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Year 4 - Toxicology > Liver > Flashcards

Liver Flashcards

1
Q

What tests are we going to order?

A
  • total bilirubin
  • alanine transaminase
  • prothrombin time
  • alkaline phosphatase
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2
Q

What is the most common drug causing drug-induced liver injury?

A

amoxicillin/clavulanate

*used to be acetaminophen

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3
Q

What are common drugs for acute liver failure

A

Antibiotic medications

  • isoniazid
  • sulfur antibiotics (sulfa/trim)
  • nitrofurantoin
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4
Q

What are the functions of the liver?

A
  • Protein synthesis
  • Bile secretion
  • Biotransformation & detoxification
  • Regernative organ
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5
Q

Describe protein synthesis

A
  • materials essential for homeostasis - clotting factors

- materials essential for drug binding and osmolarity - albumin and lipoprotein

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6
Q

Describe bile secretion

A

aids in digestion and excretion

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7
Q

Describe biotransformation & detoxification

A
  • ammonia, steroid hormones, lipid, cholesterol, heme and bilirubin
  • drug metabolism through two phase reactions (phase 1 = oxidation/reduction), (phase 2 = conjugation)
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8
Q

__% of liver function is enough for normal function

A

30

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9
Q

Describe biotransformation (slide 10)

A
  • Can enter as prodrug, drug or xenobiotic
  • Through phase 1 and phase 2 reactions
  • Can leave as active agent, inactive compound, toxic metabolite, or mutagenic or carcinogenic compound
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10
Q

List the 2 mechanisms of drug-induced liver injury

A

1) Metabolic induced pathogenesis
- oxidative stress
- mitochondria

2) Immune-mediated pathogenesis
- immune reaction
- ADCC
- CDC

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11
Q

Toxic metabolite of acetaminophen

A

NAPQI

  • leads to glutathione
  • mitochondrial dysfunction
  • leads to necrosis of the liver
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12
Q

Describe the immune-mediated pathogenesis

A
  • drug will cause antigen to stimulate immune system to generate antibody
  • antibody will attack the liver and cause liver toxicity
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13
Q

List factors that affect drug toxicity

A
  • Age
  • Gender
  • Diet
  • Diseases
  • Enzyme Polymorphism
  • Drug/Drug Interactions
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14
Q

How does age affect drug toxicity?

A
  • children are healthy where immune system is stronger therefore immune-mediated liver toxicity is the major cause
  • adults have a poor immune response where most damage is due to metabolite injury (elderly)
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15
Q

How does gender affect drug toxicity?

A

hormones (estrogen, testosterone) play a role

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16
Q

How does diet affect drug toxicity?

A
  • Nutrients - calcium, iron, magnesium, copper, zinc
  • Caffeine
  • Alcohol
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17
Q

How do diseases affect drug toxicity

A
  • Diabetes has effect on liver where glucagon is the sugar stored in the liver cells
  • Renal disease where drug does not get secreted adds more burden to the liver
  • Hepatic disease
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18
Q

What are the types of liver injury (clinical approach)?

A

Type A: intrinsic (direct) injury

Type B: idiosyncratic injury

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19
Q

What are the types of liver injury (temporal approach)?

A
  • acute

- chronic

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20
Q

What are the types of liver injury (morphological approach)?

A
  • hepatocellular
  • cholestatic
  • miscellaneous reaction
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21
Q

Describe direct hepatotoxicity

A
  • expected, dose-related, common
  • distinctive morphologic pattern
  • reproducible in animals
  • no extrahepatic signs of hypersensitivity
  • serum enzyme elevations
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22
Q

What are some phenotypes of direct hepatotoxicity?

A
  • acute hepatic necrosis
  • sinusoidal obstruction syndrome
  • lactic acidosis
  • hepatic steatosis
  • nodular regernative hyperplasia
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23
Q

Pathogenesis of direct hepatotoxicity?

A

likely oxidative stress-mediated

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24
Q

Describe acute hepatic necrosis

A
  • sudden direct hepatic toxicity
  • ALT increases, ALP & bilirubin may increase
  • R > 30
  • INR may be elevated
  • rapid improvement
  • slide 18
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25
Q

what drugs can cause acute hepatic necrosis

A
  • acetaminophen
  • niacin
  • amiodarone (IV)
  • cocaine
  • ecstasy
  • cancer chemotherapeutics
26
Q

______ is usually immune-mediated hepatotoxicity

A

idiosyncratic (unknown cause)

27
Q

Describe idiosyncratic hepatotoxicity

A
  • unexpected outcome, not dose-related, rare
  • highly variable lesions
  • not reproducible in animals
  • hypersensitivity signs
  • phenotypes (acute hepatitis, hepatocellular, cholestatic or “mixed”)
  • pathogenesis: likely immune-mediated
28
Q

For idiosyncratic hepatotoxicity, Describe the different R values and what they correspond to

A

R = ALT/ALP

R > 5 = hepatocellular
R < 2 = cholesatatic
R 2-5 = Mixed

29
Q

What are some associated clinical features of idiosyncratic hepatotoxicity

A
  • immunoallergic (rash, fever, eosinophilia)

- autoimmune (ANA, SMA IgG elevation)

30
Q

Describe the third form of hepatotoxicity (indirect)

