Hepatotoxicity of Non-Narcotic Analgesics
Keith G. Tolman, MD, Salt Lake City, Utah
The central role of the liver in drug metabolism sets
the stage for drug-related hepatotoxicity. The inci-
dence of hepatotoxicity associated with non-nar-
cotic analgesics is low, but their widespread use—
both prescription and over-the-counter—makes an-
algesic-associated hepatotoxicity a clinically and
economically important problem. Hepatotoxicity is
considered a class characteristic of nonsteroidal
anti-inflammatory drugs (NSAIDs), despite the fact
that they are a widely diverse group of chemicals. In
fact, there are many differences in the incidence,
histologic pattern, and mechanisms of hepatotoxic-
ity between, as well as within, chemical classes.
Most NSAID reactions are hepatocellular and occur
because of individual patient susceptibility (idiosyn-
crasy). Aspirin, however, is a dose-related intrinsic
hepatotoxin. Acetaminophen is also an intrinsic hep-
atotoxin but rarely demonstrates hepatotoxicity at
therapeutic doses. It does cause hepatotoxicity with
massive overdoses and with therapeutic doses in
susceptible patients such as chronic users of alco-
hol. No hepatotoxicity has been reported to date with
tramadol, another non-narcotic analgesic. Am J
Med. 1998;105(1B):13S–19S. © 1998 by Excerpta Med-
ica, Inc.
From the Division of Gastroenterology, Section of Hepatology, Univer-
sity of Utah School of Medicine, Salt Lake City, Utah.
From a presentation at the National Institute of Diabetes and Diges-
tive and Kidney Diseases (NIDDK) conference: Non-Narcotic Analge-
sics: Renal and GI Considerations, held in Bethesda, Maryland on April
28 –29, 1997.
Requests for reprints should be addressed to K.G. Tolman, MD, Uni-
versity Medical Center, 50 North Medical Drive, Salt Lake City, Utah
84132.
© 1998 by Excerpta Medica, Inc.
All rights reserved.
T
he importance of drug-induced liver injury can-
not be overstated. Virtually every drug has been
associated with hepatotoxicity—almost certainly
due to the pivotal role of the liver in drug metabolism.
The liver is involved in 3–10% of all adverse drug reac-
tions, and the frequency may be increasing. In the United
States, drugs and toxins account for as many as one-third
of the cases of fulminant hepatic failure. The prognosis
for drug-induced hepatitis is somewhat worse than that
for viral hepatitis, with fatality rates approaching 10%.
Drug injury can mimic all forms of liver disease includ-
ing cirrhosis and hepatocellular carcinoma. Thus, when-
ever a patient presents with liver disease, the possibility
of drug-induced liver injury should be considered. The
diagnosis of nonsteroidal anti-inflammatory drug
(NSAID)-induced liver injury is often compromised by
the minor elevations of aminotransferase enzymes seen in
up to 25% of patients with systemic lupus erythematosus
and rheumatoid arthritis—2 of the diseases NSAIDs are
used to treat.1,2 Thus, accurate and timely diagnosis re-
quires a high level of suspicion.
DRUG METABOLISM AND
HEPATOTOXICITY
The central role of the liver in drug metabolism predis-
poses the liver to toxic injury, not only by nature of the
bioaccumulation of drugs in the liver, but by the fact that
drug metabolism may go awry, leading to formation of
toxic metabolites.3
Most medications are ingested orally and, because of
their lipophilic nature, are not only absorbed from the
gastrointestinal tract, but can also be reabsorbed by the
renal tubular epithelium. To be eliminated, drugs must
be made more hydrophilic so that they can be excreted in
urine or bile. This process, known as biotransformation,
typically occurs in 2 phases and is ordinarily protective to
the host (Figure 1).
Phase 1 reactions are usually oxidation or demethyl-
ation and are mediated by cytochrome P-450 (CYP)-de-
pendent enzymes.4 The P-450 enzymes are composed of
heme and a unique apoprotein, which characterize the
isoenzymes that are classified based on homology to fam-
ilies (e.g., CYP2E1). This reaction results in aliphatic or
aromatic hydroxylation. The hydroxyl group can then
participate in the phase 2 reaction in which a polar group
is attached to the hydroxyl oxygen by glucuronidation or
sulfation. The drug is now rendered water soluble and can
be eliminated. This biotransformation process, while or-
dinarily protective, can go awry leading to the formation
0002-9343/98/$19.00 13S
PII S0002-9343(98)00070-9
 A Symposium: Non-narcotic Analgesics—Renal and GI Considerations/Tolman
Figure 1. Drug metabolism of the liver. Solid lines represent major pathways.
