acute liver failure brandi gallagher, dvm. “peaches mcdonald” 7 year-old sf english bulldog 3-4...
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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