Download Drug-induced Hepatotoxicity

Hepatology Rev. 2007;4:14-23
2007;4
Drug-induced Hepatotoxicity
Raúl J Andrade, M.a Carmen López-Vega and M.a Isabel Lucena
Liver Unit, Gastroenterology Service and Clinical Pharmacology Service “Virgen de la Victoria” University Hospital and School of Medicine,
Málaga, Spain
Abstract
H E P A T O L O G Y REVIEWS
Pharmaceutical preparations, but also herbal products and dietary supplements,
are emerging contributors to severe forms of liver disease, with hepatotoxicity
ranking as the most frequent cause for acute liver failure. Although
acetaminophen intoxication is still the reason for many severe cases of druginduced liver injury, the bulk of hepatic reactions to drugs are idiosyncratic.
Indeed, the rarity of this serious adverse event prevents its detection in clinical
trials. Therefore, in order to collect reliable data, prospective post-marketing
studies are needed, especially with commonly used drugs that have been shown
to be associated with drug-induced liver injury. Recently, different databases have
described acetaminophen, antibiotics, nonsteroidal anti-inflammatory drugs,
and anticonvulsants as being associated with drug-induced liver injury. Clinical
presentations of drug-induced liver injury include predominantly a hepatocellular
type of damage, yet cholestatic and mixed types are also common, the
determinants of the type of damage induced by a given drug being poorly
understood. Recent analysis of pooled data has underlined the influence of older
age in the cholestatic/mixed expression of the liver injury, as well as the
independent association of female gender, older age, aspartate aminotransferase
levels/hepatocellular type of damage and high bilirubin levels with the risk of
fulminant liver failure/death. In the long-term (proving the patient survives to the
initial episode) cholestatic mixed type of damage is more prone to become
chronic, while in the hepatocellular pattern the severity is greater, with further
likelihood of evolution to cirrhosis. Cardiovascular and central nervous system
drugs have been found to be the main groups leading to chronic liver damage.
The diagnosis of hepatotoxicity remains a difficult task because of the lack of
reliable markers for use in general clinical practice. To incriminate any given drug
in an episode of liver dysfunction is a step-by-step process that requires a high
degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic
potential, the exclusion of alternative causes of liver damage, and the ability to
detect the presence of subtle data that favors a toxic etiology. This process is
time-consuming and the final result is frequently inaccurate. Diagnostic
algorithms may add consistency to the diagnostic process by translating the
suspicion into a quantitative score. Such scales are useful since they provide,
14
Correspondence to:
Raúl J Andrade
Unidad de Hepatología, Departamento de Medicina
Facultad de Medicina
Boulevard Louis Pasteur 32
29071 Málaga, Spain
E-mail: [email protected]
Raúl J Andrade, et al.: Drug-induced Hepatotoxicity
as well, a framework that emphasizes the features that merit attention in cases
of suspected hepatic adverse reaction. Nowadays, the CIOMS/RUCAM instrument
is considered the gold standard in the causality assessment of hepatotoxicity,
although there is probably room for improvement. Current efforts in collecting
bona fide cases of drug-induced hepatotoxicity will make refinements of existing
scales feasible by accommodating relevant data within the scoring system and
deleting low-impact items. Efforts should also be directed toward the development
of an abridged instrument for use in evaluating suspected drug-induced
hepatotoxicity at the very beginning of the diagnosis and treatment process when
clinical decisions need to be taken. The treatment of idiosyncratic drug-induced
liver injury is largely supportive. In addition to administration of fat-soluble
vitamins, ursodeoxycholic acid could also be of benefit in cases of prolonged
cholestasis. (Hepatology Rev. 2007;4:14-23)
Corresponding author Raúl J Andrade, [email protected]
Key words
Introduction
Epidemiology
Toxic liver disease due to pharmaceuticals, herbal preparations, or dietary supplements1 has a considerable impact on health. A survey from the Acute
Liver Failure Study Group (ALFSG) of the patients
admitted in 17 U.S. hospitals showed that prescribed
drugs (including acetaminophen) accounted for >
50% of cases of acute liver failure2. Although intentional or unintentional acetaminophen (paracetamol)
overdosage still ranks in some countries as the
cause of many severe drug-induced liver injury
(DILI) cases, the bulk of hepatic reactions to drugs
are idiosyncratic. Indeed, idiosyncratic DILI is seldom detected in pre-marketing clinical trials and
hence it remains as the main reason for post-approval drug regulatory decisions, including removal of several culprit drugs from the market. Advances in the understanding of the pathogenesis
of hepatotoxicity are hampered by the fact that no
satisfactory animal models for idiosyncratic DILI
have been developed. Hence, the unique affected individual would be nowadays the best
model for genome-wide studies looking for candidate genes involved in susceptibility. Thus, cooperative efforts are being encouraged so as to prospectively collect bona fide cases of DILI from
which quality data and biological samples could
be obtained3,4.
