Clinical Case Presentation

• Lily, a 10-year-old sterile female Yorkshire terrier with an increase in ALP (brief return on a common endocrine cause: Cushing disease)
• Griffin, a 10-year-old male American Cocker with an increase in ALT, ALP and bilirubins (discussion leading to the diagnosis and management of a biliary mucocele)

Interpretation of complete blood count (CBC), biochemistry profile and liver function assays in hepatobiliary disease in the dog

1. CBC

• Poikilocytosis: including acanthocytes, echinocytes, target cells, and stomatocytes (reflecting a decreased tolerance to oxidative stress)
• Anemia of chronic disease or chronic GI blood loss
• Microcytic and hypochromic anemia (iron deficiency)

2. Biochemistry Profile

a. Markers of Hepatocellular Injury

Increases in ALT (alanine aminotransferase). Refer to Conference proceeding on «How I Approach a Dog with Increased Serum ALT» for more information)

• Increases occur due to cell damage (increased membrane permeability or necrosis) and induction (increased synthesis).
• The degree of elevation of serum ALT activity is roughly proportional to disease severity and affected hepatic mass. However, liver injury can be present despite a normal ALT activity due to a decrease in the number of hepatocytes (i.e., advanced fibrosis, portosystemic shunting), in cases of non-inflammatory primary or secondary neoplasia (e.g., hepatocellular carcinoma or hemangiosarcoma), and potentially very early in the course of disease.
• Increased ALT supports hepatocellular injury, but does not provide information on liver function.

Increases in AST (aspartate aminotransferase):

• Not specific to the liver (present in muscles, but also in brain, liver, kidney and erythrocytes).
• Muscle damage (CK activity may help differentiate origin as it should remain normal unless there is concomitant muscle disease) and hemolysis can cause considerable increases in AST activity.
• The enzyme half-life is about 22 hours in the dog.

b. Markers of Cholestasis

Increases in ALP activity (alkaline phosphatase):

• Can indicate primary hepatobiliary disease, such as cholestasis, as well as canalicular cell necrosis, or alternatively increased hepatic synthesis.
• Not specific to the liver, as several ALP isoenzymes have been identified in liver, bone, intestines, kidney and placenta.
• An increase in ALP has a good sensitivity (86%), but a poor specificity (49–51%) for the diagnostic of hepatobiliary disease.
• The specificity of ALP for the diagnostic of hepatobiliary disease increases to 94% if combined with an increased serum GGT.¹
• Considered significant if increase is 2–3x normal
• The enzyme half-life is about 72 hours in the dog
• Enzymatic induction (isoenzyme):
• Hepatic: with usage of glucocorticoids or anticonvulsant therapy in dogs (ex.: phenobarbital)
• Bone: in young animal or with bone tumor

General Rule (If Not a Growing Animal)

• Obtain a complete history including glucocorticoid administration (PO or other route) and any clinical signs suggestive of hyperadrenocorticism
• If slight to moderate increase (2–4x), recheck in 1 month
• If persistent or severe increase (>4x), abdominal ultrasound is recommended

Table 1. Causes of increased serum ALP activity in dogs

Biliary duct disease

• Biliary neoplasm
• Cholelithiasis
• Cholecystitis
• Biliary mucocele

Hepatic parenchymal disease

• Cholangitis
• Chronic canine hepatitis
• Hepatic neoplasm: primary or secondary
• Nodular hyperplasia
• Toxins (e.g., aflatoxin, amanita fungus, blue green algae, copper, herbicides, insecticides, iron, zinc, xylitol, sago)
• Vacuolar hepatopathy (idiopathic)

Extrahepatic disease

• Bone neoplasm/osteolytic condition
• Growth
• Congestive heart disease
• Diabetes mellitus
• Hypothyroidism
• Pancreatitis/pancreatic neoplasm
• Sepsis
• Exogenous or endogenous glucocorticoids (Cushing): enzymatic induction and vacuolar hepatopathy

Increases in GGT Activity (Gamma-Glutamyltransferase)

• Increases parallel ALP
• In dogs, GGT is often considered more specific but less sensitive than ALP for the detection of hepatobiliary disease.
• GGT has a half-life of approximately 72 hours in dogs.

Hyperbilirubinemia

• Poor sensitivity and specificity for hepatobiliary disease
• May be caused by hemolysis, primary hepatic disease and extrahepatic cholestasis

Changes on biochemistry profiles suggestive of liver dysfunction/failure include hypoalbuminemia, decreased urea, hypoglycemia (liver failure) and hypocholesterolemia.

Important: Because the liver has a considerable reserve capacity, patients with liver disease can have normal liver function test results.

