Extrahepatic Biliary Obstruction

Anatomy

The intrahepatic portion of the biliary system originates where bile, produced by sheets of liver cells surrounded by blood sinuses, is discharged into minute bile canaliculi that lie between these cells [1]. Interlobular ducts are formed from the unification of the canaliculi and lie between the lobules in the interstitial tissue. The interlobular ducts unite further to form lobar or bile ducts that exit the liver parenchyma as a variable number of hepatic ducts, beginning the extrahepatic portion of the biliary system. Usually there are four such ducts, two originating from the central division of the liver (quadrate and right medial lobes), and one each from the right (right lateral lobe and caudate process of the caudate lobe) and left (left lateral and medial lobes, papillary process of the caudate lobe) divisions.

The gallbladder is a pear-shaped structure, located within a fossa formed between the right medial and quadrate lobes of the liver. It is divided into a fundus, body, and neck and connects with the bile duct via the cystic duct. Its function is to store and concentrate bile and secrete a mucoid substance for lubrication and protection. The cystic duct extends from the neck of the gallbladder to the site of its junction with the first hepatic duct from the central liver division. From this level distally to the duodenum the main excretory channel that receives bile from the hepatic ducts from the left and right liver divisions is the bile duct [1].

The free portion of the canine bile duct is approximately 5 cm long and 2.5 mm in diameter and courses through the lesser omentum to the duodenum within the hepatoduodenal ligament [1]. The intramural portion of the bile duct enters the mesenteric wall of the duodenum and courses obliquely for an additional 1.5 to 2 cm before terminating at the major duodenal papilla, separate from the ventral pancreatic duct. A double layer of smooth muscle (sphincter of Oddi) exists around the intramural portion of the bile duct, resulting in the discharge of bile being largely dependent on activity of the duodenum itself [1].

An auxiliary retroportal network of bile ducts is reported to exist in dogs [2]. These additional ducts connect the intrahepatic lobar ducts of adjacent liver lobes to allow for continued drainage of bile when primary pathways are obstructed.

Specific features of note in the cat include the flexuosity of the feline cystic duct, and the existence of double or even triple gallbladders on occasion [3,4]. Additionally, the terminal intramural portion of the bile duct usually merges with the major pancreatic duct to empty into the duodenum through a common ampulla [3-5].

Bile Formation, Flow, and Pathophysiologic Alterations

Bile is a slightly alkaline, isotonic solution that consists of water, inorganic electrolytes, and organic solutes such as bile acids, cholesterol, phospholipids, and bilirubin [5,6]. Primary bile is produced in the canaliculi as a result of several different active transport processes, with secretion of bile salts the most important factor in promoting bile flow [7]. This active transport of solutes by the hepatocytes is accompanied by passive water flow [5].

Bile acids are produced from cholesterol, conjugated by hepatocytes, and secreted continuously into canaliculi. They are essential for the emulsification and absorption of fat from the small intestine [6,8]. The term bile acid refers to the molecular form in which the carboxylic acid side chain is nonionized; while the term bile salt refers to the ionized configuration. At physiologic pH the ionized bile salt form predominates [5]. More than 90% of the solutes within bile consist of bile acids and can represent a concentration 105-fold greater than serum bile acid concentrations [5]. They are maintained in solution in bile by formation of micelles, so an isosmotic balance is maintained with plasma. The rate of bile acid production is determined by the amount delivered to the liver for resecretion via enterohepatic circulation. With biliary obstruction, a decrease in bile acid production results from the increased plasma levels of bile acids.

Cholesterol is synthesized primarily in the liver, with the rate of synthesis related inversely to its level of dietary intake. Synthesis of bile acids from cholesterol with excretion through the gastrointestinal tract represents the major method of excretion of cholesterol from the body. Although not water-soluble, cholesterol exists in normal bile in the form of micelles. Because lipid solubility is the major determining factor for absorption of solutes by the gallbladder mucosa, cholesterol is present within bile in lower quantities than water-soluble compounds such as conjugated bile acids and bilirubin [5].

