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Residency Exam > Drug induced Liver Injury (Panopto Video Link) > Flashcards

Drug induced Liver Injury (Panopto Video Link) Flashcards

1
Q

How many drugs have been implicated in causing liver disease on more than one occasion?

A

Thousands

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2
Q

What are 10 drugs which have been withdrawn due to serious liver toxicity?

A
  1. Ximelagatran
  2. Troglitazone
  3. Benoxaprofen
  4. Perhexiline (now available)
  5. Bromofenac
  6. Felbamate
  7. Pemoline
  8. Tolcapone
  9. Nafazadone
  10. Trovafloxacin
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3
Q

What are 10 drugs which have been withdrawn due to serious liver toxicity?

A
  1. Ximelagatran
  2. Troglitazone
  3. Benoxaprofen
  4. Perhexiline (now available)
  5. Bromofenac
  6. Felbamate
  7. Pemoline
  8. Tolcapone
  9. Nafazadone
  10. Trovafloxacin
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4
Q

What are 10 drugs which have been withdrawn due to serious liver toxicity?

A
  1. Ximelagatran
  2. Troglitazone
  3. Benoxaprofen
  4. Perhexiline (now available)
  5. Bromofenac
  6. Felbamate
  7. Pemoline
  8. Tolcapone
  9. Nafazadone
  10. Trovafloxacin
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5
Q

Why is perhexiline now available on the market despite being associated with serious liver toxicity?

A

Toxicity is associated with supratherapeutic levels

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6
Q

What are 10 drugs which have been withdrawn due to serious liver toxicity?

A
  1. Ximelagatran
  2. Troglitazone
  3. Benoxaprofen
  4. Perhexiline (now available)
  5. Bromofenac
  6. Felbamate
  7. Pemoline
  8. Tolcapone
  9. Nafazadone
  10. Trovafloxacin
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7
Q

What are 10 drugs which have been withdrawn due to serious liver toxicity?

A
  1. Ximelagatran
  2. Troglitazone
  3. Benoxaprofen
  4. Perhexiline (now available)
  5. Bromofenac
  6. Felbamate
  7. Pemoline
  8. Tolcapone
  9. Nafazadone
  10. Trovafloxacin
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8
Q

What are 10 drugs which have been withdrawn due to serious liver toxicity?

A
  1. Ximelagatran
  2. Troglitazone
  3. Benoxaprofen
  4. Perhexiline (now available)
  5. Bromofenac
  6. Felbamate
  7. Pemoline
  8. Tolcapone
  9. Nafazadone
  10. Trovafloxacin
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9
Q

What are 10 drugs which have been withdrawn due to serious liver toxicity?

A
  1. Ximelagatran
  2. Troglitazone
  3. Benoxaprofen
  4. Perhexiline (now available)
  5. Bromofenac
  6. Felbamate
  7. Pemoline
  8. Tolcapone
  9. Nafazadone
  10. Trovafloxacin
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10
Q

What are 10 drugs which have been withdrawn due to serious liver toxicity?

A
  1. Ximelagatran
  2. Troglitazone
  3. Benoxaprofen
  4. Perhexiline (now available)
  5. Bromofenac
  6. Felbamate
  7. Pemoline
  8. Tolcapone
  9. Nafazadone
  10. Trovafloxacin
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11
Q

Why is perhexiline now available on the market despite being associated with serious liver toxicity?

A

Toxicity is associated with supratherapeutic levels

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12
Q

What is the relationship between LFT derangement and drug-induced liver injury?

A

There is not always a link between drug-induced liver injury and LFT derangement (i.e. DILI can be idiosyncratic)

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13
Q

What are 9 drugs where LFTs should be routinely monitored?

A
  1. Statins
  2. Carbamazepine
  3. Valproate
  4. Methotrexate
  5. Leflunomide
  6. Flucloxacillin
  7. Clavulanic acid
  8. Amiodarone
  9. Minocycline
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14
Q

What are 9 drugs where LFTs should be routinely monitored?

A
  1. Statins
  2. Carbamazepine
  3. Valproate
  4. Methotrexate
  5. Leflunomide
  6. Flucloxacillin
  7. Clavulanic acid
  8. Amiodarone
  9. Minocycline
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15
Q

What are 9 drugs where LFTs should be routinely monitored?

A
  1. Statins
  2. Carbamazepine
  3. Valproate
  4. Methotrexate
  5. Leflunomide
  6. Flucloxacillin
  7. Clavulanic acid
  8. Amiodarone
  9. Minocycline
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16
Q

What are 9 drugs where LFTs should be routinely monitored?

