PATHOLOGY OF THE LIVER

General comments Normal structure and function The liver has a central role in metabolism. It is responsible for much of the protein (including clotting proteins) production in the body; it has a role to play in digestion in fats in the gut; it is an essential organ in carbohydrate-lipid metabolism and storage; and it is a key organ for detoxification and excretion of harmful waste products. As a consequence, hepatocytes are highly metabolically active and require sufficient amounts of oxygen and nutrients to perform their functions. The downside of this is that deficiencies easily damage hepatocytes. Moreover, hepatocytes are frequently coming in contact with blood borne poisons and toxins, some of which can cause degeneration and necrosis. The structure of the liver can be understood on the basis of these functions: 1. The liver has a dual blood supply - portal vein tributaries primarily bringing in the products of gut assimilation (including potential poisons) and blood from the spleen; and hepatic artery tributaries providing relatively high oxygen blood. Branches of both of these vessels can be seen microscopically in areas referred to as portal areas accompanying biliary ducts (hence the name portal triads). The two systems mix when they enter sinusoids which are vessels surrounding, and in intimate contact with, plates of hepatocytes. Blood from the sinusoids drains to small microscopic branches of hepatic veins called central or centrilobular veins. Arterial blood provides oxygen and nutrients to all parts of the liver whereas portal venous blood has a greater impact on hepatocytes. The dual blood supply of the liver is essential for its function and also means that infarction is relatively rare in this organ. The sinusoids have leaky walls which allows blood plasma (with nutrients) to pass into surrounding spaces called Disse's spaces which are in direct contact with hepatocytes. Once the hepatocytes have extracted what they wish, excess fluid in Disse's spaces travels to portal areas and enters lymphatics. Lymphatic fluid from the liver is protein rich compared to lymphatic fluid in other parts of the body, and any interference in lymphatic drainage or increased production of lymph in the liver may spill over to the abdomen causing a high protein effusion. Hepatic stellate cells (cells of Ito) are also present in the Space of Disse. These cells are involved in storage of Vitamin A and contain fat vacuoles, however, are also able to proliferate and transform into a myofibroblast morphology and are the major source of collagen and fibrosis in the repair process. 2. Bile (consisting of some detoxified waste products such as bilirubin and cholesterol, and bile acids to facilitate fat and fat soluble vitamins assimilation in the gut) is primarily produced by hepatocytes and secreted into surrounding microscopic bile canaliculi. These flow into small bile ducts present in portal areas. Apparent contractions of hepatocytes assist with this flow and, consequently, damage to hepatocytes will slow down bile movement. Bile eventually makes it way into the duodenum but can be

stored in a gall bladder in most species prior to release. Note that the horse and rat do not have gall bladders.

Any interference with bile flow (from the level of the hepatocyte to its entry into the gut) is referred to as cholestasis. Often cholestasis is referred to as intrahepatic or extrahepatic in origin. Jaundice is often referred to mechanistically as pre-hepatic, hepatic or post-hepatic in origin. 3. The microscopic unit of structure of the liver refers to the minimum functional unit. Classically this was the lobule with the central vein (centrilobular area), surrounding cords and plates of hepatocytes and peripheral portal areas (portal triads). This unit is easy to see microscopically but is not truly representative of a functional unit as blood supply is from several portal areas. Therefore, the acinus structure has been suggested. This has a portal area as the centre (usually represented as a length of

