Drug-induced liver injury in Oncology
Authors: A.D. Ricart
Journal: Annals of Oncology (2017)

Although serious drug-related hepatotoxicity is uncommon, it has been the most frequent single cause of safety-related drug marketing withdrawals according to the US Food and Drug Administration (FDA) [1.FDA. Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009.Google Scholar]. The regenerative properties of the liver are also uncommon for an internal organ [2.Fausto N. Campbell J.S. Riehle K.J. Liver regeneration.Hepatology. 2006; 43: S45-S53Crossref PubMed Scopus (1262) Google Scholar]. Being located between the gastrointestinal tract and the 'central compartment' of foreign substances (including drugs), the liver is essential to metabolism and detoxification. Liver regeneration has been an adaptation of vertebrates through evolutionary events to protect them from environmental pressures (e.g. ingested toxins). It was eloquently described by the ancient Greeks in the myth of Prometheus. It is extremely difficult to exclude drug-induced liver injury (DILI) as a potential complication of nearly every prescribed drug, except for a few that have been extensively studied like digoxin and theophylline [3.Lee W.M. Drug-induced hepatotoxicity.N Engl J Med. 1995; 333: 1118-1127Crossref PubMed Scopus (343) Google Scholar]. Hepatotoxicity is also a frequent reason for limitation of use, as well as discontinuation of clinical development programs. Several different cases of hepatotoxicity have emerged in oncology, as the new therapeutic options have evolved from traditional cytotoxic effects to signal transduction inhibition, antiangiogenesis, and immunotherapy. The traditional every 3-week schedule of administration of cytotoxic drugs has a low incidence of hepatotoxicity, except when high doses of alkylating agents are administered. Some hormonal and continuing therapies give the impression of a higher incidence of DILI. And this tendency seems to accentuate with some of the new anticancer paradigms that have shifted the scheme to oral daily administration. Moreover, several particularities apply to hepatotoxicity in the setting of oncology (Table 1).Table 1Several particularities that apply to hepatotoxicity in the setting of oncology•Cancer patient heterogeneity•Some comorbidities that are susceptibility factors for hepatotoxicity are common in cancer patients: malnutrition, polypharmacy•Confounding factors are also common: disease progression in liver metastasis, bile duct obstruction, bone metastasis as source of elevated alkaline phosphatase, congestive heart failure, etc.•Often use of complementary and alternative therapies: several compounds are hepatotoxic•'High dose' therapy for some indications•New anticancer paradigms that have shifted the scheme to oral daily administration until disease progression•New drugs with significant intracellular pathway inhibition properties•New drugs with immunologic effects•Reactivation of viral hepatitis: e.g. anti-CD20 therapy, romidepsin, etc.•Frequent blood sampling that makes baseline liver test usually available and repeatable•Different treatment settings: incidence of DILI for some drugs could be different in the first-line setting compared with extensive previous treatment setting (chemotherapy, radiotherapy, bone marrow transplantation)•For some indications: if the DILI case was not serious, liver function remained within normal values, and other drugs are not available, rechallenge might be desirable•Increased incidence of hepatotoxicity due to combination of agents, new formulations, and alternative schedules of administration: e.g. combination of ipilimumab and vemurafenib Open table in a new tab DILI is first classified as predictable or unpredictable (idiosyncratic). Predictable DILI is dose-related and occurs shortly after exposure. Acetaminophen is the usual example of a predictable hepatotoxin, but other drugs in oncology show dose-dependency (Table 2): methotrexate, trabectedin, gemtuzumab ozogamicin, cyclophosphamide and other alkylating agents [4.Lee W.M. Drug-induced hepatotoxicity.N Engl J Med. 2003; 349: 474-485Crossref PubMed Scopus (1090) Google Scholar, 5.Beumer J.H. Schellens J.H. Beijnen J.H. Hepatotoxicity and metabolism of trabectedin: a literature review.Pharmacol Res. 2005; 51: 391-398Crossref PubMed Scopus (40) Google Scholar, 6.Fetterly G.J. Owen J.S. Stuyckens K. et al.Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment.Cancer Chemother Pharmacol. 2008; 62: 135-147Crossref PubMed Scopus (30) Google Scholar, 7.Ricart A.D. Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin.Clin Cancer Res. 2011; 17: 6417-6427Crossref PubMed Scopus (248) Google Scholar, 8.van Kesteren C. Cvitkovic E. Taamma A. et al.Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 in a phase I dose-finding study.Clin Cancer Res. 2000; 6: 4725-4732PubMed Google Scholar]. Unpredictable reactions result from a succession of unlikely events, a 'multihit' process [4.Lee W.M. Drug-induced hepatotoxicity.N Engl J Med. 2003; 349: 474-485Crossref PubMed Scopus (1090) Google Scholar]. They occur in low incidence rate, usually without warning, are not related to dose, and develop after a variable period of latency.Table 2Drug-induced liver injury phenotypesPhenotypesEffect on cellsExamples of drugs in oncologyaThere are other agents that can cause these reactions.Hepatocellular—acute hepatic necrosisDirect effect on hepatocytes, necrosisAcetaminophen, methotrexate, sunitinib, pazopanib, regorafenib, brentuximab vedotinHepatocellular—acute hepatitisDirect effect on hepatocytes leads to cell dysfunctionLapatinib, imatinib, idelalisib; possibly many others TKi but clinical cases are not well describedCholestasisInjury to canalicular membrane and transportersEstrogens, chlorambucil, cyclophosphamide, temozolomide, lenalidomideMixed hepatocellular-cholestatic hepatitisCytoplasmic and canalicular injury, damage to bile ductsAzathioprine, flutamide, trabectedinEnzyme elevations without jaundice (Hepatocellular, cholestatic, or mixed)Acetaminophen, methotrexate, erlotinib, gefitinib, ketoconazole, trabectedin, bosutinibBland cholestasisEstrogens, azathioprine, mercaptopurineMicrovesicular steatosis and lactic acidosisMitochondrial injury, β-oxidation leads to the metabolic abnormalitiesValproic acid, nucleoside reverse transcriptase inhibitorsNonalcoholic fatty liverMultifactorialTamoxifen, methotrexate, corticosteroids, l-asparaginase, trabectedinChronic hepatitisProbably multifactorial, but ill-defined at presentDiclofenac, imatinibSinusoidal obstruction syndrome (veno-occlusive disease)Direct cytotoxicity toward endothelial cells, subsequent obstruction of sinusoids in central areas with hepatocyte necrosis and hemorrhageHigh doses of alkylating agents (busulfan, melphalan, cyclophosphamide, etc.), high doses of mitomycin-C and carboplatin, chronic administration of thiopurines (azathioprine, mercaptopurine and 6-thioguanine), dacarbazine, oxaliplatin, and gemtuzumab ozogamicinNodular regenerative hyperplasiaPathogenesis is not well defined. The injury is likely vascular (small portal veins)Azathioprine, thioguanine, mercaptopurine, and possibly methotrexateHepatic adenoma and hepatocellular carcinomaCarcinogenesisEstrogen, androgensOther featuresFibrosis or cirrhosisActivation of stellate cellsMethotrexateIschemic damage (or vascular collapse)IschemiaPossibly sunitinib and pazopanibImmune-mediated hepatitisT lymphocytes response directed at liver componentsAlpha interferon, CTLA-4 and PD-1 blocking antibodiesAdapted in part from LiverTox: http://livertox.nlm.nih.gov/index.html and Lee [4].TKI, tyrosine kinase inhibitor.a There are other agents that can cause these reactions. Open table in a new tab Adapted in part from LiverTox: http://livertox.nlm.nih.gov/index.html and Lee [4]. TKI, tyrosine kinase inhibitor. Elevated serum levels of aminotransferases generally indicate liver injury, but do not necessarily reflect or predict hepatotoxicity. Aspartate aminotransferase (AST) isozymes are present in mitochondria and cytoplasm, while alanine aminotransferase (ALT) is confined to the cytoplasm. A high ratio of AST to ALT (>2 : 1) often indicates significant liver injury attributable to alcohol. ALT is the main biomarker to diagnose DILI; it is more sensitive and has a longer half-life than AST [9.Ozer J.S. Chetty R. Kenna G. et al.Enhancing the utility of alanine aminotransferase as a reference standard biomarker for drug-induced liver injury.Regul Toxicol Pharmacol. 