The incidence of drug-related liver disease is, in
general, poorly documented because most of the
data come from retrospective studies in specific
cohorts or using databases of prescriptions5-12.
There is a single published prospective community-based study, which was performed in France
over a three-year period and found an annual incidence of hepatic reactions to drugs of 14 cases
per 100,000 inhabitants13 (16 times as high as the
number notified to the French reporting system
of adverse drug reactions). To be included as
true cases in this study, the patients had to have
symptoms, so this latter figure is probably an
underestimation of the actual number of cases
that occurred.
The relative incidence of DILI as compared with
other liver diseases has also been assessed in a
number of studies. The diagnosis of drug hepatotoxicity is considerably less common than that of
other causes of liver disease. In the total of jaundiced patients admitted to a general hospital, toxic
liver injury accounted for 4-10% of instances14-16,
but most cases of DILI in a recent study were as
a result of acetaminophen toxicity, with idiosyncratic hepatotoxicity occurring in only 0.7% of
patients16. In a study carried out in England of patients hospitalized with serum aspartate amino-
H E P A T O L O G Y REVIEWS
Drug-induced liver injury. Causality assessment. Determinant of prognosis.
Chronic DILI.
15
Hepatology Rev. 2007;4
transferase (AST) levels greater than 400 IU/l, the
prevalence of drug hepatotoxicity was 9%17. Among
hospitalized patients, the incidence of DILI has
been found to range between 0.7 and 1.4%18,19. In
a large cohort of patients with severe acute hepatitis, 30% were of unknown cause and almost of
them had previous exposure to drugs. In this
study, the incidence of serious acute liver disease
probably related to drugs was 7.4 per 10 6 inhabitants per year20.
The frequency of DILI associated to specific
drugs is unknown. At best, scattered data for the
numerator (total number of affected subjects) are
available for some medications, but information on
the denominator is derived mainly from prescribing
data (as a surrogate for data on number of persons
and time of exposure), which inaccurately reflect
the population exposed. Some studies (mainly retrospective) have yielded consistent figures on the
absolute frequency of hepatotoxicity for a few drugs
(e.g. isoniazid, aspirin or diclofenac). Although data
are lacking, the frequency of unpredictable hepatotoxicity associated with the use of most medications is believed to be between 1 per 10,000 to
1 per 100,000 exposed persons.
Among group of drugs, antibacterial agents,
nonsteroidal anti-inflammatory drugs, and anticonvulsants rank as the main compounds incriminated
in DILI in two recent studies reporting the results
of the Spanish and American Registries of hepatotoxicity4,21. In these two large case series, amoxicillinclavulanate was also the single agent responsible
for the highest number of incidences.
H E P A T O L O G Y REVIEWS
Clinical Presentation
and Determinants of Outcome
16
In standard clinical practice, DILI may present
in several ways (clinical and pathological) that
simulate known forms of acute and chronic liver
disease, with the severity ranging from subclinical elevations in liver enzyme concentrations to
acute liver failure. Mainly, drugs tend to induce
acute hepatitis, cholestasis, or a mixed condition.
A clinical picture resembling acute viral hepatitis with
jaundice, malaise, anorexia, nausea, and abdominal
pain is the principal presentation, but because every
liver cell may be the target of drug-induced toxicity, many other expressions of hepatotoxicity may
be evident, including chronic hepatitis, cirrhosis,
vein occlusion disease or neoplasm22.
Liver histology (although not very specific and at
best “compatible with”) is the ideal tool to date for
defining the pattern of liver damage. However,
since a liver biopsy specimen is often not available,
the pattern of drug-related liver injury is, from a
practical standpoint, classified according to laboratory data23.
Acute hepatocellular (cytotoxic, cytolytic) type of
liver injury is defined by alanine aminotransferase
(ALT) > 2-fold that of the upper limit of normal
(ULN) or an ALT/AP ratio ≥ 523. Patients with this
particular type of liver damage have nonspecific
clinical features, and jaundice is not always evident. Sometimes there are clues of drug allergy
such as fever, rash, or peripheral eosinophilia. Serum levels of aminotransferase are markedly increased. Liver histology shows variable degrees
of cell necrosis and inflammation, mainly in zone
3 of the hepatic acini, sometimes with an abundance of eosinophils in the liver infiltrate, which is
consistent with a toxic etiology22,24-27. These expressions of hepatotoxicity are observed with many
drugs (Table 1). Patients with acute hepatocellular
injury related to drugs are at risk of acute liver
failure. The observation by the late Hyman Zimmerman, known as “Hy’s rule”22, predicts a mean mortality (or its surrogate marker, liver transplantation)
of 10% for jaundiced patients with acute toxic
hepatocellular damage (providing total bilirubin is
not elevated as a result of other causes such as
biliary obstruction or Gilbert’s disease). Two recent
studies4,28 have validated this observation and, using multivariate analysis, had indicated that apart
from total bilirubin and the hepatocellular type of
injury, other variables such older age, female gender, and AST levels were independently associated
with a poor outcome4,28. On the contrary, it has
been recently suggested that eosinophilia accompanying DILI may be associated with a better
short-term prognosis. This comes from the observation that in a large case-series of disulfiram-induced hepatocellular hepatitis, peripheral and hepatic eosinophilia was significantly more common in
patients who survived to the hepatic injury than
in those who had a fulminant course29, findings that
later on were confirmed in a retrospective review
of 570 case reports and case series published of
DILI from several drugs30. Similarly, none of the
patients included in the Spanish Registry with idiosyncratic DILI who died, evolved to liver failure, or
required a liver transplantation had eosinophilia,
whereas this feature was found in the 23% of the
patients with milder outcomes4.
