Acute Liver Failure Brandi 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)

CBCOther 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 BiochemistryOther 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 pole Mineral 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-acetylcysteine Supplies 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 minutes of ingestion but can take 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 ingestion Histopathology – 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) Vasopressors Colloids (includes blood products) NAC

Medical therapy cont.  Correct electrolyte imbalances Hypophosphatemia Hypokalemia Hyponatremia Hypernatremia 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  Approach Check BG q 4 hours in all patients Bolus 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 restriction Laculose (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 etiology Mortality – progressive increase in bilirubin and ALT, progressive decline in albumin or development of hypoglycemia