Year 4 - Toxicology > Liver > Flashcards

Liver Flashcards

(62 cards)

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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
what drugs can cause acute hepatic necrosis
- acetaminophen - niacin - amiodarone (IV) - cocaine - ecstasy - cancer chemotherapeutics
26
______ is usually immune-mediated hepatotoxicity
idiosyncratic (unknown cause)
27
Describe idiosyncratic hepatotoxicity
- 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
For idiosyncratic hepatotoxicity, Describe the different R values and what they correspond to
R = ALT/ALP R > 5 = hepatocellular R < 2 = cholesatatic R 2-5 = Mixed
29
What are some associated clinical features of idiosyncratic hepatotoxicity
- immunoallergic (rash, fever, eosinophilia) | - autoimmune (ANA, SMA IgG elevation)
30
Describe the third form of hepatotoxicity (indirect)
- not due to direct toxicity of drug or idiosyncratic response to it - the medication induces or alters a pre-existing liver condition
31
Give examples of the medication induces or alters a pre-existing liver condition
- 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
Describe the phenotypes of indirect hepatotoxicity
- acute hepatitis - chronic hepatitis - acute liver failure - fatt liver **often can be predicted and prevented
33
List the 3 types of liver injury
- Direct - Indirect - Idiosyncratic
34
What are some phenotypes of drug induced liver injury
- 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
What are some adverse outcomes of all those phenotypes?
- Acute liver failure - Vanishing bile duct syndrome - Cirrhosis
36
How do we diagnose the 12 phenotypes?
- histological features - clinical features - laboratory tests - noninvasive imaging
37
What are types of acute hepatitis
- zonal necrosis - diffse, spotty necrosis - viral hepatitis-like injury - granuloma
38
What drugs can cause zonal necrosis
- paracetamol | - yellow phosphorus
39
what drugs can cause diffuse, spotty necrosis
-aspirin
40
What drugs can cause virus hepatitis-like injury
- diclofenac - halothane - isoniazid - sulfonamides
41
what drugs can cause granuloma
- allopurinol - carbamazepine - phenytoin - quinidine
42
what are types of chronic hepatitis
1) Autoimmune like injury | 2) Chronic viral hepatitis-like
43
What drugs can cause auto-immune like injury
- alpha-methyldopa - dantrolene - diclofenac - nitrofurantoin
44
What drugs can cause chronic viral hepatitis-like?
- aminoeptin - amiodraone - aspirin - etretinate - isoniazid
45
what drugs cause micro vesicular steatosis
- aspirin - didanosine - fialuridine - tetracycline - valproate
46
what drugs cause nonalcoholic steatohepatitis
- amiodarone - calcium channel blockers - perhexiline
47
what drug causes phospholipidosis
amiodarone
48
What causes bland cholestasis (acute)
- estrogens | - 17-alkylated steroids
49
what causes acute cholestasis with inflammation
- amox/clav - erythromcyin estolate - peroxicam
50
What can cause Ductopenia and secondary biliary cirrhosis (a form of chronic cholestasis) ?
- ajmaline - carbamazepine - chlorpromazine - chlorpropamide - haloperidol - penicillins - thiobendazole - TCA - tolbumatide
51
what can cause macroscopic duct sclerosis
intra-arterial floxuridine
52
What can cause perisinusoidal fibrosis?
- methotrexate | - vitamin A
53
Vascular alterations: | what can cause veno-occulsive disease (VOD)?
- pyrrolizidine alkaloids - azathioprine - aklylating agents
54
Vascular alterations: | What can cause hepatic vein thrombosis?
estrogens
55
Vascular alterations: | What causes non-cirrhotic portal hypotension or nodular regenerative hyperplasia
- azathioprine | - 6-thioguanidine
56
What can cause adenoma
estrogens
57
what can cause hepatocellular carcinoma
estrogens, anabolic steroids, cyproterone
58
signs and symptoms of liver disease
-fatigue, nausea, anorexia, malaise, fatigue, RUQ pain, jaundice, itching
59
what is Hy's law?
jaundice that appears after drug induced hepatocellular injury suggests a serious and potentially fatal liver problem
60
Hy's Law: -drug-induced hepatocellular jaundice has a mortality rate of ___ *unlike viral hepatitis and drug-induced cholestatic hepatitis - 1% mortality rate
>10%
61
Describe the elevations in normal lab values for Hy's Law
ALT > 3 x ULN TBL > 2 x ULN
62
What do we need to exclude before saying it's drug induced liver injury?
-viral hepatitis -alcohol -autoimmune disease etc.
Year 4 - Toxicology
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