Drug-induced liver disease encompasses a broad spectrum of liver disorders. Since the liver is both
anatomically and physiologically complex, drug hepatotoxicity can result in diverse patterns of liver
disease. In general, drug-induced liver disease is an important and relatively common form of liver
disease, and it is a leading cause of acute liver failure. Drug-induced liver disease is less frequent
in children than in adults. Although children may somehow be protected metabolically from drug
hepatotoxicity, in fact most children are not given many medications. Moreover, since the features
of drug-induced liver disease may differ in children compared to adults, it can be difficult to make the
diagnosis of drug-induced liver disease in children. Nevertheless drug-induced hepatotoxicity is
sufficiently common in children that it should be considered in every instance of childhood liver disease
of uncertain etiology. The key to identifying drug hepatotoxicity in adults and children is consistently
to include it in the differential diagnosis of any clinical presentation of liver disease. It is
essential to review methodically all the medications the patient is taking or has taken recently
including over-the-counter and herbal (complementary) medications and recreational drugs. Hepatic drug
metabolism plays an important role in the mechanism of hepatotoxicity of many drugs, including most of
the those which cause hepatotoxicity in children. Typically an imbalance exists between generation of
toxic metabolite(s) and detoxification processes.
The purpose of this brief review is to focus on a mechanistic and practical approach to the problem of
drug hepatotoxicity, in the context of clinical liver disease. For extensive and detailed discussions of
individual drugs and the types of hepatotoxicity they may cause, recent textbooks should be consulted .1-3
Hepatic drug metabolism
The liver plays an important role in the metabolism of drugs. How the liver acts upon drugs can have
important implications for both drug-induced hepatic damage and liver cancers. Hepatic drug metabolism
is categorized as activation (Phase I processes) and detoxification (Phase II processes). For most hepatotoxicity, the balance between
activation and detoxification is critical. Numerous factors influence this balance including age or
developmental stage, fasting or undernutrition, other drugs and chemical inducers, immunomodulators
resulting from viral infection or inflammation. Chemical inducers may have different effects on Phase I
and Phase II processes. The rate of absorption of the toxic drug, how it is distributed in the body, and
how long it and its metabolites linger in the body, and whether it is toxic to other organ systems may
all influence the nature and extent of drug hepatotoxicity. Whether the drug is taken as a large single
dose (acute ingestion) or many smaller doses repeatedly (chronic ingestion) may also influence or modify
its metabolism in the liver. Genetic features, namely, polymorphisms of cytochromes P450 and various
Phase II enzymes also affect this critical balance. Hepatic drug metabolism also shows developmental
variability. Different drug-metabolizing enzymes may be expressed differently in infants compared to
adults, and in general clearance of many drugs is more rapid in pre-pubertal children than in adults.
Phase I processes generally involve the cytochromes P450.4 These processes include hydroxylation,
dealkylation, and dehalogenation. Cytochromes P450 are diverse hemoproteins and, compared to most
enzymes, they have less specificity for substrate. Thus the same cytochrome P450 may act on numerous
drugs. Many cytochromes P450 are inducible: they become more abundant in response to treatment with
various chemicals. The cellular mechanisms by which induction occurs are different for different
cytochromes P450. Cytochrome P450 are grouped within families and subfamilies depending on the degree of
similarity in gene sequence of the apoprotein. The cytochrome P450 3A (CYP3A) subfamily includes
cytochromes induced by pregnenolone and by glucocorticoids, and CYP3A4 is the most abundant cytochrome
P450 in human liver. Other important human hepatic P450s include CYP1A2 (induced by polycyclic aromatic
hydrocarbons anvironmental contaminants), CYP2B6 (induced by phenobarbital), CYP2D6 (polymorphic),
CYP2C19, CYP2E1 (induced by ethanol), and CYP4A subfamily (induced by drugs which cause peroxisome
Phase I processes typically make the drug into a more polar chemical. Sometimes a Phase I process
converts a drug to its active form (for example, prednisone is converted to prednisolone), but the usual
effect is to expedite excretion by adding a chemical moiety ready for a conjugation reaction via a Phase
II process. Phase II processes are performed by numerous different classes of enzymes, including
glutathione S-transferases, glucuronosyl transferases, epoxide hydrolase,
sulfotransferases, and N-acetyltransferases. Typically these reactions
complete the transformation of a hydrophobic chemical to a hydrophilic one which can be excreted easily
in urine or bile. A few Phase II enzymes, such as some glucuronosyl transferases, can be induced. Some
are polymorphic, such as N-acetyltransferase (either rapid or slow
acetylators). In some metabolic diseases the activity of Phase II enzymes may be abnormal.5, 6
The product of a Phase I reaction may be an unstable or reactive metabolite, and Phase II reactions
may inactivate such chemicals before cell damage occurs. Whether reactive metabolites actually
damage a liver cell also depends on how much reactive metabolite binds to cellular components, whether
these components are critical to cell integrity, and whether repair is possible. A reactive metabolite
binding to vital intracellular proteins or membranes may lead to necrosis. Reactive metabolites may
initiate apoptosis by directly damaging mitochondria or by initiating immune mechanisms. Binding to DNA
may lead to mutagenesis or carcinogenesis. Besides lipid peroxidation, membranes can be altered by
alkylation (addition of an aliphatic radical such as methyl or ethyl groups), arylation (addition of an
aromatic group such as a phenyl group) or acylation (adding a radical derived from a carboxy
Reactive metabolites are electrochemically unstable. Electrophilic intermediates (or electrophiles)
are formed when electrons are lost from the original chemical; they carry a net positive charge.