Acute cholestatic injury, defined as an increase in
serum alkaline phosphatase (AP) >2 x ULN, or by
an ALT/AP ≤ 2, is classified into two subtypes: pure,
“bland” or canalicular cholestasis; and acute cholestatic or hepatocanalicular hepatitis. Patients with
acute cholestasis usually present with jaundice and
itching. The canalicular pattern is characterized by
an increase in conjugated bilirubin, AP and gamma
glutamyl transpeptidase with minimal or no impair-
Raúl J Andrade, et al.: Drug-induced Hepatotoxicity
Table 1. Medications, herbal products and illicit drugs related to the hepatocellular-type of damage
Acarbose
Allopurinol
Amiodarone
Amoxicillin, ampicillin
Anti-HIV: (didanosine, zidovudine, protease inhibitors)
NSAIDs (AAS, ibuprofen, diclofenac, piroxicam, indometacin)
Asparaginase
Bentazepam
Chlormethiazole
Cocaine, ecstasy and amphetamine derivatives
Diphenytoin
Disulfiram
Ebrotidine
Fluoxetine, paroxetine
Flutamide
Halothane
Hypolipemics; lovastatin, pravastatin, simvastatin, Atorvastatin
Isoniazid
Ketoconazole, mebendazole, albendazole, pentamidine
Mesalazine
Methotrexate
Minocycline
Nitrofurantoin
Nefazodone
Omeprazole
Penicillin G
Pyrazinamide
Herbal remedies:
Germander (Teucrium chamaedrys), senna
Pennyroyal oil, kava-kava
Camellia sinensis (green tea); Chinese herbal medicines
Risperidone
Ritodrine
Sulfasalazine
Telithromycin
Terbinafine
Tetracycline
Tolcapone
Topiramate
Trazodone
Trovafloxacin
Valproic acid
Venlafaxine
Verapamil
Vitamin A
Ximelagatran
Other injury
Granuloma
Phospholipidosis, cirrhosis
Comments
FHF
Hypersensitivity
Nimesulide; withdrawn
Steatosis
Chronic hepatitis
Cholestatic hepatitis
Cirrhosis
Chronic hepatitis
FHF
FHF
Hypersensitivity
FHF
FHF
FHF
Granuloma, chronic hepatitis
Chronic hepatitis
Steatosis, fibrosis, cirrhosis
Chronic hepatitis, steatosis
Chronic hepatitis
FHF
FHF
Autoimmune features
Autoimmune features
FHF, withdrawn
Prolonged cholestasis
FHF
Hypersensitivity
Cholestatic hepatitis
Micro-steatosis
FHF
FHF
FHF, withdrawn
Chronic hepatitis
FHF, withdrawn in
Europe
Micro-steatosis
Granuloma
Fibrosis, cirrhosis
FHF, discontinued
Features of hypersensitivity include fever, rash and eosinophilia. FHF: Fulminant hepatic failure.
