it is concentrated. Bile is returned, via the cystic duct, to the common bile duct, which delivers bile from the liver and gallbladder to the duodenum (see Fig. 18.15). The endocrine-like functions of the liver are represented by its ability to modify the structure and function of many hormones.


Histology_Ross

Histology_Ross. The endocrine-like functions of the liver are represented by its ability to modify the structure and function of many hormones. The liver modifes the action of hormones released by other organs. The liver’s endocrine-like actions involve  vitamin D, which is converted by the liver to 25hydroxycholecalciferol, the predominant form of circulating vitamin D (page 629).  thyroxine, a hormone secreted by the thyroid gland as tetraiodothyronine (T4), which is converted in the liver to the biologically active form, triiodothyronine (T3), by deiodination.  growth hormone (GH), a hormone secreted by the pituitary gland. The action of GH is modified by liver-produced growth hormone–releasing hormone (GHRH) and inhibited by somatostatin, which is secreted by enteroendocrine cells of the gastrointestinal tract.  insulin and glucagon, both pancreatic hormones. These hormones are degraded in many organs, but the liver and kidney are the most important sites of their degradation.


Histology_Ross

Histology_Ross.  insulin and glucagon, both pancreatic hormones. These hormones are degraded in many organs, but the liver and kidney are the most important sites of their degradation. Blood Supply to the Liver To appreciate the myriad functions of the liver introduced previously, one must first understand its unique blood supply and how blood is distributed to the hepatocytes. The liver has a dual blood supply consisting of a venous (portal) supply via the hepatic portal vein and an arterial supply via the hepatic artery. Both vessels enter the liver at a hilum or porta hepatis, the same site at which the common bile duct, carrying the bile secreted by the liver, and the lymphatic vessels leave the liver. Therefore, bile flows in a direction opposite to that of the blood. The liver receives the blood that initially supplied the intestines, pancreas, and spleen.


Histology_Ross

Histology_Ross. The liver receives the blood that initially supplied the intestines, pancreas, and spleen. The liver is unique among organs because it receives its major blood supply (about 75%) from the hepatic portal vein, which carries venous blood that is largely depleted of oxygen.


Histology_Ross

Histology_Ross. 631 TABLE Composition of Bile18.1 Component Function Water Serves as solute in which other components are carried Phospholipids (i.e., lecithin) and cholesterol Are metabolic substrates for other cells in the body; act as precursors of membrane components and steroids; largely reabsorbed in the gut and recycled Bile salts (also called bile acids): primary (secreted by liver): cholic acid, chenodeoxycholic acid; secondary (converted by bacterial flora in the intestine): deoxycholic acid, lithocholic acid Act as emulsifying agents that aid in the digestion and absorption of lipids from the gut and help to keep the cholesterol and phospholipids of the bile in solution, largely recycled, going back and forth between the liver and gut Bile pigments, principally the glucuronide of the bilirubin produced in the spleen, bone marrow, and liver by the breakdown of hemoglobin Detoxify bilirubin, the end product of hemoglobin degradation, and carry it to the gut for disposal Electrolytes: Na,


Histology_Ross

Histology_Ross. produced in the spleen, bone marrow, and liver by the breakdown of hemoglobin Detoxify bilirubin, the end product of hemoglobin degradation, and carry it to the gut for disposal Electrolytes: Na, K, Ca2, Mg2, Cl, and HCO3 Establish and maintain bile as an isotonic fluid; also largely reabsorbed in the gut


Histology_Ross

Histology_Ross. Digestive System III: Liver, Gallbladder, and Pancreas LIVER The blood delivered to the liver by the hepatic portal vein comes from the digestive tract and the major abdominal organs, such as the pancreas and spleen. The portal blood carried to the liver contains  nutrients and toxic materials absorbed in the intestine.  blood cells and breakdown products of blood cells from the spleen. endocrine secretions of the pancreas and enteroendocrine cells of the gastrointestinal tract. Thus, the liver stands directly in the pathway of blood vessels that convey substances absorbed from the digestive tract. Although the liver is the first organ to receive metabolic substrates and nutrients, it is also the first exposed to toxic substances that have been absorbed.


Histology_Ross

Histology_Ross. The hepatic artery, a branch of the celiac trunk, carries oxygenated blood to the liver, providing the remaining 25% of its blood supply. Because blood from the two sources mixes just before it perfuses the hepatocytes of the liver parenchyma, the liver cells are never exposed to fully oxygenated blood. Within the liver, the distributing branches of the portal vein and hepatic artery, which supply the sinusoidal capillaries (sinusoids) that bathe the hepatocytes, and the draining branches of the bile duct system, which lead to the common hepatic duct, course together in a relationship termed the portal triad. Although a convenient term, it is a misnomer because one or more vessels of the lymphatic drainage system of the liver always travel with the vein, artery, and bile duct (Fig. 18.2).


Histology_Ross

Histology_Ross. The sinusoids are in intimate contact with the hepatocytes and provide for the exchange of substances between the blood and liver cells. The sinusoids lead to a terminal hepatic venule (central vein) that in turn empties into the sublobular veins. Blood leaves the liver through the hepatic veins, which empty into the inferior vena cava. Structural Organization of the Liver As introduced previously, the structural components of the liver include  parenchyma, consisting of organized plates of hepatocytes, which in the adult are normally one cell thick and are separated by sinusoidal capillaries. In young individuals up to 6 years of age, the liver cells are arranged in plates two cells thick.  connective tissue stroma that is continuous with the fibrous capsule of Glisson. Blood vessels, nerves, lymphatic vessels, and bile ducts travel within the connective tissue stroma.


Histology_Ross

Histology_Ross.  connective tissue stroma that is continuous with the fibrous capsule of Glisson. Blood vessels, nerves, lymphatic vessels, and bile ducts travel within the connective tissue stroma.  sinusoidal capillaries (sinusoids), the vascular channels between the plates of hepatocytes.  perisinusoidal spaces (spaces of Disse), which lie between the sinusoidal endothelium and the hepatocytes. With this information as background, one can now consider several ways to describe the organization of these structural elements to understand the major functions of the liver. periportal space (space of Mall) capillary terminal branch of hepatic artery terminal branch of portal vein portal canal


Histology_Ross

Histology_Ross. FIGURE 18.2 • Blood supply to the liver: the portal triad. The portal triad is composed of the branches of the hepatic artery, portal vein, and bile duct. Blood from the terminal branches of the hepatic artery and portal vein enters the hepatic sinusoids. The mixture of venous and arterial blood is transported by the sinusoids toward the terminal hepatic venule (central vein). From here, blood drains into the sublobular veins, the tributaries of the hepatic vein. Note the small vessels and capillary network in the perivascular connective tissue surrounding each hepatic triad within the portal canal. Also note the periportal space of Mall, located between the portal canal and the outermost hepatocytes. This space is also filled with a small amount of connective tissue in which lymph drainage begins. From here, blind-ended lymphatic capillaries form larger lymphatic vessels that accompany branches of the hepatic artery.


Histology_Ross

Histology_Ross. There are three ways to describe the structure of the liver in terms of a functional unit: the classic lobule, the portal lobule, and the liver acinus. The classic lobule is the traditional way to describe the organization of the liver parenchyma, and it is relatively easy to visualize. It is based on the distribution of the branches of the portal vein and hepatic artery within the organ and the pathway that blood from them follows as it ultimately perfuses the liver cells. The classic hepatic lobule is a roughly hexagonal mass of tissue.


Histology_Ross

Histology_Ross. The classic hepatic lobule is a roughly hexagonal mass of tissue. The classic lobule (Fig. 18.3 and Plate 65, page 656) consists of stacks of anastomosing plates of hepatocytes, one cell thick, separated by the anastomosing system of sinusoids that perfuse the cells with the mixed portal and arterial blood. Each lobule measures about 2.0 0.7 mm. At the center of the lobule is a relatively large venule, the terminal hepatic venule (central vein), into which the sinusoids drain. The plates of cells radiate from the central vein to the periphery of the lobule, as do the sinusoids. At the angles of the hexagon are the portal areas (portal canals), loose stromal connective tissue characterized by the presence of the portal triads. This connective tissue is ultimately continuous with the fibrous capsule of the liver. The portal canal is bordered by the outermost hepatocytes of the


Histology_Ross

Histology_Ross. FIGURE 18.3 • Diagram of a classic liver lobule. A classic liver lobule can be schematically diagramed as a six-sided polyhedral prism with portal triads (hepatic artery, portal vein, and bile duct) at each of the corners. The blood vessels of the portal triads send distributing branches along the sides of the lobule, and these branches open into the hepatic sinusoids. The long axis of the lobule is traversed by the terminal hepatic venule (central vein), which receives blood from the hepatic sinusoids. Note that a wedge of the tissue has been removed from the lobule for better visualization of the terminal hepatic venule. Interconnecting sheets or plates of hepatocytes are disposed in a radial pattern from the terminal hepatic venule to the periphery of the lobule.


Histology_Ross

Histology_Ross. lobule. At the edges of the portal canal, between the connective tissue stroma and the hepatocytes, is a small space called the periportal space (space of Mall). This space is thought to be one of the sites where lymph originates in the liver. In some species (e.g., the pig; Fig. 18.4a), the classic lobule is easily recognized because the portal areas are connected by relatively thick layers of connective tissue. In humans, however, there is normally very little interlobular connective tissue, and it is necessary, when examining histologic sections of liver, to draw imaginary lines between portal areas surrounding a central vein to get some sense of the size of the classic lobule (Fig. 18.4b). The portal lobule emphasizes the exocrine functions of the liver.