Examples include hydroxylamines, quinoneimines, and arene oxides. Nucleophiles are negatively-charged
species, formed through activation of oxygen, such as halocarbon and nitroso radicals. They tend to bind
to intracellular lipids, leading to lipid peroxidation. Glutathione reacts with electrophiles via
conjugation reactions catalyzed by glutathione S-transferases. It also
reacts with hydrogen peroxide and activated oxygen species via glutathione peroxidase. As a general
rule, when toxic metabolites are the important cause of cell damage, high tissue concentrations of the
parent drug are not found. Metabolite(s) covalently bound to cellular constituents may be
The anatomical complexity of the liver accounts in part for the diversity of patterns of
hepatotoxicity. Drug-associated injury may involve hepatocytes or non-parenchymal cells in the liver
besides hepatocytes. Cytotoxic damage to bile duct cells, hepatic stellate cells or endothelial cells
accounts for some of the clinical diversity of drug-induced liver disease. Within the hepatocyte, a drug
or its reactive metabolites may interfere with biliary excretion or damage proteins within the biliary
excretion apparatus, thus leading to cholestasis.7 The cellular specialization of hepatocytes is also
important. For example, most drug metabolism occurs in zone 3 of the Rappaport acinus: necrosis of
hepatocytes due to generation of a toxic metabolite may be most prominent in a zonal pattern.
Classification of drug hepatotoxicity
Drug hepatotoxicity can be acute or chronic. Acute hepatotoxic injuries develop over a relatively short
time and show no histopathological features of chronicity. Subacute hepatotoxicity includes damage
developing over weeks to months, with fibrosis and possibly cellular regeneration histologically.
Chronic hepatotoxic lesions include those with fibrosis or cirrhosis, predominantly vascular lesions, and
neoplasia. Some drugs can cause clinical liver disease indistinguishable from autoimmune hepatitis.
These drugs include oxyphenisatin (generally no longer in use), a-methyldopa (rarely used), isoniazid,
nitrofurantoin, and minocycline.
Our knowledge of mechanisms of hepatotoxicity is evolving. For a long time, hepatotoxicity has been
categorized on the basis of predictability. Intrinsic hepatotoxins are differentiated from idiosyncratic
heptatotoxins. The intrinsic hepatotoxin causes predictable hepatic damage in almost any individual.
The toxicity is dose-related in that higher doses cause worse damage, and animal models can be developed
which exhibit the same type of hepatotoxicity. This classification has limited clinical
applicability and delineates mechanisms of hepatotoxicity only superficially. In practice, most
instances of hepatotoxicity, mainly those associated with medications, are unpredictable, infrequent,
and thus apparently sporadic. If such a reaction is accompanied by systemic features including fever,
rash, eosinophilia, atypical lymphocytosis and possibly other major organ involvement, then classically
it has been regarded as an idiosyncratic hypersensitivity reaction, where "hypersensitivity" with its
connotation of allergy is left undefined.
