Hepatobiliary System and Exocrine Pancreas


Hepatobiliary System and Exocrine Pancreas

Liver and Intrahepatic Biliary System

Structure and Function


Early in embryogenesis, the origins of the liver are evident. The hepatic diverticulum, also termed the liver bud, arises from embryonic endoderm as a hollow out-pouching of the primitive duodenum. Primitive hepatic epithelial cells of the hepatic diverticulum extend into the adjacent mesenchymal stroma and surround the vessels that form the vitelline venous plexus, a complex of vessels that drain the yolk sac. This relationship between the epithelial cells of the liver and the small-caliber vitelline vessels is the earliest developmental form of the hepatic sinusoids. The caudal part of the hepatic diverticulum develops into the gallbladder and the cystic duct. Hepatic connective tissue is derived from the septum transversum, a sheet of cells that incompletely separates the pericardial and peritoneal cavity, and an ingrowth of mesenchymal cells from the coelomic cavity.

The biliary epithelium also arises from the hepatic diverticulum. Intrahepatic ducts develop from a structure, termed the ductal plate, which is composed initially of a single row of hepatoblasts that surround the portal vein branches and ensheathe the mesenchyme of the primitive portal tract. A second discontinuous outer layer of primitive hepatoblasts forms subsequently, and the two-cell-thick regions remodel into tubules and become the intrahepatic biliary ductular system. Development of the ducts begins at the porta hepatis and extends to the margins of the liver until the later stages of gestation. The residual portion of the hollow outpouching of the hepatic diverticulum persists to become the extrahepatic bile ducts.

It is known that the hepatocytes and the biliary epithelial cells share a common embryonic origin, but the factors that lead to the final characteristic morphology of the primitive hepatoblasts are not well understood. Epithelial-mesenchymal interactions are believed to play a role. Primitive hepatic epithelial cells in contact with vascular endothelium are destined to become hepatocytes, and those in contact with the developing mesenchyme of the portal tracts develop into bile ducts.

Macroscopic and Microscopic Structure

The liver is the largest internal organ in the body. In adult carnivores, the liver constitutes 3% to 4% of the body weight. In adult omnivores, it is about 2% of body weight and about 1% of the body weight in herbivores. In the neonate of all species, the liver is a larger percentage of body weight than in the adult. In monogastric animals, the liver abuts the diaphragm and occupies the central area of the cranial abdomen. In ruminants the liver is displaced to the right side of the cranial abdominal cavity. A series of ligaments maintains the liver in its position. The coronary ligament attaches the liver to the diaphragm near the esophagus. The falciform ligament attaches the midline of the liver to the ventral midline of the abdomen. The round ligament, a remnant of the umbilical vein, is embedded within the falciform ligament. The liver is supplied with blood from two sources. The portal vein drains the digestive tract and provides 60% to 70% of the total afferent hepatic blood flow. The hepatic artery provides the remainder of hepatic blood flow. Blood leaves the liver via the hepatic vein, which is very short, and enters the caudal vena cava. The liver has a smooth capsular surface, and the parenchyma consists of friable red-brown tissue that is divided into lobes. Gross subdivision of the liver into lobes differs among the domestic species. At the periphery, the lobes taper to a sharp edge.

The classic functional subunit of the liver is the hepatic lobule, a hexagonal structure, 1 to 2 mm wide. At the center, the lobule has a central vein (also termed the terminal hepatic venule), which is a tributary of the hepatic vein, and at the angles of the hexagon, it has portal tracts (Fig. 8-1). The portal tracts contain bile ducts, branches of the portal vein, the hepatic artery, nerves, and lymph vessels, all supported by a collagenous stroma (Fig. 8-2). The limiting plate, a discontinuous border of hepatocytes, forms the outer boundary of the portal tract. Blood flows into the sinusoids from the terminal distributing branches of the hepatic artery and portal veins that leave the portal tracts and form an outer perimeter of the lobule (see Figs. 8-1 and 8-2). Portal blood and hepatic arterial blood mix in the sinusoids. Blood drains from the sinusoids into the central veins and to progressively larger sublobular veins and then into the hepatic veins.


