Introduction

• Cause: infectious agents, inflammation/immune-mediated, nutritional/metabolic disorders, biliary obstruction, toxins, neoplasia, trauma, idiopathic, iatrogenic.
• Signs: can be mild and non-specific (lethargy, dysrexia/anorexia, weight loss/poor body condition), emesis, altered mentation, jaundice/icterus, abdomen/coelomic enlargement.
• Diagnosis: clinical examination, CBC/biochemistry, urinalysis, peritoneal fluid analysis, abdominal imaging, hepatic biopsy.
• Treatment: parenteral fluid therapy, analgesia (if indicated), treatment of underlying cause, manage secondary effects (gastrointestinal ulceration and emesis, hepatic encephalopathy, peritoneal effusion, coagulopathy, protein-calorie malnutrition), hepatic support using antioxidants.
• Prognosis: dependent on etiology, can range from fair to poor.

Pathogenesis

Etiology

Bacterial infection

• Can be associated with ascending spread from the gastrointestinal tract through the bile duct or from hematogenous spread.
• Campylobacter jejuni Bacterial gastroenteritis:
  • Can be isolated from the feces of normal ferrets.
  • Experimental infection of young ferrets resulted in diarrhea and a severe inflammatory response. The organism can be isolated in the liver but was not associated with any inflammatory response or histologic change.
• Escherichia coli:   
  • E. coli-associated septicemia have been diagnosed in black-footed ferrets.
  • Organism may be cultured from the liver, kidney, or spleen of affected animals.
• Helicobacteriosis:
  • Helicobacter mustelae gastritis Helicobacter mustelae gastritis well established, but its pathogenicity in liver disease remain undetermined.
  • H. cholecystus identified as a potential cause of cholangiohepatitis in ferrets.
• Leptospirosis (Leptospira spp): Leptospira interrogans most commonly reported pathogenic species (rare in ferrets).
• Listeria monocytogenes:
  • Usually associated with contaminated vegetable feed.
  • Experimental infection showed rapid colonization of the liver following oral inoculation.
• Mycobacteriosis Mycobacteriosis:
  • Important disease in the feral ferret population in New Zealand: may act as both a spillover and maintenance host for M. bovis infection in cattle.
  • Sporadic disease reported in ferrets globally:
    • M. bovis, M. avium, M. avium complex and M. triplex most commonly implicated.
    • Granulomatous enteritis and hepatitis frequently reported.
• Salmonellosis (Salmonella spp):
  • Incidence in pet ferrets low, and infection is often associated with feeding of uncooked meat or meat products.
  • Typically characterized by pyrexia, enteritis and bloody diarrhea.
  • The organism can be found in the liver, spleen, intestinal content and blood. The liver, spleen and mesenteric lymph nodes often contains necrotic foci.
• Corynebacterium mustelae: single report causing septicemia in a ferret with organisms isolated in the lung, liver and kidneys.

Viral infection

• Canine distemper virus Canine distemper:
  • Morbillivirus.
  • Acute systemic disease primarily associated with dermatologic and respiratory signs in ferrets.
  • Hematogenous dissemination by white blood cells.
  • Intracytoplasmic or intranuclear inclusion bodies of CVD can be identified on histopathology in a wide variety of epithelial cells including the liver.
• Epizootic catarrhal enteritis (ECE) Epizootic catarrhal enteritis:
  • Highly transmissible diarrheal disease of ferrets caused by ferret enteric coronavirus.
  • Outbreaks occur in groups of ferrets kept in close contact, eg pet shops, multi-ferret households.
  • Older animals tend to be more severely affected, with young ferrets typically showing milder signs and can be asymptomatic carriers.
  • Causes significant hepatitis and enteritis.
• Ferret systemic coronavirus (FSCV) Ferret systemic coronavirus:
  • Progressive systemic pyogranulomatous disease in ferrets that resembles the dry form of feline infectious peritonitis.
  • High mortality rate.
  • Hepatomegaly and granulomatous lesions in the liver can be found.
• Aleutian disease Aleutian disease:
  • Parvovirus.
  • Immune complex-mediated disorder resulting in hypergammaglobulinemia.
  • Many ferrets are asymptomatic carriers.
  • Deposits of immune complexes in various organs and immunosuppression contribute to clinical signs.
  • In the liver, there is typically periportal lymphoplasmacytic cholangiohepatitis with or without bile duct hyperplasia and periportal fibrosis.
• Ferret hepatitis E virus Hepatitis:
  • Identified in both laboratory and pet ferrets.
  • Shown to result in subclinical, acute or persistent infection. Can cause acute hepatocellular damage
  • Virus is shed in the feces of infected animals, transmission is via the oral route.
• Influenza Influenza:  
  • Ferrets are highly susceptible.
  • Experimental infection of some strains can induce hepatic disease, including severe portal hepatitis.
• Pseudorabies:
  • Natural infection not reported.
  • Experimental infection in ferrets demonstrated multifocal coagulative necrosis and Kupffer cell proliferation in the liver and cholangitis.  