2010; 56: 237-246Crossref PubMed Scopus (61) Google Scholar, 10.M'Kada H. Munteanu M. Perazzo H. et al.What are the best reference values for a normal serum alanine transaminase activity (ALT)? Impact on the presumed prevalence of drug induced liver injury (DILI).Regul Toxicol Pharmacol. 2011; 60: 290-295Crossref PubMed Scopus (28) Google Scholar]. However, there is a very poor correlation between the incidence of elevated ALT and the incidence of severe liver injury (e.g. acute liver failure). For example, trastuzumab is occasionally associated with instances of transient, marked serum enzyme elevations (even in healthy volunteers), but has not been linked to instances of clinically apparent liver injury with jaundice [11.Yin D. Barker K.B. Li R. et al.A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01).Br J Clin Pharmacol. 2014; 78: 1281-1290Crossref PubMed Scopus (63) Google Scholar, 12.Hudis C.A. Trastuzumab–mechanism of action and use in clinical practice.N Engl J Med. 2007; 357: 39-51Crossref PubMed Scopus (1896) Google Scholar]. As Navarro and Senior have explained, hepatotoxicity is injury to the liver associated with impaired liver function cause by a foreign substance [13.Navarro V.J. Senior J.R. Drug-related hepatotoxicity.N Engl J Med. 2006; 354: 731-739Crossref PubMed Scopus (814) Google Scholar]. This distinction is very important, as hepatic dysfunction usually precede liver disease [13.Navarro V.J. Senior J.R. Drug-related hepatotoxicity.N Engl J Med. 2006; 354: 731-739Crossref PubMed Scopus (814) Google Scholar]. The liver could develop tolerance, an 'adaptive response', after exposure to certain drugs like the statins, isoniazid, and tacrine: mild elevations in aminotransferases that do not progress beyond laboratory abnormalities or return to baseline despite continuation of the drug [14.Lewis J.H. The adaptive response (drug tolerance) helps to prevent drug-induced liver injury.Gastroenterol Hepatol (NY). 2012; 8: 333-336PubMed Google Scholar]. Bilirubin is a metabolite produced at a relatively constant rate by the liver and its serum level correlates well with liver function. Other commonly available tests that measure liver function are those that measure protein synthesis [albumin concentration and international normalized ratio (INR)]. Isolated bilirubin elevation may be related to benign disorders (e.g. Gilbert syndrome) or to uridinediphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) inhibition by kinase inhibitors (erlotinib, sorafenib, regorafenib, pazopanib, nilotinib) [15.Dy G.K. Adjei A.A. Understanding, recognizing, and managing toxicities of targeted anticancer therapies.CA Cancer J Clin. 2013; 63: 249-279Crossref PubMed Scopus (229) Google Scholar, 16.Motzer R.J. Johnson T. Choueiri T.K. et al.Hyperbilirubinemia in pazopanib- or sunitinib-treated patients in COMPARZ is associated with UGT1A1 polymorphisms.Ann Oncol. 2013; 24: 2927-2928Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Hyman Zimmerman linked the measures of liver injury (aminotransferases) and function (bilirubin) after observing that drug-induced hepatocellular jaundice is a serious lesion (potential for death) [17.Zimmerman H.J. Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver.2nd edition. Lippincott Williams and Wilkins, Philadelphia, PA1978Google Scholar, 18.Reuben A. Hy's law.Hepatology. 2004; 39: 574-578Crossref PubMed Scopus (140) Google Scholar]. Dr Robert Temple referred to this observation as 'Hy's law', which has shown remarkable consistency to indicate idiosyncratic DILI [18.Reuben A. Hy's law.Hepatology. 2004; 39: 574-578Crossref PubMed Scopus (140) Google Scholar, 19.Bjornsson E. Olsson R. Outcome and prognostic markers in severe drug-induced liver disease.Hepatology. 