Fig. 8-2 Liver, hepatic lobules, normal dog.
A, Low magnification. A central vein (C) is located in the center of the lobule. Branches of the portal vein, hepatic artery, bile duct, and lymphatic vessels are located on the periphery of the lobule in portal tracts (P) (also Fig. 8-2, C). H&E stain. B, Higher magnification. Plates of hepatocytes arranged radially between portal tracts (P) to a central vein (C). H&E stain. C, Higher magnification, portal tract. The normal portal tract contains the hepatic artery (HA), bile duct (BD), portal vein (PV), and several lymphatic vessels (LV). These structures are surrounded by a collagenous extracellular matrix that forms an abrupt border with a circumferential row of hepatocytes, termed the limiting plate (LP—dotted line). Note that the profile of the portal vein is typically larger than those of the hepatic artery and bile duct. H&E stain. (A and C courtesy Dr. J.M. Cullen, College of Veterinary Medicine, North Carolina State University. B courtesy Dr. J.F. Zachary, College of Veterinary Medicine, University of Illinois.)

Alternatively, when the liver is viewed as a bile-secreting gland, the acinus is the anatomic subunit of the hepatic parenchyma. Terminal afferent branches (penetrating vessels) of the portal vein and hepatic artery project into the parenchyma, like branches from the trunk of a tree, forming the long axis of the diamond-shaped acinus. Thus terminal afferent branches of the portal vein and hepatic artery are at the center of the acinus and the terminal hepatic venule is located at the periphery. Each terminal hepatic venule (central vein) receives blood from several acini. There are three zones within the acinus. Zone 1 is closest to the afferent blood coming from the hepatic artery and the portal vein. Zone 2 is peripheral to zone 1, and zone 3 borders the terminal hepatic venule (see Fig. 8-1). In this anatomic unit, bile flow begins in the canaliculi of the hepatocytes in zone 3 and flows through zones 2 and 1 then into the interlobular bile ducts in the portal areas.

The ultrastructural appearance of hepatocytes reflects the cell’s active metabolism, bile secretion, and close contact with the plasma (Web Fig. 8-1). The surface of the hepatocyte that faces the lumen of the sinusoids contains an abundance of microvilli, which increase the hepatocytic surface area and facilitate uptake of plasma-borne substances, such as bilirubin and amino acids, and the secretion of products of hepatic metabolism, such as lipoproteins and clotting factors. Basolateral aspects of hepatocytes are characterized by the presence of canaliculi, modified portions of the cell membrane in two adjacent hepatocytes, which form a lumen for bile secretion. The cytoplasm contains glycogen and a variety of organelles, including numerous mitochondria, lysosomes, and abundant smooth and rough endoplasmic reticulum.

Within the liver, hepatocytes are arranged in one-cell-thick branching plates, which extend radially from the terminal hepatic venule. Hepatic plates are separated by vascular sinusoids. Blood from the terminal afferent branches of the hepatic artery and portal vein mixes in the hepatic sinusoids and flows to the terminal hepatic venule. Hepatic sinusoids differ from capillaries in that they are lined by discontinuous endothelial cells that lack a typical basement membrane (Fig. 8-3), whereas capillaries have a continuous endothelial lining and are ensheathed in the basement membrane. The sinusoids are critical for appropriate hepatic function. The architecture of the sinusoids enables efficient uptake of plasma constituents by hepatocytes and facilitates hepatocellular secretion. A fine scaffold of electron lucent basement membrane that contains collagen types III, IV, and XVIII, and other extracellular matrix (ECM) components supports the sinusoidal endothelial cells (Web Fig. 8-2; see Fig. 8-3). These elements collectively make up the “reticulin” of the liver (Fig. 8-4).

Although blood cells are normally excluded from the space of Disse because they are too large to pass through endothelial gaps, the modified endothelial cells and basement membrane permit plasma to pass freely into a gap between the endothelial cells and the hepatocytes (see Fig. 8-3). This critical anatomic feature of the liver is termed the space of Disse. Within this space, plasma constituents come into contact with the luminal surface of the hepatocytes. This surface of the hepatocytes is characterized by the presence of numerous microvilli, which increase the surface area of the hepatocytes and facilitate uptake of a variety of plasma-borne substances, as well secretion of synthesized products. Any damage to this area has significant impact on hepatic function.