Fungal infection

• Cryptococcosis Cryptococcosis:
  • C. bacillisporus and Cryptococcus neoformans var grubii reported to cause disease in ferrets.
  • Infected ferrets can have a spectrum of clinical signs, including respiratory, cardiac, abdominal, central nervous system and skin manifestations.
  • Infiltration of the liver via lymphatic and hematogenous spread has been reported.
• Pneumoncystis carinii: under experimental conditions, extrapulmonary P. carinii infection could be induced in the ferret liver.  

Parasitic infection

• Coccidiosis Coccidiosis:
  • Enteric coccidiosis typically asymptomatic in ferrets or causes only transient diarrhea in young or stressed animals.
  • Hepatic coccidiosis reported in a weanling ferret resulting in cholangiohepatitis and periportal biliary fibrosis. Coccidian meronts and oocysts were present within the epithelial cells of the gallbladder and bile ducts.
• Toxoplasma gondii Toxoplasmosis:
  • Clinical disease rare.
  • Clinical signs reflect organ involvement.
  • Toxoplasma cysts have been identified in the hepatic parenchyma of affected ferrets.
• Sarcocystosis (Sarcocystis neurona):  
  • Diagnosis rare in ferrets which act as intermediate hosts; the opossum is the definitive host. 
  • Signs of sarcocystosis typically localized to the central nervous system in intermediate hosts.
  • Rhinitis and disseminated disease reported in one recently obtained ferret with organisms identified in the liver amongst other organs. Immunocompromise was thought to have played a role.

Inflammatory/immune-mediated conditions

• Lymphocytic hepatitis Hepatitis:
  • Common in pet ferrets and potentially underdiagnosed.
  • Usually associated with gastrointestinal disease such as inflammatory bowel disease or chronic inflammation from Coronavirus infection:
    • Suggestive of an ascending inflammatory process suggested.
    • Biliary inflammation often noted.
• Eosinophilic gastroenteritis Eosinophilic gastroenteritis:
  • Considered a form of inflammatory bowel disease.
  • No causative agent identified at present.
  • Mild to extensive infiltration of the gastric and small intestinal wall with eosinophils.
  • Focal eosinophilic granulomas may be found in the mesenteric lymph nodes and abdominal viscera including the liver.
  • Usually associated with peripheral eosinophilia.

Nutritional and metabolic disorders

• Hepatic lipidosis Hepatic lipidosis:
  • Overwhelming fatty acid accumulation within hepatocytes.
  • Can be associated with obesity but also in catabolic states where there is alteration in the insulin-glucagon ratio and subsequent mobilization of fatty acids and glycerol from body fat stores for energy production.
  • Anorexic Anorexia, obese Obesity animals most at risk.
  • Diabetes mellitus Diabetes mellitus in ferrets is rare, and usually iatrogenic after aggressive pancreatectomy.
  • Hepatic lipidosis secondary to megaesophagus reported.
• Pregnancy toxemia:
  • Risk factors include a decline in nutritional plane or reduced food intake (such as caused by stress) particularly in late gestation where fetal demands are high, maternal obesity, starvation, and presence of concurrent disease, eg odontogenic disease.
  • Mobilization of fatty acids from body stores with resultant hyperlipidemia and hepatic lipidosis.

Biliary obstruction 

• Associated with cholelithiaisis and/or biliary sediment accumulation in ferrets. Resultant cholestasis and potentially cholecystitis and cholangiohepatitis.
• Rupture of the gallbladder reported in one ferret following severe cholangiohepatitis and cholecystitis Gallbladder disease overview.

