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1. Drug-induced liver injury Clinical Practice Guidelines

2. About these slides These slides give a comprehensive overview of the EASL clinical practice guidelines on the management of drug-induced liver injury The guidelines were first presented at the International Liver Congress 2018 and are published in the Journal of Hepatology The full publication can be downloaded from the Clinical Practice Guidelines section of the EASL website Please feel free to use, adapt, and share these slides for your own personal use; however, please acknowledge EASL as the source

3. About these slides Definitions of all abbreviations shown in these slides are provided within the slide notes When you see a home symbol like this one: , you can click on this to return to the outline or topics pages, depending on which section you are in Please send any feedback to: [email protected] These slides are intended for use as an educational resource and should not be used in isolation to make patient management decisions. All information included should be verified before treating patients or using any therapies described in these materials

4. Guideline panel EASL CPG DILI. J Hepatol 2019;70:1222  61. Chair Raul J Andrade Panel members Guruprasad P Aithal, Einar S Björnsson, Neil Kaplowitz, Gerd A Kullak-Ublick, Dominique Larrey ; Tom Hemming Karlsen (EASL Governing Board Representative) Reviewers EASL Governing Board, Didier Samuel, Tom Lüdde , Naga Chalasani

5. Outline EASL CPG DILI. J Hepatol 2019;70:1222  61.

6. Methods Grading evidence and recommendations

7. Evidence 1. Oxford Centre for Evidence Based Medicine. Levels of evidence (March 2009). Available at: https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed March 2019; 2. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:1222  61. Level of evidence based on the Oxford Centre for Evidence-based Medicine 1,2 Level Therapy / Prevention , Aetiology / Harm 1a SR (with homogeneity) of RCTs 1b Individual RCT with narrow confidence interval 1c All or none* 2a SR (with homogeneity) of cohort studies 2b Individual cohort study (including low quality RCT [e.g. <80% follow-up]) 2c ‘Outcomes’ research; ecological studies 3a SR (with homogeneity) of case-control studies 3b Individual case-control study 4 Case-series (and poor quality cohort and case-control studies) 5 Expert opinion without explicit critical appraisal, or based on physiology, bench research or ‘first principles’ *Met when all patients died before the treatment became available, but some now survive on it; or when some patients died before the treatment became available, but none now die on it

8. Evidence 1. Oxford Centre for Evidence Based Medicine. Levels of evidence (March 2009). Available at: https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed March 2019; 2. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:1222  61. Level of evidence based on the Oxford Centre for Evidence-based Medicine 1,2 Level Prognosis 1a SR (with homogeneity) of inception cohort studies; CDR validated in different populations 1b Individual inception cohort study with >80% follow-up; CDR validated in a single population 1c All or none case-series 2a SR (with homogeneity) of either retrospective cohort studies or untreated control groups in RCTs 2b Retrospective cohort study or follow-up of untreated control patients in an RCT; Derivation of CDR or validated on split-sample only 2c ‘Outcomes’ research 4 Case-series (and poor quality prognostic cohort studies) 5 Expert opinion without explicit critical appraisal, or based on physiology, bench research or ‘first principles’

9. Evidence 1. Oxford Centre for Evidence Based Medicine. Levels of evidence (March 2009). Available at: https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed March 2019; 2. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:1222  61. Level of evidence based on the Oxford Centre for Evidence-based Medicine 1,2 Level Diagnosis 1a SR (with homogeneity) of Level 1 diagnostic studies; CDR with 1b studies from different clinical centres 1b Validating cohort study with good reference standards; or CDR tested within one clinical centre 1c Absolute SpPins and SnNouts * 2a SR (with homogeneity) of Level >2 diagnostic studies 2b Exploratory cohort study with good reference standards; CDR after derivation, or validated only on split-sample or databases 3a SR (with homogeneity) of 3b and better studies 3b Non-consecutive study; or without consistently applied reference standards 4 Case-control study, poor or non-independent reference standard 5 Expert opinion without explicit critical appraisal, or based on physiology, bench research or ‘first principles’ *Absolute SpPin = a diagnostic finding whose Sp ecificity is so high that a P ositive result rules- in the diagnosis; Absolute SnNout = a diagnostic finding whose S e n sitivity is so high that a N egative result rules- out the diagnosis

10. Evidence 1. Oxford Centre for Evidence Based Medicine. Levels of evidence (March 2009). Available at: https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed March 2019; 2. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:1222  61. Level of evidence based on the Oxford Centre for Evidence-based Medicine 1,2 Level Differential diagnosis / symptom prevalence study 1a SR (with homogeneity) of of prospective cohort studies 1b Prospective cohort study with good follow-up 1c All or none case-series 2a SR (with homogeneity) of 2b and better studies 2b Retrospective cohort study, or poor follow-up 2c Ecological studies 3a SR (with homogeneity) of 3b and better studies 3b Non-consecutive cohort study, or very limited population 4 Case-series or superseded reference standards 5 Expert opinion without explicit critical appraisal, or based on physiology, bench research or ‘first principles’

