34th Annual Scientific Meeting proceedings

A gall bladder mucocele (GBM) is an accumulation of tenacious and immobile, bile-laden mucus within the gall bladder lumen. Extension of mucus into the cystic, hepatic and common bile ducts can result in various degrees of gall bladder distension and biliary obstruction. Ultimately, progressive distension and pressure necrosis of the gall bladder wall may lead to gall bladder rupture and ensuing biliary peritonitis .^1-2

The prevalence of canine GBM appears to have increased dramatically over the past 20 years, factoring for general increases in awareness of the condition and ultrasound availability for diagnosis. Breed predispositions for the Border terrier, Shetland Sheepdog, American Cocker Spaniel, Chihuahua, Pomeranian and Miniature Schnauzer exist.^3-5  Clinical disease associated with GBM typically manifests later in life (median age at presentation 9 to 11 years) and with non-specific clinical signs including vomiting, lethargy and inappetence. Detection of icterus varies from 10-57% of dogs presenting with GBM. Common serum biochemical and haematological abnormalities in dogs presenting with clinical disease include increased ALP and ALT activities, hyperbilirubinaemia, hypercholesterolaemia, hypertriglyceridaemia, leukocytosis and neutrophilia. In some instances, a diagnosis of GBM may be made incidentally in the absence of apparent clinical disease. Gall bladder biliary sludge has been proposed as a precursor to GBM formation, with the distinction between extensive luminal nongravity-dependent biliary sludge and early GBM currently poorly defined.⁶

Abdominal ultrasound examination findings may result in a high suspicion of GBM; however, the definitive diagnosis is based on gross inspection and histopathological analysis of the gall bladder wall and content following cholecystectomy. Ultrasonographically, GBMs are characterized by the presence of immobile, echogenic bile within the gall bladder lumen progressing to a stellate and then striated pattern as the mucocele matures². This continuum likely reflects increased inspissation of the mucocele and has resulted in the classification of mucoceles into 6 types based on ultrasonographic criteria⁷. On gross inspection following cholecystectomy, turgid distension of the gall bladder wall due to a gelatinous, viscoelastic mucoid luminal content is appreciated. Histopathologically, cystic mucinous hyperplasia/ hypertrophy of the gall bladder epithelium and abnormal accumulation of mucus within the gall bladder lumen have traditionally been the criteria used to diagnose GBM^4,8. The presence of concurrent neutrophilic cholecystitis has been reported with varying frequency (10-84%). Identification of bacterial isolates from gall bladder content and wall samples is also variable (10-34% in larger studies) with inconsistencies likely reflecting differences in isolation technique and use of perioperative antimicrobial therapy. Isolates are typically enteric commensal organisms (E.coli and Enterococcus spp.) and are considered secondary to rather than an inciting factor in the aetiopathogenesis of GBM.

The cause of GBM is poorly understood with a multifactorial aetiology likely. Historically cystic mucinous hyperplasia/ hypertrophy of the gall bladder epithelium has been considered instrumental in the development of GBM however this concept has been refuted by recent work documenting that glandular epithelial proliferation is not a feature. Rather the gall bladder epithelium acquires a mucin-secretory phenotype with a disproportionate increase in the gel-forming mucin Muc5ac and defective mucin maturation following exocytosis into the gall bladder lumen with an overall effect to increase viscosity of luminal content⁹.

Hypersecretion of mucin is recognised as a typical epithelial response to injury however the trigger for this response in GBM remains elusive. Alterations to bile constituents, principally increased hydrophobic bile salts and cholesterol, have been proposed as an inciting cause for mucin hypersecretion although such changes are yet to be identified in GBM¹⁰. The gall bladder epithelium plays a complex role in reabsorption of water and electrolytes via epithelial ABC protein transporters which serve as ion channels and impact the hydration of luminal content. Transporter dysfunction has been associated with disease states characterized by viscous epithelial secretions (e.g. CFTR gene mutations and cystic fibrosis) and this possibility has been investigated for GBM with potential metabolic and genetic factors influencing transporter function. Reductions in the cellular messenger cAMP, necessary for enabling secretory functions of the biliary epithelium, have been identified within GBM bile and an ABCB4 insertion mutation coding for translocation of phosphatidylcholine into biliary canaliculi (responsible for micelle formation and reducing cytotoxic effects of bile on epithelial cells) was postulated but later disproven^10,11.