vessels) and two central veins at the periphery. Consequently, blood flows outwards through the sinusoids to the central veins while bile flows to the central portal area. This has implications for hepatocytes for function and disease. The hepatocytes immediately surrounding the portal region are in zone 1 and are bathed in blood high in nutrients and oxygen causing them to be metabolically active. Poisons from the portal blood contact these hepatocytes first. Regenerative capacity after injury is high in this zone. Hepatocytes in zones 2 and 3 (closest to the central veins) are more susceptible to hypoxia as they are presented with lower oxygen anyway. Moreover, some of these hepatocytes are particularly susceptible to certain poisons as they contain microsomal enzymes which are involved in poison metabolism (in some cases the initial substance is not toxic to the cell but the intermediate product formed through metabolism). 4. The liver plays a role in erythrodynamics and, in many species, general haematopoiesis. Erythrocyte aging and breakdown is the key source of bilirubin from haemoglobin metabolism. In excess red cell breakdown (haemolysis) iron from haemoglobin may be deposited in hepatocytes as haemosiderin. Macrophages that line the sinusoids, called Kuppfer cells, can also accumulate iron and may in fact contribute to excess erythrocyte breakdown if erythrocytes are abnormal (ie Kuppfer cells have a general scavenging role). In addition, in times of increased need for erythrocytes, leucocytes or platelets, the liver can be involved in extramedullary haematopoiesis. Extramedullary erythropoiesis is most common and groups of erythroid cells can be seen microscopically adjacent to sinusoids. Disease of the liver Liver disease can be clinical or subclinical. Subclinical disease (ie not severe enough to produce overt signs of liver dysfunction) can sometimes be detected by examining blood for changes in chemicals related to hepatocyte metabolism eg increase in an enzyme such as alanine transaminase due to hepatocyte damage. Subclinical disease can be progressive and produce clinical disease and ultimately liver failure. This does not always happen as the inflammatory response can remove debris and agents of disease, and the liver has a tremendous capacity for regeneration of hepatocytes following injury. Liver failure refers to the situation where the liver can no longer perform normal functions to maintain life. It can be acute or chronic. Acute liver failure occurs with overwhelming destruction of hepatocytes in a short period of time eg toxic insult, bacterial or viral infection. If the animal can be kept alive in the short term with supportive therapy and removal of any agent of disease, then it is possible that the hepatocytes will regenerate to the level to restore adequate function. In contrast, chronic liver failure means end stage disease as surviving hepatocytes can not cope with the functional demands and regenerative capacity is markedly diminished. For chronic liver failure to occur, 80-90% of hepatocytes have to be destroyed or removed ie the reserve capacity of the liver is enormous. Of course, clinical signs of liver disease may occur with less damage and will be mentioned later.

Liver disease can be primary (an agent of disease specifically targeting the liver) or secondary to diseases elsewhere in the body. Secondary liver diseases can occur in relation to endocrinopathies such as diabetes mellitus where fat accumulates in the liver; or they may occur due to other abdominal organs impinging on and occluding the common bile duct eg pancreatic or intestinal neoplasms or granulomas. Irrespective of whether the liver disease is primary or secondary, it can have similar effects on the animal and is investigated in the same manner. Liver diseases (hepatopathies) have numerous causes and can have a variety of appearances but they will produce a limited number of clinical and laboratory signs of disease. A specific diagnosis of the type of liver disease usually requires histological/cytological examination of the liver by biopsy or at necropsy. The following information is grouped according to specific diseases or changes in liver rather than according to the clinical signs produced. The final section will, however, comment on specific clinical and laboratory signs of liver disease.

Degeneration and Necrosis As mentioned previously, hepatocytes are particularly susceptible to a range of poisons, hypoxia, and disturbances of carbohydrate/lipid metabolism. Degeneration involves changes in the cytoplasm and can be reversible up to a point. Past that point cells undergo necrosis with changes in both the cytoplasm and nucleus. There is some overlap between degenerative changes and deposits and pigments (see next section). Fatty change (hepatic lipidosis) is a common degenerative change to the liver and can be caused by hypoxia (eg heart failure), an imbalance of nutritional and metabolic factors (eg high fat diets, starvation, endocrinopathies), bacterial toxins and various endogenous and exogenous poisons. It commonly involves enlargement of the liver (hepatomegaly) and microscopically is characterised by variably sized droplets of fat within the cytoplasm of hepatocytes. If the degeneration is severe, some cells may be necrotic. if the degeneration is mild, and if the agent of disease is removed, then the cells will recover. Remember that not all fatty livers are abnormal, for example, the pre-weaned animal will commonly have a liver with lots of fat due to simple accumulation for metabolic requirements. In summary, fatty accumulations and fatty degeneration within hepatocytes can be attributed to a couple of basic mechanisms; either the hepatocyte is overwhelmed by the amount of fatty acids to metabolise, or cell damage limits metabolic processes, or cell damage limits the export machinery i.e. 1. fatty acids entering liver a. Diet high in fatty acids b. mobilisation of fat due to starvation or metabolic derangement 2. CHO intake in the diet 3. Hepatocellular injury a. apoprotein synthesis (due to membrane damage)

b. lipoprotein export (due to energy production & membrane damage)