11. Grades of recommendation *Data used in a situation that has potentially clinically important differences from the original study situation 1. Oxford Centre for Evidence Based Medicine. Levels of evidence (March 2009). Available at: https://www.cebm.net/2009/06/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed March 2019; 2. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:1222  61. Grading is adapted from the Oxford Centre for Evidence-based Medicine 1,2 Grade of recommendation is not applicable where an evidence-based statement, rather than recommendation, is provided Grade of recommendation A Consistent level 1 studies B Consistent level 2 or 3 studies OR extrapolations* from level 1 studies C Level 4 studies OR extrapolations* from level 2 or 3 studies D Level 5 evidence OR troublingly inconsistent or inconclusive studies of any level

12. Background General concepts Epidemiology

13. Idiosyncratic DILI: a complex drug–host interaction 1 1. Chen, et al. J Hepatol 2015;63:503–14. EASL CPG DILI. J Hepatol 2019;70:1222  61. Possible host factors Genetic variants Race/ethnicity Age Gender Reproductive state Nutrition/alcohol/smoking Lifestyles Disease conditions Medications Gut flora Cellular injury initiation Pharmacological responses Reactive metabolites, drug elimination Toxicological responses Covalent binding, haptenization, oxidative stress, mitochondrial injury, ER stress Cell death Apoptosis, necrosis, DAMP release Host response to injury insult Clinical manifestation and outcome Drug Immune/inflammation Repair Tissue injury Drug properties Physicochemical P harmacological T oxicological B iophysical effects

14. Epidemiology *Lower incidence may be due to: use of higher liver enzyme cut-offs vs. previous prospective studies; limitation of surveillance to subspecialists. 1. Sgro C, et al. Hepatology 2002;36:451–5; 2. Björnsson ES, et al. Gastroenterology 2013;144:1419–25.e3; 3. Suk KT, et al. Am J Gastroenterol 2012;107:1380–7; 4. Vega M, et al. Drug Saf 2017;40:783–87; 5. Andrade RJ, et al. Gastroenterology 2005;129:512–21; 6. Chalasani N, et al. Gastroenterology 2015;148:1340–52.e7; 7. Bessone F, et al. Int J Mol Sci 2016;17:313. EASL CPG DILI. J Hepatol 2019;70:1222  61. The incidence of DILI in the general population is not well known Population-based studies: France: 14 cases per 100,000 inhabitants per year 1 Iceland: 19 cases per 100,000 inhabitants per year 2 Korea: 12 cases of hospitalization per 100,000 inhabitants per year 3 USA: 2.7 cases per 100,000 adults attending gastroenterology practices* 4 Prospective registries: recruit bona fide cases, a bias for more severe hospitalized DILI Spanish DILI Registry 5 DILIN 6 LATINDILIN 7

15. Most common causative drug classes in large DILI populations 1. Andrade RJ, et al. Gastroenterology 2005;129:512–21; 2. Chalasani N, et al. Gastroenterology 2015;148:1340–52.e7; 3. Bessone F, et al. Int J Mol Sci 2016;17:313; 4. Björnsson ES, et al. Gastroenterology 2013;144:1419–25.e3. EASL CPG DILI. J Hepatol 2019;70:1222  61.

16. DILI qualification 1. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:1222  61. DILI can present with a very heterogeneous phenotype Liver biopsy is not available in most instances Qualification of liver injury for practical and scientific purposes is made by liver biochemistry 1 ALT ≥5x ULN ALP ≥2x ULN ALT ≥3x ULN + TBL >2x ULN Pattern of liver injury is classified according to R (ALT x ULN/ALP x ULN) 1 Hepatocellular = R≥5 Cholestatic = R≤2 Mixed = 2>R<5

17. ALT >3x ULN; TBL >2x ULN R ≥5; TBL >2x ULN nR ≥5; TBL >2x ULN Sensitivity, % 90 83 90 Specificity, % 44 67 63 AUROC 0.67 0.74 0.77 Hy’s law: a sensitive and specific predictor of a drug’s potential to cause severe liver injury *whichever higher 1. Robles–Diaz M, et al, Gastroenterology 2014;147:109–18; 2. Hayashi PH, et al. Hepatology , 2017; 66:1275–85. EASL CPG DILI. J Hepatol 2019;70:1222  61. In the late 1960s, Hyman Zimmerman discovered a combination of jaundice and drug-induced hepatocellular injury was associated with a 10–50% fatality rate from liver failure Temple’s definition of ‘Hy’s Law cases’ used by the FDA in drug development: ALT >3x ULN and TBL >2x ULN without significant ALP increase ‘New Hy’s Law’ proposed by the Spanish DILI Registry : nR [(ALT or AST*/ULN)/(ALP/ULN)] >5 and TBL >2 ULN 1

