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HPIM Gastro > 361: Toxic and Drug-Induced Hepatitis > Flashcards

361: Toxic and Drug-Induced Hepatitis Flashcards

1
Q

Most common cause of acute liver failure

A

Drug-induced liver injury

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2
Q

Review: Drug metabolism

A

Drugs: water-insoluble –> water-soluble
Phase I: oxidation or methylation by cytochrome p450
Phase II : Glucuronidation or sulfation or inactivation by glutathione

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3
Q

Two major types of chemical hepatotoxicity

A
  1. Direct toxic (dose-dependent)

2. Idiosyncratic (infrequent and unpredictable)

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4
Q

Lethal dose of the toxin from Amanita phalloides that produces massive hepatic necrosis

A

10mg

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5
Q

Drugs that cause mild, transient, nonprogressive serum aminotransferase elevation that resolve with continued drug use

A

Isoniazid
Valproate
Phenytoin
Statins

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6
Q

Drug-induced cholestasis from mild to severe

A
  1. Bland cholestasis with limited hepatocellular injury
  2. Inflammatory cholestasis
  3. Sclerosing cholangitis
  4. Disappearance of bile ducts, “ductopenic” cholestasis
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7
Q

Most frequently implicated antibiotic among cases of drug-induced liver injury

A

Amoxicillin-clavulanic acid

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8
Q

Ratio of alanine aminotransferase (ALT) to alkaline phosphatase values the shows distinction between hepatocellular and cholestatic reaction

A

R value

if >5.0 = hepatocellular injury
if <2.0 = cholestatic injury
if 2.0-5.0 = mixed

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9
Q

Mechanism behind the severe hepatotoxicity associated with steatohepatitis due to antiretroviral therapy with reverse transcriptase inhibitors for HIV infection

A

Mitochondrial toxicity

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10
Q

6 Mechanisms of liver injury (Figure 361-1)

A
  1. Rupture of cell membrane
  2. Injury of bile canaliculus (disruption of transport pumps)
  3. P-450-drug covalend binding (drug adducts)
  4. Drug adducts targeted by cystolytic T lymphocytes/cytokines
  5. Activation of apoptotic pathway by TNF alpha/Fas
  6. Inhibition of mitochondrial function
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11
Q

Major types of drug-induced hepatotoxicity with the specific drugs

A

Direct Toxic effect: Carbon tetrachloride, Acetaminophen
Idiosyncratic: Amoxicillin-clavulanate, Isoniazid, Ciprofloxacin
Others: Estrogens/Androgenic steroids

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12
Q

Clinical drug trial named after Hyman Zimmerman that states that jaundice occurring during Phase III trial, more serious liver injury was likely, 10:1 ratio: 10 patients with jaundice to 1 patient with acute liver failure

A

“Hy’s Law”

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13
Q

Treatment for Toxic and Drug-Induced hepatic disease

A

Supportive except in acetaminophen hepatotoxicity

Fulminant hepatitis : Liver transplantation may be lifesaving

Withdrawal indicated at first sign of adverse reaction

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14
Q

Recommendations of these drugs for treatment:

  1. Glucocorticoids for drug hepatotoxicity with allergic features
  2. Silibinin for hepatotoxic mushroom poisoning
  3. Ursodeoxycholic acid for cholestatic drug hepatoxicity
A

NOT RECOMMENDED

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15
Q

Drugs causing moderate to severe chronic hepatitis with autoimmune features

A
  1. Nitrofurantoin
  2. Minocycline
  3. Hydralazine
  4. Methyldopa
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16
Q

Drugs causing cirrhosis

A
  1. Methotrexate
  2. Tamoxifen
  3. Amiodarone
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17
Q

Drugs causing portal hypertension in the absence of cirrhosis resulting in alteration in hepatic architecture

A
  1. Vitamin A
  2. Arsenic intoxication
  3. Industrial exposure to vinyl chloride
  4. Administration of thorium dioxide

Last 3 drugs associated with angiosarcoma of the liver

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18
Q

Effects of oral contraceptives on liver

A
  1. Hepatic adenoma
  2. Rarely = Hepatocellular carcinoma
  3. Hepatic vein occlusion (Budd-Chiari syndrome)
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19
Q

Unusual lesions caused by anabolic or contraceptive steroids

A

Peliosis hepatis (blood cysts of the liver)

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20
Q

Pathology of liver injury caused by acetaminophen after single-time-point ingestions (overdose), multiple drug preparations or inappropriate drug amounts used daily for several days

A

Dose-related centrilobular hepatic necrosis

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21
Q

Twice daily recommended maximum dose for acetaminophen that leads to liver failure

