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Hyperbilirubinemia and recognizing gallbladder mucoceles (Proceedings)
The gallbladder is a thin-walled, muscular tear-dropped shaped sac that lies on the visceral surface of the liver, between the quadrate lobe and the right medial lobe. The gallbladder consists of a fundus, body, and neck, which opens into the cystic duct. The cystic duct then empties into the common bile duct which travels to the duodenum, ending in the major duodenal papilla.
Anatomy and physiology
The gallbladder is a thin-walled, muscular tear-dropped shaped sac that lies on the visceral surface of the liver, between the quadrate lobe and the right medial lobe. The gallbladder consists of a fundus, body, and neck, which opens into the cystic duct. The cystic duct then empties into the common bile duct which travels to the duodenum, ending in the major duodenal papilla. A sphincter is present here, which in humans is termed the sphincter of Oddi. The pancreatic duct also enters the duodenum near the major duodenal papilla, while the larger accessory pancreatic duct enters the duodenum about 2.5 cm caudal at the minor duodenal papilla. Anatomical variations in the canine pancreatic ducts include the presence of an accessory pancreatic duct alone, and the presence of 3 duodenal openings (Slatter). The gallbladder wall is composed of a mucosal epithelial cell layer, a submucosal layer with lamina propria, a middle smooth muscle layer, a layer of connective tissue, and a serosal layer. Blood supply is from the hepatic artery to the cystic artery and into the lamina propria.
The gallbladder's function is to store and modify bile. Bile consists of water, bile acids, pigments, cholesterol, and other inorganic salts; it may also include drugs (such as antimicrobial agents). Bile is secreted continuously by the liver, stored in the gallbladder, and then discharged through the cystic and common bile duct into the duodenum after a meal. During storage in the gallbladder, bile is acidified and concentrated. Hydrogen ions are secreted by the mucosal epithelial cells to acidify the bile, while sodium, chloride, and water are transported across the mucosal lining and reabsorbed. After a meal, bicarbonate-rich fluid is secreted into the gallbladder contents, facilitated by secretin and vasoactive intestinal polypeptide. When fat from a meal enters the duodenum, enterocytes release cholecystokinin (CCK) which is the major trigger for gallbladder contraction as well as relaxation of the sphincter (of Oddi).
Introduction to mucoceles
Gallbladder mucoceles are distended gallbladders formed by excessive accumulation of thick greenish-black gelatinous mucus within the lumen. Mucoceles have become a common cause of hyperbilirubinemia and extrahepatic biliary obstruction in dogs. They have also been reported in human beings and ferrets, but they have not been reported in cats. While they can cause substantial morbidity including gallbladder rupture from distension and ischemic necrosis of the wall, they can also be found incidentally at necropsy (Kovatch, 1965).
Pathogenesis of mucoceles
The primary abnormality with gallbladder mucoceles is proliferation and dysfunction of the mucus-secreting cells in the gallbladder epithelium, characterized histopathologically by cystic mucinous hyperplasia. However, the reason for these changes is not fully understood and is likely multifactorial. Many theories have been proposed including obstruction, inflammation, infection, endocrine, and genetic roles. Many dogs have normal accumulation of biliary sludge in their gallbladders, composed of precipitated cholesterol crystals, mucin, bile pigments, and bile salts. Alterations in gallbladder motility, biliary stasis, and water absorption from the gallbladder predispose sludge formation and may play a role in mucocele formation; however, many dogs have sludge and never develop mucoceles. One theory is that obstruction of the cystic or common bile duct may cause mucoceles to form; however, this theory was disproved when experimental ligation of these ducts did not cause cystic mucinous hyperplasia. Furthermore, extrahepatic bile duct obstruction is not present in all cases of mucoceles, suggesting it can be a secondary complication rather than an inciting cause. A second theory is that choleliths may trigger mucocele formation, but choleliths have only rarely been diagnosed in combination with mucoceles in dogs.