Feline Idiopathic Hepatic Lipidosis This is a distinct syndrome of idiopathic hepatic lipidosis in cats. Cat affected by this are usually obese and anorectic with no other observable disease process responsible for the fatty degeneration of hepatocytes. These cats have enlarged jaundiced friable livers with an accentuated lobular pattern on capsular and cut surface. The liver usually has a greasy texture and float in 10% formalin. Cats of any age or either sex may be affected. There are regional differences in prevalence. It is a common disease in North America, less common in Europe and even less common in the United Kingdom. It is not that common in Australia. It is possible that these regional differences are due to genetic differences in the cat population or dietary differences. Typically these cats have a poor prognosis despite intensive supportive therapy, with only about 50% surviving. Therapy should be aimed at reversing the catabolic state by force feeding or feeding via nasogastric tube with a high quality protein source. Restoration of normal hydration and electrolyte balance is important. Other types of degeneration, such as hydropic change, are not common and not easily detected. Glycogen accumulation in hepatocytes can be loosely called a degeneration if it is excessive and causes hepatomegaly. This may occur in hyperadrenocorticism in the dog, iatrogenic, pituitary dependent or adrenal dependent. Like fatty change, necrosis can be caused by a wide variety of disease agents. Necrosis can progress from initial fatty change or be preceded by another form of degeneration. It can occur in certain patterns in the liver such as focal necrosis (scattered foci due to bacterial infection or parasite migration), centrilobular (periacinar) necrosis (often due to hypoxia/anoxia such as in cardiac failure or due to direct effect of certain poisons), periportal necrosis (zone 1 hepatocytes around portal triads are preferentially selected; and can occur due to certain poisons or due to inflammation centred around portal triads), and massive necrosis (a number of connecting whole acini are affected; and can occur due to bacterial or parasitic infections, or due to particular poisons). Other patterns of necrosis do occur but are not common. Bridging necrosis refers to the confluence of areas of necrosis and may link centrilobular areas or periportal areas. It can be followed by bridging fibrosis which is usually a prelude to cirrhosis. Pyrrolizidine Alkaloidosis Many different plants contain this family of alkaloids, of which there are over 100 different recognised types. Some of the best known plants containing these toxins include Senescio spp. (Fireweed), Crotolaria spp., Heliotropium spp. and Echium spp (Pattersons Curse). The toxic effects depend on the alkaloid present, the species of animal and the duration of the toxic insult. Pigs are the most susceptible of the domestic herbivores, while sheep and goats are the most resistant and horses are more susceptible than cattle. Typically the plant alkaloid is converted to a pyrrolic ester by the livers P450 cytoc hrome system. These

pyrrolic esters are alkylating agents which can react with nuclear constituents (antimitotic effect but still allowing DNA replication) and cytoplasmic constituents (coagulation necrosis). This leads to the characteristic microscopic lesions of megalocytosis and hepatic necrosis. Megalocytes are hepatocytes that have survived, attempted to replicate and become larger, with nuclei and cytoplasm up to ten to twenty fold greater in volume than normal. Megalocytosis, however, is not pathognomonic as it can be induced by aflatoxins and nitrosamines and other alkylating agents. In addition to the presence of megalocytes, chronically affected animals likely have hepatic fibrosis, biliary duct proliferation and may or may not show nodular regeneration. Chronic hepatic changes may well lead to hepatic failure including jaundice, hepatic encephalopathy and photosensitisation. Tissue Deposits & Pigmentations Deposits in the cytoplasm of hepatocytes can be related to disease eg excess iron in chronic anaemias; lipofuscin in chronic disease but they can also occur due to diet e.g. copper storage and melanosis. Melanosis in sheep in western NSW is the deposition of a melanin-like pigment associated with the ingestion of certain pasture plants. Dont forget about cholestasis and the accumulation of bile pigments. Amyloid is a deposit that usually occurs outside hepatocytes, in the Spaces of Disse and elsewhere. It is commonly related to chronic disease associated with antigenic stimulation (although there are some familial forms recorded in animal species as well as course) and can lead to pressure atrophy of hepatocytes and even necrosis. In the cat it can give rise to fatal abdominal haemorrhage due to increased fragility of the liver capsule. Amyloidosis of the liver is usually accompanied by amyloid deposits in other organs, including the kidneys and pancreatic islets with associated clinical signs of organ dysfunction. Note that there are a number of described heritable lyposomal storage diseases of domestic animals, many of which also manifest themselves in accumulation of intracellular substances in hepatocytes although clinical signs are often the result of neuronal dysfunction. Storage diseases in general, represent absence or dysfunction of lysosomal enzymes resulting in the accumulation of metabolites in lysosomes. Copper Storage Diseases Copper is transported bound to caeruloplasmin and within the cell is bound to metallothionein. Initially copper excess is distributed throughout the cytoplasm but eventually aggregates into lysosomes causing a refractile granular golden-brown pigmented histologic appearance. Excess copper can induce production of free radicals, leading to membrane disruption. Sheep are particularly prone to inappropriate hepatic copper storage because of limited biliary excretion of copper in this species. There are four main scenarios through which chronic copper accumulations occur in hepatocytes causing hepatic dysfunction. 1. Hereditary disorders of Copper metabolism of Bedlington and West Highland White Terriers. In the Bedlington Terrier, this is an autosomal recessive heritable disease of impaired biliary excretion of copper, leading to copper accumulation within hepatocytes. This leads to hepatocellular necrosis. The tissue damage results in an inflammatory response, which becomes chronic in the face of continuing hepatocellular damage, leading to fibrosis and alteration of lobular structure and eventually hepatic failure.

