An update on gallbladder mucoceles in dogs

Before 2000, gallbladder mucoceles were rarely reported in dogs. However, they are now considered one of the more common causes of extrahepatic biliary disease. While gallbladder mucoceles were initially treated by cholecystectomy, case-based evidence indicates that some may resolve with medical therapy.1

In this article, we review gallbladder anatomy and physiology and discuss the pathophysiology of mucocele development. We also describe the clinical presentation, diagnosis, and management of dogs with gallbladder mucoceles.

GALLBLADDER ANATOMY

The gallbladder is an excretory organ found between the quadrate and right medial liver lobes. It is pear-shaped and composed of a fundus, body, and neck. From the gallbladder's neck, the hepatic ducts join the cystic duct to form the common bile duct, which leads to the duodenum.

The gallbladder wall has five layers: epithelium, mucosa, tunica muscularis externa, tunica serosa, and tunica adventitia.2

1. The epithelium is simple columnar and highly absorptive. It plays an important role in gallbladder function because it secretes mucin, immunoglobulins, and acid.

2. The mucosa is a combined layer consisting of the lamina propria and tunica submucosa.2 These layers of the mucosa are indistinguishable and contain a dense population of lymphocytes and plasma cells.

3. The tunica muscularis externa consists of scant, randomly organized smooth muscle fibers.

4. The tunica serosa is a membranous layer surrounding the gallbladder that faces away from the liver.

5. The tunica adventitia is the outermost gallbladder layer and faces the liver.

GALLBLADDER FUNCTIONS

The gallbladder plays many important roles in digestive health and function, including storing and concentrating bile. Within the gallbladder, water, electrolytes, lipids, and proteins are absorbed from the bile. This absorption allows for a five- to 20-time increase in bile bilirubin and bile salt concentrations. The gallbladder also acidifies bile through epithelial acid secretions and adds mucin to bile by bile acid stimulation of the mucosa.

GALLBLADDER PHYSIOLOGY

Bile

Bile is required for the successful digestion and absorption of nutrients. It aids in fat digestion and absorption by emulsifying large fat particles into smaller ones that are more susceptible to pancreatic lipase. Bile also enhances intestinal absorption of digested fats and aids in the excretion of waste products, including cholesterol and bilirubin.

Bile is produced by hepatocytes and collected in the hepatic canaliculi. From the canaliculi, bile drains into interlobular ducts. These ducts progressively merge to form hepatic ducts, which join the cystic duct to form the common bile duct.

The common bile duct enters the duodenal lumen at the major duodenal papilla; this junction is commonly referred to as the sphincter of Oddi. The pancreatic duct also empties into the small intestine at this point.

The pH of bile ranges from 5.9 to 7.8. Bile is made of water, bile acids, bilirubin, cholesterol, lecithin, and electrolytes.3 Although some bile flows directly into the small intestine from the liver, most of it is temporarily stored in the gallbladder. Substantial bile modifications occur within the gallbladder: sodium, chloride, and water are removed and hydrogen ions are added. After a meal, the gallbladder also secretes bicarbonate-rich mucin, which mixes with the stored bile. The gallbladder contents become inspissated (sludgelike) when more fluid is reabsorbed or more mucin is added.

Biliary sludge

Biliary sludge is a mobile mixture of precipitated cholesterol crystals, bile pigments, bile salts, and mucin. In people, inspissated bile is considered abnormal and is associated with cholestasis, choleliths, cholecystitis, biliary infection, fasting, and partial parenteral nutrition.4 In dogs, biliary sludge may be associated with disease but is also often seen in clinically normal geriatric dogs.5 At present, the significance of biliary sludge in dogs is unknown.

Gallbladder contraction

The gallbladder musculature contracts in response to cholecystokinin; this hormone is released from enterocytes after the ingestion of a fatty meal. In particular, proteoses, peptones, and long-chain fatty acids stimulate cholecystokinin release. Cholecystokinin concentrations peak about 20 minutes after a meal and may remain elevated for almost two hours. Once the gallbladder contracts, its contents are emptied into the duodenum within about 60 minutes.3 Cholecystokinin also causes relaxation of the sphincter of Oddi and the release of pancreatic digestive enzymes.

