Toxic Hepatic Disease

Question 1

What are the 2 types of toxic hepatic disease?

Answer 1

1. Dose-dependent, drug induced
2. Idiosyncratic, due to reactive metabolite that is produced in susceptible individuals

Question 2

Acetaminophen leads to what type of hepatotoxicosis? How is it treated?

Answer 2

dose-dependent; fine at standard dose. Too high leads to centrilobular necrosis
- in cats, leads to methemoglobin (before liver necrosis)
Tx = N-acetylcysteine, SAMe

Question 3

Phenobarbital leads to what type of hepatotoxicosis? How is it treated?

Answer 3

Cumulative hepatotoxicity - usually when on for >1y.
-histologically: bridging portal fibrosis, bile duct hyperplasia, and nodular regeneration
- biochem: monitor for increases in bile acids, decreases in albumen, or discordant increased in ALT> ALP
- if sedation is noted when patient has been stable
Tx = reduce dose/ change anticonvulsant
cats seems to be fine with phenobarbital

Question 4

Azole antifungal leads to what type of hepatotoxicosis? How is it treated?

Answer 4

Dose dependent, fluconazole seems to be less hepatotoxic compared to intraconazole or ketoconazole
- if notice increased in liver enzymes, can decrease the dose or try a different antifungal
- can use SAMe concurrently
Tx = switch to another antifungal, sue SAMe

Question 5

Azathioprine leads to what type of hepatotoxicosis? How is it treated?

Answer 5

dose dependent.
- increase in liver enzymes is usually noted in the first 14 days
- oxidative damage
- German Shepherds seem to be more sensitive
- important to monitor the ALT>ALP, bilirubin
Tx = dose reduction

Question 6

Amiodarone leads to what type of hepatotoxicosis? How is it treated?

Answer 6

dose dependent.
- increases in ALT, also causes neutropenia; noted in the first 16 weeks
- need to monitor blood work closely
Tx = dose reduction or discontinuation

Question 7

CCNU leads to what type of hepatotoxicosis? How is it treated?

Answer 7

Dose dependent/ cumulative; median = 4 doses
- can increase ALT significantly, also leads to increase in bilirubin
- histologically: portal aggregates of hemosiderin laden Kupffer cells, enlargement of hepatocyte nuclei, and hepatocyte vacuolation
Tx = concurrent SAMe and silybin

Question 8

Potentiated sulfonamides leads to what type of hepatotoxicosis? How is it treated?

Answer 8

Idiosyncratic
- watch for subtle signs of liver dysfunction
- increased in ALT –> will eventually lead to hepatic necrosis
- Dobermans are at increased risk, though tend to see joint and renal issues
Tx = SAMe and vitamin C

Question 9

Carprofen leads to what type of hepatotoxicosis? How is it treated?

Answer 9

idiosyncratic
- most likely noted median 19 days
- ALP will be normal, while ALT Increases
- low incidence, so routine blood work doesn’t help
- can be very acute; need to teach O to watch for signs of anorexia, vomiting, diarrhea, lethargy, dark stool
Tx = discontinue, switch to another NSAID

Question 10

Methimazole leads to what type of hepatotoxicosis? How is it treated?

Answer 10

idiosyncratic
- 1-2% of treated cats
- bilirubin tend to stay normal, but ALT and ALP will increase
- can have lethargy and anorexia –> need to screen for idiosyncratic toxicities (facial excoriation, blood dyscrasia)
Tx = discontinuation, or else could be fatal

Question 11

Diazepam leads to what type of hepatotoxicosis? How is it treated?

Answer 11

idiosyncratic in cats
- rare, but mechanisms unknown
- note sedation and jaundice after >5 days of treatment
- dramatic increase in ALT
Tx = should have picked something else first

Question 12

Aflatoxin leads to what type of hepatotoxicosis? How is it treated?

Answer 12

environmental contamination from moldy food
- aflatoxin B1 –> bioactivated by CYP450 –> electrophilic epoxide metabolites –> protein and DNA adducts & glutathione depletion
- clinical signs = acute liver failure
- will notice a decrease in Protein C, antithrombin, and cholesterol first, then
- negative prognostics factors: hyperbilirubinemia, hypoalbuminemia, and hypocholesterolemia
- need a careful diet hx of the past 8 weeks
- guarded prognosis, only 1/3 will survive with intensive treatment for hepatic failure

Question 13

Xylitoal leads to what type of hepatotoxicosis? How is it treated?

Answer 13

stimulates insulin release –> hypoglycemia, and liver failure may follow
- don’t need to be hypoglycemic to have liver failure
- induce emesis immediately, but don’t if already hypoglycemic
- activated charcoal may not be effective
- need to monitor for signs of liver failure in the next 72h
Tx = SAMe

Question 14

Amanita mushrooms leads to what type of hepatotoxicosis? How is it treated?

Answer 14

Amatoxins –> inhibits RNA polymerase –> decreases mRNA generation –> arrest protein synthesis –> necrosis of metabolically active cells
- intestinal crypt cells, hepatocytes, and renal tubular cells most affected
- clinical signs: vomiting, bloody diarrhea, abdominal pain (6-24h)
- severe hypoglycemia (alpha-amanitin induces insulin release) (24-48h)
- massive hepatonecrosis and renal tubular necrosis (36-84h)
Tx = silybin

Question 15

Blue -green algae leads to what type of hepatotoxicosis? How is it treated?

Answer 15

Cyanotoxin microcystin & nodularin
- inhibits serine/ threonine protein phosphatase –> hyperphosphorylation –> disruption of cell cytoskeleton –> hepatocyte dissociation, necrosis, and glutathione depletion
- can develop acute illness and signs of acute liver failure within hours
- can also have kidney damage –> ddx: leptospirosis
- can be rapidly fatal
Tx = SAMe, cholestyramine

Question 16

Cycad palms leads to what type of hepatotoxicosis? How is it treated?

Answer 16

Cycasin –> bioactivated to methylazoxymethanol by GI bacteria –> GI and liver toxicosis
- the seed is most toxic, but the leaves and roots are too
- GI signs noted within minutes to hours
- hyperbilirubinemia and increased in hepatocellular leakage and cholestatic enzymes noted 24-48h
- mortality rate around 50%
Tx = can try activated charcoal