An alternate view is that idiosyncratic hepatotoxicity has a biochemical basis and is due to
defective hepatic drug metabolism (often termed "metabolic idiosyncrasy"). Individuals who have
specific abnormalities in drug metabolism at risk for adverse drug reactions. If this abnormal
metabolism is expressed in liver cells, then these rare individuals will develop hepatotoxicity—if they
are exposed to the appropriate drug. In most instances a metabolite, not the drug itself, is responsible
for hepatotoxicity. Typically, the problem is a defect in detoxification of the reactive metabolite
because the detoxification system is itself focally defective and cannot meet the normal demands of
metabolite production. Sometimes these individuals show systemic features interpreted as
hypersensitivity: it is likely that interaction of the reactive metabolite with cellular components,
such as the cell membrane, elicits an immune response. In such cases hypersensitivity is itself the
consequence of metabolic idiosyncrasy, not a separate mechanism of drug hepatotoxicity. There may be
strictly allergic drug hepatotoxicity, but investigations of the mechanism of drug-induced hepatotoxicity
suggest that metabolic idiosyncrasy is much more common than previously supposed. It seems likely to
account for hepatotoxicity with drugs which show two main patterns of toxicity: mild reversible toxicity
in a comparatively large segment of patients and severe hepatotoxicity in a few individuals. Toxic
metabolites are probably involved in both patterns of toxicity. Severe reactions occur in rare persons
with abnormal generation of toxic metabolites or detoxification, irrespective of the appearance of drug
The major implication of the metabolic idiosyncrasy thesis is that most drug hepatotoxicity is
predictable if one understands the pathways of hepatic biotransformation and detoxification for each
drug. Given the plethora of drugs and hepatic biotransformation pathways, it is no wonder that most
clinically-important drug hepatotoxicity appears sporadic and fortuitous. However, there is enough
experimental data available now to warrant rethinking the intrinsic/idiosyncratic-allergic classification
of drug hepatotoxicity. These definable metabolic defects in hepatic drug metabolism are particularly
common in the types of drug hepatotoxicity which occur in children.
Recent research has focused on the role of the immune system in drug hepatotoxicity.8 With some
drugs the connection between immune-mediated mechanisms and hepatic damage may be very direct:
autoantibodies are elaborated against hepatic cytochromes P450. The P450 involves varies with different
drugs: CYP2C9 for tienilic acid, CYP1A2 for dihydralazine, CYP2E1 for halothane. Reactive metabolites
may alter other components of hepatocytes to form neo-antigens. Hepatocyte damage mediated through
immune mechanisms may involve apoptosis or necrosis. Bile acid associated hepatocyte injury involves Fas
activation leading to apoptosis. When toxic metabolites or reactive oxygen species or cytokines
stimulate Kupffer cells specific mechanisms of cell damage are set into motion involving tumor necrosis
factor-a (TNF-a) or nitric oxide (NO) produced by Kupffer cells. NO elaborated by Kupffer cells and
hepatocytes appears to play a role in acetaminophen hepatotoxicity. Other cytokines, including CXC
chemokines regulating leukocyte action, may modulate these effects. The vigor of the immune response in
general, an individual polygenic trait, may also determine the importance of immune mechanisms in drug
The following classification of types of drug hepatotoxicity is designed to avoid the drawbacks of
other systems currently in use (Table 1). Drugs are categorized as being intrinsic hepatotoxins or
contingent hepatotoxins. The intrinsic hepatotoxin is a true poison: it is causes predictable hepatic
damage in almost any individual in a dose-dependent fashion. The contingent hepatotoxin causes liver
damage only in certain individuals either because of pre-existing genetic or environmental factors.
Instead of being a universal poison, it is a "personal" poison. An example of a genetic factor
potentiating a contingent hepatotoxin is carbamazepine hepatotoxicity which occurs in an individual who
pharmacogenetically has inadequate Phase II processes to detoxify the reactive metabolite formed. An
example of an environmental factor leading to a drug being a contingent hepatotoxin is moderate or
appropriate doses of acetaminophen causing liver damage in an individual who uses alcohol chronically and
therefore has induced hepatic CYP2E1. To specify the role of immune mechanisms in drug hepatotoxicity,
drugs can be further categorized as "eliciting and immuno-allergic response." This may be a special type
of contingent hepatotoxicity since genetic aspects of immune responsiveness may play an important role in
whether an individual is likely to have an immune component with drug hepatotoxicity. Examples of
possible immuno-allergic responses include (1) fever, rash, atypical lymphocytosis, eosinophilia, and
multi-systemic involvement—the so-called systemic "hypersensitivity syndrome," (2) hepatic
granulomatosis, and (3) clinical and histological features of "chronic active hepatitis," that is, a
process resembling autoimmune hepatitis.
