The spectrum of drug-induced liver injury (DILI) is both diverse and complex. The first step in diagnosis is a suspicion of DILI based on careful consideration of recent comprehensive reports on the disease. There are some situations in which the suspicion of DILI is particularly strong. Exclusion of other possible etiologies according to the pattern of liver injury is essential for the diagnosis. In patients with suspected DILI, diagnostic scales, such as the Councils for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) scale, may be helpful for the final diagnosis. Early management of DILI involves prompt withdrawal of the drug suspected of being responsible, according to serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin (T-Bil). However, as DILI patients may show resolution of liver injury without discontinuation of the drug, it should be carefully evaluated whether the suspected drug should be discontinued immediately with adequate consideration of the importance of the medication.

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Figure 1 Percentages of methods for causality assessment utilized for diagnosis of DILI, reported during the last decade.

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Figure 2 Algorithm for management of DILI. A: When new drugs are started; B: When liver dysfunction is recognized. The type, severity, and causes of liver injury should be assessed promptly. ¹Imaging studies such as ultrasonography should be performed in cases with suspected bile duct disorders.

Drug-induced liver injury (DILI) is a common liver disease which generally occurs between 5 and 90 d after drug ingestion. The clinical picture of the disease is variable, ranging from transient mild elevation of liver enzymes to fulminant liver failure leading to death. DILI has been reported to be a cause of fulminant liver failure in 13%-30% of cases[1-3]. DILI is divided into three types: hepatocellular, cholestatic, and mixed according to the Councils for International Organizations of Medical Sciences (CIOMS)[4,5]. Hepatocellular type is defined by alanine aminotransferase (ALT) > 2 ULN (upper limits of normal) or R ≥ 5, where R is the ratio of serum activity of ALT/serum activity of alkaline phosphatase (ALP), both of which are expressed as multiples of the ULN. Liver injury is likely to be more severe in hepatocellular type than in cholestatic/mixed type, and patients with elevated bilirubin levels in hepatocellular liver injury indicating serious liver injury with fatalities, are found at a rate of 0.7 to 1.3/100 000 individuals receiving a given drug[2]. Cholestatic type is defined by ALP > 2 ULN or R ≤ 2 and mixed type is defined by ALT > 2 ULN and 2 < R < 5. Patients with cholestatic/mixed type are likely to develop chronic disease more frequently than those with hepatocellular type[6]. For most drugs, the risk of liver injury is estimated to be 1-10/100 000 persons exposed. A recent report indicated that DILI occurs in 1/100 patients hospitalized in internal medicine departments[7]. Thus, DILI is not a rare condition and sometimes leads to serious disease. Rapid and accurate diagnosis of DILI is important in daily practice. However, diagnosis of DILI is not easy and is mainly based on circumstantial evidence. As there is no gold standard for diagnosis, it is essential to exclude other possible etiologies for accurate diagnosis. A number of scoring systems have been proposed, but even experts may make different judgments using these systems[8]. This review summarizes recent trends regarding DILI and proposes practical guidelines for its diagnosis and early management.

