Chapter 5C DIGESTIVE SYSTEM  THE LIVER AND BILIARY SYSTEM

 

 5.1 AN OVERVIEW

The liver is essential for the maintenance of life; it functions in numerous diverse metabolic activities which maintain the body's normal homeostatic mechanism. The more prominent of these functions are the synthesis of plasma proteins, catabolism and maintenance of carbohydrate storage, mobilization of body fat, detoxification, and the formation and elimination of bile. The liver is subject to injury from a wide variety of toxic, infectious, and metabolic diseases. However, because of its large functional reserve, and its remarkable regenerative ability, extensive damage may be incurred before clinical manifestations of hepatic insufficiency are observed. In experimental animals, it has been shown that only 10% of hepatic parenchyma is required to maintain normal liver function. Given optimal regenerative conditions (adequate blood supply, bile drainage, and intact stromal framework), the liver can regenerate up to 75% of its parenchymal mass within a few weeks. 

5.2 OBJECTIVES

After completing this section, each student should be able to perform the following tasks:

5.4 GENERAL CONSIDERATIONS

Before embarking on a study of the pathologic alterations that affect the liver, the student should review the normal anatomic features, etc. as discussed below.

Two main concepts have been proposed concerning the microscopic structural unit of the liver: the first and more accepted is the classic concept of liver lobules; the second is the acinus concept.

The liver lobule

Is just large enough to be distinguishable with the naked eye (0.5 to 2.0 mm in diameter). At its center is a central vein from which cords of liver cells radiate out to the periphery of the lobule. The outer boundaries of the lobule (periphery) are incompletely demarcated by the portal triads. Portal triads are connective tissue septa which contain a branch of the hepatic artery, portal vein, and bile duct. The radiating cords of hepatocytes seen with the microscope represent a continuous system of communicating liver cell plates, of single layer thickness. On one side of the liver cell plates are sinusoids which are lined by fenestrated endothelial cells and by Kupffer cells. Primary bile caniculi are located on the opposite side (between adjacent hepatic parenchymal plates). The Kupffer cells are phagocytic and their cytoplasm contain numerous phagocytic vacuoles. A narrow space (the space of Disse) lies between the endothelium of sinusoids and the surface of the hepatocytes. This space communicates with the sinusoids via the fenestrae of the endothelial cells. Primary bile caniculi (l to 2u in diameter) are located between adjacent hepatic parenchymal plates, and their walls are formed by specialized portions of the cytoplasmic membrane of hepatocytes. The caniculi interconnect extensively and increase in size as they approach the portal triads.

The liver receives two nutrient supplies (one from the hepatic artery and the other from the portal vein). The hepatic artery (a branch of the celiac artery) supplies the liver with arterial blood, and the portal vein brings venous blood from the intestine and spleen. Although the portal blood is incompletely saturated with oxygen (80%), it supplies 50 to 60% of the oxygen requirement of the hepatocytes because of its greater flow. This dual blood supply accounts for the rarity of liver infarcts. Smaller branches of the portal vein and hepatic artery traverse the liver in the connective tissue of the portal triads. The microcirculation of the liver and its functional importance are best understood by the concept of the "acinus" as the microscopic structural unit.

The acinus consists of a central portal triad that contains a terminal portal venule, a hepatic arteriole and a bile duct. The surrounding hepatocytes are arranged in concentric zones. Hepatic arterioles and portal venules empty blood into sinusoids of the inner zone, and it flows through the sinusoids toward a terminal venule (referred to in the liver-lobule concept as the central vein). Consequently, hepatocytes nearer the portal tract receive blood with a higher oxygen saturation, and a higher concentration of solutes than do the hepatocytes located more peripherally in the acinus.

This explains why, in diseases that cause necrosis of liver cells, the periportal hepatocytes are usually the last to undergo necrosis and the first to regenerate.

Ultrastructurally, the cytoplasm of hepatocytes are packed with organelles. Mitochondria account for 25% of the cell volume: they are responsible for oxidative phosphorylation and oxidation of fatty acids. The numerous functions of the smooth endoplasmic reticulum include synthesis of cholesterol and bile acids; conjugation of bilirubin, drugs and steroids prior to biliary excretion; metabolism of drugs and steroids; and breakdown of glycogen. Also, the smooth endoplasmic reticulum contains essential enzymes for its metabolic role (mixed-function oxidase system, which includes NADPH, cytochrome reductase, cytochrome P450, etc.). The rough endoplasmic reticulum is responsible for the synthesis of protein. The Golgi complex is relatively large and lysosomes are numerous in hepatocytes. Numerous metabolic and synthetic processes occur in the liver. The so-called liver function tests permit biochemical estimates of deranged liver function, and these tests can be conveniently categorized to indicate the type of liver injury which they monitor:

• (1) liver cell necrosis;
• (2) inhibition of bile secretion;
• (3) defects in cell synthesis; (4) etc.

Numerous serum enzyme determinations are used to evaluate the status of the liver. Some enzymes are released into the bloodstream subsequent to necrosis of cells and/or increased permeability of cell membranes; thus, elevated serum concentrations of these enzymes are indicative of recent cell damage. The enzymes found to be the most useful indicators of recent hepatocellular damage and/or necrosis are alanine amino transferase (ALT) and aspartate amino transferase(AST). Since it is elevations in the serum concentrations of these enzymes which indicate damage, the measurement taken would be serum ALT (SALT) and serum AST (SAST). SALT and SAST are also widely referred to as serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) respectively. ALT is found in very high concentrations in the liver, and therefore it is a more specific indicator of liver cell injury or necrosis. Other enzymes that might indicate recent liver damage, if found in abnormally high concentrations in serum include: sorbitol dehydrogenase (SD), ornithine carbamyl transferase (OCT), and lactic dehydrogenase (LDH). Elevations in the concentration of Alkaline phosphatase are often indicative of biliary obstruction or impaired biliary secretion. This enzyme is found in a variety of tissues other than the liver (bone, intestine, placenta, etc.), and elevated serum concentrations could represent damage in any of those tissues; however, recent evidence suggests that each of these tissues has distinctly different isoenzymes. Measurements that reflect the synthetic capacity of the liver cells include serum albumin levels and prothrombin time. Measurement of the serum bilirubin (conjugated and nonconjugated) is a frequently used liver function test (Van den Bergh test). Certain exogenous organic ions [e.g., sulfobromophthalein (BSP)] are excreted via the same pathway as bilirubin; this is the basis for a number of sensitive liver function tests.

As mentioned previously, the liver is subject to injury from a wide variety of infectious, toxic and metabolic diseases. Regardless of the cause, necrosis is the most common response of the organ to injury. 

5.5 HEPATIC FAILURE 

Hepatic failure implies that a less than normal level of organ function exists, and it results from damage to the hepatic parenchymal cells of sufficient magnitude to cause abnormalities in clinical or biochemical findings. Regardless of the cause, overwhelming acute liver damage or extensive chronic liver disease may lead to hepatic failure. Also, the clinical manifestations are similar in both acute and chronic disease; they differ primarily with regard to the severity and number of complications that develop. In general, any severe disease of the liver interferes with most or all of its functions to about the same degree. The major hepatic functions which, when altered, are responsible for clinical signs include:

• (l) maintenance of normal blood glucose levels by providing the glycogen source; (
• 2) formation of some of the plasma proteins;
• (3) Formation and excretion of bile salts:
• (4) excretion of bile pigments;
• (5) formation of prothrombin;
• (6) detoxification and excretion of many toxic substances. The two types of liver processes which most commonly lead to hepatic failure are massive necrosis and chronic liver disease.

Widespread or massive necrosis of hepatocytes (acute liver damage) may be caused by a variety of etiologic factors (bacteria, viruses, chemicals, etc.). In acute hepatic failure due to massive liver necrosis, the liver is usually reduced in size, jaundice is a prominent feature, and the necrosis is progressive. Both conjugated and unconjugated hyperbilirubinemia is found. Liver function tests may reflect the extent of hepatocellular damage.

Amino Transferases reach very high levels; hypoglycemia can occur due to altered carbohydrate metabolism. A prolonged "prothrombin time" reflects impaired ability of the damaged liver to synthesize proteins, specifically the blood clotting factors II, VII, IX, and X. Plasma fibrinogen concentrations are also decreased. (Factors I, V, XI, XII, and XIII are also produced by the liver.)

The second major mechanism of hepatic failure is encountered in end stage liver disease or cirrhosis. Cirrhosis refers to generalized involvement of the liver by concurrent hepatic cell necrosis, regeneration, and diffuse fibrosis resulting in disorganization of the lobular architecture.

Cirrhosis of the liver leads to increased resistance to venous blood flow within the liver and the development of portal hypertension and ascites. Liver function tests may show only mild abnormalities. 

Hepatic encephalopathy refers to a spectrum of central nervous system disturbances associated with chronic liver failure. It is manifested by changes ranging from reduced mental alertness, restlessness, and confusion in the initial stages to loss of consciousness, convulsions and coma in the terminal stages. Ammonia toxicity due to a failure of damaged hepatic cells to convert ammonia to urea is most frequently incriminated as the cause of this condition. In cases of hepatic encephalopathy, ammonia is almost always elevated in both the blood and in the cerebrospinal fluid. Despite the severe neurologic abnormalities associated with hepatic encephalopathy, few lesions have been observed in the brain. The usual finding is hypertrophy and hyperplasia of protoplasmic astrocytes in the cerebral cortex and subcortical nuclei. In horses, hepatic encephalopathy is usually caused by hepatotoxic plants (e.g., crotalaria, senecio, and amsinckia). The condition occurs most frequently when horses, subjected to inadequate pastures, are forced to eat these poisonous plants. 