A relationship between mucoceles and glucocorticoids has been proposed, as in one study 9/30 dogs with mucoceles had either hyperadrenocorticism or were receiving exogenous steroids (Pike, 2004). A retrospective investigating the relationship between endocrinopathies and mucoceles found that the odds of mucocele in dogs with hyperadrenocorticism were 29x that of dogs without hyperadrenocorticism (Mesich, 2009). The odds of mucocele in dogs with hypothyroidism were 3x that of dogs without hypothyroidism, but no difference was found in dogs with diabetes mellitus (Mesich, 2009). One possible explanation for the link between mucoceles and glucocorticoids is immunosuppression leading to cholecystitis with bacterial infection, causing increased mucus production; however inflammation and infection are inconsistently present. Glucocorticoids may also affect the bile composition and motility of gallbladders, affecting the pathogenesis of mucoceles, but much further research is needed in this area. An association has also been suggested between mucoceles and hyperlipidemia or dyslipidemia of genetic origin in Shetland sheepdogs, with 70% of shelties with biliary disease showing hypercholesterolemia and 50% showing hypertriglyceridemia after 48 hours of anorexia (Aguirre, 2007).
Studies have shown mixed results for the role of infection in gallbladder mucoceles. Positive bacterial cultures were identified from 6/9 cases (Besso, 2000), 2/23 cases (Pike, 2004), 1/6 cases (Mayhew, 2008), and 1/8 cases (Worley, 2004), and included E. coli, Enterobacter, Staphylococcus, Streptococcus, Proteus, and Enterococcus spp. Although perioperative use of antibiotic administration prior to sampling may have contributed to differences in bacterial growth in these studies, histopathology of the surgical cases did not support a primary bacterial etiology. Proposed sources of bacteria include ascension through the common bile duct from the duodenal flora or hematogenous spread. The role of inflammation has also been discussed regarding the pathogenesis of mucoceles, but there is no clearly established cause or effect relationship; secondary inflammation may be a result of ischemia from overdistension, bacteria, or toxic effects of retained bile acids.
Finally, a recent study identified an insertion mutation in ABCB4, which functions as a phospholipid translocator on cannalicular membranes of hepatocytes, translocating phosphatidylcholine into the biliary lumen. This insertion mutation was found to be associated with gallbladder mucocele in shelties and other breeds and may contribute to the pathogenesis of this condition (Mealey, 2010). While the breed predisposition of mucoceles supports the role of genetics in the pathogenesis of mucoceles, the apparent increase in frequency of gallbladder mucoceles overall suggests there could also be a role for environmental or nutritional factors that have yet to be determined.
The typical signalment of dogs with gallbladder mucoceles is older (median age 9yrs), small to medium-sized dogs, with no sex predilection. Commonly affected breeds include Shetland sheepdogs, cocker spaniels, miniature poodles, miniature schnauzers, and terriers. Gallbladder mucoceles may not cause any clinical signs (23%) or may cause signs consistent with hepatobiliary disease, including anorexia (65%), vomiting (70%), lethargy (65%), polyuria/polydipsia (27%), and diarrhea (12.5%); these are summarized percentages from multiple studies (Cornejo, 2005). Owners may note icterus prior to presentation. Many affected dogs are acutely ill, with signs occurring for less than 1 week prior to presentation; however chronic mild vague signs could be due to a developing mucocele or concurrent disease (such as hyperadrenocorticism).
Dogs may be normal on physical exam, but icterus and abdominal pain are common. Fever may be present. In dogs whose gallbladders have ruptured and have developed bile or bacterial peritonitis, shock may be evident.
A complete blood count may be normal or show a mature neutrophilia, with normal hematocrit and platelet counts. Increased liver enzyme activity and hyperbilirubinemia are very common, occurring in greater than 2/3 of all cases. Interestingly, when evaluating only cases with documented gallbladder rupture at surgery, Pike et al found that 12/14 had elevated bilirubin preoperatively. Median ALT (797 vs. 392 U/L) and ALP (6369 vs. 448 U/L) were significantly greater in dogs with ruptured gallbladders than those with nonruptured gallbladders. Hypercholesterolemia and hypertriglyceridemia are common in dogs with mucoceles, from a combination of genetic predisposition, cholestasis, and in some cases concurrent hypothyroidism. Elevated lactate was found in 8/8 dogs with ruptured gallbladders, while 3/3 dogs with nonruptured gallbladders had normal lactate concentrations (Pike, 2004). Affected dogs may also have prolonged clotting times, perhaps due to cholestasis interfering with intestinal absorption of vitamin K.