The lumen of the sinusoids contains hepatic macrophages, termed Kupffer cells (Fig. 8-5). These cells are members of the monocyte-macrophage system, and they clear infectious agents and senescent cells, such as erythrocytes, particulate material, endotoxin, and other substances, from the sinusoidal blood. They are mobile and able to migrate along the sinusoids and into areas of tissue injury and regional lymph nodes. Kupffer cells are involved in cytokine-driven interactions with hepatocytes, endothelial cells, and the stellate cells discussed later. They can express class II histocompatibility antigens and function as antigen-presenting cells, although they are not as efficient as the macrophages in other tissue. Phagocytosis and clearance of immune complexes are the primary roles of Kupffer cells. Kupffer cells are derived from in situ replication and recruitment of blood-borne monocytes.

Hepatic stellate cells (also termed lipocytes or Ito cells) are found within the space of Disse and between hepatocytes at the edge of the space of Disse (Web Fig. 8-3). Normally, hepatic stellate cells are primarily responsible for storing vitamin A in their characteristic cytoplasmic vacuoles. During hepatic injury, hepatic stellate cells alter their morphology and their function. These activated hepatic stellate cells lose their vitamin A content and synthesize collagen and other ECM components that lead to hepatic fibrosis.

Bile flows within the lobule in the opposite direction to blood flow, which facilitates the concentration of bile. The biliary system commences as canaliculi within the centrilobular (periacinar) areas of the hepatic lobule. The walls of canaliculi are formed entirely by the cell membranes of adjacent hepatocytes. Just outside the limiting plate, canaliculi drain into the canals of Hering that are lined partially by hepatocytes and partially by biliary epithelium. These drain into cholangioles with low cuboidal biliary epithelium. The cholangioles converge into interlobular bile ducts that are lined with cuboidal epithelium and located in the portal areas. Bile then flows into the right and left hepatic ducts that unite to form the hepatic duct. The confluence of the common hepatic duct and the cystic duct from the gallbladder form the common bile duct by which bile is carried to the duodenum. The gallbladder is responsible for storage and concentration of bile in most species. It is absent in the horse, elephant, and rat.

Bipotential progenitor cells that have the ability to differentiate into hepatocytes or biliary epithelium are believed to reside in the area of the cholangiole, although their precise location and nature is not resolved. These cells may proliferate in circumstances in which mature hepatocytes or bile duct epithelium cannot replicate such as severe injury or nutritional deficits. When these cells proliferate, they form islands or crude tubules of small basophilic cells found initially at the margin of the limiting plate. This proliferation is termed the ductular reaction and is a hallmark of severe injury.

Both sympathetic and parasympathetic nerves running along the portal vein and the hepatic artery innervate the liver. The nerve fibers enter the liver at the hilus and ramify to the level of the portal tracts and then extend along the sinusoids. Nerve supply is believed to affect sinusoidal blood flow, the balance of hepatic blood flow from the portal vein and the hepatic artery, and metabolic functions of the liver.

Normal Function

The liver performs many critical functions, including the following:

Bilirubin Metabolism: Excretion of bile is the main exocrine function of the liver. Bile is composed of water, cholesterol, bile acids, bilirubin, inorganic ions, and other constituents. Bile formation is continuous, but the rate of secretion can vary significantly. There are three major purposes for bile synthesis. The first purpose is excretory; many of the body’s waste products, such as surplus cholesterol, bilirubin, and metabolized xenobiotics, are eliminated in bile. The second purpose is the facilitation of digestion; bile acids secreted into the intestine aid in the digestion of lipids within the intestine. The third is to provide buffers to neutralize the acid pH of the ingesta.

Bilirubin, a major component of bile, is produced from the metabolic degradation of hemoglobin, and to a lesser extent, other heme proteins including myoglobin and the hepatic hemoproteins, such as cytochromes (Fig. 8-6). The majority of bilirubin is derived from normal extrahepatic breakdown of senescent erythrocytes in cells of the monocyte-macrophage phagocytic cell series. Senescent erythrocytes normally are phagocytosed by macrophages of the spleen, bone marrow, and liver. Within the phagocyte, the globin portion is degraded and the constituents are returned to the amino acid pool. The heme iron is transferred to iron-binding proteins, such as transferrin, for recycling. The remaining portion of heme is first oxidized by heme oxygenase to biliverdin. In the next metabolic step, biliverdin reductase converts biliverdin to bilirubin. Subsequently, the bilirubin, which is poorly soluble in an aqueous medium, is then released into the blood in its unconjugated form and bound to albumin to increase its solubility in plasma.

