1118 THE NEW ENGLAND JOURNAL OF MEDICINE
26, 1995
REVIEW ARTICLES
MEDICAL PROGRESS
DRUG-INDUCED HEPATOTOXICITY
WILLIAM M. LEE, M.D.
D RUG-induced liver injury is a potential complica-
tion of nearly every medication that is prescribed,
because the liver is central to the metabolic disposition
of virtually all drugs and foreign substances.1-3 Al-
though drugs are usually metabolized without injury to
the liver, many fatal and near-fatal drug reactions oc-
cur each year. A few compounds produce metabolites
that cause liver injury in a uniform, dose-dependent
fashion.4-6 Most agents form a toxic byproduct only in
rare persons. Injury to hepatocytes results either di-
rectly from the disruption of intracellular function or
membrane integrity or indirectly from immune-mediat-
ed membrane damage. Factors promoting the accumu-
lation of hepatocyte toxins include genetic alterations in
enzymes that allow the formation of the harmful me-
tabolite, competition by other drugs, and depletion of
the substrates required to detoxify the metabolite.
In this article I provide a theoretical background for
understanding drug-induced liver injury; outline the
most common types of injury; address hepatotoxicity
due to combination agents, new formulations, and alter-
native treatment regimens (vitamins and herbal reme-
dies); and discuss diagnosis, treatment, and prevention.
BACKGROUND
Most drugs and toxins enter the body through the
gastrointestinal tract, with a minority absorbed directly
through the lungs or skin or by a parenteral route. Each
foreign compound is eliminated unchanged or metabo-
lized by enzymes, undergoes a spontaneous chemical
transformation, or is simply not eliminated. Most com-
pounds are lipophilic, entering the body through the
gastrointestinal tract and hepatocyte membrane barri-
ers. Biotransformation is the process by which thera-
peutic agents are rendered more hydrophilic so that they
can be filtered by the glomerulus or excreted in bile.
Biotransformation from a nonpolar to a polar compound
takes place in several steps, grouped as phase 1 and
phase 2 reactions.
Phase 1 Reactions
In the phase 1 reaction, oxidation or demethylation
occurs, mediated by cytochrome P450, a gene super-
family (CYP) that has nearly 300 members. A variety
of oxidative phase 1 reactions are performed by the en-
From the Liver Unit, Department of Internal Medicine, University of Texas
Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-8887,
where reprint requests should be addressed to Dr. Lee.
Supported by the Houghton Foundation and the estate of Alison B. Harwood.
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Oct.
zymes that make up the P450 system.7-12 Found primar-
ily in the liver but also in the gastrointestinal tract,
kidneys, brain, and other tissues, P450 enzymes are
composed of a unique apoprotein and a heme prosthet-
ic group, which binds oxygen after electron-transfer
reactions from NADPH, resulting in aliphatic and aro-
matic hydroxylation; O -, N-, or S -dealkylation; or de-
halogenation. A typical reaction of this type generates
a hydroxyl group, which can then participate in the
phase 2 reactions. Each group of genes with 40 per-
cent amino acid homology composes a family whose
gene products (isozymes) may function in a similar
fashion. For example, CYP3 is a family that contains an
A subfamily and several genes, numbered 1, 2, and so
forth. The primary enzyme for the metabolism of
erythromycin in humans is P450 3A4.
Phase 2 Reactions
After a phase 1 reaction, most compounds are still
not very water-soluble and require further metabolism.
In a typical phase 2 reaction, a large, water-soluble po-
lar group is attached to a hydroxyl oxygen by glucuron-
idation or sulfation, forming ether or ester linkages.
These are the sole steps required for the hepatic metab-
olism of some compounds, but for most, the phase 2 re-
action is preceded or followed by phase 1 oxidation.
Compounds requiring glucuronidation include aceta-
minophen, morphine, and furosemide, as well as biliru-
bin. Sulfation is as important as glucuronidation, par-
ticularly for the metabolism of steroid compounds and
bile acids. There are several species of sulfotransferases
with overlapping specificities, each employing 3-phos-
phoadenosine-5-phosphosulfate synthesized from ATP
and sulfate ions. Although phase 2 reactions are usually
accomplished without a detrimental effect, they can oc-
casionally lead to toxic or carcinogenic byproducts.
Glutathione Metabolism
A third metabolic pathway for detoxifying many com-
pounds involves glutathione, a thiol-containing tripep-
tide capable of binding to potentially harmful elec-
trophilic compounds through glutathione S -transferase.
Glutathione substrate is depleted in the process of detox-
ification and must be replenished by sulfhydryl com-
pounds from the diet or by cysteine-containing drugs
such as N-acetylcysteine. The glutathione S-transferase
reaction is therefore central to the detoxification of a
number of compounds, including acetaminophen. Other
enzymes, such as alcohol dehydrogenase, are important
for the elimination of a few compounds, but the princi-
pal metabolic pathways for most agents are those dis-
cussed above.