of reactive (electrophilic) molecules that are potentially
toxic. These toxic compounds are then detoxified
through a third metabolic pathway involving binding by
glutathione. Glutathione, which is available in limited
supply, is depleted in this process and has to be replen-
ished. Massive overloads of drugs or circumstances that
deplete glutathione, such as fasting or alcoholism, predis-
pose to hepatotoxicity—such is the case with acetamino-
phen. In essence, metabolic toxicity occurs when oxida-
tion leads to the formation of toxic electrophiles. These
electrophiles interact with critical cellular target mole-
cules leading to either direct cell injury or formation of
protein– drug adducts that become targets for immune
mediated injury. The reactive metabolites also act as ox-
idizing species that can accelerate programmed cell death
(apoptosis).
MECHANISM OF DRUG-INDUCED
LIVER INJURY
The mechanism of injury in hepatotoxicity is usually clas-
sified as idiosyncratic or intrinsic. Idiosyncratic reactions
occur as the consequence of individual susceptibility and
may result from either metabolic idiosyncrasy or im-
mune idiosyncrasy— both leading to cell death (Figure
1). Idiosyncratic reactions are unpredictable. They are
not dose dependent and are not detected in preclinical
testing. They occur with a very low incidence. A typical
example of metabolic idiosyncrasy is that which is seen
14S July 27, 1998 THE AMERICAN JOURNAL OF MEDICINEt Volume 105 (1B)
with valproic acid. This agent is metabolized to a 4-ene
metabolite, which is toxic to the liver.5,6 Immunologic
idiosyncrasy, on the other hand, results from the forma-
tion of neoantigens or drug–protein adducts. A typical
example is the formation of trifluoroacetylated adducts
after exposure to halothane.7 Another mechanism in-
volves dysregulation of the immune system resulting in
autoimmune reactions. These typically result in forma-
tion of autoantibodies such as liver and kidney microso-
mal (LKM) antibodies, which react against microsomal
enzymes. An example is tienelic acid, in which the LKM
antibodies react against CYP2C9,8 and halothane, in
which they react against CYP2E1.9 Nonspecific antibod-
ies such as antinuclear antibodies are often present in
these reactions of which a-methyldopa is an example.10
Intrinsic hepatotoxicity is unique to the drug and oc-
curs in all people if exposed to a high enough concentra-
tion of the drug. Aspirin and acetaminophen are exam-
ples of intrinsically hepatotoxic drugs.11
RISK FACTORS FOR DRUG-INDUCED
LIVER INJURY
For most drugs, the risk of hepatotoxicity is 1–10 cases
per 100,000 individuals exposed. Certain factors, how-
ever, appear to increase the probability of toxic reactions
(Figure 2).3
In general, people .40 years of age are more likely to
have drug-induced liver disease. This may be influenced
 A Symposium: Non-narcotic Analgesics—Renal and GI Considerations/Tolman
Figure 2. Risk factors for drug-induced liver damage. It appears that most of the risk factors alter drug metabolism leading to
accumulation.
by higher exposure rates, use of multiple drugs, and al-
tered drug disposition. Important exceptions are aspirin
and valproic acid, both of which are more commonly
associated with liver injury in children.
Women are predisposed to drug-induced necro-
inflammatory reactions. This is especially true for diclofe-
nac. Interestingly, men appear to be more predisposed to
cholestatic reactions such as that which occurs with
azathioprine.
Drug formulation may also influence toxicity. For ex-
ample, erythromycin estolate appears more likely to
cause toxicity than plain erythromycin—perhaps because
of the higher blood levels obtained with estolate.
Patients taking multiple drugs may be more suscepti-
ble to drug-induced injury. This probably results from
induction of cytochrome P-450 –mediated metabolism
of parent compounds to toxic metabolites. Examples of
agents in this category include acetaminophen, isoniazid,
and valproic acid.
Chronic ethanol ingestion lowers the threshold for in-
jury possibly by inducing the microsomal enzyme system
as occurs with acetaminophen and perhaps with isonia-
zid, niacin, and methotrexate.
The nutritional state of the patient also affects toxicity.
Obesity, for example, increases susceptibility to halo-
thane hepatitis and perhaps methotrexate fibrosis,
whereas fasting increases susceptibility to acetaminophen
toxicity, probably due to glutathione depletion.