The process of bilirubin elimination can be divided into three phases: uptake, conjugation, and secretion. Uptake refers to the process by which hepatocytes remove the bilirubin bound to albumin from the circulation. Unconjugated bilirubin is separated from albumin at the sinusoidal surface and bilirubin is taken up by hepatocytes by a carrier-mediated process. In the second phase of bilirubin metabolism, bilirubin is conjugated, principally with glucuronic acid, by bilirubin UDP-glucuronyltransferase in the endoplasmic reticulum. After conjugation, bilirubin becomes water soluble and less toxic. It is then excreted, in the third phase of bilirubin metabolism, into the bile by active transport through specialized portions of hepatocyte membranes that form the margins of the bile canaliculi. The excretion phase is the rate-limiting step in most species.

Within the gastrointestinal tract, conjugated bilirubin is converted to urobilinogen by bacteria and a fraction of this is reabsorbed into the portal blood, a process called enterohepatic circulation, and returned to the liver. The majority of urobilinogen that is absorbed from the gastrointestinal tract is resecreted into bile. Urobilinogen has a small molecular weight and is freely filtered through the glomerulus, and small amounts are normally found in the urine. Urobilinogen that is not absorbed from the intestine becomes oxidized to stercobilin, which is responsible for the color of the feces.

Bile Acid Metabolism: The three principal functions of bile acids, important constituents of bile, are maintenance of cholesterol homeostasis, stimulation of bile flow and digestion, and absorption of fats and fat-soluble vitamins. Bile acids are synthesized in the liver from cholesterol and are conjugated to glycine or taurine to facilitate their interaction with other components of bile and to prevent precipitation into calculi when they are secreted into the bile. The major bile acids are cholic acid and chenodeoxycholic acid, but there are various types and proportions of bile acids found in different species. Bile acids are actively secreted into the bile canaliculi from the hepatocyte cytoplasm by specific intramembranous molecular pumps against a concentration gradient, which creates an osmotic gradient, stimulating the inflow of water and solutes into the bile canaliculi. Conjugated bile acids are therefore the principal physiologic stimulus for bile production through a process termed bile acid–dependent flow. Bile acids are effective detergents that assist in the digestion of lipids within the intestine and increasing the solubility of lipids secreted into the bile. The quantities of bile acids required far exceed the liver’s capacity to produce them. For this reason, bile acids are avidly reabsorbed from the ileum, extracted from the portal blood, and resecreted into bile via a process known as enterohepatic circulation. This is a very efficient system. As much as 95% of secreted bile acids are recycled, and the proportion of reabsorbed bile acids in the liver greatly exceeds that of recently synthesized bile acids; bile acids may be recycled 15 times a day. Interruption of this process results in fat malabsorption and a deficiency of fat-soluble vitamins.

Protein Synthesis: Synthesis of the majority of plasma proteins, mainly within the rough endoplasmic reticulum, is a principal function of the liver. Proteins produced in the liver include plasma proteins, such as albumin; a variety of transport proteins; lipoproteins; clotting factors II, V, and VII to XIII; fibrinolysis proteins; some acute phase proteins; and components of the complement system. The liver is responsible for synthesis of approximately 15% of body proteins.

The liver is also the principal site of ammonia metabolism. Highly toxic ammonia is generated through catabolism of amino acids. Metabolic conversion of ammonia into urea, a far less toxic compound, occurs through the urea cycle, which occurs almost exclusively in the liver. Urea then enters the systemic circulation (blood urea nitrogen) and is excreted in the urine.

