liver injury Flashcards
with cirrhosis, the inflammatory process destroys ____
lobules
causes of cirrhosis
alcohol, viruses, toxins
regeneration with cirrhosis?
there are limits if too much damage. liver structure and function are disrupted, advanced stages are irreversible
normal hepatic system blood pressure
1-5 mmHg
portal hypertension
5-10 subclinical, 10-12 symptoms and complications
how does portal hypertension occur
scar tissue has replaces lost hepatocytes, liver structure is disrupted, blood flow is impeded, and portal pressure increases
complication of portal hypertension
esophageal and gastric varices: blood backs up into small veins, inc pressure, risk of rupture. also accum of fluid into peritoneal cavity
diagnosis of liver injury by liver functions
serum albumin decreases, coagulation factors decrease, ammonia increases (dec ability of liver to convert to less toxic urea)
damaged liver cells release what enzymes that enter the circulation
ALT (more specific for liver), AST (liver, heart, skeletal muscle, kidney, etc)– both increased with damage to hepatocytes
magnitude of serum enzymes with acute liver injury
<3 months and enzyme increases are higher, >25 x ULN, more cells damaged in shorter time
magnitude of serum enzymes with chronic liver failure (alcoholic liver disease)
<15 X ULN; gradual destruction, slower release of enzymes
magnitude of serum enzymes with cirrhosis
most hepatocytes are destroyed; serum levels may not be increased since there are not hepatocytes left to be destroyed and release enzymes.
define cholestasis
stoppage or decrease in flow of bile (intrahepatic or extrahepatic)
symptoms of cholestasis
jaundice, itching, dark urine, hyperbilirubinemia
define jaundice
accumulation of bilirubin in the body: yellow skin, scleral icterus
define hyperbilirubinemia
increased unconjugated bilirubin (indirect)
how does indirect bilirubin increase
increased hemolysis of red blood cells, or decreased conjugation because of liver disease
how does direct bilirubin increase
biliary obstruction
normal total bilirubin?
0.3-1.1
what is itching from
bile salts in the skin that are acidic
explain why total serum bilirubin increases with liver failure
liver conjugation process is reduced with liver injury which increases unconjugated bilirubin. biliary obstruction leads to an increase in conjugated bilirubin.
with injury to the ducts, the cells lining the bile ducts contain high amounts of ___
alkaline phosphatase (ALP) and GGT; both increase with injury to ducts
2 major types of DILI
predictable (dose dependent) and unpredictable (idiosyncratic)
conventional medications include
OTC and prescription medications
complimentary medications
medications used WITH conventional medications: vitamins, food, herbals, supplements
alternative medications
used IN PLACE OF conventional medications
diagnosis of DILI?
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
when is liver biopsy useful for DILI
helps identify diagnosis or extent of injury; it will not direct you to the cause
what is the R value
ratio of elevated enzymes; helps identify if the injury is primarily hepatocyte, injury to ducts, or both
why is DILI important
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
3 patterns of liver injury
hepatocellular, cholestatic (bile duct damage), or mixed (both types)
what is the most common pattern of liver injry
hepatocellular
lessons learned: reason for drug withdrawal/warning
liver failure requiring liver transplant or death, severe liver/kidney damage, liver toxicity
lessons applied: example of drug Ximelegatran (Exanta), why was it not approved?
liver enzymes were increased during clinical studies, not approved because of liver injury compared to comparator group
liver injury related to the drug dose may be caused by formation of ____
toxic, reactive intermediate metabolite
why is the liver particularly susceptible to injury
it is the major organ that metabolizes drugs, herbals, toxins
phase 1 vs phase 2 metabolism?
phase 1 is oxidation/CYP, phase 2 is conjugation/more hydrophilic products
active metabolites that can be responsible for the hepatic injury are formed by phase _
1
toxicity with acetaminophen is dependent on
dose; short latency period, toxicity can occur rapidly
most common cause of DILI and acute liver failure cases in US
acetaminophen
risk factors for acetaminophen toxicity
chronic alcohol use (increase CYPE1), malnutrition (depletes glutathione that converts toxic to nontoxic), drugs/herbals that induce CYPE1, polypharmacy
toxic blood concentrations of acetaminophen
> 200 mcg/mL (dose of 10-12 grams in one day); measure at 4 hours (max blood level) after acute overdose
at what blood levels of acetaminophen should you treat
> 150 mcg/mL
metabolism of APAP at a therapeutic dose
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)
metabolism of APAP at a toxic dose
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
what is the antidote for acetaminophen toxicity
N-acetylcysteine (NAC) within 8 hours of ingestion (before significant liver damage can occur)
how does NAC work
provides glutathione to conjugate the toxic metabolite, NAPQI
2 forms of NAC
IV (Acetadote) given as loading and intermittent IV dose, and oral (unpleasant, mix with juice but administer within 1 hr of mixing)
2 pathways of niacin metabolism and what they cause
amidation pathway causes hepatotoxicity, glycine pathway causes flushing
characteristics of amidation pathway
high affinity, low capacity (niacin selects first, but quickly saturated so the rest of the dose enters glycine pathway)
the amidation pathway is saturated when the dissolution rate is ___
40 mg/hour
characteristics of the glycine pathway
low affinity, high capacity. used after amidation pathway saturated
describe pathways the IR niacin formulation takes at a 1000 mg dose
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
describe pathways the ER niacin formulation takes at a 1000 mg dose
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
describe pathways the SR niacin formulation takes at a 1000 mg dose
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.
liver injury with supplements and herbals is an emerging threat because
people have the false assumption that they are safe since they are natural. they do not disclose to their doctor.
key regulatory differences between Rx drugs and supplements: proof of safety?
required for Rx, not required for supplement unless it contains a new dietary ingredient
key regulatory differences between Rx drugs and supplements: proof of effectiveness?
required for Rx, not required for supplements
key regulatory differences between Rx drugs and supplements: surveillance?
required for Rx drugs, not required for supplements (but must report serious adverse effects to FDA)
key regulatory differences between Rx drugs and supplements: good manufacturing practices?
required Rx drugs, supplements not required until recently
key regulatory differences between Rx drugs and supplements: disease treatment claims?
Rx drugs allowed (FDA approved indications), supplements not allowed
specific examples of liver injury from natural substances
garcina cambogia (weight loss supplement), green tea extract (concentrated, for weight loss, cancer), oxyelite pro (fat burning for weight loss)