5.6 NECROSIS OF THE LIVER

Necrosis of parenchymal cells is the most common and the most prominent feature of an acute response of the liver to injurious agents. However, an inflammatory reaction may be associated with some necrotizing diseases. The term hepatosis is sometimes used to refer to necrotic or degenerative diseases of the liver, and hepatitis refers to inflammation of the liver.

Liver necrosis is usually classified on the basis of its anatomic location within the liver lobule. Thus, multifocal hepatic necrosis may be categorized into focal, centrilobular, midzonal, periportal (peripheral), or massive forms. Focal necrosis tends to have a random distribution within the hepatic lobule and both focal necrosis and massive necrosis are usually randomly distributed throughout the liver as a whole. The reason certain agents induce random lesions while others localize their effect to certain zonal regions within lobules is not clearly understood in most disease situations. 

5.6.1 Focal necrosis

Refers to the development of small areas of necrosis with a random distribution, as it relates to the liver lobule. The lesions are microscopic or barely visible to the naked eye. Many bacterial infections which run a bacteremic or septicemic course tend to produce such focal lesions (pseudotuberculosis in the fetus or newborn, and listeriosis, salmonellosis, etc.). Usually these lesions develop in numerous lobules throughout the liver and would be referred to as multifocal as it relates to the entire organ. Because of the large functional reserve of the liver, focal necroses are themselves of very little significance to the liver, and even when numerous produce little or no hepatic dysfunction. 

5.6.2 Centrilobular (periacinar) necrosis

Refers to necrosis of hepatic cells in the zone around the central vein. This pattern of necrosis occurs in cases of congestive heart failure (subsequent to anoxia resulting either from reduced blood flow or lowered oxygen tension of the blood), and from a large number of toxic agents (e.g. carbon tetrachloride, chloroform, etc.). Grossly, when the necrosis is mild, normal architectural markings of the lobules are exaggerated; however, in severe cases, the necrotic tissue around central veins is replaced by blood and subsequently by fibrinous tissue.

 5.6.3 Midzonal necrosis

Refers to necrosis of hepatocytes in a zone midway between the central vein and portal triads. The feature of hepatic cirrhosis is the formation of pseudolobules. Cirrhosis is a chronic condition. 

5.6.4 Periportal necrosis

Refers to necrosis of hepatocytes located in a zone along the periphery of lobules. This pattern occurs in many types of poisoning, including cases of phosphorus poisoning, pyrolizidine alkaloid toxicosis, etc. 

5.6.5Paracentral necrosis

Refers to necrosis of a wedge-shaped area with the apex located at the central vein and the base of the wedge located at the portal area. This pattern of necrosis is associated with occlusive lesions in branches of the portal vein.

(Note: As it relates to the lobule, the paracentral distribution represents a portion of a necrotic acinus. 

5.6.6 Massive necrosis

Refers to necrosis that involves entire hepatic lobules. The whole liver is not affected however, and usually there is a random distribution within the organ, with some lobules being completely necrotic, whereas others are normal or exhibit a lesser degree of necrosis. Even though necrotic lobules may be distributed throughout the liver, the left lobe is usually more severely involved in milder cases. The relative restriction of massive necrosis to the left lobe in some cases is explained on the basis of streamlined portal flow. The portal circulation to the left lobe comes from the spleen and colon and this blood is relatively deficient in nutrients compared to the portal circulation to the right lobe which comes from the small intestine. Grossly, the affected liver may be normal or abnormally small in size, with a mosaic appearance of reddish-grey or yellow areas intermingled with darker red areas. the grey or yellow areas represent surviving tissue, and the darker red areas represent areas of necrosis and hemorrhage. The sequela to massive necrosis is collapse of the reticular and fibrous framework of the lobules so that portal areas and central veins are approximated. Collapse of lobules and subsequent heavy connective tissue scarring is referred to as "post-necrotic scarring" or "post-necrotic cirrhosis". 

In swine, the condition known as hepatosis dietetica is characterized by massive necrosis of the liver. The condition occurs primarily in rapidly growing pigs (3-weeks to 4-months of age), fed on diets which are deficient in both vitamin E and selenium. The diets commonly are deficient in both vitamin E and selenium. The diet commonly associated with hepatosis dietetica include those which contain mixture of soybean, high-moisture corn, and the cereal grains grown on soils with low levels of selenium. Grossly, the liver is mottled to mosaic-like in appearance (completely necrotic lobules may be observed adjacent to normal lobules). Remember, in addition to hepatosis dietetica, vitamin E and selenium deficiency has been incriminated as the cause of mulberry heart diseases and white muscle disease in young swine. 

In sheep, massive liver necrosis has been reported in areas of California. The condition is most frequently observed in animals grazing on pastures in which bird foot trefoil (Lotus tenuis) is abundant.

There is no unified opinion relative to the manner in which the responses of the liver to injury are classified. Traditionally, the term hepatitis (inflammation of the liver) has been used to refer to liver changes that vary from necrosis to healing by fibrosis. Actually, the characteristic response of the liver to most injurious agents is necrosis rather than a classical inflammatory reaction. The term hepatosis has not achieved general acceptance for retrogressive liver changes (necrosis, etc.). Thus, in this discussion, the term hepatitis is used to refer to reactions of the liver of injury in the following context.

5.7 INFECTIOUS HEPATITIS:

Refers to a liver disease in which the liver has been invaded by infectious organism (e.g. bacteria, viruses, fungi, etc.). Liver changes may consist of a classical inflammatory response or necrosis may be the prominent feature.

5.8 TOXIC HEPATITIS:

Refers to liver changes caused by a wide-variety of hepatotoxins (chemicals, plants, etc.). The typical response is necrosis of hepatocytes and the various changes that precede cell death (e.g. cellular swelling and fatty change.

5.9 CHRONIC SCLEROSING HEPATITIS:

Refers to a disease of the liver in which the production of fibrous connective tissue is a prominent feature. This is considered to be the stage of healing, which occurs in response to a wide variety of causes. Thus, this response may be a sequelae of infectious hepatitis, toxic hepatitis, etc.

5.10 CIRRHOSIS:

This term is reserved for generalized involved of the liver with concurrent hepatic cell necrosis, regeneration, and diffuse fibrosis resulting in disorganization of the liver lobules. A characteristic feature of hepatic cirrhosis is the formation of pseudolobules. Cirrhosis is a chronic condition.

5.11 INFECTIOUS HEPATITIS 

Infectious hepatitis

May be caused by a wide variety of invading organisms (bacteria, viruses, fungi, etc.). These organisms may reach the liver via the portal vein, the hepatic artery, the bile duct system, by direct extension, and by the umbilical vein in the newborn. Infectious agents that attack the liver include a few which are peculiar to the organ and several which localizes elsewhere in the body with equal or greater facility.

The following are some diseases in which infectious hepatitis is a prominent feature.

 5.11.1INFECTIOUS CANINE HEPATITIS 

Infectious canine hepatitis is a contagious adenovirus infection (canine adenovirus-I) which occurs primarily in young dogs. The disease is characterized by fever, severe depression, and by the presence of intranuclear inclusion bodies in hepatic and endothelial cells. Clinically, the disease may be unapparent or signs may consist of anorexia, thirst, depression, fever, vomition, diarrhea, conjunctivitis, serous ocular and nasal discharges, leukopenia, and prolonged clotting time. In addition, disseminated intravascular coagulation is commonly observed. The virus has an affinity for hepatic parenchymal cells, Kupffer cells and endothelial cells throughout the body. Gross lesions are not diagnostic and may consist of hemorrhages in various organs and tissues, enlargement of the liver and spleen, edema of the gallbladder, and corneal opacity. Microscopic lesions consist of random multifocal necrosis of the liver with intranuclear inclusion bodies in hepatic parenchymal cells, Kupffer cells, and endothelial cells. Remember, hemorrhages in various organs and tissues are related directly to endothelial cell damage. During the recovery phase (7 - 10 days after the disappearance of acute signs) some affected dogs may develop so-called "hepatitis blue eyes" which is a transient unilateral or bilateral corneal opacity. This ocular lesion is considered to be an Arthus-type hypersensitivity reaction. Infected dogs rarely exhibit central nervous system involvement; however, in foxes, the infectious canine hepatitis virus is a common cause of encephalitis ("Fox encephalitis").

 5.11.2 CANINE HERPESVIRUS INFECTION

 Canine herpesvirus infection is a fatal disease of young puppies characterized by focal necrosis and hemorrhages in various visceral organs. Death occurs usually in infected pups from one to three weeks of age; occasionally, fatal cases occur up to one month of age. Pups infected in utero are stillborn. The onset is sudden and death occurs in young pups after an illness of 24-hours or less. 