Genetic polymorphism of the cytochrome P-450 sys-
tem may predispose to toxic injury. For example, 10% of
July 27, 1998
the population has a relative deficiency of CYP2D6,
which leads to propranolol and quinidine toxicity.12,13
Finally, it appears that patients with certain diseases are
predisposed to toxicity. This is the case with aspirin hep-
atotoxicity, which is more common in patients with sys-
temic lupus erythematosus, juvenile rheumatoid arthri-
tis, and rheumatic fever.11
NSAID HEPATOTOXICITY
NSAID-induced liver injury is rare, occurring with an
incidence of ,0.1%, but results in 2.2 hospitalizations
per 100,000 population per year.14,15 Due to the wide-
spread use of these drugs (15 million users per year in the
United States), however, the accompanying medical and
economic cost is high. The issue of NSAID hepatotoxicity
came into focus after the introduction of benoxaprofen in
April 1982. Striking cholestatic reactions, usually consid-
ered benign, were observed; 11 of 14 patients in the
United States and .70 patients around the world died.
Benoxaprofen was withdrawn from the US market a few
months after its introduction.16 Other NSAIDs (e.g., cin-
chophen, ibufenac) had also been withdrawn from the
market because of unacceptable levels of hepatotoxicity
and, as a result, NSAID-associated liver toxicity was re-
viewed by the US Food and Drug Administration (FDA)
Arthritis Advisory Committee.17 When it became appar-
ent that virtually all NSAIDs were associated with some
liver injury, hepatotoxicity was designated a class charac-
teristic of NSAIDs. This designation, however, is an over-
simplification for several reasons. First, many different
THE AMERICAN JOURNAL OF MEDICINEt Volume 105 (1B) 15S
 A Symposium: Non-narcotic Analgesics—Renal and GI Considerations/Tolman

chemical classes with little in common comprise the Table 1. Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
NSAIDs (Table 1). There is no clear correlation between by Chemical Class
chemical class and the risk of hepatotoxicity—the rates of Salicylates Oxicams
hepatotoxicity vary markedly within chemical classes. Aspirin Piroxicam
For example, benoxaprofen has a very high incidence of Diflunisal Sudoxicam*
hepatotoxicity, and ibuprofen, which is chemically simi- Propionic acids Fenamates
lar, has a very low incidence. Similarly, the adjusted odds Benoxaprofen* Meclofenamic acid
ratio for hepatotoxicity with sulindac has been estimated Fenoprofen Mefenamic acid
at almost twice that of indomethacin (5.0 vs 2.6, respec- Flurbiprofen Indoles
Ibuprofen Indomethacin
tively) despite their being in the same chemical class.18
Ketoprofen Sulindac
Several groups have reviewed the published cases, as well Naproxen Tolmetin
as unpublished cases, reported to the FDA and estimated Oxaprozin Naphthylalkanone
the relative incidence of NSAID hepatotoxicity inferred Pirprofen* Nabumetone
from that data.18 –20 Pyrazolones Pyranocarboxylic acid
Second, the histologic type of injury varies within, as Phenylbutazone Etodolac
well as between, chemical classes (Table 2). Hepatocellu- Phenylacetic acids Acetic acid
lar injury is the most common, but cholestatic injury and Diclofenac Bromfenac*
mixed injury are also seen as well as steatosis and granu- * Withdrawn from the market due to hepatotoxicity.
lomatous changes. Autoimmune injury, as occurs with
diclofenac, has also been reported. Different types of in- Table 2. Histologic Types of Liver Injury Associated with Se-
jury have also been reported with the same drug. For ex- lected Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
ample, sulindac causes both cholestatic and hepatocellu-
Histology Associated NSAIDs
lar reactions.
Finally, there is no consistent mechanism of liver in- Hepatocellular f Aspirin, diclofenac, indomethacin,
jury for NSAIDs (Table 3). With the exception of aspirin, phenylbutazone, etodolac,
most are associated with idiosyncratic toxicity mediated nabumetone, oxaprozin, ibuprofen
Cholestatic f Ibuprofen, sulindac, nabumetone,
either immunologically (immune idiosyncrasy) or as the
naproxen, piroxicam, etodolac
consequence of toxic metabolites (metabolic idiosyncra- Mixed f Sulindac, diflunisal
sy). Nevertheless, most NSAID-induced injury is hepato- Steatosis f Aspirin, indomethacin, ibuprofen
cellular and idiosyncratic. Unlike the gastrointestinal and Autoimmune f Diclofenac
renal effects of NSAIDs, liver injury is not related to pros- Granulomatous f Phenylbutazone
taglandin inhibition. Of the 18 NSAIDs approved for use
in the United States, all except ketorolac and meclofe-
namate have been reported to be hepatotoxic. Table 3. Intrinsic Versus Idiosyncratic Hepatotoxins

Diclofenac Hepatotoxicity Type of

Hepatotoxicity Associated NSAIDs
Significant hepatotoxicity occurs in approximately 1–5
per 100,000 exposed patients. This injury is more com- Intrinsic f Aspirin, phenylbutazone(?)
