Liver Flashcards
What tests are we going to order?
- total bilirubin
- alanine transaminase
- prothrombin time
- alkaline phosphatase
What is the most common drug causing drug-induced liver injury?
amoxicillin/clavulanate
*used to be acetaminophen
What are common drugs for acute liver failure
Antibiotic medications
- isoniazid
- sulfur antibiotics (sulfa/trim)
- nitrofurantoin
What are the functions of the liver?
- Protein synthesis
- Bile secretion
- Biotransformation & detoxification
- Regernative organ
Describe protein synthesis
- materials essential for homeostasis - clotting factors
- materials essential for drug binding and osmolarity - albumin and lipoprotein
Describe bile secretion
aids in digestion and excretion
Describe biotransformation & detoxification
- ammonia, steroid hormones, lipid, cholesterol, heme and bilirubin
- drug metabolism through two phase reactions (phase 1 = oxidation/reduction), (phase 2 = conjugation)
__% of liver function is enough for normal function
30
Describe biotransformation (slide 10)
- 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
List the 2 mechanisms of drug-induced liver injury
1) Metabolic induced pathogenesis
- oxidative stress
- mitochondria
2) Immune-mediated pathogenesis
- immune reaction
- ADCC
- CDC
Toxic metabolite of acetaminophen
NAPQI
- leads to glutathione
- mitochondrial dysfunction
- leads to necrosis of the liver
Describe the immune-mediated pathogenesis
- drug will cause antigen to stimulate immune system to generate antibody
- antibody will attack the liver and cause liver toxicity
List factors that affect drug toxicity
- Age
- Gender
- Diet
- Diseases
- Enzyme Polymorphism
- Drug/Drug Interactions
How does age affect drug toxicity?
- 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)
How does gender affect drug toxicity?
hormones (estrogen, testosterone) play a role
How does diet affect drug toxicity?
- Nutrients - calcium, iron, magnesium, copper, zinc
- Caffeine
- Alcohol
How do diseases affect drug toxicity
- 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
What are the types of liver injury (clinical approach)?
Type A: intrinsic (direct) injury
Type B: idiosyncratic injury
What are the types of liver injury (temporal approach)?
- acute
- chronic
What are the types of liver injury (morphological approach)?
- hepatocellular
- cholestatic
- miscellaneous reaction
Describe direct hepatotoxicity
- expected, dose-related, common
- distinctive morphologic pattern
- reproducible in animals
- no extrahepatic signs of hypersensitivity
- serum enzyme elevations
What are some phenotypes of direct hepatotoxicity?
- acute hepatic necrosis
- sinusoidal obstruction syndrome
- lactic acidosis
- hepatic steatosis
- nodular regernative hyperplasia
Pathogenesis of direct hepatotoxicity?
likely oxidative stress-mediated
Describe acute hepatic necrosis
- sudden direct hepatic toxicity
- ALT increases, ALP & bilirubin may increase
- R > 30
- INR may be elevated
- rapid improvement
- slide 18
what drugs can cause acute hepatic necrosis
- acetaminophen
- niacin
- amiodarone (IV)
- cocaine
- ecstasy
- cancer chemotherapeutics
______ is usually immune-mediated hepatotoxicity
idiosyncratic (unknown cause)
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
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
What are some associated clinical features of idiosyncratic hepatotoxicity
- immunoallergic (rash, fever, eosinophilia)
- autoimmune (ANA, SMA IgG elevation)
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
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)
Describe the phenotypes of indirect hepatotoxicity
- acute hepatitis
- chronic hepatitis
- acute liver failure
- fatt liver
**often can be predicted and prevented
List the 3 types of liver injury
- Direct
- Indirect
- Idiosyncratic
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
What are some adverse outcomes of all those phenotypes?
- Acute liver failure
- Vanishing bile duct syndrome
- Cirrhosis
How do we diagnose the 12 phenotypes?
- histological features
- clinical features
- laboratory tests
- noninvasive imaging
What are types of acute hepatitis
- zonal necrosis
- diffse, spotty necrosis
- viral hepatitis-like injury
- granuloma
What drugs can cause zonal necrosis
- paracetamol
- yellow phosphorus
what drugs can cause diffuse, spotty necrosis
-aspirin
What drugs can cause virus hepatitis-like injury
- diclofenac
- halothane
- isoniazid
- sulfonamides
what drugs can cause granuloma
- allopurinol
- carbamazepine
- phenytoin
- quinidine
what are types of chronic hepatitis
1) Autoimmune like injury
2) Chronic viral hepatitis-like
What drugs can cause auto-immune like injury
- alpha-methyldopa
- dantrolene
- diclofenac
- nitrofurantoin
What drugs can cause chronic viral hepatitis-like?
- aminoeptin
- amiodraone
- aspirin
- etretinate
- isoniazid
what drugs cause micro vesicular steatosis
- aspirin
- didanosine
- fialuridine
- tetracycline
- valproate
what drugs cause nonalcoholic steatohepatitis
- amiodarone
- calcium channel blockers
- perhexiline
what drug causes phospholipidosis
amiodarone
What causes bland cholestasis (acute)
- estrogens
- 17-alkylated steroids
what causes acute cholestasis with inflammation
- amox/clav
- erythromcyin estolate
- peroxicam
What can cause Ductopenia and secondary biliary cirrhosis (a form of chronic cholestasis) ?
- ajmaline
- carbamazepine
- chlorpromazine
- chlorpropamide
- haloperidol
- penicillins
- thiobendazole
- TCA
- tolbumatide
what can cause macroscopic duct sclerosis
intra-arterial floxuridine
What can cause perisinusoidal fibrosis?
- methotrexate
- vitamin A
Vascular alterations:
what can cause veno-occulsive disease (VOD)?
- pyrrolizidine alkaloids
- azathioprine
- aklylating agents
Vascular alterations:
What can cause hepatic vein thrombosis?
estrogens
Vascular alterations:
What causes non-cirrhotic portal hypotension or nodular regenerative hyperplasia
- azathioprine
- 6-thioguanidine
What can cause adenoma
estrogens
what can cause hepatocellular carcinoma
estrogens, anabolic steroids, cyproterone
signs and symptoms of liver disease
-fatigue, nausea, anorexia, malaise, fatigue, RUQ pain, jaundice, itching
what is Hy’s law?
jaundice that appears after drug induced hepatocellular injury suggests a serious and potentially fatal liver problem
Hy’s Law:
-drug-induced hepatocellular jaundice has a mortality rate of ___
*unlike viral hepatitis and drug-induced cholestatic hepatitis - 1% mortality rate
> 10%
Describe the elevations in normal lab values for Hy’s Law
ALT > 3 x ULN
TBL > 2 x ULN
What do we need to exclude before saying it’s drug induced liver injury?
-viral hepatitis
-alcohol
-autoimmune disease
etc.