In young puppies, characteristic lesions consist of necrosis and hemorrhages in various visceral organs, including the liver, lungs, kidneys, adrenals, and intestine. The spleen and lymph nodes are often congested and enlarged. Microscopically, there is random multifocal necrosis of affected organs and tissues and intranuclear inclusion bodies may be found. A non-suppurative encephalomyelitis with focal areas of malacia has been reported. Remember, the virus may be recovered from puppies and adult dogs in the absence of recognizable signs. 

In adult dogs, a mild rhinitis, a mild tracheobronchitis, and a vesicular vaginitis have been reported. There is evidence that the virus may cause abortions, stillbirths, and infertility. Infected bitches develop antibodies, and litters subsequent to the first infected litter receive maternal antibodies in the colostrum; thus, no disease results,. Dogs appear to be the natural and reservoir host for the virus. 

5.11.3 EQUINE VIRAL RHINOPNEUMONITIS

Please refer to the section on the "Respiratory System" for a more detailed discussion.

In the fetus, equine viral rhinopneumonitis is characterized by small grayish-white necrotic foci distributed throughout liver lobules. Microscopically, acidophilic intranuclear inclusion bodies are found associated with the necrotic hepatocytes. In addition, necrosis and inclusion bodies may be observed in the lungs and spleen. Mares infected with "equine herpes-"areusuallyasymptomatic, but they tend to abort between the 8th and 11th months of gestation. 

5.11.4 INFECTIOUS BOVINE RHINOTRACHEITIS 

Infectious bovine rhinotracheitis (IBR) is a disease of cattle caused by a herpesvirus. It is also known as Infectious Pustular Vulvovaginitis, Coital Exanthema, Vesicular Venereal Disease, Vesicular Vaginitis, Coital Vesicular Vaginitis, and Coital Vesicular Exanthema. It has a worldwide distribution and in adult cattle it causes an upper respiratory disease and a vesicular genital disease.

(Refer to your respiratory system and reproductive systems syllabi for further details.)

In pregnant cows, IBR infections and use of the modified live IBR vaccine have been associated with late gestational abortions. The critical period for exposure seems to be the second trimester. Reportedly, aborted fetuses are usually severely autolysed making gross and microscopic lesions obscure. Multiple foci of necrosis may be identified in liver, lymph nodes, spleen, and kidney and intranuclear inclusion bodies may be evident in cells near the necrotic foci. 

5.11.5 FELINE VIRAL RHINOTRACHEITIS 

Feline viral rhinotracheitis is an disease of cats caused by a herpesvirus. It is primarily characterized by upper respiratory problems, and like many of the herpesvirus infections, it has been associated with a fatal systemic disease in neonates and late gestational abortions.

PSEUDORABIES 

Pseudorabies is caused by a herpesvirus and natural infections occur in many species. It is also known as Infectious Bulbar Paralysis, Aujeszky's Disease, and Mad Itch. It has a worldwide distribution and swine and rats are considered reservoir hosts. In adult swine, infections usually result in a mild febrile condition followed by recovery but infections in most other domestic species, most importantly cattle, are usually fatal.

Pseudorabies infections in weanling pigs usually results in CNS disease (encephalitis) characterized by incoordination, convulsions, paralysis, and death.

Intrauterine infections occur in swine and they usually result in abortion and stillbirth. Postmortem findings in aborted or stillborn piglets include random multifocal necrosis in the liver, the spleen, tonsils and kidney with intranuclear inclusion bodies in cells surrounding the foci on necrosis. 

5.11.6 BACILLARY HEMOGLOBINURIA 

Bacillary hemoglobinuria is an acute, highly fatal toxemia of cattle and sheep caused by Clostridium hemolyticum. The condition is characterized by a high fever, icterus, hemoglobinuria, and infarction of the liver. Clostridium hemolyticum is a soil-borne anaerobe which lodges in the liver until there is sufficient damage to the parenchyma to create conditions suitable for its proliferation (hypoxic conditions). The development of organized thrombi in branches of the portal vein is responsible for the large infarcts which are characteristic of the disease. The majority of the bacteria are found within these infarcts and it is presumed that under the prevailing anaerobic conditions, toxins are produced and liberated in large amounts, resulting in a severe toxemia. Two toxins, a hemolysin and a necrotizing agent, are produced by the bacteria. At necropsy, characteristic anemic or red infarcts (one or more) may be found in any part of the liver; the infarcts may vary in size from 5 to 20 cm. Extensive petechial or diffuse hemorrhages occur in the subcutaneous tissue and over serosal surfaces. Red urine (hemoglobinuria) is present in the kidneys and urinary bladder. Clostridium hemolyticum can be isolated from heart blood, liver infarcts, and many other organs from a fresh carcass; however, postmortem invaders quickly obscure its presence. Remember, multiple liver infarcts have also been associated with bracken fern (pteridium aquilina) poisoning in ruminants. In this disease, the infarcts are caused by embolic clumps of bacteria (usually saprophytes). The bacterial emboli localize in small branches of the portal vein, sinusoids, and the central veins.

5.11.7RIFT VALLEY FEVER 

Rift Valley Fever is an acute, febrile disease of cattle, sheep, and man caused by an arbovirus. The condition is characterized by hepatitis and high mortality in lambs and calves, by abortion and hepatitis in adult sheep and cattle, and by an influenza-like disease in man. Rift Valley Fever is still confined to the African continent, but it has great potential for spread to this and other countries. Eight species of mosquitoes have been identified as vectors. In lambs and calves, after an incubation period of about twelve hours, there is sudden onset of high fever and incoordination followed by collapse and sudden death within 36 hours. At necropsy extensive hepatic necrosis is the characteristic lesion; multiple small grayish-white necrotic foci are distributed throughout the liver. Other lesions include venous congestion and petechial hemorrhages in the heart, lymph nodes and alimentary tract. Microscopically, acidophilic intranuclear inclusion bodies may be present in hepatocytes.

5.11.8 TULAREMIA

Tularemia is a highly fatal disease of rodents and rabbits which may spread to other animals and man. The disease is caused by Pasteurella (Francisella) tularensis, an organism that has remarkable invasive powers. In rabbits and rodents, tularemia is characterized by random multifocal necrosis throughout the liver that vary in size from pin point to several millimeters in diameter.

5.11.9 ABSCESSES OF THE LIVER

Liver abscesses may be caused by a variety of pyogenic bacteria, and they are especially common in cattle (however, they occur in all animals). The causative organisms may reach the liver by way of the portal vein, by direct extension of an omphalophlebitis, by direct implantation with a foreign body from the reticulum, or by the biliary system. Liver abscesses do not cause clinical signs of hepatic dysfunction unless they are particularly massive. They may, however cause signs of toxemia because of the destruction of hepatic tissue or the liberation of potent toxins. Organisms commonly recovered from liver abscesses include Corynebacterium pyogenes, streptococci, and staphylococci. Remember, in cattle, abscesses oftentimes eroded into hepatic vessels to produce thrombophlebitis of the vena cava, endocarditis, or pulmonary abscessess.

5.11.10 POST-VACCINAL HEPATITIS OF HORSES (EQUINE SERUM HEPATITIS)

Post-vaccinal hepatitis is a condition recorded in horses following vaccination against several diseases (equine encephalomyelitis, anthrax, enterotoxemia, tetanus (tetanus antitoxin), influenza, and African horse sickness). Attempts to transmit the disease have not been successful , and it is thought that a hepatotoxic agent may be present in any equine serum or tissue extract used as a vaccine. Clinically the disease is characterized by intense icterus, cessation of alimentary tract movement, oliguria, absence or rare occurrence of fever, and severe central nervous system signs (including stupor and mania). Most affected animals die within 12-48 hours; however, some may recover. At necropsy, the characteristic are primarily found in the liver. The liver is usually normal in size (it may slightly enlarged or shrunken), friable, stained by bile pigments, with a mottled appearance. Microscopically, evidence of cellular swelling, fatty change, and necrosis is present within affected lobules.

5.12 TOXIC HEPATITIS

A wide variety of hepatotoxin is capable of causing injury to hepatocytes. Depending on the dosage and duration of exposure, these agents produce fatty changes, and necrosis of hepatocytes, and fibrosis of the liver. Some of the more important hepatotoxins are discussed in this section.

5.12.1 PYRROLIZIDINE ALKALOID TOXICOSIS

The pyrrolizidine alkaloids have been found in plants belonging to various unrelated botanical families; they are especially prominent in Crotalaria spp., Senecio jacobaea (rag wort), Amsinckia intermedia (tar weed), and Lantana. These plants cause hepatic insufficiency plus photosensitization and in some instances marked signs of central nervous system derangement. In the liver, a characteristic action of pyrrolizidine alkaloids is the induction of hypertrophic changes in hepatocytes (megalocytosis). The volume of affected cells may be increased as much as twenty times; the nucleolus, nucleus, an cytoplasm are affected. Concurrent with the development of megalocytosis, there is fibrosis and proliferation of bile ducts in the portal areas. The fibrosis is minimal in sheep, moderate in horses, and may be marked in cattle. The pyrrolizidine alkaloids of Senecio spp and Crotalaria cause proliferation of endothelial cells and occlusion of hepatic vessels. Grossly, affected livers may be normal or pale in color, nodular, small in size, firm, and inflexible. Acute poisoning by pyrrolizidine alkaloid is unnatural; because of unpalatability of the plants, the amount of toxin naturally ingested is usually too small to produce acute effects. Lesions develop gradually and they are usually chronic when observed. In addition to liver lesions, central nervous system signs occur (hepatic encephalopathy). Remember, plants containing pyrrolizidine alkaloids, in general, are rather unpalatable and not readily eaten by animals.

