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doi: 10.1111/j.1472-8206.2008.00566.x REVIEW Assessment of drug-induced liver injury in ARTICLE clinical practice Ma Isabel Lucenaa*, Miren Garcı´a-Corte´sb, Raquel Cuetoa, JL Lopez- Durana, Rau´l J Andradeb a Servicio de Farmacologı´a Clı´nica, Hospital Universitario Virgen de la Victoria, School o...

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Assessment of drug-induced liver injury in clinical practice Raul Andrade Fundamental & Clinical Pharmacology

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doi: 10.1111/j.1472-8206.2008.00566.x REVIEW ARTICLE

Assessment of drug-induced liver injury in clinical practice Ma Isabel Lucenaa*, Miren Garcı´a-Corte´sb, Raquel Cuetoa, JL LopezDurana, Rau´l J Andradeb a

Servicio de Farmacologı´a Clı´nica, Hospital Universitario Virgen de la Victoria, School of Medicine, Ma´laga, Spain; Coordinating Centre of the Grupo de Estudio para las Hepatopatı´as Asociadas a Medicamentos (GEHAM), Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Campus Universitario de Teatinos s/n, Ma´laga; Universidad de Ma´laga, Ma´laga, Spain b Unidad de Hepatologı´a, Servicio de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, School of Medicine, Ma´laga, Spain; Co-ordinating Centre of the Grupo de Estudio para las Hepatopatı´as Asociadas a Medicamentos (GEHAM), Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Campus Universitario de Teatinos s/n, Ma´laga; Universidad de Ma´laga, Ma´laga, Spain

Keywords causality assessment, drug-induced idiosyncratic hepatotoxicity, mechanism, pharmacovigilance, risk factors, type of injury

Received 4 October 2007; Revised 18 December 2007; Accepted 8 January 2008

*Correspondence and reprints: [email protected]

ABSTRACT

Currently, pharmaceutical preparations are serious contributors to liver disease, with hepatotoxicity ranking as the most frequent cause for acute liver failure and postmarketing regulatory decisions. The diagnostic approach of drug-induced liver injury (DILI) is still rudimentary and inaccurate 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 favour a toxic aetiology. Clinical and laboratory data may also be assessed with algorithms or clinical scales, which may add consistency to the clinical judgment by translating the suspicion into a quantitative score. The CIOMS/RUCAM instrument is considered at present the best method for assessing causality in DILI, although it could be improved through the use of large database of bona fide DILI cases for validation criteria.

Conflict of Interest: None. Supported partly by research grants from the Agencia Espan˜ola del Medicamento and from the Fondo de Investigacio´n Sanitaria (FIS 07-0980).

Drug-induced liver injury (DILI) is a leading health problem especially in a globally expanding commercialization of new drugs and the increasing exposure of patients to new compounds. This is expected to increase because of the number of drugs being consumed, prescription and non-prescription, as well as because of the current tendency towards pharmacologically active complementary and alternative medicines, dietary supplements, recreational substances and special diets [1]. As a consequence, DILI ranks as the first cause of acute liver failure in USA [2] and Scandinavian countries and

is the main reason for post-commercialization decisions by regulatory bodies and withdrawal of drugs from the market despite of a rigorous pre-clinical and clinical review process. However, DILI is a relatively neglected disease because of the rarity of its diagnosis and the difficulty of attribution of causality. EPIDEMIOLOGY The incidence of drug-related liver disease is, in general, poorly documented, because most of the methods for

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screening populations for DILI have notorious drawbacks such as under-reporting, and data come from retrospective studies with insufficient information content particularly with regard to knowledge about automedication and herbal products [3–7]. Another drawback is that reports of specific drugs thought to have caused DILI in the period before the advent of serologic tests for the hepatitis B and C viruses could well have been mistaken for DILI when in fact the liver injury occurred as a result of infection with one of these two viruses. There is a single published prospective communitybased study, which was performed in France over a 3-year period and found an annual incidence of hepatic reactions to drugs of 14 cases per 100 000 inhabitants [8] (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. In a study performed in Spain, recruiting a large cohort of patients with acute hepatitis, the incidence of serious acute liver disease probably related to drugs was estimated to be 7.4 per 106 inhabitants per year [9]. In a recent retrospective study from the UK, among 800 jaundiced patients referred to a single centre 3.5% of patients had DILI. In this study, the annual incidence rate of DILI was 1.27 per 100 000 inhabitants [10]. The diagnosis of DILI is considerably less frequent than that of other causes of liver disease. As the whole of jaundiced patients admitted to a general hospital, toxic liver injury accounted for 3.5–10% of instances [10–13]. However, in a recent survey, most cases of DILI were as a result of acetaminophen toxicity with idiosyncratic hepatotoxicity occurring in only 0.7% of patients [13]. In a study carried out in England of patients hospitalized with serum aspartate aminotransferase levels greater than 400 IU/L, the prevalence of drug hepatotoxicity was 9% [14]. Among hospitalized patients, the incidence of DILI has been found to range between 0.7 and 1.4% [15,16]. 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 upon the absolute frequency of adverse hepatic reactions for a few drugs (e.g. isoniazid, aspirin or diclofenac) [7]. Although data are lacking, the frequency of unpredict-

