Definition

• Hepatic injury associated with active necroinflammatory liver injury.
• Nonsuppurative inflammation-most common; lymphocytes, plasma cells, macrophages, occasional neutrophils.
• Chronicity-progressive remodeling, regenerative nodule formation, fibrosis, eventuating in cirrhosis (see Fibrosis and Cirrhosis of the Liver).

Pathophysiology

• Multitude of initiating events cause hepatic injury that alter hepatic architecture, damage membranes and/or organelles, and activate cytokine and cell-mediated immune responses; hepatic components become targeted foci.
• Initial injury may include infectious agents, toxins, or therapeutic agents but cause often remains undetermined.
• Inflammatory cells, including predominantly lymphocytes (T-cells, NK T-cells), Kupffer cells (hepatic macrophages resident in the lumen of sinsusoids), and neutrophils are initial effector cells; INF-g, TNF-a, FasL, IL-4, and numerous chemokines and oxidative free radicals are commonly involved.
• Oxidant injury an important pathomechanism of membrane and organelle injury.
• Initial zone of injury demarcates area of necroinflammatory response-zone 1 (periportal) common in many forms of idiopathic hepatitis whereas zone 3 incriminates Cu associated injury, NSAID and other toxins, or repeated ischemic/hypoxic insult.
• Lesions progression is variable and may include portal and periportal lymphoplasma-cytic infiltrates, interface hepatitis with piecemeal necrosis of the limiting plate and variable lobular necroinflammatory activity. Chronic inflammation-progressive fibrosis with bridging between involved zones.
• Bridging fibrosis and regenerative nodules distort lobular architecture leading to cirrhosis.
• Progressive development of cholestasis.
• Cirrhosis and hepatic failure-late stage.
• Cirrhosis-consequence of chronic fibrogenesis and hepatic regenerative response; typified by: regenerative nodules; reduced functional hepatic mass; collagen deposition along sinusoids and/or around portal triads that compromises sinusoidal perfusion.
• Fibrosis-usually reflects chronic injury; associated with release of cytokines/mediators that stimulate ECM production or accumulation.
• Cirrhosis/fibrosis-leads to hepatic dysfunction, sinusoidal hypertension; intrahepatic shunting in collagenized sinusoids or through recanalized vascular pathways within fibrotic partitions between regenerative nodules.
• Sinusoidal hypertension-leads to (1) hepatofugal portal venous flow (away from the liver), (2) mesenteric splanchnic hypertension, (3) formation of APSS, (4), episodic HE, (5) splanchnic pooling of blood, decreased effective blood volume, renal sodium and water retention that culminate in ascites formation, (6) portal hypertensive enteric vasculopathy predisposing to enteric bleeding.

Systems Affected

• Hepatobiliary-inflammation; necrosis; cholestasis; fibrosis.
• GI-emesis; diarrhea; anorexia, portal hypertension leads to ascites formation and propensity for enteric bleeding (portal hypertensive gastroenteric vasculopathy).
• Neurologic-HE.
• Hemic-RBC microcytosis reflecting APSS; bleeding tendencies: failed factor synthesis or activation or thrombocytopenia; coagulopathy (advanced stage).
• Renal/Urologic-PU/PD; isosthenuria; ammonium biurate crystalluria (advanced stage).
• Endocrine/Metabolic-hypoglycemia if end-stage liver failure (provoked by prolonged inappetence).
• Respiratory-tachypnea if tense ascites; bicavity effusion (leakage across diaphragm (rare), pulmonary edema (rare).
• Nervous-HE (advanced stage).

Genetics

• Breed or familial predisposition for chronic hepatitis-Doberman pinscher, Labrador retriever, West Highland white terrier, and Dalmatians may develop chronic hepatitis related to low tolerance to Cu levels in commercial diets; Cocker spaniel, standard poodle, Maltese, Skye terrier, others.
• Inherited copper associated hepatopathy only proven in the Bedlington terrier-autosomal recessive, genetic test available.

Incidence/Prevalence

N/A

Signalment

Signs

Causes

• Chronic necroinflammatory, oxidant, or immune-mediated liver injury has many causes.
• Infectious-canine hepatitis virus; leptospirosis, enteric portal bacteremia or endotoxemia affiliated with IBD; accidental parenteral administration of intranasal Bordetella vaccine.
• Immune-mediated-autoimmune with positive ANA; acquired immune sensitization, nonsuppurative inflammation.
• Toxic-copper associated hepatopathy; acute or chronic exposure to drugs-predictable or idiosyncratic toxicity: e.g., azole antifungals, trimethoprim-sulfa, zonisamide, phenobarbital, primidone, phenytoin, CCNU, NSAIDs (esp. carprofen); repeat exposure to environmental or food-borne toxins, e.g., dimethylnitrosamine, aflatoxin, cycad, cyanobacteria.