Survey radiographs may be helpful to rule out other causes of acute abdominal pain such as intestinal obstruction, but ultrasonography is the primary tool for diagnosing mucoceles. The ultrasonographic appearance of a mucocele is echogenic material within the lumen of a distended gallbladder, having a stellate, striated, or mixed pattern. Gallbladder contents will be immobile, regardless of patient positioning, which differs from normal biliary sludge that is quite mobile. The gallbladder wall should be closely inspected for continuity and evidence of intramural gas, which would suggest rupture. Other suggestive signs of rupture include hyperechoic cranial abdominal fat, a hypoechoic ring surrounding the gallbladder, free abdominal fluid, or the presence of striated or stellate echogenic material in the peritoneal cavity (Pike, 2004). Despite these clues, a skilled ultrasonographer was only able to detect rupture in 85% of patients with ruptured gallbladder mucoceles in the review by Pike et al.
The benefit of an ultrasound-guided bile aspirate to collect a sample for culture and susceptibility is yet to be determined. If the patient will proceed to surgery, collection of this sample should be obtained at surgery. Risks of an ultrasound-guided bile aspirate in a patient with a mucocele could include iatrogenic leakage of bile into the peritoneum, peritonitis, hemorrhage, and vasovagal reaction. If this procedure is elected, it may be helpful to aspirate as much bile as possible in attempt to minimize pressure and post-procedural leakage, although this can be challenging due to its viscous nature. The benefits of a bile culture should be strongly weighed against potential procedural risks for each individual patient.
Therapeutic options for gallbladder mucoceles
In many cases, medical management may be appropriate for gallbladder mucoceles, but case selection is essential. Although case reports have suggested success with medically managing gallbladder mucoceles, no prospective studies have been performed to determine appropriate case selection and which medications, if any, may be helpful (Walter, 2008). Medical management should be reserved for asymptomatic patients documented with ultrasound to have non-obstructive disease, with no evidence of gallbladder rupture. Medical management may also be preferred in cases where concurrent disease suggests the risk of anesthesia and surgery outweigh their benefits. Treatment can include ursodeoxcholic acid (ursodiol), at the recommended dose of 15mg/kg by mouth every 24 hours. Ursodiol is a choleretic that can stimulate bile flow, thus improving clearance of biliary secretions; however its use is contraindicated in cases of complete biliary obstruction. Ursodiol is also a hydrophilic non-toxic bile acid, which can compete with and balance out more toxic bile acids secreted during the cholestatic state that can otherwise contribute to further hepatic damage. Other properties of ursodiol may include reducing hepatocellular injury and fibrosis, modulating immune responses, and preventing bile-acid induced peroxidation. These patients should be monitored closely for changes in clinical signs, and should be reevaluated if they develop acute vomiting, lethargy, anorexia, or icterus. Liver enzyme activity, serum bilirubin, and abdominal ultrasound should also be monitored routinely (every 1-3 months) so that changes may be followed. Antimicrobial therapy may also be indicated for medical management of mucoceles, based on culture and susceptibility of bile. Prospective research evaluating medical therapy versus no medication would be very beneficial for future management of stable patients with this condition.
Cholecystectomy is the preferred method of treatment for a patient with an ultrasonographic appearance of a gallbladder mucocele with evidence of obstruction or rupture, and consistent clinical signs and laboratory abnormalities. The timing of surgical intervention depends on the stability of the patient and whether the gallbladder and bile duct remains intact. For patients with evidence of gallbladder rupture, emergency surgery is indicated. For patients with evidence of mucocele and biliary obstruction (not ruptured), with consistent clinical and laboratory signs, surgery should be scheduled as soon as possible (within 24-48 hours); as long as these patients remain stable, it is wise to wait until full surgical and anesthetic staff and resources are available to assist with the procedure. Surgery can also be considered for mucoceles without evidence of obstruction, as an elective procedure to minimize future complications.