2. Herbivores grazing on pastures with a soil deficiency of Molybdenum but normal copper levels. These pastures selectively absorb copper leading to excessive intake of copper by the grazing animal. 3. Herbivores grazing pastures containing hepatotoxins (usually pyrrolizidine alkaloids). Because copper is normally excreted in bile, any disease causing chronic cholestasis may produce excessive storage of copper within hepatocytes. In sheep, copper accumulation can occur chronically due to the latter two scenarios, but an event may precipitate sudden release of copper leading to acute, severe intravascular haemolysis and hepatocellular necrosis (which may affect predominantly periacinar and midzonal hepatocytes or the whole lobule). 4. Simple dietary excess has been documented in a number of species including sheep oversupplemented and dogs accessing copper compounds. Note that acute copper toxicity can also occur (usually due to the 4th category above), with non-specific periacinar hepatic necrosis, acute gastroenteritis and intravascular haemolysis.

Inflammatory Disease Inflammation involving the plates of hepatocytes is called hepatitis. This term is used when inflammatory cells are the main component of the liver reaction or when an infectious agent is known to be present. Some infectious agents cause death so quickly that inflammatory cells are few as they have little time to accumulate eg viral hepatitis, some bacterial infections. However most infectious agents take time to cause death, therefore strong inflammation will be present at least in some areas. For example, if examining a biopsy or necropsy tissue from a bacterial hepatitis, there may be a variety of lesions ranging from simple focal necrosis with no inflammatory cells, to intermediate lesions with many inflammatory cells, to later lesions with fibrosis and attempts at regeneration. Other forms of inflammation of the liver include cholangiohepatitis (inflammation of bile ducts and hepatocytes) and cholangitis (inflammation primarily affecting the biliary system). Cholangiohepatitis and cholangitis can be due to parasites (both multicellular, such as liver flukes, and protozoal, such as coccidia), due to ascending bacterial infections from the gut or be idiopathic in nature (as in the relatively common cholangitis/cholangiohepatitis syndrome in cats). Cholecystitis refers to inflammation of the gall bladder and may accompany cholangitis or be a distinct entity.

Blacks Disease This is a clostridial disease most common in sheep and cattle, although can occur in other species. It is caused by Clostridium novyi. Clostridial spores lodge in the hepatic sinusoids. Germination is stimulated by reduced oxygen tension, with the subsequent release of toxins that cause foci of hepatocellular necrosis. The initial stimulus for germination is usually provided by the necrosis caused by migrating liver fluke

Fasciola hepatica, however, any cause of massive hepatic necrosis will generate the right conditions for this clostridial disease. Necropsy examination may reveal 1 or more pale areas of hepatic necrosis surrounded by an area of hyperaemia, visible tracts of migrating liver fluke and evidence of widespread congestion including increased amounts of pericardial, pleural and peritoneal fluid.