Histology_Ross

Histology_Ross. The portal lobule emphasizes the exocrine functions of the liver. The major exocrine function of the liver is bile secretion. Thus, the morphologic axis of the portal lobule is the interlobular bile duct of the portal triad of the classic lobule. Its outer margins are imaginary lines drawn between the three central veins that are closest to that portal triad (Fig. 18.5). These lines define a roughly triangular block of tissue that includes those portions of three classic lobules that secrete the bile that drains into its axial bile duct. This concept allows a description of hepatic parenchymal structure comparable to that of other exocrine glands. The liver acinus is the structural unit that provides the best correlation between blood perfusion, metabolic activity, and liver pathology.


Histology_Ross

Histology_Ross. The liver acinus is the structural unit that provides the best correlation between blood perfusion, metabolic activity, and liver pathology. The liver acinus is lozenge shaped and represents the smallest functional unit of the hepatic parenchyma. The short axis of the acinus is defined by the terminal branches of the portal triad that lie along the border between two classic lobules. The long axis of the acinus is a line drawn between the two central veins closest to the short axis. Therefore, in a two-dimensional view (Fig. 18.6) the liver acinus occupies parts of adjacent classic lobules. This concept allows a description of the exocrine secretory function of the liver comparable to that of the portal lobule.


Histology_Ross

Histology_Ross. The hepatocytes in each liver acinus are described as being arranged in three concentric elliptical zones surrounding the short axis (see Fig. 18.6).  Zone 1 is closest to the short axis and the blood supply from penetrating branches of the portal vein and hepatic artery. This zone corresponds to the periphery of the clas sic lobules.  Zone 3 is farthest from the short axis and closest to the ter minal hepatic vein (central vein). This zone corresponds to the most central part of the classic lobule that surrounds the terminal hepatic vein.  Zone 2 lies between zones 1 and 3 but has no sharp boundaries.


Histology_Ross

Histology_Ross. The zonation is important in the description and interpretation of patterns of degeneration, regeneration, and specific toxic effects in the liver parenchyma relative to the degree or quality of vascular perfusion of the hepatic cells. As a result of the sinusoidal blood ﬂow, the oxygen gradient, metabolic activity of the hepatocytes, and distribution of hepatic enzymes vary chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas LIVE R 633


Histology_Ross

Histology_Ross. FIGURE 18.4 • Photomicrographs of pig and human livers. a. This photomicrograph shows a cross section of a pig liver lobule stained by the Mallory-Azan method to visualize connective tissue components. Note the relatively thick interlobular connective tissue (stained blue) surrounding the lobules. The terminal hepatic venule (central vein) is visible in the center of the lobule. 65. b. Photomicrograph of a human liver from a routine H&E preparation. Note that in contrast to the pig liver, the lobules of the human liver lack connective tissue septa. The plates of hepatocytes of one lobule merge with those of adjacent lobules. The boundaries of a lobule can be approximated, however, by drawing a line (dashed line) from one portal canal to the next, thus circumscribing the lobule. 65.


Histology_Ross

Histology_Ross. across the three zones. The distribution of liver damage result-are the first to show ischemic necrosis (centrilobular necrosis) ing from ischemia and exposure to toxic substances can be ex-in situations of reduced perfusion and the first to show fat ac-plained using this zonal interpretation. cumulation. They are the last to respond to toxic substances Cells in zone 1 are the first to receive oxygen, nutrients, and bile stasis. Normal variations in enzyme activity, the and toxins from the sinusoidal blood and the first to show number and size of cytoplasmic organelles, and the size of cymorphologic changes after bile duct occlusion (bile stasis). toplasmic glycogen deposits are also seen between zones 1 These cells are also the last to die if circulation is impaired and 3. Cells in zone 2 have functional and morphologic char-and the first to regenerate. On the other hand, cells in zone 3 acteristics and responses intermediate to those of zones 1 and 3.


Histology_Ross

Histology_Ross. FIGURE 18.5 • Comparison of the classic liver lobule, portal lobule, and liver acinus. The area indicated in blue shows the territory of each of the three units relating to liver organization and function. The classic lobule has the terminal hepatic venule (central vein) at the center of the lobule and the portal canals containing portal triads at the peripheral angles of the lobule. The portal lobule has a portal canal at the center of the lobule and terminal hepatic venules (central veins) at the peripheral angles of the lobule. The liver acinus has distributing vessels at the equator and terminal hepatic venules (central veins) at each pole.


Histology_Ross

Histology_Ross. FIGURE 18.6 • The liver acinus. The liver acinus is a functional interpretation of liver organization. It consists of adjacent sectors of neighboring hexagonal fields of classic lobules partially separated by distributing blood vessels. The zones, marked 1, 2, and 3, are supplied with blood that is most oxygenated and richest in nutrients in zone 1 and least so in zone 3. The terminal hepatic venules (central veins) in this interpretation are at the edges of the acinus instead of in the center, as in the classic lobule. The vessels of the portal canals, namely, terminal branches of the portal vein and hepatic artery that, along with the smallest bile ducts, make up the portal triad, are shown at the corners of the hexagon that outlines the cross-sectioned profile of the classic lobule.  FOLDER 18.2 Clinical Correlation: Congestive Heart Failure and Liver Necrosis


Histology_Ross

Histology_Ross. Liver injury may be triggered by hemodynamic changes in the circulatory system. In congestive heart failure, the heart is unable to provide sufficient oxygenated blood to meet the metabolic requirements of many tissues and organs, including the liver, which is readily affected by hypoperfusion and hypoxia (low blood oxygen content). Zone 3 of the liver acinus is the first to be affected by this condition. The hepatocytes in this zone are the last to receive blood as it passes along the sinusoids; as a result, these cells receive a blood supply already depleted in oxygen. Examination of a liver biopsy specimen from an individual with congestive heart failure shows a distinct pattern of liver necrosis. Hepatocytes in zone 3, which is located around the central vein, undergo ischemic necrosis. Typically, no noticeable changes are seen in zones 1 and 2, representing the periphery of a classic lobule. Necrosis of this type is referred to as centrilobular necrosis. Figure F18.2.1 shows the


Histology_Ross

Histology_Ross. Typically, no noticeable changes are seen in zones 1 and 2, representing the periphery of a classic lobule. Necrosis of this type is referred to as centrilobular necrosis. Figure F18.2.1 shows the centrilobular portion of a classic lobule. The multiple round vacuoles indicate lipid accumulation, and the atrophic changes are the result of dying hepatocytes undergoing autophagocytosis. Centrilobular necrosis as a result of hypoxia is referred to as cardiac cirrhosis; however, unlike true cirrhosis, nodular regeneration of hepatocytes is minimal.


Histology_Ross

Histology_Ross. FIGURE F18.2.1 • Photomicrograph of centrilobular necrosis in human liver. This photomicrograph shows a routine H&E liver biopsy specimen from an individual with congestive heart failure. Pathologic changes (referred to as ischemic necrosis) are most severe in hepatocytes in zone 3. This zone surrounds the terminal hepatic venule (central vein). This type of necrosis is referred to as centrilobular necrosis. Note the presence of multiple round vacuoles, which indicates extensive lipid accumulation. No noticeable changes are seen in the periphery of the lobule, that is zone 1 and much of zone 2. 320. Digestive System III: Liver, Gallbladder, and Pancreas LIVER Blood Vessels of the Parenchyma


Histology_Ross

Histology_Ross. Digestive System III: Liver, Gallbladder, and Pancreas LIVER Blood Vessels of the Parenchyma The blood vessels that occupy the portal canals are called interlobular vessels. Only the interlobular vessels that form the smallest portal triads send blood into the sinusoids. The larger interlobular vessels branch into distributing vessels that are located at the periphery of the lobule. These distributing vessels send inlet vessels to the sinusoids (Fig. 18.7). In the sinusoids, the blood flows centripetally toward the central vein. The central vein courses through the central axis of the classic liver lobule, becoming larger as it progresses through the lobule and empties into a sublobular vein. Several sublobular veins converge to form larger hepatic veins that empty into the inferior vena cava.


Histology_Ross

Histology_Ross. The structure of the portal vein and its branches within the liver is typical of veins in general. The lumen is much larger than that of the artery associated with it. The structure of the hepatic artery is like that of other arteries (i.e., it has a thick muscular wall). In addition to providing arterial blood directly to the sinusoids, the hepatic artery provides arterial blood to the connective tissue and other structures in the larger portal canals. Capillaries in these larger portal canals return the blood to the interlobular veins before they empty into the sinusoid.


Histology_Ross

Histology_Ross. The central vein is a thin-walled vessel receiving blood from the hepatic sinusoids. The endothelial lining of the central vein is surrounded by small amounts of spirally arranged connective tissue fibers. The central vein, so named because of its central position in the classic lobule, is actually the terminal venule of the system of hepatic veins and, thus, is more properly called the terminal hepatic venule. The sublobular FIGURE 18.7 • Diagram of the fow of blood and bile in the liver. This schematic diagram of a part of a classic lobule shows the components of the portal triads, hepatic sinuses, terminal hepatic venule (central vein), and associated plates of hepatocytes. Red arrows indicate the direction of the blood flow in the sinusoids. Note that the direction of bile flow (green arrows) is opposite that of the blood flow.


Histology_Ross

Histology_Ross. vein, the vessel that receives blood from the terminal hepatic venules, has a distinct layer of connective tissue fibers, both collagenous and elastic, just external to the endothelium. The sublobular veins and the hepatic veins, into which they drain, travel alone. Because they are solitary vessels, they can be readily distinguished in a histologic section from the portal veins that are members of a triad. There are no valves in hepatic veins. Hepatic sinusoids are lined with a thin discontinuous endothelium. The discontinuous sinusoidal endothelium has a discontinuous basal lamina that is absent over large areas. The discontinuity of the endothelium is evident in two ways:  Large fenestrae, without diaphragms, are present within the endothelial cells.  Large gaps are present between neighboring endothelial cells.


