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Fulminant Hepatic Failure in Small Animals


Sharon A. Center

, DVM, DACVIM, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University

Reviewed/Revised Aug 2023

Fulminant hepatic failure is characterized by the abrupt critical decline in liver function in a patient without preexistent liver disease, associated with a 2-3–fold increase in liver enzymes, jaundice, variable coagulopathy, and in some cases, eventual development of hepatic encephalopathy and ascites of variable onset.

Fulminant hepatic failure (FHF) is a syndrome defined as the abrupt critical decline in liver function in a patient without preexistent liver disease, associated with a 2-3–fold increase in liver enzymes, jaundice, variable coagulopathy, and in some cases, eventual development of hepatic encephalopathy and ascites of variable onset.

FHF as an acute injury in a patient without preexistent liver disease often reflects the impact of hepatotoxins, severe systemic sepsis, or acquired acute circulatory failure (hepatic arterial, hepatic vein, or hilar vena caval thrombosis). In patients with preexisting liver disease, acute escalation of liver injury after a "second hit" phenomenon (ie, another impacting cause of liver injury) also can culminate in FHF. This process is categorized as acute-on-chronic liver failure.

An example of this scenario is observed in a subset of dogs with severe copper-associated liver injury after exposure to a nonsteroidal anti-inflammatory drug causing centrilobular necrosis. Thereafter, massive panlobular hepatic necrosis can evolve as injury is amplified by widespread release of copper from necrotic hepatocytes causing critical oxidative injury. These dogs often display an acquired Fanconi syndrome (ie, euglycemic glucosuria with granular casts due to proximal renal tubular injury).

Appropriate intervention for animals with suspected fulminant hepatic failure requires a complete physical examination. The following are additional considerations:

  • meticulous attention to prior health records

  • environmental and travel history

  • recent vaccination history

  • potential for exposure to leptospirosis

  • feeding of new treats, rawhides, or foods (especially imported brands)

  • feeding of a raw meat diet

  • potential for hepatotoxin exposure (eg, including hepatotoxic chemicals, drugs, herbal, holistic or traditional remedies, or hepatotoxic plant exposures)

  • possibility of malignant infiltration (ie, widespread lymphoma)

  • consideration of imaging findings (ie, impacted hepatic vasculature causing acute ischemic or hypoxic injury)

In dogs, it is also important to consider the potential for severe hepatic copper accumulation. Physical examination should include a complete system consideration, including assessment of the following:

  • jaundice

  • hepatomegaly

  • abdominal effusion (ballottement is inconsistent; focused assessment with sonography in trauma ultrasound scanning, definitive)

  • evidence of surface or enteric hemorrhage (ie, oral, ophthalmic [sclera, anterior chamber, retinal] examination)

  • inspection of haired and nonhaired surfaces

  • digital rectal examination (melena, hematochezia)

Early intervention in FHF provides supportive care designed to bridge survival to allow time for hepatic regeneration and functional compensation and, when appropriate, acquisition of a liver biopsy to detect any chronic injury process. After removal of a massive hepatocellular carcinoma (ie, leaving < 20% functional hepatic mass), some dogs transiently display clinical signs consistent with liver failure; these can often be bridged with supportive care to achieve hepatic regeneration.

Sequential assessments in patients with FHF inform syndrome status and treatment response; these include reevaluation of physical status, liver enzyme activity, concentration of total bilirubin and hepatic synthetic markers, assessment for ascites, development of acquired portosystemic shunts (APSSs), and hyperammonemia (blood ammonia, ammonium biurate crystalluria).

Specific treatments in FHF are recommended for certain underlying causes.

Decontamination of oral, dermal, and enteric surfaces is mandatory if toxin exposure is suspected, particularly within an exposure window of 36 hours. Mild dishwashing soap is used for surface decontamination. For some hepatotoxins, emesis is initiated if presentation is within a few hours of ingestion (emesis initiated with apomorphine by SC injection or conjunctival tablet, oral administration of 3% hydrogen peroxide, or syrup of ipecac). However, emesis should not be initiated if there is historic observation that vomiting has already occurred or if the patient is somnolent, comatose, exhibiting frequent seizure activity, or predisposed to aspiration.