Drug hepatotoxicity produces a broad spectrum of clinical liver disease, summarized in Table 2. Most
drug-associated liver disease involves cytotoxicity: direct severe damage to hepatocytes. Serum
aminotransferases are elevated, and liver failure may occur. The exact mechanism of cell death is highly
variable and probably differs with each drug or toxins. Necrosis is the predominant pattern, but
apoptosis may play a role. Hepatocyte damage may be zonal, reflecting metabolic specialization in
various parts of the hepatic lobule. Specifically, hepatocytes in have the highest concentration of
drug-metabolizing enzymes and thus the greatest potential for producing toxic intermediates. Zonal
hepatocellular necrosis mainly in zone 3 of the Rappaport acinus suggests that metabolic activation of
toxic metabolites has an important role in the pathogenesis of the toxicity; however, spotty necrosis
scattered throughout the lobule does not exclude a mechanism involving toxic metabolites. Whenever
hepatocellular damage is sufficiently severe, some degree of cholestasis will develop. Some
drug-associated liver damage is mainly cholestatic. Clinically findings include jaundice, pruritus,
markedly elevated serum alkaline phosphatase and mild elevations of serum aminotransferases. This type
of drug-associated liver disease is often due to direct damage to the bile secretory apparatus by toxic
metabolites.7 In particular, the bile salt excretory pump (BSEP, abnormal in Progressive Familial
Intrahepatic Cholestasis type 2) appears to be an important target in forms of drug hepatotoxicity with
prominent cholestatic features.
Principles of clinical management
In the individual patient any drug suspected of causing hepatotoxicity should be stopped. Most
drug-induced liver disease resolves spontaneously when the hepatotoxic drug is discontinued. Severe
chronic changes may not resolve. Certain hepatotoxins require timely treatment with specific antidotes,
such as N-acetylcysteine in acetaminophen hepatotoxicity. Steroid treatment
has appeared beneficial when severe acute hepatitis dominates a multisystemic hypersensitivity reaction
as with phenytoin, carbamazepine, or phenobarbital,9, 10 but large prospective studies are not
available. In general, the use of steroids in drug-induced liver disease remains controversial. When
drug hepatotoxicity leads to acute liver failure, the usual supportive measures are required and liver
transplantation may be life-saving.
Making the diagnosis of drug-associated liver disease is critically important and not necessarily
easy. A high index of clinical suspicion is essential. A meticulous history of the illness and a
detailed history of all drugs taken, including over-the-counter preparations, with specific questions
relating to potential exposure to environmental or industrial toxins are absolutely necessary. It is
important to determine that the appropriate dosage was actually given. This is especially important with
children and may involve having the parent or caregiver bring in the (possibly empty) bottles of the
drug(s) used. Chemical analysis of herbal remedies may be required.
Liver biopsy, including electron microscopic examination if possible, is often helpful and can be
definitive. Algorithms for determining the likelihood of an adverse drug reaction 11-13 may be
helpful. Clinical rechallenge is rarely possible because it poses too much risk to the patient. In vitro rechallenge of the patient's lymphocytes with generated toxic metabolites
usually provides important corroborative evidence,14 but this remains a research investigation which
is not generally available. Other rechallenge assays based on purely immunological mechanisms have
proven difficult to interpret. Determination of a pharmacogenetic defect in drug metabolism or drug
detoxification may have important implications for other primary relatives.
Resources for documenting drug hepatotoxicity include Meyler's Side Effects of
Drugs, which is a published book series, a compendium plus regular updates. Databases of the
reported experience of adverse reactions with drugs, including drug hepatotoxicity, are also available on
the Internet (Table 3). Most algorithms to test likelihood of an adverse drug reaction attach importance
to whether the adverse event has ever been reported before. It is sometimes useful to approach the
pharmaceutical company which has developed the drug or the FDA to find out about reports not in the
public domain. These resources however will provide little direct assistance with the greatest challenge
in drug hepatotoxicity, which is to identify the first occurrence of significant drug hepatotoxicity,
except where the experience with chemically similar compounds may provide some guidance or clues to the
mechanism of hepatotoxicity.
Table 2. Examples of patterns of drug hepatotoxicity
|Asymptomatic AST, ALT ||pemoline|
|Acute hepatitis ||isoniazid, halothane|
|Zonal hepatocellular necrosis ||acetaminophen|
|Bland cholestasis ||cyclosporine, estrogens|
|Steatohepatitis (= NASH) ||perhexiline, methotrexate|
|Microvesicular steatosis ||valproic acid, fialuridine|
|Liver cell adenoma ||estrogens|
|Malignant tumours ||estrogens, anabolic steroids|
|Peliosis ||estrogens, androgens|
|Hepatic vein thrombosis ||estrogens (N.B. oral contraceptive pill)|
|Veno-occlusive disease ||thioguanine, busulfan|
|Non-cirrhotic portal hypertension ||azathioprine|
Table 3. Databases relating to drug hepatotoxicity available on the
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