PATHOGENESIS OF TOXIC REACTIONS
Since the hepatocyte is the main metabolic engine of
the liver, most adverse drug reactions result first in hep-
atocyte necrosis. The most common reaction leading to
cell necrosis is the formation of covalent bonds between
a reactive metabolite of the parent compound and cell
 Vol. 333 No. 17 MEDICAL PROGRESS 1119

proteins or DNA. Oxidation may go

awry if a reactive electrophilic com- Acetaminophen
pound accumulates or if oxygen in-
O O O
termediates (such as the superoxide
anion or free radicals) are formed, HN C CH3 HN C CH3 HN C CH3
which then react with cellular com-
ponents. Perhaps the best example is
acetaminophen.
Although used universally for
UDP – glucuronosyl- Sulfotransferase
nonnarcotic pain relief, acetamino- transferase
phen has a predictable toxic effect if
taken in quantities exceeding those Glucuronate OH SO4
recommended in the package insert,
causing dose-related centrilobular Cytochrome P450 2E1
necrosis in the liver. The metabolic
pathway for acetaminophen involves
O O O
phase 1 and 2 reactions, glutathione
detoxification, and the formation of HN C CH3 N C CH3 HN C CH3
reactive intermediates, which dis-
rupt cell macromolecules (Fig. 1).
As a general rule, the capacity for GSH Cell proteins
glucuronidation is much greater Glutathione-
than that typically required each S-transferase
day; even patients with advanced liv- SG S -Protein
er disease continue to have adequate OH O OH
glucuronidation. If glucuronyl trans-
ferase and sulfotransferase are avail- Mercapturic Acid NAPQI Covalent Binding
4
able, phase 2 reactions predomi-
nate, with only a small fraction of Figure 1. Metabolic Pathway of Acetaminophen.
acetaminophen metabolized directly Acetaminophen primarily undergoes sulfation and glucuronidation (phase 2 reac-
by cytochrome P450, unless the tions) but is metabolized by cytochrome P450 2E1 (in a phase 1 reaction) to
quantity of acetaminophen exceeds N-acetyl-p-benzoquinoneimine (NAPQI) if the capacity of the phase 2 reactions is
the capacity of these phase 2 en- exceeded or if cytochrome P450 2E1 synthesis is induced. Glutathione-S -trans-
ferase is capable of detoxifying NAPQI to yield mercapturic acid and its derivatives,
zymes. At this point, an avidly elec- if glutathione is available. In the absence of glutathione substrate, covalent binding
trophilic compound, N-acetyl-p -ben- to cell proteins occurs. N-acetylcysteine is an excellent source of glutathione sub-
zoquinoneimine (NAPQI), is formed strate. UDP denotes uridine diphosphate, and GSH reduced glutathione.
through cytochrome P450 and may
bind covalently to cell macromolecules, thereby disrupt- rare toxic events include genetically variant P450
ing mitochondrial and possibly nuclear function. The isozymes, which contribute either to lack of metabolism
formation of covalent bonds is prevented if NAPQI of a given precursor or excess formation of a toxic me-
can be detoxified by conjugation (through glutathione- tabolite. One example is debrisoquin, an antihyperten-
S-transferase) to generate, through a series of steps, sive compound marketed in Europe and studied exten-
mercapturic acid, a harmless, water-soluble product ex- sively, since its urinary metabolites can be readily
creted by the kidney. Depletion of glutathione reduces analyzed. Debrisoquin is hydroxylated by P450 2D6, as
this last defense against the formation of NAPQI-related are perhexiline maleate, propranolol, quinidine, and
intracellular adducts. Thus, any situation that leads to desipramine, among other drugs. Almost 10 percent of
the depletion of glutathione will increase toxicity, where- normal people lack detectable levels of P450 2D6. In
as an increase in available glutathione stores will dimin- such persons, any drug metabolized primarily by this
ish this effect. Starvation and alcohol deplete mitochon- enzyme will have a greatly prolonged half-life. This de-
drial glutathione, whereas N-acetylcysteine replenishes fect, which is inherited as an autosomal recessive trait,
glutathione stores and protects against acetaminophen- involves abnormal production of messenger RNA, so
induced injury.13-15 In a similar fashion, the P450 iso- that the appropriate apoprotein is not made.7,8 The
zyme (P450 2E1), which is responsible for the conver- studies of P450 2D6 suggest that genetic enzyme vari-
sion of acetaminophen to NAPQI, is induced by ethanol ants are one explanation for the occasional and isolated
and inhibited by cimetidine.11-13 Thus, at several meta- toxic reactions to substances that virtually everyone
bolic stages, ethanol increases toxicity, whereas cimeti- can metabolize.