ment in serum transaminases. Liver biopsy shows
hepatocyte cholestasis and dilated biliary canaliculi
with bile plugs, but with little or no inflammation
and necrosis27. Anabolic and contraceptive steroids typically produce this expression of hepatotoxicity. Symptoms in the hepatocanalicular type of
H E P A T O L O G Y REVIEWS
Compound
17
Hepatology Rev. 2007;4
Table 2. Compounds associated with the cholestatic or mixed-type damage
Compound
Injury
Comment
Chronic cholestasis
Chronic cholestasis
Chronic cholestasis
VBDS
Cholestasis without hepatitis (canalicular/bland/pure jaundice)
Estrogens, contraceptive steroids and anabolic-steroids
Cholestasis with hepatitis (hepatocanalicular jaundice)
Amoxicillin-clavulanic acid
Atorvastatin
Azathioprine
Benoxaprofen (withdrawn)
Bupropion
Captopril, enalapril, fosinopril
Carbamazepine
Carbimazole
Cloxacillin, dicloxacillin
Clindamycin
Ciprofloxacin, norfloxacin
Cyproheptadine
Diazepam, nitrazepam
Erythromycins
Gold compounds, penicillamine
Chronic cholestasis
Chronic cholestasis
VBDS
Chronic cholestasis
Chronic cholestasis
VBDS
Chronic cholestasis
VBDS
Herbal remedies: Chaparral leaf (Larrea tridentate); glycyrrhizin,
FHF*
greater celandine (Chelidonium majus), Herbalife ®*
Irbesartan
Chronic cholestasis
Lipid lowering agents (“statins”)
Macrolide antibiotics
Mianserin
Mirtazapine
Chronic cholestasis
Phenothiazines (chlorpromazine)
Chronic cholestasis
Rofecoxib, celecoxib
Rosiglitazone, Pioglitazone
Roxithromycin
Chronic cholestasis
Sulfamethoxazole-trimethoprim
Chronic cholestasis
VBDS
Sulfonamides
Chronic cholestasis
Sulfonylureas (glibenclamide, chlorpropamide)
Sulindac, piroxicam, diclofenac, Ibuprofen
Terbinafine
Chronic cholestasis
VBDS
Tamoxifen
Hepatocellular, peliosis Chronic cholestasis
Tetracycline
Chronic cholestasis
Ticlopidine & clopidogrel
Chronic cholestasis
Thiabendazole
VBDS
Tricyclic antidepressants (Amitryptiline, Imipramine)
Chronic cholestasis
VBDS
Sclerosing cholangitis-like cholangiodestructive
(primary biliary cirrhosis)
Floxuridine (intra-arterial)
Chlorpromazine, ajmaline
H E P A T O L O G Y REVIEWS
VBDS: Vanishing bile duct syndrome; FHF: Fulminant hepatic failure.
18
damage include abdominal pain and fever and, as
such, resembling acute biliary obstruction. However,
the associated hypersensitivity features which sometimes occur are an important clue toward the diagnosis of hepatotoxicity. Liver biopsy reveals variable
degrees of portal inflammation and hepatocyte necrosis, in addition to marked cholestasis of centri-
lobular predominance22,24,27. Older age has been
found to increase the likelihood of drug-induced hepatotoxicity being expressed as cholestatic damage4,31.
Typical examples of drugs that cause this variety
of liver damage are amoxicillin-clavulanate, macrolide antibiotics, and phenothiazine neuroleptics,
but many others have a similar capacity (Table 2).
In the mixed hepatic injury, the clinical and biological picture is intermediate between the hepatocellular and the cholestatic patterns, and features
of either type may predominate. By definition, the
ALT/AP ratio is between 2 and 5. Allergy manifestations are often present, as well as a granulomatous
reaction in the liver biopsy specimen. When faced
with mixed hepatitis clinical picture, the gastroenterologists should always seek a culprit medication since this type of injury is far more characteristic of drug-induced hepatotoxicity than of
viral hepatitis22. Almost all drugs that produce
cholestatic injury are also capable of inducing a
mixed pattern.
Although drug-induced acute cholestatic and
mixed lesions less frequently progress to acute
liver failure than does the hepatocellular type, their
resolution is generally slower. Indeed, a long-term
follow-up of a large cohort in the Spanish Registry
demonstrated a significantly higher trend towards
becoming chronic in cholestatic/mixed cases (9%)
compared to hepatocellular-type disease (4%)32,
although in the hepatocellular pattern the severity
was greater, with further cases of cirrhosis. Besides
this, cardiovascular and central nervous system
drugs were the main groups leading to chronic
liver damage32. A more detailed study (three-year)
on the natural history of DILI is ongoing.
An Approach to the Diagnosis
The diagnosis of DILI remains a challenge because, except for the very rare circumstances in
which an unintentional positive rechallenge may
confirm the putative involvement of a drug, the
evidence that is usually collected is often circumstantial, based on subjective impressions from previous experiences, and which can lead to inaccurate diagnosis33. The process is time-consuming
and delays clinical judgment, at least until other
possible causes of liver disease have been excluded. The use of causality assessment methods
does add consistency to the diagnostic process,
either by translating the suspicion into a quantitative score, or by providing a framework that emphasizes the features that merit attention in cases
of suspected hepatic adverse reaction. The causality assessment is a complex process whose detailed discussion is beyond the scope of this review
due to limitations of space, and hence, readers are
referred to a recent review34.
The diagnosis is subjective and is made with
varying levels of confidence based on a combination of factors including temporal associations and
with respect to latency, the rate of improvement
after cessation of the drug, and the definitive exclu-
sion of alternative possible causes (Table 3)35.
Confounding features include multiple drugs prescribed, lack of information on doses consumed,
as well as the stop and start dates36. A careful
“step-by-step” approach is outlined in figure 137.
A controversial issue is the role of liver biopsy
in the diagnosis of DILI. Indeed, since there are
no histologic findings specific for toxic damage,
liver biopsy should not be performed routinely for
this indication27,38. Furthermore, a liver biopsy
specimen, which is often taken several days after
the clinical presentation of the symptoms when the
pathologic features are beginning to wane, may
generate perplexity and confusion in cases in
which chronologic sequence criteria are critical
and when exclusion of alternative causes appear
to incriminate the drug.