Toxins

• Aflatoxins.  
• Drugs, eg itraconazole Itraconazole, azathioprine Azathioprine, diclofenac, amoxicillin/clavulanate Amoxicillin/clavulanate, ivermectin Ivermectin.  
• Paracetamol/acetaminophen toxicity Acetaminophen toxicity:
  • Glucuronidation of acetaminophen is relatively slow compared to other animal species (except the cat).
  • Mechanism uncertain, does not appear to be associated with any identifiable genetic mutations causing slower metabolism of the drug.
  • Clinical signs typically present 12-48 h after ingestion. Methemoglobinemia and liver damage.
• Copper-associated hepatopathy:
  • Dietary copper is enterically absorbed and circulates protein-bound, with hepatocyte uptake and storage.
  • Excess copper is exported in bile.
  • Hepatic copper accumulation can be deleterious, resulting in apoptotic hepatocyte death and copper-associated hepatitis.
  • Primary copper-associated hepatopathy can be caused by genetic mutations affecting copper homeostasis or through excessive copper intake.
  • Secondary hepatic copper accumulation can occur by chronic cholestasis.
  • One report of copper toxicosis in two related ferrets suggested a possible genetic cause:
    • Affected ferrets showed CNS depression and lethargy.
    • One ferret was icteric.
    • Hepatocytes and hepatic macrophages stained positive for copper on histopathology.
    • Hepatic fibrosis, hepatocellular necrosis and vacuolation.
  • A recent study determined that hepatic copper concentrations in ferrets can exceed the upper reference limits for canine or feline liver and was not definitively associated with hepatobiliary disease.
  • Commercially available dry ferret diets have also been demonstrated to show consideration variation in copper concentration.

Neoplasia

• Lymphoma/lymphosarcoma Lymphoma overview:
  • Clinical presentation can be non-specific and vary with the organ system(s) affected.
  • Involvement of the liver more common as part of multicentric disease with hepatosplenomegaly observed.
  • Effacement of normal hepatic parenchymal architecture by neoplastic lymphoid cells.
• Insulinoma Insulinoma:
  • Metastatic potential generally considered to be low.
  • Metastases to local lymph nodes and liver have been occasionally reported.
• Biliary cystadenoma:
  • Commonly exhibit infiltrative expansion, replacing one or more lobes of the liver.
  • Often arise at the border or edge of liver lobes, composing of interconnected oval or spherical cysts with minimal intervening fibrous stroma.
• Other neoplasms:
  • The liver can be a primary site for neoplasms.
  • Hemangiosarcoma, adenocarcinoma and hepatoma have been reported Gastrointestinal neoplasia.
  • The liver is also a common site for metastasis.  

Trauma

• Hepatic contusions: may be associated with falls or mishandling.
• Liver lobe torsion:
  • Reported in one ferret.
  • Results in venous occlusion within affected lobe, leading to passive congestion, and subsequent lobar necrosis, abdominal effusion with or without hemorrhage, and shock.
• Iatrogenic/idiopathic:
  • Vacuolar hepatitis.
  • Reported in ferrets, usually subclinical.
  • Common histopathological finding with increased vacuolization of hepatocytes. Suspected to be associated with hormonal triggers:
    • High estradiol secondary to adrenal gland disease.
    • Corticosteroid administration, although steroid hepatopathy thought to be uncommon in ferrets.

Predisposing factors

General

• Suboptimal husbandry and sanitation, including inappropriate diet and/or housing resulting in obesity Obesity.

Specific

• Contact with infected conspecifics or exposure to a contaminated environment with pathogen(s) implicated in hepatopathy. Includes humans diagnosed with influenza.
• Ferrets recently vaccinated with live canine distemper vaccine (vaccine-induced distemper).
• Exposure to hepatotoxins.
• Feeding of excessive levels of dietary copper.
• Obese animals in late gestation.
• Neoplasia more common in aged animals.

Pathophysiology

Primary hepatic insult

• Pathophysiology will vary depending on etiology.
• Direct hepatocellular damage:
  • Certain hepatotoxins can have a direct effect on hepatocytes or through enzyme-toxin binding.
  • Results in cellular and/or membrane dysfunction, and cytotoxic T-cell response.
• Cholestasis: injury to canalicular membrane and transporters.
• Immune-mediated:
  • Immunoglobulin E response induced by enzyme-toxin or enzyme-pathogen binding on hepatocytes.
  • Auto-immune cytotoxic lymphocyte response directed at hepatocyte membrane components.
• Granulomatous: infiltration of hepatic lobules by macrophages and lymphocytes.
• Steatosis/lipidosis Hepatic lipidosis:
  • Increased uptake and/or reduced hepatic clearance of fatty acids.
  • Acquired or congenital alteration in mitochondrial metabolism and subsequent β-oxidation of fatty acids.
  • Hepatocyte macrovesicular vs. microvesicular lipid accumulation and subsequent degeneration. Varies depending on etiology.
  • Acute liver failure can occur from overwhelming hepatocyte degeneration.
  • Prolonged hepatic lipid accumulation may progress to chronic liver failure through hepatic metabolic dysfunction and oxidative stress, inflammation, and fibrosis.
• Fibrosis:
  • Activation of hepatic stellate cells into proliferative fibrogenic myofibroblasts and subsequent deposition of extracellular matrix.
  • Stimulated by production of pro-inflammatory mediators during hepatocyte damage and disruption of the extracellular matrix.
  • Release of chemokines and other leukocyte chemoattractants by activated hepatic stellate cells also upregulates expression of inflammatory receptors and mediators.
  • Perpetuation of inflammation and activation of hepatic stellate cells.
• Vascular collapse: ischemic or hypoxic injury.
• Oncogenesis.
• Mixed pathogenesis is typical for most acute liver injuries.