2005; 42: 481-489Crossref PubMed Scopus (485) Google Scholar, 20.Andrade R.J. Lucena M.I. Fernandez M.C. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.Gastroenterology. 2005; 129: 512-521Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar]. Hy's law is defined as combined elevations in serum ALT >3 times the upper limit of normal (ULN) and bilirubin >2 ULN in the absence of alkaline phosphatase (ALP) elevation (<2 ULN) [1.FDA. Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009.Google Scholar, 21.Zimmerman H.J. The spectrum of hepatotoxicity.Perspect Biol Med. 1968; 12: 135-161Crossref PubMed Scopus (89) Google Scholar, 22.Zimmerman H.J. Drug-induced liver disease.Drugs. 1978; 16: 25-45Crossref PubMed Scopus (79) Google Scholar, 23.Zimmerman H.J. Drug-induced liver disease.in: Schiff E. Schiff's Diseases of the Liver. Lippincott-Raven, Baltimore, MD1999: 973-1064Google Scholar, 24.Lewis J.H. ′Hy′s law,' the ′Rezulin Rule,′ and other predictors of severe drug-induced hepatotoxicity: putting risk-benefit into perspective.Pharmacoepidem Drug Safe. 2006; 15: 221-229Crossref PubMed Scopus (66) Google Scholar, 25.Senior J.R. How can ′Hy′s law' help the clinician?.Pharmacoepidemiol Drug Saf. 2006; 15: 235-239Crossref PubMed Scopus (39) Google Scholar, 26.Temple R. Hy's law: predicting serious hepatotoxicity.Pharmacoepidemiol Drug Saf. 2006; 15: 241-243Crossref PubMed Scopus (261) Google Scholar, 27.Watkins P.B. Seligman P.J. Pears J.S. et al.Using controlled clinical trials to learn more about acute drug-induced liver injury.Hepatology. 2008; 48: 1680-1689Crossref PubMed Scopus (95) Google Scholar]. It is essential to exclude other possible causes of elevated bilirubin rather than drug administration. Consequently, idiosyncratic DILI is a diagnosis of exclusion when Hy's law is met (Table 3) [1.FDA. Guidance for Industry. Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009.Google Scholar, 9.Ozer J.S. Chetty R. Kenna G. et al.Enhancing the utility of alanine aminotransferase as a reference standard biomarker for drug-induced liver injury.Regul Toxicol Pharmacol. 2010; 56: 237-246Crossref PubMed Scopus (61) Google Scholar].Table 3Diagnosis of drug-induced liver injury (DILI) in oncologyRemember, DILI is a diagnosis of exclusion when Hy's law is met. Laboratory tests should include usual liver enzymes, bilirubin, and other commonly available tests that measure liver function: albumin concentration and international normalized ratio.Rule outPerformViral hepatitisSerologic tests for hepatitis A, B, and C infection as per CDC. If epidemiology suggests, consider adding hepatitis E test. History of recent travels.Liver injury due to alcoholSuspect if past medical history, or an AST/ALT ratio of 2:1. Perform history of alcohol use, serum alcohol level, and liver enzymes over time.Biliary tract disorders: obstructive and non-obstructiveUltrasound. Others: CT scan, MRI, MRCP, ERCP.Non-prescription over-the-counter medicationMeticulous history of non-prescribed and prescribed medicines, including herbal products, 'natural supplements', and recreational drugs.Autoimmune hepatitis or immune mediatedImmunoglobulin levels. ANA and ASMA, others could be: ANCA, AMA, anti-LKM. For immune-mediated due to new drugs consider lymphocyte transformation test and patch skin tests during clinical development.Hemodynamic abnormalitiesEcocardiogram, further workup if necessary.AMA, antimitochondrial antibody; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; ASMA, anti-smooth-muscle antibody; anti-LKM, anti-liver/kidney microsomal antibody; CDC, centers for disease control and prevention; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging. Open table in a new tab AMA, antimitochondrial antibody; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; ASMA, anti-smooth-muscle antibody; anti-LKM, anti-liver/kidney microsomal antibody; CDC, centers for disease control and prevention; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging. The correct incidence of hepatotoxicity for a certain drug could be difficult to determine. It has been usually underestimated, clearly illustrated in oncology by a study of trabectedin (read below) [13.Navarro V.J. Senior J.R. Drug-related hepatotoxicity.N Engl J Med. 2006; 354: 731-739Crossref PubMed Scopus (814) Google Scholar, 28.FDA Briefing Document. Oncologic Drugs Advisory Committee Meeting. NDA 22-447 Yondelis (Trabectedin) Ortho Biotech Products, L.P. 2009.Google Scholar, 29.Monk B.J. Herzog T.J. Kaye S.B. et al.Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer.J Clin Oncol. 2010; 28: 3107-3114Crossref PubMed Scopus (337) Google Scholar]. Severe hepatotoxicity may not occur during the process of drug approval due to its low frequency. However, severe increases in aminotransferase levels or Hy's law cases should suggest hepatotoxicity potential. The acute liver failure incidence of troglitazone (1 : 10 000) has been proposed as a comparator for other drugs that could induce idiosyncratic DILI [24.Lewis J.H. ′Hy′s law,' the ′Rezulin Rule,′ and other predictors of severe drug-induced hepatotoxicity: putting risk-benefit into perspective.Pharmacoepidem Drug Safe. 2006; 15: 221-229Crossref PubMed Scopus (66) Google Scholar, 30.Senior J.R. Drug-induced liver diseases.in: Kaplowitz N. Regulatory Perspectives. Marcel Dekker, New York, NY2003Google Scholar, 31.Goldkind L. Laine L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience.Pharmacoepidem Drug Saf. 2006; 15: 213-220Crossref PubMed Scopus (132) Google Scholar]. Lee has calculated the number of patients that require testing to detect a single case of significant hepatotoxicity when its frequency is 1 in 10 000: it is about 30 000 patients [4.Lee W.M. Drug-induced hepatotoxicity.N Engl J Med. 2003; 349: 474-485Crossref PubMed Scopus (1090) Google Scholar]. Depending on the hepatotoxicity potential, regulatory agencies could require a specific post-marketing safety surveillance program. Should a new drug be considered a significant therapeutic improvement, it might continue in use despite hepatotoxic risks. Therefore, for several indications in oncology a toxicity signal might not be a 'deal breaker' with regard to approval of the drug. Nevertheless, it would be only after the drug approval, with its use in a larger and broader population of patients, that its truly benefit/risk ratio could be defined. A simple way to sort patterns of liver injury is to consider the predominant initial enzyme elevation: the pattern is 'hepatocellular' (also 'cytolytic injury') if it is the ALT, or is 'cholestatic' if it is the serum ALP. There is also an 'intermediate' or 'mixed' pattern [13.Navarro V.J. Senior J.R. Drug-related hepatotoxicity.N Engl J Med. 2006; 354: 731-739Crossref PubMed Scopus (814) Google Scholar]. The 'hepatocellular' reaction reminds a clinical picture of viral hepatitis and if it is severe could conclude in acute liver failure. On the other hand, cholestatic-induced injury is not usually serious but if prolonged could translate in 'vanishing bile duct syndrome' [32.Desmet V.J. Vanishing bile duct syndrome in drug-induced liver disease.J Hepatol. 1997; 26: 31-35Abstract Full Text PDF PubMed Google Scholar]. The R-ratio of ALT to alkaline phosphatase, with both values expressed as multiples of the ULN range, would best define the hepatocellular pattern at presentation (since the pattern of injury can change over time). R-ratios >5 are considered hepatocellular, <2 cholestatic, and 'in between' mixed injuries [33.Haque T. Sasatomi E. Hayashi P.H. Drug-induced liver injury: pattern recognition and future directions.Gut Liver. 