5.12.2 AFLATOXICOSIS

The alfatoxins are a group of hepatoxic metabolites produced by certain strains of Aspergillus flavus. Several toxins (B1, B2, G1, G2, M1) have been identified, but aflatoxin B1 is most important. The first observed (and most common) source of aflatoxin was groundnuts infested with Aspergillus flavus; however, cotton seed meal, sorghum grain and corn may also be sources. The site of action of aflatoxin is the nucleolus. There is a direct toxic effect on DNA-dependant RNA polymerase and thus protein synthesis. Also, DNA synthesis is affected by the affinity of aflatoxin to bind to DNA molecules. Even though aflatoxins are not related to the pyrrolizidine alkaloids, clinical signs and lesions are quite similar. Grossly, in acute cases, the liver is normal size or slightly small and greenish-yellow in color (due to bile-staining and fatty changes). In more chronic cases, the liver is shrunken, yellowish, and it may be nodular. Fibrosis is most prominent in the portal areas and around the central veins. Bile duct proliferation, evident due to the presence of newly formed bile ducts, is a prominent feature. Bile ducts may invade the parenchyma and link up with central veins. Also, icterus is usually a prominent feature.

5.12.3 PHOSPHORUS POISONING

Phosphorus poisoning is characterized by severe fatty changes and necrosis of the liver as well as severe inflammation of the alimentary mucosa. Phosphorus poisoning occurs in animals when they are exposed to rat bait containing white phosphorus. (Today, phosphorus is rarely used as a rodenticide.) Grossly the liver is enlarged and fatty, and the alimentary mucosa is hemorrhagic. Microscopically, fatty changes and acute necrosis of hepatocytes, primarily at the periphery of lobules, are prominent liver changes.

5.12.4 CARBON TETRACHLORIDE POISONING

Carbon tetrachloride was used as an anthelminthic and toxicosis usually occurs in animals dosed with this compound. Unlike many hepatotoxins, it is enzymatically converted into its toxic form by hepatocytes. This enzymatic conversion is performed by mixed function oxidases in the smooth endoplasmic reticulum and it occurs progressively as the blood flows through the hepatic lobule. The actual toxic principle is the free radical CCl3. Because of this, the toxic principle reaches greater concentrations in the center of hepatic lobules and this results in centrilobular necrosis. (Hepatotoxins that are toxic in their primary forms usually exist in greater concentrations at the periphery of hepatic lobules and therefore hepatic lesions caused by these toxins are typically more severe in the periportal regions of the hepatic lobule.) The CCl3 free radicals initiate lipoperoxidation of the endoplasmic reticulum membranes, inhibit protein synthesis, and depress enzyme activity. Grossly and microscopically, centrilobular fatty changes and acute centrilobular necrosis are prominent morphologic features carbon tetrachloride toxicosis.

NOTE: In addition to the hepatotoxins discussed in this section, there are many others capable of causing liver injury.

5.13 CHRONIC SCLEROSING HEPATITIS

As stated previously, chronic sclerosing hepatitis refers to liver disease in which fibrous connective tissue is a prominent feature.

This is the healing stage which occurs in response to a wide variety of causes. Resulting liver lesions are referred to as "fibrosis of the liver".

5.13 CIRRHOSIS OF THE LIVER

For the purpose of this course, the essential features of cirrhosis as set forth by the fifth Pan American Congress of Gastroenterology are acceptable

Cirrhosis refers to generalized involvement of the liver by concurrent parenchymal necrosis, regeneration, and diffuse fibrosis resulting in disorganization of the lobular architecture and the formation of pseudolobules.

Thus cirrhosis is a chronic progressive condition that results in liver cell failure and portal hypertension. The scarring of cirrhosis is considered to be irreversible. Based on the above definition, cirrhosis may be distinguished from "chronic sclerosing hepatitis" which has been identified as simply the "stage of healing" by connective tissue replacement. It should be noted that cirrhosis is also chronic in duration.

Remember,

as is commonly used in your textbook and other reference sources, the term cirrhosis is used to refer to sclerosis or scarring of the liver and the term "chronic hepatitis" is often used as a synonym. Presently, the above distinctions are being made between cirrhosis and a simple chronic hepatitis, such as chronic sclerosing hepatitis.

The causes of cirrhosis are variable, and the specific cause frequently cannot be established in individual cases. In general, however, the causes are the same as those discussed for toxic hepatitis. (Thus, the condition may represent the end-stage of acute toxic hepatitis or recurrent acute toxic hepatitis.) In farm animals, chronic poisoning by plants (known or unknown) should be suspected as the most likely cause of cirrhosis. For example, senecio poisoning in horses and amsinckia (tarweed) poisoning in horses, cattle and sheep are oftentimes characterized by cirrhosis of the liver. Cirrhosis is occasionally seen in dogs but the causative mechanism is not clearly established.

Even though the patterns of cirrhosis have been classified on the basis of the pathogenesis, anatomic features, etiology, as well as gross and microscopic features, there are many difficulties encountered with this approach. For example, similar morphologic patterns can be produced by a number of etiologic agents, and often the same agent can produce a variety of morphologic patterns. However, the following patterns are commonly encountered in the veterinary literature.

5.13.1 PORTAL CIRRHOSIS (Hobnail Liver)

Refers to liver cirrhosis in which the proliferating connective tissue originates in the periportal areas and tends to encircle the lobules. There is distortion of the lobular architecture with the formation of irregular nodules on the liver surfaces. These nodules consist of regenerating and/or hyperplastic hepatic cells. Bile duct proliferation is minimal. This is the common pattern of cirrhosis that follows acute toxic hepatitis.

5.13.2 BILIARY CIRRHOSIS

Refers to liver cirrhosis that results from some chronic inflammation of the intrahepatic bile ducts. This pattern of cirrhosis can be distinguished from portal cirrhosis only with difficulty.

5.13.3 POST-NECROTIC CIRRHOSIS

Refers to liver cirrhosis that results directly from extensive acute necrosis of hepatic parenchymal cells.

Grossly, the liver is smaller in size than normal. This develops as the cirrhosis progresses. Proliferation of fibrous connective tissue is a prominent feature, and the normal architecture is distorted by the formation of irregular nodules. Also, the organ is firm or hard. Microscopically, the proliferating fibrous connective tissue may be found in periportal areas, within lobules, and/or around central veins. Regeneration of hepatic cells is also a prominent feature. In addition, regenerative hyperplasia of hepatocytes may result in the presence of rather bizarre cells with large hyperchromatic nuclei. Newly formed bile ducts are often found within proliferating connective tissue. In some cases, necrosis may still be active within the lobules.

Remember,

portal cirrhosis is the most commonly encountered type in animals and the condition is characterized by hepatic failure and portal hypertension.

5.14 BASIC HEPATIC DISORDERS AND OTHERS

Many of the alterations discussed below were considered in the General Pathology course. The General Pathology notes and other sources should be reviewed as the need arises. Remember, the liver is one of the most frequently damaged organs in the body.

5.14.1 SAWDUST LIVER:

"Sawdust" is a descriptive term which refers to the presence of minute yellowish foci of coagulative necrosis distributed throughout the bovine liver in an irregular fashion. The liver appears as if granules of sawdust were scattered over its surfaces. Well fattened young calves are most commonly affected. Microscopically, the yellowish foci consist of hepatic cells in a state of coagulative necrosis. The exact etiologic mechanism has not been elucidated, but vitamin E deficiency has been suggested as the cause. "Sawdust" lesions are often concomitant with telangiectasis and liver abscesses. In fact, it has been suggested that "sawdust" lesions may be the forerunners of telangiectatic spots and possibly of abscesses.

5.14.2 TELANGIECTASIS OF THE LIVER

The term "telangiectasis" refers to dilatation of the functional blood vessels anywhere in the body. In the liver, telangiectatic lesions consist of small groups of greatly dilated sinusoids within any part of the lobule. Microscopically, the cells of hepatic cords between the dilated sinusoids will have partially or completely disappeared. Grossly, the condition is characterized by dark red foci, irregular in shape, that are from one to several millimeters in diameter. Telangiectatic lesions are seen in heavily fattened as well as old debilitated cattle. Remember, it has been suggested that "sawdust" liver lesions may be the forerunner of telangiectatic foci.

5.14.3 FATTY CHANGE:

Fatty change occurs with frequency in the liver since it is the major organ involved in fat metabolism. The accumulated fat within hepatic cells reflects some imbalance in its production, utilization, or mobilization. Thus fat may accumulate in the cytoplasm of injured cells, or it may accumulate in cells which were initially normal. Microscopically, (routine H & E) fatty change is first manifested by the appearance of small vacuoles within the cytoplasm of hepatocytes. As the process progresses, the small vacuoles coalesce to form larger vacuoles. To identify the lipid, it is necessary to prepare frozen tissue sections on either fresh or formalin fixed tissues in order to preserve the lipid content of the vacuoles. These sections are stained with a suitable fat stain (e.g. Oil-Red-O, etc.). Grossly, the liver is enlarged, friable, tan to yellow in color, and the cut surfaces bulge when incised. In severe cases, liver sections will float when placed in water or formalin.