Secondary to multi-organ failure (MOF)

• Initiation of innate immune response caused by sepsis.
• Production of reactive oxygen species (a subset of free radicals) and pro-inflammatory mediators.
• Stimulation of a systemic inflammatory response syndrome and subsequent MOF.
• Direct hepatocyte damage.
• Dysregulation of systemic vascular tone leading to low systemic vascular resistance and reduced hepatic perfusion.

Chronic liver failure

• Continuous and progressive hepatic fibrosis, liver tissue architectural distortion, and regeneration nodule formation.
• Hepatic cirrhosis represents end-point of chronic liver failure.

Portal hypertension

• Most commonly occurs secondary to hepatic fibrosis and cirrhosis.
• May also be prehepatic (portal vein thrombosis), or post hepatic (infrequently reported in veterinary medicine) in origin.
• Results in congestion of splanchnic vessels with pooling of blood in the splanchnic circulation.
• Resultant drop in circulating blood volume and systemic arterial blood pressure causes a reduction in glomerular filtration rate and therefore stimulation of the renin-angiotensin-aldosterone system:
  • Leads to further fluid retention precipitating formation of ascites.
  • Reduced venous return due to increased pressure of the caudal vena cava.
• Creates a vicious cycle of renal sodium retention and ascites.

Clinical manifestations of hepatopathy

• Gastrointestinal (GI) disorders:
  • Emesis, diarrhea and anorexia.
  • Thought to be associated with local inflammation, portal hypertension, hepatic encephalopathy (HE).
  • Hematemesis and melena may be seen with upper GI ulceration caused by portal hypertension:
    • Vascular congestion and fragility.
    • Poor GI mucosal perfusion and reduced epithelial cell turnover resulting in GI ulceration.
• Protein-calorie malnutrition:
  • Result of reduced food intake caused by anorexia, vomiting and diarrhea.
  • Increased loss/wastage of calories caused by hypermetabolism and liver dysfunction.
  • Malnutrition may also predispose to GI ulceration and HE due to muscle catabolism (body protein).
• Polyuria and polydipsia:
  • Underlying mechanisms poorly understood. Possible causes may include:
    • Altered sense of thirst due to HE.
    • Changes in the function of portal vein osmoreceptors demonstrated in humans and rodents.
    • Loss of the renal medullary-concentrating gradient for urea due to decreased hepatic production.
• Peritoneal effusion:
  • Associated with increased venous hydrostatic pressure caused by portal hypertension with or without decreased intravascular oncotic pressure from reduced serum albumin concentration due to reduced functional hepatic mass.
  • Effusion is typically a transudate or a modified transudate.
  • Altered vascular permeability in SIRS can also contribute to ascites.
• Hepatic encephalopathy:
  • Neurologic dysfunction.
  • Caused by derangement to neurotransmitter systems from defective hepatic metabolic processes.
  • Ammonia is most important toxin implicated.
• Jaundice/icterus:
  • Yellow-staining of tissues or serum caused by hyperbilirubinemia.
  • Associated with impaired excretion of bilirubin and other constituents of bile by diffuse hepatocellular or biliary disease (cholestasis).
• Coagulopathy:
  • Reduced synthesis of clotting factors.
  • Acquired vitamin K deficiency due to biliary obstruction and resultant reduced or absent bile acid-dependent fat absorption.
  • Hemorrhage and loss of clotting factors through hematemesis and melena (see above).
  • Disseminated intravascular coagulopathy (DIC) as a consequence to SIRS.

Timecourse

• Varies with etiology.
• Can range from days (eg most bacterial hepatitis, some viral etiologies (ECE, distemper), pregnancy toxemia, hepatoxic drugs) to months or years (inflammatory conditions, systemic amyloidosis, neoplasia).

Epidemiology

• Manifestations of infectious hepatopathies in many exotic animals can be a sequela of inappropriate husbandry and sanitation measures resulting in stress and immunocompromise.
• Enteric coccidiosis Coccidiosis in ferrets more common in young, weanling ferrets.
• Epizootic catarrhal enteritis Epizootic catarrhal enteritis caused by ferret enteric coronavirus causes more significant disease in older ferrets.
• Mycobacteriosis Mycobacteriosis is common in the wild ferret population of New Zealand. Hepatic involvement has been reported.

Diagnosis

Treatment

Prevention

Outcomes