mon in women. It is idiosyncratic and probably the con- Idiosyncratic f Ibuprofen, sulindac, phenylbutazone,
sequence of drug metabolism since inhibition of CYP2C (immunological) piroxicam, diclofenac
reduces cell injury.21 However, protein adducts are also Idiosyncratic f Benoxaprofen, diclofenac,
formed and may be involved with immune-mediated (metabolic) indomethacin, naproxen
toxicity.22 A chronic autoimmune type injury also occurs. NSAIDs 5 nonsteroidal anti-inflammatory drugs.
Fatalities have been reported.

Sulindac Hepatotoxicity Salicylate Hepatotoxicity

Sulindac is one of the most commonly reported causes of
NSAID hepatotoxicity.23,24 Approximately 75% of the
patients are female, usually .50 years of age. Injury typ-
ically occurs within 8 weeks of initiating therapy. Most of
the reactions are cholestatic (50%) but 25% are hepato-
cellular and 12% are mixed. Immune features are present
in most patients. Deaths have been reported typically in
the presence of a hypersensitivity reaction. The mecha-
nism is immunologic idiosyncrasy.
Aspirin causes dose-dependent toxicity and thus, is an
intrinsic hepatotoxin. This is supported by experimental
studies demonstrating that aspirin is a dose-related toxin
in animals25 and cell culture.26 The exact mechanism of
injury is unknown, but probably related to mitochondrial
injury. Toxicity usually occurs with blood levels near or
above the upper therapeutic concentration of 25 mg/dL.
The injury is hepatocellular and usually mild with 3–5-
fold increases in aminotransferase enzymes. Jaundice is

16S July 27, 1998 THE AMERICAN JOURNAL OF MEDICINEt Volume 105 (1B)
 A Symposium: Non-narcotic Analgesics—Renal and GI Considerations/Tolman
Figure 3. Acetaminophen metabolism and possible mechanisms of enhanced toxicity.
unusual. Patients with juvenile rheumatoid arthritis, sys-
temic lupus erythematosus, and rheumatic fever appear
to be more susceptible.11 The nonacetylated salicylates,
sodium and choline salicylate as well as diflunisal, a di-
fluorophenyl derivative, have also been implicated with
hepatotoxicity although these reactions are probably im-
mune idiosyncrasy.
Of special concern with aspirin is its apparent associa-
tion with Reye’s syndrome in patients being treated for
influenza or varicella. Aspirin should not be used in such
patients, especially in children.
Acetaminophen
Acetaminophen is one of the most commonly used drugs
in the United States. It inhibits both isoforms of the cyclo-
oxygenase enzyme, COX-1 and COX-2, but has little, if
any, anti-inflammatory activity and is used for its analge-
sic and antipyretic properties. It is a dose-related hepato-
toxin that can cause fulminant hepatic necrosis but rarely
does so at therapeutic doses.14 Hepatotoxicity is seen
most frequently with massive overdoses. Under normal
circumstances, acetaminophen undergoes direct glu-
curonidation and sulfation. However, approximately
5–15% of acetaminophen is metabolized through oxida-
tion by the cytochrome P-450 isoenzymes 2E1 and 1A2 to
form a toxic metabolite, N-acetyl-p-benzoquinoneimine
(NAPQI) (Figure 3),27,28 and hepatic injury from acet-
aminophen is due primarily to this metabolite. NAPQI is
a reactive species that can covalently bind nucleophilic
proteins in the cell leading to hepatic necrosis. At normal
therapeutic doses of acetaminophen, NAPQI is detoxi-
fied by binding with glutathione to form mercapturic
July 27, 1998
acid, a stable metabolite excreted in urine. Hepatic necro-
sis occurs when the formation of NAPQI exceeds the
binding capacity of glutathione. This occurs whenever
the glutathione stores are reduced or excess NAPQI is
formed. There are several reports of acetaminophen-in-
duced liver injury occurring with apparently therapeutic
doses in the setting of chronic alcohol ingestion, so-called
“therapeutic misadventure.”29 In fact, most of these cases
have occurred with acetaminophen doses greater than the
recommended 4 g/day, albeit at doses less than those or-
dinarily considered hepatotoxic. Nevertheless, it is now
clear that chronic alcohol ingestion enhances susceptibil-
ity to acetaminophen injury. It does this by 2 mecha-
nisms: (1) chronic alcohol use enhances acetaminophen
hepatotoxicity by inducing CYP2E1 isoenzyme, leading
to excess formation of NAPQI; and (2) alcohol depletes
glutathione stores, which compromises the detoxifica-
tion mechanism.30,31 Patients who take enzyme-inducing
drugs such as isoniazid, omeprazole, phenobarbital,
phenytoin, or carbamazepine also may be at increased
risk.14 Cimetidine, by inhibiting CYP2E1, and acute alco-
hol ingestion, by substrate competition for 2E1, probably
reduce acetaminophen hepatotoxicity.
