Biliary diseases

Question 1

Pathogenesis of GBM

Answer 1

Epithelium mucin hypersecretory phenotype (without cystic glandular hyperplasia)
→ increased gel forming mucin content and abnormal mucin profile (altering physical properties)
→ reduction in bile acids important for biliary motility (unclear if causative)
→ expansion of lumen with mucocoele → wall stretch, reduced blood flow
→ morbidity from ischaemic necrosis and rupture as well as predisposition to bacterial infection and neutrophilic cholangitis (possibly)

Question 2

Theories for the causation GBM

Answer 2

• Altered GB motility
  –> retention of bile is suspected to result in distension of the GB and irritation of the GB lining.
• Altered bile fraction composition: increased gel forming mucins, increased cross-linking proteins, reduced glutathione
• Impaired secretion of fluid by biliary epithelial cells may promote mucus dehydration

Question 3

Breed predispositions and theories for cause

Answer 3

Shetland sheepdog, Min Schnauzer, Cocker Sp; Border terrier; Chihuahua, Pomeranian, Maltese, Toy poodle

Sheepdog - initial investigations in 2010 reported canalicular transporter protein mutation with strong assoc. Later not repeated in another group of SS. Though the latter study did demonstrate hepatobiliary abnormalities in the dogs with this mutation

Border Terriers - OR of 85x other breeds in retrospective study with dyslipidaemias and endocrine disease less common in BT with GBM.
JVIM 2020 - border terriers with GBM had elevated anti-canine transglutaminase-2-IgA autoantibodies which was significantly different to control border terriers but not significantly different to other breeds of dog with GBM.
Also reduced CCK in GBM dogs - reported in coeliacs as well. Same findings in non-BT dogs with GBM so may just be disease and not causation

Question 4

Disease assoc with increased risk of GBM - and how it might be causative

Answer 4

HAC - 8-21% of dogs with GBM have this.
Cortisol can alter bile acid composition and increase mucin production and can trigger leptin release

HypoTH - 14-26% of dogs with GBM
May alter cholesterol metabolism and GB motility

GB Dysmotility:
- Elevated leptin
leptin modulates the contractions and emptying of the gallbladder, as well as promoting relaxation of the sphincter of Oddi. In addition, leptin alters gene transcription affecting gallbladder water and electrolyte secretions
leptin resistance decreases the sensitivity of vagal afferent neurons to CCK, thus inhibiting motility and emptying of the gallbladder
- Dyslipidaemia
in humans reduces GB motility - recent study in hyperlipidaemic dogs reported larger GB volume but not statistically different ejection fractions.
- Reduced CCK sensitivity

Vit D deficiency
another cause of GB hypomotility in people. Observational study in dogs reported decreasing levels correlating with progression of GBM on ultrasound. Lower Vit D in dogs with GBM was not associated with inflammatory state

Question 5

Sensitivity and Specificity for u/s in GB rupture detection

Answer 5

sens 56.1 and Spec 91.7%

CT much more sensitive

Question 6

What dont we know about medical mgmt of GBM

Answer 6

We don’t know the proportion of dogs that have GBM that will go on to become clinical
JVIM 2022 - 20/154 dogs with biliary sludge developed GBM with follow up >12 months
→ Shetland sheepdog OR 40; Border Terrier OR 11 were independent risk factors for GBM development

Lack of evidence for the efficacy of medical Tx. Dissolution is reported. Also no standardised approach
Likely may be beneficial in endocrine cases

Retrospective studies:
Confounded by the fact that owners who declined surgical intervention may also be more likely to decline other interventional therapies for unrelated conditions. As well as inherent bias through targeted selection of less clinically affected animals for medical management

Question 7

Intrahepatic biliary disease in dogs - types and predisposing factors

Answer 7

Canine neutrophilic cholangitis
–> Any mechanical or functional reduction in bile flow → increases intraductal pressure
→ reduced bile acids in bile and reduced antimicrobial properties
→ increased intraductal pressure favours bacterial and endotoxin translocation into epithelium (may be ascending or haemotogenous)
Isolation of bacteria in previous studies has been low but may be a result of prior ABx, fastidious organisms, type of tissues submitted.

Destructive cholangitis

Question 8

Mechanisms causing intrahepatic cholestasis and DDx

Answer 8

Reduction in one or more of:
(1) uptake of biliary constituents from sinusoidal blood into hepatocytes
(2) excretion of hepatocellular substances into the canalicular lumen
(3) flow of bile along the intrahepatic bile ductules/ducts
(4) exit of bile from the liver into the extrahepatic bile ducts.

The liver has a tremendous reserve capacity to accommodate multi-focal regions of intrahepatic cholestasis; however, severe diffuse disease will result in accumulation of bile acids, bilirubin, cholesterol and other biliary constituents into the bloodstream

DDX:drugs, toxins, endotoxemia, endocrinopathies, bacterial infections, Distemper virus, chronic hepatitis, cirrhosis, Caroli’s disease and neoplasia

Question 9

Complication rate of percutaneous cholecystocentesis in dogs

Contraindications

Answer 9

low complication rate reported 2.5-3.4% (bile peritonitis <1% in 200 cases)

Contraindications: GBM, emphysematous cholecystitis

Question 10

Normal biliary defences preventing bacterial colonisation

Answer 10

bile salts,
Kupffer cells,
IgA → prevent adhesion and colonisation