Managing disorders of the gallbladder in dogs (Proceedings)

Basic Gallbladder Anatomy and Physiology

The gallbladder is a small, pear-shaped organ located in the cranial abdomen between the right medial and quadrate liver lobes.1 Bile is synthesized by hepatocytes and collects within canaliculi and is sequentially drained from into bile ductules, interlobular, lobar and hepatic ducts. 1,2 Hepatic ducts coalesce and join the cystic duct (extends from the neck of the gallbladder) to form the common bile duct 3. In the dog, the common bile duct empties into the duodenum at the major duodenal papilla. Bile is composed of water, bile acids, bilirubin, cholesterol and electrolytes1,3. The physiologic functions of bile are to: (1) Enhance fat digestion by emulsifying fat into smaller particles that are more susceptible to the actions of pancreatic lipase; (2) Enhance ileal absorption of digested fats; (3) Aid in the excretion of cholesterol1,3. Within the gallbladder bile is acidified and concentrated via the absorption of water, lipids, proteins and electrolytes2,3. Glands within the gallbladder mucosa secrete mucin into the gallbladder lumen to protect the organ from the cytotoxic effects of bile acids2. Gallbladder contraction is stimulated by cholecystokinin; a gastrointestinal peptide released from enterocytes in response to fat and proteins entering the small intestine1,3.

Extrahepatic Biliary Obstruction (EHBO):

Obstruction of bile flow through the common bile duct can occur secondary to gallbladder mucocele, cholelithiasis, pancreatitis, neoplasia (biliary, hepatic, pancreatic, intestinal, surrounding structures) and stricture, among other causes2,4. Regardless of the underlying cause, surgical exploration of the abdomen, focusing on the biliary tree and liver, is generally required. As such, prompt diagnosis of EHBO is important. Clinical signs of acute EHBO can include lethargy, vomiting, fever and rapid development of icterus2. Although gradual obstruction of the common bile duct is most common, most patients will present acutely when clinical icterus develops4. Additional clinical signs include lethargy, anorexia, vomiting and cranial abdominal pain. Occasionally, clinical signs may wax and wane for several weeks4. Icterus of post-hepatic origin is characterized by hyperbilirubinemia, bilirubinuria, increased serum activities of cholestatic (ALP and GGT) +/- hepatocellular leakage (ALT, AST) enzymes, +/- hypercholesterolemia and consistent diagnostic imaging findings. Hematocrit is expected to be normal or near normal except in cases with concurrent hemorrhage (often due to gastrointestinal ulceration) or if the icterus is of pre-hepatic origin (i.e. hemolytic anemia). Abdominal ultrasound is an important tool is assessing the hepatobiliary system. Distension of the gallbladder and common bile duct is evident ultrasonographically within 24-48 hours of complete EHBO, while distension of the intra-hepatic bile ducts is evident after 5-7 days2,5. Bile duct diameter cannot be used to determine the chronicity or severity of obstruction2. Treatment generally requires surgical exploration of the hepatobiliary system and biliary decompression, cholecystectomy or cholecystoenterostomy, depending on the site and cause of the obstruction. If the common bile duct can be catheterized across the obstructive lesion, choledochal biliary stenting may be an appropriate option2,6.

Gallbladder Mucocele

A gallbladder mucocele is an abnormal accumulation of bile laden mucoid material within the gallbladder1,3,7. In recent years, gallbladder mucoceles have emerged as a common cause of canine extrahepatic biliary disease1,3,7,8. Whether this represents a true increase in disease prevalence or is a reflection of the increasingly routine use of abdominal ultrasound is unknown9. Inspissated bile and mucus can extend into the biliary tree, resulting in varying degrees of extrahepatic biliary obstruction (EHBO)2,7,10. Gallbladder rupture and bile peritonitis secondary to ischemic necrosis of the gallbladder wall are potential complications1,11. Hyperplasia of the mucosal mucus-secreting glands is a consistent histological feature of gallbladder mucoceles7,8. Mucocele formation likely results from hyperplasia of the mucus secreting glands with resultant hypersecretion of mucus into the gallbladder lumen3,7. Progressive biliary stasis with continued water absorption leads to the formation of solid, immobile gallbladder contents3. The etiology of gallbladder mucosal cell hyperplasia is unknown, although decreased gallbladder motility with prolonged exposure to cytotoxic biliary salts has been proposed.

