Toxic and Drug-Induced Hep Flashcards
POSSIBLE CAUSES of Liver injury
- industrial toxins
- pharmacologic agents
- complementary and alternative medications (CAMs)
is the most common cause of liver Injury
Drug-induced liver injury (DILI)
Toxic and Drug-Induced Hepatic Injury
Liver morphology: Necrosis, fatty infiltration
CARBON TETRACHLORIDE
Toxic and Drug-Induced Hepatic Injury
Liver morphology: Centrilobular necrosis
ACETAMINOPHEN
Toxic and Drug-Induced Hepatic Injury
Liver morphology: Hepatocellular injury resembling viral hepatitis
- ISONIAZID
- CIPROFLOXACIN
Toxic and Drug-Induced Hepatic Injury
Liver morphology: Cholestasis without ortal inflammation
ESTROGENS/ ANDROGENIC STEROIDS
Direct Toxicity: periportal injury
Yellow phosphorus poisoning
Direct Toxicity: produce a centrilobular zonal necrosis
Carbon tetrachloride and trichloroethylene
Direct Toxicity: produce massive hepatic necrosis
Octapeptides of Amanita phalloides-
- usually infrequent and unpredictable
- not dose-dependent
- may occur at any time
Idiosyncratic Drug Reactions
ADAPTATION MECHANISM resolved with continuous drug
use
- isoniazid (INH)
- valproate
- phenytoin
- HMG-CoA
- reductase inhibitors (statins)
featuring spotty necrosis in the liver lobule with a
predominantly lymphocytic infiltrate
- MOST COMMON FORM
Hepatocellular injury
- estrogens, 17,a-substituted androgen- bland cholestasis with limited hepatocellular injury
- amoxicillin-clavulanic acid, oxacillin, erythromycin estolateinflammatory cholestasis
- floxuridine- sclerosing cholangitis
- carbamazepine, levofloxacin- disappearance of bile ducts
Cholestatic Injury
- Indicates the distinction between a hepatocellular and a cholestatic reaction
- ratio of alanine aminotransferase (ALT) to alkaline phosphatase values
R value
R value:
- > 5.0 is associated:
- <2.0:
- Between 2.0 and 5.0
- > 5.0 is associated: hepatocellular injury
- <2.0: cholestatic injury
- Between 2.0 and 5.0: mixed hepatocellular-cholestatic injury
Other Medications associated with Morphologic alterations
venoocclusive disease in sinusoidal lining cells
Chemotherapeutic agents
Other Medications associated with Morphologic alterations
Severe hepatotoxicity associated with steatohepatitis
ARTs
Other Medications associated with Morphologic alterations
hepatic granulomas
Sulfonamides
Other Medications associated with Morphologic alterations
bridging hepatic necrosis
Methyldopa
- most prevalent cause of acute liver failure in the Western world
- up to 72% progress to encephalopathy and coagulopathy
- centrilobular hepatic necrosis
- opiocid-acetaminophen combinations - harmful
- Blood levels of acetaminophen correlate with severity of hepatic injury
ACETAMINOPHEN HEPATOTOXICITY (DIRECT TOXIN)
ACETAMINOPHEN HEPATOTOXICITY (DIRECT TOXIN)
- 4-12h
- 24-48 h
- 3—5 days
- 4-12h
+ Nausea, vomiting, diarrhea, abdominal pain, and shock - 24-48 h
+ hepatic injury becomes apparent. - 3—5 days
+ Maximal abnormalities and hepatic Failure
+ aminotransferase levels may exceed 10,000 IU/L
Acetaminophen
8 g/d:
10-15 g:
>/=25 g:
8 g/d: over several days can readily lead to liver failure
10-15 g: single dose may produce clinical evidence of liver injury
>/=25 g: Fatal fulminant disease
Opioid-acetaminophen combinations appears to be particularly harmful
ACETAMINOPHEN HEPATOTOXICITY (DIRECT TOXIN)
e 3g:
e 325mg per tablet -
e 2g:
- 3g: FDA recommendation for daily dose of acetaminophen
- 325mg per tablet - opioid combination products
- 2g: for chronic alcoholics
- Associated with severe hepatic toxicity predominantlyvin
children - most common antiepileptic drug implicated among children candidate for liver transplantation
- 4-pentenoic acid - metabolite
+ may be responsible for hepatic injury - mitochondrial enzyme deficiencies
+ IV administration of carnitine
SODIUM VALPROATE HEPATOTOXICITY (TOXIC AND IDIOSYNCRATIC REACTION)
- antibiotic for urinary tract infections
- acute hepatitis = fatal outcome / chronic hepatitis frequent use and reuse of the drug for treatment of recurrent
cystitis in women - Autoantibodies to nuclear components, smooth muscle, and mitochondria are seen and may subside after resolution of infection
- glucocorticoid may be necessary to resolve the autoimmune injury
=NITROFURANTOIN HEPATOTOXICITY (IDIOSYNCRATIC REACTION)
- most common agent implicated as causing DILI (most frequent brand name: Augmentin
- high prevalence of hepatotoxicity reflects in part the very
frequent use of this drug mixed or primarily cholestatic injury - caused by amoxicillin toxicity that is potentiated in some way by clavulanate, which itself appears not to be toxic
- “vanishing bile duct syndrome”- permanent injury to small bile ducts
AMOXICILLIN-CLAVULANATE HEPATOTOXICITY (IDIOSYNCRATIC MIXED REACTION)
- severe hepatitis-like liver injury leading to fulminant hepatic
failure - striking fever, lymphadenopathy, rash (Stevens-Johnson
syndrome or exfoliative dermatitis), leukocytosis, and
eosinophilia - suggests an immunologically mediated hypersensitivity
mechanism - manifest within the first 2 months after beginning phenytoin therapy
PHENYTOIN HEPATOTOXICITY (Idiosyncratic Reaction)
- 15-50% of patients treated have elevations of serum
