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liver injury Flashcards

1
Q

with cirrhosis, the inflammatory process destroys ____

A

lobules

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2
Q

causes of cirrhosis

A

alcohol, viruses, toxins

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3
Q

regeneration with cirrhosis?

A

there are limits if too much damage. liver structure and function are disrupted, advanced stages are irreversible

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4
Q

normal hepatic system blood pressure

A

1-5 mmHg

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5
Q

portal hypertension

A

5-10 subclinical, 10-12 symptoms and complications

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6
Q

how does portal hypertension occur

A

scar tissue has replaces lost hepatocytes, liver structure is disrupted, blood flow is impeded, and portal pressure increases

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7
Q

complication of portal hypertension

A

esophageal and gastric varices: blood backs up into small veins, inc pressure, risk of rupture. also accum of fluid into peritoneal cavity

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8
Q

diagnosis of liver injury by liver functions

A

serum albumin decreases, coagulation factors decrease, ammonia increases (dec ability of liver to convert to less toxic urea)

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9
Q

damaged liver cells release what enzymes that enter the circulation

A

ALT (more specific for liver), AST (liver, heart, skeletal muscle, kidney, etc)– both increased with damage to hepatocytes

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10
Q

magnitude of serum enzymes with acute liver injury

A

<3 months and enzyme increases are higher, >25 x ULN, more cells damaged in shorter time

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11
Q

magnitude of serum enzymes with chronic liver failure (alcoholic liver disease)

A

<15 X ULN; gradual destruction, slower release of enzymes

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12
Q

magnitude of serum enzymes with cirrhosis

A

most hepatocytes are destroyed; serum levels may not be increased since there are not hepatocytes left to be destroyed and release enzymes.

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13
Q

define cholestasis

A

stoppage or decrease in flow of bile (intrahepatic or extrahepatic)

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14
Q

symptoms of cholestasis

A

jaundice, itching, dark urine, hyperbilirubinemia

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15
Q

define jaundice

A

accumulation of bilirubin in the body: yellow skin, scleral icterus

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16
Q

define hyperbilirubinemia

A

increased unconjugated bilirubin (indirect)

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17
Q

how does indirect bilirubin increase

A

increased hemolysis of red blood cells, or decreased conjugation because of liver disease

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18
Q

how does direct bilirubin increase

A

biliary obstruction

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19
Q

normal total bilirubin?

A

0.3-1.1

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20
Q

what is itching from

A

bile salts in the skin that are acidic

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21
Q

explain why total serum bilirubin increases with liver failure

A

liver conjugation process is reduced with liver injury which increases unconjugated bilirubin. biliary obstruction leads to an increase in conjugated bilirubin.

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22
Q

with injury to the ducts, the cells lining the bile ducts contain high amounts of ___

A

alkaline phosphatase (ALP) and GGT; both increase with injury to ducts

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23
Q

2 major types of DILI

A

predictable (dose dependent) and unpredictable (idiosyncratic)

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24
Q

conventional medications include

A

OTC and prescription medications

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25
Q

complimentary medications

A

medications used WITH conventional medications: vitamins, food, herbals, supplements

26
Q

alternative medications

A

used IN PLACE OF conventional medications

27
Q

diagnosis of DILI?

A

diagnosis of exclusion: rule out other causes, based primarily on Hx of drugs and supplements, when they started taking, timing of onset of symptoms, lab tests for liver failure, imaging or biopsy

28
Q

when is liver biopsy useful for DILI

A

helps identify diagnosis or extent of injury; it will not direct you to the cause

29
Q

what is the R value

A

ratio of elevated enzymes; helps identify if the injury is primarily hepatocyte, injury to ducts, or both

30
Q

why is DILI important

A

most common cause of acute liver failure, most frequent reason for withdrawal of an approved drug from the market, most common cause for discontinuation of development of a new drug

31
Q

3 patterns of liver injury

A

hepatocellular, cholestatic (bile duct damage), or mixed (both types)

32
Q

what is the most common pattern of liver injry

A

hepatocellular

33
Q

lessons learned: reason for drug withdrawal/warning

A

liver failure requiring liver transplant or death, severe liver/kidney damage, liver toxicity

34
Q

lessons applied: example of drug Ximelegatran (Exanta), why was it not approved?

