Definition

• Endogenous or exogenous substances (drugs, xenobiotics, toxins) that cause hepatic injury.
• Direct-(“Dose dependent”) causes predictable injury.
• Idiosyncratic-(“Dose independent” or “Type II”) unpredictable.

Pathophysiology

• Liver highly susceptible because of location and central role in metabolic and detoxification pathways. Liver is most commonly reported organ associated with true adverse drug reactions.
• Mechanisms of damage are direct (active metabolic byproducts) orindirect (oxidative processes from free radical metabolites).
• May cause hepatocellular or cytolytic injury (necrosis and apoptosis), cholestasis, immunologic (innocent bystander or hapten-mediated), or mixed histopathologic patterns of injury.
• Susceptibility and severity of injury-affected by age, species, nutritional status, concurrent drug administration, antecedent disease, antioxidant status; level of hepatic copper accumulation; hereditary factors, and current or prior exposure to the same or similar compounds.

Systems Affected

• Hepatobiliary
• Nervous-hepatic encephalopathy
• Renal-proximal tubular necrosis or renal tubular acidosis/Fanconi syndrome; hepatorenal syndrome (rare)

Genetics

Some dog breeds seem predisposed to certain drug-associated hepatotoxicities.

Signalment

Signs

Causes

Any drug, toxin, or xenobiotic may cause hepatotoxicity, variable severity, any individual.

Risk Factors

• Medications influencing hepatic metabolism (enzyme inducers and P450 inhibitors).
• Antecedent hepatic disease.

Differential Diagnosis

• Infectious disorders affecting liver/biliary tract: leptospirosis, cholecystitis, FIP, toxoplasmosis, rickettsial diseases (RMSF, ehrlichiosis).
• Acute necrotizing pancreatitis.
• Traumatic or hypoxic liver injury.
• Hepatic neoplasia
• Diagnosis of hepatotoxicity requires integration of history, environment, food, medications, and temporal relationship(s).

CBC/Biochemistry/Urinalysis

• PCV and total solids-often normal or high in acute hepatotoxicosis (shock or dehydration).
• ALT reflects cellular membrane damage and leakage of this cytosolic enzyme; may be 10- to 100-fold normal; monitor for subsequent decline over 3–28 days; prognosis not correlated with magnitude of increase. Increased ALT may precede increases in bilirubin and ALP.
• AST-may reflect more severe injury (mitochondrial) than ALT; also increased in myonecrosis.
• ALP-usually continues to rise for days/ weeks while ALT falls.
• CK-high activity associated with myonecrosis; some hepatotoxins also damage muscle (e.g., feline diazepam toxicity); high AST with normal CK confirms hepatic damage.
• Bilirubin, Albumin, BUN, and glucose-variable.
• Glucosuria and granular casts if proximal renal tubular injury (e.g., carprofen, copper). Some toxins suppress hepatic enzyme synthesis impairing clinical recognition of hepatic injury (e.g., blue-green algae, aflatoxin).

Other Laboratory Tests

• Coagulation profile-PT, APTT, FDP, platelets, and AT variable; monitor for DIC. Buccal mucosal bleeding time if others unavailable.
• Low protein C activity: biomarker for blocked protein transcription in aflatoxicosis.
• Non-icteric-paired TSBA (pre- and post-meal) assess hepatic function.

Imaging

• Abdominal radiography-acute toxicity: normal to large liver; chronic injury: variable liver size.
• Abdominal ultrasonography-variable echogenicity, hepatic size, and margins.

Diagnostic Procedures

• Hepatic biopsy-seldom indicated in acute toxicity (excessive risk/unnecessary for diagnosis/treatment); more helpful in confusing chronic hepatic injury; laparoscopic sampling more dependable; if desire core needle biopsies, need multiple samples using 14- to 16-gauge biopsy needle.
• Fine needle aspiration helpful if find neoplasia or etiologic agents; many toxins induce hepatocyte lipid vacuolation; variable dysplastic cell morphology in aflatoxin and cycad toxicity.

Pathologic Findings

Variable, depends on toxin, mechanism of cell injury, acinar zone of metabolism or product accumulation, or vascular injury and chronicity.

Appropriate Health Care

Inpatient-critical care setting

Nursing Care

• Prevention/correction of shock imperative.
• Fluid therapy-maintain hepatic perfusion to improve oxygenation and toxin removal; administer maintenance requirements-monitor oncotic pressure and ongoing losses/hydration status; administer colloid or plasma if albumin <2.0 g/dL; fluid therapy-avoid lactate-containing fluids in fulminant hepatic failure.
• Colloid administration-plasma initially preferred for delivery of clotting and anticoagulant precursor proteins followed by cautious use of synthetic colloid, if warranted.
• Bleeding tendencies-provide vitamin K₁ (0.5–1.5 mg/kg SC or IM q12–24h); administer fresh whole blood or fresh frozen plasma as needed. (Caution: stored blood products may have high ammonia concentration, causing HE.)
• Nasal oxygen-if compromised peripheral perfusion (hypotension) or pulmonary edema; may improve oxygen delivery to hepatic tissue.
• Oxidant damage likely involved in most hepatotoxic events-administer thiol or GSH donors (see below); GSH important for direct conjugation of certain toxins, may facilitate detoxification of some metabolites, enhances antioxidant protection, helps correct cell redox status conferring resistance to apoptosis, promoting cell membrane repair, and cell regeneration.
• Monitor urine output-diuretics as appropriate; see Renal Failure, Acute.
• Hypoglycemia-administer dextrose (2.5–5%) to maintain euglycemia as needed.