Bilirubin, the major pigment in bile, is a product of hemoprotein degradation, two thirds of which is estimated to come from erythrocyte breakdown [5]. The unconjugated bilirubin is poorly water-soluble and binds to plasma proteins (predominantly albumin) for transport within the vascular space. Only a very small amount of unconjugated bilirubin remains unbound to plasma proteins because of albumin's high binding affinity for it, and this minimizes its renal filtration and excretion. Protein-bound unconjugated bilirubin is transported to liver for conversion by hepatocytes into a water-soluble form. The bilirubin is conjugated with glucuronic acid to diglucuronide in the smooth endoplasmic reticulum of the hepatocytes. Conjugated bilirubin is then either excreted into the bile canaliculi or removed from the body via renal filtration. More than two thirds of the bilirubin present within the liver at any time is unconjugated, yet less than 3% of bilirubin excreted within the bile is in this form [5,9]. This illustrates the importance of enzymatic presence and function as the rate-limiting steps in bilirubin conjugation [5]. Once excreted into the intestinal tract, the conjugated bilirubin undergoes bacterial deconjugation, with conversion to urobilinogen, some of which is resorbed through the enterohepatic circulation. The majority of this is returned to the liver, and a small portion is excreted in the urine. The remaining urobilinogen in the intestinal tract is further converted to stercobilin, which imparts normal fecal color [9]. Feces absent of normal color are termed acholic. This occurs from either a lack of bilirubin present within the intestinal tract (biliary obstruction) or a deficiency in intestinal bacterial activity [5]. Since only a small amount of bilirubin is needed for normal fecal pigmentation, complete cessation of bilirubin excretion is usually required for the formation of acholic feces. This is not seen until 7 to 10 days after complete blockage of the biliary system, when jaundice is also readily apparent [5,9].

Biliary obstruction can occur in a variety of disease processes (Table 33-1). With biliary obstruction, bilirubin conjugation occurs normally but secretion in the bile is inhibited. Regurgitation of conjugated bile back into the plasma then occurs, causing hyperbilirubinemia. While the majority remains protein-bound in plasma, it has a less profound binding affinity when compared with unconjugated bilirubin. The liver maintains a high reserve capacity for bilirubin excretion, capable of increasing up to 30 to 60 times above normal [5]. Because of this reserve, dogs must regurgitate considerable amounts of bilirubin into the bloodstream before a significant increase in plasma levels occurs. The dog's renal threshold for bilirubin is low, with active excretion within the renal tubules possible. The renal threshold in cats is 9 times greater than that in the dog, and because of this, any bilirubin in the urine of cats should be considered abnormal [10]. In cases of bile duct obstruction, renal filtration and excretion become essential [5].

Intra- or extrahepatic obstruction of the biliary system is the most common cause of conjugated hyperbilirubinemia (Table 33-1). However, nearly all hepatic diseases associated with hyperbilirubinemia consist of a mixture of conjugated and unconjugated bilirubinemia; differentiation is unlikely to be clinically useful [9]. Serum bilirubin levels over 0.3 mg/dl in the cat and 0.6 mg/dl in the dog are considered abnormal; at higher values, jaundice becomes visible clinically as yellow-stained tissues (serum levels > 2.0 mg/dl) or in serum (serum levels > 1.5 mg/dl) [9].

Flow of bile within the canine biliary system is dependent on pressure gradients because no valves are present. The increased pressure of the intramural component of the bile duct results in direction of the bile flow from the liver into the cystic duct and the gallbladder. The capacity of the gallbladder is about 1 ml per kg bodyweight; however, a much greater volume of bile can be accommodated by the gallbladder by mucosal absorption of water and electrolytes [5]. Active transport of sodium through the gallbladder epithelium is followed by passive transport of chloride, water, and other soluble constituents. Thus, bile is concentrated between 5- and 20-fold while in the gallbladder and this prevents a rise in pressure within the biliary system [5,8].

