Background


Drugs are an
important cause of liver injury. More than 900 drugs, toxins, and herbs
have been reported to cause liver injury, and drugs account for 20-40%
of all instances of fulminant hepatic failure. Approximately 75% of the
idiosyncratic drug reactions result in liver transplantation
or death. Drug-induced hepatic injury is the most common reason cited
for withdrawal of an approved drug. Physicians must be vigilant in
identifying drug-related liver injury because early detection can
decrease the severity of hepatotoxicity if the drug is discontinued. The
manifestations of drug-induced hepatotoxicity are highly variable,
ranging from asymptomatic elevation of liver enzymes to fulminant
hepatic failure. Knowledge of the commonly implicated agents and a high
index of suspicion are essential in diagnosis.
For excellent patient education resources, visit eMedicine's Poisoning Center , Public Health Center , and Substance Abuse Center . Also, see eMedicine's patient education articles Acetaminophen (Tylenol) Poisoning , FDA Overview , Pain Medications , and Alcoholism .
Mortality/morbidity


In the United States, approximately 2000 cases of acute liver failure
occur annually and drugs account for over 50% of them (39% are due to
acetaminophen, 13% are idiosyncratic reactions due to other
medications). Drugs account for 2-5% of cases of patients hospitalized
with jaundice and approximately 10% of all cases of acute hepatitis.
Internationally, data on the incidence of adverse hepatic drug reactions in the general population remain unknown.
Drugs withdrawn from the market secondary to hepatotoxicity


In
the last few years, the US Food and Drug Administration (FDA) has
withdrawn 2 drugs from the market for causing severe liver injury:
bromfenac and troglitazone. Bromfenac (Duract), a nonsteroidal
anti-inflammatory drug (NSAID), was introduced in 1997 as a short-term
analgesic for orthopedic patients. Although approved for a dosing period
of less than 10 days, patients used it for longer periods. This
resulted in more than 50 cases of severe hepatic injury, and the drug
had to be withdrawn in 1998. Troglitazone (Rezulin) is a
thiazolidinedione and was approved in 1997 as an antidiabetic agent.
Over 3 years, more than 90 cases of hepatotoxicity were reported, which
resulted in withdrawal of this drug.
Kava kava, an herb used for anxiety, was reported as being hepatotoxic and was withdrawn from the German market.[1] The
FDA has also issued a warning in this country. This demonstrates the
importance of postmarketing surveillance to identify reactions that are
not reported or are underreported in drug trials.
Pemoline
(Cylert), used for attention deficit disorder and narcolepsy is no
longer available in the United States. The Food and Drug Administration
(FDA) concluded that the overall risk of liver toxicity from pemoline
outweighs the benefits. In May 2005, Abbott chose to stop sales and
marketing of their brand of pemoline (Cylert) in the U.S. In October
2005, all companies that produced generic versions of pemoline also
agreed to stop sales and marketing of pemoline.
Other drugs that
have significant limitations of use because of their hepatotoxic effects
are felbamate (Felbatol), an antiepileptic used for complex partial
seizures; zileuton (Zyflo), indicated for asthma; tolcapone (Tasmar),
used for Parkinson disease; trovafloxacin (Trovan), an antibiotic;
benoxaprofen, an NSAID; and tienilic acid, a diuretic.
Recent warnings issued by the FDA


In
April 2010, the US Food and Drug Administration (FDA) had added a boxed
warning, the strongest warning issued by the FDA, to the prescribing
information for propylthiouracil. The boxed warning emphasizes the risk
for severe liver injury and acute liver failure, some of which have been
fatal. The boxed warning also states that propylthiouracil should be
reserved for use in those who cannot tolerate other treatments such as
methimazole, radioactive iodine, or surgery.
The decision to
include a boxed warning was based on the FDA's review of postmarketing
safety reports and meetings held with the American Thyroid Association,
the National Institute of Child Health and Human Development, and the
pediatric endocrine clinical community.
In June 2009, the FDA
issued a report that identified 32 cases (22 adult and 10 pediatric) of
serious liver injury associated with propylthiouracil (PTU). Of the
adults, 12 deaths and 5 liver transplants occurred, and among the
pediatric patients, 1 death and 6 liver transplants occurred. PTU is
indicated for hyperthyroidism due to Graves disease.
These reports
suggest an increased risk for liver toxicity with PTU compared with
methimazole. Serious liver injury has been identified with methimazole
in 5 cases (3 resulting in death). PTU is considered as a second-line
drug therapy, except in patients who are allergic or intolerant to
methimazole, or for women who are in the first trimester of pregnancy.
Rare cases of embryopathy, including aplasia cutis, have been reported
with methimazole during pregnancy.
The FDA recommends the following criteria be considered for prescribing PTU. For more information, see the FDA Safety Alert .


  • Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole.


  • Closely
    monitor PTU therapy for signs and symptoms of liver injury, especially
    during the first 6 months after initiation of therapy.


  • For
    suspected liver injury, promptly discontinue PTU therapy and evaluate
    for evidence of liver injury and provide supportive care.


  • PTU
    should not be used in pediatric patients unless the patient is allergic
    to or intolerant of methimazole, and no other treatment options are
    available.


  • Counsel patients to
    promptly contact their health care provider for the following signs or
    symptoms: fatigue, weakness, vague abdominal pain, loss of appetite,
    itching, easy bruising, or yellowing of the eyes or skin.


Severe
hepatic injury, including cases of hepatic failure, has been reported
in patients taking interferon beta-1a (Avonex) used in treatment of
multiple sclerosis. Asymptomatic elevation of hepatic transaminases have
also been reported and, in some patients, recurred upon rechallenge. In
some cases, these events occurred in the presence of other drugs that
have been associated with hepatic injury. The potential risk of Avonex
used in combination with known hepatotoxic drugs or other products (eg,
alcohol) should be considered prior to Avonex administration or when
adding new agents to the regimen of patients already on Avonex.
In
January 2006, the US Food and Drug Administration (FDA) issued a
warning after 3 cases of serious liver toxicity were reported with
taking telithromycin. In June 2006, the prescribing information for
telithromycin (Ketek) was changed to include a warning describing the
drug's association with rare cases of serious liver injury and liver
failure. Four of these events resulted in deaths and one resulted in
liver transplant. The added warning follows evaluation by the FDA on
postmarketing surveillance reports. If clinical hepatitis or liver
enzyme elevations combined with other systemic symptoms occur,
telithromycin should be permanently discontinued. Telithromycin is an
antibiotic of the ketolide class, approved by the FDA in April 2004 for
the treatment of respiratory infections in adults. It is marketed and is
widely used in several countries including Japan and countries in
Europe.
In February 2007, the FDA took further action and removed
2 of the 3 indications: acute bacterial sinusitis and acute bacterial
exacerbations of chronic bronchitis. Following comprehensive scientific
analysis, the FDA determined that the balance of benefits and risks no
longer supports the approval of the drug for these indications.
Telithromycin is now indicated for treatment of mild-to-moderate
community-acquired pneumonia.
In October 2005, the manufactures
of duloxetine (an anti-depressant) reported postmarketing cases of
hepatitis and cholestatic jaundice. The new package insert now states,
"Cymbalta should not be administered to patients with substantial
alcohol use or any hepatic insufficiency."
Risk factors for drug-induced liver injury




  • Race:
    Some drugs appear to have different toxicities based on race. For
    example, blacks and Hispanics may be more susceptible to isoniazid (INH)
    toxicity. The rate of metabolism is under the control of P-450 enzymes
    and can vary from individual to individual.


  • Age:
    Apart from accidental exposure, hepatic drug reactions are rare in
    children. Elderly persons are at increased risk of hepatic injury
    because of decreased clearance, drug-to-drug interactions, reduced
    hepatic blood flow, variation in drug binding, and lower hepatic volume.
    In addition, poor diet, infections, and multiple hospitalizations are
    important reasons for drug-induced hepatotoxicity.


  • Sex: Although the reasons are unknown, hepatic drug reactions are more common in females.


  • Alcohol
    ingestion: Alcoholic persons are susceptible to drug toxicity because
    alcohol induces liver injury and cirrhotic changes that alter drug
    metabolism. Alcohol causes depletion of glutathione (hepatoprotective)
    stores that make the person more susceptible to toxicity by drugs.


  • Liver
    disease: In general, patients with chronic liver disease are not
    uniformly at increased risk of hepatic injury. Although the total
    cytochrome P-450 is reduced, some may be affected more than others. The
    modification of doses in persons with liver disease should be based on
    the knowledge of the specific enzyme involved in the metabolism.
    Patients with HIV infection who are co-infected with hepatitis B or C
    virus are at increased risk for hepatotoxic effects when treated with
    antiretroviral therapy. Similarly, patients with cirrhosis are at
    increased risk of decompensation by toxic drugs.