Other factors that contribute to gallbladder contraction include parasympathetic stimulation by the vagus nerve, sympathetic inhibition of the splanchnic nerve, neurotensin, and substance P.6-8

Gallbladder relaxation

The gallbladder relaxes in response to somatostatin, vasoactive intestinal polypeptide, nitric oxide, and pancreatic polypeptide.3,6,9 The relaxation phase is associated with bile storage and modification. During this period, the sphincter of Oddi is closed.

GALLBLADDER MUCOCELE PATHOPHYSIOLOGY

A gallbladder mucocele is an abnormally distended gallbladder containing a buildup of luminal mucus. Grossly, the gallbladder appears enlarged (unless it is ruptured) and contains gelatinous material that may be congealed mucus, a mucus cast, or inspissated bile (Figures 1 & 2).

Figure 1. A surgically removed canine gallbladder with a mucocele. The cystic duct has been ligated and removed, and the resultant opening allows visualization into the distended gallbladder. (Image courtesy of Dr. Roy R. Pool, Texas A&M University's Department of Veterinary Pathobiology.)

Before 2000, mucoceles were considered rare.10 In fact, most were noted as incidental necropsy findings.11 Given the diagnostic tools available at the time, the true clinical impact and incidence of mucoceles before the 1990s are unknown.

Figure 2. A longitudinal cross section of the gallbladder shown in Figure 1. The yellow material is the mucocele, and the black material is bile. The pink area is a hematoma that developed during surgical excision. (Image courtesy of Dr. Roy R. Pool, Texas A&M University's Department of Veterinary Pathobiology.)

Predisposition to mucoceles may be associated with dyslipidemias in particular breeds such as Shetland sheepdogs.12 While extrahepatic biliary duct obstruction is a recognized cause of mucocele formation in people, prospective studies in dogs do not support this finding.13 Conversely, it appears that extrahepatic biliary duct obstruction is secondary to mucocele formation.14 Other suggested causes of canine mucocele formation include progestational therapy or progestational compounds, cholecystitis, and glucocorticoid excess.4,15,16 To date, none of these theories has been widely supported.

It has been proposed that mucocele formation is the result of progressive biliary sludging.17 As biliary sludge forms and progresses, gallbladder motility may be decreased, resulting in biliary stasis and increased water absorption. As the gallbladder continues to absorb water, its contents become more solid and immobile.

The most widely supported theory of canine mucocele formation implicates mucus-secreting cell proliferation and dysfunction.18 In this condition, cystic mucinous hyperplasia of the gallbladder epithelium occurs, and the gallbladder epithelial cells secrete excessive mucus into the gallbladder lumen. This condition may be a primary defect (an inherent disorder of the mucous cells) or a secondary defect (exposure to excessive bile salts).19

DIAGNOSING GALLBLADDER MUCOCELES

History and signalment

Most patients with mucoceles are older (average age of 9 years), and no sex predilection has been established.11 Mucoceles are usually reported in small or medium-sized dogs, and Shetland sheepdogs and cocker spaniels are overrepresented.20 In one study, 66% of Shetland sheepdogs with gallbladder disease had confirmed mucoceles.12

Clinical signs

About 77% of patients with mucoceles are clinically ill, often with an acute onset of signs.21 Vomiting, anorexia, lethargy, polyuria, polydipsia, and diarrhea are most often reported.21 Cumulatively, studies have shown that almost one-quarter of patients with mucoceles were asymptomatic.10,14,17,18,22

Physical examination findings

The most common physical examination findings in patients with mucoceles are abdominal pain and icterus. A small percentage of patients may be febrile or have abdominal distention.18