Histology_Ross

Histology_Ross. Hepatic sinusoids differ from other sinusoids in that a second cell type, the stellate sinusoidal macrophage, or Kupffer cell (Fig. 18.8 and Plate 66, page 658), is a regular part of the vessel lining. Kupffer cells belong to the mononuclear phagocytotic system. Like other members of the mononuclear phagocytotic system, Kupffer cells are derived from monocytes. The scanning electron microscope (SEM) and transmission electron microscope (TEM) clearly show that the Kupffer cells form part of the lining of the sinusoid. Previously, they had been described as lying on the luminal surface of the endothelial cells. This older histologic description was probably based on the fact that processes of the Kupffer cells occasionally overlap endothelial processes on the luminal side. Kupffer cells do not form junctions with neighboring endothelial cells.


Histology_Ross

Histology_Ross. Processes of Kupffer cells often seem to span the sinusoidal lumen and may even partially occlude it. The presence of red cell fragments and iron in the form of ferritin in the cytoplasm of Kupffer cells suggests that they may be involved in the final breakdown of some damaged or senile red blood cells that reach the liver from the spleen. Some of the ferritin iron may be converted to hemosiderin granules and stored in the cells. This function is greatly increased after splenectomy when it is then essential for red blood cell disposal. Perisinusoidal Space (Space of Disse) The perisinusoidal space is the site of exchange of materials between blood and liver cells. The perisinusoidal space (space of Disse) lies between the basal surfaces of hepatocytes and the basal surfaces of endothelial cells and Kupffer cells that line the sinusoids. Small, irregular microvilli project into this space from the basal surface of the hepatocytes (Fig. 18.9).


Histology_Ross

Histology_Ross. The microvilli increase the surface area available for exchange of materials between hepatocytes and plasma by as much as six times. Because of the large gaps in the endothelial layer and the absence of a continuous basal lamina, no FIGURE 18.8 • Electron micrograph of two hepatic sinusoids of the liver. One hepatic sinusoid (top) displays a stellate sinusoidal macrophage (Kupffer cell). The remainder of the sinusoid as well as the other sinusoid is lined by thin endothelial cell cytoplasm. Surrounding each sinusoid is the perisinusoidal space (space of Disse), which contains numerous hepatocyte microvilli. Also present in the perisinusoidal space is a hepatic stellate cell (Ito cell) with a large lipid droplet and several smaller droplets. Its nucleus conforms to the curve of the lipid droplet. 6,600.


Histology_Ross

Histology_Ross. significant barrier exists between the blood plasma in the sinusoid and the hepatocyte plasma membrane. Proteins and lipoproteins synthesized by the hepatocyte are transferred into the blood in the perisinusoidal space; this pathway is for liver secretions other than bile. In the fetal liver, the space between blood vessels and hepatocytes contains islands of blood-forming cells. In cases of chronic anemia in the adult, blood-forming cells may again appear in the perisinusoidal space.


Histology_Ross

Histology_Ross. FIGURE 18.9 • Electron micrograph showing the perisinusoidal space (of Disse). The perisinusoidal space (D) is located between the hepatocytes (H) and the sinusoid. A gap (large arrow) separates the endothelial cells (En) that line the sinusoid. Such gaps allow easy passage of small substances between the sinusoid and the perisinusoidal space. Numerous microvilli extend from the hepatocytes into the perisinusoidal space. These processes are long and frequently branch (small arrow). A red blood cell (RBC) is within the sinusoid. 18,000. The hepatic stellate cells (Ito cells) store vitamin A; however, in pathologic conditions, they differentiate into myofibroblasts and synthesize collagen.


Histology_Ross

Histology_Ross. The hepatic stellate cells (Ito cells) store vitamin A; however, in pathologic conditions, they differentiate into myofibroblasts and synthesize collagen. The other cell type found in the perisinusoidal space is the hepatic stellate cell (commonly called an Ito cell). These cells of mesenchymal origin are the primary storage site for hepatic vitamin A in the form of retinyl esters within cytoplasmic lipid droplets. Vitamin A is released from the hepatic stellate cell as retinol (alcohol form) bound to retinol chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas LIVE R 637 binding protein (RBP). It is then transported from the liver to the retina, where its stereoisomer 11-cis retinal binds to the protein opsin to form rhodopsin, the visual pigment of rods and cones of the retina. For many years, fish liver oils (e.g., cod liver oil) were medically and economically important nutritional sources of vitamin A.


Histology_Ross

Histology_Ross. In certain pathologic conditions, such as chronic inﬂammation or liver cirrhosis, hepatic stellate cells lose their lipid and vitamin A storage capability and differentiate into cells with characteristics of myofibroblasts. These cells appear to play a significant role in hepatic fibrogenesis; they synthesize and deposit type I and type III collagen within the perisinusoidal space, resulting in liver fibrosis. This collagen is continuous with the connective tissue of the portal space and the connective tissue surrounding the central vein. An increased amount of perisinusoidal fibrous stroma is an early sign of liver response to toxic substances. The cytoplasm of hepatic stellate cells contains contractile elements, such as desmin and smooth muscle -actin filaments. During cell contraction, they increase the vascular resistance within the sinusoids by constricting the vascular channels, leading to portal hypertension. In addition, hepatic stellate cells play a role in remodeling the


Histology_Ross

Histology_Ross. they increase the vascular resistance within the sinusoids by constricting the vascular channels, leading to portal hypertension. In addition, hepatic stellate cells play a role in remodeling the extracellular matrix during recovery from liver injury.


Histology_Ross

Histology_Ross. Hepatic lymph originates in the perisinusoidal space. Plasma that remains in the perisinusoidal space drains into the periportal connective tissue, where a small space, the periportal space (space of Mall) (see Fig. 18.10b), is described between the stroma of the portal canal and the outermost hepatocytes. From this collecting site, the fluid then enters lymphatic capillaries that travel with the other components of the portal triad. The lymph moves in progressively larger vessels, in the same direction as the bile (i.e., from the level of the hepatocytes, toward the portal canals and eventually to the


Histology_Ross

Histology_Ross. FIGURE 18.10 • Canals of Hering and the intrahepatic ductile. a. Photomicrograph showing an area near a portal canal. Arrows indicate regions where bile canaliculi are draining into canals of Hering. Note that the canal of Hering is partially lined by hepatocytes and partially by cholangiocytes. It drains into intrahepatic bile ductule surrounded by hepatocytes, in contrast to the interlobular bile duct, which is embedded in the connective tissue of the portal canal. The terminal branch of a portal vein (lower right) accompanied by a small bile ductule are evident.800. b. Electron micrograph showing an intrahepatic bile ductule. The ductule collects bile from the canals of Hering. It is close to the hepatocytes, but the actual connection between bile canaliculi and the intrahepatic ductule is not evident in this plane of section. The ductule is composed of cholangiocytes (CH) surrounded by a complete basal lamina (BL). The narrow space (asterisks) into which microvilli of hepatocytes


Histology_Ross

Histology_Ross. is not evident in this plane of section. The ductule is composed of cholangiocytes (CH) surrounded by a complete basal lamina (BL). The narrow space (asterisks) into which microvilli of hepatocytes project is the periportal space (of Mall), not the perisinusoidal space (of Disse). 6,000.


Histology_Ross

Histology_Ross. chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas LIVE R 639 hilum of the liver). About 80% of the hepatic lymph follows this pathway and drains into the thoracic duct, forming the major portion of the thoracic duct lymph. Hepatocytes make up the anastomosing cell plates of the liver lobule. Hepatocytes are large, polygonal cells measuring between 20 and 30 m in each dimension. They constitute about 80% of the cell population of the liver. Hepatocyte nuclei are large and spherical and occupy the center of the cell. Many cells in the adult liver are binucleate; most cells in the adult liver are tetraploid (i.e., they contain the 4d amount of DNA). Heterochromatin is present as scattered clumps in the nucleoplasm and as a distinct band under the nuclear envelope. Two or more well-developed nucleoli are present in each nucleus.


Histology_Ross

Histology_Ross. Hepatocytes are relatively long-lived for cells associated with the digestive system; their average lifespan is about 5 months. In addition, liver cells are capable of considerable regeneration when liver substance is lost to hepatotoxic processes, disease, or surgery. The hepatocyte cytoplasm is generally acidophilic. Specific cytoplasmic components may be identified by routine and special staining procedures, including  basophilic regions that represent rough endoplasmic retic ulum (rER) and free ribosomes.  numerous mitochondria; as many as 800 to 1,000 mito enzyme histochemistry.  multiple small Golgi complexes seen in each cell after specific staining. large numbers of peroxisomes demonstrated by immunocytochemistry.  deposits of glycogen stained by means of the periodic acid–Schiff (PAS) procedure. However, in a well-preserved hematoxylin and eosin (H&E) preparation, glycogen is also visible as irregular spaces, usually giving a fine foamy appearance to the cytoplasm.


Histology_Ross

Histology_Ross.  lipid droplets of various sizes seen after appropriate fixation and Sudan or toluidine blue staining (Plate 66, page 658). In routinely prepared histologic sections, round spaces are sometimes seen that represent dissolved lipid droplets. The number of lipid droplets increases after injection or ingestion of certain hepatotoxins, including ethanol.  lipofuscin pigment within lysosomes seen with routine H&E staining in various amounts. Well-delineated brown granules can also be visualized by the PAS method.


