Hepatotoxicants
Justine A. Lee, DVM, DACVECC, DABT CEO, VetGirl [email protected] @VetGirlOnTheRun @drjustinelee
Introduc1on
Garret Pach1nger, VMD, DACVECC
COO, VetGirl
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Introduc1on
Jus1ne A. Lee, DVM, DACVECC, DABT CEO, VetGirl
Financial disclosure
Hepatotoxicants
• Xylitol • NSAIDs • Veterinary drugs • Oral diazepam (cats) • Metaldehyde • Mushrooms • Blue-‐green algae • Sago palm • Acetaminophen
Why do we see hepatotoxicity? • Liver common site à receives 25-‐30% of cardiac output
• Site of first-‐pass clearance for most oral drugs
• P450 and other biotransforma1on enzymes can generate reac1ve metabolites
• 2 types of drug-‐induced hepatoxicity: – Cytotoxic (à hepatocyte necrosis) – Cholesta1c (à due to inhibi1on of biliary transporters)
• Sugar-free, natural sweetener
• Found in everything! – Sugar-free gums, candies, mints – Chewable multivitamins – Baked goods – Mouthwashes – Toothpastes – Anything “sugar-free”
Xylitol
Xylitol • Variable amounts in everything
– 2 mg -1 gm/piece of gum is average
• How toxic is it? – > 0.1 g/kg à hypoglycemia – > 0.5 g/kg à acute hepatic necrosis
• Clinical signs: – Signs of hypoglycemia: weakness, collapse, vomiting,
ataxia (< 1 hour) – Liver injury (days later)
Xylitol toxicity for a 30 kg dog • Trident and Orbit gums (2 mg to 0.2 g/piece):
– 15 pieces à hypoglycemia – 75 pieces à liver failure
• Ice Breakers gum (1 g/piece): – 3 pieces à hypoglycemia – 15 pieces à liver failure
How do we treat xylitol toxicosis?
• STAT blood glucose (BG) + chemistry – Treat hypoglycemia STAT
• 1 mg/kg 50% dextrose IV diluted
• Decontamination – Delayed emesis induction if asymptomatic! – Do not give activated charcoal!
What doesn’t bind to AC: “ols”
• Alcohols – Ethylene glycol – Methanol
• Xylitol
• Heavy metals – Zinc – Iron
Xylitol treatment
• If hypoglycemic or toxic dose à BG monitoring with 2.5-5% dextrose CRI in IVF
• Recheck BG q. 4 hours à slowly wean off
• Maintain BG for several hours OFF any dextrose
• If hepatotoxic dose: – SAM-e – Chemistry q. 24 hours X 2 days
Veterinary NSAIDs • NSAIDs inhibit conversion of arachadonic acid to
prostaglandins by inhibition of COX enzymes
• General wide margin of safety in dogs
• Adverse effects (AE): – GI: vomiting, diarrhea
• Less common AE: – GI ulcer – Hepatotoxicity (1.4 cases out of every 10,000 dogs)
Veterinary NSAIDS: DOGS • General rule with veterinary NSAIDs:
– 5X therapeu1c dose = GI – 10X therapeu1c dose = AKI
• Carprofen: – 20 mg/kg: GI ulcers – 40 mg/kg: AKI
• Deracoxib: – 10-15 mg/kg: GI ulcers – 30 mg/kg: AKI
REFERENCES: • Peterson. Veterinary NSAIDS. In Five-‐Minute Veterinary Consult Clinical Companion Small Animal Toxicology Wiley-‐Blackwell 2011,pp 354-‐361. • Talcon PA, Gwaltney-‐Brant SM. Nonsteroidal An1inflammatories. Small Animal Toxicology Elsevier 2013, pp. 687-‐708.
Veterinary NSAIDS: DOGS • Chronic dosing: Hepatotoxicity
– Associated with carprofen à no known dose – Develops 5-‐30 days; median 19 days – ñññALT – If ALT normal, it’s not from carprofen
– Associated with Labrador retrievers? • Are these the breeds that get osteoarthri1s? • Over-‐represented breed
MacPhail et al, 1998
Veterinary NSAIDS: DOGS • Discuss rare risks with pet owner!
• Baseline blood work • Recheck in 2 weeks; q. 3-‐6 months thereaser
– Rare with acute toxicity – Treatment:
• Immediate discon1nua1on • Treatment for hepa1c failure • Hepatoprotecants (e.g., SAMe)
How do we treat NSAID toxicosis? • Decontaminate! (e.g., emesis, activated charcoal)
– Recent ingestion? – Type of pill?