Nowadays, a reasonable approach for performing a liver biopsy in patients with suspected DILI
is restricted26 to when the patient may have an
underlying liver disease, and hence it is difficult to
ascribe the picture to the candidate drug or to a
recrudescence of the disease, to characterize the
pattern of injury with those drugs that had not been
previously incriminated in hepatotoxicity25,39,40 and
for identifying more severe or residual lesions (e.g.
fibrosis), which could have prognostic significance
(Table 4). For instance, in some chronic variants of
hepatotoxicity, clinical and laboratory features reflect poorly the severity of the liver injury39,41 and a
liver biopsy may clarify its true magnitude. Furthermore, severe bile duct injury during cholestatic
hepatitis has been shown to be predictive of clinical evolution into chronic cholestasis53, and in a
retrospective study, the presence of fibrosis in the
index liver biopsy had been related to the development of chronic liver disease42.
Over the last three decades, several groups
have developed methods to improve the consistency, accuracy, and objectiveness in causality assessment of adverse drug reactions. The qualities
required for any scoring system are, usually, reproducibility and validity43. Reproducibility ensures an
identical result when the scales are applied and
irrespective of the user. Validity refers to the capacity to distinguish between cases when the drug
is responsible, and cases when the drug it is not
responsible.
The Council for International Organizations of
Medical Sciences/Russel Uclaf Causality Assessment (CIOMS/RUCAM) scale provides a scoring
system for six axes in the decision strategy. The
categories of suspicion are “definite or highly probable” (score > 8), “probable” (score 6-8), “possible”
(score 3-5), “unlikely” (score 1-2), and “excluded”
(score (≤ 0)44,45. The major drawback is its complexity. It requires training and is less efficient when
H E P A T O L O G Y REVIEWS
Raúl J Andrade, et al.: Drug-induced Hepatotoxicity
19
Hepatology Rev. 2007;4
Table 3. Clinical work-up to identify other possible causes of liver disease
Test
Condition
Commentary
Viral serology:
IgM anti-HAV
IgM anti-HBc
Anti-HCV, RNA-HCV (RT-PCR)
IgM-CMV
IgM-EBV
Herpes virus
Bacterial serology: Salmonella,
Campylobacter, Listeria, Coxiella
Serology for syphilis
Viral hepatitis
Less frequent in older patients, especially
Hepatitis A
Search for epidemiologic risk factors
Outcome may be similar to that of DILI
following de-challenge
Bacterial hepatitis
If persistent fever and/or diarrhea
Secondary syphilis
Autoimmunity (ANA, ANCA, AMA, ASMA,
anti-LKM-1) AST/ALT ratio > 2
Autoimmune hepatitis,
Primary biliary cirrhosis
Alcoholic hepatitis
Ceruloplasmine, urine cooper
Alpha-1 antitrypsin
Transferrin saturation
Brilliant eco texture of the Liver.
Wilson’s disease
Deficit of α-1 antitrypsin
Hemochromatosis
Nonalcoholic steatohepatitis
Transaminase levels markedly high
Ischemic hepatitis
Dilated bile ducts by image procedures (AU,
CT, MRCP and ERCP)
Biliary obstruction
Multiple sexual partners.
Disproportionately high serum AP
levels
Women, ambiguous course following dechallenge. Other autoimmunity features
Alcohol abuse. Moderate increase in
transaminases despite severity at
presentation
Patients < 40 years
Pulmonary disease
In anicteric hepatocellular damage.
Middle-aged men and older women
In anicteric hepatocellular damage.
Obesity, metabolic syndrome
Disproportionately high AST levels.
Hypotension, shock, recent surgery,
heart failure, antecedent vascular
disease, elderly
Colic abdominal pain, cholestatic/mixed
pattern
H E P A T O L O G Y REVIEWS
ALT: alanine aminotransferase; AP: alkaline phosphatase; AST: aspartate aminotransferase; AU: abdominal ultrasound examination; AntiHAV: hepatitis A antibody; Anti-HBc: hepatitis B core antibody; Anti-HCV: hepatitis C antibody; anti-LKM-1: liver-kidney microsomal
antibody type 1; AMA: antimitochondrial antibody; ANA: antinuclear antibody; ANCA: perinuclear antineutrophil cytoplasmic antibody;
ASMA: anti-smooth muscle antibody; BPC: Biliary primary cirrhosis; CMV: cytomegalovirus; CT: computed tomography; EBV: EpsteinBarr virus; ERCP: endoscopic retrograde cholangiography; MRCP: magnetic resonance cholangiography.
20
a user is unfamiliar with the format. The scale may
seem cumbersome and, while reading across the
page, care needs to be taken not to misunderstand the questions, otherwise careless errors
can be made34.