A
  1. Statins
  2. Carbamazepine
  3. Valproate
  4. Methotrexate
  5. Leflunomide
  6. Flucloxacillin
  7. Clavulanic acid
  8. Amiodarone
  9. Minocycline
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17
Q

What are 9 drugs where LFTs should be routinely monitored?

A
  1. Statins
  2. Carbamazepine
  3. Valproate
  4. Methotrexate
  5. Leflunomide
  6. Flucloxacillin
  7. Clavulanic acid
  8. Amiodarone
  9. Minocycline
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18
Q

What is the typical pattern of LFT derangement seen with statins?

A

Transaminitis (i.e. AST and ALT are elevated)

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19
Q

Why are statins thought to cause transaminitis (AST and ALT elevation)?

A

It is thought to be more a result of the pharmacodynamic effect of lipid lowering, which can alter the composition of the membrane of hepatocytes.

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20
Q

How common are ALT levels > 3 times the upper limit of normal on > 2 measurements with statins?

A

This is dose-related and generally less than 3% in incidence

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21
Q

How common are ALT levels > 3 times the upper limit of normal on > 2 measurements with statins?

A

This is dose-related and generally less than 3% in incidence

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22
Q

What is the estimated incidence of fulminant liver failure attributable to lovastatin?

A

2 in one million patients

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23
Q

What is the estimated incidence of fulminant liver failure attributable to lovastatin?

A

2 in one million patients

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24
Q

What is the incidence of statin-associated liver failure estimated to be?

A

1 per million person-years of use

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25
Q

What are 10 drugs associated with DRESS syndrome?

A
  1. Aromatic antiepileptics (phenytoin, carbamazepine,
    oxcarbazepine and the barbiturates)
  2. Lamotrigine
  3. sulfonamide antibacterials
  4. dapsone
  5. minocycline
  6. azathioprine
  7. abacavir
  8. nevirapine
  9. allopurinol
  10. strontium ranelate
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26
Q

What are 3 options when a patient presents with statin-induced transaminitis?

A
  1. Reduce the dose
  2. Change the statin
  3. Ignore the transaminitis as it may not lead to functional issues
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27
Q

When do we usually consider reducing the dose of a statin as a result of LFT derangement?

A

When transaminases rise to around three times the upper limit of normal

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28
Q

What is Hy’s law for drug-induced hepatotoxicity?

A

If hepatocellular injury and jaundice occur concurrently (i.e. elevation of transaminases and bilirubin together), the risk of mortality is at least 10%

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29
Q

What are the FDA clinical Trial discontinuation thresholds for LFT derangement?

A
  1. ALT or AST >8 × ULN
  2. ALT or AST >5 × ULN for more than 2 weeks
  3. ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
  4. ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
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30
Q

What are the FDA clinical Trial discontinuation thresholds for LFT derangement?

A
  1. ALT or AST >8 × ULN
  2. ALT or AST >5 × ULN for more than 2 weeks
  3. ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
  4. ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
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31
Q

What are the FDA clinical Trial discontinuation thresholds for LFT derangement?

A
  1. ALT or AST >8 × ULN
  2. ALT or AST >5 × ULN for more than 2 weeks
  3. ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
  4. ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
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32
Q

What are the FDA clinical Trial discontinuation thresholds for LFT derangement?

A
  1. ALT or AST >8 × ULN
  2. ALT or AST >5 × ULN for more than 2 weeks
  3. ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
  4. ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
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33
Q

What are the FDA clinical Trial discontinuation thresholds for LFT derangement?

A
  1. ALT or AST >8 × ULN
  2. ALT or AST >5 × ULN for more than 2 weeks
  3. ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
  4. ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
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34
Q

What are the FDA clinical Trial discontinuation thresholds for LFT derangement?

A
  1. ALT or AST >8 × ULN
  2. ALT or AST >5 × ULN for more than 2 weeks
  3. ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
  4. ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
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35
Q

What does TBL stand for?

A

Total bilirubin

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36
Q

What does TBL stand for?

A

Total bilirubin

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37
Q

What are the symptoms of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia indicative of?

A

DRESS

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38
Q

What does DRESS stand for?

A

Drug rash with eosinophilia and systemic symptoms

39
Q

What is the concening pattern of liver injury observed with methotrexate?

A

Hepatic fibrosis and cirrhosis

40
Q

What are 10 drugs associated with DRESS syndrome?