able hepatotoxicity associated with the use of most medications is believed to be between 1 per 10 000 to 1 per 100 000 exposed persons. DILI in paediatric patients is an important field and there is obvious need to develop strategies to accomplish implementation of a specific network in this age group [17]. The antiinfectives, central nervous system (anticonvulsants drugs in the USA) and NSAIDs group of drugs were the most frequently incriminated in DILI in two recent studies [18,19]. In these two large case series as in the UK cohort of jaundiced patients, amoxicillin-clavulanate was the single agent responsible for the highest number of incidences. In this scenario, efforts to enhance the identification of adverse hepatic reactions and to obtain reliable information that could provide new insights into the epidemiology and pathogenesis of DILI are clearly needed. To attain this goal a multicenter, collaborative network was set up in Spain in 1994 to prospectively collect all suspicious of DILI, using a structured reporting form [18]. In the United States, the Drug Induced liver injury network was established in 2000 to gather data prospectively of cases of hepatotoxicity (http://dilin. dcri.duke.edu/ web) [20]. Further collections of cases of drug-induced hepatotoxicity, identified through the existing farmacovigilance system for spontaneous reporting of suspected adverse drug reactions to national centres in several European countries, are underway with the EUDRAGENE project, funded by the European Commission 5th Framework Programme [21]. These collaborative networks have helped to create a ‘pharmacoepidemiological culture’, prompting attending physicians to become more sensitized towards the detection of DILI and consequently favouring the recruitment of well-characterized cases. But it has also highlighted the need to agree upon common definitions, diagnostic criteria, terminologies and instruments to assess the causality as well as of integrating into routine clinical practice the necessary tools to increase the degree of certainty in diagnosing DILI, that would ultimately promote research and understanding of complex mechanisms involved in DILI. Mechanism of DILI Most cases of drug-induced liver injury are idiosyncratic, in that the reaction is unpredictable from the known pharmacology of the drug and cannot usually be predicted from preclinical studies. A recent definition states that idiosyncratic reactions are toxic responses determined by individual susceptibility to (host) factors

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Assessment of drug-induced liver injury in clinical practice

that increase the penetrance and expressivity of the intrinsic toxicity of a drug (or a drug metabolite) [22]. Indeed, development of DILI is a complex, multi-step process in which the toxic potential of the drug, genetic and acquired factors (Figure 1) as well as individual deficiencies in the adaptive processes that limit the extent of the injury, determine the susceptibility to the rare occurrence of idiosyncratic hepatotoxicity [23]. Thus, most patients tolerate the drug without adverse liver effects or there exists a background of mild, and often transient, asymptomatic liver injury (i.e. statins, isoniazid) indicating an adaptation to the drug and further tolerance. It is frequently stated that these reactions show no apparent dose–response relationship although this may be misleading. It has been observed that drugs that cause idiosyncratic hepatotoxicity were given at a daily dose of 100 mg or higher, being the likelihood of hepatotoxicity greatly reduced with potent drugs administered at a dose below 10 mg per day [24]. Therefore, the combination of susceptibility factors coupled with a high dose (due to variation in handling between different phases of drug metabolism, detoxification, and transport)/low potency drugs that reach a threshold for exposure to drug or toxic metabolites, enhances the risk of idiosyncratic hepatotoxicity. Determinants of prognosis Although drugs can cause toxic effects on the liver which can mimic all forms of acute and chronic

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hepatobiliary liver disease, the predominant pattern of lesion is acute hepatitis. Hence, physicians should always consider the possibility of drug toxicity when conducting a differential diagnosis in all patients who present with liver disease. Those drugs that cause hepatocellular damage may have the worst outcome in DILI. The observation by the late Hyman Zimmerman, known as ‘Hy’s rule’ [25], (term coined by Robert Temple of the FDA), 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 syndrome). Two recent large case series studies from Spain [18] and Sweden [26] have validated this observation finding 11.7 and 12.7%, respectively of death/liver transplantation in patients with hepatocellular jaundice. Indeed, female gender, hepatocellular type of injury and high bilirubin levels on presentation have been identified as independent risk factors for the development of fulminant hepatic failure. In the Sweden cohort [26], mortality ranged from 40% of the halothane and naproxen cases to zero in reports related to many other drugs notably in all 32 patients with erythromycin-associated hepatocelullar injury who survived this adverse drug reaction, suggesting that might be prognostic factors linked to specific compounds. On the contrary, drugs that cause a cholestatic mixed form of liver disease rarely result in death but resolution

Figure 1 Risk factors operating in the development of drug-induced idiosyncratic hepatotoxicity.