The clinical presentation of acetaminophen toxicity is
characterized by an initial several hours of anorexia, nau-
sea, and vomiting followed by 1–2 days of being relatively
symptom free (although biochemical changes start oc-
curring during this period and there may be right upper
quadrant discomfort). This is followed by overt hepatic
injury in which the aminotransferase enzyme levels are
typically in the thousands.32 Hepatic failure with jaun-
THE AMERICAN JOURNAL OF MEDICINEt Volume 105 (1B) 17S
 A Symposium: Non-narcotic Analgesics—Renal and GI Considerations/Tolman
dice, bleeding, and encephalopathy ensues. Acute renal
failure occurs in 25–30% of patients. Recovery typically
occurs in 5–10 days. The course of alcohol-associated
acetaminophen toxicity is similar. However, intervention
with N-acetylcysteine, which serves as a substitute sulfhy-
dryl donor for glutathione, almost universally reverses
the course of acetaminophen hepatotoxicity.32 The prog-
nosis can be estimated by measuring blood levels and
plotting a nomogram within the first few hours. How-
ever, patient history in this setting is notoriously unreli-
able and the nomogram is dependent on knowing time of
ingestion. Furthermore, the patients typically feel well for
most of the first 48 hours when the damage is occurring.
For these reasons, all patients presenting with acetamin-
ophen overdose should be treated initially with N-acetyl-
cysteine. Further administration of the antidote can be
discontinued if subsequent blood levels indicate no risk
for hepatic injury.
Acetaminophen injury should be suspected in alco-
holic patients who present with aminotransferase levels
.1,000 U/L, since acute alcoholic hepatitis alone rarely
presents with enzyme levels .300 U/L. Such patients
should have acetaminophen levels measured and be
treated appropriately.
Tramadol
Tramadol is a centrally acting, non-narcotic analgesic
that has been available in the United States since 1995. It
is a pure analgesic that does not affect prostaglandin syn-
thesis and does not possess anti-inflammatory activity.
No hepatotoxicity has been reported to date. (See article
by T. J. Schnitzer in this Supplement.)
HEPATOTOXICITY IN PATIENTS WITH
PRE-EXISTING LIVER DISEASE
In general, pre-existing liver disease does not enhance
susceptibility to drug-induced liver disease. Important
exceptions include methotrexate toxicity, alcoholic cir-
rhosis, alcohol in the presence of chronic hepatitis C, vi-
tamin A use concurrent with alcoholic liver disease and,
perhaps, halothane in patients with alcoholic liver dis-
ease. NSAIDs, however, enhance the renal disease associ-
ated with cirrhosis. Such patients are predisposed to re-
taining fluid, in part, due to their vasodilated state, which
decreases arterial blood flow and thus renal blood flow
with subsequent activation of the renin–angiotensin sys-
tem leading to sodium and water retention. The normal
adaptive response to this state is the release of prostaglan-
dins which cause natruresis. NSAIDs inhibit this adaptive
response leading to further sodium retention.33,34
SUMMARY AND CONCLUSIONS
All of the available non-narcotic analgesics—with the ex-
ception of ketorolac, meclofenamate, and tramadol—
18S July 27, 1998 THE AMERICAN JOURNAL OF MEDICINEt Volume 105 (1B)
have been associated with hepatotoxicity. Furthermore,
NSAIDs have enhanced nephrotoxicity in the presence of
liver disease and alcohol enhances the susceptibility to
acetaminophen toxicity. There continues to be a need for
the development of new drugs for the treatment of pa-
tients with underlying liver disease.
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