A

8g/d

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22
Q

Dose of acetaminophen that produce clinical evidence of liver injury

A

10-15g

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23
Q

Dose of acetaminophen that produces fatal fulminant disease

A

> /= 25g

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24
Q

Blood levels of acetaminophen predictive of development of severe damage

A

> 300 ug/ml 4h after ingestion

<150ug/ml: injury is unlikely

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25
Q

Symptoms related to time of intake of acetaminophen

A

4-12 h after ingestion: nausea and vomiting, diarrhea, abdominal pain, shock

24-48 h after ingestion: hepatic injury becomes apparent

3-5 days post ingestion: Maximal abnormalities and hepatic failure evident

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26
Q

Laboratory finding that increases your clinical suspicion of acetaminophen hepatotoxicity

A

Extremely high aminotransferase levels with low bilirubin levels

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27
Q

The antidote: safe and effective drug effective in acetaminophen hepatotoxicity

A

N-acetylcysteine

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28
Q

A promising diagnostic marker of acetaminophen hepatoxicity

A

acetaminophen-Cys adducts in serum measured by high performance liquid chromatography

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29
Q

Metabolite formed from acetaminophen under Phase I reaction that is detoxified by binding to glutathione to become a water-soluble mercapturic acid; in the absence of glutathione, binds covalently to nucleophilic hepatocyte macromolecules forming the acetaminophen-protein “adducts”

A

N-acetyl-p-benzoquinone-imine (NAPQI)

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30
Q

A factor associated with increased risk of acute liver injury in patients who overdose acetaminophen

A

Hepatitis C infection

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31
Q

FDA recommended daily dose of acetaminophen

A

3g (from 4g)

If with opioid combination: dose should be lowered to 325mg per tablet

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32
Q

Treatment of acetaminophen overdose

A
  1. Gastric lavage
  2. Supportive measures
  3. Oral administration of activated charcoal or cholestyramine to prevent absorption or residual drug (Not effective if ingestion is more than 30 mins)
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33
Q

Administration of N-acetylcysteine at what blood levels of acetaminophen reduces the severity of hepatic necrosis

A

> 200ug/mL at 4h post ingestion OR

>100ug/mL at 8h post ingestion

34
Q

Optimal time that therapy for acetaminophen overdose should be started

A

Within 8h of ingestion

Partially effective if as late as 24-36h

35
Q

Administration of N-acetylcysteine

A

Loading dose: 140mg/kg over 1h then
70mg/kg every 4h for 15-20 doses

Treatment can be stopped when plasma acetaminophen levels indicate that risk of liver damage is LOW

If with signs of hepatic faliure: liver transplantation

36
Q

Lactate levels in acute liver failure that will distinguish patients highly likely to require liver transplantation from those likely to survive without liver replacement

A

lactate levels >3.5mmol/L

37
Q

T or F: Acute renal injury occurs in 75% of patients with severe acetaminophen injury but is always self-limited

A

True

38
Q

Prognosis for acute acetaminophen overdose

A

Survivors rarely have ongoing liver injury or sequalae

39
Q

T or F:
Elevations (ALT<200 IU/L) in serum aminotransferase levels during first few weeks of therapy of Isoniazid (INH) should warrant stopping of the drug immediately.

A

False.

Usually self-limited and will resolve despite continued drug use

40
Q

Latency period of acute hepatocellular drug-induced liver injury secondary to INH

A

Up to 6 months

More frequent among alcoholics and those taking barbiturates, rifampin and pyrazinamide

41
Q

Liver biopsy findings in INH hepatotoxicity

A

Morphology similar to viral hepatitis or bridging hepatic necrosis

42
Q

T or F:

Liver injury is age-related

A

True

Increasing after age 35, highest frequency at >50 y/o, lowest under age 20

43
Q

T or F:

In INH hepatotoxicity: fever, rash, eosinophilia and drug allergy manifestation are unusual.

A

True

INH produces toxic and idiosyncratic reaction

44
Q

Most common antiepileptic drug implicated among candidates of liver transplant in children

A

Valproate

45
Q

Metabolite of sodium valproate responsible for hepatic injury

A

4-pentenoic acid

46
Q

Depleted compound in valproate therapy that ameliorates valproate hepatotoxicity by administration through IV

A

Carnitine

47
Q

T or F:

Nitrofurantoin has a longer latency period due to its intermittent, recurrent use in cystitis among women.

A

True

48
Q

T or F:
Glucocorticoid and other immunosuppresants may be necessary to resolve the autoimmune injury in Nitrofurantoin hepatotoxicity.

A

True

49
Q

Adverse effect seen in nitrofurantoin hepatotoxicity presenting as chronic cough and dyspnea that resolve slowly with medication withdrawal.

A

Interstitial pulmonary fibrosis

50
Q

T or F:

Hepatotoxicity in amoxicillin-clavulanate can manifest during withdrawal of drug or even after.