Histology_Ross

Histology_Ross.  lipofuscin pigment within lysosomes seen with routine H&E staining in various amounts. Well-delineated brown granules can also be visualized by the PAS method. As noted previously, the hepatocyte is polyhedral; for convenience, it is described as having six surfaces, although there may be more. A schematic section of a cuboidal hepatocyte is shown in Figure 18.11. Two of its surfaces face the perisinusoidal space. The plasma membrane of two surfaces faces a neighbo ring hepatocyte and a bile canaliculus. Assuming that the cell is cuboidal, the remaining two surfaces, which cannot be seen in the diagram, would also face neighboring cells and bile canaliculi. The surfaces that face the perisinusoidal space correspond to the basal surface of other epithelial cells; the surfaces that face neighboring cells and bile canaliculi correspond to the late ral and apical surfaces, respectively, of other epithelial cells.


Histology_Ross

Histology_Ross. FIGURE 18.11 • Schematic diagram of a plate of hepatocytes interposed between hepatic sinusoids. This diagram shows a one-cell-thick plate of hepatocytes interposed between two sinusoids. If it is assumed that the cell is cuboidal, two sides of each cell (shown) would face hepatic sinusoids, two sides of each cell (shown) would face bile canaliculi, and the additional two sides (not shown) would face bile canaliculi. Note the location and features of a hepatic stellate cell (Ito cell) filled with cytoplasmic vacuoles containing vitamin A. The sparse collagen fibers found in the perisinusoidal space (of Disse) are produced by the hepatic stellate cells (Ito cells). In certain pathologic conditions, these cells lose their storage vacuoles and differentiate into myofibroblasts that produce collagen fibers, leading to liver fibrosis. Observe that the stellate sinusoidal macrophage (Kupffer cell) forms an integral part of the sinusoidal lining.


Histology_Ross

Histology_Ross. FIGURE 18.12 • Electron micrographs of a hepatocyte. a. This electron micrograph shows organelles and other cytoplasmic structures near the nucleus (N). These include a peroxisome (P), mitochondrion (M), glycogen inclusions (Gl), smooth endoplasmic reticulum (sER), and rough endoplasmic reticulum (rER). In the lower left, the membranes of the rER have been cut in a tangential plane showing the ribosomes (encircled by a dashed line) on the cytoplasmic face of the membrane. 12,000. b. This micrograph shows a region of cytoplasm near a bile canaliculus (C). It includes a lysosome (L), mitochondria (M), and both sER and rER. Note the microvilli in the bile canaliculus. 18,000. Peroxisomes are numerous in hepatocytes.


Histology_Ross

Histology_Ross. Peroxisomes are numerous in hepatocytes. Hepatocytes have as many as 200 to 300 peroxisomes per cell. They are relatively large and vary in diameter from 0.2 to 1.0 m (see Fig. 18.12a). Peroxisomes are a major site of oxygen use and in this way perform a function similar to that of mitochondria. They contain a large amount of oxidase that generates toxic hydrogen peroxide, H2O2. The enzyme catalase, also residing within peroxisomes, degrades hydrogen peroxide to oxygen and water. These types of reactions are involved in many detoxification processes occurring in the liver (e.g., detoxification of alcohol). In fact, about one half of the ethanol that is ingested is converted to acetaldehyde by enzymes contained in liver peroxisomes. In humans, catalase and D-amino acid oxidase, as well as alcohol dehydrogenase, are found in peroxisomes. In addition, peroxisomes are also involved in breakdown of fatty acids ( oxidation) as well as gluconeogenesis and metabolism of purines.


Histology_Ross

Histology_Ross. sER can be extensive in hepatocytes. The sER in hepatocytes may be extensive but varies with metabolic activity (see Fig. 18.12b). The sER contains enzymes involved in degradation and conjugation of toxins and drugs as well as enzymes responsible for synthesizing cholesterol and the lipid portion of lipoproteins. Under conditions of hepatocyte challenged by drugs, toxins, or metabolic stimulants, the sER may become the predominant organelle in the cell. In addition to stimulating sER activity, certain drugs and hormones induce synthesis of new sER membranes and their associated enzymes. The sER undergoes hypertrophy after administration of alcohol, drugs (i.e., phenobarbital, anabolic steroids, and progesterone), and certain chemotherapeutic agents used to treat cancer.


Histology_Ross

Histology_Ross. Stimulation of the sER by ethanol enhances its ability to detoxify other drugs, certain carcinogens, and some pesticides. On the other hand, metabolism by the sER can actually increase the hepatocyte-damaging effects of some toxic compounds, such as carbon tetrachloride (CCl4) and 3, 4-benzpyrene. The large Golgi apparatus in hepatocytes consists of as many as 50 Golgi units.


Histology_Ross

Histology_Ross. Examination of hepatocytes with the TEM shows the Golgi apparatus to be much more elaborate than those seen in routine histologic specimens. Heavy-metal preparations (Golgi stains) of thick sections of liver give an indication of the extent of the Golgi network. As many as 50 Golgi units, each consisting of three to five closely stacked cisternae, plus many large and small vesicles, are found in hepatocytes. These “units” are actually branches of the tortuous Golgi apparatus seen in heavy-metal preparations. Elements of the Golgi apparatus concentrated near the bile canaliculus are believed to be associated with the exocrine secretion of bile. Golgi cisternae and vesicles near the sinusoidal surfaces of the cell, however, contain electron-dense granules 25 to 80 nm in diameter that are believed to be VLDL and other lipoprotein precursors. These substances are subsequently released into the circulation as part of the endocrine secretory function of the hepatocytes. Similar dense


Histology_Ross

Histology_Ross. are believed to be VLDL and other lipoprotein precursors. These substances are subsequently released into the circulation as part of the endocrine secretory function of the hepatocytes. Similar dense globules are seen in dilated portions of the sER and, occasionally, in the dilated ends of rER cisternae, where they are synthesized.


Histology_Ross

Histology_Ross. Lysosomes concentrated near the bile canaliculus correspond to the peribiliary dense bodies seen in histologic sections. Hepatocyte lysosomes are so heterogeneous that they can only be positively identified, even at the TEM level, by histochemical means. In addition to normal lysosomal enzymes, TEM reveals other components: Hepatocyte lysosomes may also be a normal storage site for iron (as a ferritin complex) and a site of iron accumulation in certain storage diseases. FIGURE 18.13 • Scanning electron micrograph of the luminal surface of the bile duct. Bile duct is lined by epithelial lining cells called cholangiocytes. Their apical surfaces exhibit numerous short microvili projecting into the lumen of the bile duct. Each cholangiocyte possesses a long primary cilium which sense changes in luminal flow of the bile. Note that all cilia are bent in the same direction of a bile flow. 3,600. (Courtesy of Dr. Tetyana V. Masyuk.)


Histology_Ross

Histology_Ross. The number of lysosomes increases in a variety of pathologic conditions, ranging from simple obstructive bile stasis to viral hepatitis and anemia. However, although the range of normal liver function—particularly the rate of bile secretion—is quite wide, no statistically significant morphologic changes take place in the Golgi apparatus or lysosomes of the peribiliary cytoplasm to correlate with the rate of bile secretion. The biliary tree is the three-dimensional system of channels of increasing diameter that bile flows through from the hepatocytes to the gallbladder and then to the intestine. In the adult human liver, there are more than 2 kilometers of interconnecting bile ductules and ducts of different sizes and shapes. These structures are not only passive conduits, but they are also capable of modifying bile flow and changing its composition in response to hormonal and neural stimulation.


Histology_Ross

Histology_Ross. The biliary tree is lined by cholangiocytes which monitor bile flow and regulate its content. Cholangiocytes are epithelial cells that line the biliary tree. When examined in TEM, cholangiocytes are identified by their organelle-scant cytoplasm, presence of tight junctions between adjacent cells, and presence of complete basal lamina. An apical domain of cholangiocytes appears similar to hepatocytes with microvilli projecting into the lumen. In addition, each cholangiocyte contains primary cilium that sense changes in lumenal flow resulting in alterations of cholangiocytes secretion (Fig. 18.13). Small bile ductules are lined by small cholangiocytes, mainly cuboidal in shape, but as the diameter of the bile duct increases, they become progressively larger and more columnar in shape. The bile canaliculus is a small canal formed by apposed grooves in the surface of adjacent hepatocytes.


Histology_Ross

Histology_Ross. The smallest branches of the biliary tree are the bile canaliculi into which the hepatocytes secrete bile. They form a complete loop around four sides of the idealized six-sided hepatocytes (Fig. 18.14 and Plate 66, page 658). They are approximately 0.5 m in luminal diameter and are isolated from the rest of the intercellular compartment by tight junctions, which are part of junctional complexes that also include zonulae adherentes and desmosomes. Microvilli of the two adjacent hepatocytes extend into the canalicular lumen. Adenosine triphosphatase (ATPase) and other alkaline phosphatases can be localized on the plasma membranes of the canaliculi, suggesting that bile secretion into this space is an active process. Bile flow is centrifugal, that is from the region of the terminal hepatic venule (central vein) toward the portal canal (a direction opposite to the blood flow). Near the portal canal but still within the lobule, bile canaliculi transform into the short canals of Hering.


Histology_Ross

Histology_Ross. A characteristic feature of the canal of Hering is its lining made of two types of cells, hepatocytes and cholangiocytes. chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas LIVE R 641 FIGURE 18.14 • Photomicrograph of bile canaliculi. This high-magnification photomicrograph shows several one-cell-thick plates of hepatocytes separated by hepatic sinusoids. The plane of section in certain areas is parallel to the bile canaliculi. In this plane, the canaliculi reveal their arrangement on four sides of the hepatocytes (arrows). Arrowheads indicate those bile canaliculi that appear only in cross-sectional profile. 1,240.


