liver injury

Question 1

with cirrhosis, the inflammatory process destroys ____

Answer 1

lobules

Question 2

causes of cirrhosis

Answer 2

alcohol, viruses, toxins

Question 3

regeneration with cirrhosis?

Answer 3

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

Question 4

normal hepatic system blood pressure

Answer 4

1-5 mmHg

Question 5

portal hypertension

Answer 5

5-10 subclinical, 10-12 symptoms and complications

Question 6

how does portal hypertension occur

Answer 6

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

Question 7

complication of portal hypertension

Answer 7

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

Question 8

diagnosis of liver injury by liver functions

Answer 8

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

Question 9

damaged liver cells release what enzymes that enter the circulation

Answer 9

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

Question 10

magnitude of serum enzymes with acute liver injury

Answer 10

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

Question 11

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

Answer 11

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

Question 12

magnitude of serum enzymes with cirrhosis

Answer 12

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

Question 13

define cholestasis

Answer 13

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

Question 14

symptoms of cholestasis

Answer 14

jaundice, itching, dark urine, hyperbilirubinemia

Question 15

define jaundice

Answer 15

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

Question 16

define hyperbilirubinemia

Answer 16

increased unconjugated bilirubin (indirect)

Question 17

how does indirect bilirubin increase

Answer 17

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

Question 18

how does direct bilirubin increase

Answer 18

biliary obstruction

Question 19

normal total bilirubin?

Answer 19

0.3-1.1

Question 20

what is itching from

Answer 20

bile salts in the skin that are acidic

Question 21

explain why total serum bilirubin increases with liver failure

Answer 21

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

Question 22

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

Answer 22

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

Question 23

2 major types of DILI

Answer 23

predictable (dose dependent) and unpredictable (idiosyncratic)

Question 24

conventional medications include

Answer 24

OTC and prescription medications

Question 25

complimentary medications

Answer 25

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

Question 26

alternative medications

Answer 26

used IN PLACE OF conventional medications

Question 27

diagnosis of DILI?

Answer 27

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

Question 28

when is liver biopsy useful for DILI

Answer 28

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

Question 29

what is the R value

Answer 29

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

Question 30

why is DILI important

Answer 30

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

Question 31

3 patterns of liver injury

Answer 31

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

Question 32

what is the most common pattern of liver injry

Answer 32

hepatocellular

Question 33

lessons learned: reason for drug withdrawal/warning

Answer 33

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

Question 34

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

Answer 34

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

Question 35

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

Answer 35

toxic, reactive intermediate metabolite

Question 36

why is the liver particularly susceptible to injury

Answer 36

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

Question 37

phase 1 vs phase 2 metabolism?

Answer 37

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

Question 38

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

Answer 38

1

Question 39

toxicity with acetaminophen is dependent on

Answer 39

dose; short latency period, toxicity can occur rapidly

Question 40

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

Answer 40

acetaminophen

Question 41

risk factors for acetaminophen toxicity

Answer 41

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

Question 42

toxic blood concentrations of acetaminophen

Answer 42

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

Question 43

at what blood levels of acetaminophen should you treat

Answer 43

>150 mcg/mL

Question 44

metabolism of APAP at a therapeutic dose

Answer 44

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)

Question 45

metabolism of APAP at a toxic dose

Answer 45

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

Question 46

what is the antidote for acetaminophen toxicity

Answer 46

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

Question 47

how does NAC work

Answer 47

provides glutathione to conjugate the toxic metabolite, NAPQI

Question 48

2 forms of NAC

Answer 48

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

Question 49

2 pathways of niacin metabolism and what they cause

Answer 49

amidation pathway causes hepatotoxicity, glycine pathway causes flushing

Question 50

characteristics of amidation pathway

Answer 50

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

Question 51

the amidation pathway is saturated when the dissolution rate is ___

Answer 51

40 mg/hour

Question 52

characteristics of the glycine pathway

Answer 52

low affinity, high capacity. used after amidation pathway saturated

Question 53

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

Answer 53

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

Question 54

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

Answer 54

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

Question 55

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

Answer 55

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.

Question 56

liver injury with supplements and herbals is an emerging threat because

Answer 56

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

Question 57

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

Answer 57

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

Question 58

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

Answer 58

required for Rx, not required for supplements

Question 59

key regulatory differences between Rx drugs and supplements: surveillance?

Answer 59

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

Question 60

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

Answer 60

required Rx drugs, supplements not required until recently

Question 61

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

Answer 61

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

Question 62

specific examples of liver injury from natural substances

Answer 62

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