A recent report on DILI based on the database of the World Health Organization (WHO) indicated that the number of cases of DILI has been increasing since the 1990s[9]. The WHO began monitoring adverse drug reactions in 1968, and there are more than 3 million reports on their database (http://www.who-umc.org). This large database is useful for obtaining information on previous reports regarding adverse reactions to drugs. Acetaminophen, drugs against human immunodeficiency virus (HIV), troglitazone, anti-convulsants (such as valproate), analgesics, antibiotics, and anti-cancer drugs are common causative agents of DILI with fatalities (Table 1)[9]. Therefore, particular attention should be paid to patients taking one or more of these drugs who show liver injury. Analysis of 461 cases in Spain over a 10-year period indicated that amoxicillin/clavulanate was the most common drug involved in DILI (59/461 cases, 12.8%)[10]. Moreover, in addition to amoxicillin/clavulanate, they reported that bentazepam, atorvastatin, and captopril were frequent causative drugs leading to chronic liver damage[6]. In a retrospective study in Italy, hydroxymethylglutaryl-CoA reductase inhibitors were the most frequent causative drugs among 1069 cases of DILI (4.5% of cases of adverse drug reactions)[11]. Other studies also showed acetaminophen, anti-retroviral therapy, antibiotics, lipid-lowering drugs, and anti-convulsants to be responsible for DILI[12-18]. In recent analyses in Asia, traditional alternative medicines were reported to be the most common causes of DILI, in contrast to those in Western countries[19]. Table 2 summarizes the drugs suspected to be responsible for DILI and the types of liver injury reported in the literature from various regions[3,6,7,10,12,17-19]. In general, antibiotics, non-steroidal anti-inflammatory drugs, and anti-convulsants are frequent causative drugs of DILI. Importantly, although not shown in Table 2, two or more drugs were suspected to be responsible for DILI in about 10% of cases[10,13]. Furthermore, it is notable that the incidences of DILI caused by herbal remedies or traditional medicines have been increasing over the last decade. The causative drugs for DILI are therefore becoming more diverse and complex. The first and most important step in managing cases of suspected DILI is to gain a detailed understanding of the causative drugs. In the United States of America, the Food and Drug Administration (FDA) records drug toxicity (http://www.fda.gov/medwatch), and the Drug Induced Liver Injury Network was established in 2003 to collect data on DILI in a prospective manner[1]. A similar network is also in place in Spain[6]. A worldwide network which collects all the reports on adverse drug reactions is needed to provide comprehensive information on DILI, which would facilitate accurate diagnosis and early management.

As described above, DILI has a wide spectrum of manifestations, ranging from asymptomatic mild biochemical abnormalities to severe hepatitis with jaundice. In most cases of DILI, liver injury would be expected to improve following discontinuation of the drug suspected to be responsible. On the other hand, some DILI patients may even show resolution of liver injury without discontinuation of the drug. Therefore, it should be carefully evaluated whether the suspected drug should be discontinued with adequate consideration of the importance of the medication. However, once liver injury progresses to acute liver failure, this has a high fatality rate without liver transplantation[107]. Although there are no definitive criteria for cessation of the suspected causative drug, some textbooks suggest that ALT less than 5 × ULN and no symptoms allow continuation of the suspected drug with close observation, whereas ALT of more than 8 × ULN indicates the need to discontinue the suspected drug[108,109]. Another textbook suggests that the suspected drug should be stopped only when abnormalities in serum bilirubin, albumin, or prothrombin time-international normalized ratio (PT-INR) are found in addition to elevated serum ALT[20]. Zimmerman reported that elevation of transaminase activities in combination with jaundice suggests serious liver injury with fatalities. These findings were discussed at the National Institutes of Health in Bethesda, and are recognized as Hy’s rule for monitoring DILI, which states that elevation of liver enzymes (AST or ALT more than 3 × ULN or ALP more than 1.5 × ULN) in combination with elevated bilirubin (more than 3 × ULN) at any time after starting a new drug may imply serious liver injury and the suspected drug should be stopped[110]. Two recent studies have shown that hepatocellular liver injury with jaundice is sometimes fatal even if the suspected drug is stopped[9,10]. On the other hand, a recent study showed that cases fulfilling Hy’s rule did not always lead to death from DILI[18]. As many drugs can induce asymptomatic elevation of liver enzyme levels without severe hepatotoxicity, mild elevations in transaminases do not always require withdrawal of the causative drug. Based on these observations, the FDA recently proposed draft guidelines (http://www.fda.gov/cder/guidance/7507dft.htm) in which ALT greater than 8 × ULN, ALT greater than 5 × ULN for two weeks, ALT greater than 3 × ULN in association with serum bilirubin greater than 2 × ULN, more than 1.5 × PT-INR, or symptoms of liver injury should be used to predict severe hepatotoxicity and recommend discontinuing the drug[2]. Hepatocellular liver injury with severe jaundice should be treated carefully, and requires prompt referral to a center with hepatologists. As mentioned above, severe liver injury and fatality occur in cases of hepatocellular injury with jaundice. On the other hand, cholestatic DILI cases could be observed with continuation of the suspected causative drug, except if symptoms related to liver injury occur, such as jaundice, elevation of serum bilirubin (more than 3 × ULN), or prolongation of PT-INR (more than 1.5 × ULN). There have been no reports of beneficial therapies except the use of N-acetylcysteine for acetaminophen hepatotoxicity. Corticosteroid therapy may be used in DILI cases with evident hypersensitivity, but it does not have proven benefits[107]. Management of DILI involves prompt withdrawal of the drug suspected to be responsible. A positive de-challenge is a 50% decrease in serum ALT within 8 d of discontinuation of the suspected drug in the hepatocellular type, which is also included in the CIOMS/RUCAM criteria[5,21]. On the other hand, improvement of biliary enzymes after cessation of the suspected drug usually requires a longer period in cholestatic type. However, the time course after cessation of the suspected drug does not always help in early diagnosis and management of DILI, because some patients should be evaluated promptly and managed as suspected DILI on first presentation.