Biliary Mucocele

A biliary mucocele corresponds to the excessive dilation of the gallbladder following the accumulation of mucus (hyperplasia of the mucosa of the gallbladder and overproduction of very compact mucus that can accumulate within the gallbladder). This accumulation of thick, gelatinous mucus may eventually fill the entire bladder, obstruct the hepatic and cystic ducts, and lead to extrahepatic cholestasis. The pressure exerted on the wall of the gallbladder can lead to necrosis and eventually to a rupture of the gallbladder.

Although this condition is now recognized frequently in certain dog breeds, it has been described for less than 20 years, which may reflect increased awareness of the condition, improvement (quality and access) of modern imaging and/or an actual increase in its prevalence.

Several risk factors have been identified, including:

1.  Genetic predisposition (Shetland sheepdog, American cocker spaniel, Chihuahua, Pomeranian, Miniature Schnauzer and Border terriers)³

2.  Presence of an endocrinopathy⁴ and/or dyslipidemia (e.g., hyperadrenocorticism [29x more at risk] and hypothyroidism)

3.  Increased serum leptin⁵

4.  Older dogs (age >10 years)

Clinical signs may vary greatly from an accidental finding on abdominal ultrasound to shock in patients presented with a ruptured gallbladder and bile peritonitis. Other clinical signs include nonspecific chronic GI signs (dysorexia, diarrhea, vomiting), lethargy, abdominal pain and fever.

Biochemistry profile may reveal a significant increase in liver enzymes (ALP and GGT, ALT, AST). Increased bilirubins will reflect the degree of obstruction. Neutrophilia has been documented in 50% of cases, reflecting the inflammatory nature of the disease. Abdominal ultrasound will allow confirmation of the condition. Ultrasonographically, mucoceles are characterized by the appearance of the stellate or finely striated bile patterns and differ from biliary sludge by the absence of gravity-dependent bile movement.⁶ A recent retrospective study including 219 dogs with gallbladder mucocele revealed that dogs presented with a ruptured gallbladder and bile peritonitis at the time of surgery were 2.7 times more likely to die than dogs without gallbladder rupture and bile peritonitis. Although ultrasound was fairly specific to diagnose a gallbladder rupture (91.7%), it only had a 56.1% sensitivity.⁷ When the patient does not have clinical or biochemical abnormalities (i.e., when gallbladder mucocele is a fortuitous finding), close monitoring by follow-up ultrasound examinations may be considered along with a medical treatment (ex.: ursodiol, investigate and treat for predisposing condition, antibiotics ideally based on fine needle aspirate). In the presence of a distended gallbladder with an immobile ultrasonographic stellate or finely striated bile pattern, a surgical cholecystectomy is indicated when clinical or biochemical signs of hepatobiliary disease are present. Because 22–75% of mucocele has been documented to be infected, aerobic and anaerobic cultures are always indicated. Interestingly, no significant associations were identified between survival and positive bacteriologic cultures, antibiotic administration, or time (days) from ultrasonographic identification of gallbladder mucocele to the time of surgery.⁷

References

1.  Webster RL. Interpretation of serum alkaline phosphatase in dogs. NACV Clinician’s Brief - Consultant on call. 2004:[9–12 pp.].

2.  Chapman SE, Hostutler RA. A laboratory diagnostic approach to hepatobiliary disease in small animals. Clinics in Laboratory Medicine. 2015;35(3):503–19.

3.  Allerton F, Swinbourne F, Barker L, Black V, Kathrani A, Tivers M, et al. Gall bladder mucoceles in Border terriers. Journal of Veterinary Internal Medicine. 2018;32(5):1618–28.

4.  Mesich ML, Mayhew PD, Paek M, Holt DE, Brown DC. Gall bladder mucoceles and their association with endocrinopathies in dogs: a retrospective case-control study. The Journal of Small Animal Practice. 2009;50(12):630–5.

5.  Lee S, Kweon OK, Kim WH. Increased leptin and leptin receptor expression in dogs with gallbladder mucocele. Journal of Veterinary Internal Medicine. 2017;31(1):36–42.

6.  Besso JG, Wrigley RH, Gliatto JM, Webster CR. Ultrasonographic appearance and clinical findings in 14 dogs with gallbladder mucocele. Veterinary Radiology and Ultrasound. 2000;41(3):261–71.

7.  Jaffey JA, Graham A, VanEerde E, Hostnik E, Alvarez W, Arango J, et al. Gallbladder mucocele: variables associated with outcome and the utility of ultrasonography to identify gallbladder rupture in 219 dogs (2007–2016). Journal of Veterinary Internal Medicine. 2018;32(1):195–200.