Gallbladder mucoceles occur most commonly in mature (median age of 10-11 years), medium to small breed dogs7,11. Shetland sheepdogs9 and seemingly Cocker Spaniels and Miniature Schnauzers7,11 are predisposed1-3. Clinical signs are non-specific and most commonly include vomiting, abdominal pain, anorexia, lethargy, polyuria/polydipsia and diarrhea2,3,7,11. The duration of clinical signs will depend on the rate of mucocele formation, degree of EHBO and development of complications such as bile peritonitis. Clinical illness is generally acute ( ≤ 5-7 days) but can wax and wane for several weeks or months2,11. As many as 25% of dogs with gallbladder mucoceles are asymptomatic for the condition with the mucocele identified incidentally on routine abdominal ultrasound1,3,7. Abnormalities observed on physical examination often include icterus, tachypnea, tachycardia, fever and abdominal distension2,7-9. Abdominal pain, icterus, tachycardia, tachypnea and fever are suggestive of gallbladder rupture2. The most common serum biochemistry abnormality is increased ALP activity1,9. Increased serum activities of GGT, ALT and AST and hyperbilirubinemia are also common2,3,7. Hypercholesterolemia is suggestive of bile duct obstruction1 or dyslipidemia. Leukocytosis characterized by a mature neutrophilia and monocytosis are the most common complete blood count abnormalities2,7. Toxic changes to neutrophils, especially in conjunction with a left shift, should raise concern for bile peritonitis1. Serum ALP and AST activities, serum bilirubin concentration and total white blood cell count are higher in dogs with gallbladder rupture than in dogs without7.

Although useful for excluding other conditions, abdominal radiographs are generally inadequate for diagnosis of a gallbladder mucocele1. The classic ultrasonographic features of a gallbladder mucocele are a "kiwi fruit" pattern of hyperechoic striations12. Other irregular, stellate or finely striated bile patterns are also possible8. Importantly, the biliary pattern is immobile (i.e. absence of gravity dependent movement), thereby differing from biliary sludge8. Cystic and / or common bile duct dilation is often absent despite confirmed biliary obstruction8. The sensitivity of ultrasound for detection of gallbladder rupture in dogs with mucoceles is only 86%7. Discontinuity of the gallbladder wall is indicative of while pericholecystic hyperechoic fat, pericholecystic fluid and free abdominal fluid are each suggestive of gallbladder rupture2,8.

Exploratory laparotomy with cholecystectomy or cholecystoenterostomy is indicated in dogs with gallbladder rupture, bile or septic peritonitis or clinical and or biochemical abnormalities consistent with extrahepatic biliary obstruction. Referral to a centre with surgical and critical care expertise is strongly recommended. Because vitamin K is a fat soluble vitamin that requires bile for absorption, prolongation of clotting time can occur in animals with EHBO. As such, a pre-operative coagulation profile is indicated. Vitamin K1 (0.5 mg/kg SQ q12 hours for 3 doses) has been recommended for all dogs, even if coagulation profile results are normal3. A liver biopsy should be obtained at the time of surgery as concurrent hepatic abnormalities are common. Peri-operative mortality rates are reported to range from 21.7-40%7,8,11. Peri-operative mortality is higher in dogs with gallbladder rupture (62%) compared to dogs without (32%)9. Peri-operative complications include pancreatitis, bile or septic peritonitis, cholecystitis and aspiration pneumonia. Long term survival can be expected in patients that survive the peri-operative period. Long term management of post operative patients should include cholerectics and antioxidants (see below).