Vomiting is not recommended for ingested toxins involving strong acid or alkali or an oily physicochemical nature, or emitting volatile organic products that might be inhaled. Cholestyramine, an enteric binding resin, can adsorb a number of hepatotoxic substances undergoing enterohepatic circulation (eg, blue green algae toxin microcystin is one example). Administration of cholestyramine at a dose of 100–175 mg/kg, PO, every 24 hours is recommended. Because cholestyramine may impair intestinal absorption of other medications, bile acids, and fat-soluble vitamins, it should be administered 1 hour before, or 4 hours after, meals or administration of other oral medications.

If an adverse drug reaction is implicated as the cause of fulminant hepatic failure, the drug in question is discontinued and antidotes investigated. Appropriate interventions for specific toxins are best investigated by contacting the ASPCA Animal Poison Control Center at (888) 426-4435. Life-threatening infections, cerebral edema, and coagulopathies are major complications of fulminant hepatic failure.

Attention to fluid, electrolyte, and acid-base balance; glycemic status; and nutritional support are important considerations. Restoration of intravascular volume may prevent or mitigate organ failure that may accompany fulminant hepatic failure (eg, renal, cardiac, adrenal, pancreatic dysfunction). Crystalloid fluids rather than colloids are recommended; colloid administration can increase risk for bleeding and development of acute renal injury. Lactated Ringer’s solution should be avoided if there is evidence of compromised hepatic lactate metabolism (hyperlactatemia fails to improve with volume expansion).

Although balanced crystalloids buffered with either bicarbonate or acetate are often administered, a subset of patients with severe acute FHF may have decreased ability to metabolize acetate. When repetitious violent vomiting and diarrhea accompany FHF, these can provoke dehydration, hyponatremia linked with cerebral edema, hypokalemia, hypochloremia, and metabolic alkalosis. Alkalosis and hypokalemia must be avoided because each can escalate renal ammonia production, contributing to hyperammonemia and hepatic encephalopathy (HE).

Neuroglycopenia can induce neurologic signs confused with HE and also may worsen HE. Hypoglycemia has a multifactorial pathogenesis, including increased hepatic glucose extraction, increased hepatic glycolysis, impaired gluconeogenesis, and failure of compensatory renal gluconeogenesis.

Dextrose (2.5%) and potassium (based on Green's sliding scale) should be judiciously added to IV fluids, along with water-soluble vitamins (fortified B-soluble vitamins at 2 mL/L of fluid). Administration of sodium (0.9% NaCl) solution with supplemental vitamins and glucose is usually a safe first intervention unless portal hypertension and ascites complicate clinical status (ie, patients with previous chronic liver disease or animals with acute liver injury causing sinusoidal collapse). It is important to avoid hypernatremia, which can foster hypertension and tissue edema that can compromise microcirculation.

In cats, a B12 injection (250 mcg total dose, IM or SC) should be considered if severe gut disease, pancreatic disease, hyperthyroidism, or starvation is a suspected complication. A plasma sample for assessment of B12 status should be collected before treatment. Definitive diagnosis of B12 insufficiency relies on detection of methylmalonic acidemia; however, this analysis cannot be completed in a timely manner for patients with emergent liver failure.

Conventional B12 measurement detects the inactive parenterally administered form of B12 (cyanocobalamin) as well as activated forms adenosyl- and methylcobalamin. Thiamine deficiency (B1) may also complicate clinical status of animals with fulminant hepatic failure, producing neurobehavioral signs indistinguishable from HE.

Although hyperglycemia should be avoided because it can worsen cerebral edema, euglycemia must be established before thiamine administration. Otherwise, thiamine-provoked neuroglycopenia can aggravate neurologic injury and clinical signs. Thiamine is especially important in cats (especially those with hepatic lipidosis) and can be supplemented orally (100 mg/cat, PO, every 12 hours initially, then 50 mg/cat, PO, every 12 hours) or slowly with IV fluids (fortified B-soluble vitamin solution).