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follows a protracted course being more prone to chronicity with prolongued cholestasis and vanishing bile duct syndrome. Cardiovascular and central nervous system drugs have been the main groups identified leading to chronic liver damage [27]. Diagnostic approach in the clinical setting The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. In the absence of a ‘gold standard’, the diagnosis relies on ‘circumstantial evidence’. At present, the diagnosis of drug-induced liver injury is complex and not standardized, relying largely on exclusion of other causes of liver disease and identification of a signature pattern of disease manifestations in relationship to initiation and discontinuation of the suspected drug or herbal medication [28]. Therefore, the diagnosis is usually reached when information on follow-up is collected and retrospectively analyzed all the available biochemical and imaging studies performed upon drug discontinuation. There is a need for more accurate and simple tools for diagnosing and evaluating cases of hepatotoxicity. Causality assessment, the ‘proof of causality’ stands nowadays as a significant challenge in DILI and it has been addressed as the Achilles heel in the field of hepatotoxicity. This issue bears important implications not only for practicing clinicians, for conducting research into the risk factors, mechanisms and natural history of DILI but also from a medico-legal and drug regulation/development standpoint [29]. A straightforward and definitive diagnosis of hepatotoxicity in clinical practice is seldom accomplished, except in the rare circumstances in which symptoms of hepatitis rapidly ensue following the obvious exposure to an overdosage of intrinsic hepatotoxins, such as acetaminophen, herbal agents (Amanita phalloides) or industrial hepatotoxins, and blood level monitoring of the compound or the presence of paracetamol-cystein adducts can be detected to confirm the suspicion [30]. Hypersensitivity reactions to a few drugs, most of them already withdrawn from the market, have been associated with the detection of serum circulating autoantibodies to specific forms of cythocrome P450 (i.e. anti-CYP 2E1 for halothane, anti-liver kidney microsomal 2 antibody for tienilic acid, antimitochondrial autoantibody for iproniazid) [31]. Further jeopardizing diagnosis is the fact that patients with suspected DILI have complex medical histories and are frequently receiving multiple drugs. Hence, in the absence of an

acceptable and convenient ‘gold standard’ and because there is no diagnostic biomarker, hepatotoxicity is essentially a diagnosis of exclusion. To incriminate any given drug in an episode of liver dysfunction a systematic step-by-step approach [32] is proposed that requires a high index of suspicion, a detailed pharmacological history and 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 (Figure 2). Exclusion of other etiologies of liver injury Diagnostic evaluation of any patient with acute liver disease of unknown origin should comprise a careful history to exclude alcohol abuse, recent episodes of hypotension, epidemiological risk factors of infectious hepatitis, specific serology and molecular biology studies for common viruses involved in viral hepatitis and screening for autoimmune hepatitis All patients should also have an abdominal ultrasound examination to exclude mechanical biliary obstruction. The appropriateness of additional investigation to exclude competing causes of liver disease would depend on the type of liver damage on presentation, the patient’s age and presence of particular symptoms or analytical features. Establishing the pattern of liver injury Drugs can cause a wide range of clinico-pathological patterns including in rare occasions phospholipidosis, steatohepatitis, granulomatous hepatitis, chronic hepatitis and even cirrhosis. Vascular lesions and neoplasms are also a possible result of an offending drug although their diagnosis is exceptionally uncommon, reflecting the capability of drugs of altering any hepatic cell and the multiple pathways of injury (Table I). Each of these patterns of injury requires a liver biopsy for proper characterization. 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 data (Table II): the alanine aminotransferase (ALT) and alkaline phosphatase (AP) levels [33]. The classification scheme was proposed by the Council for International Organizations of Medical Sciences (CIOMS) and recently updated by the Food and Drug Administration Drug Hepatotoxicity Committee [34]. Acute hepatocellular (cytotoxic, cytolytic) type of liver injury is defined by ALT > three-fold that of Upper Limit of Normal (3N) or an ALT/AP ratio ‡ 5 [33]. Patients

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LIVER DISEASE Suspicion

•

Check for pre-existent liver disease (baseline liver test)

• • • •

Drug addiction Alcohol intake Blood transfusions Hypotension, cardiac failure

Drug exposure data and chronology

Not compatible

If compatible assess Hepatotoxic potential

Search for an alternative diagnosis

Not found: Assess features suggesting drug-toxicity Found Allergic manifestations Course on de-challenge

Specific therapy

Look for possible unintentional re-challenge data

Figure 2 Approaching a suspected case of drug-induced hepatotoxicity.

Liver biopsy findings (if performed) and biochemical “signature”

with this particular type of liver damage have non-specific 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 accini sometimes with an abundance of eosinophils in the liver infiltrate which is consistent with a toxic aetiology [35]. These expressions of hepatotoxicity are observed with many drugs (Table III). Patients with acute hepatocellular injury related to drugs are at risk of acute liver failure [18,26]. The presence of combined increases in ALT and bilirubin levels in DILI reflects a substantial loss in hepatocellular function and potential for liver fa...