• Gel cap vs. chewable – Does it undergo enterohepatic recirculation? – Activated charcoal + cathartic
NSAIDS that undergo enterohepa2c recircula2on (Give me mul2ple doses of charcoal, please!)
NSAIDs that DO NOT undergo enterohepa2c recircula2on (NO mul2ple dose charcoal, please!)
NSAIDs we don’t know about
Meloxicam (significant) Carprofen (limited) Ketoprofen (suspected)
Deracoxib Tepoxalin (unknown)
NSAIDs: Treatment • Clinicopathologic monitoring
– Baseline CBC, chemistry, UA, USG – If nephrotoxic dose:
• PCV/TS, renal panel q. 24 hours X 2-3 days • Recheck 1-2 days later
– If hepatotoxicity: • PCV/TS, chemistry q. 24 hours while hospitalized • PT/PTT à Vitamin K dependent factors • If neurologic à NH3 or bile acids
NSAIDs: Treatment • Aggressive IVF
– Does not aid in elimination – Vasodilate renal vessels à prevent AKI – 2.5-3.5X maintenance – Goal of fluid therapy:
• Hemodilution: PCV/TS 35%/5 mg/dL
• Anti-emetic therapy – Especially if MD A/C
• Gastric protectants – Sucralfate – H2 blocker vs. misoprostol vs. omeprazole
• Treatment for liver failure
Veterinary drugs: Dose-‐dependent hepatotoxicity
• Azathioprine (NAC?) • Ketoconazole
– 10 vs. 5 mg/kg/day
• Amiodarone (an1-‐arrhythmic) – 45% of dogs affected
• Lomus1ne (CCNU) – 6% hepatotoxicity – 29% ñLES by 5 fold – Boxers?
• Acetaminophen • Phenobarbital
Phenobarbital • Can result in subclinical ñin bile acids to clinical hepatopathy à
fulminant liver failure
• Signs typically develop > 1 year of treatment
• Higher phenobarbital serum concentra1ons have not be correlated with development of ñbile acids!
• CATS: doesn’t cause enzyme induc1on (ñLES) or hepatotoxicity
Reference: Trepanier LA. Drug-‐associated liver disease. Kirk CVT XV
Veterinary drugs: Idiosyncra1c hepatotoxicity
• Poten1ated sulfonamides (NAC?) – Black or tan with white feet!
• Zonisamide – 2 dogs; 1 euthanized due to severe liver failure – CS developed in 10-‐21 days
• Felbamate (with phenobarbital)
• Methimazole – 1-‐2% of cats – Different from ñALT, ALP from ñT4
Veterinary drugs: Idiosyncra1c hepatotoxicity
• Primidone • Valproate (Depakote) • Anabolic steroids • Doxycycline • Metronidazole • Phenytoin • Arsenical an1helminthics (sodium thiacetarsamide) • Diazepam (cats)
Veterinary drugs • Acute toxicosis is rare, but can be seen with massive inges1on
• Chronic inges1on à hepatotoxic
• Monitor pa1ent carefully – Monitoring blood work – Discon1nua1on of meds PRN – Hepatoprotectants
Benzodiazepines (BZO)
• Common brand names: Valium, Clonazepam, Alprazolam
• Parenteral routes: very safe
• Dog: oral route OK
• Cat: oral route à acute hepa1c necrosis
Benzodiazepines: Cats • Not recommended for behavioral reasons, appe1te s1mulant, FUO,
etc. in cats due to repe11ve dosing
• Likely idiosyncra1c – CS develop > 5011 days of oral treatment – Seda1on, malaise, ataxia, jaundice
• ñññALT, AST, TBILI, PT/PTT
• Center SA et al 1996: 91% died
• NO ORAL generic or brand BZO for cats!
Metaldehyde
• Snail and slug bait
• “Shake and bake”
• Clinical signs: tremors, seizures, hyperthermia
• Rare reports of possible hepatotoxicity – No biopsy? – Overhyped?
• Slowly being replaced off the market by iron sulfate (less toxic)
Metaldehyde: Treatment • Decontamina1on
– Not if symptoma1c! – ETT + gastric lavage instead! – One dose of ACC
• Radiographs?
• Temperature regula1on
• IVF
• An1-‐convulsants and muscle relaxants!
MUSHROOMS
Mushrooms
• Several thousand species in North America
• < 100 toxic – Most are Amanita
• No simple test, hard to ID – North American Mycology Associa1on – hnp://www.namyco.org/toxicology/iden1fiers.html
Mushrooms
• Unless you’re a mycologist or experienced mushroom hunter… – Never trust a mushroom unless it’s from the grocery store!