Animals with acute liver failure have high energy expenditure and protein catabolism; in humans with fulminant hepatic failure, there is a ~15%–30% increase in maintenance energy requirements. Nutritional support should be initially attempted enterically with protein intake restricted to 2.5 g/kg in dogs and 3.5 g/kg in cats if overt HE is suspected or ammonium biurate crystalluria is documented. If neurologic signs are inapparent and there is no ammonium biurate crystalluria, protein restriction is not advised.

Broad-spectrum antimicrobials are often empirically prescribed for animals with fulminant hepatic failure, especially those evidencing HE or renal failure or that display components of a systemic inflammatory response syndrome (SIRS). A state of acquired immunoparesis associated with decreased phagocytosis of circulating leukocytes also is thought to predispose to infection. As for other suspected bacterial infections involving the liver, a combination of ticarcillin or ampicillin-sulbactam, metronidazole (7.5 mg/kg, every 12 hours, PO or IV), and enrofloxacin are initially advised because of the broad diversity of potential complicating bacteria.

In most animals with fulminant hepatic failure, N-acetylcysteine (NAC) is administered for at least the first 2 days to provide cysteine for glutathione (GSH) synthesis. Intravenous NAC also is suggested to improve microcirculatory perfusion (microvascular integrity and oxygen delivery); has anti-inflammatory effects, modulating nuclear factor kappa B (NFkB) production; and protects against development of SIRS.

A loading dose (140 mg/kg, IV) of NAC is initially administered over 20 minutes because prolonged infusions may precipitate hyperammonemia via NAC inhibition of carbamyl phosphate synthetase, the enzyme catalyzing carbamyl phosphate, an obligatorily essential substrate that combines with ammonia prior to its detoxification in the urea cycle. Thereafter, NAC is repeated (70 mg/kg, IV) at intervals of 6–8 hours with treatment duration based on clinical status assessment by the managing clinician. In some cases treatment is continued for 7 days to support GSH synthesis. Rare adverse reaction to NAC manifests as urticaria, pruritic rash, vomiting, and most severely as angioneurotic edema.

When oral medications can be tolerated, biologically available S-adenosylmethionine (SAMe) is recommended at 20–40 mg/kg, PO on an empty stomach, every 24 hours to sustain hepatic GSH availability. SAMe provides diverse metabolic benefits. It is the principal methyl donor of most transmethylation reactions, and via this biochemical function it orchestrates synthesis of a broad range of substances, including phospholipids, nucleic acids, and proteins. SAMe also orchestrates entry of cysteine availability for transsulfuration reactions (ie, synthesis of GSH, taurine [in dogs, not cats] and sulfation reactions), and methylthioadenosine for synthesis of ATP, AMP, and polyamines. Comparatively, NAC provides only cysteine for transsulfuration reactions.

Initially, vitamin K1 (0.5–1.5 mg/kg, IM or SC, for three doses at 12-hour intervals) is given. Repeated dosing may be necessary in animals with overt coagulopathies. However, overt bleeding is uncommon in acute FHF, reflecting presence of a "balanced" hemostatic defect.

In most cases, loss of hepatic procoagulant synthesis is paralleled by loss of hepatic-derived anticoagulants. Consequently, the complexity of interrupted coagulation homeostasis can lead to overt or covert bleeding tendencies or thrombotic tendencies. However, there are no data supporting propriety of routine use of blood component therapies in patients with liver disease in the absence of bleeding.

Indiscriminate administration of blood transfusion, plasma, or packed RBC imposes risk for volume overload, microvascular thrombosis and lung injury, and intracerebral hypertension that can provoke or worsen HE. In the circumstance of overt hemorrhagic tendencies, fresh frozen plasma or cryoprecipitate (von Willebrand factor [VWF] and fibrinogen) is used. Desmopressin acetate (0.3 mcg/kg, IV, diluted to 10% in saline solution) can sometimes assist in arresting serious clinical hemorrhage by improving primary hemostasis (release of preformed VWF monomers from endothelium).

