Acute Liver Failure – A review of recent publications

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Acute liver failure is a severe, often fatal condition of the liver, characterised by severe and widespread liver injury resulting in cellular necrosis, inflammation, and associated loss of liver function. The aim of this blog is to summarise findings from two recent literature reviews on acute liver failure in dogs and cats1,2, and a recent retrospective review of 49 clinical cases of acute liver failure in dogs3.

Acute liver failure is defined as acute liver injury that is severe enough that it compromises liver functions, including the following:

  1. Protein synthesis
  2. Glucose metabolism – glycogen production and glycogenolysis
  3. Fat metabolism
  4. Coagulation factor production
  5. Immune function
  6. Bile acid secretion
  7. Bilirubin metabolism
  8. Ammonia metabolism

In addition, further characterization of acute liver failure, based on recent human definitions may also include:

  1. The absence of pre-existing liver disease
  2. The presence of hepatic encephalopathy
  3. Elevated bilirubin concentrations
  4. The presence of coagulopathy

Aetiology1-3

Numerous causes of acute liver failure exist in dogs and cat, including toxins, drugs, infectious agents, and even some cancers.

  • Among the most common toxins associated with acute liver failure are
    • Cycads (Sago Palms)
    • Blue-green algae
    • Amanita phalloides
    • Aflatoxins
    • Xylitol 

  • Drugs may cause acute liver failure in a dose-dependent manner (intrinsic toxins), or an idiosyncratic manner. Drugs that are known to cause acute live failure include
    • Carprofen
    • Acetaminophen (Paracetamol)
    • Phenazopyridine
    • Sulfonamides
    • Lomustine (CCNU)
    • Zonisamide
    • Stanozolol (cats)
    • Oral benzodiazepines (cats)4
  • Infectious agents such as leptospirosis and canine adenovirus-1 are known to cause acute liver failure in dogs
    • Leptospirosis
    • Canine adenovirus-1
  • Idiopathic hepatic lipidosis in cats
  • Trematodes
    • Platynosomum fastosum is a small liver fluke that invades the biliary ducts and gallbladder of cats after the cat ingests lizards containing the fluke. Infected cats may remain asymptomatic, or may present with biliary obstruction and liver failure
  • Neoplasia
    • Round cell tumours and lymphoma have been associated with development of acute liver failure in dogs

Clinical signs1-3

Clinical signs of acute liver failure reflect the important role of the liver in metabolism, protein synthesis and immune-function. Aside from non-specific symptoms, such as nausea, vomiting, diarrhoea, and anorexia, the following are key components of acute liver failure – both in terms of diagnostic value, and prognostic value.

  • Icterus
  • Coagulopathy
  • Hepatic encephalopathy
  • Hypoglycaemia
  • Sepsis

 Diagnosis1

The diagnosis of acute liver failure is usually made based on documentation of elevations in transaminases (ALT, AST) and inducible enzymes (ALP, GGT), combined with elevations in ammonia, bilirubin and coagulation times.

Treatment1,2

Treatment of acute liver failure falls into three (3) categories:

