Anatomy

The liver is one of the largest organs in the body. It weighs approximately 3% of the total body weight in adult dogs and cats. In very young growing animals, it accounts for 5% of the body weight.

In dogs, the liver lies entirely within the rib cage and, there­fore, is normally not palpable. Depending on the shape of the rib cage, the liver lies more or less hidden within it. In brachy­cephalic dogs, which have a wide rib cage and a more flat­tened diaphragm, any enlargement will result in the liver being palpable. In contrast, in racing hounds with a deep rib cage, the liver may only become palpable behind the last rib when it is severely enlarged.

The stomach is in contact with the visceral surface of the liver. As a result, changes in size or shape of the liver cause displace­ment of the stomach. This is one possible explanation why vomiting is often a major clinical sign in patients with liver disease.

The peritoneal capsule of the liver forms ligaments, which fixate the organ in its position while maintaining a degree of movability. The falciform ligament is located in the midline and attaches the liver to the ventral abdominal wall and also contains the abdominal retroperitoneal fat mass. The other fixation points of the liver are the left and right triangular ligaments and the short coronary ligament, which connect the liver with the diaphragm laterally and in the midline, respec­tively. Finally, the right hepatorenal ligament connects the liver with the right kidney.

7.1.1 Biliarysystem

One of the main functions of the liver is the detoxification or catabolism of many exogenous and endogenous compounds. Many compounds undergo biotransformation in the hepato­cytes. Larger molecules (i.e., molecular weight > 300), such as steroid hormones, bilirubin, bile salts, and many toxins are ex­creted by the biliary system. In contrast, smaller exogenous or endogenous molecules (i.e., urea or allantoin) are excreted via the urine.

The biliary system is a branched tree, which serves as a collec­tion system for bile from each individual hepatic cell. In each hepatic lobule, the hepatocytes are organized in liver cell plates, which radiate around a central vein. These hepatocyte plates connect the central vein with several portal areas. Blood flows from the portal areas to the central vein, while bile flows from the central areas to the portal areas and the common bile duct.

The lateral membranes connecting adjacent liver cells contain a specialized region, the canalicular membrane. The space be­tween the canalicular membranes of adjacent cells is sealed by tight junctions and forms the smallest branches of the biliary system, the canaliculi. This excretory region of the hepatocyte membrane constitutes 15% of the hepatocellular surface. Most molecules are excreted across this membrane by their own specialized transporters, which can actively excrete against a very high concentration gradient. Thus, the canalicular mem­brane is a highly specialized section of the hepatocellular membrane.

Figure 7.1:

Bile flow. This figure shows a schematic representation of bile flow in dogs and cats. Bile is produced by the transport of a large number of molecules across the canalicular membranes of the hepatocytes (1) into the canaliculi (2). The canaliculi drain into the canals of Hering (3), which drain into the intrahepatic bile ductules (4). These then drain into the interlobular ducts (5), septal ducts (6), and hilar ducts (7), which collect all the bile from one liver lobe. The hilar ducts merge to form the common bile duct (ductus choledochus; 8), which opens into the duode­num (9) on Vater's papilla and is protected against the reflux of duodenal contents by the muscular sphincter of Oddi (10). The gall bladder (11) is connected to the common bile duct by the cystic duct (12).

Bile is excreted by hepatocytes into the canaliculi, which then transport the bile to the portal tracts where they enter the canals of Hering (Figure 7.1).

The canals of Hering drain into the smallest branches of the intrahepatic bile ducts, which are completely lined by cholan- giocytes. From the smallest bile ductules, the bile flows to the interlobular ducts, the septal ducts, and via the hilar ducts of each liver lobe into the common bile duct (ductus choledo- chus). The ductus choledochus is only 2-3 mm in diameter in dogs and cats, and may be difficult to find with ultrasonogra­phy. However, in patients with a common bile duct obstruc­tion, dilation of the common bile duct is easily visible ultra­sonographically and serves as the hallmark feature of common bile duct obstruction. The common bile duct runs to the duo­denum and enters the major duodenal papilla some 3-6 cm caudal to the pylorus, depending on the size of the animal. The junction of the common bile duct and the duodenum, Vater’s papilla, is located close to the head of the pancreas and is sur­rounded by the muscular sphincter of Oddi. In cats, the pan­creatic duct and the common bile duct merge and enter the duodenum together on the major duodenal papilla. This may explain why in cats concurrent pancreatitis and cholangiohep- atitis /cholangitis occur quite frequently. In contrast to cats, the bile duct and the pancreatic duct usually end separately in dogs. The gallbladder is connected with the common bile duct via the short cystic duct.