dine may serve as an antidote.16 Advanced age and renal
insufficiency may have important adjunctive roles.17 Hepatocyte Necrosis
The actual cause of cell death remains unclear. One
Enzyme Polymorphism result of the covalent binding of substrate or lipid per-
Most drugs cause toxic reactions only rarely and oxidation within cells is an increase in levels of cytosol-
without a dose-related pattern. Explanations for these ic calcium. Calcium is important for the regulation of a
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 1120 THE NEW ENGLAND JOURNAL OF MEDICINE
number of cell functions, including maintenance of the
cytoskeleton and membrane integrity. Actin depolymer-
ization and polymerization are dependent on calcium-
ion fluxes within the cytosol. The results of studies
using NAPQI in isolated hepatocytes suggest that alter-
ations in calcium homeostasis occur with the influx of
calcium ions into the cytosol. Whether this is the cause
or the result of disordered membrane transport is un-
clear, but altered permeability may lead to blebs in the
cell membrane and loss of membrane integrity. Other
mechanisms may also be at play; in each instance, the
covalent binding of reactive intermediates to cell pro-
teins seems to be the initiating step.
In addition to producing direct toxic effects, the for-
mation of drug–protein adducts may lead to allergic re-
actions, such as those observed with halothane. None-
theless, the formation of antibodies to P450 enzyme
species after hepatotoxic reactions does not necessar-
ily indicate that these antibodies have a pathogenetic
role.18
Role of Physiologic Factors
The metabolic fate of any compound is a complex
process. Table 1 outlines the variables (other than the
toxic potential of the compound itself) that may play a
part in the metabolic outcome.17,19-25 Multiple factors
are often involved, the most frequent being enzyme in-
duction.17 Common inducing agents include ethanol,
phenobarbital, and phenytoin, but cigarette smoke is
also a potent inducer of certain P450 enzyme species.
TYPES OF DRUG REACTIONS
Although most hepatotoxic effects involve hepato-
cyte necrosis, some drugs injure bile ducts or canaliculi,
causing cholestasis without marked damage of hepato-
cytes. Other therapeutic agents affect sinusoidal or en-
dothelial cells (resulting in veno-occlusive disease or
fibrosis) or fat-storing Ito cells (causing vitamin A tox-
icity, which leads to fibrosis) or cause a particular pat-
tern of liver injury affecting multiple cell types. Drug
reactions can be classified as hepatocellular, cholestatic,
or mixed, but these are general terms and do not apply
Table 1. Variables Affecting Drug
Metabolism.
Age19,20
Sex20
Diet
Micronutrients (calcium, iron, magnesium,
copper, and zinc)
Caffeine
Vegetable-enzyme inducers
Lipids21
Ethanol11,12
Pregnancy
Diabetes22
Hepatic disease
Renal disease23
Immune stimuli
Interferon
Interleukin-624
Enzyme polymorphism25
Drug–drug interference
Enzyme induction
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Oct. 26, 1995
to all circumstances. The most practical way of catego-
rizing drug reactions is according to the type of reac-
tion observed, which takes into account the histologic
changes and cell type involved, as well as the clinical
picture (Table 2).
Direct Toxic Reactions (Acetaminophen)
Acetaminophen is an example of an agent that caus-
es a direct toxic reaction. Two clinical scenarios ac-
count for most cases of acetaminophen-related hepatic
necrosis: the intentional suicidal overdose and the
“therapeutic misadventure.” In the latter scenario, an
alcoholic takes acetaminophen for pain relief in doses
that exceed those recommended in the package insert
(4 g per 24 hours). The result is a direct toxic reaction
due to the enzyme-induction and glutathione-depletion
mechanisms outlined above.26 Starvation may also play
a part, presumably because of glutathione depletion.27
This alcohol–acetaminophen syndrome, which is often
unrecognized, may be the most common form of acute
liver failure in the United States and Australia.28,29 Ex-
tremely elevated serum alanine and aspartate amino-
transferase values (mean, approximately 9000 U per li-
ter in one study) distinguish this condition from viral or
alcoholic hepatitis, but very high levels are also ob-
served in patients who take an intentional overdose of
acetaminophen. Even with the measurement of aceta-
minophen levels in the blood, it may be difficult to pre-
dict the outcome in such patients.30 If there is uncer-
tainty about the dose or time of ingestion or if the dose
appears to have been excessive regardless of the blood
acetaminophen level, N-acetylcysteine should be given
through a nasogastric tube immediately and for the en-
suing 48 hours, to provide glutathione substrate. The
expected survival rate is higher than 80 percent, but
liver transplantation is occasionally necessary.