Many drugs can cause abnormalities in liver function tests without any symptoms suggestive of liver disease. Preplanned liver function tests should be performed whenever treatment with a new drug is started. In patients with abnormalities in liver function tests without an obvious cause, a careful history, including not only hospital medications but also herbal remedies or supplements, should first be obtained. History taking should also include drug dosage, administration route, previous administration, any concomitant drugs, alcohol consumption, and underlying chronic liver disease and symptoms such as arthralgia. Moreover, family history of adverse drug reactions may be useful for the diagnosis of DILI. On physical examination, patients should be checked for fever, rash, or jaundice. In particular, jaundice should be evaluated carefully, because it is a sign of severe liver injury indicating the necessity for prompt cessation of the suspected drug. Liver function tests including serum transaminase, ALP, γ-glutamyl transpeptidase, and bilirubin, as well as hematological tests including eosinophil count and coagulation tests should be performed. Classification of the pattern of liver injury should be done as early as possible because clinical course, possible etiologies, and causative drugs are different for each pattern[111]. Other etiologies, such as viral infection, autoimmune liver disease, or biliary disease, should be excluded by serological tests or imaging studies if necessary. DILI cases with severe hepatitis showing elevation of serum bilirubin to more than 3 × ULN may lead to liver failure, and should be treated carefully with referral to the hepatologist after discontinuing all suspected drugs. The list of recommended tests which should be performed in the diagnosis of DILI in patients with liver injury are shown in Table 5. Although accidental readministration of the causative drug may be beneficial for diagnosis of DILI, it may lead to severe liver injury and may even be fatal, and so is not recommended. Moreover, the probability of DILI should also be evaluated using a diagnostic scoring system, such as the CIOMS/RUCAM criteria. However, there is as yet no gold standard set of diagnostic criteria. The initial treatment usually involves withdrawal of the suspected drug. If the causative drug cannot be discontinued because the patient is receiving many drugs or the underlying disease is serious, medications may be continued with careful monitoring. Additional tests, such as the DLST, LMT, or cytokine production test, may be beneficial to identify the causative drug (Figure 2).

The spectrum of DILI is both diverse and complex. Although liver injury is often mild and does not require treatment in these patients, DILI may lead to severe hepatitis with a risk of death. Therefore, adequate initial management after achieving an accurate diagnosis is important for physicians. Although the incidence of DILI is reported to be increasing, the precise frequency is difficult to estimate because of the lack of a worldwide monitoring system and the lack of a gold standard for diagnosis. Establishment of a worldwide network for monitoring the adverse events of drugs and a universal diagnostic system for DILI are important for accurate diagnosis, and may lead to better management of DILI.