5.14.4 FAT COW SYNDROME/PREGNANCY TOXEMIA

Fat cow syndrome/pregnancy toxemia are sporadic conditions that occur in cows that have become fat because of heavy feeding in early pregnancy, but suffer from a severe nutritional stress during the 2 months before calving or in the period immediately following calving. Affected cows are invariably fat, completely anorexic, and are either in the last stage of pregnancy or have just calved. Grossly, the liver is markedly enlarged and severely fatty; also, there is a heavy deposition of fat in storage depots. The condition is characterized by ketonemia, ketonuria, hypoglycemia, and proteinuria. Mortality is near 100% in clinical cases.

5.14.5 INFARCTION OF THE LIVER

In general, infarcts of the liver are uncommon, probably because of the dual blood supply already discussed. If an infarct does occur, it is usually the result of some obstruction in a branch of the hepatic artery. Portal vein obstruction will not by itself cause sufficient obstruction and needs to be accompanied by arterial insufficiency. Liver infarcts have been reported in cases of bacillary hemglobinuria as well in cases of Bracken-fern poisoning in ruminants. (Please refer to slides #19 and 20.)

5.14.6 CIRCULATORY CHANGES

Circulatory changes in the liver are quite common. They are found in virtually every animal necropsied because whatever the underlying cause of death, some element of circulatory failure occurs in the agonal stages of life leading to hepatic alterations. Remember, liver cells are very sensitive to hypoxia, and therefore cardiac or vascular insufficiency is an important cause of hepatocellular damage. Congestive heart failure is a common cause of hepatic congestion and subsequent liver cell necrosis and fibrosis which are prominent around central veins.

In chronic passive congestion, the liver is slightly enlarged with an irregular or granular capsular surface. When a cut surface of the liver is examined, the congested centers of the lobules contrast with the relative paleness of the peripheral zone. Thus, the congested liver looks somewhat like the surface of a "nutmeg" cut in half, hense the term "nutmeg liver." (Nutmeg liver is also seen in high altitude disease.) Over a period of time, fibrous connective tissue scarring occurs around central veins of liver lobules (cardiac sclerosis or cardiac cirrhosis). Remember, in so-called cardiac cirrhosis, the essential features described for cirrhosis are usually absent.

5.14.7 NODULAR HYPERPLASIA

Hyperplastic nodules may occur in the liver of animals in the absence of cirrhosis (as described earlier). The nodules may be single or multiple. The condition occurs with frequency in the liver, pancreas and spleen of old dogs. Even though the cause is unknown, there is evidence that high fat-low protein diets result in a combination of nodular hyperplasia and atrophy of fatty areas to produce a small nodular liver.

5.14.8 AMYLOIDOSIS

The liver is a common site of deposition of amyloid in systemic forms of amyloidosis.

(Remember, reactive systemic amyloidosis and immunocyte-derived systemic amyloidosis.)

The amyloid is deposited in the walls of sinusoids and adjacent to hyperplastic Kupffer cells. Grossly, the liver may be markedly enlarged with a pale gray, waxy appearance; in some instances, the liver may rupture. Remember, in birds, the liver is the usual site of amyloid deposition.

5.14.9 DISPLACEMENT AND RUPTURE OF THE LIVER:

Caudal displacements of the liver are the result of enlargement of the organ or displacement of the diaphragm (pleural effusion, etc.). Congenital or acquired displacements in ventral and diaphragmatic hernias occur with frequency. In diaphragmatic hernias, usually, only one lobe goes into the thorax with other viscera; the herniated lobe becomes congested and, in time, indurated. Torsion of individual liver lobes occurs in dogs and swine; necrosis of the twisted lobe occurs and the animal may die from shock or hemorrhage. Rupture of the liver occurs commonly as a result of trauma (automobile accidents, etc.). Small capsular ruptures may clot and heal; larger ones frequently lead to exsanguination.

5.14.10 CONGENITAL ANOMALIES OF THE LIVER

Congenital anomalies occur in the liver, but they are seldom important. In fact, a variety of defects may accompany generalized malformations.

Congenital cyst of the liver occur in all animal species. Intrahepatic congenital cysts are probably derived from embryonic bile ducts. Also, serous cysts (multiple or single) are occasionally found attached to the liver capsule in calves, lambs, and foals. Their origin is not known.

5.14.11 PORTOSYSTEMIC SHUNTS

Portosystemic shunts are vascular channels which allow blood from the portal vein to bypass the liver and go directly to the systemic circulation. In actuality, this is a circulatory system defect but these shunts create a situation that indirectly results in hepatic failure. Portosystemic shunts may be either congenital or acquired and they may exist in the form of either intrahepatic or extrahepatic channels. Congenital shunts are more easily diagnosed because they are usually formed of a solitary channel that is more readily discernable. A common intrahepatic congenital shunt allows for shunting of blood from the portal vein to the posterior vena cava (portocaval shunt) via a persistent ductus venosus. Extrahepatic congenital shunts occur more often as either portocaval shunts or porto-azygous shunts. Acquired shunts are usually extrahepatic and they develop in many locations. They usually arise subsequent to portal hypertension. Individuals with portosystemic shunts often develop hepatic encephalopathy and this is probably due to ammonia toxicity.

5.14.12 LYSOSOMAL STORAGE DISEASES

Lysosomal storage diseases are conditions resulting from inherited defects that allow for abnormal accumulations of certain substances in lysosomes. These syndromes have been most extensively studied in humans but many have counterparts in various animal species. The substances tend to accumulate in lysosomes in multiple tissues, and the liver is frequently involved. Some of the more common lysosomal storage diseases are listed in the following chart.

5.14.13 PARASITES OF THE LIVER AND BILE DUCTS

5.14.13.1 Liver Flukes

A variety of nematodes, cestodes, and other parasites produce inflammatory changes in the liver and bile ducts. (These will be discussed most extensively in system as their final habitat whereas others produce liver lesions in the course of their natural or accidental migrations. Liver flukes (distomiasis) may cause characteristic liver lesions and the parasites can usually be found in the parenchyma of the affected biliary systems.

5.14.13.2 Fasciola Hepatica (common liver fluke)

Is about 20-30 mm long, flattened, reddish brown, and leaf-like. The metacercarial stage is ingested by cattle and sheep. They penetrate the intestinal wall and enter the peritoneal cavity. The young fluke penetrates the liver capsule and wanders in the parenchyma for several weeks, growing and destroying the tissues. Later, the young fluke enters a bile duct and matures. Adults deposit ova in the biliary passages, through which they reach the intestines and are expelled with the feces. Immature wandering flukes destroy liver tissue and hemorrhage is often present. Mature flukes cause severe damage to bile ducts (fibrosis, etc.).

5.14.13.3Fascioloides magna (the large liver fluke)

Is about 75mm long, thick and oval. Deer and moose are probably the normal hosts, but the fluke occurs in domestic ruminants. The life cycle is similar to that of Fasciola hepatica. In sheep and goats, a few flukes can cause death due to the inability of the host to limit the migration of the parasites in the liver parenchyma. Tissue damage is severe and marked clinical disease results. In cattle, young flukes wander briefly through the liver parenchyma, destroying tissue and eliciting a reaction of the host which encapsulates the parasites. (The life cycle is not completed in cattle). Excreta and ova accumulate around the flukes within the liver parenchyma, and black granular pigment forms. This characteristic pigment is believed to be part of the excrement of the fluke. The failure of the fluke to establish and maintain continuity within the bile duct of cattle prevents ova and excrement from escaping. In deer and moose, there is little tissue reaction, and the flukes are enclosed in thin fibrous cysts that communicate with bile ducts.

5.14.13.4 Metorchis conjunctus

Is the common liver fluke of cats and dogs in North America. Immature flukes crawl into the bile ducts from the duodenum and mature in 28 to 30 days. Infestations may persist for more than 5 years.

5.14.14 COCCIDIOSIS IN RABBITS:

Coccidiosis is one of the most common diseases of rabbits. There are two (2) forms:

• (1) hepatic coccidiosis (caused by Eimeria stiedae),
• (2) intestinal coccidosis (caused by E. magna, E.. irresidua, E. media, or E. perforans). The so-called "nasal coccidosis" is the result of rabbits contaminating the mucous membranes of their nose while practicing coprophagy.

5.14.15 HEPATIC COCCIDOSIS:

Young rabbits are most susceptible. There may be an infection with no apparent signs or death may follow a short course. Affected animals exhibit diarrhea, anorexia and a rough hair coat. Growing rabbits fail to make normal gains. At necropsy, small, grayish white nodules or cysts are found throughout the parenchyma of the hepatic tissue. These nodules may be sharply demarcated in the early stages, while in the later stages, they coalesce with other affected areas. The early lesions have a milky content, whereas older lesions may have a cheese-like consistency. Microscopically, the nodules are composed of hypertrophied bile ducts. A large number of oocysts are seen.

5.14.16 INTESTINAL COCCIDIOSIS:

This form of the disease may occur in rabbits receiving the best of care, as well as in those raised under unsanitary conditions. Inability to gain weight, anorexia, and "pot belly" are prominent clinical signs. Lesions are inconsistent; in early infections there are few changes; later, the intestine may be thickened and pale. Any of the responsible coccidia may develop in the small intestine.