– Deadly mushrooms exist everywhere! • Amanitas
– Worst case scenario! • Not all deadly mushrooms look deadly
– White bunon cap
Types of mushrooms
• Amani1ns – liver failure: – Develop GI signs (6-‐24 hours) – “False recovery” period – Fulminant liver failure (36-‐48 hours) – Possible AKI too – Tx: decontamina1on, IVF, hepatoprotectants, symptoma1c suppor1ve care, monitoring
• Types: Amanita, Galerina, Lepiota, A. phalloids (death cap, death angel), A. ocreata
Types of mushrooms • Muscarine
– CS: SLUDGE signs – Tx: Decontamina1on, atropine, suppor1ve care – Types of mushroom: Inocybe, Clitocybe dealbata – “Swea1ng mushroom”
• Muscimol and ibotenic acid – CS: ataxia, seda1on, muscle spasms, seizures – Types: Amanita muscaria, A.pantherina
Types of mushrooms • False morel
– CS: vomi1ng, diarrhea, seizures (rare) – Tx: Decontamina1on, symptoma1c suppor1ve care – Types of mushroom: Gyromitra spp.
• Gastrointes1nal irrita1on – CS: vomi1ng, diarrhea – Tx: Decontamina1on, symptoma1c suppor1ve care, an1-‐eme1cs, IVF – Seen in 1-‐6 hours; last 1-‐2 days – Types: Agaricus, Boletus, Entoloma
Types of mushrooms • Hallucinogenic mushrooms
– CS: ataxia, howling, aggression, nystagmus, hyperthermia – Treatment not generally necessary – Type: Psilocybe, Conocybe, Gymnopilus spp.
Cyanobacteria: Blue-‐green algae • Algae blooms
– Most non-‐toxic, but hard to iden1fy with naked eye – Toxic to everything!
• Stagnant, hot, humid condi1ons – Brackish water – Freshwater
• Wind blows the algae to one side of the lake • MOA:
– Neurotoxins: Anabeana, Aphanizomenon,etc. – Hepatotoxins: MicrocysAs, Nodularia
Cyanobacteria: Blue-‐green algae • Microcys1ns inhibit protein phosphatases 1 and 2A à sevre liver
damage and acute centrilobular necrosis
• Anatoxin-‐a à potent cholingeric agonist at nico1nic acetylcholine receptors à con1nuous electrical s1mula1on at NMJ
• Anatoxin-‐as àirreversible acetylcholinesterase inhibitor (OP like); doesn’t cross BBB
• Toxic dose? 50-‐11,000 mcg/kg
Blue-‐green algae • Can see very acute clinical signs
• Death can occur within minutes to hours (neurotoxin) or hours to days (hepatotoxin)
• Dermal irrita1on
• Grave prognosis
Blue-‐green algae: Clinical signs
• Microcys1ns: – GI: vomi1ng, diarrhea – Weakness, collapse – CARDIAC: pallor, tachycardia, shock
• Anatoxin-‐a: – CNS: paralysis, cyanosis, death
• Anatoxin-‐as: s = saliva1on – SLUDGE like signs – Tremors, ataxia, seizures, respiratory arrest
Blue-‐green algae: Treatment
• Decontamina1on: osen too late – Emesis? – Gastric lavage + ac1vated charcoal – Bathe (using protec1ve gear)
• Clinicopathologic tes1ng: – PCV/TS/BG – Baseline CBC, chemistry, PT/PTT
Sago Palm Cycas Revoluta
• Highly poisonous to both pets and humans
• Plant thrives in hot, humid climates (tropical/subtropical) – Southern states – Hawaii
• Found as Bonsai plants, outside, houseplants
• Used to be a toxicant of the SE SW USA – Now everywhere!
Sago Palm
• Not a true palm • Of the Cycadacae order
• Genera Cycads, Macrozamia, and Zamias
• Common names: – Cycad – Cardboard palm – Japanese cycad – Coon1e plant
Cycas revoluta
Sago Palm Cycas Revoluta
• All parts of plant poisonous
• Seeds contain the largest amount of toxin
• Inges1on of as linle as 1-‐2 seeds à severe clinical signs: – Vomi1ng – Diarrhea – Depression/lethargy – Seizures – Liver failure
Toxicity
• Hepatotoxicity – Centrolobular and mid-‐zonal coagula1ve hepa1c necrosis
• Gastrointes1nal
• Central nervous system (CNS)
• Cardiotoxicity?