The gallbladder does not simply fill continuously during fasting; rather, partial emptying occurs intermittently; approximately 75% of the bile excreted from the liver is released directly into the duodenum in this way [5]. The gallbladder has emptied 50% or more of its bile into the intestinal tract within 30 minutes following a meal [4]. The presence of chyme in the duodenum stimulates the release of cholecystokinin from duodenal mucosa as the primary regulator of gallbladder emptying. Cholecystokinin causes contraction of the gallbladder as well as relaxation of the terminal bile duct (sphincter of Oddi). In addition, vagal parasympathetic stimulation and, even more importantly, the presence of duodenal peristalsis itself contributes to relaxation of the smooth muscle surrounding the intramural bile duct, resulting in bile being expelled into the intestine with intermittent spurts [1,5,8]. Obstruction of the bile duct increases intraductal pressure proximal to the obstruction, causing vascular dilatation. With increasing pressure bile flow decreases; at pressures of approximately 30 mm Hg it stops [11]. This increased hydrostatic pressure produces characteristic morphologic alterations to the liver.

Morphologic Alterations of the Liver

Soon after obstruction, intrahepatic cholestasis is followed by bile duct dilation and edema with inflammatory cell infiltration of portal areas. These changes occur from both initial increased hydrostatic pressure and toxic effects of bile leakage into periportal areas. In any disease process where cholestasis occurs there is the potential for hepatocellular damage. Bile acid retention causes injury to organelles, hydropic degeneration of hepatocellular tissue, and destruction of the cytochrome P-450 system [5,7]. In cases of chronic severe cholestasis, hepatocytes undergo degenerative necrosis and cirrhosis can occur [5,7,12] An increase occurs in both fibroblast and hepatocyte collagen synthesis, with a concomitant reduction in hepatic collagenase activity, which results in fibrosis [7,10].

Following bile duct obstruction, proliferation of both hepatocellular and preexisting biliary epithelial cells occurs, resulting in a new tortuous periportal ductal system. With prolonged duct obstruction, metaplasia of hepatocytes can occur and further contribute to the neo-duct network. Increased hydrostatic pressure in obstructed ducts is necessary for this proliferation, and once obstruction is relieved, additional bile ducts may regress [5].

Physiologic Alterations of Digestion

Efficient digestion of fats in the intestinal tract largely depends on the presence and function of bile salts and the phospholipid lecithin [5,8]. Bile salts and lecithin act to first emulsify ingested lipids into smaller particles, and then to form micelles around monoglycerides and free fatty acids derived from pancreatic lipase activity. This allows for continued digestion of remaining fat globules and for efficient transport of the monoglycerides and free fatty acids to the intestinal epithelium. Bile salts and lecithin perform a similar transportation role in digestion of dietary cholesterol. Although intestinal absorption of free fatty acids can occur without bile salt micelles, absorption of cholesterol cannot, making the presence of bile even more critical [8]. The most important cause of clinically significant bile acid deficiency is extrahepatic biliary obstruction. Steatorrhea, weight loss, and acholic feces may result.

In situations of decreased intestinal absorption of fats, there is concurrent malabsorption of fat-soluble vitamins (A,D, E, and K), vitamin K being the most clinically significant [7-9]. The formation of functionally active forms of five important clotting factors (prothrombin, factors VII, IX, X, and protein C) is dependent on vitamin K, with its deficiency leading to potential blood dyscrasias. Because factor VII has the shortest half-life of these clotting factors, prothrombin time will usually be prolonged before partial thromboplastin time [13]. Vitamin K is continually produced by intestinal bacteria and clinical manifestation of deficiency is uncommon, except in cases of impaired fat absorption [5,8,10,13].