A

liver enzymes were increased during clinical studies, not approved because of liver injury compared to comparator group

35
Q

liver injury related to the drug dose may be caused by formation of ____

A

toxic, reactive intermediate metabolite

36
Q

why is the liver particularly susceptible to injury

A

it is the major organ that metabolizes drugs, herbals, toxins

37
Q

phase 1 vs phase 2 metabolism?

A

phase 1 is oxidation/CYP, phase 2 is conjugation/more hydrophilic products

38
Q

active metabolites that can be responsible for the hepatic injury are formed by phase _

A

1

39
Q

toxicity with acetaminophen is dependent on

A

dose; short latency period, toxicity can occur rapidly

40
Q

most common cause of DILI and acute liver failure cases in US

A

acetaminophen

41
Q

risk factors for acetaminophen toxicity

A

chronic alcohol use (increase CYPE1), malnutrition (depletes glutathione that converts toxic to nontoxic), drugs/herbals that induce CYPE1, polypharmacy

42
Q

toxic blood concentrations of acetaminophen

A

> 200 mcg/mL (dose of 10-12 grams in one day); measure at 4 hours (max blood level) after acute overdose

43
Q

at what blood levels of acetaminophen should you treat

A

> 150 mcg/mL

44
Q

metabolism of APAP at a therapeutic dose

A

90% is conjugated by glucuronidation and 4% is oxidized by CYP2E1 to form the toxic intermediate NAPQI that causes hepatocellular injury (normally avoided because NAPQI is usually conjugated with glutathione to form nontoxic products)

45
Q

metabolism of APAP at a toxic dose

A

conjugation pathways are saturated, more drug is oxidized by CYP2E1 to form more NAPQI. if glutathione is insufficient, increased amounts of NAPQI binds to cell proteins can cause injury/hepatocellular death

46
Q

what is the antidote for acetaminophen toxicity

A

N-acetylcysteine (NAC) within 8 hours of ingestion (before significant liver damage can occur)

47
Q

how does NAC work

A

provides glutathione to conjugate the toxic metabolite, NAPQI

48
Q

2 forms of NAC

A

IV (Acetadote) given as loading and intermittent IV dose, and oral (unpleasant, mix with juice but administer within 1 hr of mixing)

49
Q

2 pathways of niacin metabolism and what they cause

A

amidation pathway causes hepatotoxicity, glycine pathway causes flushing

50
Q

characteristics of amidation pathway

A

high affinity, low capacity (niacin selects first, but quickly saturated so the rest of the dose enters glycine pathway)

51
Q

the amidation pathway is saturated when the dissolution rate is ___

A

40 mg/hour

52
Q

characteristics of the glycine pathway

A

low affinity, high capacity. used after amidation pathway saturated

53
Q

describe pathways the IR niacin formulation takes at a 1000 mg dose

A

dissolution rate 500 mg/hr. so dissolves fully in 2 hours. only 80 mg goes through amidation pathway, 920 mg goes through glycine pathway and causes extensive flushing

54
Q

describe pathways the ER niacin formulation takes at a 1000 mg dose

A

dissolution rate 100 mg/hr. so fully dissolves in 10 hours. 400 mg goes through amidation, 600 through glycine. acceptable hepatotoxicity and flushing. better than IR

55
Q

describe pathways the SR niacin formulation takes at a 1000 mg dose

A

dissolution rate 50 mg/hr. so fully dissolves in 20 hours. so 800 mg goes through amidation and only 200 glycine. unacceptable hepatotoxicity, not approved.

56
Q

liver injury with supplements and herbals is an emerging threat because

A

people have the false assumption that they are safe since they are natural. they do not disclose to their doctor.

57
Q

key regulatory differences between Rx drugs and supplements: proof of safety?

A

required for Rx, not required for supplement unless it contains a new dietary ingredient

58
Q

key regulatory differences between Rx drugs and supplements: proof of effectiveness?

A

required for Rx, not required for supplements

59
Q

key regulatory differences between Rx drugs and supplements: surveillance?

A

required for Rx drugs, not required for supplements (but must report serious adverse effects to FDA)

60
Q

key regulatory differences between Rx drugs and supplements: good manufacturing practices?

A

required Rx drugs, supplements not required until recently

61
Q

key regulatory differences between Rx drugs and supplements: disease treatment claims?

A

Rx drugs allowed (FDA approved indications), supplements not allowed

62
Q

specific examples of liver injury from natural substances

A

garcina cambogia (weight loss supplement), green tea extract (concentrated, for weight loss, cancer), oxyelite pro (fat burning for weight loss)

GI (15 decks)

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