Idiosyncratic Reactions (Isoniazid)
Unlike acetaminophen, the majority of drug-related
reactions, such as those observed with isoniazid, are id-
iosyncratic and unpredictable.31 Fifteen to 20 percent of
patients receiving isoniazid as a single agent for pro-
phylaxis against tuberculosis may have increased se-
rum alanine and aspartate aminotransferase levels, but
only 1 percent have hepatic necrosis severe enough to
require the withdrawal of the drug. Several factors ex-
plain the relatively common (albeit sporadic) toxic re-
actions observed. First, the simultaneous use of alcohol
or rifampin may augment the toxicity of isoniazid. Sec-
ond, elderly persons may be more likely to have toxic
reactions than younger persons.32 Third, genetic differ-
ences are important, since persons who are capable of
rapid acetylation of isoniazid have an increased likeli-
hood of toxic reactions resulting from the formation
of acetylhydrazine, which is then transformed by cyto-
chrome P450 into a reactive metabolite. Some studies
suggest that persons with slow acetylation are at great-
er risk for a toxic reaction through a separate pathway
that leads to the formation of hydrazine, which itself
may be toxic.32 In the case of isoniazid and perhaps of
other drugs causing idiosyncratic reactions, such reac-
tions are not truly idiosyncratic but occur when a series
 Vol. 333 No. 17 MEDICAL PROGRESS 1121

Table 2. Types of Toxic Reactions Occurring granulomas in liver-biopsy specimens. This allergic re-
in the Liver. action is accompanied by both hepatocyte necrosis and
TYPE OF REACTION EXAMPLES OF AGENTS
cholestasis.37,38 The mechanisms responsible for the com-
bined allergic and hepatotoxic reactions are unknown,
Direct reaction Acetaminophen, carbon tetra- but the slow resolution of the illness suggests that the
chloride, mushrooms, phos-
phorus allergen remains on the hepatocyte surface for weeks or
Idiosyncratic reaction Isoniazid, disulfiram, propyl- months.
thiouracil* This drug-induced hypersensitivity hepatitis syn-
Toxic–allergic reaction Halothane, isoflurane, ticrynafen
Allergic hepatitis Phenytoin, amoxicillin–clavulan- drome results in a mononucleosis-like illness that may
ic acid, sulfonamides be confused with a viral illness or streptococcal pharyn-
Cholestatic reaction Chlorpromazine, erythromycin
estolate, estradiol, captopril,
gitis, so that the agent is not withdrawn, despite signs
sulfonamides of developing hepatitis. The result is often a severe
Granulomatous reaction Diltiazem, quinidine, phenytoin, form of the Stevens–Johnson syndrome, with fever last-
procainamide
Chronic hepatitis Nitrofurantoin, methyldopa, iso- ing for weeks. The substitution of phenobarbital for
niazid, trazodone phenytoin occasionally results in cross-reactivity and a
Alcoholic hepatitis–like Amiodarone, perhexiline male- similar hypersensitivity reaction. As with any therapeu-
reaction ate, valproic acid
Microvesicular steatosis Tetracyclines, aspirin, zidovu- tic agent, rapid recognition of a possible toxic reaction
dine, didanosine, fialuridine and discontinuation of the drug are the keys to limiting
Fibrosis or cirrhosis alone Methotrexate, vitamin A, meth-
yldopa
hepatic damage. The features of the allergic reaction
Veno-occlusive disease Cyclophosphamide, other are sometimes not obvious, although eosinophilia or
chemotherapeutic agents, granulomas may be present in liver-biopsy specimens.
herbal teas
Ischemic damage Cocaine, sustained-release nico-
tinic acid, methylenedioxyam- Cholestatic Reactions (Estradiol)
phetamine The drugs that mainly affect bile flow, causing chole-
*There are hundreds of other agents that can cause idiosyncratic reac- static injury, include estradiol, chlorpromazine, tri-
tions. methoprim–sulfamethoxazole, rifampin, erythromycin
estolate, nafcillin,39 and captopril. Typically, jaundice
of genetic and environmental influences coincide to pro- appears early, with associated pruritus but little alter-
duce a sufficient quantity of one or more toxic metab- ation in the patient’s general well-being. A liver biopsy
olites. In most patients, there is no evidence of an al- reveals engorgement of the canaliculi with bile and
lergic reaction, and the histologic picture is virtually minimal hepatocellular injury (Fig. 2C). Eosinophils
indistinguishable from that of viral hepatitis (Fig. 2B). may be found in mildly inflamed portal tracts. The
Diclofenac is another example of a commonly used mechanism of cholestatic injury remains unclear. Estra-
agent that, like other nonsteroidal agents, occasionally diol and other estrogens have been shown to decrease
causes severe hepatotoxic reactions.33 bile flow and Na/K –ATPase, change tight junctions
between cells, and alter the fluidity of the hepatocyte
Combined Toxic and Allergic Reactions (Halothane) membrane. Given the large number of women (and
A seldom-used anesthetic agent that was very popu- men) taking estrogens, this form of cholestasis is re-
lar for a number of years, halothane can induce a com- markably rare.