Although resolution of gallbladder mucocele with medical management alone was recently described in 2 dogs13 , the true therapeutic efficacy, risks and prognosis of medical management are unknown. Surgical management remains the treatment of choice until additional data regarding medical management is available. Medical management of gallbladder mucoceles should only be considered in asymptomatic patients without EHBO or ultrasonographic evidence of gallbladder rupture and owners that are unable / unwilling to pursue surgical treatment. Dogs treated medically should be prescribed cholerectics (ursodeoxycholic acid 7.5 mg/kg PO q12hrs or 15 mg/kg PO q24 hrs) and an antioxidant (s-adenosylmethionine 20-40 mg/kg PO q24hrs on empty stomach or silymarin 20-50 mg/kg PO q24 hrs). Empirical antibiotic therapy is not indicated as intact mucoceles are infrequently associated with bacterial infection. Dogs with hypertriglyceridemia or pancreatitis (acute or chronic) should be fed a fat restricted diet. Patients should be re-evaluated monthly including abdominal ultrasound to monitor gallbladder status, serum biochemical / hepatic profile +/- complete blood count2,3 until the mucocele resolves or after 6 months of stable disease. Owners must be made aware of the clinical signs, risks and potential complications of EHBO and gallbladder rupture. Mucocele resolution, stable disease and progression to gallbladder rupture have all been reported as sequelae of medical management9.

Cholecystitis

Cholecystitis is a broad term describing inflammation of the gallbladder attributed to infection (bacterial or parasitic), blunt abdominal trauma, cystic duct occlusion (e.g. cholelithiasis) cystic artery thrombosis or neoplasia2. Cholecystitis is often categorized as non-necrotizing, necrotizing or emphysematous. Dogs with mild, non-necrotizing cholecystitis may be asymptomatic. Clinical signs of chronic inflammation may be intermittent and include anorexia, vomiting, and weight loss1. Dogs with moderate to severe, potentially necrotizing cholecystitis, typically present with anorexia, vomiting, abdominal pain and fever1,2. Increased serum liver enzyme activities, specifically ALP and GGT, are common but the finding of hyperbilirubinemia is variable1,2. CBC findings are as per "Gallbladder mucocele" above. Abdominal radiographs may reveal decreased cranial or generalized serosal detail secondary to abdominal effusion, ileus, cholelithiasis or dystrophic mineralization of the gallbladder wall1,2. Abdominal ultrasound findings often include thickened gallbladder wall, thickened common bile duct, EHBO and, less commonly, choleliths or mineralization of the gallbladder wall1,2. Evidence of gallbladder rupture is as per "Gallbladder mucocele" above. Pericholecystic and / or abdominal fluid should be sampled for cytological analysis and bacterial culture (aerobic and anaerobic). Suppurative, septic or non-septic, inflammation is characteristic. Abdominal fluid total bilirubin concentration greater than twice the serum total bilirubin concentration is consistent with bile peritonitis1.

Medical management can be considered for patients with mild clinical signs without evidence of EHBO or gallbladder rupture. Medical management should focus on fluid therapy, nutritional support, pain management and antibiotics. Antibiotic choice is ideally based on bacterial culture and sensitivity testing of bile obtained by cholecystocentesis or abdominal fluid collected by abdominocentesis. Alternatively, empiric antibiotic choices should target the most common bacterial, Enterococcus spp., Bacteroides spp., Streptococcus spp., and Clostridium spp. is indicated14. Treatment with amoxicillin/clavulanate (anaerobes and gram-positive aerobes) and a fluorquinolone (gram negative aerobes) is a rational choice14. Antibiotic therapy should be continued for 4 weeks beyond resolution of clinical signs. Cholerectics and antioxidants can be administered as per "Gallbladder mucocele". Exploratory laparotomy with cholecystectomy or cholecystoenterostomy is indicated in dogs clinical, hematological, biochemical or imaging data suggestive of EHBO, gallbladder rupture or peritonitis. Referral to a centre with surgical and critical care expertise is strongly recommended. In addition to gallbladder and liver histology, aerobic and anaerobic of bile, gallbladder wall, liver and abdominal fluid should be submitted2. The prognosis is good (75% survival rate) for dogs with cholecystitis treated surgically4. Dogs with septic peritonitis have significantly higher mortality rates4.