Diagnostic test results

Laboratory evaluation and radiographic findings may vary, but common results are listed in Table 1. It may be difficult to appreciate the differences between biliary sludge and a true mucocele on ultrasonographic examination. Biliary sludge is movable and gravity-dependent, whereas a mucocele is immobile and displays a distinctive striated or stellate (kiwi fruit or starfish) pattern (Figures 3 & 4).17

Figure 3. A transverse ultrasonogram of a canine gallbladder containing normal biliary sludge. The echogenic material within the gallbladder has fallen dorsally, and the supernatant of more normal bile can be appreciated ventrally as an anechoic area. (Image courtesy of Dr. Benjamin D. Young, Texas A&M University's Large Animal Clinical Sciences Department of Radiology.)

If differentiation is difficult, a second ultrasonographic examination after the administration of a cholagogue (an agent that promotes increased bile flow from the gallbladder, such as cholecystokinin octapeptide given intravenously over one minute at a dose of 0.04 µg/kg23 ) may be helpful. If a patient has biliary sludge, gallbladder contraction occurs within 10 minutes, and a substantial (about 40%) reduction in gallbladder volume will be evident.23

Figure 4. A transverse ultrasonogram of a canine gallbladder containing a mucocele. This image demonstrates the classic stellate pattern and nongravity-dependent gallbladder contents pathognomonic for mucoceles. (Image courtesy of Dr. Benjamin D. Young, Texas A&M University's Large Animal Clinical Sciences Department of Radiology.)

In addition to the tests listed in Table 1, cholecystocentesis may be performed, as well as aerobic and anaerobic bacterial cultures of the bile. Anywhere from 9% to 43% of patients with mucoceles may have biliary bacterial infections, and bacterial populations are often mixed. The most common isolates are Escherichia coli and Enterobacter, Enterococcus, and Clostridium species.24 The bacterial infections are thought to ascend from the intestines but may also be hematogenous in origin.

Table 1: Common Diagnostic Test Results in Dogs with Gallbladder Mucoceles

Histopathology

A true mucocele has hyperplastic mucus-secreting glands and may also demonstrate inflammatory infiltrates.17 In one study, gallbladder wall necrosis was diagnosed in 80% of patients with mucoceles, and hepatic pathology was often present.17 The most common hepatic changes include cholestasis, neutrophilic inflammation, and bacterial infection.20

TREATMENT OPTIONS

Emergency surgery is necessary if the gallbladder has ruptured or a patient has septic peritonitis. Surgery is also indicated if a dog is clinically compromised or has evidence of extrahepatic biliary duct obstruction, but the patient may need to be stabilized with fluids, intravenous antibiotics (Table 2), antiemetics, and analgesics before anesthesia.21 Time to stabilization will vary greatly for each patient and may require one to three days. If the patient has biochemical changes but is asymptomatic or has only mild clinical signs, medical management appears to be an appropriate choice.1

Surgical management

Preoperative diagnostic tests, including a complete blood count, serum chemistry profile, urinalysis, and coagulation panel, are indicated. Treat all patients with appropriate intravenous fluids, and any electrolyte derangements must be addressed before surgery. Vitamin K1 therapy is also recommended (Table 2) in all dogs, even if the results of preoperative coagulation panels are normal.21 Start subcutaneous vitamin K1 therapy 24 hours before surgery to allow adequate time for the production of vitamin K-dependent coagulation factors. Continue therapy until bile flow is normal, typically two to four days after surgery.

Table 2: Drugs Commonly Used in the Perioperative and Medical Management of Dogs with Gallbladder Mucoceles

During surgery, a complete abdominal exploratory is recommended so that concurrent or occult problems can be identified and addressed. While several surgical techniques are described, cholecystectomy has many advantages, as removal of the gallbladder prohibits secondary gallbladder infection and rupture.18 Other surgeries that have been described include cholecystotomy, cholecystoduodenostomy, and cholecystojejunostomy.25 Cholecystotomy is a suboptimal choice given the disease process and possible associated gallbladder wall compromise.