bination of toxic and allergic reactions leading to liver
injury.34,35 Severe halothane-related hepatitis generally Granulomatous Reactions
develops after multiple exposures to the drug such as Noncaseating granulomas resembling sarcoidosis in
those that can occur on subspecialty surgical services. the liver are caused by a variety of drugs. The clinical
Although there is usually no rash, fever and eosino- picture is the same as that of other forms of granulo-
philia are commonly observed, and the histologic fea- matous hepatitis: low-grade fever and chronic fatigue,
tures of liver-biopsy specimens are similar to those with jaundice only in rare cases. The list of possible
seen with idiosyncratic reactions. The initial elevations agents is long (Table 3).
in serum alanine and aspartate aminotransferase levels
are delayed, but the interval between the administra- Drug-Induced Chronic Hepatitis (Methyldopa)
tion of halothane and toxic reactions becomes shorter Methyldopa and a number of other compounds have
with each exposure. Protein adducts formed from the been found to cause a more indolent form of liver dam-
initial toxic reaction provide the hapten for the forma- age that closely resembles autoimmune chronic active
tion of antibodies, so that with subsequent exposure, hepatitis (Fig. 2). Hyperglobulinemia may be present,
antibody and cellular recognition of the halothane–pro- with positive tests for antinuclear antibodies. The classic
tein-adduct antigen on the hepatocyte surface leads to agent producing this reaction is oxyphenisatin, a laxa-
cell lysis.35 A similar process occurs with other halo- tive that has been withdrawn from the market.40 Early
genated, volatile anesthetic agents.36 identification of drug-related chronic hepatitis is not
easy; cirrhosis may develop before the hepatitis is diag-
Allergic Hepatitis (Phenytoin) nosed. Identifying the drug or toxin that has caused the
Drugs such as phenytoin can cause a systemic aller- cirrhosis is difficult retrospectively if the patient has
gic reaction characterized by fever, rash, lymphadenop- been consuming alcohol or if unrecognized viral hepati-
athy, eosinophilia, and the presence of eosinophils or tis is present. Nevertheless, in addition to methyldopa,41
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 1122 THE NEW ENGLAND JOURNAL OF MEDICINE Oct. 26, 1995

A B

C D
Figure 2. Photomicrographs of Normal Hepatic Tissue and Tissue with Various Types of Injury Due to Drugs.
Panel A shows a normal hepatic lobule, with a portal tract (P) and a hepatic venule (V) (hematoxylin and eosin, 145). Hepatic-
cell plates are typically one cell thick. In this specimen, there is slight sinusoidal dilatation but no inflammation, necrosis, or regen-
eration. Panel B shows a liver-biopsy specimen obtained at autopsy from a 24-year-old man in whom subacute fatal liver failure
developed after he had taken sulfasalazine for several months for ulcerative colitis (hematoxylin and eosin, 145). Several years
earlier, sulfasalazine had been discontinued after an episode of hepatitis thought to be caused by the drug. The doctor who pre-
scribed the second course of the drug was not aware of the previous episode. Moderately severe necrosis of hepatocytes is present
throughout the lobule, with mononuclear cells, eosinophils, and a few polymorphonuclear leukocytes. Signs of cellular regeneration
are indicated by the presence of binucleate and trinucleate cells (arrow). Panel C shows an example of isolated cholestatic liver
injury due to treatment with ethinyl estradiol (hematoxylin and eosin, 185). The specimen is from a 59-year-old woman in whom
pruritus and jaundice developed two months after the initiation of estrogen-replacement therapy. She recovered completely one
month after discontinuing the medication. Prominent casts of inspissated bile are visible as green, translucent deposits in the cana-
liculi, and there is bile staining of hepatocytes but no evidence of necrosis or inflammation. Panel D shows a specimen from a
patient with chronic hepatitis due to treatment with methyldopa, which the patient had taken for more than one year (hematoxylin
and eosin, 185). The classic histologic features of autoimmune hepatitis are present: intense infiltration of the portal triads with
mononuclear cells, including plasma cells (lower right), and piecemeal necrosis (the encroachment of these cells into the hepatic
lobule, with the ballooning of adjacent hepatocytes, upper left). Panel E shows a specimen from a patient with nonalcoholic steato-
hepatitis who had been treated with amiodarone (hematoxylin and eosin, 185). Marked Mallory’s bodies are present within hep-
atocytes (small arrow), as well as macrovesicular fat (large arrow) and polymorphonuclear leukocytes (P). Panel F shows a speci-
men from a patient with indolent hepatic injury due to treatment with methotrexate (Masson’s trichrome, 185). The patient had
taken methotrexate for seven years, receiving a total dose of more than 5 g. The drug was discontinued after this biopsy specimen
had been obtained. Little or no inflammation is present, but there is evidence of increased fibrosis and expansion of the portal triad