Cycad: Three Primary Toxins
• Cycasin, an azoglycoside – In GIT à converted to methylazoyxmethanol (MAM) by a B-‐glucosidase
– Hepatotoxic
• B-‐methylamino-‐L-‐lanine (BMAA) – Neurotoxic amino acid
• High molecular weight substance – S1ll uniden1fied
Sago Palm: GIT Clinical Signs
• Gastrointes1nal: • Anorexia • Protracted vomi1ng • Hematemesis • Plant contents seen in emesis? • Diarrhea (melena, hematochezia) • Abdominal pain • Dehydra1on
• Seen within 15 minutes to several hours
Sago Palm: Hepa1c Clinical Signs
• Hepatotoxicity: • Lethargy • Icterus • Increased LFT • Melena • Petechhia/ecchymoses • Coagulopathic • Ascites
• Seen within 24-‐72 hours post-‐inges1on
Sago Palm: CNS Clinical Signs
• CNS: – Lethargy – Mentally obtunded – Hepa1c encephalopathy – Ataxia – Tremors – Seizures – Coma – Death
• Seen within 48-‐72 post-‐inges1on
Sago Palm: Cardiac?
• Long-‐term cardiotoxicity? • Anecdotally reported 18 months out • Cardiomyopathy?
Baseline Blood Work
• CBC • Biochemistry • PCV/TS/BG/liver panel q. 24 hours X 3 day • PT/PTT • Bile acids vs NH3
+ • Repeat blood work once discharged
– May see éLFT at 24-‐48 hrs; can last from 2-‐9 days long
Clinicopathologic Changes:
• Anemia vs. hemoconcentra1on • Hypoalbuminemia • Hypocholesterolemia • é bilirubin • é or ê glucose • é lactate • é WBC • Thrombocytopenia/coagulopathy • é or ê BUN
Histopathologic Lesions
• Cirrhosis
• Focal centrolobular and midzonal coagula1on necrosis
• Secondary changes due to hepa1c encephalopathy – Brain and spinal cord demyelina1on and axonal degenera1on
Ferguson et al. JVIM 2011
Ferguson et al. JVIM 2011
• 34 dogs exposed to sago palm
• Overall outcome: • 50% died/euthanized
• Results: • Non-‐survivors : ↑ ALT, TBILI on presenta1on, ↓ albumin compared to survivors
• NS: ↑ coagula1on 1mes • A/C correlated with longer survival • Nega1ve prognos1c factor: ↑AST
Sago Palm: Treatment
• Decontamina1on – Emesis induc1on? – Ac1vated charcoal: mul1ple doses – An1-‐eme1c
GENERAL TREATMENT FOR ANY HEPATOTOXICANT!
General Treatment for Hepatotoxicants
• Fluid therapy – Balanced crystalloid – Fluid closest to pa1ent’s sodium – Avoid LRS
• Colloidal support? – If TS < 5 mg/dL, consider Hetastarch – 1 ml/kg/hour
Treatment: Gastrointes1nal support
• An1-‐eme1cs – Maropitant? (1/2 dose) – Ondansetron, dolasetron
• Gastric protectants – High gastrin levels
• Sucralfate • H2 blocker vs. misoprostol vs. omeprazole
Hepatoprotectants
• SAMe – Increases glutathione – Improves membrane stability – Cytokine modula1on – An1-‐apop1c – Dose: 20 mg/kg PO X 30 days
Hepatoprotectants
• Milk thistle (Silbyin) – Reac1ve oxygen species scavenger
– An1-‐inflammatory – An1-‐fibro1c – Increases protein synthesis – Cholere1c – Dose: 20 – 50 mg/kg q. 6-‐24 hrs PO
– FOR HOW LONG?
Hepatoprotectants
• N-‐acetylcysteine (NAC) – Increases glutathione – An1-‐inflammatory – Improved microcircula1on – Improved oxygen delivery? – Dose: 280 mg/kg IV, then 70 mg/kg q 6 hrs X 2 days
Treatment for Coagulopathy
• If coagulopathic à – Vitamin K SQ or PO
• 1 mg/kg PO, SQ q 12 hours
– Fresh frozen plasma or frozen plasma • 6-‐20 ml/kg IV
Treatment
• An1convulsants – Diazapem or injectable Keppra: lowest effec1ve dose!
• Blood work monitoring:
– Recheck chemistry/PT/PTT q 24 hours while hospitalized
– Recheck 2-‐3 days aser discharge – Weekly thereaser un1l LES WNL
ACETAMINOPHEN & PARACETAMOL
Bud, 30 kg, 5 yo, MC, Labrador
• Ate 2 tablets of Tylenol Cold & Flu
• Owner just came home from work
• Dog is asymptoma1c at home • Plan?