Diversion of bile from the duodenum (extrahepatic biliary obstruction or surgical diversion via cholecystojejunostomy) not only affects fat digestion but also results in increased gastric acid secretion, with duodenal ulceration as a frequent sequela [5,14]. It is theorized that decreased absorption of fat in the duodenum results in a decrease in cholecystokinin activation (a competitive gastrin inhibitor), causing increased serum gastrin levels and subsequent peptic ulceration [14]. Also, hormonal inhibition of gastric acid secretion may be decreased in cases of biliary obstruction or surgical diversion of bile away from the duodenum [14]. Finally, neutralization of gastric acid is decreased in the absence of bile, which can lead to duodenal ulceration.

Cholelithiasis

Cholelithiasis is uncommon in animals and is often an asymptomatic incidental finding, usually at necropsy. Clinical signs are seen when biliary stones are associated with cholecystitis, biliary obstruction, or gallbladder rupture [15]. The incidence of cholelithiasis in dogs is reported at less than 1% of patients with biliary disease [16]; only a few cases have been reported in cats [10,17]. In animals, bile pigment stones predominate, in contrast to the cholesterol-based stones seen in people [5]. Choleliths seen in dogs and cats also tend to be lower in calcium than are human stones because of the efficiency of the gallbladder in resorbing free calcium from bile [5].

Biliary stasis has been theorized as a potential cause of cholelith formation in animals because this is a common element seen in clinical disease. In contrast to humans, abnormal cholesterol metabolism does not seem to be a significant component of canine and feline choleliths [5,15,18]. Trauma, cholecystitis, dietary alterations, and parasitic or bacterial infections have also been proposed as predisposing factors [10,15]. Bile stasis results in pigment sludge formation with mucin-bilirubin particles present in the gallbladder. As the mucin component increases, sludge particles precipitate as stones [5].

Both bile stasis and biliary infection are commonly seen in disease associated with cholelithiasis in animals; however, infection is not thought to be a necessary component of stone formation because choleliths occur frequently in the absence of infection. Also, the relatively high incidence of stones seen as an incidental finding at necropsy suggests clinical disease arises only when the biliary system containing stones becomes obstructed or infected. However, suppurative cholecystitis is inherently lithogenic because of prostaglandin-mediated inflammatory processes, increased mucin production, and the presence of bacterial enzymes [5].

Although the gallbladder is the most common site of choledocholith formation, stones can form primarily within the bile duct [11,19]. This usually requires an abnormality that produces bile stasis such as partial obstruction and marked dilatation [11].

Surgical Considerations

Preoperative Considerations

A vitamin K deficiency and subsequent coagulopathy can occur with complete bile duct obstruction over a period of weeks, but is unlikely in most clinical cases in the dog and cat [5,9 ].Hemostasis testing is recommended, however, in patients with potentially chronic obstruction, most commonly by determination of prothrombin and partial thromboplastin times [10,20]. Prolonged partial thromboplastin time has been identified as a poor prognostic indicator in dogs undergoing extrahepatic biliary surgery [21]. The more specific test for potential vitamin K deficiency is that for "proteins induced by vitamin K absence or antagonists" (PIVKA) [5,22]. This test evaluates the occurrence of both depleted vitamin K-dependent coagulation factors and build-up of PIVKA. PIVKA are circulating nonfunctional precursor forms of vitamin K-dependent proteins that are normally stored in the liver but accumulate and spill into the circulation when a vitamin K deficiency occurs. Results are expressed in seconds, with marked elevations in PIVKA time warranting treatment. Parenteral administration of vitamin K1 can correct the coagulopathy in these cases [10,20], with an initial loading dose of 5 mg/kg bodyweight, followed by a 2.5 mg/kg bodyweight daily dose divided every 8 hours until the biliary obstruction has been relieved and coagulation times returned to normal [22]. Although tests for PIVKA are sensitive and can detect early evidence of vitamin K deficiency, they are not as widely used clinically as other coagulation profile assessments [22].

In addition to administration of vitamin K, patients with evidence of coagulopathies may require transfusion of whole fresh blood or fresh frozen plasma to replenish coagulation factors or packed red blood cells if they are anemic. It may take up to 12 hours for vitamin K administration to significantly decrease the prothrombin time and subsequently decrease bleeding [22].

