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), altered mentation, jaundice/icterus, abdominal 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, 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.
• Clostridium perfringens:
  • Can be associated with typhlocolitis caused by intestinal dysbiosis in guinea pigs.
  • C. perfringens Type A can also result in enterotoxemia.
  • Acute infection can be associated with hepatic and splenic infarcts.
• Clostridium piliforme:
  • Tyzzer’s disease Tyzzer's disease.
  • Typically associated with ileitis and typhlitis.
  • Hepatic lesions can be present.
• Escherichia coli:
  • Not normally present within the gastrointestinal tract of healthy guinea pigs, but can be associated with enteritis, hepatitis and septicemia in poorly managed colonies.
  • Organism may be cultured from the liver, kidney, or spleen of affected animals.​
• Leptospirosis (Leptospira spp):
  • ​Leptospira interrogans most commonly reported pathogenic species.
  • Guinea pigs commonly used as a model of leptospirosis, but natural infections are rare:
    • Natural infection reported in domestic guinea pigs in Europe.
    • Presumably through exposure to wild rats with entry of infection through abraded skin and mucous membranes.
    • Affected animals jaundiced with focal hepatic necrosis and disseminated multifocal hemorrhages.
• Listeria monocytogenes:
  • Naturally occurring infections rare in guinea pigs.
  • Usually associated with contaminated vegetable feed.
  • Experimental infection showed rapid colonization of the liver following oral inoculation.
• Mycobacteriosis:
  • Guinea pigs are highly susceptible but natural disease rare:
    • M. tuberculosis and M. bovis reported.
    • Infection presumed to be through human exposure.
    • Disseminated disease associated with granulomatous lesions within lungs, abdominal organs (including the liver), and lymph nodes.
• Salmonellosis (Salmonella spp) Salmonellosis:
  • Previously common in laboratory guinea pigs, but incidences now rare due to improved standards of husbandry and hygiene:
    • S. enterica serotype Typhimurium and S. enterica serotype Enteritidis most common isolates in guinea pigs.
    • Young weanlings and sows during farrowing most at risk.
    • High mortality rate often reported in outbreaks.
    • Ingestion of contaminated feed or feces considered usual source of infection.
    • Can be associated with multifocal granulomatous hepatitis, mesenteric lymphadenopathy splenomegaly.
• Streptococcus equi subsp Zooepidemicus:
  • Cervical lymphadenitis Cervical lymphadenitis and septicemia in guinea pigs.
  • Usual route of infection is via abrasions in the oral mucosa, other routes also reported.
  • Affected adults usually have lesions confined to the regional lymph nodes.
  • Acute systemic disease seen in younger animals which can result in focal hepatitis.
• Streptococcus pneumoniae:
  • Guinea pig colonies can be enzootically infected.
  • Up to 50% animals can be subclinical carriers, with colonization of the upper respiratory tract.
  • Transmission primarily through aerosols.
  • Epizootics most often occur in winter months.
  • Younger animals and gravid sows most at risk.
  • Infection is typically associated with upper respiratory tract infection, bronchopneumonia and otitis media Otitis externa/media/interna, but splenitis, focal hepatic necrosis, peritonitis and meningitis also reported.
• Yersinia pseudotuberculosis Pseudotuberculosis:
  • Spontaneous outbreaks and mortality rare in guinea pigs.
  • Acute, subacute and chronic forms of disease reported.
  • Multifocal miliary nodular lesions can be present in the liver.
• Brucellosis (Brucella spp):
  • Natural infection rare in guinea pigs as infection requires contamination of feed by animal by-products.
  • Abscesses within the liver reported in one guinea pig.

Viral infection

• Guinea pig cytomegalovirus (GPCMV, Caviid herpesvirus 2) Cytomegalovirus:
  • Common amongst conventionally housed guinea pigs, seroconversion typically occurs by a few months of age.
  • Transmitted by exposure to infection saliva or urine, or vertically as transplacental infection.
  • Natural infection rarely causes detectable clinical disease:
    • May persist as inapparent or latent infection.
    • Typically identified as salivary gland lesions.
  • Acute systemic disease can result in interstitial pneumonitis with multifocal areas of necrosis in lymph nodes, spleen, liver, and other viscera.
• Lymphocytic choriomeningitis virus (LCMV) Lymphocytic choriomeningitis:
  • Infection is rare, but has public health significance.
  • Lymphocytic infiltrates in various organs including the liver.

Fungal infection

• Cryptococcosis (rare) Cryptococcosis.
• Encephalitozoon cuniculi:
  • Subclinical infection identified in guinea pigs.
  • Organs of high blood flow including the liver and kidneys are targeted.
  • Lesions similar to those reported in the rabbit.

​Parasitic infection

• Fasciola spp infection:
  • Natural infestation with Fasciola hepatica and Fasciola gigantica reported in domestic guinea pigs.
  • Associated with feeding of contaminated grass or hay.
  • Fibrotic cysts containing fluid and flukes identified in kidneys, liver and lungs
  • Guinea pigs appear to be an important factor in the life cycle of F. hepatica in cattle in Peru.
• Toxoplasma gondii Toxoplasmosis:
  • Clinical disease rare.
  • Clinical signs reflect organ involvement.

Inflammatory/immune-mediated conditions

• Systemic amyloidosis:
  • May be an incidental finding at post-mortem.
  • Deposition of hyaline AA amyloid between hepatic cords and other organs such as the kidneys and spleen.
  • Tend to occur in animals with chronic bacterial infection such as pododermatitis Pododermatitis.

​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.
  • Can be associated with poorly controlled diabetes mellitus in guinea pigs.
• Pregnancy toxemia 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:​

Toxins

• Aflatoxins.
• Drugs, eg itraconazole, azathioprine, diclofenac, amoxicillin-clavulanate, ivermectin Ivermectin.
• Chronic idiopathic cholangiofibrosis:
  • Periportal fibrosis with bile ductular proliferations occasional reported as an enzootic condition in adult colonies.
  • Etiopathogenesis not confirmed, but suggestive of a toxin-induced change.

Neoplasia

• Cavian leukemia Leukemia:
  • Peripheral lymphocytosis with predisposition of lymphoblastic cells typically seen.
  • Associated with lymphadenopathy Peripheral lymphadenopathy and hepatosplenomegaly Hepatomegaly Splenomegaly.
• Other neoplasms:
  • The liver can be a primary site for neoplasms, eg hemangiosarcoma, adenocarcinoma, hepatoma.
  • The liver is also a common site for metastasis.

Trauma

• Hepatic contusions:
  • Capsular rupture of the liver with hemorrhage into the peritoneal cavity is occasionally observed at post-mortem in guinea pigs.
  • May be associated with falls or mishandling.

Iatrogenic/idiopathic

• Vacuolar hepatitis.

Predisposing factors

General

• Suboptimal husbandry and sanitation:
  • Includes sudden dietary modifications in guinea pigs, which can predispose to intestinal dysbiosis Nutrition: overview.
  • Includes 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.
• Exposure to hepatotoxins.
• Obese animals in late gestation.
• Neoplasia Neoplasia overview 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:
  • Diarrhea and anorexia.
  • Thought to be associated with local inflammation, portal hypertension, hepatic encephalopathy (HE).
  • 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 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) 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.
• Fascioliasis in guinea pigs appears to be an important factor in the life cycle of F. hepatica in cattle in Peru.

Diagnosis

Treatment

Prevention

Outcomes