Definition

• Severe acute hepatic injury incapacitating the ability to meet synthetic, metabolic, and detoxification needs.
• Sudden loss of >75% of functional hepatic mass due to acute, massive hepatic necrosis.
• May lead to catastrophic multi-organ dysfunction/failure in a previously healthy individual; may rapidly progress to death.

Pathophysiology

• Necrosis-secondary to insufficient perfusion, hypoxia, hepatotoxins or their adducts (drugs, other xenobiotics, toxins), heat excess, or infectious agents.
• Severity of hepatic dysfunction depends on insult type and lobular (zonal) distribution.
• Reduced perfusion or hypoxia usually affect zone 3 (pericentral or centrilobular region).
• Ingested toxins-affect zone where toxin is metabolized or adducts formed, or where there is specific organelle tropism or propensity for oxidative injury (copper accumulation increases zone 3 vulnerability).
• Accompanied by enzyme leakage and markers of impaired liver function, hyperbilirubinemia and acute onset splanchnic hypertension due to sinusoidal or centrilobular collapse.
• Lethal organ failure associated with coagulopathy, enteric hemorrhage, acute onset hepatic encephalopathy (HE).
• Hepatic failure-associates with a myriad of metabolic derangements: i.e., altered glucose homeostasis, protein synthesis (albumin, transport proteins, procoagulants, and anticoagulants), and detoxification capabilities.

Systems Affected

• Hepatobiliary-hepatocellular necrosis; hepatic failure, and jaundice.
• Nervous-HE; cerebral edema.
• Gastrointestinal-vomiting; diarrhea; melena; hematochezia due to acute splanchnic hypertension ± coagulopathy.
• Hemic/Lymphatic/Immune-pro- and anticoagulant factor imbalances; DIC.
• Renal/Urologic-renal tubule damage from certain toxins or physiologic vasoconstriction; tubular injury: i.e., copper associated hepatopathy, leptospirosis, xylitol toxicity, NSAID toxicity.
• Hyperdynamic circulatory status: low systemic and pulmonary vascular resistance, increased cardiac output and metabolic rate, systemic hypotension; this associates with endotoxemia, TNF-, dehydration, and splanchnic hypertension.

Incidence/Prevalence

• Variable depending on pre-existent liver disease: i.e. hepatocellular copper accumulation, chronic immune-mediated hepatitis or cholangitis.
• Panlobular hepatic necrosis leading to acute liver failure is uncommon; examples: idiosyncratic drug toxicity: dogs-zonisamide, phenobarbital, primidone, diphenylhydantoin, NSAIDs (e.g., carprofen), xylitol; cats-diazepam; dogs or cats-sulfa-antibiotics; primary toxins: dogs and cats-primary copper accumulation, acetaminophen; dogs-zonisamide, xylitol, cycad (sago palm), blue-green algae, Amanita mushrooms, aflatoxin; infectious disease: dogs-leptospirosis, infectious canine hepatitis.

Geographic Distribution

N/A

Signalment

Signs

• Acute-onset nonspecific clinical signs; lethargy, inappetence, GI disturbances (vomiting, small intestinal diarrhea may be bloody), PU/PD.
• Tender hepatomegaly.
• Bleeding tendencies.
• Jaundice.
• Hepatic encephalopathy.
• Seizures.

Causes

Risk Factors

• Administration of any potentially hepatotoxic substance or drug.
• Exposure to environmental toxins (e.g., Amanita mushroom, foodborne aflatoxin, cycad [sago palm] ingestion, blue-green algae, artificial sweetener xylitol (gum, candy)-dogs.
• Enzyme inducers (e.g., phenobarbital)-may increase risk for certain toxicities by enhancing xenobiotic toxin formation: e.g., acetaminophen toxicity is greatly enhanced by phenobarbital.
• Indiscriminate substance ingestion-puppies; polyphagic animals.

Differential Diagnosis

• Severe acute pancreatitis or gastroenteritis-differentiated via laboratory tests and imaging.
• Acutely decompensated chronic liver disease-distinguished by review of medical records, blood tests, abdominal ultrasonography, and liver biopsy.