Immune Function: The liver has a significant immune function. It is involved in systemic, local, and mucosal immunity. Hepatocytes participate in the response to systemic inflammation through the synthesis and release of acute phase proteins. Approximately 10% of the cells in the liver belong to the adaptive immune system (T and B lymphocytes) or the innate immune system (Kupffer cells, natural killer lymphocytes, and natural killer T lymphocytes). Compared with other organs, the liver is particularly enriched with cells of the innate immune system, likely a result of the fact it is the site where foreign antigens from the gastrointestinal tract first encounter the innate immune system defenses. The liver contains the largest pool of mononuclear phagocytes and natural killer cells in the body in most species. The Kupffer cells lining the sinusoids provide the first line of defense against infectious agents, endotoxin, and foreign material absorbed from the intestines before they gain access to the systemic circulation. Most blood-borne foreign material is cleared by Kupffer cells in all domestic species, except members of the Order Artiodactyla (pigs, goats, and cattle), in which this function is performed by intravascular macrophages in the pulmonary alveolar capillaries. The liver is also involved in transport of secretory immunoglobulin A (IgA), the primary immunoglobulin of the mucosal surfaces, from plasma cells and recirculation into the biliary tree and intestine.

Response of the Liver to Injury

Necrosis and Apoptosis

The epithelial cells of the liver, hepatocytes, and biliary epithelium are the principal targets of most liver diseases. Sublethal injury to hepatocytes is characterized by cell swelling (hydropic degeneration), steatosis, or atrophy. Cells that have sustained a sublethal injury often remove damaged organelles by forming autophagosomes. Material that cannot be digested further is retained as lipofuscin, which is why after sublethal injury, this pigment can often be found in affected cells and associated phagocytes.

By convention, cell death has been divided into two distinct processes. These are necrosis, which is characterized by cytoplasmic swelling, destruction of organelles, and disruption of the plasma membrane, and apoptosis, or programmed cell death, which is characterized by one of several active processes involving caspases that lead to cell shrinkage and an intact cell membrane. Necrosis is triggered by lethal injury. Necrotic cells typically exhibit karyorrhexis and fragmentation of the cell body. Coagulative necrosis results from sudden denaturation of hepatocytes and produces swollen hepatocytes with a preserved eosinophilic cytoplasmic outline and karyorrhexis or karyolysis. Lytic necrosis is characterized by a loss of hepatocytes and an influx of erythrocytes into the vacant space or condensation of the reticular connective tissue (collagen and other ECM) scaffolding of the liver that once supported the hepatocytes.

Classic apoptosis is triggered by an interaction between tumor necrosis factor-α (TNF-α) or Fas ligand and specific receptors on the cell membrane leading to caspase activation, although other pathways, including those involving mitochondrial cytochrome-c, have been identified. Apoptosis is recognized by the formation of acidophilic bodies, which are brightly eosinophilic, homogeneous, round structures that can be found between hepatocytes, within the lumen of sinusoids, or within macrophages or hepatocytes. A detailed review of cell death is beyond the scope of this section but is covered in Chapter 1. However, recent evidence reveals that there may some overlap between necrosis and apoptosis, depending on the cell type and the type and dose of injurious agent. Thus both hepatic necrosis and apoptosis can be produced by the same agent and can occur in the same liver.

Patterns of Hepatocellular Degeneration and Necrosis: Although the liver is subjected to a wide variety of different insults, the cellular degeneration and/or necrosis that results invariably occurs in one of following three morphologic patterns:

Random Hepatocellular Degeneration: Random hepatocellular degeneration and/or necrosis is characterized by the presence either of single cell necrosis throughout the liver or multifocal areas of necrotic hepatocytes. These areas are scattered randomly throughout the liver; there is no predictable location within a lobule. This pattern is typical of many infectious agents, including viruses, bacteria, and certain protozoa. Lesions may be obvious grossly as discrete, pale, or less often, dark red foci that are sharply delineated from the adjacent parenchyma (Fig. 8-7, A). The size of such foci is variable, ranging from tiny (<1 mm) to several millimeters. Hepatocytes in affected areas are either degenerated or necrotic because of the injurious effects of the infectious agents and the stage of the process (Fig. 8-7, B).