5.14.17 VISCERAL LARVAL MIGRATION

Migrating larva of many nematode parasites are often responsible for liver damage. Examples of nematode parasites whose migrating larva cause hepatic injury include Ascaris suum and Stephanurus dentatus in swine and strongyles in horses.

5.14.18 NEOPLASMS OF THE LIVER AND BILE DUCTS

The liver is a frequent site of primary and metastatic neoplasms. Primary adenomas and adenocarcinomas may originate from hepatic cells or from bile ducts. Primary hemangiomas may originate in the liver. Malignant lymphoma is considered to be the most common metastatic neoplasm found in liver.

5.14.18.1 THE GALLBLADDER

Inflammation of the gallbladder and bile ducts (cholecystitis and cholangitis respectively) may result from chemical irritation by concentrated bile, bacterial infection, reflux of pancreatic enzymes, and invasion by parasites. However, in animals, inflammation of the biliary system is usually attributable to Parasites (flukes. etc.). Bacterial infection of the biliary, system is usually caused by non-specific organisms (coliforms, streptococci) which are probably of enteric origin. It should be noted that a number of bacterial species which produce a bacteremia are eliminated in the bile (Salmonella being the best known example). Remember, bacterial infections of the biliary system are uncommon in animals.

Distension of the gallbladder with viscous or "inspissated" bile occurs when a sick animal fails to eat. Remember, bile is secreted continually and stored in the gallbladder (except horses and other animals lacking a gallbladder), to be discharged when a full meal begins to reach the intestine.

5.14.18.2 CHOLELITHIASIS:

Gallstones occur infrequently in animals; however, all species may be affected. They usually form in the gallbladder and are composed of a mixture of cholesterol, bile pigments, salts of bile acids, calcium phosphate and carbonate. Such stones tend to be yellowish-black or greenish black in color, and friable. Many gallstones are silent (no symptoms produced). Occasionally, however, they lodge within and obstruct bile ducts, and in doing so, they produce jaundice.

5.15 POST-INSTRUCTIONAL SELF EXAMINATION DIGESTIVE SYSTEM: PART C

After completing this section, each student should be in a position to provide appropriate answers for the following questions.

SLIDE SESSION 5

PART C

LIVER AND BILIARY SYSTEM 

SLIDE 1: CANINE LIVER (gross): HEPATIC FAILURE SUBSEQUENT TO CIRRHOSIS - This liver is from a 12-year-old German Shepherd that died subsequent to hepatic failure. Note the small size and irregular nodular surfaces of the liver denoted in this slide. In this progressive condition, there was concurrent hepatic necrosis, regeneration, and fibrous connective tissue proliferation. Ascites was a prominent feature in this dog. (Under what circumstances would you expect "hepatic failure" to occur? What is an "end stage" liver? Would you expect icterus to be a prominent feature in this dog? Explain. How would you explain the presence of the transudate in the abdominal cavity of this dog? What is hepatic failure? What is hepatic encephalopathy? Is it possible for an animal with a liver as denoted in this slide to have hepatic encephalopathy syndrome?)

SLIDE 2: PORCINE LIVER (gross): NECROSIS OF THE LIVER (HEPATOSIS DIETETICA) - This liver is from a 6-month old pig that was receiving a ration deficient in vitamin E and selenium. In this slide, note that the liver surface is irregular and many red foci are present. The red foci represent necrotic areas within the liver. This is an example of massive necrosis in which entire lobules are necrotic (refer to slide #3).

SLIDE 3: PORCINE LIVER (gross): NECROSIS OF THE LIVER (HEPATOSIS DIETETICA) - This is a close-up of liver denoted in slide #2. Observe the well-demarcated necrotic foci. In microscopic sections, normal and necrotic lobules were observed in the same low-powered field... (Explain how massive necrosis of this nature may lead to hepatic failure. In hepatosis dietetica, would you expect to find more severe necrotic changes in the left or right lobes of the liver? Explain. What factor(s) is believed to be responsible for this disease? What is "mulberry heart diseases?").

SLIDE 4: BOVINE LIVER (gross): NECROSIS OF THE LIVER - the liver sections denoted in this slide are from a steer in which "necrobacillosis" was diagnosed. Observe the well-defined necrotic liver lesions caused by Fusobacterium necrophorus. This organism is probably a secondary invader; however its necrotizing endotoxin undoubtedly plays a role in the production of the lesions... (What is "necrobacillosis"? Name at least 3 diseases and/or conditions in which Fusobacterium necrophorus has been incriminated as a likely cause.).

SLIDE 5: OVINE LIVER (gross): CASEOUS NECROSIS OF THE LIVER (REFER TO CASEOUS LYMPHADENITIS) - This liver is from an apparently health sheep that was sent to a local slaughter plant. The lesions were caused by Corynebacterium pseudotuberculosis. (refer to the respiratory system section of this syllabus). In this slide, note the caseous areas distributed throughout the liver.

SLIDE 6: GERBIL ABDOMINAL CAVITY/LIVER (gross): NECROSIS OF THE LIVER (TYZZER'S DISEASE) - In this slide, observe the well-defined foci of coagulative necrosis in the liver; the intestine is severely hemorrhagic. Tyzzer's disease` disease is principally a disease of mice caused by Bacillus piliformis, but the condition has been reported in rats, hamsters, gerbils, rabbits, and foals. Bacillus piliformis is a slender, gram-negative rod which is an obligate intracellular parasite and which can only be grown in tissue culture. The organism appears to live as saprophyte in may mouse colonies, producing disease under various forms of stress. Clinical signs include diarrhea, humped back, and poor hair coat. Gross lesions consist of random multifocal necrosis of the liver and inflammation of terminal ileum and cecum. Microscopically, organisms (B. piliformis) are present in the vicinity of the necrotic liver foci which can be demonstrated by special stains (Giemsa, etc.)

SLIDE 7: CAPRINE FETAL LIVER (gross): NECROSIS OF THE LIVER (LISTERIOSIS) - This liver is from a caprine fetus that was aborted during the last trimester of pregnancy. A bacteremia developed in the fetus and the causative organism localized in the liver. Observe the pale necrotic foci over the liver surface.

SLIDE 8: BOVINE FETAL LIVER (gross): NECROSIS OF THE LIVER (INFECTIOUS BOVINE RHINOTRACHEITIS) - In this fetal liver, observe the multiple focal areas of necrosis. On microscopic examination, there were necrotic foci distributed throughout the liver in a random fashion... (What is the most common response of the liver to injurious agents? How would you use the following terms: hepatitis, hepatosis, focal necrosis, hepatic failure, hepatic encephalopathy)?

SLIDE 9: BOVINE FETAL LIVER (photomicrograph): NECROSIS OF THE LIVER (INFECTIOUS BOVINE RHINOTRACHEITIS) - Observe the area of necrosis in the central portion of this slide; note the more or less normal hepatic cords along the edges. This is a good example of "random multifocal necrosis." Remember, the classification of necrosis on the basic of its anatomic location (focal, midzonal, etc.) is made on microscopic examination.

SLIDE 10: CANINE LIVER (gross): INFECTIOUS CANINE HEPATITIS - Observe the congested and swollen liver. Note the thickened (edematous) gallbladder wall. (What clinical signs would you expect in this dog prior to death? What diagnostic gross lesions are expected with this disease? How would you distinguish this disease from canine distemper on the basis of gross lesions? Give the likely etiologic agent. What cells within the body are usually attacked by the etiologic agent? How would you explain the development of the so-called "hepatitis blue eyes" in dogs with this disease? What is Arthus reaction? What is Shwartzman reaction?)

SLIDE 11: CANINE LIVER (photomicrograph): INFECTIOUS CANINE HEPATITIS - In this microscopic section of the liver, observe the well-defined intranuclear inclusion bodies within hepatic parenchymal cells. Note the clear halo around the inclusions due to the margination of the nuclear chromatin. Remember, well defined random multifocal areas of necrosis are found in the liver of affected dogs. (On the basis of the inclusion bodies found within the liver, kidneys, and brain, how would you distinguish this disease from canine distemper? What are so-called Cowdry type A and type B inclusion bodies? What is fox encephalitis?)

SLIDE 12: CANINE ABDOMINAL CAVITY (gross): CANINE HERPESVIRUS INFECTION--Observe the enlarged liver and spleen; note the hemorrhage over the kidney, liver surfaces. Seven of eight pups from an infected litter died between 9 and 14 days of age. (What significant lesions are expected on microscopic examination of the kidneys, liver, and lungs? What lesions are expected in the brain. What lesions are expected in adult dogs with this disease? How can subsequent litters from the dam be protected against this disease?)

SLIDE 13: CANINE ABDOMINAL CAVITY (gross): CANINE HERPESVIRUS INFECTION - This is a close-up view of the pup denoted in slide #12. Observe the hemorrhages over the intestinal serosa and kidney capsule. Also, note the enlarged liver (rounded edges, etc.) as well as the hepatic hemorrhage. Observe closely to see pale necrotic foci in this liver. (Why would you expect hemorrhage to be associated with this condition? What etiologic agent is responsible for this disease? How would you distinguish this disease from canine distemper and infectious canine hepatitis? In what age-group would you expect the syndrome observed in this slide to occur?)