The gall bladder provides the main storage facility for bile and concentrates the bile approximately tenfold. Bile is also con­centrated in the larger bile ducts. In healthy dogs and cats, a completely filled gallbladder contains around 1 ml of bile/kg body weight. Less than half of the bile produced is stored and concentrated. The remainder is immediately transported into the duodenum via the common bile duct. Stimulation of the muscular wall of the gall bladder to contract (by cholecystoki­nin released from the duodenal mucosa) produces a gradual release of bile that lasts for several hours. The bile then enters the duodenum by rhythmic relaxations of the sphincter of Oddi. Emptying of the gall bladder is very variable and almost never complete.³ An empty gall bladder during ultrasonogra­phy is an abnormal finding. Opioid drugs can cause complete closure of the sphincter of Oddi, so that during anesthesia the gall bladder may appear dilated; this usually resolves after an­esthesia. Dilation of the larger bile ducts and /or the common bile duct indicates abnormalities such as cholangitis or bile duct obstruction.

7.1.2 Bloodsupply

The blood supply of the liver is both arterial and venous. Arte­rial blood comes from the hepatic artery, while venous blood is supplied through the portal vein. The outflowing blood is collected by a number of hepatic veins that enter into the in­ferior vena cava near the diaphragm. The total blood flow to the liver accounts for about 20-25% of the cardiac output (100-130 ml/min/100 g liver tissue). The portal vein accounts for 70% of the total blood flow to the liver and separates into two main branches entering the liver at the hilus. The right branch of the portal vein supplies the right side of the liver, while the bigger and longer left branch supplies the left and central portions of the liver. The intrahepatic portal vein divides into smaller branches, with the smallest branches end­ing in the portal areas.

distributes the portal blood to the sinusoids. The hepatic artery also enters the liver at the hepatic hilus. Its branches accom­pany the portal vein. Terminal arterial branches end into the periportal sinusoids and connect with the venous and sinusoi­dal system. The biliary system of the liver is only supplied with arterial blood, while the parenchyma receives both portal and arterial blood. The sinusoidal blood enters the central veins, also known as terminal hepatic veins, in the liver lobule. The central veins then drain into branches of the hepatic vein. Finally, several branches of the hepatic vein enter into the cau­dal vena cava.⁴

The ratio between portal and arterial blood supply is not con­stant but varies with both physiological and pathological con­ditions. Portal blood flow increases following food ingestion, whereas the arterial blood supply increases when the portal blood flow is insufficient and decreases in the case of hepatic venous congestion. In patients with diseases that are associated with a severely decreased or total lack of portal blood flow (i.e., congenital portosystemic shunts, portal vein thrombosis), the arterial blood flow may increase by 100%, but even then the total hepatic blood flow remains subnormal. However, without this compensatory arterial blood flow the liver would not be able to survive. Histologically, the arterialization of the liver becomes visible after about 2 weeks. The hepatic arteries respond to the hypoperfusion of the liver and increase their blood flow. In addition, the arterial branches become tortuous and hypertrophic. Histologically, this can be recognized as an increased number of arterial sections in the portal areas. In the parenchyma, portal hypoperfusion causes hepatocellular atro­phy.

In comparison, changes in arterial blood flow do not affect portal blood flow.⁴ During periods of fasting, the hepatic ar­tery and the portal vein each supply approximately 50% of the hepatic oxygen requirement. In the case of hypoxia, which can occur in patients with anemia, the hepatic blood supply re­mains unchanged. When the oxygenation of the liver becomes deficient, either due to reduced erythrocyte oxygen binding or due to decreased perfusion, the liver adapts by an increased efficiency of oxygen uptake from approximately 40% up to nearly 100%. Hypoxia does not affect the total perfusion of the liver or the ratio between arterial and portal blood supply. Due to the large volume and the compliance of the hepatic vascu­lar bed approximately 10-15% of the total blood volume is contained in the liver. This may increase by 100% in patients with severe congestive heart disease. Also, the large hepatic blood reservoir plays a role in compensating for acute blood loss.

It is important to note that, at the histological level, the liver consists of functional hemodynamic units or acini that are different from the lobules that are mere anatomically de­scriptive units. The acinar concept, which was proposed by Rappaport, places the portal vein at the center of the acinus with several central veins, also known as terminal hepatic veins (THV), at the periphery. The arteries and portal vein branches enter the liver via the portal areas. Portal blood is distributed from the larger portal veins throughout the aci­nus and drains into the sinusoids via short perpendicular inlet venules, which have a sphincter function and regulate the portal blood flow into the capillary bed. The THV collect blood at the outlet side of the sinusoids. Small tributaries of the hepatic artery enter the sinusoidal system at different places. Their blood flow is also controlled by a sphincter, which intermittently allows the flow of arterial blood, thus regulating the difference in pressure between the arterial sys­tem (100-110 mmHg) and the portal (0-5 mmHg) and si­nusoidal (5-10 mmHg) systems.