Histology_Ross

Histology_Ross. The canal of Hering is a channel partially lined by hepatocytes and partially by cuboidal shaped cholangiocytes. Similar to other cholangiocytes, hepatocytes possess microvilli at their apical surface and tight junctions, and their basal domain is rested on basal lamina, as is the rest of the distal biliary epithelium. Functionally, as demonstrated by video-microscopy, the canal of Hering exhibits contractile activity that assists with unidirectional bile flow toward the portal canal. Because the canal of Hering represents the smallest and most proximal tributary of the biliary tree containing cholangiocytes, it often is involved in the same diseases that affect small bile ducts. Functional disturbance in contractile activity as well as injury or destruction of the canals of Hering may contribute to intrahepatic cholestasis (obstruction of the bile ﬂow). Canal of Hering serves as a reservoir of liver progenitor cells.


Histology_Ross

Histology_Ross. Due to their location at the crucial interface between hepatocytes and cholangiocytes, it has been proposed that the hepatic stem cells’ niche is present either in the canals of Hering or in their vicinity. This hypothesis was supported by the appearance of liver cell precursors near the canals of Hering in most of pathologic conditions characterized by extensive damage to hepatocytes. These cells could migrate and differentiate into either hepatocytes or bile duct cells. Recently, the three-dimensional reconstruction of ductular reactions in liver necrosis suggests that small cholangiocytes lining the canals of Hering proliferate extensively and migrate into the parenchyma of the liver. In immunocytochemical staining, these cells express dual markers of both biliary and hepatocyte antigens and appear to be involved in the repair of liver tissue damaged by chronic pathologic processes. Therefore, it has been concluded that the canal of Hering consists of or harbors specific hepatic


Histology_Ross

Histology_Ross. and appear to be involved in the repair of liver tissue damaged by chronic pathologic processes. Therefore, it has been concluded that the canal of Hering consists of or harbors specific hepatic stem cells. Laboratory studies suggest that in the future, hepatic stem cells may ultimately have therapeutic use in the treatment of liver diseases.


Histology_Ross

Histology_Ross. The bile ductule represents the part of the biliary tree that is lined entirely by cholangiocytes. The bile from the canal of Hering continues to flow into the intrahepatic bile ductule, which is lined entirely by cholangiocytes. Three-dimensional analysis of immunocytochemical-stained serial sections of the liver reveals that the canal of Hering often crosses the boundary of the lobule and becomes bile ductule in the periportal space (of Mall). The main distinction between the canal of Hering and the bile ductule is not its location within the lobule, but whether the structure is partially or completely lined by cholangiocytes. Intrahepatic bile ductules carry bile to hepatic ducts.


Histology_Ross

Histology_Ross. Intrahepatic bile ductules carry bile to hepatic ducts. The ductules have a diameter of about 1.0 to 1.5 m and carry bile to the interlobular bile ducts that form part of the portal triad (see Fig. 18.10b). These ducts range from 15 to 40 m in diameter and are lined by cholangiocytes that are cuboidal near the lobules and gradually become columnar as the ducts near the porta hepatis. The columnar cells have well-developed microvilli, as do those of the extrahepatic bile ducts and gallbladder. As the bile ducts get larger, they gradually acquire a dense connective tissue investment containing numerous elastic fibers. Smooth muscle cells appear in this connective tissue as the ducts approach the hilum. Interlobular ducts join to form the right and left hepatic ducts, which in turn join at the hilum to form the common hepatic duct (Fig. 18.15).


Histology_Ross

Histology_Ross. In some individuals, the ducts of Luschka are located in the connective tissue between the liver and the gallbladder, near the neck of the gallbladder. These ducts connect with the cystic duct, not with the lumen of the gallbladder. They are histologically similar to the intrahepatic bile ducts and may be remnants of aberrant embryonic bile ducts. Extrahepatic bile ducts carry the bile to the gallbladder and duodenum. The common hepatic duct is about 3 cm long and is lined with tall columnar epithelial cells that closely resemble those of the gallbladder. All of the layers of the alimentary canal (see page 569) are represented in the duct, except the muscularis mucosae. The cystic duct connects the common hepatic duct to the gallbladder and carries bile both main of common sphincter of main pancreatic duct major duodenal hepatopancreatic papilla ampulla (of Vater) sphincter of hepatopancreatic ampulla (of Oddi)


Histology_Ross

Histology_Ross. FIGURE 18.15 • Diagram showing the relationship of hepatic, pancreatic, and gallbladder ducts. The gallbladder is a blind pouch joined to a single cystic duct in which numerous mucosal folds form the spiral valve (of Heister). The cystic duct joins with the common hepatic duct, and together they form the common bile duct that leads into the duodenum. At the entry to the duodenum, the common bile duct is joined by the main pancreatic duct to form the hepatopancreatic ampulla (of Vater), and together they enter the second part of the duodenum. Sphincters can be found at the distal part of these ducts. The sphincters of the common bile duct (of Boyden), the main pancreatic duct, and the hepatopancreatic ampulla (of Oddi) control the flow of bile and pancreatic secretion into the duodenum. When the common bile duct sphincter contracts, bile cannot enter the duodenum; it backs up and flows into the gallbladder, where it is concentrated and stored.


Histology_Ross

Histology_Ross. into and out of the gallbladder. Distal to the junction with the cystic duct, the fused duct is called the common bile duct and extends for about 7 cm to the wall of the duodenum at the ampulla of Vater. A thickening of the muscularis externa of the duodenum at the ampulla constitutes the sphincter of Oddi, which surrounds the openings of both the common bile duct and the pancreatic duct and acts as a valve to regulate the flow of bile and pancreatic juice into the duodenum. The adult human liver secretes, on average, about 1 L of bile a day. The bile fulfills two major functions. It is involved in the absorption of fat and is used by the liver as a vehicle for excretion of cholesterol, bilirubin, iron, and copper. The composition of bile and the specific functions of most of its components are listed in Table 18.1. As noted in the table, many components of the bile are recycled via the portal circulation.


Histology_Ross

Histology_Ross.  About 90% of the bile salts, a component of bile, is reab sorbed by the gut and transported back to the liver in the portal blood. The bile salts are then reabsorbed and rese creted by hepatocytes. Hepatocytes also synthesize new bile salts to replace those that are lost.  Cholesterol and the phospholipid lecithin, as well as most of the electrolytes and water delivered to the gut with the bile, are also reabsorbed and recycled. Bilirubin glucuronide, the detoxified end product of hemoglobin breakdown, is not recycled. It is excreted with the feces and gives them their color. Failure to absorb bilirubin or failure to conjugate it or secrete glucuronide can produce jaundice.


Histology_Ross

Histology_Ross. Bile fow from the liver is regulated by hormonal and neural control. The rate of blood flow to the liver and the concentration of bile salts in the blood exert regulatory effects on the bile flow. Bile flow is increased when hormones such as cholecystokinin (CCK), gastrin, and motilin are released by enteroendocrine cells during digestion. Steroid hormones (i.e., estrogen during pregnancy) decrease bile secretion from the liver. In addition, parasympathetic stimulation increases bile flow by prompting contraction of the gallbladder and relaxation of the sphincter of Oddi. Bile that leaves the liver via the common hepatic duct flows through the cystic duct to the gallbladder. Following stimulation, the gallbladder contracts steadily and delivers the bile to the duodenum via the common bile duct. The liver has both sympathetic and parasympathetic innervation.


Histology_Ross

Histology_Ross. The liver has both sympathetic and parasympathetic innervation. The liver (and gallbladder) receives nerves from both sympathetic and parasympathetic divisions of the autonomic nervous system. The nerves enter the liver at the porta hepatis and ramify through the liver in the portal canals along with the members of the portal triad. Sympathetic fbers innervate blood vessels, and increased stimulation in this system causes an increase of vascular resistance, decreased hepatic blood volume, and a rapid increase of serum levels of glucose. The parasympathetic fbers are assumed to innervate the large ducts (those that contain smooth muscle in their walls) and possibly blood vessels; their stimulation promotes glucose uptake and utilization. The cell bodies of parasympathetic neurons are often present near the porta hepatis.


Histology_Ross

Histology_Ross. The gallbladder is a pear-shaped, distensible sac with a volume of about 50 mL in humans (see Fig. 18.15). It is attached to the visceral surface of the liver. The gallbladder is a secondary derivative of the embryonic foregut, arising as an evagination of the primitive bile duct that connects the embryonic liver to the developing intestine. The gallbladder concentrates and stores bile.


Histology_Ross

Histology_Ross. The gallbladder concentrates and stores bile. The gallbladder is a blind pouch that leads, via a neck, to the cystic duct. Through this duct it receives dilute bile from the chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas GALLB LADDE R 643 hepatic duct. The gallbladder can store and remove about  Localized concentrations of mitochondria in the apical 90% of the water from the incoming bile, which results in an and basal cytoplasm increase of bile salts, cholesterol, and bilirubin concentrations  Complex lateral plications up to 10-fold. Hormones secreted by the enteroendocrine cells of the small intestine, in response to the presence of fat in the proximal duodenum, stimulate contractions of the smooth muscle of the gallbladder. Because of these contractions, concentrated bile is discharged into the common bile duct, which carries it to the duodenum. Mucosa of the gallbladder has several characteristic features.


Histology_Ross

Histology_Ross. Mucosa of the gallbladder has several characteristic features. The empty or partially filled gallbladder has numerous deep mucosal folds (Fig. 18.16). The mucosal surface consists of simple columnar epithelium (Fig. 18.17). The tall epithelial cells exhibit the following features:  Numerous, but short and not well-developed apical microvilli  Apical junctional complexes that join adjacent cells and form a barrier between the lumen and the intercellular compartment These cells closely resemble the absorptive cells of the intestine. Both cells share the above characteristics, as well as localization of Na/K–activated ATPase on their lateral plasma membranes and secretory vesicles filled with glycoproteins in their apical cytoplasm.