aminotransferase levels that may remain stable or diminish
despite continuation of the drug - major metabolite desethylamiodarone accumulate in
hepatocyte lysosomes and mitochondria and in bile duct
epithelium - Pseudoalcoholic liver injury- rare patient may have liver injury resembling that seen in alcoholic liver disease
- demonstration of phospholipid-laden lysosomal lamellar
bodies can help to distinguish amiodarone hepatotoxicity from typical alcoholic hepatitis
AMIODARONE HEPATOTOXICITY (Toxic and Idiosyncratic Reaction)
- Cholestatic reaction: most important adverse effect
more common in children - begins during the first 2 or 3 weeks of therapy
+ nausea, vomiting, fever, RUQ abdominal pain, jaundice, leukocytosis, and moderately elevated aminotransferase and alkaline phosphatase levels - resemble acute cholecystitis or bacterial cholangitis
- Liver biopsy = cholestasis; portal inflammation and scattered foci of hepatocyte necrosis
- Symptoms and laboratory findings usually subside within a few days of drug withdrawal
ERYTHROMYCIN HEPATOTOXICITY (CHOLESTATIC IDIOSYNCRATIC REACTION)
- intrahepatic cholestasis with pruritus and jaundice
- laboratory studies are normal and extra-hepatic
manifestations of hypersensitivity are absent - Liver biopsy = cholestasis with bile plugs in dilated canaliculi
and striking bilirubin staining of liver cells. - Oral contraceptives are contraindicated in patients with a
history of recurrent jaundice of pregnancy - Lesion is reversible on withdrawal of the agent
- Estrogen may be primarily responsible
ORAL CONTRACEPTIVE HEPATOTOXICITY (CHOLESTATIC REACTION)
- can be profound cholestasis associated with anabolic steroids among body builders
- injure bile transport pumps and to cause intense cholestasis time to onset is variable and resolution may require many weeks to months
- anorexia, nausea, malaise and pruritus may follow
- Serum aminotransferase levels are usually <100 IU/L And serum alkaline phosphatase levels are generally moderately elevated
- Bilirubin levels frequently exceeding 20 mg/dL
- cholestasis without substantial inflammation or necrosis
ANABOLIC STEROIDS (CHOLESTATIC REACTION)
- uniform latency period of several weeks and is often
accompanied by eosinophilia, rash, and other features of a
hypersensitivity reaction - acute hepatocellular necrosis predominates, but cholestatic features are quite frequent
- sulfamethoxazole component = hepatotoxic
- risk of is increased in persons with HIV infection
TRIMETHOPRIM-SULF AMETHOXAZOLE HEPATOTOXICITY (IDIOSYNCRATIC REATION)
- asymptomatic, reversible elevations (>3x) of aminotransferase activity
- Acute hepatitis-like histologic changes, centrilobular necrosis, and centrilobular cholestasis in a very small number of patients
- Panel of liver experts: liver test monitoring was not necessary and that statin therapy need not be discontinued if asymptomatic isolated aminotransferase elevations during
therapy - Safe in patients with chronic hepatitis C, hepatic steatosis, or other underlying liver diseases
MG-COA REDUCTASE INHIBITORS (STATINS) (IDIOSYNCRATIC MIXED HEPATOCELLULAR AND CHOLESTATIC REACTION)
- cholestatic hepatitis
+ steatosis, cholestasis, or gallstones
> excess carbohydrate calories
+ balanced TPN formulas = reduces complication
> lipid as an alternative caloric source - absence of stimulation of bile flow and secretion resulting from the lack of oral intake- the predominant form of TPN-associated liver disease in infants
- In adults: balancing the TPN formula with more lipid is the intervention of first recourse
- In infants: addition of oral feeding may ameliorate the
problem
TOTAL PARENTERAL NUTRITION (STEATOSIS, CHOLESTASIS)
- 20% of drug-induced liver injury
- Weight loss agents- most common category of dietary or
herbal products - Herbal medications
o Jin Bu Huan, xiao-chai-hu- tang, germander, chaparral, etc. - Vitamin A megadose can injure the liver
- Widespread use of poorly defined herbal preparation hepatotoxicity is likely to be encountered with increasing
frequency
ALTERNATIVE AND COMPLEMENTARY MEDICINES (IDIOSYNCRATIC HEPATITIS, STEATOSIS)
- HIV patients possible causes of liver Injury: chronic viral
hepatitis, fatty infiltration, infiltrative disorders, mycobacterial infection - 10% of treated patients- hepatotoxixity from combined
regimen - Predominantly hepatocellular injury but cholestatic injury
HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) FOR HIV INFECTION (MITOCHONDRIAL TOXIC, IDIOSYNCRATIC, STEATOSIS; HEPATOCELLULAR, CHOLESTATIC, AND MIXED)
HAART hepatotoxicity and hepatitis virus co-infection
1. both chronic hepatitis B and hepatitis C can affect the natural history of HIV infection and the response to HAART
2. HAART can have an impact on chronic viral hepatitis
- Low CD4+ T cell count- increase the rate of hepatic fibrosis associated with chronic hepatitis C
o HAART therapy can increase levels of serum aminotransferases and HCV RNA in patients with hepatitis C co-infection
HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART)
FOR HIV INFECTION (MITOCHONDRIAL TOXIC, IDIOSYNCRATIC, STEATOSIS; HEPATOCELLULAR, CHOLESTATIC, AND MIXED)