A

True

51
Q

Presentation of amoxicillin-clavulanate hepatotoxicity

A

Nausea, anorexia, fatigue, jaundice with pruritus

Rash is uncommon

52
Q

Amoxicillin-clavulanate causes cholestatic hepatotoxicity that can cause permanent injury to small bile ducts called

A

“vanishing bile duct syndrome”

53
Q

Formerly diphenylhydantoin, mainstay treatment of seizure disorders associated with severe hepatitis-like liver injury leading to fulminant hepatic failure

A

Phenytoin

54
Q

Presentation of phenytoin hepatotoxicity

A

Striking fever, lymphadenopathy, RASH (SJS or exfoliative dermatitis), leukocytosis, eosinophilia

Duration: within 2 months of therapy

55
Q

Metabolite of phenytoin causing hepatic injury

A

Arene oxides

Metabolized by epoxide hydrolases

56
Q

T or F:

In long-term phenytoin therapy, elevations of aminotransferase and alkaline phosphatase levels are usually asymptomatic

A

True

57
Q

Hepatotoxicity with this antiarrhythmic drug presents with elevated aminotransferase levels with hepatomegaly

A

Amiodarone

58
Q

Metabolite of Amiodarone

A

Desethylamiodarone

59
Q

T or F: Elevations in aminotransferase levels in Amiodarone hepatotoxicity is dose-dependent

A

True

60
Q

Condition seen on long-term recipients of Amiodarone indicating its effect on the liver

A

Phospholipidosis

61
Q

T or F:

Liver injury in Amiodarone persist for months after the drug is stopped.

A

True

Reason: Due to its long half-life

62
Q

Most important adverse effect associated with Erythromycin seen more in children

A

Cholestatic reaction

63
Q

Presentation of erythromycin hepatotoxicity

A

Nausea, vomiting, fever, RUQ pain, jaundice, leukocytosis, mod elevated aminotransferases and alk phosphatase.

Duration: first 2 or 3 weeks of therapy

64
Q

Prognosis of erythromycin hepatotoxicity

A

Symptoms subside with drug withdrawal.

No evidence of chronic liver disease on follow-up.

65
Q

Effect of oral contraceptive combinations of estrogenic and progestational steroids on liver

A

Intrahepatic cholestasis

66
Q

Presentation of oral contraceptive hepatotoxicity

A

Pruritus, jaundice

Duration: Weeks to months after intake

67
Q

Liver biopsy in oral contraceptive hepatotoxicity

A

Cholestasis with bile plugs in dilated canaliculi and striking bilirubin staining of liver cells. Portal inflammation is ABSENT.

68
Q

Prognosis in oral contraceptive hepatotoxicity

A

Reversible on withdrawal

69
Q

Contraindication of oral contraceptives on these types of patients

A

With history of recurrent jaundice of pregnancy

70
Q

T or F:

Malignant neoplasm of the liver are associated with oral contraceptives

A

False

Primarily benign, rarely malignant

71
Q

Most common form of liver injury caused by complementary and alternative medications associated with anabolic steroids used by body builders

A

Profound cholestasis
With NO inflammation or necrosis

Duration: Weeks to months before resolution

72
Q

Laboratories in anabolic steroid hepatotoxicity

A

Serum aminotransferase <100 IU/L
Mod elevated alk phos
Bilirubin >342 umol/L (20mg/dL)

73
Q

Presentation of Co-trimoxazole (sulfamethoxazole) hepatotoxicity

A

Eosinophilia, rash, hypersensitivity reactions

Self-limited
Duration: Several weeks

74
Q

T or F:
Statins cause a reversible elevations (>3x) of aminotransferase activity producing a mixed hepatocellular and cholestatic reaction

A

True

75
Q

Recommendation of liver test monitoring in patients treated with statins

A

Monitoring NOT necessary

Should not be discontinued in asymptomatic isolated aminotransferase elevations

76
Q

Effect of Total Parenteral Nutrition (TPN) on liver

A

Cholestatic hepatitis

Due to excess carbohydrate calories.
Mechanism: Due to absence of stimulation of bile flow and secretion from lack of oral intake
Intervention: Balancing TPN formula with more lipids

77
Q

Herbal remedies associated with toxic hepatitis

A
  1. Jin Bu Huan
  2. xiao-chai-hu-tang
  3. germander
  4. chaparral
  5. senna
  6. mistletoe
  7. skullcap
  8. gentian
  9. comfrey
  10. ma huang
  11. bee pollen
  12. valerian root
  13. pennyroyal oil
  14. kava
  15. herbal teas containing Camellia sinensis (green tea extract)
  16. herbal nutritional supplements
78
Q

T or F: Megadoses of vitamin A can injure the liver

A

True

79
Q

Alkaloid often in Chinese herbal preparations that can cause venoocclusive injury leading to sinusoidal hepatic vein obstruction

A

Pyrrolizidine alkaloids

80
Q

Emerging and common type of liver injury in HIV-infected persons

A

HAART therapy hepatotoxicity

Zidovudine, Didanosine, stavudine
Ritonavir, Indinavir
Nevirapine, Efavirenz

81
Q

Effect of HAART on liver

A

Hepatocellular, cholestatic and mixed

HPIM Gastro (7 decks)

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