A
  1. Aromatic antiepileptics (phenytoin, carbamazepine,
    oxcarbazepine and the barbiturates)
  2. Lamotrigine
  3. sulfonamide antibacterials
  4. dapsone
  5. minocycline
  6. azathioprine
  7. abacavir
  8. nevirapine
  9. allopurinol
  10. strontium ranelate
41
Q

What are 4 aromatic antiepileptics?

A
  1. Phenytoin
  2. Carbamazepine
  3. Oxcarbazepine
  4. Barbiturates
42
Q

What is a common, but less problematic presentation of methotrexate-induced liver toxicity?

A

There is a frequency asymptomatic transient rise in serum transaminases in 30 to 80% of patients after the start of treatment

43
Q

What is the concening pattern of liver injury observed with methotrexate?

A

Hepatic fibrosis and cirrhosis

44
Q

What are 6 factors which predispose a patient to methotrexate-associated liver toxicity?

A
  1. Genetic factors
  2. Alcohol excess
  3. Chronic viral hepatitis
  4. Renal insufficiency
  5. Diabetes
  6. Concurrent NSAID use
45
Q

What are 6 factors which predispose a patient to methotrexate-associated liver toxicity?

A
  1. Genetic factors
  2. Alcohol excess
  3. Chronic viral hepatitis
  4. Renal insufficiency
  5. Diabetes
  6. Concurrent NSAID use
46
Q

What is a common, but less problematic presentation of methotrexate-induced liver toxicity?

A

There is a frequency asymptomatic transient rise in serum transaminases in 30 to 80% of patients after the start of treatment

47
Q

In which patients are we most concerned about the potential for methotrexate-induced hepatic fibrosis and cirrhosis?

A

In patients on long-term therapy (especially with cumulative doses > 1.5 grams)

48
Q

How does autoimmune hepatitis induced by minocycline typically present?

A

It is associated with lupus-like symptoms, usually after a year or more of exposure to minocycline

49
Q

If a patient has a cumulative dose of methotrexate of over 1.5 grams and is showing signs of liver toxicity, what should you do?

A

Take a liver biopsy

50
Q

What are 6 factors which predispose a patient to methotrexate-associated liver toxicity?

A
  1. Genetic factors
  2. Alcohol excess
  3. Chronic viral hepatitis
  4. Renal insufficiency
  5. Diabetes
  6. Concurrent NSAID use
51
Q

What are 6 factors which predispose a patient to methotrexate-associated liver toxicity?

A
  1. Genetic factors
  2. Alcohol excess
  3. Chronic viral hepatitis
  4. Renal insufficiency
  5. Diabetes
  6. Concurrent NSAID use
52
Q

What are 6 factors which predispose a patient to methotrexate-associated liver toxicity?

A
  1. Genetic factors
  2. Alcohol excess
  3. Chronic viral hepatitis
  4. Renal insufficiency
  5. Diabetes
  6. Concurrent NSAID use
53
Q

What are 6 factors which predispose a patient to methotrexate-associated liver toxicity?

A
  1. Genetic factors
  2. Alcohol excess
  3. Chronic viral hepatitis
  4. Renal insufficiency
  5. Diabetes
  6. Concurrent NSAID use
54
Q

What are two protective factors against methotrexate-induced liver injury?

A
  1. concurrent folate supplementation
  2. concurrent hydroxychloroquine use
55
Q

How does DRESS induced by minocycline typically present?

A

As a hypersensitivity reaction associated with eosinophilia and exfoliative dermatitis, usually occurring within the first 35 days of therapy

56
Q

When does the rare, fatal hepatic failure associated with valproate tend to occur?

A

Within the first three months of therapy

57
Q

When does the rare, fatal hepatic failure associated with valproate tend to occur?

A

Within the first three months of therapy

58
Q

What should you always consider regarding transaminases in patients taking methotrexate?

A

Persistently high abnormal transaminases could be potential indicators of methotrexate toxicity

59
Q

What are 3 forms of liver toxicity which can be caused by minocycline?

A
  1. Acute hepatitis
  2. Autoimmune hepatitis
  3. DRESS
60
Q

How does acute hepatitis induced by minocycline typically present?

A

As a hepatocellular pattern of liver injury, typically 1 to 3 months after starting therapy

61
Q

What are two protective factors against methotrexate-induced liver injury?

A
  1. concurrent folate supplementation
  2. concurrent hydroxychloroquine use
62
Q

What is a concern regarding valproate related to the liver besides LFT derangement?

A

Valproate can cause an asymptomatic rise in ammonia levels - these can rise to above therapeutic range without causing hepatic encephalopathy

63
Q

What are 3 forms of liver toxicity which can be caused by minocycline?

A
  1. Acute hepatitis
  2. Autoimmune hepatitis
  3. DRESS
64
Q

How does acute hepatitis induced by minocycline typically present?