Zonal Hepatocellular Degeneration and/or Necrosis: Zonal hepatocellular degeneration and/or necrosis or as it is more simply termed, zonal change, affects hepatocytes within defined areas of the hepatic lobule. The zones are centrilobular (periacinar), midzonal (between centrilobular and periportal areas), or periportal (centroacinar) areas. Extensive zonal change within the liver, regardless of location within the lobule, typically produces a liver that is pale and modestly enlarged with rounded margins, has increased friability, and characteristically has an enhanced lobular pattern on the capsular and cut surface of the organ (Fig. 8-8). Degenerated hepatocytes swell and when the majority of hepatocytes in a zone are affected, that portion of the lobule appears pale. In contrast, once the hepatocytes in a particular zone of the lobule have become necrotic, this results in dilation and congestion of sinusoids so that the affected zone appears red. Although zonal change typically produces an enhanced lobular pattern, microscopic examination is usually required to determine the type of zonal change. Specific forms of zonal change are described next.

Centrilobular degeneration and necrosis: Centrilobular degeneration and necrosis of hepatocytes is particularly common (Fig. 8-9), as this portion of the lobule receives the least oxygenated blood and is therefore susceptible to hypoxia, and it has the greatest enzymatic activity (mixed-function oxidases) capable of activating compounds into toxic forms. Centrilobular necrosis can result from a precipitous and severe anemia or right side heart failure. Similarly, passive congestion of the liver results in hypoxia as a result of stasis of blood and produces atrophy of centrilobular hepatocytes.

Paracentral (periacinar) cellular degeneration: Paracentral (periacinar) cellular degeneration involves only a wedge around the central vein because only the periphery of one acinus is affected, typically reflecting the action of a direct-acting toxin that requires bioactivation (Fig. 8-10) or severe, acute anemia. As several acini border on a single central vein (terminal hepatic venule), changes induced by hypoxia may not be present equally in all acini, and thus hepatocytes at the periphery of one acinus can have more severe change than those in adjacent acini.

Periportal degeneration and necrosis: Periportal degeneration and necrosis are also uncommon but may occur following exposure to toxins, such as phosphorus, that do not require metabolism by mixed function oxidases (most active in the centrilobular hepatocytes) to cause injury (Fig. 8-12). Some of these compounds may be metabolized to injurious intermediates by cytoplasmic enzymes found in periportal hepatocytes. Alternatively, some of these toxins may not require metabolism and produce hepatocyte injury in the first hepatocytes that they encounter as they flow from the portal areas.

Massive Necrosis: Massive necrosis is not necessarily, as the name might be taken to imply, necrosis of the entire liver, but rather the term describes necrosis of an entire hepatic lobule or contiguous lobules (Fig. 8-14, A). All hepatocytes within affected lobules are necrotic. The gross appearance of the liver varies with the maturity of the lesion. If, in acute cases, the majority of the parenchyma is affected, the liver may initially be modestly increased in size with a smooth external surface and dark parenchyma because of extensive congestion. At first, necrotic hepatocytes lyse and the residual stroma becomes condensed. Regeneration does not occur because virtually all hepatocytes in the lobule are affected. Microscopically, affected areas consist of blood-filled spaces within a connective tissue stroma devoid of hepatocytes (Fig. 8-14, B). Later in the course of the process, stellate cells or other ECM–producing cells from the portal and centrilobular areas that may survive or migrate to the site of injury contribute new collagen (collagen I, in particular). The final result is collapse of the lobule and replacement of the lost hepatic parenchyma with a scar consisting of condensed stroma, including variable amounts and types of collagen. Grossly the liver may be smaller than normal with a wrinkled capsule. Partial involvement of the liver is characterized by depressed areas of parenchymal necrosis and vascular congestion scattered throughout the organ.

Disturbances of Bile Flow and Icterus

Hepatic injury is frequently manifested as an increased concentration of conjugated or unconjugated bilirubin in blood called hyperbilirubinemia. High concentrations of bilirubin (>approximately 2 mg/dL) can produce jaundice (icterus), a yellow discoloration of tissue that is especially evident in tissue rich in elastin such as the aorta and sclera (Fig. 8-15). This concentration is within the reference range for horses, so horses may not be hyperbilirubinemic at this level. However, in other species, hyperbilirubinemia can occur once the concentration exceeds 0.5 mg/dL (dog) and therefore the patient is hyperbilirubinemic, but icterus will not be detected until it exceeds 2 mg/dL. Maximal accumulation of bilirubin in tissues takes about 2 days and explains why some animals with acute hepatic failure may have only slight icterus.