Infectious Canine Hepatitis ICH is caused by Canine Adenovirus 1 (CAV1). This is not a common disease anymore with the high prevalence of vaccination; however, it will be seen on occasion in unvaccinated dogs. It is also necessary for clinicians to be aware of the nature of the common vaccines against this disease and their suitability for use in pregnant bitches. CAV-1 has a tropism for hepatocytes and vascular endothelium; therefore the two most common clinical manifestations of this disease are massive hepatic necrosis with subsequent acute hepatic failure and DIC. Grossly, the liver is enlarged and friable with a distinct yellow discolouration with patchy pale areas of necrosis (mainly periacinar necrosis). An accentuated lobular pattern may be evident. The characteristic lesion of ICH is the presence of eosinophilic intranuclear viral inclusion bodies in hepatocytes. These may also be detected in vascular endothelial cells. Puppies often die quickly from the disease whereas older dogs often survive and the severity of lesions depends on the clinical course of the disease. A noted finding is the propensity to corneal oedema (blue eye) in survivors. This is caused by an immune complex uveitis (type III hypersensitivity or Arthus reaction) which causes degeneration of the corneal endothelium. This may sometimes be seen in vaccinated animals.

Cholangitis/Cholangiohepatitis in Cats Cats can be affected by either acute neutrophilic cholangitis or chronic lymphocytic cholangitis. acute neutrophilic cholangitis is induced by an ascending bacterial infection of the biliary tract (usually a coliform) with a suppurative inflammatory response centred on the portal triads and neutrophils even present in the biliary lumen. These cats are usually jaundiced and have a 1-3 week history of malaise with or without fever. Chronic cholangitis/cholangiohepatitis may be the chronic sequela to unresolved acute cholangitis, however, the pathogenesis is unclear. There is usually no observed acute phase of the disease. These cats are usually older than 4 years of age. The bile is sterile, hepatomegaly is usually present (although some cases can progress to cirrhosis), cholestasis evident, rarely ascites or hepatic encephalopathy. The main finding is a lymphocytic infiltrate of the periportal region with variable numbers of plasma cells and in some cases eosinophils. Neutrophils are not a feature of the inflammatory infiltrate in this condition. Diagnosis depends on histopathology.

Parasitic Hepatopathies

The most important parasitic diseases affecting the liver are the encysted stages of the cestodes Taenia spp. (Cysticercus spp.) and Echinococcus granulosus (hydatids) found in intermediate hosts, and the trematode Fasciola hepatica (liver fluke). Migrating cysticerci and liver fluke can cause extensive damage to the liver, although hydatid cysts rarely cause clinical signs of liver disease.

Consequences of Liver Damage These remarks generally apply to disease caused by either poisons/hypoxia or infectious agents. The liver has only a limited number of ways that it can respond to damage and its response to injury usually takes much the same form no matter what the agent of disease. The exact course of the response can be altered by the chronicity of damage and to some extent the nature of the agent itself. The basic pattern of response is as follows. 1. 2. 3. 4. 5. Degeneration & Intracellular Accumulation Necrosis Inflammation Regeneration Fibrosis

As mentioned previously, damaged liver parenchyma has a strong capacity to regenerate. This is irrespective of what is causing the damage. However, the overall impact of a disease agent on the liver will depend on the type of disease agent, the extent of damage, and the time course of damage. An acute single toxic insult that perhaps principally causes periacinar (centrilobular) necrosis but no loss of architecture of the acini can recover completely over a period of time with the liver looking normal grossly and microscopically. The necrotic cells are washed away by the blood or are degraded by local macrophages. Because the connective tissue framework of the acinus is still intact, new hepatocytes are produced, usually from zone 1, which 'migrate' along the connective tissue framework to replace those hepatocytes lost. Of course this is an ideal situation. In most cases, some acini are distorted but grossly the liver still appears normal In a single episode of massive damage or due to repetitive or prolonged periods of damage, regeneration (if the animal lives) is accompanied by degrees of liver fibrosis. This is because the basic architecture of acini have been severely disrupted. the fibrous tissue may be derived from the collapsed connective tissue framework of the acini or be newly formed fibrous tissue. The fibrous tissue obviously distorts the liver so that it can be seen grossly. The fibrosis pattern will vary with the cause of disease. Small numbers of inflammatory cells may accompany the fibrosis unless an infective agent is involved and still present when inflammatory cells become a significant component.