In animals with clinical anemia evidencing HE with suspected hyperammonemia, it is prudent to avoid administration of stored whole blood or packed RBCs, deferring to fresh whole blood. Stored blood generates considerable ammonia while decreased RBC viability in stored products can impact a serious protein load (RBC senescence, hemolysis), each provoking HE.

In animals developing acute portal hypertension, diapedesis of blood into the enteric lumen precedes opening of APSSs. This phenomenon can lead to critical blood loss that will aggravate HE. In this scenario, only a fresh whole blood transfusion or administration of packed RBCs and fresh frozen species-specific plasma can replace extracorporeal losses. Propranolol administration or nadolol may decrease portal hypertension, which may lessen the rate of blood loss but remains a controversial intervention.

Inhibition of gastric acid secretion with an H2 receptor antagonist (eg, famotidine) or preferably proton pump inhibitor (eg, omeprazole, pantoprazole: 1 mg/kg, IV or PO, every 12–24 hours) is initially advised in animals with repeated vomiting. This is done to protect against development of esophagitis and may decrease likelihood of gastric ulceration. Cimetidine (H2 receptor antagonist) should be avoided because of its potent inhibition of certain cytochrome P450s that may provoke adverse drug interactions in a polypharmacy setting. However, once enteral feeding is established, inhibition of gastric acid secretion is physiologically contraindicated.

The goal of therapeutic strategies relevant to HE in animals with fulminant hepatic failure is to prevent onset of HE, limit its severity, and decrease risk for cerebral edema. Intracranial hypertension from severe cerebral edema is a critical lethal factor in FHF. Detection of HE is subjective in animals. Cognitive alterations may initially be subtle; more overt clinical signs are described in the section on hepatic encephalopathy Hepatic Encephalopathy in Small Animals Hepatic encephalopathy is a metabolic neurologic disorder that develops secondary to liver disease. Hepatic encephalopathy (HE) is a neurobehavioral syndrome affiliated with either critical... read more .

Cerebral edema is a complex multifactorial process involving mediators of systemic and local inflammation, oxidative injury, and circulating neurotoxins (especially ammonia). Onset or worsening of HE can be precipitated by systemic infection, hypotension and systemic vasodilation in the absence of sepsis, neuroglycopenia, altered cerebral endothelial permeability (response to neurotoxins including ammonia and inflammatory mediators), and altered transcerebral perfusion.

In the advent of HE causing obtundation, the head and neck should be maintained in a neutral or slightly elevated position, avoiding compression of jugular blood flow. Elevation of the head and neck on a slant board (25º–35º angle) may decrease intracranial pressure and CSF hydrostatic pressure. Central venous lines should be avoided because these increase risk of serious iatrogenic hemorrhage that may require compression bandaging.

Spontaneous hyperventilation inducing hypocapnia and mild respiratory alkalosis promotes cerebral arterial vasoconstriction that may transiently decrease intracerebral pressure due to cerebral hyperemia. However, sustained hyperventilation should be avoided. Hypoxia must be avoided because of its associated cerebral vasodilatory effect.

Mannitol (0.5–1.0 g/kg, IV, over 20 minutes) can help decrease cerebral edema with boluses repeated if serum osmolality has not increased. Furosemide (0.5–1 mg/kg, every 6–8 hours) has also been administered to increase renal elimination of sodium and water.

Use of hypothermia, barbiturate coma, hypertonic saline, or flumazenil infusions (cited in experimental literature) is not recommended. Cleansing warm water enemas followed by rectal instillation of dose-appropriate lactulose, neomycin, or low-dose metronidazole can decrease colonic sources of encephalogenic toxins. Oral administration of these agents in a somnolent patient is hazardous. Furthermore, some patients with FHF have gastric and intestinal atony, increasing risk for vomiting and aspiration.

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