361: Toxic and Drug-Induced Hepatitis Flashcards
Most common cause of acute liver failure
Drug-induced liver injury
Review: Drug metabolism
Drugs: water-insoluble –> water-soluble
Phase I: oxidation or methylation by cytochrome p450
Phase II : Glucuronidation or sulfation or inactivation by glutathione
Two major types of chemical hepatotoxicity
- Direct toxic (dose-dependent)
2. Idiosyncratic (infrequent and unpredictable)
Lethal dose of the toxin from Amanita phalloides that produces massive hepatic necrosis
10mg
Drugs that cause mild, transient, nonprogressive serum aminotransferase elevation that resolve with continued drug use
Isoniazid
Valproate
Phenytoin
Statins
Drug-induced cholestasis from mild to severe
- Bland cholestasis with limited hepatocellular injury
- Inflammatory cholestasis
- Sclerosing cholangitis
- Disappearance of bile ducts, “ductopenic” cholestasis
Most frequently implicated antibiotic among cases of drug-induced liver injury
Amoxicillin-clavulanic acid
Ratio of alanine aminotransferase (ALT) to alkaline phosphatase values the shows distinction between hepatocellular and cholestatic reaction
R value
if >5.0 = hepatocellular injury
if <2.0 = cholestatic injury
if 2.0-5.0 = mixed
Mechanism behind the severe hepatotoxicity associated with steatohepatitis due to antiretroviral therapy with reverse transcriptase inhibitors for HIV infection
Mitochondrial toxicity
6 Mechanisms of liver injury (Figure 361-1)
- Rupture of cell membrane
- Injury of bile canaliculus (disruption of transport pumps)
- P-450-drug covalend binding (drug adducts)
- Drug adducts targeted by cystolytic T lymphocytes/cytokines
- Activation of apoptotic pathway by TNF alpha/Fas
- Inhibition of mitochondrial function
Major types of drug-induced hepatotoxicity with the specific drugs
Direct Toxic effect: Carbon tetrachloride, Acetaminophen
Idiosyncratic: Amoxicillin-clavulanate, Isoniazid, Ciprofloxacin
Others: Estrogens/Androgenic steroids
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
“Hy’s Law”
Treatment for Toxic and Drug-Induced hepatic disease
Supportive except in acetaminophen hepatotoxicity
Fulminant hepatitis : Liver transplantation may be lifesaving
Withdrawal indicated at first sign of adverse reaction
Recommendations of these drugs for treatment:
- Glucocorticoids for drug hepatotoxicity with allergic features
- Silibinin for hepatotoxic mushroom poisoning
- Ursodeoxycholic acid for cholestatic drug hepatoxicity
NOT RECOMMENDED
Drugs causing moderate to severe chronic hepatitis with autoimmune features
- Nitrofurantoin
- Minocycline
- Hydralazine
- Methyldopa
Drugs causing cirrhosis
- Methotrexate
- Tamoxifen
- Amiodarone
Drugs causing portal hypertension in the absence of cirrhosis resulting in alteration in hepatic architecture
- Vitamin A
- Arsenic intoxication
- Industrial exposure to vinyl chloride
- Administration of thorium dioxide
Last 3 drugs associated with angiosarcoma of the liver
Effects of oral contraceptives on liver
- Hepatic adenoma
- Rarely = Hepatocellular carcinoma
- Hepatic vein occlusion (Budd-Chiari syndrome)
Unusual lesions caused by anabolic or contraceptive steroids
Peliosis hepatis (blood cysts of the liver)
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
Dose-related centrilobular hepatic necrosis
Twice daily recommended maximum dose for acetaminophen that leads to liver failure
8g/d
Dose of acetaminophen that produce clinical evidence of liver injury
10-15g
Dose of acetaminophen that produces fatal fulminant disease
> /= 25g
Blood levels of acetaminophen predictive of development of severe damage
> 300 ug/ml 4h after ingestion
<150ug/ml: injury is unlikely
Symptoms related to time of intake of acetaminophen
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
Laboratory finding that increases your clinical suspicion of acetaminophen hepatotoxicity
Extremely high aminotransferase levels with low bilirubin levels
The antidote: safe and effective drug effective in acetaminophen hepatotoxicity
N-acetylcysteine
A promising diagnostic marker of acetaminophen hepatoxicity
acetaminophen-Cys adducts in serum measured by high performance liquid chromatography
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”
N-acetyl-p-benzoquinone-imine (NAPQI)
A factor associated with increased risk of acute liver injury in patients who overdose acetaminophen
Hepatitis C infection
FDA recommended daily dose of acetaminophen
3g (from 4g)
If with opioid combination: dose should be lowered to 325mg per tablet
Treatment of acetaminophen overdose
- Gastric lavage
- Supportive measures
- Oral administration of activated charcoal or cholestyramine to prevent absorption or residual drug (Not effective if ingestion is more than 30 mins)
Administration of N-acetylcysteine at what blood levels of acetaminophen reduces the severity of hepatic necrosis
> 200ug/mL at 4h post ingestion OR
>100ug/mL at 8h post ingestion
Optimal time that therapy for acetaminophen overdose should be started
Within 8h of ingestion
Partially effective if as late as 24-36h
Administration of N-acetylcysteine
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
Lactate levels in acute liver failure that will distinguish patients highly likely to require liver transplantation from those likely to survive without liver replacement
lactate levels >3.5mmol/L
T or F: Acute renal injury occurs in 75% of patients with severe acetaminophen injury but is always self-limited
True
Prognosis for acute acetaminophen overdose
Survivors rarely have ongoing liver injury or sequalae
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.
False.