The surgical evaluation should also include expressing or cannulating the common bile duct, performing liver biopsy, and collecting bile and liver samples for aerobic and anaerobic culture. In patients with biliary rupture, extensively flush the peritoneal cavity, and place abdominal drains.

Perioperative care includes broad-spectrum antibiotics (adjusted based on culture results), hepatoprotectants, and a low-fat diet. The most common complications of cholecystectomy include pancreatitis and bile peritonitis; death is also common.14,17,18 Chronic vomiting occurs infrequently. The perioperative mortality rate associated with cholecystectomy is moderate, with 22% to 40% of patients dying within 14 days of surgery.14,17,18 Patients that survive this period have excellent long-term survival rates. In general, the morbidity and mortality rates of patients with extrahepatic biliary duct obstruction undergoing biliary diversion procedures are higher than those undergoing cholecystotomy.26 Unfortunately, no reliable predictors for survival exist.

Medical management

To date, no prospective studies have been completed regarding the risks associated with medical management of mucoceles. Medical management can be considered in asymptomatic and mildly symptomatic patients without evidence of extrahepatic biliary duct obstruction or gallbladder rupture, as long as the clinician and client are aware of the potential complications.1,21

Antibiotics. Because some mucoceles are associated with bacterial infection, performing an ultrasound-guided cholecystocentesis to obtain a sample for aerobic and anaerobic bacterial culture is recommended. Although considered relatively safe, rare complications of percutaneous cholecystocentesis may include bile leakage, bradycardia due to a vasovagal reaction, bacteremia, and local hemorrhage.27,28 Studies have indicated that risks associated with percutaneous cholecystocentesis in normal dogs and those with cholecystitis are minimal, but complication rates have not been determined in dogs with mucoceles.27,29

If bacteria are isolated, a six- to eight-week course of antibiotics is recommended. Gram-negative anaerobes are the most common bacteria isolated, but infections may be mixed. For this reason, antibiotic therapy with a combination of two medications is often pursued. In cases in which ultrasound-guided cholecystocentesis is not feasible, empirical antibiotic therapy should be prescribed (Table 2).21 Use caution when prescribing antibiotics in patients with hepatic insufficiency since they may be unable to metabolize certain antibiotics appropriately.

Choleretics. Choleretics, drugs that stimulate hepatic bile excretion, should be administered (Table 2). Ursodiol (ursodeoxycholic acid) is a naturally occurring bile acid that increases bile flow by decreasing the cholesterol content of bile and thinning biliary secretions by producing bicarbonate-rich enhanced bile flow. Ursodiol is also considered hepatoprotective since it reduces the hepatotoxic effects of bile salts and protects liver cells from endogenous hydrophobic bile acids such as lithocholate and deoxycholate.30 It is important to note that ursodiol is contraindicated in cases of extrahepatic biliary duct obstruction. Anecdotally, mucoceles have recurred after ursodiol discontinuation.

Other hepatoprotectants. Silymarin (milk thistle) should also be instituted (Table 2). This nutraceutical alters the composition of hepatocyte membranes and limits the entry of hepatotoxins into cells.31 It also stimulates protein synthesis and hepatic regeneration.31 Silymarin contains flavonoids such as silybin, silydianin, and silychristin, which increase glutathione concentrations and provide antioxidant effects.31 Inhibition of the inflammatory effects of leukotrienes is also reported.31

S-adenosylmethionine (SAMe) is a precursor to glutathione and has antioxidant effects (Table 2).32 It also enhances DNA repair.32 While studies clearly indicate that milk thistle and SAMe protect hepatocytes from damage, studies have not confirmed that either is useful in dogs with mucoceles.31,32

Monitoring. Reexamine dogs undergoing medical therapy for mucoceles after four to six weeks. The recheck should include abdominal ultrasonography, a complete blood count, and a serum chemistry profile. In one report involving two dogs, alanine aminotransferase and alkaline phosphatase activities and total bilirubin concentrations remained elevated for weeks to months after ultrasonographic resolution of the mucocele.1 These persistent elevations are most likely associated with the extension of pathological processes from the gallbladder to the liver or from a concurrent hepatic or endocrine (e.g. hyperadrenocorticism, hypothyroidism, diabetes mellitus) condition.