by fibrous tissue (upper left). Nuclear atypia, vacuolization, and mild fatty metamorphosis, which are also present, are typical find-
ings in patients treated with methotrexate. Panel G shows the histologic features of moderately severe vitamin A toxicity (Masson’s
trichrome, 185). Ingestion of excess vitamin A results in the engorgement of the sinusoidal fat-storing (or Ito) cells, which appear
here principally as vacuolated spaces because of the removal of the lipid (vitamin A) in the fixation process. The marked surrounding
fibrosis, indicated by blue-staining collagen, is derived from the Ito cells. Panel H shows the features of severe veno-occlusive
disease in a liver-biopsy specimen obtained at autopsy 31 days after allogeneic bone marrow transplantation following conditioning
with busulfan and cyclophosphamide (Masson’s trichrome, 185). The lumen of the small hepatic venule shown is completely oc-
cluded with loose extracellular material and entrapped red cells. No endothelium is visible. There is extensive necrosis of hepato-
cytes and sinusoidal congestion surrounding the venule, with only a few remaining hepatocytes (lower right). Panels E and G are
provided courtesy of Dr. K.G. Ishak, Armed Forces Institute of Pathology, Washington, D.C., and Dr. M.A. Rothschild, Manhattan
Veterans Affairs Medical Center, New York. Panel H is provided courtesy of Drs. H.M. Shulman and G.B. McDonald, Fred Hutchinson
Cancer Research Center, Seattle.

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 Vol. 333 No. 17 MEDICAL PROGRESS 1123

E F

G H

acetaminophen,42 nitrofurantoin,43 trazodone, and phen-
ytoin have been determined to cause this syndrome
(Fig. 2D). Because these drugs are used for the long-
term treatment of relatively benign conditions, moni-
toring for untoward effects may be inadequate. Multi-
ple prescription renewals may be a problem in the case
of nitrofurantoin, which is used to control recurrent uri-
nary tract infections.
Fatty Liver and Alcoholic Hepatitis–Like Reactions
(Amiodarone)
Although fatty liver is most commonly related to
obesity, diabetes, alcoholism, or corticosteroid therapy,
amiodarone and several other drugs can cause a disor-
der similar to alcoholic hepatitis, termed nonalcoholic
steatohepatitis. Amiodarone, which has a unique histo-
logic and clinical profile, is a potent antiarrhythmic
agent used to treat life-threatening ventricular tachy-
cardia. This drug (and some related compounds) has
been shown to cause severe liver toxicity, in an acute or
chronic form,44-47 as part of a multisystem syndrome.
Patients typically have moderately elevated serum ala-
nine and aspartate aminotransferase levels, with the
characteristic lesion of steatohepatitis (Fig. 2E), and
cirrhosis can develop in just a few months.
The presence of microvesicular fat within hepato-
cytes has a different meaning from that of the macrove-
sicular steatosis discussed above. Fine vesicles are asso-
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Copyright © 1995 Massachusetts Medical Society. All rights reserved.
ciated with considerable cellular dysfunction but without
cell death. This is the characteristic lesion of fatty liver
caused by pregnancy, high doses of tetracyclines, and
Reye’s syndrome associated with aspirin.29 Macrovesic-
ular and microvesicular steatosis occur in association
with the acquired immunodeficiency syndrome (AIDS)
and with the use of zidovudine.48-50 Such lesions have
been reported in eight patients receiving zidovudine48
and in one patient treated with didanosine.51 These re-
ports are of particular interest in the light of the recent
tragic outcome with fialuridine, a new nucleoside ana-
logue for the treatment of hepatitis B.52-54 Like the pa-
tient treated with didanosine, several patients receiving
fialuridine had severe or fatal lactic acidosis in asso-
ciation with microvesicular steatosis after eight weeks
of therapy. These changes were assumed to be due to
a gradual uncoupling of mitochondrial oxidative me-
tabolism.
Indolent Cirrhosis (Methotrexate)
Of the several agents capable of causing a gradual
progression to cirrhosis without any manifestation of
clinical illness, methotrexate is the most frequently cit-
ed example. This agent is used in patients with severe
psoriasis or rheumatoid arthritis, and toxicity may de-
velop over a period of several years without any symp-
toms or evidence of hepatitis or other biochemical ab-
normalities.55,56 A liver biopsy is the only sure way to
 1124 THE NEW ENGLAND JOURNAL OF MEDICINE
Table 3. Drugs Associated with Granuloma-
tous Liver Disease.*
Allopurinol
Aspirin
Carbamazepine
Cephalexin
Diazepam
Diltiazem
Halothane
Hydralazine
Isoniazid
Methyldopa
Metolazone
Nitrofurantoin
Oxyphenbutazone
Penicillin
Phenytoin
Procainamide
Procarbazine
Quinidine
Sulfonamides
Sulfonylureas
Trichlormethiazide
*Adapted from Zimmerman and Maddrey.1
establish the diagnosis of indolent cirrhosis caused by a
drug reaction. Although guidelines vary, a pretreatment
biopsy is not indicated unless the patient has abnormal
liver-function values or there is a suspicion of alcohol-
ism. Many clinicians routinely perform a biopsy after
administering a total dose of 2500 mg of methotrexate
(Fig. 2F). Methyldopa41 and vitamin A57 (Fig. 2G) have
been reported to cause a similar syndrome.