2016; 10: 27-36Crossref PubMed Scopus (32) Google Scholar, 34.http://livertox.nlm.nih.gov/index.html (April 2017, date last accessed).Google Scholar]. Having said that, it is important to keep in mind that most drugs display a particular cluster of hepatotoxic characteristics, and the patterns of injury could expand to about 12 phenotypes (Table 2). For some drug reactions, other histologic cell types could be the target or could intensify the injury: Kupffer's cells, stellate cells, macrophages, or sinusoidal endothelial cells (Table 2). The 12 phenotypes can have distinctive immunological features: immunoallergic or autoimmune. And the 12 phenotypes also have adverse outcomes: acute liver failure, vanishing bile duct syndrome, or cirrhosis [34.http://livertox.nlm.nih.gov/index.html (April 2017, date last accessed).Google Scholar]. Immune-mediated injury could be delayed and severe on repeated exposure, being 'rechallenge' potentially more serious. Some reactions show allergic components: fever, eosinophilia, eosinophilic infiltrates or granulomas, and rash. The major histocompatibility complex (MHC) modulates immune reactions and some MHC variants are predictors of increased risk for DILI. For example, HLA-DRB1*07:01 allele carriage is a predictor of increased risk of lapatinib-induced liver injury [35.Schaid D.J. Spraggs C.F. McDonnell S.K. et al.Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury.J Clin Oncol. 2014; 32: 2296-2303Crossref PubMed Scopus (60) Google Scholar]. Predictable DILI could be detected in preclinical studies, but idiosyncratic DILI usually escapes this screening. Obviously, first-in-human studies are the first step to detect DILI in humans. However, the small size of the sample and the limited exposure to the drug clearly restrict this first step. Randomized studies are a much more appropriate scenario to monitor DILI. It is very important to implement recommendations for dose reduction, temporary hold, and permanent discontinuation of therapy during the drug development process of drugs with proved liver injury. Patients should be alert about symptoms related to DILI: malaise, abdominal pain, jaundice, and pruritus. In oncology, it is sometimes more difficult to associate other non-specific signs and symptoms like nausea, vomiting, anorexia, fever, and rash. Once DILI is diagnosed in a particular patient, the use of the suspected agent should stop as well as, if possible, the use of any other drug with potential hepatotoxic effects. The potential for drug–drug interactions and their effects on the liver should be carefully considered. The patient should be closely followed with serial laboratory tests, with appropriate specialty consultations. If the case is severe, rechallenge usually should not be carried out, particularly if immunologic features are present (Figure 1). Nevertheless, mild to moderate cases without liver dysfunction may warrant rechallenge especially if no other therapies are available and a liver adaptive response is probable. Specific treatments of hepatotoxicity are seldom available for anticancer agents; but dexamethasone premedication has decreased the incidence of trabectedin injury, high-dose corticosteroids and mycophenolate mofetil have been used for immune-mediated hepatitis (CTLA-4 and PD-1 blocking antibodies), and defibrotide sodium has been recently approved for sinusoidal obstruction syndrome (SOS) following hematopoietic stem-cell transplantation (HSCT) [6.Fetterly G.J. Owen J.S. Stuyckens K. et al.Semimechanistic pharmacokinetic/pharmacodynamic model for hepatoprotective effect of dexamethasone on transient transaminitis after trabectedin (ET-743) treatment.Cancer Chemother Pharmacol. 2008; 62: 135-147Crossref PubMed Scopus (30) Google Scholar, 36.Donald S. Verschoyle R.D. Greaves P. et al.Complete protection by high-dose dexamethasone against the hepatotoxicity of the novel antitumor drug yondelis (ET-743) in the rat.Cancer Res. 2003; 63: 5902-5908PubMed Google Scholar, 37.YONDELIS® (Trabectedin) Product Monograph. Janssen Products, LP, Horsham, PA2015Google Scholar, 38.Richardson P.G. Riches M.L. Kernan N.A. et al.Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.Blood. 2016; 127: 1656-1665Crossref PubMed Scopus (189) Google Scholar, 39.Weber J.S. Yang J.C. Atkins M.B. Disis M.L. Toxicities of immunotherapy for the practitioner.J Clin Oncol. 2015; 33: 2092-2099Crossref PubMed Scopus (445) Google Scholar]. There is no evidence that routine monitoring prevents clinically significant idiosyncratic DILI. However, liability seems to advice to add instructions and warnings for frequent monitoring on drug labels (please read note in Figure 1 about the importance of monitoring). Pharmacogenomics might help to prevent hepatotoxicity in the near future [35.Schaid D.J. Spraggs C.F. McDonnell S.K. et al.Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury.J Clin Oncol. 2014; 32: 2296-2303Crossref PubMed Scopus (60) Google Scholar]. After a case of DILI most patients recover, although not always immediately, with the course of recovery influenced by several factors [13.Navarro V.J. Senior J.R. Drug-related hepatotoxicity.N Engl J Med. 2006; 354: 731-739Crossref PubMed Scopus (814) Google Scholar]. High dose i.v. methotrexate schedules are related to elevated serum ALT, but usually enzyme levels return to baseline rapidly with only sporadic cases of hepatotoxicity [40.Chabner B.A. Longo D.L. Cancer Chemotherapy and Biotherapy. Principles and Practice.5th edition. Wolters Kluwer/Lipincott Williams & Wilkins, Philadelphia PA2011Google Scholar]. Long-term methotrexate therapy, typically for severe psoriasis or rheumatoid arthritis, can cause hepatic fibrosis with gradual progression to cirrhosis over years without clinical manifestation [3.Lee W.M. Drug-induced hepatotoxicity.N Engl J Med. 1995; 333: 1118-1127Crossref PubMed Scopus (343) Google Scholar]. Liver tests may be normal or transiently elevated and the diagnosis requires a liver biopsy. The pathogenesis of fibrosis is not clear, but hepatic stellate cells seem to be involved in the injury process. Co-administration of folic acid decreases liver disease and guidelines for monitoring of patients are available [34.http://livertox.nlm.nih.gov/index.html (April 2017, date last accessed).Google Scholar]. Cytidine analogues have been associated with transient serum liver enzyme elevations, but they have rarely been implicated in cases of severe hepatotoxicity. Gemcitabine has shown transient elevations of AST and ALT in clinical trials (in ∼30%–70% of patients), but there has been no evidence of increasing hepatic toxicity with either longer exposure to gemcitabine or with greater total dose. Almost all severe DILI cases related to gemcitabine has occurred in patients with underlying liver disease or extensive hepatic metastases. Thiopurines have various clinical presentations of DILI, which may be dose related or idiosyncratic in nature, ranging from acute to chronic hepatotoxicity with a mixed or cholestatic pattern [40.Chabner B.A. Longo D.L. Cancer Chemotherapy and Biotherapy. Principles and Practice.5th edition. Wolters Kluwer/Lipincott Williams & Wilkins, Philadelphia PA2011Google Scholar]. Although rare, two DILI presentations have been described for hydroxyurea: an acute syndrome with fever and mild hepatitis that promptly resolves after drug discontinuation and an ill-described clinical entity sometimes severe and even fatal after prolonged treatment [40.Chabner B.A. Longo D.L. Cancer Chemotherapy and Biotherapy. Principles and Practice.5th edition. Wolters Kluwer/Lipincott Williams & Wilkins, Philadelphia PA2011Google Scholar]. Most alkylating agents cause transient ALT/AST elevations in a proportion of patients, and several of them have been implicated in rare cases of idiosyncratic hepatotoxicity. The cholestatic phenotype has been well described for the oral agents chlorambucil and cyclophosphamide, as well as for the oral non-classical alkylating agent temozolomide. A class effect of high doses of alkylating agents is the SOS (previously known as veno-occlusive disease), typically dose related and probably due to direct cytotoxicity toward endothelial cells [41.DeLeve L.D. Shulman H.M. McDonald G.B. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease).Semin Liver Dis. 2002; 22: 27-42Crossref PubMed Scopus (543) Google Scholar]. As the name indicates, histology usually shows obstruction of sinusoids in central areas with hepatocyte necrosis and hemorrhage, and activation of stellate cells with increased extracellular matrix. SOS can be classified as acute, subacute, or chronic according to latency to onset. The acute form usually presents with abdominal pain, swelling, and weight gain. If severe, there are signs of portal hypertension, hepatomegaly, and jaund