Preoperatively, dogs should be stabilized as much as possible by correcting fluid and electrolyte abnormalities. Administering vitamin K1 or fresh frozen plasma may also be indicated based on clotting profile. Perioperative antibiotics are typically administered (ampicillin/enrofloxacin, or ampicillin-sulbactam). The detailed surgical procedure for the cholecystectomy can be found in a surgical text (Slatter). At surgery, the gallbladder and biliary tree should be examined to determine if they remain intact or have ruptured. In one review, of 14 cases with gallbladder rupture, 12 ruptured at the fundus, and 2 ruptured at the neck of the gallbladder (Pike, 2004). The cystic and common bile ducts should always be flushed to check for patency in patients with elevated bilirubin and/or duct system distention. The gallbladder should then be removed and submitted for histopathology, along with a liver biopsy. In one review of 22 dogs with mucoceles, all patients had hepatic abnormalities detected histologically (Worley, 2004). Aerobic and anaerobic cultures of bile should also be submitted. The abdomen should be flushed extensively with saline prior to closing; drain placement may be needed for cases of bile or bacterial peritonitis. Postoperative antibiotics are provided due to risk of iatrogenic ascending infection of the liver (4+ weeks). Reported complications in 35 summarized patients with surgical cholecystectomy include bile peritonitis (5), cardiac arrest on recovery (3), pneumonia (2), pulmonary edema (1), pulmonary thromboembolism (1), pancreatitis (1), and recurrence of signs(1) (Cornejo, 2005; Pike, 2004; Besso, 2000; Newell, 1995).
Laparoscopy has also been used to perform cholecystectomies for uncomplicated gallbladder mucocele patients (Mayhew, 2008). Six dogs with ultrasonographic confirmed mucoceles but without evidence of obstruction, rupture, or peritonitis were included in Mayhew's pilot study to evaluate the feasibility of this technique. Five of six dogs had intermittent clinical signs including vomiting, inappetance, and lethargy prior to the procedure. Laparoscopic cholecystectomy was successful in all 6 cases. One dog developed post-procedural hyperbilirubinemia which normalized within 2 days; no other perioperative complications occurred. Potential complications could include bile peritonitis, inadequate cystic duct ligation, and inadvertent ligation of the common bile duct. Surgical time ranged from 95-180 minutes, which improved with the author's learning curve, but is still likely longer than open surgery for an experienced surgeon. Two additional dogs fit initial study criteria, but when bile pigments were seen on falciform fat, liver, or omentum at the start of laparoscopy these patients' surgeries were converted to an open abdominal approach. All dogs were alive at the time the report was published (median 8 months postoperatively). Conclusions from Mayhew's study were that laparoscopic cholecystectomy is a minimally invasive procedure that can be successful for managing uncomplicated gallbladder mucoceles in dogs; however a surgeon should be always prepared to convert from laparoscopy to laparotomy during the procedure, if indicated.
It is important to work with an experienced surgeon and to monitor patients closely post-operatively, because perioperative mortality has been reported to range from 22% (Pike, 2004) to 40% (Besso, 2000). No significant difference in survival has been reported between dogs that had gallbladder rupture versus intact gallbladders; however this may be due to prompt surgical intervention and small sample study size (Pike, 2004). One study assessed pre- and postoperative risk factors involved in biliary surgery (Amsellam, 2006). Preoperative risk factors for death include: increased age, increased pre-anesthetic heart rate, high GGT activity, and high BUN, phosphorus, and bilirubin concentrations (Amsellam, 2006). Postoperative risk factors for death include: hypotension, dyspnea (aspiration pneumonia, ARDS, PTE, or overhydration), hypoalbuminemia, high percentage of band cells, and pancreatitis (Amsellam, 2006). Of dogs that survive to discharge, it is common to see complete resolution of signs related to the mucocele and an excellent prognosis. Follow-up ultrasound may show persistent dilated common bile duct (4/12 dogs), but with resolved, normal serum bilirubin, suggesting that this dilation may be of no clinical significance (Pike, 2004).
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