Inflammatory / Infectious Hepatic disease

Question 1

List the common causes of acute hepatitis including examples of each

Answer 1

1. Toxins
   
   • Mycotoxin, aflatoxin
   • amanita mushroom
   • xylitol
   • cyanobacteria - microcystin
2. Drugs
   
   • Carprofen, paracetamol
   • trimethoprim/sulfa
   • azathioprine
   • amiodarone
3. Infections
   
   • Leptospirosis
   • Clostridia
   • CAV-1 (vaccination has reduced incidence)
4. Idiopathic?

Question 2

What are the known causes of chronic hepatitis in dogs

Answer 2

1. Copper storage disease is associated and causative of chronic hepatitis
2. Idiopathic - large majority of cases of chronic hepatitis are idiopathic or immune mediated (immune mechanisms not fully elucidated)
   
   • Anti-liver membrane protein antibodies have been identified in some dogs (10/21) with chronic hepatitis
   • High ALM proteins were associated with greated increase in ALT and bilirubin
3. Infection
   
   • Can cause chronic disease after acute infeciton is cleared - may be seen following leptospirosis
   • Numerous bacterial organisms have been implicated in acute hepatitis, with some potentially causing chronic disease - Yersinia, salmonella, clostridium, campylobacter
   • Granulomatous hepatitis can be caused by infectious organisms - Bartonella, leishmania, mycobaterium, fungal organisms
   • Migrating parasite larvae can cause granulomatous inflammation with increase eosinophils
4. Drugs
   
   • Anticonvulsants

Question 3

Discuss the pathophysiological triggers that could be treatment targets in canine chronic hepatitis

Answer 3

1. Copper accumulation
2. Inflammation - extent and severity and predominant cell type
3. Fibrosis - extent and severity
4. Biliary stasis
5. Normal architecture loss and progression to cirrhosis
6. Portal hypertension
7. Functional hepatocyte loss - reduced liver function

Question 4

What is the aetiopathogenesis of LC in cats?

Do bacteria contribute to the pathogenesis of LC? What evidence exists?

Answer 4

• LC is characterised by dense aggregates of lymphocytes surrounding the bile ducts but not invading the biliary epithelium
• The presence of large numbers of lymphocytes is strongly suggestive of an immune mediated mechanism of disease
• A specific trigger for the disease and the specific immune process has not been elucidated
• FISH studies have found little evidence to support bacterial colonisation as a cause for LC. Moreover, bacterial infection has been consistently associated with NC
• Bartonella innoculation in specific pathogen free cats has caused LC in an experimental setting
• Helicobacter organisms have been identified in the bile and liver tissues in slightly increased numbers in LC cats compared with controls (26% versus 16%)

Question 5

Descirbe the various tests and results that help differentiate lymphocytic cholangitis from hepatic lymphoma in cats

Answer 5

• Routine histopathology does not definitively differentiate between LC and indolent hepatic lymphoma
  
  • Ductopenia and bile duct targeting is suggestive of LC
  • Peribiliary fibrosis suggests LC
• Immunophenotyping for B and T cells markers
  
  • B cell infiltrates are typical of LC
• PCR for T-cell receptor rearrangements
  
  • Polyclonal TCR in LC
  • Monoclonal TCR in lymphoma

Question 6

What signalment, clinical and clinicopathological differences are seen in cats with neutrophilic cholangitis/cholangiohepatitis when compared to cats with lymphocytic cholangitis

Answer 6

Signalment:

• Age - older studies have suggested LC in younger cats, while more recent studies have shown a median age of 10 y for LC.
• No breed, age or sex predispositions have been identified consistently for NC
• Male cats may be predisposed to LC
• Persian and Norwegian Forest cats may suffer worse disease with LC

Clinical:

• NC is typically acute in presentation with 0-2 week history. Acute GI signs, lethargy and inappetance
• LC is more often diagnosed as a chronic disease with weight loss. May be bright and polyphagia with weight loss is common

Clinicopathological:

• NC - elevated liver enzymes common, CBC changes are common. AST 95-100%, ALT 57-100%, ALP 33-48%, bilirubin 68-83%
• LC - variable with no specific abnormality present > 50% of the time. Icterus - 25%, hyperglobulinaemia - 42-48%, ALT/ALP ~ 50%. CBC may show non-regenerative anaemia, WBC usually normal. Ascites is common due to portal hypertension

Question 7

What evidence exists regarding treatment options for cats with lymphocytic cholangitis?

Comment on the prognosis of cats with LC

Answer 7

• There is scarce evidence detailing the specific treatment requirements for LC. There are no randomized, placebo controlled studies reported.
• Treatment with prednisolone provides an improved survival time over treatment with UDCA alone. The mechanism for improvement is not well known.
• Studies detailing repeat biopsy to identify histopathological improvement following treatment are lacking
• Treatment with prednisolone is likely to be indicated, while addition of UDCA may improve clinical signs and prognosis without significant adverse effects

Prognosis:

Reports on prognosis and survival are also lacking. Median survival of ~ 750 days is reported with prednisolone or prednisolone/UDCA treatment.

Purebred cats (Norwegian Forest Cat) may do worse with a HR of 25 for death due to LC when compared with non pedigree cats - specific survival times not reported

Question 8

Under what pathogenic conditions can bacterial hepatobiliary disease occur in cats?

Answer 8

1. Primary ascending infection from the duodenum - considered the most likely cause of NC
2. Neoplasia
3. Post-trauma
4. Liver lobe torsion / vascular compromise
5. Distant infection - sepsis
6. Immunocompromise

Question 9

What bacteria are commonly implicated in feline NC, cholecystitis or hepatic abscessation?

What specific treatment options are recommended?

Answer 9

• Mixed bacterial infection is most commonly identified in cats with either hepatic abscessation or NC/CH. >50% are polymicrobial
• Klebsiella, Salmonella, Listeria, Brucella, Yersinia, Clostridia, Enterobacter, Actinomyces, Pasturella
• Due to the common presence of mixed aerobic and anaerobic infections, broad spectrum antibiotics are indicated when infection is suspected prior to the return of culture results

Antibiotics must penetrate the liver and biliary excretion (while still active) is preferred.

• Ampicillin, amoxicillin, amoxicillin/clavulanic acid are commonly used
• Metronidazole is often added
• Treatment for 6-8 weeks has been recommended without good reference. The optimal treatment duration is not known

Question 10

Briefly note the various viruses that have been associated with feline liver disease, including the clinical significance of each

Answer 10

1. Feline Leukemia Virus (FeLV)
   
   • Has been associated with liver degeneration, fatty liver and focal necrosis.
   • Pathogeneisis is unknown and virus may not be directly responsible for the liver lesions
   • Liver lesions may be in part due to anaemia
2. Feline Calicivirus (FCV)
   
   • Typically an URT virus, a mutant form has shown hepatic trophism
   • Highly infectious and high morbidity/mortality associated with FCV hepatic infection
   • Infected cats show icterus, fever, oedema, lameness and inappetance in associated with upper respiratory tract signs
3. Feline Coronavirus (FCoV / FIP)
   
   • Often icteris without increased liver enzymes
   • FIP lesions - granulomas - often present without gross changes
   • Cytology can be helpful and indicate FIP with 64% showing marked granulomatous inflammation in one study
   • Core biopsy has been diagnostic in 16/25 cats with confirmed hepatic FIP
4. Feline Immunodeficiency Virus (FIV)
   
   • While not causing hepatic disease directly, FIV predisposes to other infection.
   • FIV affects cats are particularly susceptible to toxoplasmosis induced hepatitis