Prognosis. The prognosis for patients treated medically appears to be variable. In one study, seven of 25 patients with mucoceles were treated with ursodiol and SAMe. Two died within two weeks, two were lost to follow-up, and three survived without complications for at least six months.12

In a recent case study, two clinically ill patients with mucoceles were successfully managed with medical therapy.1 One dog was treated with SAMe, omega-3 fatty acids, famotidine, ursodiol, and levothyroxine. The second dog received ursodiol, fenbendazole, and levothyroxine and was fed a hypoallergenic diet. Levothyroxine was used to treat hypothyroidism, and fenbendazole was used for prophylactic gastrointestinal parasite therapy. These patients showed complete ultrasonographic resolution of the mucocele after two and three months.1

Surgical intervention should be recommended in all dogs that fail to improve with medical therapy, including those with unresolved clinical signs, worsening laboratory findings, and progressing ultrasonographic abnormalities.

SUMMARY

Gallbladder mucoceles are being diagnosed with increasing frequency in dogs, but their true incidence remains uncertain. The underlying cause of this condition is still controversial, but there is a strong association with mucous gland hyperplasia within the gallbladder epithelium. While surgical management has been the historic treatment of choice, recent case-based evidence suggests that some patients may respond to medical management.

Rebecca Quinn, DVM

Audrey K. Cook, BVM&S, MRCVS, DACVIM, DECVIM-CA

Department of Small Animal Clinical Sciences

College of Veterinary Medicine and Biomedical Sciences

Texas A&M University

College Station, TX 77843

REFERENCES

1. Walter R, Dunn ME, d'Anjou MA, et al. Nonsurgical resolution of gallbladder mucocele in two dogs. J Am Vet Med Assoc 2008;232(11):1688-1693.

2. Samuelson DA. Textbook of veterinary histology. 1st ed. Philadelphia, Pa: WB Saunders Co, 2006;367-369.

3. Guyton AC, Hall JE. Textbook of medical physiology. 11th ed. Philadelphia, Pa: Elsevier Inc, 2006;802-804.

4. Ko CW, Sekijima JH, Lee SP. Biliary sludge. Ann Intern Med 1999;130(4):301-311.

5. Brömel C, Barthez PY, Léveillé R, et al. Prevalence of gallbladder sludge in dogs as assessed by ultrasonography. Vet Radiol Ultrasound 1998;39(3):206-210.

6. Tsurumi K, Onda M. A fluorescence histochemical study for the motility of the gallbladder. Gastroenterol Jpn 1979;14(2):147-154.

7. Guo YS, Singh P, Gomez G, et al. Contractile response of canine gallbladder and sphincter of Oddi to substance P and related peptides in vitro. Dig Dis Sci 1989;34(6):812-817.

8. Milenov K, Vassileva M, Marinova D, et al. Effect of neurotensin on the canine gallbladder motility: in vivo and in vitro experiments. Neuropeptides 1993;25(4):233-239.

9. Strah KM, Melendez RL, Pappas TN, et al. Interactions of vasoactive intestinal polypeptide and cholecystokinin octapeptide on the control of gallbladder contraction. Surgery 1986;99(4):469-473.

10. Harkema JR, Mason MJ, Kusewitt DF, et al. Cholecystotomy as treatment for obstructive jaundice in a dog. J Am Vet Med Assoc 1982;181(8):815-816.

11. Neer TM. A review of disorders of the gallbladder and extrahepatic biliary tract in the dog and cat. J Vet Intern Med 1992;6(3):186-192.

12. Aguirre AL, Center SA, Randolph JF, et al. Gallbladder disease in Shetland sheepdogs: 38 cases (1995-2005). J Am Vet Med Assoc 2007;231(1):79-88.