Risk Factors

• Immunostimulants (vaccinations?) and molecular mimicry of cell epitopes by infectious agents or infection of sinusoidal endothelium may promote inflammatory reactions associated with chronic hepatitis.
• Cu associated hepatopathy-neoepitope formation from oxidant injury.
• Hepatic iron accumulation: supplementation.
• Drugs-inducers or inhibitors of microsomal enzymes or conditions diminishing hepatic antioxidant status may augment liver damage from certain toxins.

Differential Diagnosis

• Acute hepatitis-history; liver biopsy
• Congenital portosystemic shunt (PSVA)-abdominal ultrasonography; radiographic or multisector CT contrast venography (latter preferred); colorectal scintigraphy; liver biopsy
• Primary hepatic neoplasia-radiography or ultrasonography; cytology; biopsy
• Metastatic neoplasia or carcinomatosis
• Chronic pancreatitis
• Causes of abdominal effusion-hypoalbuminemia; right heart failure; carcinomatosis (see Hypertension, Portal); bile peritonitis
• Other causes of portal hypertension-see Hypertension, Portal
• Jaundice-EHBDO; bile peritonitis, hemolysis

CBC/Biochemistry/Urinalysis

Other Laboratory Tests

• TSBA-variable depending on extent of hepatic remodeling, sinusoidal hypertension, and cholestasis.
• Ammonia intolerance-reflects APSS; insensitive to cholestatic changes.
• Coagulation tests-reflect panlobular injury and/or chronicity; early disease has no abnormalities but perhaps high fibrinogen; advanced stage or severe panlobular injury may note prolonged PT, APTT, and PIVKA, low fibrinogen, increased FDP or D-dimers (note: some D-dimer tests are too sensitive for differential diagnostic utility); coagulation tests reflect severity of liver dysfunction, synthetic failure, DIC, and vitamin K adequacy (see Coagulopathy of Liver Disease); low protein C activity suggests APSS or hepatic failure.
• Abdominal effusion-chronic liver disease or portal hypertension: pure or modified transudate.
• Liver zinc values-low with chronic disease and especially if APSS.
• Serologic tests-for possible infectious agents, e.g., leptospirosis, rickettsial diseases, Borrelia, Bartonella, endemic fungal agents.
• ANA titer-for potential autoimmune-mediated disease; note: low level positive titers are nonspecific.
• Immunohistochemical staining of liver sample-confirm infectious agent or origin of infiltrative cells.

Imaging

Diagnostic Procedures

Pathologic Findings

• Gross-early: no gross change; late stage: microhepatia with irregular surface or margins (fine or coarse nodules), tortuous APSS.
• Microscopic-nonsuppurative inflammation involving zone of necroinflammatory injury; variable cholestasis and biliary hyperplasia; piecemeal and/or bridging necrosis; interface hepatitis; disruption of limiting plate in zone 1 lesions; in late-stage disease: bridging between or within zones; regenerative nodules, and transition to cirrhosis.

Appropriate Health Care

• Inpatient-for diagnostic testing and therapy in overtly ill dogs.
• Outpatient-if condition is stable at diagnosis; slowly titrated onto medical therapy.

Nursing Care

• Depends on underlying condition.
• Fluid therapy-balanced polyionic fluids supplemented to correct electrolyte aberrations or hypoglycemia; restrict sodium if ascites.
• Water-soluble vitamins (2 mL/L fluids).
• Ascites: managed with sodium-restricted diet, enforced rest, diuretics (furosemide combined with spironolactone); see Cirrhosis and Fibrosis of the Liver.
• Therapeutic abdominocentesis-aseptic procedure for removing large-volume symptomatic ascites compromising food intake, ventilation, or sleep; if diuretics and sodium restriction ineffectual.
• For diuretic-resistant ascites: calculate sodium intake against measured renal sodium excretion (collect urine over 12 hours, measure sodium and creatinine in well-mixed sample, and in sera); guides adjustments in management (i.e., increase sodium restriction vs. increase diuretic).

Activity

Keep patient warm, inactive, and hydrated; inactivity may promote hepatic regeneration, euglycemia, and ascites mobilization.

Diet

• Adequate calories and protein-avoid catabolism to maintain muscle mass (attenuates hyperammonemia); monitor body condition.
• Dietary protein-restrict quantity ONLY if signs of HE (see Hepatic Encephalopathy) or observed ammonium biurate crystalluria; feed balanced diet; if HE, avoid fish and red meat source protein (dogs).
• Meal frequency-feed several small meals per day to optimize nutrient assimilation.
• Sodium restriction-with ascites or severe hypoalbuminemia: <100 mg/100 kcal or <0.2% dry matter basis formula.
• Good-quality vitamin supplement-vitamin metabolism perturbed with liver disease and losses in urine; avoid copper supplements if copper associated hepatopathy.
• Thiamin-ensure repletion to avoid Wernicke's encephalopathy; 50–100 mg PO q24h; caution: anaphylactoid reactions may occur with injectable thiamin.
• Partial parenteral nutrition-may consider, if short-term inappetence to minimize catabolism.
• Total parenteral nutrition-if inappetence lasts >7 days; branched-chain amino acids remain controversial in dogs with liver dysfunction.
• Fat restriction rarely needed.

