Acute Liver FailureBrandi Gallagher, DVM

“Peaches McDonald” • 7 year-old SF English Bulldog• 3-4 days vomiting, diarrhea,

PU/PD• PE: QAR, weak, ataxic,

intermittent collapse, pytalism, icteric

• No known toxin exposure or dietary indiscretion (owner admitted to giving 1 aspirin tablet)

CBC Other

Diagnostic Tests

Increased HCT (58%) Neutrophilia (17 K/uL) Lymphopenia (0.36 K/uL) Normal platelets (342 K/uL)

Leptospirosis panel (MAT) – all negative

Fecal – NPS

Serum Biochemistry Other

Diagnostic Tests

Hypokalemia (3.5 mEq/L) Hyperbilirubinemia (18.9 mg/dL) Liver enzymes (ALP 350, GGT

12, ALT 1736, AST 360) Amylase (4078 U/L) Hyperlactatemia (5.3 mmol/L)

Ammonia 120 umol/L PT 40.7 secs PTT 27.6 secs Normal blood pH, albumin, and

glucose

Imaging Abdominal ultrasound

Mildly enlarged liver, normal echogenicity/echotexture, normal GB, moderate enlargement of hepatic LNs (7-11mm)

Right adrenal – 11mm nodule caudal poleMineral sediment bladder

3 View Thoracic Radiographs: Normal

Acute Liver Failure ALD v. ALF

ALF occurs when >70% of hepatocellular mass is lost

Acute onset clinical signs (fewer than 8 weeks)

In veterinary case reports ALF mortality rates of 25%-100%

In humans survival rate of ALF only 65%

Acute Liver Failure (review article)

Johanna Cooper, DVM and Cynthia R.L. Webster, DVM, DACVIM

Compendium July 2006 (Vol 28, No 7)

Majority of slides

ALF Clinical Signs Weakness/Depression Anorexia PU/PD GI signs (vomiting/diarrhea/abdominal pain) Icterus Hepatomegaly Abnormal fundic exam Bleeding tendencies Siezures/Coma

ALF Diagnostic Abnormalities Increase in ALT and AST Increase ALP and GGT Hypoglycemia Hypoalbuminemia (chronic v. acute) Hyperbilirubinemia Prolonged PT and aPTT

ALF Diagnostic Abnormalities CBC – varies UA and renal values may

suggest concurrent disease Serology for infectious disease,

serum lipase levels, and autoantibody testing

Cytology of ascites may indicate cause

Radiographs – hepatomegaly, choleliths, abdominal effusion or free gas

Ultrasound – enlarged liver that is normal to hypoechoic (except cats w/ HL or LSA)

Thoracic radiographs – neoplasia, pleural effusion, pulmonary edema

Histopathology vs FNA

Acetaminophen

Normal pathway: metabolized in liver by phase II enzymes to nontoxic glucuronic or sulfate conjugates and excreted in urine.

If amount exceeds phase II enzymes, phase I enzymes (cytochrome P-450) metabolize into N-acetyl-p-benzoquinoneimine

When adequate hepatocyte glutathione stores this metabolite can be conjugated to a harmless mercapturic acid and excreted in kidneys.

If glutathione reserves depleted by oxidant stress and/or starvation, this metabolite leads to hepatocellular necrosis

Acetaminophen cont. Cats have inability to metabolize

by phase I conjugation (oxidant damage to rbcs = methemoglobinemia)

Treatment: N-acetylcysteineSupplies cysteine which is the

rate limiting step in hepatic production of glutathione

Xylitol In dogs, leads to a dose-dependent 2.5- to 7-fold increase in insulin

levels Severe hypoglycemia Hepatic necrosis (2 proposed mechanisms)

1. Metabolism via the pentose phosphate pathway produces phosphorylated intermediates. These deplete ATP and keep liver cells from performing vital functions (eg. protein synthesis and maintenance of membrane integrity). Cellular necrosis follows.

2. Metabolism results in high concentrations of cellular nicotinamide adenine dinucleotide. Reactive oxygen species are produced that damage cellular membranes and macromolecules, leading to decreased hepatocyte viability.