SLIDE 14: CANINE LIVER (gross): CANINE HERPESVIRUS INFECTION - Observe the enlarged liver with hemorrhages over the surface. This pup died acutely after the onset of clinical signs.

SLIDE 15: CANINE LIVER (photomicrograph): CANINE HERPESVIRUS INFECTION - In this microscopic section of liver from a pup with canine herpesvirus infection, note evidence of necrosis, disrupted and congested sinusoids, as well as well defined intranuclear inclusion bodies.

SLIDE 16: EQUINE FETAL LIVER (gross): EQUINE VIRAL RHINOPNEUMONITIS This is the liver from an aborted foal in which a diagnosis of equine viral rhinopneumonitis was made. In this slide, observe the tiny pale necrotic foci distributed over the surfaces of the liver (please refer to the respiratory system section of this syllabus). Remember, the necrotic foci within the liver may be quite tiny, and a careful examination of the organ is mandatory. (Briefly describe the syndromes, if any, caused by equine herpesviruses I, II, and III. Briefly discuss the clinical signs and gross lesions in feti, foals, and adult horses with equine viral rhinopneumonitis. What is the so-called "equine respiratory disease complex"?)

SLIDE 17: EQUINE LIVER (photomicrograph): EQUINE VIRAL RHINOPNEUMONITIS - This microscopic section, taken from an aborted equine fetus, is characterized by rather extensive necrosis, denoted by the pale areas located within the central portion of the slide.

SLIDE 18: EQUINE LIVER (photomicrograph): EQUINE VIRAL RHINOPNEUMONITIS - In this slide, you should be able to observe a few intranuclear inclusion bodies. Note the distorted hepatic cords and the congested sinusoids.

SLIDE 19: BOVINE LIVER (gross): BACILLARY HEMOGLOBINURIA - This liver is from an 8 year old Holstein bull in which a diagnosis of bacillary hemoglobinuria was made. The causative agent was recovered from the liver lesions. Observe the well defined reddened areas along the liver surfaces; these areas represent infarcts and well defined thrombi were observed within vessels. (Under what circumstances would you expect to observe red and/or pale infarcts in the liver? Give a reason(s) why infarcts are seldom observed in the liver of animals. Explain the mechanism by which liver infarcts develop in cases of bacillary hemoglobinuria. What causative agent is responsible for this disease? Briefly discuss the clinical signs and gross lesions expected in cases of bacillary hemoglobinuria.)

SLIDE 20: BOVINE LIVER (gross): BRACKEN FERN POISONING - Observe the infarcts in the liver that came from one of several steers that died from bracken fern toxicosis. Note that the larger infarct is in the process of liquifying. Remember, bracken fern is widely distributed in this country and it is a cumulative type of poisoning that requires 1 to 3 months to develop. Clinical signs may not appear until 2 or more weeks after removal of animals from bracken fern infested areas. In cattle, bracken fern poisoning results in depressed bone marrow function with a reduction of circulating platelets and leukocytes. Hemorrhage from or within various organs and tissues is a characteristic lesion. In long-term, low-level feeding of bracken fern to cattle, endemic hematuria associated with urinary bladder tumors develops. In horses, cats, and some other animals, bracken fern poisoning is manifested, due to a thiaminase activity of the plant, as a thiamine deficiency.

SLIDE 21: RABBIT LIVER (gross): TULAREMIA - Observe the multiple focal areas of necrosis (pale foci) in the liver of this rabbit. This disease is transmissible to man. (Give the likely etiologic agent. What is the public health importance of this disease?)

SLIDE 22: BOVINE LIVER (gross): ABSCESSATION OF THE LIVER - observe the abscesses in the liver of this 12-day old lamb. At necropsy, the umbilical vein was patent and its lumen was filled with purulent exudate. The animal was born and housed in a filthy barn. Based on the lesions observed, a diagnosis of "naval ill" with subsequent abscessation of the liver was made. (How would you define or describe the following: Naval ill, omphalophlebitis, abscess, embolism, pyogenic bacteria, phlegmon.)

SLIDE 23: BOVINE UMBILICAL VEIN/LIVER (gross): OMPHALOPHLEBITIS - This 6-day old calf developed an infection of the umbilical vein shortly after birth. In this slide, observe the patent umbilical vein and the purulent exudate within its lumen. This condition oftentimes results in abscessation of the liver and/or bacteremia. Remember, hepatic abscessess of omphalogenic origin are often restricted to the left lobe (but they may be restricted to the right lobe or be diffuse in their distribution.

SLIDE 24: BOVINE LIVER (gross): ABSCESSATION OF THE LIVER - This liver is from a Holstein cow that had a septic metritis; subsequently a septicemia developed and the cow died. Observe the multiple embolic abscess distributed throughout the liver denoted in this slide. (Briefly, give a likely pathogenesis for the liver observed in this slide.)

SLIDE 25: BOVINE LIVER/VENA CAVA (gross): ABSCESSATION OF THE LIVER AND SEPTIC THROMBOSIS OF THE POSTERIOR VENA CAVA - Locate and observe the abscesses present within the hepatic parenchyma. Also, note the septic thrombi located within the posterior vena cava. In this sheep, a hepatic abscess eroded into the hepatic vessels resulting in thrombosis of the posterior vena cava; sudden death is the usual sequela. (What organisms are commonly recovered from liver abscesses? What routes are commonly used by pyogenic organism to reach the liver? Briefly, discuss the effects of liver abscess on hepatic function.)

SLIDE 26: BOVINE LIVER (photomicrograph): ABSCESSATION OF THE LIVER This microscopic section of the liver is characterized by a heavy accumulation of neutrophils. (What type necrosis is denoted in this slide?)

SLIDE 27: CANINE LIVER (gross): HISTOPLASMOSIS - This enlarged liver (note the rounded edges) is from a dog infected with Histoplasma capsulatum. This was a fatal systemic disease and treatment was not effective.

SLIDE 28: CANINE LIVER (photomicrograph): HISTOPLASMOSIS - In this microscopic liver section, there are numerous irregular, egg-shaped, yeast-like bodies within the cytoplasm of Kupffer and hepatic parenchymal cells. Remember, histoplasmosis is one of the most frequently encountered systemic fungal diseases in dogs and man. The disease is characterized by extensive proliferation of reticuloendothelial cells.

SLIDE 29: EQUINE LIVER (gross): EQUINE INFECTIOUS ANEMIA - This liver is from a horse with subacute to chronic equine infectious anemia. Observe the enlarged, dark-brown liver with well-defined lobular markings. Such liver lesions along with typical clinical signs would suggest equine infectious anemia as a differential diagnosis. Note the fibrous tags over the liver surfaces which are most likely due to migrating parasites. Equine infectious anemia is an acute, subacute, or chronic viral disease of horses. Once infected, the virus remains within leukocyte of the horse for life.

SLIDE 30: EQUINE BONE MARROW (gross): EQUINE INFECTIOUS ANEMIA - This 6 year old Quarter horse died subsequent to equine infectious anemia. Observe the red bone marrow which is replacing the yellow bone marrow in this long bone. (Under what circumstances would you expect bone marrow hyperplasia to occur? Define the following terms: hyperplasia, hypoplasia, metaplasia, atrophy, and anaplasia.)

SLIDE 31: EQUINE LIVER (photomicrograph): EQUINE INFECTIOUS ANEMIA Observe the accumulations of reticulo-endothelial cells within sinusoids of the liver; this lesion occurs in the subacute and chronic forms of the disease. A tentative diagnosis of equine infectious anemia can be confirmed by the Coggin's test (immunodiffusion test). There is no treatment or vaccine available for the disease.

SLIDE 32: BOVINE FETUS ABDOMINAL CAVITY (gross): EPIZOOTIC BOVINE ABORTION - Note the blood tinged fluid in the abdominal and thoracic cavities. Also observe the mottled and enlarged liver (see slide 33). Epizootic bovine abortion (chlamydial abortion, foothill abortion) is an infectious disease of cattle caused by a strain of Chlamydia psittaci, and characterized by abortion between the 5th and 7th months of gestation. The disease has been reported primarily from the western portion of the U.S.

SLIDE 33: BOVINE FETAL LIVER (gross): EPIZOOTIC BOVINE ABORTION - Observe the enlarged liver with a roughened or granular surface. Microscopically, there was a diffuse proliferation of reticuloendothelial cells.

SLIDE 34: BOVINE FETAL LIVER (gross): EPIZOOTIC BOVINE ABORTION - The incised surface of this liver is characterized by multiple focal areas of necrosis.

SLIDE 35: PORCINE LIVER (gross): CHRONIC SCLEROSING HEPATITIS - This liver is from a pig that died subsequent to a prolonged illness. Observe the enlarged, pale, firm liver with whitish areas over the surface that denote connective tissue proliferation.

SLIDE 36: PORCINE LIVER (gross): CHRONIC SCLEROSING HEPATITIS - Observe the marked proliferation of fibrous connective tissue over the surface of the liver. The liver was initially damaged by migrating ascarid and stephanurus larvae. It is now in the stage of repair by connective tissue replacement.

SLIDE 37: CANINE ABDOMINAL CAVITY (gross): CIRRHOSIS OF THE LIVER AND ASCITES - Observe the small nodular liver and the heavy accumulation of a transudate in the abdominal cavity. Apparently, an irritant initiated the cirrhotic changes; however, a specific etiologic agent was not identified. No heart lesions were observed. (Give a likely pathogenesis for the alterations observed in this slide. What changes are expected in the spleen? How would the hepatic lesions interfere with the flow of blood to the heart? How would you explain the ascites?)