Simple fibrosis due to poisons or hypoxia is theoretically reversible up to a point but it can also be progressive (as can fibrosis in chronic infections) and contribute to a condition of cirrhosis (the term is most commonly used in relation to chronic alcohol poisoning in people). Cirrhosis is defined as a self perpetuating condition of the liver characterised by varying degrees of fibrous tissue, inflammatory cells, regeneration and degeneration. The regeneration is often in the form of distorted (and often non-functional) nodules, while degeneration is ongoing primarily due to interference with blood supply via continuing fibrosis. It is non-reversible and will ultimately lead to liver failure. In the earlier stages it can lead to portal hypertension (increased pressure in the portal venous system - can also be caused by simple fibrosis and certain other conditions affecting blood flow through the liver such as neoplasia). Prolonged portal hypertension can lead to ascites, splenomegaly and portosystemic shunting of blood which will be discussed later. By this time it is difficult to determine the cause of the cirrhosis (as is the case for all chronic conditions, unless, of course, the agent of disease can be detected in the tissue).

Vascular Conditions Important specific vascular conditions of the liver include acute and chronic congestion of the liver and congenital and acquired shunting of blood. Telangiectasis (peliosis) can affect the liver and is thought to be due to dilated or damaged sinusoids giving rise to blood filled spaces. In cattle they may be visible grossly but they have little functional significance. Acute heart failure or shock will give rise to marked congestion of the sinusoids of the liver. Haemorrhage may occur from the sinusoids and some periacinar hepatocytes may be necrotic. Grossly the liver will be enlarged due to engorgement with blood. This is not as common as chronic congestion of the liver which commonly occurs due to prolonged right-sided heart failure. In chronic congestion, hypoxia leads to periacinar hepatocyte (zone 3) atrophy, degeneration and necrosis with consequent dilation and congestion of hepatic sinusoids with red cells (therefore centrilobular areas grossly appearing red) and fatty change in periportal /zone 1 hepatocytes, causing this area to appear pale or yellow. Increased lymph production may lead to ascites. Grossly the liver may be normal in size or slightly enlarged, and has a so-called 'nutmeg' appearance due to dark red congested periacinar regions alternating with paler (fatty) periportal areas. As the condition progresses, fibrosis increases as dying hepatocytes are not replaced, and this may grossly distort the congested liver.

Portosystemic Shunts (PSS) PSS can be acquired or congenital. Shunting of more than 10% of portal blood flow away from the liver is considered abnormal. Acquired PSS are generated by portal hypertension. Portal hypertension is caused by post-hepatic pathology (e.g. obstruction to the Hepatic vv.), intra-hepatic pathology restricting blood flow through the

sinusoids (e.g. cirrhosis) or prehepatic pathology (e.g. obstruction/thrombosis of the Portal V.). Increased pressure within the Portal vv. leads to venous anastomoses between the mesenteric vv. and the Caudal Vena Cava. These are usually numerous. Additionally, because Portal hypertension is present, ascites is also likely to be present. Acquired PSS is usually not amenable to correction unless the underlying cause can be removed. Congenital PSS can be either intra-hepatic or extra-hepatic, however, are usually limited to a single vessel. In large breed dogs, this is often a persistent ductus venosus (i.e. intrahepatic), whereas in small breed dogs and cats it is usually extrahepatic and may involve connections between the Portal V and the Caudal Vena Cava or the Portal V and the Azygous V. There is no Portal hypertension associated with congenital PSS, therefore, ascites is not a feature of this disorder. Affected animals are usually stunted and often have signs of hepatic encephalopathy. The liver is reduced in size, having failed to develop because of reduced blood flow, and may exhibit lobular atrophy but most importantly, histologically, may exhibit duplication of the Hepatic arterioles in the Portal triads with small or absent Portal venules. The actual vascular anastomoses of portosystemic shunting, be it acquired or congenital, is difficult to identify post-mortem. Note that with PSS there will be histological (at least) evidence of a circulatory disturbance of the liver with centrilobular (periacinar) degeneration and necrosis and possibly fibrosis, depending on the chronicity of the lesion.

Neoplasia Primary neoplasms are called hepatomas and hepatocarcinomas if they involve hepatocytes and cholangiocellular adenomas and adenocarcinomas if they involve biliary cells. Primary neoplasms can also be derived from resident connective tissues or vessels and are named accordingly. Overall, primary neoplasms are uncommon in most domestic species. However, in old dogs, nodular hyperplasia, a benign condition usually involving multiple masses, is common. It may be difficult to distinguish some of these nodules from hepatomas but both are unlikely to cause any great dysfunction. Secondary neoplasms (ie metastases to the liver), on the other hand, are not uncommon due to the central position and high vascularity of the liver. In dogs and cats, lymphosarcoma, pancreatic and intestinal carcinomas, and haemangiosarcomas (often derived from the spleen) are most common.