13. Bernhoft RA, Pellegrini CA, Broderick WC, et al. Pigment sludge and stone formation in the acutely ligated dog gallbladder. Gastroenterology 1983;85(5):1166-1171.

14. Newell SM, Selcer BA, Mahaffey MB, et al. Gallbladder mucocele causing biliary obstruction in two dogs: ultrasonographic, scintigraphic, and pathological findings. J Am Anim Hosp Assoc 1995;31(6):467-472.

15. Selman PJ, van Garderen E, Mol JA, et al. Comparison of the histological changes in the dog after treatment with the progestins medroxyprogesterone acetate and proligestone. Vet Q 1995;17(4):128-133.

16. Lee SP, Nicholls JF. Nature and composition of biliary sludge. Gastroenterology 1986;90(3):677-686.

17. Besso JG, Wrigley RH, Gliatto JM, et al. Ultrasonographic appearance and clinical findings in 14 dogs with gallbladder mucocele. Vet Radiol Ultrasound 2000;41(3):261-271.

18. Pike FS, Berg J, King NW, et al. Gallbladder mucocele in dogs: 30 cases (2000-2002). J Am Vet Med Assoc 2004;224(10):1615-1622.

19. Klinkspoor JH, Yoshida T, Lee SP. Bile salts stimulate mucin secretion by cultured dog gallbladder epithelial cells independent of their detergent effect. Biochem J 1998;332(Pt 1):257-262.

20. Worley DR, Hottinger HA, Lawrence HJ. Surgical management of gallbladder mucoceles in dogs: 22 cases (1999-2003). J Am Vet Med Assoc 2004;225(9):1418-1422.

21. Cornejo L, Webster CRL. Canine gallbladder mucoceles. Compend Contin Educ Pract Vet 2005;27(12)912-930.

22. North DC. Sudden death in a dog associated with cholelithiasis. Vet Rec 1977;101(11):203.

23. Finn ST, Park RD, Twedt DC, et al. Ultrasonographic assessment of sincalide-induced canine gallbladder emptying: an aid to the diagnosis of biliary obstruction. Vet Radiol 1991;32(6):269-276.

24. Wagner KA, Hartmann FA, Trepanier LA. Bacterial culture results from liver, gallbladder, or bile in 248 dogs and cats evaluated for hepatobiliary disease: 1998-2003. J Vet Intern Med 2007;21(3):417-424.

25. Amsellem PM, Seim HB 3rd, MacPhail CM, et al. Long-term survival and risk factors associated with biliary surgery in dogs: 34 cases (1994-2004). J Am Vet Med Assoc 2006;229(9):1451-1457.

26. Mehler SJ, Mayhew PD, Drobatz KJ, et al. Variables associated with outcome in dogs undergoing extrahepatic biliary surgery: 60 cases (1988-2002). Vet Surg 2004;33(6):644-649.

27. Vörös K, Sterczer A, Manczur F, et al. Percutaneous ultrasound-guided cholecystocentesis in dogs. Acta Vet Hung 2002;50(4):385-393.

28. Herman BA, Brawer RS, Murtaugh RJ, et al. Therapeutic percutaneous ultrasound-guided cholecystocentesis in three dogs with extrahepatic biliary obstruction and pancreatitis. J Am Vet Med Assoc 2005;227(11):1782-1786.

29. Rivers BJ, Walter PA, Johnston GR, et al. Acalculous cholecystitis in four canine cases: ultrasonographic findings and use of ultrasonographic-guided, percutaneous cholecystocentesis in diagnosis. J Am Anim Hosp Assoc 1997;33(3):207-214.

30. Crosignani A, Setchell KDR, Invernizzi P, et al. Clinical pharmacokinetics of therapeutic bile acids. Clin Pharmacokinet 1996;30(5):333-358.

31. Flora K, Hahn M, Rosen H, et al. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 1998;93(2):139-143.

32. Muriel P, Rivera-Espinoza Y. Beneficial drugs for liver diseases. J Appl Toxicol 2008;28(2):93-103.