Diagnosis of a concurrent endocrinopathy with GBM is thought to be significant with odds of GBM significantly increased in dogs with hyperadrenocorticism as well as hypothyroidism. This relationship may be underestimated given the potential for undiagnosed endocrinopathies at the time of GBM diagnosis¹². Interestingly breeds predisposed to GBM such as the Shetland Sheepdog and Miniature Schnauzer also have a predisposition to hyperlipidaemia. Both hypertriglyceridaemia and hypercholesterolaemia have been significantly associated with GBM^4,5. The high potential for dyslipidaemia with both endocrinopathies, and altered steroid metabolism with hyperadrenocorticism, could impact bile composition and gall bladder motility with implications for GBM formation. Gall bladder dysmotility may enable luminal bile supersaturation and stasis with resultant epithelial damage and mucus hypersecretion. Gall bladder dysmotility could simply be a consequence of mucoid distension, although dysmotility in the presence of mild gall bladder disease (biliary sludge) has been documented giving support to a potential primary role.

The aetiopathogenesis of GBM remains largely uncertain and further work is required to validate current hypotheses and explore new ones. In the meantime, an increased understanding of breed predisposition and concurrent disease processes should serve to heighten surveillance in at-risk individuals with potential implications for earlier GBM diagnosis and improved patient management.

References

1. Center, S. A. (2009) Diseases of the gallbladder and biliary tree. Veterinary Clinics of North America, Small Animal Practice 39(3), 543–598.
2. Pike, F. S., Berg, J., King, N. W., Penninck, D. G. and Webster, C. R. (2004) Gallbladder mucocele in dogs: 30 cases (2000-2002). Journal of the American Veterinary Medical Association 224(10), 1615–1622.
3. Allerton, F., Swinbourne, F., Barker, L., Black, V., Kathrani, A., Tivers, M., Henriques, T., Kisielewicz, C., Dunning, M. and Kent, A. (2018) Gall bladder mucoceles in Border terriers. Journal of Veterinary Internal Medicine 32(5), 1618–1628.
4. Aguirre, A. L., Center, S. A., Randolph, J. F., Yeager, A. E., Keegan, A. M., Harvey, H. J. and Erb, H. N. (2007) Gallbladder disease in Shetland Sheepdogs: 38 cases (1995-2005). Journal of the American Veterinary Medical Association 231(1), 79–88.
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8. Kovatch, R. M., Hildebrandt, P. K. and Marcus, L. C. (1965) Cystic mucinous hypertrophy of the mucosa of the gall bladder in the dog. Pathologia Veterinaria 2(6), 574–584.
9. Kesimer, M., Cullen, J., Cao, R., Radicioni, G., Mathews, K. G., Seiler, G. and Gookin, J. L. (2015) Excess Secretion of Gel-Forming Mucins and Associated Innate Defense Proteins with Defective Mucin Un-Packaging Underpin Gallbladder Mucocele Formation in Dogs. PloS one 10(9), e0138988.
10. Gookin, J. L., Mathews, K. G., Cullen, J. and Seiler, G. (2018) Qualitative metabolomics profiling of serum and bile from dogs with gallbladder mucocele formation. PloS one 13(1), e0191076.
11. Cullen, J. M., Willson, C. J., Minch, J. D., Kimbrough, C. L. and Mealey, K. L. (2014) Lack of association of ABCB4 insertion mutation with gallbladder mucoceles in dogs. Journal of Veterinary Diagnostic Investigation 26(3), 434–436.
12. Mesich, M. L., Mayhew, P. D., Paek, M., Holt, D. E. and Brown, D. C. (2009) Gall bladder mucoceles and their association with endocrinopathies in dogs: a retrospective case-control study. Journal of Small Animal Practice 50(12), 630–635.