  • Genetic
    factors: A unique gene encodes each P-450 protein. Genetic differences
    in the P-450 enzymes can result in abnormal reactions to drugs,
    including idiosyncratic reactions. Debrisoquine is an antiarrhythmic
    drug that undergoes poor metabolism because of abnormal expression of
    P-450-II-D6. This can be identified by polymerase chain reaction
    amplification of mutant genes. This has led to the possibility of future
    detection of persons who can have abnormal reactions to a drug.


  • Other
    comorbidities: Persons with AIDS, persons who are malnourished, and
    persons who are fasting may be susceptible to drug reactions because of
    low glutathione stores.


  • Drug formulation: Long-acting drugs may cause more injury than shorter-acting drugs.


  • Host factors that may enhance susceptibility to drugs, possibly inducing liver disease


    • Female - Halothane, nitrofurantoin, sulindac

    • Male - Amoxicillin-clavulanic acid (Augmentin)

    • Old age - Acetaminophen, halothane, INH, amoxicillin-clavulanic acid

    • Young age - Salicylates, valproic acid

    • Fasting or malnutrition - Acetaminophen

    • Large body mass index/obesity - Halothane

    • Diabetes mellitus - Methotrexate, niacin

    • Renal failure - Tetracycline, allopurinol

    • AIDS - Dapsone, trimethoprim-sulfamethoxazole

    • Hepatitis C - Ibuprofen, ritonavir, flutamide

    • Preexisting liver disease - Niacin, tetracycline, methotrexate


    </li>


Pathophysiology and mechanisms of drug-induced liver injury




  • Pathophysiologic
    mechanisms: The pathophysiologic mechanisms of hepatotoxicity are still
    being explored and include both hepatocellular and extracellular
    mechanisms. The following are some of the mechanisms that have been
    described:


    • Disruption of the hepatocyte: Covalent binding of the
      drug to intracellular proteins can cause a decrease in ATP levels,
      leading to actin disruption. Disassembly of actin fibrils at the surface
      of the hepatocyte causes blebs and rupture of the membrane.

    • Disruption
      of the transport proteins: Drugs that affect transport proteins at the
      canalicular membrane can interrupt bile flow. Loss of villous processes
      and interruption of transport pumps such as multidrug
      resistance–associated protein 3 prevent the excretion of bilirubin,
      causing cholestasis.

    • Cytolytic T-cell activation: Covalent
      binding of a drug to the P-450 enzyme acts as an immunogen, activating T
      cells and cytokines and stimulating a multifaceted immune response.

    • Apoptosis
      of hepatocytes: Activation of the apoptotic pathways by the tumor
      necrosis factor-alpha receptor of Fas may trigger the cascade of
      intercellular caspases, which results in programmed cell death.

    • Mitochondrial
      disruption: Certain drugs inhibit mitochondrial function by a dual
      effect on both beta-oxidation energy production by inhibiting the
      synthesis of nicotinamide adenine dinucleotide and flavin adenine
      dinucleotide, resulting in decreased ATP production.

    • Bile duct injury: Toxic metabolites excreted in bile may cause injury to the bile duct epithelium.


    </li>


  • Drug
    toxicity mechanisms: The classic division of drug reactions is into at
    least 2 major groups, (1) drugs that directly affect the liver and (2)
    drugs that mediate an immune response.


    • Intrinsic or predictable
      drug reactions: Drugs that fall into this category cause reproducible
      injuries in animals, and the injury is dose related. The injury can be
      due to the drug itself or to a metabolite. Acetaminophen is a classic
      example of a known intrinsic or predictable hepatotoxin at
      supertherapeutic doses. Another classic example is carbon tetrachloride.

    • Idiosyncratic drug reactions: Idiosyncratic drug reactions can
      be subdivided into those that are classified as hypersensitivity or
      immunoallergic and those that are metabolic-idiosyncratic.


      • Hypersensitivity:
        Phenytoin is a classic, if not common, cause of hypersensitivity
        reactions. The response is characterized by fever, rash, and
        eosinophilia and is an immune-related response with a typical short
        latency period of 1-4 weeks.

      • Metabolic-idiosyncratic: This type
        of reaction occurs through an indirect metabolite of the offending
        drug. Unlike intrinsic hepatotoxins, the response rate is variable and
        can occur within a week or up to one year later. It occurs in a minority
        of patients taking the drug, and no clinical manifestations of
        hypersensitivity are noted. INH toxicity is considered to fall into this
        class. Not all drugs fall neatly into one of these categories, and
        overlapping mechanisms may occur with some drugs (eg, halothane).


      </li>


    </li>