Antibiotics should be administered perioperatively when surgery is performed for biliary obstruction. Although normal bile is sterile, in situations of impaired bile flow, positive cultures have been frequently reported in people [5]. Hepatocellular damage secondary to biliary obstruction may decrease the effectiveness of the Kupffer cells in removing bacteria and bacterial endotoxins from the liver [5]. Empirical preoperative administration of broad spectrum intravenous antibiotics is recommended and should be active against enteric organisms commonly detected in biliary obstruction (Escherichia coli, Klebsiella, Proteus, Streptococcus, Pseudomonas, and Clostridium species). Examples include cephalosporins, or potentiated ampicillin, and fluoroquinolones plus metronidazole. These should be continued postoperatively depending on surgical findings, patient condition, and results of bacterial culture and antibiotic sensitivity testing of bile.

It has been well established that bilirubin is damaging to cells, with unconjugated bilirubin more toxic than the conjugated form because of its increased lipid affinity. However, the high binding affinity of unconjugated bilirubin with albumin reduces widespread tissue distribution and, therefore, limits its deleterious effects [5]. Free unconjugated bilirubin crosses the blood-brain barrier, causing neurotoxicity; this has been shown to result in hypotensive shock and death in dogs [5]. Additionally, hyperbilirubinemia is associated with renal failure in dogs and cats, theorized to be caused by direct cellular toxicity, hypotensive ischemia, or absorption of bacterial endotoxins [5,21]. Hypotension is commonly seen in cases of biliary obstruction and has been identified as a poor prognostic indicator. This is thought to be a result of a combination of the toxic effects of bilirubin and the development of systemic inflammatory response syndrome (SIRS) [21]. Both preoperative and intraoperative efforts to monitor and maintain systemic blood pressure are essential in these patients.

Intraoperative Considerations

Liver biopsy should be performed routinely during surgery for extrahepatic biliary obstruction, including cases of cholelithiasis. Histopathologic evaluation of the liver provides information on the severity and progression of structural liver alterations and may prove beneficial in the diagnosis, prognosis, and long-term management of the patient postoperatively. A biopsy taken from the margin of a liver lobe (guillotine method) or from a more centrally located region of a lobe (biopsy punch technique) should be representative of the generalized parenchymal changes associated with extrahepatic biliary obstruction. Intraoperative culture of bile is essential to appropriately direct antimicrobial therapy in the postoperative period, as well as to provide prognostic information. The presence of septic bile peritonitis (traumatic rupture, cholecystitis, or extrahepatic biliary obstruction) is a negative prognostic indicator with 50% to 75% mortality in dogs, compared with less than 15% mortality for those patients with a nonseptic effusion [21].

Cholecystectomy is preferred over cholecystotomy for stone removal. Secondary changes to the gallbladder that result from the presence of stones or concurrent infection include mucosal hyperplasia, inflammation, and necrosis. Removing the gallbladder eliminates a reservoir for subsequent stone formation and minimizes potential risks of dehiscence or increased morbidity that might occur with cholecystotomy.

Determination of patency of the remaining extrahepatic biliary tract is vital to surgical outcome. A duodenotomy created over the major duodenal papilla allows retrograde cannulation of the bile duct when patency cannot be determined from cannulation through the cystic duct. In cases of biliary obstruction or stricture unrelated to stones, a bile flow diversion procedure should be employed when the obstruction cannot be relieved. Furthermore, in extremely ill patients, temporary external biliary decompression using a cholecystostomy tube or intermittent percutaneous aspiration of the gallbladder should be considered until improved patient homeostasis can be achieved [23]. A definitive but more complicated diversion technique can be used when the patient's condition improves.

When bile diversion is required, cholecystoduodenostomy is the procedure of choice for the dog and cat. A wide anastomotic stoma (2.5 to 4 cm) can be created to reduce the possibility of postoperative stricture and secondary cholangitis. Bile that is redirected into the duodenum maintains normal digestion and intestinal homeostasis.