+++
Drug-Induced
Liver Injury
++
Adverse drug reactions in children are uncommon. Nevertheless, drug-induced
hepatotoxicity, when it occurs, must be promptly recognized, and
the offending agent discontinued, although cessation does not always
result in rapid recovery. Delays in recognizing hepatic injury may
significantly contribute to morbidity, resulting in a need for liver
transplantation or in death.1-5
++
The role of the liver in the processing or biotransformation
of xenobiotics (foreign substances) is discussed in Chapter 418. Mechanisms of hepatoxicity vary, as they depend on the
drug, dosage, and patient factors such as age, gender, nutrition,
and genetic predisposition. In general, medicinal and environmental
agents known to cause hepatotoxicity have been characterized as
predictable (intrinsic) or unpredictable (idiosyncratic) hepatotoxins.
The patterns of liver injuries are clinically and histopathologically
diverse (Table 422-1).
++
++
Specific hepatotoxins that are commonly prescribed for the pediatric
population include analgesics (acetaminophen), anticonvulsants, and
antibiotics. Acetaminophen is a predictable or intrinsic hepatotoxicant
and acetaminophen overdose has been recognized as one of the most
common causes of liver failure in the United Kingdom and the United
States. Specific therapy for acetaminophen overdose is available. N-Acetylcysteine,
when provided in the first hours or days after overdose, replenishes
glutathione stores and enables the liver to metabolize acetaminophen
without generating toxic metabolites (see Chapter 120).
++
Examples of idiosyncratic hepatotoxic reactions are those associated
with phenytoin, an anticonvulsant, and sulfasalazine, used in the treatment
of inflammatory bowel disease. These drugs may cause an illness
that resembles a hypersensitivity reaction, with lymphadenopathy, fever,
sore throat, and peripheral as well as tissue eosinophilia. Other
idiosyncratic reactions may depend on drug metabolism and are not necessarily
associated with this clinical picture.
++
Commonly prescribed antibiotics such as erythromycin have been
associated with hepatic injury, although antibiotic-associated hepatotoxicity
appears to be more common in adults. Nevertheless, fulminant hepatic
failure has been reported in a child receiving trimethoprim-sulfamethoxazole.
Minocycline, frequently used in the treatment of adolescent acne,
has been associated with the development of autoimmune hepatitis.
The loss of intrahepatic bile ducts or “vanishing bile
duct syndrome” has been associated with synthetic penicillins
and the anticonvulsant carbamazepine. Pemoline, a stimulant used
in the treatment of attention deficit disorder, has been reported
to cause hepatic necrosis. Oral contraceptives have been associated
with hepatic vein thrombosis (Budd-Chiari syndrome) and liver tumors.
Recreational drugs of abuse are increasingly reported as causes
of hepatic injury in adolescents.
++
It is mandatory that a history of prescribed, over-the-counter,
or illicit drug usage be sought in any child who presents with evidence of
hepatic dysfunction. The treatment of drug-induced liver injury depends
largely on timely recognition, which may be evident by increased
serum aminotransferase values, conjugated hyperbilirubinemia, coagulopathy,
jaundice, or more systemic side effects such as fever, lymphadenopathy,
and rash. Once a drug-induced liver injury is identified, therapy
is mainly supportive, but withdrawal of the offending agent is critical
to minimize hepatotoxicity. With the exception of acetaminophen overdose,
no specific therapies exist.1-5
+++
Toxin-Induced
Liver Injury
++
There are several types of environmental hepatotoxins. These
include herbal preparations used as nutritional or health aids,
contaminated food (fungicide-treated wheat), and household items such
as pesticides or cleaning products. Occasionally, liver toxicity
results when these toxins are ingested either as a form of drug
abuse (inhalants) or as a suicide attempt.
++
As discussed for pharmaceutical agents, the mechanisms of hepatotoxicity
of environmental toxins vary. Ingestion of poisonous mushrooms such
as Amanita phalloides, results in fatty liver (steatosis)
and hepatocyte necrosis that is often severe, rapidly progressive,
and fatal.6 Venoocclusive liver disease has been
reported with certain herbal teas, such as comfrey, taken as a nutritional
supplement.7
++
Treatment of liver toxicity secondary to environmental agents
is comparable to that for drug-induced liver injury. Avoidance or withdrawal
of the offending agent is crucial, and this usually depends on an
accurate historical account. Therapy is usually supportive, but there
are a few exceptions. Toxicity from iron overdose is treated with
chelation therapy.