  • Toxin decontamination and antidote therapy
    1. Most hepatic toxins do not have specific antidotes available
    2. Acetaminophen
      • N-acetylcysteine 140 mg/kg loading dose, followed by 100 mg/kg given over 16 hrs. as a CRI 
    3. Mushrooms
      • Penicillin G 300.000-1,000,000 units/kg/day IV
      • Silymarin 30-40 mg/kg/day PO for 3-4 days
    4. Hepatic lipidosis
      • Nutritional support via feeding tube
  • Supportive care
    1. Intravenous fluid therapy
      • Intravenous fluid therapy is used to correct hypovolaemia and hydration deficits. 
      • Ringers acetate is preferred to lactated Ringer’s solution, as lactate requires hepatic metabolism to form the active buffer.
      • Synthetic colloid fluid therapy is relatively contraindicated in patient with acute liver failure
    2. Vasopressors and positive inotropes
      • In patients who remain hypotensive, despite several boluses of crystalloid fluid therapy, the use of positive inotropes and vasopressors should be considered
      • Positive inotropes: dobutamine continuous infusion @ 2-10 micrograms/kg/min
      • Vasopressors: noradrenaline continuous infusion @ 0.1-2 micrograms/kg/min
      • Corticosteroids: in patients who are persistently hypotensive despite the aforementioned efforts, a physiological dose of corticosteroids may be trialed, on the assumption the patient may have critical-illness related corticosteroid insufficiency.
    3. Maintain normoglycaemia
      • Monitor for, and correct hypoglycaemia using glucose bolus (5 ml/kg of 10% glucose IV over 5 minutes) +/- continuous infusion (1-2 ml/kg/hr of 5% glucose IV continuous infusion)
    4. Correct electrolyte abnormalities as they arise
    5. Nutrition: 
      • Provide nutritional support early in disease, using enteral route (preferred) or parenteral route (if enteral route not possible)
      • 50% of calories should be provided in the form of readily digestible, soluble carbohydrates
      • 20-40% of the diet should be provided in the form of fats
      • Vitamin K1 should be supplemented at 1-2 mg/kg/day
      • Thiamine should be supplemented at a dose of 5-10 mg/kg q 12 hrs.
    6. Hepatic anti-oxidants
      • Glutathione precursors and anti-oxidants such as N-acetylcysteine (NAC), S-adenyl L-methionine (SAMe), or Silibinin may be supplemented 
      • Vitamin E is a free-radical scavenger that may be supplemented at a dose of100-400 UI/day (dog); 30-50 UI/day 9cat)
  • Management of complications 
    1. Infection
      • Routine use of antibiotics in non-septic patients is controversial
      • In septic patients, amoxycillin 20 mg/kg IV q 8 hrs.; +/- metronidazole 10 mg/kg IV q 12 hrs. may be recommended
    2. Coagulation abnormalities
      • Patients with acute liver failure usually have coagulopathy resulting from reduced hepatic production of clotting factors, as well as increased total body consumption of clotting facts (DIC)
      • Evidence for survival benefit from transfusion of fresh frozen plasma in patients without occult bleeding is lacking
      • Fresh frozen plasma should be administered at a dose of 20-30 ml/kg in patients with clinical evidence of haemorrhage, or in those patients undergoing invasive procedures (hepatic biopsy, feeding tube placement etc.)
    3. Hypoglycaemia
      • Hypoglycaemia should be managed as previously outlined
    4. Hepatic encephalopathy
      • Hepatic encephalopathy resulting from acute liver failure results from vasogenic oedema, rather than accumulation of toxins such as ammonia, mercaptans, etc.
      • Maintain systolic arterial blood pressure at 100-120 mm Hg with intravenous fluids, inotropes and vasopressors as indicated
      • Ensure adequate respiratory function
      • In the euvolaemic patient with deteriorating HE, mannitol at 0.25 g/kg IV over 10-20 minutes may be considered
      • Control convulsions with propofol continuous infusions 6 mg/kg/hr IV CRI

Prognosis1-3

The prognosis for acute liver failure in dogs varies, depending on the cause – but may be as high as 86%3. Acute liver failure cause by infectious diseases, such as leptospirosis; and pharmacological toxicosis, such as NSAID and acetaminophen appear to carry a better prognosis than acute liver failure caused by environmental toxins such as algae, cycads and mushrooms.

In addition, negative prognostic indicators in dogs and cats include1

  • Higher elevations of ALT and bilirubin in dogs with cycad ingestion
  • Low albumin concentrations in dogs with cycad ingestion
  • Mushroom poisoning
  • Blue-green algae ingestion
  • Development of clinical bleeding or ascites during hospitalization

References:

  1. Weingarten MA, Sande AA. Acute liver failure in dogs and cats. Journal of Veterinary Emergency and Critical Care. 2015 Jul;25(4):455-73.
  2. Thawley V. Acute liver injury and failure. Veterinary Clinics: Small Animal Practice. 2017 May 1;47(3):617-30.
  3. Lester C, Cooper J, Peters RM, Webster CR. Retrospective evaluation of acute liver failure in dogs (1995–2012): 49 cases. Journal of Veterinary Emergency and Critical Care. 2016 Jul;26(4):559-67.
  4. Hughes D, Moreau RE, Overall KL, Winkle TV. Acute Hepatic Necrosis and Liver Failure Associated with Benzodiazepine Therapy in Six Cats, 1986–1995. Journal of Veterinary Emergency and Critical Care. 1996 Jan;6(1):13-20.

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