Veno-occlusive Disease
Intensive chemotherapy, usually including the agent
cyclophosphamide, is most closely associated with the
development of a rapidly progressive, occlusive disease
of small hepatic venules due to endothelial-cell injury
(Fig. 2H). The abrupt onset of painful hepatomegaly,
ascites, jaundice, and other symptoms of hepatic insuf-
ficiency heralds this disease, which is the most common
complication of bone marrow transplantation.58 A sim-
ilar syndrome is observed in persons who drink Jamai-
can “bush tea.”
OTHER FACTORS IN DRUG-INDUCED LIVER DISEASE
Cocaine Abuse
Ischemic liver damage is a well-known complication
of severe heart failure but may also be caused by hy-
potensive reactions to drugs. Although cocaine abuse is
a widespread problem, little has been written about he-
patic injury due to cocaine. After the ingestion of co-
caine, shock and disseminated intravascular coagula-
tion may develop, with evidence of myonecrosis. The
associated toxic effect on the liver is likely to be ische-
mic in nature, the result of systemic hypotension in-
duced by coronary (and systemic arterial) vasospasm
with congestive heart failure.59 The task of sorting out
the more subtle forms of liver injury in cocaine abusers
is complicated by the concurrent abuse of other drugs,
including alcohol,60 and by the presence of viral hepati-
tis, but cocaine appears to be directly hepatotoxic as
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Oct. 26, 1995
well.61 A similar systemic reaction with rhabdomyolysis
has been observed with sustained-release nicotinic acid62
and methylenedioxyamphetamine (“ecstasy”).63
Nonprescription and Reformulated Agents
Over-the-counter preparations are assumed to be
safer than prescription drugs, but this is not always the
case. Laxatives that contained oxyphenisatin are exam-
ples of nonprescription drugs associated with liver
damage.40 Products sold in health food stores may be
especially hazardous, since they are assumed to be at
least nontoxic, even if not effective. Because of this im-
plicit assumption, patients are more likely to induce
toxic reactions by exceeding the recommended doses.
The list of alternative medicines that can cause toxic
reactions includes vitamin A,64 germander,65,66 chapar-
ral leaf,67,68 comfrey,69 and jin bu huan, a Chinese herbal
product.70
Safety profiles may change when drugs are reformu-
lated. For example, nicotinic acid, a relatively safe
agent, had greatly increased hepatotoxic effects when
issued in a sustained-release form. Such effects had
been recognized rarely with higher doses, but the flush-
ing reaction that occurs in most patients limited exces-
sive doses. The use of a sustained-release formulation
led to tolerance of higher doses, which in turn led to hy-
potension, ischemic liver injury, and fulminant hepatic
failure.62
Multidrug Regimens
It should not be surprising that one drug can inter-
fere with the biotransformation of another drug. What
is surprising is that such interference does not occur
more often. There are several circumstances in which
drug combinations are associated with an increased
risk of toxic reactions. First, drugs may be combined in
a single formulation, such as trimethoprim–sulfameth-
oxazole,71 amoxicillin–clavulanic acid,72,73 and isonia-
zid–rifampin.74 With each of these combination agents,
there have been numerous reports of hepatotoxic reac-
tions that were more severe than those associated with
one agent used alone. The mechanism of injury is be-
lieved to involve the induction of cytochrome P450 by
one agent, which increases the quantity of the toxic me-
tabolite formed from the other.
Isoniazid and rifampin may be used concurrently as
single agents rather than as a combined formulation.