CBC/Biochemistry/Urinalysis

• Anemia and panhypoproteinemia-bleeding, marrow toxicity, direct enteric toxicity.
• Thrombocytopenia-bleeding, DIC, or portal hypertension.
• Liver enzyme activity-high acute ALT and AST; smaller increases ALP and GGT.
• Hypoglycemia-grave prognosis (cats esp.).
• Hypocholesterolemia-impaired synthesis or enteric loss with hemorrhage.
• Normal to low BUN concentration: reduced urea cycle function, PU/PD.
• Hyperbilirubinemia: initially absent.
• Bilirubinuria may precede hyperbilirubinemia-always abnormal in cats.
• Ammonium urate crystalluria signifies hyperammonemia, hepatic insufficiency or portosystemic shunting.
• Acquired Fanconi's syndrome-granular casts and renal glucosuria indicate proximal tubule injury (e.g., carprofen, copper, leptospirosis, other toxicities especially in dogs).

Other Laboratory Tests

• TSBA-high values indicate hepatic dysfunction, cholestasis, or portosystemic shunting.
• Plasma ammonia concentration-high values coincide with high TSBA, confirm hepatic insufficiency; hyperammonemia inconsistent but reflected by ammonium biurate crystalluria; hyperammonemia may reflect concurrent myonecrosis.
• Coagulation tests-coagulation factor deficiencies, platelet dysfunction, low fibrinogen, low antithrombin or protein C activity, and DIC suggest severe liver failure, decompensated DIC, or enteric losses with hemorrhage.

Imaging

• Abdominal radiography-may identify a normal to slightly large liver ± effusion.
• Abdominal ultrasonography-may disclose non-hepatic disorders (e.g., pancreatitis), altered circulation (ratio hepatic vein:portal vein), altered liver echogenicity or surface contour reflecting chronic injury (e.g., remodeling implicated by heterogeneous liver texture, nodularity, or hepatofugal portal blood flow); rule out biliary obstruction as source of hyperbilirubinemia.
• Brain MRI-may disclose early cerebral edema.

Other Diagnostic Procedures

• Liver biopsy-confirms necrosis and characterize lesion zonal distribution.
• Fine-needle liver aspirate may identify hepatocellular degeneration, copper accumulation, dysplastic hepatocytes observed with cycad (sago palm) or aflatoxin ingestion; canalicular cholestasis. Many toxins lead to microvesicular hepatocellular lipid vacuolation.

Pathologic Findings

• Gross-slightly large, mottled liver.
• Microscopic-confirms necrosis; zonal involvement; may assist in determining underlying cause: hypoxia leading to zone 3; certain toxins cause zone 1 or 3 necrosis; reticulin staining confirms zonal involvement, confirms retention or loss of reticulin substructure that orchestrate organized regeneration.

Appropriate Health Care

Inpatient-intensive care required.

Nursing Care

• Caution: Delay inserting central catheters until bleeding diatheses controlled with vitamin K₁, fresh frozen plasma, or fresh whole blood. No advantage to prophylactic FFP administration as this may contribute to onset of HE and cerebral edema.
• Fluids-non–lactate-containing; initially at a resuscitation rate; monitor peripheral blood pressure and pulse oximetry. Mixed acid-base disturbances common.
• Colloid replacement-with low oncotic pressure from bleeding and protein loss; plasma always preferred; synthetic colloids are second line. Avoid dextran 70 and Hetastarch (as these may promote bleeding) and human albumin (may induce fatal acute allergic reaction).
• Potassium, phosphate, glucose-supplement as appropriate; low phosphate, potassium and glucose aggravate HE and other clinical signs, complicating critical supportive care.
• Fluid regimen-adjust for maintenance needs after achieving normovolemia; typically provide one-third of normal maintenance rate with polyionic crystalloids if concurrently giving slow CRI of synthetic colloid. Avoid colloids if possible as these leak from the microvasculature (exacerbated with some toxicities that affect endothelium) and disturb signaling that triggers albumin and transporter protein synthesis.
• Supplemental oxygen-if pulse oximetry 90% saturation.
• If suspect cerebral edema: use 30° head up elevation, consider mannitol, other interventions.
• Predisposition to infection from enteric bacterial translocation-cover with broad-spectrum antimicrobials; patient may not manifest fever or leukocytosis with infection. Sepsis/SIRS-major risks for cerebral edema.
• Early administration of N-acetylcysteine may improve microvascular perfusion, tissue oxygenation, and mitigate oxidative damage; dosing: see below.

Activity

Restricted activity-conserves energy and metabolites for healing and regeneration.