Signs and Effects of Functional Disturbances to the Liver This is not meant to be comprehensive as much will be presented in veterinary medicine. It is worth reiterating that many functional disturbances of the liver can be caused by a wide range of agents of disease. Therefore, disease cause has to be determined in the laboratory. Liver failure

Liver failure is a general term referring to multiorgan dysfunction related to significant loss of function of the liver. Acute (fulminant) liver failure has been mentioned previously. It commonly occurs with acute infections or poisons, but may occur as an acute episode related to more chronic liver disease (eg as in idiopathic hepatic lipidosis in cats). Clinical signs may be related to haemorrhage (presumably due to interference with clotting factors), secondary infection, renal failure, hypoglycaemia, electrolyte disturbances or neurological disturbances (due to cerebral oedema and hepatic encephalopathy). Jaundice may or may not be present. Chronic liver failure is usually characterised by more specific clinical signs of liver dysfunction such as jaundice, ascites etc and are presented following this statement. Jaundice Jaundice (or icterus) refers to yellowing of tissues due to deposition of bilirubin. Hyperbilirubinaemia is the cause of this, and this most commonly occurs due to (1) haemolytic anaemia (2) liver disease (a variety of diseases) and (3) obstruction of bile coming out of the liver and flowing to the intestine. Haemolytic anaemia means excess haemoglobin is released which is broken down to excess bilirubin. This is unconjugated bilirubin which is bound to protein and transported to the liver for conjugation and excretion. Because there is excess, hepatocytes are unable to take up all the bilirubin for processing. Consequently, hyperbilirubinaemia and jaundice develop. In liver disease, hyperbilirubinaemia may occur because (1) damaged hepatocytes are unable to take up, conjugate or excrete bilirubin and (2) the intrahepatic biliary vessels are blocked because of fibrosis, inflammation or hepatocyte swelling. Not all liver diseases cause hyperbilirubinaemia and, consequently, jaundice. Usually, both unconjugated and conjugated bilirubin increase in the blood stream due to liver disease. This occurs because there is a flow over of excess bilirubin from outside the hepatocytes to the blood stream. Conjugated hyperbilirubinaemia indicates there is a degree of cholestasis (ie interference to excretion) in the liver disease, while unconjugated hyperbilirubinaemia indicates there is interference with conjugation in the damaged hepatocytes. Post hepatic obstruction to bile flow can occur due to neoplasms or inflammatory lesions impinging on the large bile ducts (eg as in acute pancreatitis in the dog), or due to blockage of the opening of the duct into the duodenum. As it is principally cholestasis, there is principally increased conjugated bilirubin in the blood stream.

Hepatic encephalopathy This term refers to the myriad of neurological signs (eg convulsions, behavioural changes, depression) related to liver disease. It is due to a variety of compounds, such as toxic amines and ammonia, acting on the brain. In farm animals and horses, a wide variety of liver diseases, both acute and chronic, can lead to neurological signs consistent with hepatic encephalopathy. In acute (fulminant) liver failure in all species, neurological signs are often related to cerebral oedema due to suspected vascular disturbances as well as due to retention of toxic substances. In dogs and cats, most cases of hepatic

encephalopathy are related to portosystemic shunts. These may be congenital (mostly dogs) or acquired, and involve portal blood being shunted around the liver rather than passing through the sinusoids. Acquired shunts often develop in chronic liver diseases characterised by impedance of liver blood flow (eg hepatic fibrosis or cirrhosis). Portal hypertension is commonly a pre-requisite and can also give rise to splenomegaly and ascites. Because the liver requires 'hepatotrophic factors' to be delivered to it via the portal blood circulation, in significant shunting there is atrophy of hepatocytes leading to a small liver.

Photosensitisation This is observed in herbivores with cholestatic liver disease of some days duration. Photodynamic compounds, such as hypericin in the plant St. John's wort (Hypericum perforatum), may be ingested directly or be formed by the action of microbes in the gut on chlorophyll ( phylloerythrin). These photodynamic substances are usually excreted in the bile but in cholestatic disease they accumulate in the blood stream and deposit in the skin. When they are exposed to ultra-violet irradiation, these compounds are activated and cause inflammation of the skin.