More recently, Maria V and Victorino R from Portugal developed a simplified scoring system to
overcome the abovementioned problems. Called
the Clinical Diagnostic Scale46 (also termed the
M&V scale), it uses several features of the CIOMS/
RUCAM scale, while omitting and adding others
(Table 5). Concordance with the five classic degrees of probability of adverse drug reactions is
established on the basis of the tabulated score as
follows: “definite” (score > 17), “probable” (score
14-17), “possible” (score 10-13), “unlikely” (score 6-9),
and “excluded” (score < 6). The authors highlighted some limitations of the scale: the instrument
performs poorly in atypical cases of drugs with
unusually long latency periods or chronic outcome.
There is room for improvement in the exclusion of
alternative causes of liver injury by more clearly
specifying the clinical conditions to be excluded, as
well as including detailed criteria for exclusion. The
main advantage of the M&V scale is its ease of
application in standard clinical practice.
The merits of the CIOMS and the M&V scales
and their degree of concordance were compared in two studies47,48. These two studies clearly
showed that the concordance of assessment was
low because the two methods assigned different
weightings to the assessment criteria, and as such,
the reasons for discordance could be clearly identified, and the CIOMS scale, although far from
being a perfect instrument, provides a uniform basis from which to develop a more precise approach
in determining the causes of DILI. Indeed, medical
journals should insist on the application of the scale
as a quality control prior to accepting reports of
hepatotoxicity.
In the near future, it would be feasible in the
short term to develop some refinements to make
Raúl J Andrade, et al.: Drug-induced Hepatotoxicity
Liver disease
Suspicion
Drug exposure data
and chronology
Not compatible
If compatible assess
Hepatotoxic potential
Search for an alternative diagnosis
Found
Not found
Assess features suggesting drug-toxicity
– Allergic manifestations
– Course on de-challenge
– Look for possible unintentional re-challenge data
– Liver biopsy findings (if performed) and biochemical “signature”
Specific therapy
Figure 1. Diagnostic algorithm in cases of suspected drug-induced hepatotoxicity.
Table 4. Rationale for performing liver biopsy in a case suspected of having drug-induced hepatotoxicity
Clinical setting
Presentation
Any clinical context
Acute or chronic liver disease
(possible autoimmune hepatitis)*
Putative novel drugs or not previously incriminated in liver toxicity
Female with autoantibody seropositive and
high serum gamma globulin and immunoglobulin G levels at presentation
Incomplete or ambiguous de-challenge
Chronic alcoholism
Acute deterioration during aversive therapy (disulfiram, carbimide
calcium)
Any acute liver deterioration in a patient with
e.g. worsening of liver function in a patient with primary biliary cirrhosis
underlying liver disease
receiving rifampicin
Chronic impairment in liver tests in
Especially if constitutional symptoms and/or clinical signs of portal
non-jaundiced patients
hypertension are disclosed
Young patients with seronegative acute hepatitis Moderate decrease in ceruloplasmin levels or slight increases in urinary
or chronic liver disease
copper excretion
*Autoimmune hepatitis may be triggered by drugs.
Table 5. Comparison of the scores for individual axes of the CIOMS and Maria & Victorino diagnostic scales
Chronology criterion
From drug intake until event onset
From drug withdrawal until event onset
Time-course of the reaction
Risk factors
Age
Alcohol
Concomitant therapy
Exclusion of non-drug-related causes
Literature data
Rechallenge
Score
+2 to +1
+1 to 0
–2 to +3
+1 to 0
+1 to 0
–3 to 0
–3 to +2
0 to +2
–2 to +3
Maria & Victorino criteria
Score
Chronology criterion
From drug intake until event onset
From drug withdrawal until event onset
Time-course of the reaction
Exclusion of alternative causes
+1 to +3
–3 to +3
0 to +3
–3 to +3
Extrahepatic manifestations
Literature data
Rechallenge
0 to +3
–3 to +2
0 to +3
H E P A T O L O G Y REVIEWS
CIOMS criteria
21
Hepatology Rev. 2007;4
H E P A T O L O G Y REVIEWS
the CIOM scale more realistic; more relevant data
can be incorporated and low-impact items need
to be deleted from the scoring system. This task
will be helped by using large databases of bona
fide cases of hepatotoxicity34. Nevertheless, there
is the need to validate a new instrument with an
abridged scale that would provide a better approximation to the truth –the likelihood that a
given case of hepatitis is due to a specific drug–
at the very beginning of the patient evaluation
process when key clinical decisions need to be
taken. The diagnosis needs to be made with confidence on admission of the patient, and maintained while further confirmatory information is
gathered. This would be the goal of a clinical assessment tool for the evaluation of drug-induced
hepatotoxicity35.
22
5.
6.
7.
8.
9.
10.
11.
12.
Therapy
13.