Either agent alone can be the cause of a hepatotoxic re-
action, although rifampin generally impairs bilirubin
uptake, resulting only in elevated bilirubin levels.74 In
addition, acetaminophen-related toxicity may be poten-
tiated by isoniazid. The more elaborate four- and five-
drug regimens used for resistant tuberculosis have sim-
ilar hazards.75 For reasons that are unclear, patients
with AIDS have an apparently increased susceptibility
to drug-related liver injury, particularly in association
with trimethoprim–sulfamethoxazole, pentamidine,76
and oxacillin.77
DIAGNOSIS, TREATMENT, AND PREVENTION
The diagnosis of drug-induced liver injury is often
obscured by difficulty in determining the precise timing
 Vol. 333 No. 17 MEDICAL PROGRESS
of the drug ingestion from the patient’s history. Essen-
tial to the diagnosis is evidence that the patient was not
ill before ingesting the drug, became ill while taking it,
and, in most cases, had striking improvement after its
withdrawal. Since drug-related hepatitis can be fatal, it
is vital to be aware of the possible severity of the hepat-
ic reaction and to discontinue any potentially toxic
medication immediately. The best way to identify the
drug causing the reaction is to make a careful time line
of all drugs ingested and to be particularly suspicious
of any treatment with a potentially hepatotoxic drug
begun during the three months before the onset of an
illness. Many drugs, including digoxin and theophyl-
line, are virtually never implicated as causes of liver in-
jury, whereas certain classes of drugs, such as non-
steroidal agents33,78 and some antibiotic agents,79 are
commonly implicated.
The main treatment for drug-induced hepatotoxicity
is the withdrawal of the agent, with careful observation
of the patient to make sure the expected improvement
begins to occur within a few days. Certain agents, such
as amoxicillin–clavulanic acid and phenytoin, have
been associated with a syndrome in which the condi-
tion actually worsened for several weeks after the drug
was withdrawn and took months to resolve complete-
ly.73 If clinical or laboratory signs of hepatic failure ap-
pear, hospitalization is mandatory.29 The prognosis for
patients with acute liver failure caused by idiosyncratic
drug reactions is poor, with a mortality rate higher
than 80 percent in most series.80 Corticosteroid treat-
ment may be used in patients with evident hypersensi-
tivity, but controlled trials have not proved the efficacy
of such treatment. Intentional overdoses must be treat-
ed like any poisoning, with appropriate emergency
measures. A suspected overdose with acetaminophen
is treated with N-acetylcysteine even when the drug
has been ingested 36 hours or more earlier.15 Hemodi-
alysis or hemofiltration is rarely indicated. Putative
toxic agents are generally not given again, since re-
challenge may be associated with a more severe subse-
quent reaction (Fig. 2B). A cautious rechallenge should
be considered only if the toxic reaction observed was
highly questionable and if no other drug is available
for the treatment of a potentially life-threatening dis-
order.
Each year, dozens of new pharmacologic agents ap-
pear on the market. The pressure from the public, as
well as the pharmaceutical industry, to bring new
agents to the marketplace is great, and cautionary tales
of failed drugs, such as ticrynafen, are often forgotten.
During the first nine months after its introduction, this
diuretic and uricosuric agent was involved in more than
25 fatal hepatotoxic reactions.81 Although ticrynafen
was removed from the market as soon as the problem
was recognized, its toxicity was only fully realized after
its public release. Each new agent approved by the
Food and Drug Administration has undergone rigorous
clinical trials, but there is no substitute for the wider
use that follows product licensing. Some of the newer
agents associated with acute liver necrosis are listed in
Table 4.33,82-101
Physicians may wish to defer prescribing new drugs
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Copyright © 1995 Massachusetts Medical Society. All rights reserved.
1125
Table 4. A Partial List of Newer Agents As-
sociated with Hepatotoxic Reactions.
Chlorzoxazone82
Clozapine83
Diclofenac33,84
Doxepin85
Etoposide86
Etretinate87
Floxacillin88
Flutamide89
Glyburide90
Ketoconazole91
Labetalol92
Lisinopril93
Lovastatin94
Norfloxacin95
Ofloxacin96
Pentamidine97
Piroxicam98
Terbutaline99
Ticlopidine100
Trazodone101
during the first year after their introduction, particular-
ly if they offer no advantages over accepted formula-
tions. In addition, physicians should caution their pa-
tients to be alert for signs of drug-induced liver injury,
especially in the case of agents with well-recognized
hepatotoxic effects. The challenge for physicians and
pharmaceutical companies alike is to alert patients to
the potential toxic effects of drugs without frightening
them to such an extent that they avoid taking needed
medication. For known hepatotoxins, such as isoniazid
and diclofenac, monthly monitoring of serum alanine
and aspartate aminotransferase levels is suggested dur-
ing the first six months of treatment. Since many drug
reactions develop quickly, monitoring is not a complete
safeguard against toxicity. Many fatal drug reactions
might have been prevented, however, had the agent
been withdrawn at the first sign of illness. The educa-
tion of patients is therefore essential to the prevention
of drug-induced hepatotoxicity. Patients who do not
realize that drug-induced injury is possible and those
who are encouraged to continue taking a drug despite
initial signs of toxicity are at the highest risk for fatal
reactions.
I am indebted to Drs. Burton Combes and Ronald W. Estabrook for
their critical insights and to Dr. Steve Foster for assistance with the
photomicrographs.
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