Histology_Ross

Histology_Ross. The lamina propria of the mucosa is particularly rich in fenestrated capillaries and small venules, but there are no lymphatic vessels in this layer. The lamina propria is also very cellular, containing large numbers of lymphocytes and plasma cells. The characteristics of the lamina propria resemble those of the colon, another organ specialized for the absorption of electrolytes and water. Mucin-secreting glands are sometimes present in the lamina propria in the normal human gallbladder, especially near the neck of the organ, but they are more commonly found in


Histology_Ross

Histology_Ross. Mucin-secreting glands are sometimes present in the lamina propria in the normal human gallbladder, especially near the neck of the organ, but they are more commonly found in FIGURE 18.16 • Photomicrograph of the wall of the gallbladder. The mucosa of the gallbladder consists of a lining of simple columnar epithelial cells and a lamina propria of loose connective tissue, which typically exhibits numerous deep folds in the mucosa. Beneath this layer is a relatively thick layer, the muscularis externa. There is no muscularis mucosae or submucosa. The smooth muscle bundles of the muscularis externa are randomly oriented. External to the muscle is an adventitia containing adipose tissue and blood vessels. The portion of the gallbladder not attached to the liver displays a typical serosa instead of an adventitia. 175.


Histology_Ross

Histology_Ross. FIGURE 18.17 • Electron micrographs of gallbladder epithelium. a. The tall columnar cells display features typical of absorptive cells, with microvilli on their apical surface, an apical junctional complex separating the lumen of the gallbladder from the lateral intercellular space, and numerous mitochondria in the apical portion of the cell. 3,000. b. During active fluid transport, salt is pumped from the cytoplasm into the intercellular space, and water follows the salt. Both salt and water then diffuse into the cell from the lumen. As this process continues, the intercellular space becomes greatly distended (arrows). Fluid moves from the engorged intercellular space (arrows) across the basal lamina into the underlying connective tissue (CT) and then into blood vessels. The increase in size of the lateral intercellular space during active fluid transport is evident with the light microscope. 3,000.


Histology_Ross

Histology_Ross. chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas GALLB LADDE R 645 inflamed gallbladders. Cells that appear identical to enteroendocrine cells of the intestine are also found in these glands. The wall of the gallbladder lacks a muscularis mucosae and submucosa. External to the lamina propria is a muscularis externa that has numerous collagen and elastic fibers among the bundles of smooth muscle cells. Despite its origin from a foregutderived tube, the gallbladder does not have a muscularis mucosae or submucosa. The smooth muscle bundles are somewhat randomly oriented, unlike the layered organization of the intestine. Contraction of the smooth muscle reduces the volume of the bladder, forcing its contents out through the cystic duct.


Histology_Ross

Histology_Ross. External to the muscularis externa is a thick layer of dense connective tissue (see Fig. 18.16). This layer contains large blood vessels, an extensive lymphatic network, and the autonomic nerves that innervate the muscularis externa and the blood vessels (cell bodies of parasympathetic neurons are found in the wall of the cystic duct). The connective tissue is also rich in elastic fibers and adipose tissue. The layer of tissue where the gallbladder attaches to the liver surface is referred to as the adventitia. The unattached surface is covered by a serosa or visceral peritoneum consisting of a layer of mesothelium and a thin layer of loose connective tissue.


Histology_Ross

Histology_Ross. In addition, deep diverticula of the mucosa, called Rokitansky-Aschoff sinuses, sometimes extend through the muscularis externa (Fig. 18.18 and Plate 67, page 660). They are thought to presage pathologic changes and develop as the result of hyperplasia (excessive growth of cells) and herniation of epithelial cells through the muscularis externa. Also, bacteria may accumulate in these sinuses, causing chronic inﬂammation that is a risk factor for the formation of gallstones. Concentration of the bile requires the coupled transport of salt and water.


Histology_Ross

Histology_Ross. Concentration of the bile requires the coupled transport of salt and water. The epithelial cells of the gallbladder actively transport both Na, Cl and HCO3 from the cytoplasm into the intercellular compartment of the epithelium. ATPase is located in the lateral plasma membranes of the epithelial cells. This active transport mechanism is essentially identical to that described in Chapter 17 for the enterocytes of the small intestine and the absorptive cells of the colon. The epithelial cells of the gallbladder also express two types of aquaporins water channels (AQP1 and AQP8), integral membrane channel proteins that facilitate rapid passive movement of water (see Chapter 20, Folder 20.XX). The presence of water channels on apical and basolateral plasma membranes of the gallbladder epithelial cells suggests that they may be involved in both water absorption and secretion.


Histology_Ross

Histology_Ross. Active transport of Na, Cl, and HCO3 across the lateral plasma membrane into the intercellular (paracellular) compartment causes the concentration of electrolytes in the intercellular space to increase. The increased electrolyte concentration creates an osmotic gradient between the intercellular space and the cytoplasm and between the intercellular space and the lumen. Water moves from the cytoplasm and from the lumen into the intercellular space because of the osmotic gradient (i.e., it moves down its concentration gradient; see Fig. 18.17b). Although the intercellular space can distend to a degree often visible with the light microscope, this ability is limited. The movement of electrolytes and water into the space creates hydrostatic pressure that forces a nearly isotonic fluid out of the inter-cellular compartment into the subepithelial connective tissue (the lamina propria). The fluid that enters the lamina propria quickly passes into the numerous fenestrated capillaries and the


Histology_Ross

Histology_Ross. the inter-cellular compartment into the subepithelial connective tissue (the lamina propria). The fluid that enters the lamina propria quickly passes into the numerous fenestrated capillaries and the venules that closely underlie the epithelium. Studies of fluid transport in the gallbladder first demonstrated the essential role of the intercellular compartment in transepithelial transport of an isotonic fluid from the lumen to the vasculature. Therefore, the final modification of bile is mainly the result of the active transport of Na , Cl, and HCO3 , and the passive, aquaporin-mediated transport of water across the plasma membrane of epithelial cells of the gallbladder.


Histology_Ross

Histology_Ross. FIGURE 18.18 • Photomicrograph of the Rokitansky-Aschoff sinuses in the wall of the gallbladder. This photomicrograph shows deep invaginations of the mucosa extending into the muscularis externa. These invaginations are referred to as Rokitansky-Aschoff sinuses. 120. FIGURE 18.19 • Diagram of pancreas, duodenum, and associated excretory ducts. The main pancreatic duct (of Wirsung) traverses the length of the pancreas and enters the duodenum after joining with the common bile duct. An accessory pancreatic duct (of Santorini) is commonly present, as shown, and empties into the duodenum at a separate minor duodenal papilla. The site of entry of the common bile duct and main pancreatic duct into the duodenum is typically marked by a major duodenal papilla visible on the inner surface of the duodenum.


Histology_Ross

Histology_Ross. The pancreas is an elongate gland described as having a head, body, and tail. The head is an expanded portion that lies in the C-shaped curve of the duodenum (Fig. 18.19). It is joined to the duodenum by connective tissue. The centrally located body of the pancreas crosses the midline of the human body, and the tail extends toward the hilum of the spleen. The pancreatic duct (of Wirsung) extends through the length of the gland and empties into the duodenum at the hepatopan creatic ampulla (of Vater), through which the common bile duct from the liver and gallbladder also enters the duodenum.


Histology_Ross

Histology_Ross. The hepatopancreatic sphincter (of Oddi) surrounds the ampulla and not only regulates the flow of bile and pancreatic juice into the duodenum but also prevents reflux of intestinal contents into the pancreatic duct. In some individuals, an ac cessory pancreatic duct (of Santorini) is present, a vestige of the pancreas’s origin from two embryonic endodermal pri mordia that evaginate from the foregut. A thin layer of loose connective tissue forms a capsule around the gland. From this capsule, septa extend into the gland, dividing it into ill-defined lobules. Within the lob ules, a stroma of loose connective tissue surrounds the parenchymal units. Between the lobules, larger amounts of connective tissue surround the larger ducts, blood vessels, and nerves. Moreover, in the connective tissue surrounding the pancreatic duct, there are small mucous glands that empty into the duct. The pancreas is an exocrine and endocrine gland.


Histology_Ross

Histology_Ross. The pancreas is an exocrine and endocrine gland. Unlike the liver, in which the exocrine and secretory (endocrine) functions reside in the same cell, the dual functions of the pancreas are relegated to two structurally distinct components.  The exocrine component synthesizes and secretes en zymes into the duodenum that are essential for digestion in the intestine.  The endocrine component synthesizes and secretes the hormones insulin and glucagon into the blood. These hormones regulate glucose, lipid, and protein metabolism in the body. The exocrine pancreas is found throughout the organ; within the exocrine pancreas, distinct cell masses called islets of Langerhans are dispersed and constitute the endocrine pancreas. The exocrine pancreas is a serous gland.


Histology_Ross

Histology_Ross. The exocrine pancreas is a serous gland. The exocrine pancreas closely resembles the parotid gland, with which it can be confused. The secretory units are acinar or tubuloacinar in shape and are formed by a simple epithelium of pyramidal serous cells (Fig. 18.20a and Plate 68, page 662). The cells have a narrow free (luminal) surface and a broad basal surface. Periacinar connective tissue is minimal. The serous secretory cells of the acinus produce the digestive enzyme precursors secreted by the pancreas. Pancreatic acini are unique among glandular acini; the initial duct that leads from the acinus, the intercalated duct, actually begins within the acinus (Fig. 18.20b; Fig. 18.21). The duct cells located inside the acinus are referred to as centroacinar cells.