A
  • not due to direct toxicity of drug or idiosyncratic response to it
  • the medication induces or alters a pre-existing liver condition
31
Q

Give examples of the medication induces or alters a pre-existing liver condition

A
  • reactivation of hep B (rituximab, infliximab, imatinib)
  • worsening or flare of hep C (HIV therapies)
  • triggering of autoimmune hepatitis (interferon beta, ipilimumab)
  • exacerbation of NASH or ASH (mirtazapine, prednisone)
32
Q

Describe the phenotypes of indirect hepatotoxicity

A
  • acute hepatitis
  • chronic hepatitis
  • acute liver failure
  • fatt liver

**often can be predicted and prevented

33
Q

List the 3 types of liver injury

A
  • Direct
  • Indirect
  • Idiosyncratic
34
Q

What are some phenotypes of drug induced liver injury

A
  • acute hepatic necrosis
  • acute hepatitis
  • chronic hepatitis
  • cholestatic hepaptitis
  • mixed hepatocellular-cholestatic hepatitis
  • enzyme elevations without jaundice (hepatocellular, cholestatic or mixed)
  • bland cholestasis
  • hepatic steatosis and lactic acidosis
  • nonalcoholic fatty liver
  • sinusoidal obstruction syndrome (veno-occlusive disease)
  • nodular regernative hyperplasia
  • hepatic adenoma and hepatocellular carcinoma
35
Q

What are some adverse outcomes of all those phenotypes?

A
  • Acute liver failure
  • Vanishing bile duct syndrome
  • Cirrhosis
36
Q

How do we diagnose the 12 phenotypes?

A
  • histological features
  • clinical features
  • laboratory tests
  • noninvasive imaging
37
Q

What are types of acute hepatitis

A
  • zonal necrosis
  • diffse, spotty necrosis
  • viral hepatitis-like injury
  • granuloma
38
Q

What drugs can cause zonal necrosis

A
  • paracetamol

- yellow phosphorus

39
Q

what drugs can cause diffuse, spotty necrosis

A

-aspirin

40
Q

What drugs can cause virus hepatitis-like injury

A
  • diclofenac
  • halothane
  • isoniazid
  • sulfonamides
41
Q

what drugs can cause granuloma

A
  • allopurinol
  • carbamazepine
  • phenytoin
  • quinidine
42
Q

what are types of chronic hepatitis

A

1) Autoimmune like injury

2) Chronic viral hepatitis-like

43
Q

What drugs can cause auto-immune like injury

A
  • alpha-methyldopa
  • dantrolene
  • diclofenac
  • nitrofurantoin
44
Q

What drugs can cause chronic viral hepatitis-like?

A
  • aminoeptin
  • amiodraone
  • aspirin
  • etretinate
  • isoniazid
45
Q

what drugs cause micro vesicular steatosis

A
  • aspirin
  • didanosine
  • fialuridine
  • tetracycline
  • valproate
46
Q

what drugs cause nonalcoholic steatohepatitis

A
  • amiodarone
  • calcium channel blockers
  • perhexiline
47
Q

what drug causes phospholipidosis

A

amiodarone

48
Q

What causes bland cholestasis (acute)

A
  • estrogens

- 17-alkylated steroids

49
Q

what causes acute cholestasis with inflammation

A
  • amox/clav
  • erythromcyin estolate
  • peroxicam
50
Q

What can cause Ductopenia and secondary biliary cirrhosis (a form of chronic cholestasis) ?

A
  • ajmaline
  • carbamazepine
  • chlorpromazine
  • chlorpropamide
  • haloperidol
  • penicillins
  • thiobendazole
  • TCA
  • tolbumatide
51
Q

what can cause macroscopic duct sclerosis

A

intra-arterial floxuridine

52
Q

What can cause perisinusoidal fibrosis?

A
  • methotrexate

- vitamin A

53
Q

Vascular alterations:

what can cause veno-occulsive disease (VOD)?

A
  • pyrrolizidine alkaloids
  • azathioprine
  • aklylating agents
54
Q

Vascular alterations:

What can cause hepatic vein thrombosis?

A

estrogens

55
Q

Vascular alterations:

What causes non-cirrhotic portal hypotension or nodular regenerative hyperplasia

A
  • azathioprine

- 6-thioguanidine

56
Q

What can cause adenoma

A

estrogens

57
Q

what can cause hepatocellular carcinoma

A

estrogens, anabolic steroids, cyproterone

58
Q

signs and symptoms of liver disease

A

-fatigue, nausea, anorexia, malaise, fatigue, RUQ pain, jaundice, itching

59
Q

what is Hy’s law?

A

jaundice that appears after drug induced hepatocellular injury suggests a serious and potentially fatal liver problem

60
Q

Hy’s Law:
-drug-induced hepatocellular jaundice has a mortality rate of ___

*unlike viral hepatitis and drug-induced cholestatic hepatitis - 1% mortality rate

A

> 10%

61
Q

Describe the elevations in normal lab values for Hy’s Law

A

ALT > 3 x ULN

TBL > 2 x ULN

62
Q

What do we need to exclude before saying it’s drug induced liver injury?

A

-viral hepatitis
-alcohol
-autoimmune disease
etc.

Year 4 - Toxicology (24 decks)

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