Client Education

• Control rather than cure is the expected goal; medications usually will be required for life; disease is cyclic; quarterly evaluations important.
• Inform client of the lack of long-term veterinary studies proving efficacy of single or polypharmacy approaches; recommendations derived from clinical experience, studies in humans, and animal disease models.
• Antifibrotics may reduce fibrosis but limited evidence; fibrosis diminished by control of inflammation and underlying primary process.
• Attenuate factors provoking HE-dehydration; azotemia, infection; catabolism; hypokalemia; alkalemia; high protein meals; endoparasitism; enteric bleeding; certain drugs.

Surgical Considerations

• APSS-do not ligate nor band the vena cava.
• Cirrhosis-high anesthetic risk; gas anesthesia preferred-isoflurane or sevoflurane.

Drug(s) Of Choice

• Treatments for specific etiologies: chelate Cu if copper associated hepatopathy); withdraw potentially hepatotoxic drugs.
• No clinical trials prove efficacy of specific regimens to date.

Contraindications

• NSAIDs-avoid; potentiate enteric bleeding; may worsen ascites; potentially centrilobular hepatic necrosis-hepatotoxic metabolites.
• Avoid drugs requiring hepatic metabolism whenever possible.

Precautions

• Diuretics-dehydration, hypokalemia, alkalosis worsen HE.
• Glucocorticoids-increased susceptibility to infection, enteric bleeding, sodium and water retention, protein catabolism and HE.
• Avoid drugs or reduce dose if first-pass hepatic extraction, if require hepatic conjugation or biotransformation e.g. metronidazole-reduce conventional dose to 7.5 mg/kg PO q12h (often used for HE).
• Zinc overdose may cause hemolysis.

Alternative Drug(s)

• Dexamethasone-if ascites, replace prednisone or prednisolone with this drug to remove mineralocorticoid effect); divide pred. dose by 7–10, administer q3–4 days; taper dose to observed efficacy.
• Mycophenolate: alternative for azathioprine.

Patient Monitoring

• At-home behavior, body condition, muscle mass, weight-adjust protein and energy intake to nitrogen tolerance and apparent energy needs.
• CBC, biochemistry, and urinalysis-monthly or quarterly, depends on patient status; look for signs of drug toxicity, disease remission, synthetic function, ammonium biurate urolithiasis, and urinary tract infections.
• Serial monitoring of TSBA-usually does not add prognostic or diagnostic information.
• Abdominal girth: reflects ascites volume.
• Azathioprine, mycophenolate , colchicine-monitor for possible bone marrow toxicity (serial CBCs), GI toxicity, and other effects.

Possible Interactions

• Avoid medications that alter hepatic biotransformation or excretion pathways (e.g., cimetidine, quinidine, ketoconazole).
• Avoid concurrent treatment with metoclopramide if spironolactone used for diuresis (causes aldosterone release).

Possible Complications

HE, septicemia, bleeding-may be life-threatening; DIC-may be a terminal event.

Expected Course and Prognosis

• Chronic hepatitis can be a cyclic disease with occasional flare-ups indicated by sequential assessment of liver enzymes.
• Some dogs achieve solid long-term remission.
• Some dogs with Cu associated hepatopathy can achieve permanent remission of apparent “immune-mediated” inflammation upon effective Cu chelation and appropriate nutritional management.
• Presence of ascites indicates severe disease with shorter survival.
• Severe disease complicated by development of APSS have HE and ascites may require occasional hospitalizations for adjustment of nutritional and medical interventions.
• Sodium restriction and diuretics may require titration to achieve optimal control of ascites.

Zoonotic Potential

• Dogs with leptospirosis-associated chronic liver disease (rare) may shed organisms.
• Bartonella; rickettsial agents (endemic vectors).

See Also

• Ascites
• Copper Associated Hepatopathy
• Diabetic Hepatopathy
• Hepatic Encephalopathy
• Hepatic Failure, Acute
• Hepatic Fibrosis and Cirrhosis
• Hepatitis, Chronic
• Hypertension, Portal
• Portosystemic Shunting, Acquired

Abbreviations

• ACT = activated clotting time
• APSS = acquired portosystemic shunt(s)
• APTT = activated partial thromboplastin time
• ARF = acute renal failure
• Cu = copper
• EHBDO = extrahepatic bile duct occlusion
• FasL = fas-ligand
• FDP = fibrin degradation products
• HE = hepatic encephalopathy
• IL-4 = interleukin 4
• INF-g = interferon gamma
• NSAID= nonsteroidal anti-inflammatory drugs
• PPC = polyunsaturated phosphatidylcholine
• PIVKA = proteins invoked by vitamin K absence or antagonism
• PSVA = portosystemic vascular anomaly
• PT = prothrombin time
• TNF-a = tumor necrosis factor alpha
• TSBA = total serum bile acids

Client Education Handout Available Online