SLIDE 38: CANINE LIVER (gross): CIRRHOSIS OF THE LIVER - Observe the extensive nodularity and atrophy of the liver. The liver architecture is distorted. (How would you characterize a cirrhotic liver? How would you distinguish a cirrhotic liver from one that is merely fibrotic? Would you expect hepatic failure in this dog? What are some common causes of cirrhosis?)

SLIDE 39: EQUINE LIVER (gross): CIRRHOSIS OF THE LIVER (SENECIO POISONING) - This liver is from a horse that died subsequent to receiving senecio that was accidentally mixed with alfalfa that was fed by the owner. Observe the nodular and fibrous liver. At necropsy, the liver was smaller than normal. (What toxic principle is responsible for the liver lesions? What other plants are capable of producing similar lesions? What is pyrrolizidine toxicosis? Would you expect to observe CNS signs in this animal? Explain. Why would portal hypertension be expected in this horse? Explain.)

SLIDE 40: EQUINE LIVER (gross): CIRRHOSIS OF THE LIVER (SENECIO POISONING) - This is a cut surface of the liver denoted in slide #39. Observe the proliferating connective tissue as well as the nodular appearance of the hepatic parenchyma which is otherwise more or less relatively normal in appearance. The connective tissue originated in periportal areas. (What is portal cirrhosis? How would you describe a "hobnail" liver? How would you describe a "nutmeg" liver? Would you expect to observe hyperplasia in this liver on microscopic examination? Explain. Briefly explain and /or describe biliary cirrhosis and post-necrotic cirrhosis. What toxic principle is responsible for the liver lesions in poisoning by Crotalaria, Senecio, Amsinckia, and Lantana? What skin changes are likely to occur in the above horse?)

SLIDE 41: EQUINE LIVER (photomicrograph): CIRRHOSIS OF THE LIVER (SENECIO POISONING) - In this microscopic section, observe the distorted hepatic cords, the proliferation of fibrous connective tissue, and the hypertrophic/hyperplastic hepatic cells. These changes were rather diffuse throughout the liver. (Briefly, describe the microscopic changes expected in cases of portal and biliary cirrhosis.)

SLIDE 42: PORCINE LIVER (photomicrograph): CIRRHOSIS OF THE LIVER - This is an example of biliary cirrhosis that resulted from the presence of ascarids within bile ducts. In this slide, observe the proliferation of bile ducts as well as the increased fibrous connective tissue.

SLIDE 43: BOVINE LIVER (gross): "SAWDUST LIVER" - This liver is from a 12-month old steer which was in good general condition at the time of slaughter. Observe the yellowish foci of coagulative necrosis over the liver surface. (Give a likely etiologic mechanism for this condition. What is the likely interrelationship between the lesions observed in this slide and telangiectatic lesions and liver abscesses?)

SLIDE 44: BOVINE LIVER (gross): "SAWDUST LIVER" - This is a close-up view of the so-called "sawdust lesions" in the liver of a steer. Observe the well-defined yellowish foci. (What type of necrosis is denoted in this slide?)

SLIDE 45: BOVINE LIVER (gross): "SAWDUST LIVER" - This is an incised surface of the liver denoted in slide #43. Observe the yellowish foci deep within the liver parenchyma.

SLIDE 46: BOVINE LIVER (gross): TELANGIECTASIS OF THE LIVER - Observe the tiny well defined spots or foci over the liver surface. These lesions represent small groups of dilated sinusoids. (What is telangiectasis? Discuss the occurrence and significance of these lesions in cattle.)

SLIDE 47: BOVINE LIVER (gross): TELANGIECTASIS OF THE LIVER - The capsular as well as the incised surface of a telangiectatic liver are denoted in this slide. Note the well-defined lesions.

SLIDE 48: EQUINE LIVER (gross): FATTY CHANGE IN THE LIVER - This is an enlarged liver from a horse that died subsequent to acute toxic hepatitis of unknown cause. Grossly, the liver was characterized by severe fatty changes; the incised surfaces obviously bulged. Also, note the foci of connective tissue replacement that occurred subsequent to the migration of parasitic larvae.

SLIDE 49: BOVINE ABDOMINAL CAVITY (gross): FAT COW SYNDROME - This cow was fed a high CHO diet during the early stages of gestation and developed the so-called "fat cow syndrome" or "pregnancy toxemia". Observe the heavy accumulation of fat in the liver as well as in the abdominal cavity. (Briefly, discuss the causes and/or predisposing factors associated with this condition. What clinical signs are expected in this cow? What significant clinical pathologic findings would you expect? Briefly, discuss the gross findings expected in this case of fat cow syndrome.)

SLIDE 50: BOVINE LIVER (gross): FAT COW SYNDROME - Because of the heavy accumulation of fat within hepatic cells, the incised surface of this liver tended to bulge. (How would you distinguish this fatty liver from one that discolored by bile or carotine? Is this a reversible or alterations expected in a fatty liver?)

SLIDE 51: BOVINE KIDNEY/PERIRENAL FAT (gross): FAT COW SYNDROME - In this slide, observe the heavy accumulation of fat around the kidney. (What is an obese animal? What is a thin animal? Briefly explain how the so called fat cow syndrome develops.)

SLIDE 52: BOVINE LIVER (gross): FATTY CHANGE: Observe the small section of liver floating in the container of water. (Why would you expect a severely fatty liver to float in water?)

SLIDE 53: BOVINE LIVER (photomicrograph): FATTY CHANGE - In this microscopic section, observe the well defined vacuoles located within the cytoplasm of hepatic cells. (Briefly describe the methods and/or pprocedures that you would employ in order to confirm the presence of fat within the hepatic cells. How would you distinguish fat within hepatic cells from hydropic change or the accumulation of glycogen.).

SLIDE 54: BOVINE LIVER (photomicrograph): FATTY CHANGE - This is a higher magnification of the liver denoted in slide #53. Observe the large fat vacuoles and the displaced nuclei. (Discuss the causes of fatty changes in the liver and other organs.)

Slide 55: CANINE LIVER (gross): CHRONIC PASSIVE CONGESTION OF THE LIVER - This is an example of chronic passive congestion of the liver. Note the intense congestive changes as well as the irregular or granular surfaces. This dog died subsequent to right sided heart failure due to severe dirofilariasis. (What is a "nutmeg liver?" Would you expect to observe lesions similar to those denoted in this slide in cases of severe left sided heart failure? Explain.)

Slide 56: CANINE LIVER (photomicrograph): CHRONIC PASSIVE CONGESTION OF THE LIVER - In this slide, notice the increased fibrous connective tissue around the central vein. Also, the sinusoids are distended with blood.

SLIDE 57: CANINE LIVER (gross): NODULAR HYPERPLASIA OF THE LIVER - This liver from an aged dog has multiple hyperplastic nodules. The cause of this condition is poorly understood.

SLIDE 58: DUCK LIVER (gross): AMYLOIDOSIS OF THE LIVER - This liver is from a duck that was experimentally subjected to the stress of over-crowding. A large percentage of the birds maintained under these conditions developed amyloidosis with involvement of various organs and tissues. In this slide, observe the enlarged, waxy liver. (What is amyloid? Distinguish primary from secondary amyloidosis. How would you make a tentative diagnosis of amyloidosis at the time of necropsy?)

SLIDE 59: DUCK LIVER/SPLEEN (gross): AMYLOIDOSIS - In this slide, amyloidosis of the liver and spleen is denoted. Note the characteristic appearance of the organ (incised surfaces).

SLIDE 60: CANINE LIVER (photomicrograph): AMYLOIDOSIS - In the slide, observe the homogeneous deposits of amyloid between the atrophic hepatic cords. Compare normal and abnormal areas. (What special stains are employed to confirm the presence or amyloid within tissues?).

SLIDE 61: EQUINE (FOAL) ABDOMINAL CAVITY (gross): RUPTURE OF THE LIVER - This foal was kicked by its mother and died acutely. Observe the well-defined rupture and/or tear in the liver as well as the accumulation of blood in the abdominal cavity... (How would you explain the death of this foal? In your opinion, did this foal die subsequent to shock? Explain. What is hemoperitoneum? Please define the following: Ascites, hydroperitoneum, rupture, exsanquination.)

SLIDE 62: CANINE LIVER (gross): RUPTURE OF THE LIVER - Prior to being involved in an automobile accident, this dog had a condition known as right-side heart failure due to dirofilariasis. In this slide, observe the large blood clot that originated from a tear in the liver parenchyma. Also, note the nodular and/or roughened surfaces that developed subsequent to the heart lesions. (Briefly, give a likely pathogenesis for the lesions observed in the liver of this dog.).

SLIDE 63: CANINE LIVER (gross): TORSION OF A LIVER LOBE - Observe the hemorrhagic and necrotic lobe of the liver that was twisted at the time of necropsy. The exact cause of this condition was not determined.

SLIDE 64: BOVINE (calf) LIVER (gross): CONGENITAL LIVER CYST - Note the large congenital cyst attached to the liver (distinguish the cyst from the gallbladder). This was an incidental finding.

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