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5 major fcns of the liver
- 1) nutrient homeostasis
- 2) filtration of particulates
- 3) protein synthesis
- 4) biotransformation/detox
- 5) formation of bile & biliary excretion
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4 major types of cells in the liver
- 1) hepatocytes
- 2) Kupfer cells
- 3) hepatic stellate cells (lipocytes)
- 4) NK cells
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6 mechanisms of liver injury
- 1) membrane disruption
- 2) disruption of actin filaments in canaliculus
- 3) CYP disruption in ER generating ROS
- 4) inflammation by cytokines
- 5) apoptosis by casp activation
- 6) inhibition of beta-oxidation & respiration (dysfcnal mitochondria)
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2 types of drug-induced liver toxicity
- 1) predictable (pharmacological)
- 2) idiosyncratic
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predictable dose effects of APAP, cyclophosphamide, or methotrexate
inc dose: hepatocyte necrosis
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predicatable dose effects of cocaine, phencyclidine, or niacin
inc dose: ischemic necrosis
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predictable dose effects of oral contraceptives
cumulative dose: hepatic adenomas
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mechanism of EtOH-APAP syndrome
consumption of EtOH results in more CYP2E1 present due to slower degradation. after removal of EtOH, too much APAP is metabolized at once, resulting in a buildup of NAPQI -> toxicity
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how APAP can cause irreversible inhibition of fatty acid oxidation
CYP2E1-mediated metabolic activation & oxidative stress suppresses PPAR  -regulated pathways
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P450 enzymes involved in APAP metabolism
- CYP2E1 (major)
- CYP1A2
- CYP3A
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classic example of idiosyncratic rxn
isoniazid (dependent on genetic polymorphism)
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what hepatic clearance of drugs depends on
activity of transport proteins on the hepatocyte canalicular membrane
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decrease in the volume of bile formed or impaired secretion of specific solutes into bile
cholestasis
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drugs associated w/ cholestasis (5)
- 1) chlorpromazine
- 2) sulfonamides
- 3) sulfonylureas
- 4) erythromycin
- 5) captopril
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also known as cholangiodestructive cholestasis; results in inc serum levels of enzymes localized in the bile duct
bile duct damage
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liver disease that involves damage to the bile canaliculi & bile ducts
long-term estrogen therapy has been indicated in this disease
cholestatic jaundice
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treatment with this drug was assoc'd w/ a huge incidence of cholestatic jaundice
-tocopherol acetate (IV form of vit E)
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liver-specific inflammatory rxn caused by hypersensitivity to a particular drug
allergic hepatitis
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drugs assoc'd w/ allergic hepatitis (3)
- phenytoin
- erythromycin
- sulfonamides (trimethoprim, sulfamethoxazole)
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indolent liver damage that closely resemble autoimmune chronic hepatitis (difficult to ID)
drug-induced chronic hepatitis
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drugs that cause drug-induced chronic hepatitis (7)
- methyldopa
- APAP
- ASA (in high doses)
- nitrofurantoin
- trazodone
- ketoconazole
- halothane
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increase of hepatic lipid content by more than 5% (often reversible)
steatosis (fatty liver)
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characterized by an abnormal accumulation of small cytoplasmic lipid droplets in hepatocytes
microvesicular steatosis
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MOA of ASA in Reye's Syndrome
damage to mitochondria leads to depletion of acetyl-CoA & carnitine -> FA accumulation, impaired gluconeogenesis -> hypoglycemia -> advanced steatonecrosis
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end stage of chronic liver injury in which extensive amts of fibrous tissue, esp collagen fibers, are deposited in response to direct injury/inflammation
cirrhosis
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drugs assoc'd w/ cirrhosis
- methotrexate
- vit A
- methyldopa
- alcohol
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benign tumor that itself causes no sx but may rupture vessels leading to bleeding in the IP cavity
adenoma
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