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IM GASTRO > Toxic and Drug-Induced Hep > Flashcards

Toxic and Drug-Induced Hep Flashcards

1
Q

POSSIBLE CAUSES of Liver injury

A
  • industrial toxins
  • pharmacologic agents
  • complementary and alternative medications (CAMs)
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2
Q

is the most common cause of liver Injury

A

Drug-induced liver injury (DILI)

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3
Q

Toxic and Drug-Induced Hepatic Injury

Liver morphology: Necrosis, fatty infiltration

A

CARBON TETRACHLORIDE

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4
Q

Toxic and Drug-Induced Hepatic Injury

Liver morphology: Centrilobular necrosis

A

ACETAMINOPHEN

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5
Q

Toxic and Drug-Induced Hepatic Injury

Liver morphology: Hepatocellular injury resembling viral hepatitis

A
  • ISONIAZID
  • CIPROFLOXACIN
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6
Q

Toxic and Drug-Induced Hepatic Injury

Liver morphology: Cholestasis without ortal inflammation

A

ESTROGENS/ ANDROGENIC STEROIDS

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7
Q

Direct Toxicity: periportal injury

A

Yellow phosphorus poisoning

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8
Q

Direct Toxicity: produce a centrilobular zonal necrosis

A

Carbon tetrachloride and trichloroethylene

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9
Q

Direct Toxicity: produce massive hepatic necrosis

A

Octapeptides of Amanita phalloides-

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10
Q
  • usually infrequent and unpredictable
  • not dose-dependent
  • may occur at any time
A

Idiosyncratic Drug Reactions

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11
Q

ADAPTATION MECHANISM resolved with continuous drug
use

A
  • isoniazid (INH)
  • valproate
  • phenytoin
  • HMG-CoA
  • reductase inhibitors (statins)
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12
Q

featuring spotty necrosis in the liver lobule with a
predominantly lymphocytic infiltrate
- MOST COMMON FORM

A

Hepatocellular injury

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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

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14
Q
  • Indicates the distinction between a hepatocellular and a cholestatic reaction
  • ratio of alanine aminotransferase (ALT) to alkaline phosphatase values
A

R value

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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
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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
Q
  • 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
A

=NITROFURANTOIN HEPATOTOXICITY (IDIOSYNCRATIC REACTION)

26
Q
  • 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
A

AMOXICILLIN-CLAVULANATE HEPATOTOXICITY (IDIOSYNCRATIC MIXED REACTION)

27
Q
  • 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
A

PHENYTOIN HEPATOTOXICITY (Idiosyncratic Reaction)

28
Q
  • 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
A

AMIODARONE HEPATOTOXICITY (Toxic and Idiosyncratic Reaction)

29
Q
  • 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
A

ERYTHROMYCIN HEPATOTOXICITY (CHOLESTATIC IDIOSYNCRATIC REACTION)

30
Q
  • 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
A

ORAL CONTRACEPTIVE HEPATOTOXICITY (CHOLESTATIC REACTION)

31
Q
  • 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
A

ANABOLIC STEROIDS (CHOLESTATIC REACTION)

32
Q
  • 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
A

TRIMETHOPRIM-SULF AMETHOXAZOLE HEPATOTOXICITY (IDIOSYNCRATIC REATION)

33
Q
  • 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
A

MG-COA REDUCTASE INHIBITORS (STATINS) (IDIOSYNCRATIC MIXED HEPATOCELLULAR AND CHOLESTATIC REACTION)

34
Q
  • 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
A

TOTAL PARENTERAL NUTRITION (STEATOSIS, CHOLESTASIS)

35
Q
  • 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
A

ALTERNATIVE AND COMPLEMENTARY MEDICINES (IDIOSYNCRATIC HEPATITIS, STEATOSIS)

36
Q
  • 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
A

HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) FOR HIV INFECTION (MITOCHONDRIAL TOXIC, IDIOSYNCRATIC, STEATOSIS; HEPATOCELLULAR, CHOLESTATIC, AND MIXED)

37
Q

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

A

HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART)
FOR HIV INFECTION (MITOCHONDRIAL TOXIC, IDIOSYNCRATIC, STEATOSIS; HEPATOCELLULAR, CHOLESTATIC, AND MIXED)

IM GASTRO (10 decks)

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