Xylitol Toxicity in Dogs

Christopher Piscitelli, Eric Dunayer, and Marcel Aumann

Compendium Feb 2010 (Vol 32, No 2)

Xylitol Ingest >0.1 g/kg risk for hypoglycemia, >0.5 g/kg risk of

hepatotoxicosis and ALF Hypoglycemia usually occurs in 30-60 minutes of ingestion

but can take 12-48 hours. ALF can occur without initial hypoglycemia Ingested dose does not correlate with ALF survival Prognosis: uncomplicated hypoglycemia is good but

hepatotoxicosis and liver failure is guarded to poor

Xylitol Toxicity in Dogs

Christopher Piscitelli, Eric Dunayer, and Marcel Aumann

Compendium Feb 2010 (Vol 32, No 2)

Environmental Toxins Aflatoxins – toxic compounds produced by aspergillus flavus

Moldy corn ingestionHistopathology – hepatocellular fatty degeneration, bile duct

proliferation, and centrilobular hepatocellular necrosis

Amanita – mushroom; most cases fatal

Blue-green algae – microcystin, a toxic cyclic heptapeptide produced during algal bloom.Histopathology – massive centrilobular and midzonal

hemorrhagic necrosis

Medical Therapy If recent ingestion of a toxin (1-2 hours): emesis or gastric

lavage followed by activated charcoal

Administer antidote if one exists (see table 1 – last slide)

Antibiotics if infectious and chemotherapy if neoplastic

Medical therapy - hypotension Hypovolemia Low systemic vascular resistance – cytokines or factors

released by necrotic liver lead to abnormal vasomotor tone Plugging of capillary bed vessels by platelets, interstitial

edema, and/or abnormal vasomotor tone lead to peripherally impaired O2 extraction by tissues, increased lactate and acidosis

Treatment: Fluids (not LRS)VasopressorsColloids (includes blood products)NAC

Medical therapy cont. Correct electrolyte imbalances

HypophosphatemiaHypokalemia HyponatremiaHypernatremia and hyperphosphatemia – renal insufficiency

Inability to correct acidosis is poor prognostic indicator in people and one of criteria for transplant

Nutrition important (parenteral often needed)

Hypoglycemia Decreased glycogenolysis and gluconeogenesis Hyperinsulinemia due to decreased hepatic metabolism Possibly sepsis Can develop rapidly in ALF Hard to distinguish from HE or cerebral edema

ApproachCheck BG q 4 hours in all patientsBolus of dextrose and then add 2.5% to 10% into fluids

Encephalopathy Different from chronic liver disease or congenital PSS Sudden onset and rapid progression Hyperammonemia

Linked to cerebral edema and intracranial hypertension Other causes of cerebral edema

Encephalopathy Clinical presentation

rapid development of agitation, delirium, convulsions and ultimately coma

Cerebral edema: sudden deterioration in mental status, increased appendicular tone, pupillary dilation, decreased PLR

Brain herniation: acute systemic hypertension and concurrent bradycardia (Cushing reflex)

Encephalopathy: Treatment Reduce blood ammonia

Dietary protein restrictionLaculose (oral or enema)Antibiotics – NOT metronidazole?

Correct alkalosis and hypokalemia (both promote ammonia production)

Control GI bleeding and infections Beware of stored blood products, sedatives, and diuretics

Encephalopathy: Treatment If agitated/delirium: may administer short acting

benzodiazepine Protracted seizures: IV phenobarbitol or small doses of

propofol Decrease ICP:

Mannitol, hypertonic saline, barbituates, controlled hyperthermia, ventilation to achieve normocapnia

Head elevation to 10°-20°Strict rest, avoid stimulation, control seizures/cough/vomiting

(increase ICP)May require CRI of pentobarbitol, mechanical ventilation, muscle

paralysis

Coagulopathy Reduced hepatic synthesis results in hypocoagulable state Thrombocytopathy

May have decreased platelet numbers and/or decreased function Vitamin K deficiency DIC Also considerations of hyperfibrinolysis and

hypercoagulability should be made (see article slide 25)

Coagulopathy: Treatment Vitamin K (0.5-1mg/kg SC) Not necessary to correct clotting abnormalities with FFP

unless bleeding or for procedure Control upper GI hemorrhage

Causes: stress-induced ulceration, decreased gastrin clearance, and thrombocytopathy

H2 blocker – no effect on hepatic blood flow and does not decrease P-450 enzyme systems

PPI – can use but do inhibit cytochrome P-450 enzymes

Other potential effects of ALF High susceptibilty to infection

Usually gram-negative bacteria from GI tract and gram-positive bacterial from respiratory and urinary tracts

Acute renal failure Acute respiratory distress syndrome

Other causes of lung injury: aspiration pneumonia, intrapulmonary hemorrhage (DIC), and PTE

Dr. Webster’s Study Acute Liver Failure in the Dog: 52 cases Retrospective Confirmed or probable etiology in 34 cases

Most common etiology neoplasia (15 dogs)Drug toxicity, mushroom, leptospirosis, ischemia, acute

decompensation of chronic disease Seven dogs (13%) survived to discharge Predictors

Survival – very young or older age of onset or toxic etiologyMortality – progressive increase in bilirubin and ALT, progressive

decline in albumin or development of hypoglycemia