Facial Eczema This condition of sheep is related to the ingestion of a mycotoxin called sporidesmin. This mycotoxin is hepatotoxic and is produced by the fungus Pithomyces chartarum which thrives on dead pasture material in perennial ryegrass (Lolium perenne) pastures in eastern Australia and New Zealand. Humid weather after a hot dry spell is perfect for proliferation of the fungus. Ingestion of sufficient quantities of sporidesmin leads to necrosis of the bile duct epithelium and cholangiohepatitis. The subsequent cholestasis means that the excretion of phylloerythrin is disrupted. Increased circulating levels of phylloerythrin leads to tissue deposition. Since phylloerythrin is a photodynamic substance, deposition in areas of hairless skin exposed to UV light is particularly important and leads to localised cell injury and necrosis. Cattle can also be affected but are so less commonly. Necropsy examination reveals increased prominence of the bile ducts dilated by bile and oedema around the ducts. The left lobe of the liver is usually more severely affected. Chronically, there may be fibrosis surrounding the ducts and even fibrosis affecting the hepatic parenchyma more generally and shrinkage of affected lobes. This is an excellent example of the complexity of the Host-Pathogen-Environment Interaction of many diseases. The pathogen is actually the mycotoxin sporidesmin, however, the environmental interactions between animal husbandry, the fungus, plant and climate are the critical features of this disease, determining whether the host is exposed to sufficient quantities of mycotoxin to cause clinical disease.

Toxic Epidermal Necrolysis (hepatocutaneous syndrome) This is sometimes observed in dogs with hepatic failure and can sometimes even be the presenting sign of hepatic failure. The pathogenesis of this condition is not fully understood but likely involves direct effects of unmetabolised endogenous toxins on the epidermis. Peritoneal effusion ('ascites') and splenomegaly These phenomena have been mentioned in relation to portal hypertension. Generalised oedema may also develop in chronic liver due to low protein levels in the blood stream. The liver is the main source of albumin and most globulins. In chronic liver failure, protein production will be severely impaired.

Bleeding disorders Bleeding disorders (i.e. inadequate coagulation of the blood) may accompany acute or chronic liver diseases. This is primarily due to interference with clotting factor production or usage (also proteins produced by the liver). Rarely is a bleeding disorder the solitary indication of liver disease, and rarely is it seen in chronic liver diseases. The liver manufactures all of the factors of the coagulatiuon cascade with the possible exception of Factor VIII. In acute hepatic failure, diminished synthesis of those coagulation factors with a short half-life (e.g. factors V,VII,IX,X) is most significant, whereas in chronic hepatic failure factor II (prothrombin) deficiency may also contribute to a disorder of diathesis. Diminished clearance of Fibrin Degradation Products (FDPs), activated clotting factors and plasminogen may also disrupt the coagulation cascade.

Cachexia Cachexia is a non-specific muscle wasting of an animal due to chronic, overwhelming disease. It has a variety of mechanisms and can occur in chronic liver disease.

Quiz 1) Identify the correct statement a) Bilirubin is unconjugated in the liver b) Bilirubin, excreted in the bile, is involved in the digestion of fats in the small intestine c) Portal triads contain 3 structures d) Urobilinogen and bile acids are reabsorbed in the intestine and returned to the liver via the enterohepatic circulation

2) Which of the following are hepatic functions? a) Metabolism of xenobiotics b) Conjugation and excretion of bilirubin c) Haematopoiesis d) Albumin synthesis e) Glycogen metabolism & gluconeogenesis f) Production of digestive enzymes 3) What are the general responses of the liver to injury? No matter what the cause of injury! a) Degeneration and intracellular accumulation b) Hepatocellular necrosis c) Inflammation d) Regeneration e) Fibrosis 4) By what mechanisms might you get fatty change in the hepatocytes of the liver? a) fatty acids entering liver b) Dietary mobilisation of fat c) CHO intake d) Hepatocellular injury decreased apoprotein synthesis (membrane damage); decreased lipoprotein export ( energy production & membrane damage) 5) Regeneration is a normal function of the liver. What factors are important in normal regeneration turning into cirrhosis? a) Ongoing damage (usually toxic) b) Damage to the connective tissue framework of the hepatic acinus c) Disorganised regeneration failure of regenerating hepatocytes to migrate leading to distortion of the acinus d) Excessive fibrosis