Diet

• Intractable vomiting-withhold PO food until controlled; use antiemetics (see below).
• When enteric nutrition contraindicated (somnolent patient) use total or partial parenteral nutrition until enteral feeding route established; <5 days advised.
• If enteric nutrition chronically compromised, establish total parenteral nutrition (TPN) feeding catheter; use TPN formula with normal nitrogen content unless HE; branched-chain amino acids remain controversial.
• Enteral feeding-small volume, frequent meals; optimize digestion and assimilation, minimize enteric toxin formation contributing to HE.
• Diet composition-use normal protein (nitrogen) content in tolerant patients; moderate protein restriction if HE (2.5 g protein/kg bodyweight) but strive to maintain a positive nitrogen balance for hepatic regeneration.
• Supplemental vitamins are essential-water-soluble (2-fold normal); vitamin K₁ (0.5–1.5 mg/kg SC or IM, three doses at 12-h intervals, then once-to-twice weekly); vitamin E (10 IU/kg PO or by injection q24h).
• Probiotic/Prebiotic yogurt: may protect against enteric bacterial translocation; tolerated dairy protein source if HE; controversial.

Client Education

• Acute hepatic failure is a serious condition.
• Some patients succumb despite optimal treatment.
• Cause of panlobular injury (e.g., exposure to a drug or toxin) should be investigated but may remain unconfirmed.

Surgical Considerations

N/A

Drug(s) Of Choice

Contraindications

• Ideally, drugs biotransformed primarily in the liver, altering liver perfusion, or metabolizing enzyme activity should be avoided; may be difficult as many drugs are metabolized in hepatic pathways or eliminated in bile.
• Vitamin C-100–500 mg q24h, avoid if high liver iron or copper concentrations; ascorbate may augment transition metal–associated oxidative injury; no substantiation for vitamin C administration in liver failure.

Precautions

Administration of stored whole blood or packed RBCs may precipitate or exacerbate HE in dogs with hepatic failure because of spontaneously generated ammonia during storage.

Possible Interactions

Compromised hepatic metabolism

Alternative Drug(s)

Case-based considerations

Patient Monitoring

• Temperature, pulse, respiration, and mental status-q1–2h until stable.
• Maintain vigilance for infection, especially catheter-induced.
• Bodyweight-twice daily guides fluid therapy; bodyweight and condition used to assess nitrogen and energy allowances.
• Acid-base, electrolyte balances (especially potassium and phosphate), and glucose-q12–24h for the first 72 h.
• Sequential measurements of: liver enzymes, bilirubin, cholesterol, and fibrinogen q2–3 days provide evidence of recovery.

Prevention/Avoidance

• Vaccinate dogs against infectious canine hepatitis virus.
• Avoid indiscriminate ingestion of hepatotoxins and environmental exposure.
• Consider drugs as potential toxins.

Possible Complications

• Hypoglycemia
• Uncontrolled GI bleeding and DIC
• HE, cerebral edema, brain herniation
• Chronic hepatic insufficiency, cirrhosis, fibrosis from postnecrotic scarring
• Acute renal failure
• Death

Expected Course and Prognosis

Prognosis-depends on extent of liver injury, etiopathogenesis, supportive nursing care.

Associated Conditions

• Pancreatitis
• Sepsis/Endotoxemia/Shock
• Bleeding diathesis; severe enteric hemorrhage; DIC
• Renal failure
• Hepatic encephalopathy

Zoonotic Potential

• Toxins (?)
• Leptospirosis

Synonyms

• Acute hepatic necrosis
• Fulminant hepatic failure

See Also

• Ascites
• Coagulopathy of Liver Disease
• Hepatic Encephalopathy
• Hepatitis, Infectious (Viral) Canine
• Hepatotoxins
• Hyperbilirubinemia
• Icterus
• Renal Failure, Acute

Abbreviations

• ALP = alkaline phosphatase
• ALT = alanine aminotransferase
• AST = aspartate aminotransferase
• BUN = blood urea nitrogen
• CRI = constant rate infusion
• CSF = cerebrospinal fluid
• DIC = disseminated intravascular coagulation
• GGT = γ-glutamyltransferase
• GSH = glutathione
• HE = hepatic encephalopathy
• PU/PD = polyuria, polydipsia
• TSBA = total serum bile acids

Client Education Handout Available Online