According to the acinar concept, the liver circulatory units are divided into three zones, with the closest (Zone 1) around the portal area receiving blood with the highest contents of oxy­gen, growth factors, and nutrients, and Zone 3, which is far­thest away from the portal area, and thus receives blood with the lowest concentrations of these compounds. In the case of sudden hypoxia or shock, when there is not sufficient time for compensation by increasing the oxygen binding of red blood cells or a more efficient oxygen uptake by the liver, the hepa­tocytes located in Zone 3 become necrotic. This results in centrolobular (Zone 3) hepatocellular necrosis. Such condi­tions are usually associated with increases in serum hepatic enzyme activities.

7.1.3 Microanatomy

The predominant cell type of the liver is the epithelial cell or hepatocyte. Hepatocytes make up 60% of the all the cells in the liver and since they are also the largest cell type found in the liver, they make up 80% of the liver volume (approxi­mately 200,000 cells per mg hepatic tissue). Altogether, the liver contains about 100 billion hepatocytes. Other cell types that are present in the liver are endothelial cells, bile duct epi­thelial cells, Kupffer cells, and fat-storing cells. The latter cell type is also known as stellate cells.⁵

The hepatocytes are arranged in cell plates that are only one layer thick, radiating around the THVs. The free outer mem­branes on both sides of the hepatocyte are in contact with the sinusoids. Due to the numerous microvilli of that part of the membrane, the sinusoidal membrane occupies 70% of the overall hepatic cell surface area. A portion of the lateral mem­branes of adjacent cells form the bile canaliculi that are sur­rounded by tight junctions, which connect the hepatocytes on either side of the canaliculi. The canalicular membrane com­prises approximately 15% of the hepatocyte membrane, and has a specialized excretory function. The sinusoidal membrane is separated from the sinusoids by one cell layer of sinusoidal

Figure 7.2:

Arrangement of cell types in the liver. This diagram shows the arrangement of endothelial cells, sinusoidal cells, and hepatocytes, which respectively form the conduits for blood, lymph, and bile flow. Hepatocellular necrosis leads to a direct connection between the canaliculi (i.e., the space of bile flow) and the space of Disse, resulting in a leakage of bile into the circulation (intrahepatic cholestasis).

Table 7.1: Hepatocyte functions in the different sublobular regions

Note that both lipid and protein metabolism are functions that are not localized to one region.

Zone 1: periportal area Zone 3: Centrolobular area The perisinusoidal space represents the beginning of the he­patic lymphatic system and leads lymph in a direction opposite to that of the blood flow, but in conjunction with the bile flow. The sinusoidal cells (endothelial and Kupffer cells) are very efficient in removing endotoxins and particles, such as bacte­ria. This, together with the many detoxifying metabolic func­tions of the hepatocytes and the biliary excretion of toxic substances, make the liver an important guardian against toxic substances entering the body from the GI tract. The bile in the canaliculi flows opposite to the blood flow into short collect­ing ducts (canals of Hering), which drain bile from the acini into bile ductules of the portal area. The luminal surface of these ductuli and the larger bile ducts are covered with cuboi- dal biliary epithelium.

Although hepatocytes are generally uniform and thus capable of performing most metabolic functions, there is some hetero­geneity with respect to some functions. For example, enzymes that are part of the urea cycle are predominantly found in the hepatocytes of Zone 1 around the portal area. Also, the incorporation of ammonia in glutamine, which is regu­lated by glutamine synthetase, occurs exclusively in the hepa­tocytes around the central vein (THV). Carbohydrate meta­bolism also shows some degree of zonal organization, although it is not as strict as that of ammonia metabolism. Lipid and protein metabolism are not restricted to one particular zone. Drug metabolism via the cytochrome p450 mixed function oxidase system appears to be primarily located around the central veins. Copper accumulation in patients with copper storage disease mostly affects cells in Zone 3 in all dog breeds (Table 7.1).

Bilirubin excretion

Bile acid excretion, bile-salt-dependent bile production

Gluconeogenesis, glycogenolysis → glucose production

Ammonia detoxification through urea cycle enzymes

Glutathione production → protection against oxidative stress

Copper excretion

Bile-salt-independent bile production

Glycolysis, glyconeogenesis → glucose clearance

Ammonia detoxification through glutamine formation

Biotransformation; cytochrome p450 enzyme-dependant detoxification; conjugation reactions

cells (about 7% of the liver cells). Between the hepatocytes and the sinusoidal cell layers is the perisinusoidal space of Disse (Figure 7.2). The endothelial cell lining is fenestrated, and these openings permit even large molecules to be exchanged between the sinusoidal blood and the space of Disse. How­ever, cells cannot pass through the fenestrations and remain in the circulation.

7.2