The finding of gas within the lumen or tissues of the gallbladder or biliary tree is referred to as emphysematous cholecystitis. Dogs with diabetes mellitus are at increased risk. Identification of spherical gas opacity overlying the hepatic silhouette on abdominal radiographs and / or gas within the biliary tree on abdominal ultrasound is diagnostic1,2. Clostridium perfringens and E.coli are the most commonly isolated organisms1,2. Prompt patient stabilization, antimicrobial therapy (fluorquinolone or metronidazole pending culture and sensitivity results) and cholecystectomy are indicated. In addition to gallbladder and liver histology, aerobic and anaerobic of bile, gallbladder wall, liver and abdominal fluid should be submitted2.

Cholelithiasis

Gallbladder stones occur most commonly in middle-aged to older small breed dogs such as Miniature Schnauzers and Miniature Poodles1,2. Choleliths may be identified within the gallbladder (most commonly), common bile duct (choledocolithiasis), hepatic or interlobular ducts2. Canine choleliths are generally composed of cholesterol, bile pigments and calcium carbonate. Choleliths may cause obstruction and / or inflammation of the gallbladder and biliary tree or may be incidental ultrasonographic or necropsy findings5. Radiodense choleliths appear as single or multiple mineral densities in the cranioventral (lateral view) or right cranial abdomen (ventrodorsal view)1. The canine gallbladder absorbs calcium from bile, thereby limiting cholelith mineralization and possibly protecting against cholelith formation1,4,5. As such, many choleliths are of insufficient mineral density to be visualized radiographically1. Abdominal ultrasound can readily identify both radiodense and radiopaque choleliths within the gallbladder however, identification of stones within the bile ducts is more challenging2. Choleliths of sufficient size (≥ 2mm) and density should produce a strong acoustic shadow2. In the case of EHBO, secondary cholecystitis or gallbladder rupture, clinical signs, biochemical and hematological abnormalities and imaging findings are as previously described. Intermittent and chronic abdominal pain has been associated with cholelithiasis2. Surgical intervention is indicated in dogs with clinical, biochemical or imaging findings consistent with EHBO, gallbladder rupture, severe cholecystitis or bile peritonitis. Medical dissolution of choleliths has not been described. Asymptomatic patients may not require treatment but careful monitoring is recommended.

Biliary Tract Obstruction Secondary To Pancreatic Disease

Due to the close anatomic relationship of the common bile duct to the pancreas, pancreatic abnormalities (acute pancreatitis, pancreatic abscess or pseudocyst, pancreatic neoplasia or periductal fibrosis) can cause EHBO4,5,15. In most cases of EHBO secondary to acute pancreatitis, the obstruction resolves as pancreatic inflammation and edema improve15. When surgical relief of the obstruction is required peri-operative mortality rates of at least 50% are reported4,15. Recently, therapeutic percutaneous ultrasound-guided cholecystocentesis was described in three dogs with EHBO and pancreatitis.

Neoplasia

Primary tumours of the canine gallbladder or biliary tree are rare. Biliary adenocarcinoma is most common although biliary adenomas have been described. Adenocarcinomas are highly metastatic, often having spread to local lymph nodes, other abdominal organs, lungs or bone by the time of diagnosis16. Surgical excision can be considered for tumours confined to one liver lobe without evidence of metastatic disease16.

Other:Traumatic rupture of the biliary tree (blunt abdominal trauma, gunshot wounds, bite wounds, etc) is an important etiology of bile peritonitis in canine patients4. Other rare conditions of the canine gallbladder include gallbladder torsion and porcelain gallbladder (extensive calcification of the gallbladder wall).

References

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