Histology_Ross

Histology_Ross. The acinar cells are characterized by distinct basophilia in the basal cytoplasm and by acidophilic zymogen granules in the apical cytoplasm (see Figs. 18.20a and 18.21). Zymogen granules are most numerous in the pancreas of fasting individuals. The squamous centroacinar cells lack both ergastoplasm and secretory granules (see Fig. 18.21); thus, they stain very lightly with eosin. This weak staining helps identify them in routine histologic sections. Zymogen granules contain a variety of digestive enzymes in an inactive form. Pancreatic enzymes can digest most food substances. The inactive enzymes, or proenzymes, contained in pancreatic zymogen granules are listed here along with the specific substances they digest when activated.  Proteolytic endopeptidases (trypsinogen, chy carboxypeptidase, proaminopeptidase) digest proteins by by cleaving amino acids from the carboxyl or amino end of the peptide. chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas PANCR EAS 647


Histology_Ross

Histology_Ross. chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas PANCR EAS 647 FIGURE 18.20 • Pancreatic acinus and its duct system. a. In this photomicrograph of a thin, H&E–stained plastic section, an intercalated duct can be seen beginning within a pancreatic acinus. The cells forming the duct within the acinus are the centroacinar cells. The eosinophilic zymogen granules are clearly seen in the apical cytoplasm of the parenchymal cells. 860. b. In this schematic diagram, observe the beginning of the intercalated duct. Note the location and shapes of the centroacinar cells within the acinus. They represent the initial lining of the intercalated duct, which drains into an intralobular collecting duct.


Histology_Ross

Histology_Ross.  Amylolytic enzymes (-amylase) digest carbohydrates by cleaving the glycosidic linkages of glucose polymers. Lipases digest lipids by cleaving ester bonds of triglycerides, producing free fatty acids. Nucleolytic enzymes (deoxyribonuclease and ribonuclease) digest nucleic acids, producing mononucleotides. The pancreatic digestive enzymes are activated only after they reach the lumen of the small intestine. Initially, the proteolytic activity of enzymes enterokinases in the glycocalyx of the microvilli of the intestinal absorptive cells converts trypsinogen to trypsin, a potent proteolytic enzyme. Trypsin then catalyzes the conversion of the other inactive enzymes as well as the digestion of proteins in the chyme.


Histology_Ross

Histology_Ross. The cytoplasmic basophilia of the pancreatic acinar cells when observed with the TEM appears as an extensive array of rER and free ribosomes. The presence of these numerous organelles correlates with the high level of protein synthetic activity of the acinar cells (Fig. 18.22). A well-developed Golgi apparatus is present in the apical cytoplasm and is involved in concentration and packaging of the secretory products. Mitochondria are small and, although found throughout the cell, are concentrated among the rER cisternae. Acinar cells are joined to one another by junctional complexes at their apical poles, thus forming an isolated lumen into which small microvilli extend from the apical surfaces of the acinar cells and into which the zymogen granules are released by exocytosis.


Histology_Ross

Histology_Ross. FIGURE 18.21 • Electron micrograph of the pancreatic acinus and intercalated duct. Note, that pancreatic acinus is formed from a pyramidal in shape acinar cells. Their basal area contains nucleus surrounded by extensive rER and Golgi apparatus. The apical portion exhibit well preserved zymogen granules. The origin of the intercalated duct lined by the centroacinar cells is visible on this electron micrograph. 5,800. (Courtesy of Dr. Holger Jastrow.) Duct System of the Exocrine Pancreas The centroacinar cells (see Figs. 18.20a and 18.21) are the beginning of the duct system of the exocrine pancreas. They have a centrally placed, flattened nucleus and attenuated cytoplasm, which is typical of a squamous cell. Centroacinar cells are intercalated duct cells located in the acinus.


Histology_Ross

Histology_Ross. Centroacinar cells are intercalated duct cells located in the acinus. Centroacinar cells are continuous with the cells of the short intercalated duct that lies outside the acinus. The structural unit of the acinus and centroacinar cells resembles a small balloon (the acinus) into which a drinking straw (the intercalated duct) has been pushed. The intercalated ducts are short and drain into intralobular collecting ducts. There are no striated (secretory) ducts in the pancreas.


Histology_Ross

Histology_Ross. The complex, branching network of intralobular ducts drains into the larger interlobular ducts, which are lined with a low columnar epithelium in which enteroendocrine cells and occasional goblet cells may be found. The interlobular ducts, in turn, drain directly into the main pancreatic duct, which runs the length of the gland parallel to its long axis, giving this portion of the duct system a herringbone-like appearance (see Fig. 18.19). A second large duct, the accessory pancreatic duct, arises in the head of the pancreas. The intercalated ducts add bicarbonate and water to the exocrine secretion.


Histology_Ross

Histology_Ross. The intercalated ducts add bicarbonate and water to the exocrine secretion. The pancreas secretes about 1 L of fluid per day, about equal to the initial volume of the hepatic bile secretion. Whereas bile is concentrated in the gallbladder, the entire volume of the pancreatic secretion is delivered to the duodenum. Although the acini secrete a small volume of protein-rich fluid, the intercalated duct cells secrete a large volume of fluid rich in sodium and bicarbonate. The bicarbonate serves to neutralize the acidity of the chyme that enters the duodenum from the stomach and to establish the optimal pH for the activity of the major pancreatic enzymes. Pancreatic exocrine secretion is under hormonal and neural control.


Histology_Ross

Histology_Ross. Pancreatic exocrine secretion is under hormonal and neural control. Two hormones secreted by the enteroendocrine cells of the duodenum, secretin and cholecystokinin (CCK), are the principal regulators of the exocrine pancreas (see Tables 17.1 page 583). The entry of the acidic chyme into the duodenum stimulates the release of these hormones into the blood:  Secretin is a polypeptide hormone (27 amino acid residues) that stimulates the duct cells to secrete a large vol ume of fluid with a high HCO3 concentration but little or no enzyme content. CCK is a polypeptide hormone (33 amino acid residues) that causes the acinar cells to secrete their proenzymes.


Histology_Ross

Histology_Ross. The coordinated action of the two hormones results in the secretion of a large volume of enzyme-rich, alkaline fluid into the duodenum. In addition to hormonal influences, the pancreas also receives autonomic innervation. Sympathetic nerve fibers are involved in regulation of pancreatic blood flow. Parasympathetic fibers stimulate activity of acinar as well as centroacinar cells. Cell bodies of neurons occasionally seen in the pancreas belong to parasympathetic postganglionic neurons. The endocrine pancreas is a diffuse organ that secretes hormones that regulate blood glucose levels.


Histology_Ross

Histology_Ross. The endocrine pancreas is a diffuse organ that secretes hormones that regulate blood glucose levels. The islets of Langerhans, the endocrine component of the pancreas, are scattered throughout the organ in cell groupings of varying size (Fig. 18.23). It is estimated that 1 million to 3 million islets constitute about 1% to 2% of the volume of the pancreas but are most numerous in the tail. Individual islets may contain only a few cells or many hundreds of cells (Plate 68, page 662). Their polygonal cells are arranged in short, chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas PANCR EAS 649


Histology_Ross

Histology_Ross. FIGURE 18.22 • Electron micrograph of the apical cytoplasm of several pancreatic acinar cells. One pancreatic acinar cell is outlined by the dashed line. Nuclei (N) of adjoining cells are evident at the bottom left and right of the electron micrograph. The apical cytoplasm contains extensive rough endoplasmic reticulum (rER), mitochondria (M), zymogen-containing secretory granules (Z), and Golgi profiles (G). At the apices of these cells, a lumen (L) is present, into which the zymogen granules are discharged. A junctional complex (JC) is indicated near the lumen. 20,000. irregular cords that are profusely invested with a network of fenestrated capillaries. The definitive endocrine cells of the islets develop between 9 and 12 weeks of gestation.


Histology_Ross

Histology_Ross. irregular cords that are profusely invested with a network of fenestrated capillaries. The definitive endocrine cells of the islets develop between 9 and 12 weeks of gestation. In H&E–stained sections, the islets of Langerhans appear as clusters of pale-staining cells surrounded by more intensely staining pancreatic acini. It is not practical to attempt to identify the several cell types found in the islets in routinely prepared specimens (Fig. 18.24). After Zenkerformol fixation and staining by the Mallory-Azan method, however, it is possible to identify three principal cell types designated A (alpha), B (beta), and D (delta) cells (Table 18.2 and Fig. 18.25). With this method, the A cells stain red, the B cells stain brownish orange, and the D cells stain blue. About 5% of the cells appear to be


Histology_Ross

Histology_Ross. FIGURE 18.23 • Photomicrograph of the pancreas. This H&E–stained specimen shows a number of pancreatic lobules separated by connective tissue septa that are continuous with the thin surrounding capsule of the gland. The pancreatic lobules consist largely of the exocrine acini and their intralobular duct system. Most of the lobules exhibit small, round, lighter-staining profiles, which are the islets of Langerhans (arrows). Adjacent to the lobules, at the lower left, is a large interlobular duct that serves the exocrine pancreas. 25. unstained after this procedure. TEM allows identification of the principal cell types by the size and density of their secretory granules. Islet cells, other than B cells, are counterparts of the enteroendocrine cells of the gastrointestinal mucosa.


Histology_Ross

Histology_Ross. Islet cells, other than B cells, are counterparts of the enteroendocrine cells of the gastrointestinal mucosa. In addition to the three principal islet cells, three minor islet cell types have also been identified by using a combination of the TEM and immunocytochemistry (Table 18.3). Each cell type can be correlated with a specific hormone, and each has a specific location in the islet. B cells constitute about 70% of the total islet cells in humans and are generally located in its central portion. They secrete insulin (see Table 18.2). B cells contain numerous secretory granules about 300 nm in diameter with a dense polyhedral core and a pale matrix. The polyhedral core is believed to be crystallized insulin.