The treatment of idiosyncratic drug hepatotoxicity is supportive. Jaundiced patients with acute
hepatocellular hepatitis probably need close
vigilance in an in-hospital setting. Antidotal therapy is restricted to acetaminophen overdose.
N -acetylcysteine, by repletion of glutathione
stores, prevents injury if it is administered within
24 hours after intake. Currently, a randomized trial
on the efficacy of N-acetylcysteine in acute liver
failure not related to paracetamol is underway in
the USA49.
Anecdotal reports suggest that corticosteroids
may be useful in drug hepatotoxicity associated
with a general hypersensitivity syndrome. Similarly,
there appears to be a rationale for the use of ursodeoxycholic acid in patients with prolonged toxic
cholestasis. However, the lack of properly conducted controlled trials hampers a clear recommendation on the use of these two agents. In addition to cholestyramine, the molecular adsorbent
recycling system (MARS) has also been advocated
for pruritus relief in isolated case reports of druginduced toxic cholestasis50. Parenteral administration of fat-soluble vitamins in prolonged cholestasis
may also be needed.
14.
References
1. Schoepfer AM, Engel A, Fattinger K, et al. ”Herbal” does not
mean ”innocuous”: 10 cases of severe hepatotoxicity associated
with dietary supplements from Herbalife ® products. J Hepatol
2007 [in press].
2. Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in
the United States. Ann Intern Med 2002;137:947-54.
3. Hoofnagle JH. Drug-induced liver injury network (DILIN). Hepatology 2004;40:773.
4. Andrade RJ, Lucena MI, Fernández MC, et al. Drug-induced
liver injury: an analysis of 461 incidences submitted to the Span-
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
ish Registry over a 10-year period. Gastroenterology 2005;129:
512-21.
Almdal TP, Sorensen TI. Incidence of parenchymal liver diseases
in Denmark, 1981 to 1985: analysis of hospitalization registry
data. The Danish Association for the Study of the Liver. Hepatology 1991;13:650-5.
Garcia Rodriguez LA, Perez Gutthann S, Walker AM, Lueck L.
The role of nonsteroidal anti-inflammatory drugs in acute liver
injury. BMJ 1992;305:865-8.
Perez Gutthann S, Garcia Rodriguez LA. The increased risk of
hospitalizations for acute liver injury in a population with exposure
to multiple drugs. Epidemiology 1993;4:496-501.
Carson JL, Strom BL, Duff A, et al. Acute liver disease associated with erythromycins, sulfonamides, and tetracyclines. Ann
Intern Med 1993;119:576-83.
Byron D, Minuk GY. Clinical hepatology: profile of an urban,
hospital-based practice. Hepatology 1996;24:813-5.
Garcia Rodriguez LA, Ruigomez A, Jick H. A review of epidemiologic research on drug-induced acute liver injury using the
General Practice Research Database in the United Kingdom.
Pharmacotherapy 1997;17:721-8.
Duh MS, Walker AM, Kronlund KH Jr. Descriptive epidemiology
of acute liver enzyme abnormalities in the general population of
central Massachusetts. Pharmacoepidemiol Drug Saf 1999;8:
275-83.
Galan MV, Potts JA, Silverman AL, Gordon SC. Hepatitis in a
United States tertiary referral center. J Clin Gastroenterol 2005;
39:64-7.
Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced
hepatic injuries: a French population-based study. Hepatology
2002;36:451-5.
Whitehead MW, Hainsworth I, Kingham JGC. The causes of
obvious jaundice in South West Wales: 2000. Gut 2001;48:
409-13.
Björnsson E, Ismael S, Nejdet S, Kilander A. Severe jaundice in
Sweden in the new millennium: causes, investigations, treatment
and prognosis. Scand J Gastroenterol 2003;38:86-94.
Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of newonset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States? Am J Gastroenterol 2007;
102:558-62
Whitehead MW, Hawkes ND, Hainsworth I, Kingham JGC. A
prospective study of the causes of notably raised aspartate aminotransferase of liver origin. Gut 1999;45:129-33.
Bagheri H, Michel F, Lapeyre-Mestre M, et al. Detection and
incidence of drug-induced liver injuries in hospital: a prospective
analysis from laboratory signals. Br J Clin Pharmacol 2000;
50:479-84.
Meier Y, Cavallaro M, Roos M, et al. Incidence of drug-induced
liver injury in medical inpatients. Eur J Clin Pharmacol 2005;
61:135-43.
Ibáñez L, Pérez E, Vidal X, Laporte JR, the Grup d´Estudi Multicentric d´Hepatotoxicitat Aguda de Barcelona (GEMHAB). Prospective surveillance of acute serious liver disease unrelated to
infectious, obstructive, or metabolic diseases: epidemiological
and clinical features, and exposure to drugs. J Hepatol 2002;
37:592-600.
Chalasani N, Fontana R, Watkins PB, et al. Drug-induced liver
injury network (DILIN). Prospective study: initial results. Am J
Gastroenterol 2006;101:S168.