Diet

• Protein-normal, unless overt HE.
• Nutritional support-Antiemetics (maropitant or ondansetron) and antidyspepsics (pantoprazole) lessen nausea/promote appetite. If normal body condition score and acute disease, can wait up to 48 h for patient to voluntarily ingest food. If not eating within 48 h, first preference is NE tube enteral nutrition.
• Energy-strict calculation cumbersome. Initial starting points are: bodyweight kg × 50 (dogs) and bodyweight kg × 45 (cats): modified based upon size, body condition and monitoring–begin with 10–20% of calculated requirement; gradually increase to full requirement over 3–5 days. PPN only if unable to feed enterally. PPN/TPN can cause severe complications-only use if familiar with techniques/complications.

Client Education

• Potential for 3–10 days of ICU.
• Many recover, but post-necrotic cirrhosis, acquired shunting, and chronic hepatitis can develop later.

Drug(s) Of Choice

• Electrolyte supplementation-KCl (must monitor serum potassium).
• Short-acting glucocorticoids-for endotoxic shock (prednisolone sodium succinate)–controversial.
• Ampicillin or metronidazole theoretically protect against transmural migration of enteric flora.
• Antioxidant therapy-crisis intervention: N-acetylcysteine for acute or fulminant hepatic necrosis (140 mg/kg IV load, followed by 70 mg/kg IV q6–8h; give over 20 minutes not by CRI, dilute in saline, administer with non-pyrogenic 0.25 µm filter); when patient can accept oral medications and condition stabilizes, change to oral S-adenosylmethionine (SAMe; 20 mg/kg enteric-coated tablet PO q24h, on an empty stomach); vitamin E as d--tocopherol acetate (10 IU/kg q24h PO, although currently no evidence of clinically important benefit from vitamin E).
• B-complex vitamins-parenteral; co-factors for hepatic metabolism.
• Silybin (active component of silymarin [milk thistle extract]); prefer form complexed with phosphatidylcholine (2–5 mg/kg q24h PO); may augment liver regeneration and provide antioxidant, hepatoprotective, and antifibrotic effects.
• Ursodeoxycholic acid-primarily for chronic hepatopathies (15 mg/kg/day PO), give with food. Provide taurine supplementation in anorectic cats (obligate taurine bile acid conjugation).

Contraindications

Avoid known hepatotoxic drugs and those that require or inhibit hepatic metabolism.

Precautions

• Use drugs listed as hepatotoxins with caution.
• Use caution when catheterizing large vessels or doing diagnostic needle aspirates/biopsies if coagulopathy.

Patient Monitoring

• Prevent hypothermia.
• Monitor blood glucose, electrolytes, PCV-frequently; fluctuations occur rapidly in critically ill patients.
• CBC/platelet, serum biochemical analyses, coagulation tests-typically monitor q48h or as warranted.
• Monitor urine output.

Prevention/Avoidance

Close scrutiny of environment and future medications

Possible Complications

• DIC or hemorrhage
• Hepatic encephalopathy
• Progressive hepatic failure
• Post-necrotic cirrhosis with acquired shunting/ascites

Expected Course and Prognosis

• Usually need 2–5 days to estimate prognosis.
• Negative indicators: intractable emesis, hematemesis, intolerance to supportive treatments, oliguria, DIC, HE; decline of ALT with increasing bilirubin and/or lowering of serum albumin; lowering cholesterol.
• Positive indicator: ALT declining by 20–30% or more every 48–72 hours, with other evidence of improvement, is positive indicator.
• Post-necrotic cirrhosis-possible in 2–6 months.

Associated Conditions

• Hepatitis
• Fibrosis
• Hepatic encephalopathy
• Hepatic lipidosis (cats)
• Icterus
• Ascites
• Hypoglycemia
• Sepsis

Age-Related Factors

• Young animals may have greater exposure and risk for toxin ingestion.
• Older animals-may have diseases requiring drug therapies increasing their risk (e.g., cimetidine, phenobarbital, NSAIDs).

See Also

• Acetaminophen (APAP) Toxicosis
• Cirrhosis and Fibrosis of the Liver
• Hepatic Encephalopathy
• Hepatic Failure, Acute
• Poisoning (Intoxication) Therapy

Abbreviations

• AT = antithrombin
• CCNU = chloroethylcyclohexylnitrosourea
• FDP = fibrin degradation products
• FIP = feline infectious peritonitis
• GSH = glutathione
• HE = hepatic encephalopathy
• MDR1 = multidrug resistance gene 1
• NE = nasoesophageal
• NSAID = nonsteroidal anti-inflammatory drug
• PIVKA = proteins invoked by vitamin K absence or antagonism
• PPN = partial parenteral nutrition
• RMSF = Rocky Mountain spotted fever
• TPN = total parenteral nutrition
• TSBA = total serum bile acids

Authors Michael D. Willard and Sharon A. Center

Consulting Editor Sharon A. Center

Client Education Handout Available Online