A

As a hepatocellular pattern of liver injury, typically 1 to 3 months after starting therapy

65
Q

How does acute hepatitis induced by minocycline typically present?

A

As a hepatocellular pattern of liver injury, typically 1 to 3 months after starting therapy

66
Q

Describe the prognosis of acute hepatitis induced by minocycline

A

It is usually self-limiting

67
Q

How does autoimmune hepatitis induced by minocycline typically present?

A

It is associated with lupus-like symptoms, usually after a year or more of exposure to minocycline

68
Q

How does DRESS induced by minocycline typically present?

A

As a hypersensitivity reaction associated with eosinophilia and exfoliative dermatitis, usually occurring within the first 35 days of therapy

69
Q

What forms of liver damage has black cohosh been linked with?

A

Hepatitis, liver failure, LFT derangement and various other injuries

70
Q

What is an inherent risk associated with herbal and natural products?

A

Due to their less rigorous testing, they are more prone to adulterants/contaminants

71
Q

What is the consistent factor in all liver injury caused by minocycline?

A

It is always a hepatocellular pattern

72
Q

What is the consistent factor in all liver injury caused by minocycline?

A

It is always a hepatocellular pattern

73
Q

Describe the prognosis of acute hepatitis induced by minocycline

A

It is usually self-limiting

74
Q

What is the primary pattern of liver injury seen with valproate?

A

Transient, asymptomatic, dose-related hepatocellular LFT derangement

75
Q

Can minocycline liver toxicity be fatal?

A

Yes

76
Q

What is the primary pattern of liver injury seen with valproate?

A

Transient, asymptomatic, dose-related hepatocellular LFT derangement

77
Q

What should you do if you see LFT derangement with valproate?

A

In an adult patient, if derangement is mild (i.e. not exceeding Hy’s law), you don’t need to do anything, but in a child under 2 years with severe derangement (particularly if they are on other antiepileptics), you should panic

78
Q

What is a rare but serious liver-related toxicity associated with valproate?

A

Valproate is associated with rare fatal hepatic failure

79
Q

When does the rare, fatal hepatic failure associated with valproate tend to occur?

A

Within the first three months of therapy

80
Q

Which cohort of patients are most predisposed to serious liver toxicity with valproate?

A

Children < 2 years, and patients taking multiple anticonvulsants

81
Q

What should you do if you see LFT derangement with valproate?

A

In an adult patient, if derangement is mild (i.e. not exceeding Hy’s law), you don’t need to do anything, but in a child under 2 years with severe derangement (particularly if they are on other antiepileptics), you should panic

82
Q

What is the expected mechanism by which valproate causes liver toxicity?

A

It is thought to be related to carnitine deficiency

83
Q

What should you do if you see LFT derangement with valproate?

A

In an adult patient, if derangement is mild (i.e. not exceeding Hy’s law), you don’t need to do anything, but in a child under 2 years with severe derangement (particularly if they are on other antiepileptics), you should panic

84
Q

What is a concern regarding valproate related to the liver besides LFT derangement?

A

Valproate can cause an asymptomatic rise in ammonia levels - these can rise to above therapeutic range without causing hepatic encephalopathy

85
Q

Is phosphorus mostly intrinsically toxic to the liver, or dependent on patient factors?

A

It is intrinsically toxic to the liver

86
Q

Is phenytoin mostly intrinsically toxic to the liver, or dependent on patient factors?

A

It is dependent on patient factors

87
Q

Are penicillins mostly intrinsically toxic to the liver, or dependent on patient factors?

A

They are mostly dependent on patient factors

88
Q

What is the incidence of drug-induced liver injury?

A

It ranges from 1 in 10,000 to 1 in 100,000

89
Q

What is the incidence of drug-induced liver injury?

A

It ranges from 1 in 10,000 to 1 in 100,000

90
Q

How many patients are typically involved in clinical phase III study?

A

Between 2,000 and 5,000

91
Q

What is a limitation with clinical trials in their ability to detect drug-induced liver injury?

A

In order for a single case of DILI to be detected in a clinical trial, the drug would have to have a three times greater risk of DILI than most drugs associated with causing DILI

92
Q

Do CAMs have the potential to cause DILI?

A

Yes

93
Q

What forms of liver damage has black cohosh been linked with?

A

Hepatitis, liver failure, LFT derangement and various other injuries

94
Q

What is an inherent risk associated with herbal and natural products?

A

Due to their less rigorous testing, they are more prone to adulterants/contaminants

Residency Exam (22 decks)

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