Histology_Ross

Histology_Ross. A cells constitute about 15% to 20% of the human islet population and are generally located peripherally in the islets. They secrete glucagon (see Table 18.2). A cells contain secretory granules about 250 nm in diameter that are more uniform in size and more densely packed in the cytoplasm than the granules of B cells. The granule is the site of stored glucagon (Fig. 18.26). D cells constitute about 5% to 10% of the total pancreatic endocrine tissue and are also located peripherally in the islets. D cells secrete somatostatin, which is contained in secretory granules that are larger than those of the A and B cells (300 to 350 nm) and contain material of low to medium electron density (see Fig. 18.26). The minor islet cells constitute about 5% of the islet tissue and may be equivalent to the pale cells seen after Mallory-Azan staining. Their characteristics and functions are summarized in Table 18.3.


Histology_Ross

Histology_Ross. Evidence suggests that some cells may secrete more than one hormone. Immunocytochemical staining has localized several hormones in addition to glucagon in the A-cell cytoplasm. These include gastric inhibitory peptide (GIP), CCK, and adrenocorticotropic hormone (ACTH)endorphin. Although there is no clear morphologic evidence for the presence of G cells (gastrin cells) in the islets, gastrin may also be secreted by one or more of the islet cells. Certain pancreatic islet cell tumors secrete large amounts of gastrin, thereby producing excessive acid secretion in the stomach (Zollinger-Ellison syndrome). Functions of Pancreatic Hormones All of the hormones secreted by the endocrine pancreas regulate metabolic functions either systemically, regionally (in the gastrointestinal tract), or locally (in the islet itself). Insulin, the major hormone secreted by the islet tissue, decreases blood glucose levels.


Histology_Ross

Histology_Ross. Insulin, the major hormone secreted by the islet tissue, decreases blood glucose levels. Insulin is the most abundant endocrine secretion. Its principal effects are on the liver, skeletal muscle, and adipose tissue. Insulin has multiple individual actions in each of these tissues. In general, insulin stimulates  uptake of glucose from the circulation. Specific cell membrane glucose transporters are involved in this process.  storage of glucose by activation of glycogen synthase and subsequent glycogen synthesis.  phosphorylation and use of glucose by promoting its gly colysis within cells. Absence or inadequate amounts of insulin lead to elevated blood glucose levels and the presence of glucose in the urine, a condition known as diabetes mellitus. Reduced expression of insulin and insulin growth factors in the central nervous system (CNS) has recently been linked to Alzheimer’s disease (Folder 18.3).


Histology_Ross

Histology_Ross. In addition to its effects on glucose metabolism, insulin stimulates glycerol synthesis and inhibits lipase activity in adipose cells. Circulating insulin also increases the amount of amino acids taken up by cells (which may involve cotransport with glucose) and inhibits protein catabolism. Glucagon, secreted in amounts second only to insulin, increases blood glucose levels. chapter 18 Digestive System III: Liver, Gallbladder, and Pancreas PANCR EAS 651 FIGURE 18.24 • Photomicrographs of islets of Langerhans. a. In this routine H&E preparation, it is difficult to identify specific islet cell types without special stains. At best, one can identify small cells (arrows) at the periphery of the islet that are probably A cells. 360. b. This photo micrograph shows an islet of Langerhans stained with a special Grimelius silver stain that reacts with glucagonsecreting cells. The silver-impregnated A cells are arranged around the periphery of the islet. 360.


Histology_Ross

Histology_Ross. The actions of glucagon are essentially reciprocal to those gluconeogenesis, mobilizes fats from adipose cells, and of insulin. Glucagon stimulates release of glucose into the stimulates hepatic lipase. bloodstream and stimulates gluconeogenesis (synthesis Somatostatin inhibits insulin and glucagon secretion. of glucose from metabolites of amino acids) and glycogenolysis (breakdown of glycogen) in the liver. Somatostatin is secreted by the D cells of the islets. It is Glucagon also stimulates proteolysis to promote identical to the hormone secreted by the hypothalamus that regulates somatotropin (growth hormone) release from the anterior pituitary gland. Although the precise role of somatostatin in the islets is unclear, it has been shown to inhibit both insulin and glucagon secretion.


Histology_Ross

Histology_Ross. TABLE Principal Cell Types in Pancreatic Islets18.2 Cell Type % Cytoplasmic Staining with Mallory-Azan Product Granules (TEM) A 15–20 Red Glucagon About 250 nm; dense, eccentric core surrounded by light substance B 60–70 Brownish orange Insulin About 300 nm; many with dense, crystalline (angular) core surrounded by light substance D 5–10 Blue Somatostatin About 325 nm; homogeneous matrix FIGURE 18.25 • Diagram of an islet of Langerhans stained by the Mallory-Azan method. A cells display red cytoplasmic staining, B cells (comprising most of the islet cells) display brownish-orange staining, and D cells show a blue cytoplasm. The molecular characteristics of the major and some minor islet hormones are summarized in Table 18.4. Regulation of Islet Activity


Histology_Ross

Histology_Ross. The molecular characteristics of the major and some minor islet hormones are summarized in Table 18.4. Regulation of Islet Activity A blood glucose level above the normal 70 mg/100 mL (70 mg/dL) stimulates release of insulin from beta cells, leading to uptake and storage of glucose by liver and muscle. The resultant decrease in the blood glucose level stops insulin secretion. Some amino acids also stimulate insulin secretion, either alone or in concert with elevated blood glucose levels. Increased blood fatty acid levels also stimulate insulin release, as do circulating gastrin, CCK, and secretin. CCK and glucagon, released in the islet by the A cells, act as paracrine secretions to stimulate B cell secretion of insulin.


Histology_Ross

Histology_Ross. Blood glucose levels below 70 mg/100 mL stimulate release of glucagon; blood glucose levels significantly above 70 mg/100 mL inhibit glucagon secretion. Glucagon is also released in response to low levels of fatty acids in the blood. Insulin inhibits release of glucagon by A cells, but because of the cascading circulation in the islet (explained in a following paragraph), this inhibition is effected by a hormonal action of insulin carried in the general circulation. The islets have both sympathetic and parasympathetic innervation. About 10% of the islet cells have nerve endings directly on their plasma membrane. Well-developed gap junctions are located between islet cells. Ionic events triggered by synaptic transmitters at the nerve endings are carried from cell to cell across these junctions. Autonomic nerves may have direct effects on hormone secretion by A and B cells.


Histology_Ross

Histology_Ross. Parasympathetic (cholinergic) stimulation increases secretion of both insulin and glucagon; sympathetic (adrenergic) stimulation increases glucagon release but inhibits insulin release. This neural control of insulin and glucagon may


Histology_Ross

Histology_Ross. TABLE Minor Cell Types in Pancreatic Islets 18.3 Cell Type Secretion Location (in Addition to Islet) Actions PP cell (F cell)a Pancreatic polypeptide Stimulates gastric chief cells, inhibits bile secretion and intestinal motility, inhibits pancreatic enzymes and HCO3 secretion D 1 cell Vasoactive intestinal peptide (VIP) Also in exocrine acini and duct epitheliumb Similar to those of glucagon (hyperglycemic and glycogenolytic); also affects secretory activity and motility in gut; stimulates pan-creatic exocrine secretion EC cella Secretin, motilin, substance P Also in exocrine acini and duct epitheliumb Secretin: acts locally to stimulate HCO3 secretion in pancreatic juice and pancreatic enzyme secretion Motilin: increases gastric and intestinal motility Substance P: has neurotransmitter properties Epsilon cell Ghrelin Epithelium lining the fundus of the stomachc Stimulate appetite aPP, protein polypeptide; EC, enterochromaffin cell. bThis localization further emphasizes the ontogeny


Histology_Ross

Histology_Ross. properties Epsilon cell Ghrelin Epithelium lining the fundus of the stomachc Stimulate appetite aPP, protein polypeptide; EC, enterochromaffin cell. bThis localization further emphasizes the ontogeny of the pancreas from the embryonic gut. cGhrelin is produced in the stomach by P/D1 cells.


Histology_Ross

Histology_Ross. Digestive System III: Liver, Gallbladder, and Pancreas PANCR EAS FIGURE 18.26 • Electron micrograph of pancreatic islet cells. The portion of the cell in the upper part of the illustration is an A cell. It contains characteristic granules (arrows) showing a dense spherical core surrounded by a clear area and then a membrane. This cell also displays a characteristically well-developed Golgi apparatus. The cell in the bottom of the illustration is a D cell. It contains numerous membrane-bounded granules of moderately low density (arrowheads). 15,000.


Histology_Ross

Histology_Ross. TABLE Characteristics of Pancreatic Hormones18.4 Hormone Molecular Weight (daltons) Structure Insulin 5,700–6,000 Two protein chains linked by disulfide bridges: chain, 21 amino acids; chain, 30 amino acids Glucagon 3,500 Linear polypeptide: 29 amino acids Somatostatin 1,638 Cyclic polypeptide: 14 amino acids VIP 3,300 Linear polypeptide: 28 amino acids Pancreatic 4,200 Linear polypeptide polypeptide: 36 amino acids contribute to the availability of circulating glucose in stress reactions. The blood supply to the pancreas provides a cascading perfusion of the islets and acini.


Histology_Ross

Histology_Ross. The blood supply to the pancreas provides a cascading perfusion of the islets and acini. Several arterioles enter the periphery of the islets and branch into fenestrated capillaries. In humans, the capillaries first perfuse the A and D cells, peripherally, before the blood reaches the B cells, centrally. Larger vessels that travel in septa that penetrate the central portion of the islet are also accompanied by A and D cells, so that blood reaching the B cells has always first perfused the A and D cells. Large efferent capillaries leave the islet and branch into the capillary networks that surround the acini of the exocrine pancreas. This cascading flow resembles the portal systems of other endocrine glands (pituitary, adrenal). Secretions of the islet cells have regulatory effects on the acinar cells:  Insulin, the vasoactive intestinal peptide (VIP), and CCK stimulate exocrine secretion.  Glucagon, pancreatic polypeptide (PP), and somatostatin inhibit exocrine secretion.