67
Bud, 30 kg, 5 yo, MC, Labrador
• Induce emesis
• Find out what’s actually in Tylenol Cold & Flu and calculate if it’s toxic or not
• Refer away to someone else
68
Bud, 30 kg, 5 yo, MC, Labrador
• Induce emesis
• Find out what’s actually in Tylenol Cold & Flu and calculate if it’s toxic or not
• Refer away to someone else
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What’s in Tylenol Cold & Flu, anyway?
WTF?
What’s The Formula1on (WTF)? • Availability – lots of forms!
Tablets: 500 mg, 1000 mg Caplets: 500 mg Capsules: 500 mg Soluble Tablets: 120 mg, 500 mg Suspension: 120 mg/5 mL, 250 mg/5 mL Solu1on for infusion: 10 mg/mL (50 mL, 100 mL vials) Suppositories: 60 mg, 125 mg, 250 mg, 500 mg
• Common pain medica1on
• COX3 inhibitor
What’s in Tylenol Cold & Flu, anyway?
• Per tablet: – Acetaminophen – 650 mg – Pseudoephedrine – 60 mg – Dextromethorphan – 30 mg
• Toxicity: – Acetaminophen – 650 X 2/30 kgs = 43 mg/kg – Pseudoephedrine – 60 X 2/30 kgs = 4 mg/kg – Dextromethorphan – 30 X 2/30 kgs = 2 mg/kg
Acetaminophen
• Range of toxicity: – Cat/ferret: 10-‐60 mg/kg (some say 50-‐100 mg/kg) – Dog: 100-‐150 mg/kg
• MetHb seen at > 200 mg/kg
Cats
– Methemoglobinemia (metHb) vs. liver failure – Clinical signs:
• Within 1-‐2 hours: anorexia, hypersaliva1on, facial/paw edema • Progresses to lethargy, methemoglobinemia (metHb),
cyanosis, Heinz body anemia, hemoglobinuria • Death, hepa1c failure
Dogs
• KCS (dry eye) • Liver failure • Clinical signs:
– Within 4-‐12 hours: cyanosis, hemoglobinuria, anemia, metHb
– Progresses to: depression, anorexia, vomi1ng, colic, liver failure
– Takes several days before signs of liver failure seen: icterus, increased LFT (24-‐72 hours)
• ↑ ALT, AST, Tbili • ↓ albumin, BUN, cholesterol, glucose
Treatment • Decontamina1on? Rapid absorp1on!
– + emesis induc1on – Ac1vated charcoal X1 (if recent inges1on) – Some enterohepa1c recircula1on?
• Baseline blood work:
– Hematology – PCV tube (chocolate-‐colored blood) + smear (Heinz bodies)
– Chemistry – Venous blood gas?
Treatment • IV fluid therapy à perfusion
• Treatment for hypoxemia: – Blood transfusions – Oxygen therapy if dyspneic, cyano1c
• An1-‐eme1cs – Impera1ve with oral an1dote tx
• H2-‐blockers? – No clear benefit! – Contraindicated with cats
Acetaminophen: “An1dotes”
• N-‐acetylcysteine – Glutathione source – Hepatoprotectant
• Dosing: – 280 mg/kg loading dose for metHb – 70 mg/kg q. 6 hours X 7-‐17 doses – If normal at 48 hours, D/C
Acetaminophen: “An1dotes”
• SAMe (liver protectant) or Silymarin X 30 days
Bud, 30 kg, 5 yo, MC, Labrador • Non-‐toxic:
– Acetaminophen < 100 mg/kg – Dextromethorphan < 5 mg/kg
• Treat for pseudoephedrine (4 mg/kg) – Moderate to Severe clinical signs: 5-‐6 mg/kg – Death: 10-‐12 mg/kg
• Consider monitor for dry eye?
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Summary
• Treat hepatotoxicants aggressively!
• The answer to all of toxicology: symptoma1c suppor1ve care and the BIG 4 treatments
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Dr. Jus2ne Lee • June 19, 2014: Minnesota Veterinary Medical
Associa1on, Saint Paul, MN • July 26, 2014: AVMA, Denver, CO • August 12, 2014: Merck, Chicago, IL • August 13, 2014: Omaha, NE • August 15-‐16, 2014: IVS, Seanle, WA • September 11-‐12, 2014: IVECCS, Indianapolis, IN Dr. Garret Pach2nger • August 16-‐18, 2014: Pennsylvania Veterinary
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