Zimmerman HJ. Hepatotoxicity. The adverse effects of drugs and
other chemicals on the liver (2nd ed.). Philadelphia: Lippincott
Williams & Wilkins, 1999.
Benichou C. Criteria of drug-induced liver disorders. Report of an
International Consensus Meeting. J Hepatol 1990;11:272-6.
Farrell GC. Drug Induced Liver Disease. London: Churchill-Livingstone, 1994.
Andrade RJ, Lucena MI, Martín-Vivaldi R, et al. Acute liver injury
associated with the use of ebrotidine, a new H2-receptor antagonist. J Hepatol 1999;31:641-6.
Larrey D. Drug-induced liver diseases. J Hepatol 2000;32(suppl
1):77-88.
Goodman ZD. Drug hepatotoxicity. Clin Liver Dis 2002;6:
381-97.
Björnsson E, Olsson R. Outcome and prognostic markers in severe
drug-induced liver disease. Hepatology 2005;42:481-9.
Björnsson E, Nordlinder H, Olsson R. Clinical characteristics and
prognostic markers in disulfiram-induced liver injury. J Hepatol
2006;44:791-7.
Björnsson E, Kalaitzakis E, Olsson R. The impact of eosinophilia
and hepatic necrosis on prognosis in patients with drug-induced
liver injury. Aliment Pharmacol Ther 2007;25:1411-21.
Lucena MI, Andrade RJ, Fernandez MC, et al. Determinants of
the clinical expression of amoxicillin-clavulanate hepatotoxicity:
a prospective series from Spain. Hepatology 2006;44:850-6.
Raúl J Andrade, et al.: Drug-induced Hepatotoxicity
42. Aithal PG, Day CP. The natural history of histologically proved
drug-induced liver disease. Gut 1999;44:731-5.
43. Hutchinson TA, Lane DA. Assessing methods for causality assessment of suspected adverse drug reactions. J Clin Epidemiol
1989;42:5-16.
44. Danan G, Bénichou C. Causality assessment of adverse reactions to drugs I. A novel method based on the conclusions of
international consensus meetings: application to drug-induced
liver injuries. J Clin Epidemiol 1993;46:1323-30.
45. Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs. II. An original model for validation of
drug causality assessment methods: case reports with positive
rechallenge. J Clin Epidemiol 1993;46:1331-6.
46. Maria V, Victorino R. Development and validation of a clinical
scale for the diagnosis of drug-induced hepatitis. Hepatology
1997;26:664-9.
47. Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sánchez De La Cruz F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001;33: 123-30.
48. Aithal G, Rawlins M, Day C. Clinical diagnostic scale: a useful
tool in the evaluation of suspected hepatotoxic adverse drug reactions. J Hepatol 2000;33:949-52.
49. Lee WM. Acute liver failure in the United States. Semin Liver Dis
2003;23:217-26.
50. Huster D, Schubert C, Bess F, Mossner J, Caca K. Rofecoxibinduced cholestatic hepatitis: treatment with molecular adsorbent
recycling system (MARS). J Hepatol 2002;37:413-4.
H E P A T O L O G Y REVIEWS
32. Andrade RJ, Lucena MI, Kaplowitz N, et al. Outcome of acute
idiosyncratic drug-induced liver injury: Long-term follow-up in a
hepatotoxicity registry. Hepatology 2006;44:1581-8.
33. Aithal GP, Rawlins MD, Day CP. Accuracy of hepatic adverse
drug reaction reporting in one English health region. BMJ 1999;
319:1541.
34. Andrade RJ, Robles M, Fernandez-Castañer A, López-Ortega S,
López-Vega MC, Lucena MI. Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists
World J Gastroenterol 2007;13:329-40.
35. Kaplowitz N. Causality assessment versus guilt-by-association in
drug hepatotoxicity. Hepatology 2001;33:308-10.
36. Lee WM, Senior JR. Recognizing drug-induced liver injury:
current problems, possible solutions. Toxicol Pathol 2005;33:
155-64.
37. Andrade RJ, Camargo R, Lucena MI, González-Grande R. Causality assessment in drug-induced hepatotoxicity. Expert Opin
Drug Saf 2004;3:329-44.
38. Bianchi L. Liver biopsy in elevated liver function tests? An old
question revisited. J Hepatol 2001;35:290-4.
39. Andrade RJ, Lucena MI, Alcantara R, Fraile JM. Bentazepam-associated chronic liver disease. Lancet 1994;343:860.
40. Lucena MI, Andrade RJ, Rodrigo L, et al. Trovafloxacin-induced
acute hepatitis. Clin Infect Dis 2000;30:400-1.
41. Andrade RJ, Lucena MI, Aguilar J, et al. Chronic liver injury related with the use of bentazepam: an unusual instance of benzodiazepine hepatotoxicity. Dig Dis Sci 2000;45:1400-4.
23