Toxic and Drug-Induced Hep Flashcards
(37 cards)
1
Q
POSSIBLE CAUSES of Liver injury
A
- industrial toxins
- pharmacologic agents
- complementary and alternative medications (CAMs)
2
Q
is the most common cause of liver Injury
A
Drug-induced liver injury (DILI)
3
Q
Toxic and Drug-Induced Hepatic Injury
Liver morphology: Necrosis, fatty infiltration
A
CARBON TETRACHLORIDE
4
Q
Toxic and Drug-Induced Hepatic Injury
Liver morphology: Centrilobular necrosis
A
ACETAMINOPHEN
5
Q
Toxic and Drug-Induced Hepatic Injury
Liver morphology: Hepatocellular injury resembling viral hepatitis
A
- ISONIAZID
- CIPROFLOXACIN
6
Q
Toxic and Drug-Induced Hepatic Injury
Liver morphology: Cholestasis without ortal inflammation
A
ESTROGENS/ ANDROGENIC STEROIDS
7
Q
Direct Toxicity: periportal injury
A
Yellow phosphorus poisoning
8
Q
Direct Toxicity: produce a centrilobular zonal necrosis
A
Carbon tetrachloride and trichloroethylene
9
Q
Direct Toxicity: produce massive hepatic necrosis
A
Octapeptides of Amanita phalloides-
10
Q
- usually infrequent and unpredictable
- not dose-dependent
- may occur at any time
A
Idiosyncratic Drug Reactions
11
Q
ADAPTATION MECHANISM resolved with continuous drug
use
A
- isoniazid (INH)
- valproate
- phenytoin
- HMG-CoA
- reductase inhibitors (statins)
12
Q
featuring spotty necrosis in the liver lobule with a
predominantly lymphocytic infiltrate
- MOST COMMON FORM
A
Hepatocellular injury
13
Q
- 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
A
Cholestatic Injury
14
Q
- Indicates the distinction between a hepatocellular and a cholestatic reaction
- ratio of alanine aminotransferase (ALT) to alkaline phosphatase values
A
R value
15
Q
R value:
- > 5.0 is associated:
- <2.0:
- Between 2.0 and 5.0
A
- > 5.0 is associated: hepatocellular injury
- <2.0: cholestatic injury
- Between 2.0 and 5.0: mixed hepatocellular-cholestatic injury
16
Q
Other Medications associated with Morphologic alterations
venoocclusive disease in sinusoidal lining cells
A
Chemotherapeutic agents
17
Q
Other Medications associated with Morphologic alterations
Severe hepatotoxicity associated with steatohepatitis
A
ARTs
18
Q
Other Medications associated with Morphologic alterations
hepatic granulomas
A
Sulfonamides
19
Q
Other Medications associated with Morphologic alterations
bridging hepatic necrosis
A
Methyldopa
20
Q
- 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
A
ACETAMINOPHEN HEPATOTOXICITY (DIRECT TOXIN)
21
Q
ACETAMINOPHEN HEPATOTOXICITY (DIRECT TOXIN)
- 4-12h
- 24-48 h
- 3—5 days
A
- 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
22
Q
Acetaminophen
8 g/d:
10-15 g:
>/=25 g:
A
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
23
Q
ACETAMINOPHEN HEPATOTOXICITY (DIRECT TOXIN)
e 3g:
e 325mg per tablet -
e 2g:
A
- 3g: FDA recommendation for daily dose of acetaminophen
- 325mg per tablet - opioid combination products
- 2g: for chronic alcoholics
24
Q
- 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
A
SODIUM VALPROATE HEPATOTOXICITY (TOXIC AND IDIOSYNCRATIC REACTION)
25
- 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)
26
- 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)
27
- 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)
28
- 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)
29
- 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)
30
- 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)
31
- 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)
32
- 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)
33
- 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)
34
- 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)
35
- 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)
36
- 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)
37
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)