The causes of hyperbilirubinemia include the following:

1. Overproduction of bilirubin as a consequence of hemolysis, particularly severe intravascular hemolysis, which overwhelms the liver’s capacity to remove bilirubin from the plasma and to secrete conjugated bilirubin into bile. The destruction of damaged red blood cells by extravascular hemolysis can also increase the burden of bilirubin presented to the liver. Hypoxia secondary to anemia may also play a role. Decreased uptake, conjugation, or secretion of bilirubin by hepatocytes arising as a consequence of severe, diffuse hepatic disease, whether acute or chronic.

2. Reduced outflow of bile (cholestasis). Cholestasis is defined as a defect in bile secretory mechanisms that leads to an accumulation in the blood of substances normally excreted into the bile. Cholestasis occurs as a consequence of either obstruction of the biliary ducts (extrahepatic cholestasis) or impairment of bile flow within canaliculi (intrahepatic cholestasis).

Obviously, hepatic dysfunction is not the only cause of hyperbilirubinemia and icterus. In fact, icterus in ruminants is usually a consequence of severe intravascular hemolysis and less often a sequel to hepatic damage. Horses often manifest icterus with acute hepatic dysfunction, but icterus may or may not occur in horses with chronic hepatic disease. Interestingly, “physiologic icterus” is also common in the horse, and horses deprived of feed for several days can become icteric because uptake of bilirubin from the plasma by hepatocytes is decreased. Icterus in carnivores occurs as a consequence of either hemolysis or hepatic dysfunction. Inherited metabolic abnormalities can also lead to abnormal concentrations of serum bilirubin. In Southdown sheep with certain mutations, bile is ineffectively taken up from the circulation and a persistent unconjugated hyperbilirubinemia develops, although icterus is rarely apparent because there is sufficient excretion despite the mutation. Corriedale sheep may have a mutation that leads to deficient conjugated bilirubin excretion. Affected sheep have persistently elevated plasma bilirubin concentration, but jaundice is not apparent. Other compounds that are normally excreted through conjugation also accumulate in the liver of affected sheep. The livers are dark and discolored because of accumulated polymerized catecholamine metabolites that accumulate in lysosomes. These residues resemble lipofuscin histologically.

Cholestasis can be divided into two types: intrahepatic and extrahepatic. Intrahepatic cholestasis can result from (1) a wide spectrum of liver injury affecting the ability of hepatocytes to metabolize and excrete bile; (2) hemolysis, which produces an abundance of bilirubin for excretion and diminishes the supply of oxygen for hepatocyte metabolism; or (3) inherited abnormalities of bile synthesis that inhibit the excretion of bile. Extrahepatic cholestasis is produced by obstruction of the extrahepatic bile ducts. This can occur by intraluminal obstruction (calculi or possibly parasites) or extraluminal means, including neoplasia or adjacent inflammation, often involving the pancreas. Cholestasis, if sufficiently severe, can produce a greenish brown discoloration to the liver (Fig. 8-16, A).

Histologically, acute intrahepatic cholestasis is characterized by formation of bile plugs within canaliculi (Fig. 8-16, B). As intrahepatic cholestasis becomes more chronic, bile that has been released from hepatocytes is taken up by Kupffer cells and can be detected within their cytoplasm.

Acute extrahepatic obstruction is characterized by edema of the portal areas, a mild neutrophilic inflammatory cell infiltrate, and a proliferative reaction by the biliary epithelium of the bile ducts. In chronic extrahepatic biliary obstruction, portal areas are enlarged by deposition of fibrosis, and there is a prominent laminar, circumferential fibrosis of bile ducts (Fig. 8-17). Biliary hyperplasia characterized by proliferation of small-caliber bile ducts is often prominent. Pigmented macrophages, containing bile, and mixed inflammatory infiltrates are also present. In severe cases, bridging fibrosis connecting portal tracts may develop.

Sep 17, 2016 | Posted by in GENERAL | Comments Off on Hepatobiliary System and Exocrine Pancreas
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