Usually self-limited and will resolve despite continued drug use
Latency period of acute hepatocellular drug-induced liver injury secondary to INH
Up to 6 months
More frequent among alcoholics and those taking barbiturates, rifampin and pyrazinamide
Liver biopsy findings in INH hepatotoxicity
Morphology similar to viral hepatitis or bridging hepatic necrosis
T or F:
Liver injury is age-related
True
Increasing after age 35, highest frequency at >50 y/o, lowest under age 20
T or F:
In INH hepatotoxicity: fever, rash, eosinophilia and drug allergy manifestation are unusual.
True
INH produces toxic and idiosyncratic reaction
Most common antiepileptic drug implicated among candidates of liver transplant in children
Valproate
Metabolite of sodium valproate responsible for hepatic injury
4-pentenoic acid
Depleted compound in valproate therapy that ameliorates valproate hepatotoxicity by administration through IV
Carnitine
T or F:
Nitrofurantoin has a longer latency period due to its intermittent, recurrent use in cystitis among women.
True
T or F:
Glucocorticoid and other immunosuppresants may be necessary to resolve the autoimmune injury in Nitrofurantoin hepatotoxicity.
True
Adverse effect seen in nitrofurantoin hepatotoxicity presenting as chronic cough and dyspnea that resolve slowly with medication withdrawal.
Interstitial pulmonary fibrosis
T or F:
Hepatotoxicity in amoxicillin-clavulanate can manifest during withdrawal of drug or even after.
True
Presentation of amoxicillin-clavulanate hepatotoxicity
Nausea, anorexia, fatigue, jaundice with pruritus
Rash is uncommon
Amoxicillin-clavulanate causes cholestatic hepatotoxicity that can cause permanent injury to small bile ducts called
“vanishing bile duct syndrome”
Formerly diphenylhydantoin, mainstay treatment of seizure disorders associated with severe hepatitis-like liver injury leading to fulminant hepatic failure
Phenytoin
Presentation of phenytoin hepatotoxicity
Striking fever, lymphadenopathy, RASH (SJS or exfoliative dermatitis), leukocytosis, eosinophilia
Duration: within 2 months of therapy
Metabolite of phenytoin causing hepatic injury
Arene oxides
Metabolized by epoxide hydrolases
T or F:
In long-term phenytoin therapy, elevations of aminotransferase and alkaline phosphatase levels are usually asymptomatic
True
Hepatotoxicity with this antiarrhythmic drug presents with elevated aminotransferase levels with hepatomegaly
Amiodarone
Metabolite of Amiodarone
Desethylamiodarone
T or F: Elevations in aminotransferase levels in Amiodarone hepatotoxicity is dose-dependent
True
Condition seen on long-term recipients of Amiodarone indicating its effect on the liver
Phospholipidosis
T or F:
Liver injury in Amiodarone persist for months after the drug is stopped.
True
Reason: Due to its long half-life
Most important adverse effect associated with Erythromycin seen more in children
Cholestatic reaction
Presentation of erythromycin hepatotoxicity
Nausea, vomiting, fever, RUQ pain, jaundice, leukocytosis, mod elevated aminotransferases and alk phosphatase.
Duration: first 2 or 3 weeks of therapy
Prognosis of erythromycin hepatotoxicity
Symptoms subside with drug withdrawal.
No evidence of chronic liver disease on follow-up.
Effect of oral contraceptive combinations of estrogenic and progestational steroids on liver
Intrahepatic cholestasis
Presentation of oral contraceptive hepatotoxicity
Pruritus, jaundice
Duration: Weeks to months after intake
Liver biopsy in oral contraceptive hepatotoxicity
Cholestasis with bile plugs in dilated canaliculi and striking bilirubin staining of liver cells. Portal inflammation is ABSENT.
Prognosis in oral contraceptive hepatotoxicity
Reversible on withdrawal
Contraindication of oral contraceptives on these types of patients
With history of recurrent jaundice of pregnancy
T or F:
Malignant neoplasm of the liver are associated with oral contraceptives
False
Primarily benign, rarely malignant
Most common form of liver injury caused by complementary and alternative medications associated with anabolic steroids used by body builders
Profound cholestasis
With NO inflammation or necrosis
Duration: Weeks to months before resolution
Laboratories in anabolic steroid hepatotoxicity
Serum aminotransferase <100 IU/L
Mod elevated alk phos
Bilirubin >342 umol/L (20mg/dL)
Presentation of Co-trimoxazole (sulfamethoxazole) hepatotoxicity
Eosinophilia, rash, hypersensitivity reactions
Self-limited
Duration: Several weeks
T or F:
Statins cause a reversible elevations (>3x) of aminotransferase activity producing a mixed hepatocellular and cholestatic reaction
True
Recommendation of liver test monitoring in patients treated with statins
Monitoring NOT necessary
Should not be discontinued in asymptomatic isolated aminotransferase elevations
Effect of Total Parenteral Nutrition (TPN) on liver
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
Herbal remedies associated with toxic hepatitis
- Jin Bu Huan
- xiao-chai-hu-tang
- germander
- chaparral
- senna
- mistletoe
- skullcap
- gentian
- comfrey
- ma huang
- bee pollen
- valerian root
- pennyroyal oil
- kava
- herbal teas containing Camellia sinensis (green tea extract)
- herbal nutritional supplements
T or F: Megadoses of vitamin A can injure the liver
True
Alkaloid often in Chinese herbal preparations that can cause venoocclusive injury leading to sinusoidal hepatic vein obstruction
Pyrrolizidine alkaloids
Emerging and common type of liver injury in HIV-infected persons
HAART therapy hepatotoxicity
Zidovudine, Didanosine, stavudine
Ritonavir, Indinavir
Nevirapine, Efavirenz
Effect of HAART on liver
Hepatocellular, cholestatic and mixed