18. ALT >3x ULN; TBL >2x ULN R ≥5; TBL >2x ULN nR ≥5; TBL >2x ULN Sensitivity, % 90 83 90 Specificity, % 44 67 63 AUROC 0.67 0.74 0.77 Hy’s law: a sensitive and specific predictor of a drug’s potential to cause severe liver injury *whichever higher 1. Robles–Diaz M, et al, Gastroenterology 2014;147:109–18; 2. Hayashi PH, et al. Hepatology , 2017; 66:1275–85. EASL CPG DILI. J Hepatol 2019;70:1222  61. In the late 1960s, Hyman Zimmerman discovered a combination of jaundice and drug-induced hepatocellular injury was associated with a 10–50% fatality rate from liver failure Temple’s definition of ‘Hy’s Law cases’ used by the FDA in drug development: ALT >3x ULN and TBL >2x ULN without significant ALP increase ‘New Hy’s Law’ proposed by the Spanish DILI Registry : nR [(ALT or AST*/ULN)/(ALP/ULN)] >5 and TBL>2 ULN 1 In an independent population cohort n ew R ratio for Hy’s law better identified risk for death compared with the original Hy’s law 2

19. Guidelines Key recommendations

20. Topics EASL CPG DILI. J Hepatol 2019;70:1222  61. Definition and classification of liver injury Diagnosis Genetic testing Therapy Management of drug-induced acute liver failure Preventing DILI Specific phenotypes Click on a topic to skip to that section

21. Definition and classification of liver injury EASL CPG DILI. J Hepatol 2019;70:1222  61. Serum aminotransferases (ALT/AST), ALP, and TBL levels remain the mainstay for detecting and classifying liver damage in suspected DILI Recommendations General DILI should be classified as hepatocellular , cholestatic or mixed according to the pattern of elevation of liver enzymes based on the first set of laboratory tests available in relation to the clinical event Extrapolation from level 2 studies B Aminotransferases ALT, ALP and TBL are the standard analytes to define liver damage and liver dysfunction in DILI. AST values can reliably substitute ALT in calculating the pattern of injury when the latter is unavailable at DILI recognition, whereas GGT is less reliable as an ALP substitute Extrapolation from level 2b studies C Persistently elevated TBL and ALP in the second month from DILI onset should be used as a marker for chronic DILI Level 1b studies B Grade of evidence Grade of recommendation

22. Recommendations Laboratory work-up Tests for HCV-RNA and ant-HEV IgM (or HEV-RNA) are suggested in patients with suspected DILI to exclude acute hepatitis C and/or E, particularly in those cases not compatible with the drug signature of the suspected causative agent and/or with high transaminase levels Extrapolation from level 2 studies C Imaging An abdominal ultrasound should be undertaken in all patients suspected of DILI. The use of additional imaging studies relies on the clinical context Level 2a B Liver biopsy Liver biopsy may be considered during the investigation of selected patients suspected to suffer DILI, as liver histology can provide information that can support the diagnosis of DILI or an alternative diagnosis Level 5 D Liver biopsy may be performed in patients suspected to have DILI when serology raises the possibility of AIH Level 4 studies C Liver biopsy may be considered in patients when suspected DILI progresses or fails to resolve on withdrawal of the causal agent as the liver histology may provide prognostic information assisting clinical management Level 4 C Diagnosis of DILI relies largely on exclusion of alternative causes of liver damage EASL CPG DILI. J Hepatol 2019;70:1222  61. Grade of evidence Grade of recommendation

23. Diagnosis: determining causality 1. Andrade RJ, et al. Expert Opin Drug Saf 2009;8:709–14. EASL CPG DILI. J Hepatol 2019;70:1222  61. Causality assessment may increase objectivity in the evaluation of suspected DILI ‘Positive’ rechallenge with suspected drug is strong proof of causality 1 Recommendations Causality assessment methods and scales CIOMS can be used to assess causality, guiding a systematic and objective evaluation of patients suspected to have DILI Level 2b studies C Grade of evidence Grade of recommendation Recommendations Rechallenge Deliberate rechallenge with the causative drug in clinical practice is not advocated , unless the clinical scenario demands such an exposure, as it can cause more severe hepatotoxicity Level 4 C Controlled rechallenge after an episode of liver injury is , however, considered justified in relation to oncology and anti-TBC therapy, as they generally do not result in severe recurrence of hepatotoxicity Level 1b studies B

24. Genetic testing EASL CPG DILI. J Hepatol 2019;70:1222  61. Genetic testing in DILI with a number of drugs using GWAS has identified several common variants in HLA alleles implicating the immune system Recommendations HLA genotyping should be utilised in selected clinical scenarios where genetic tests assist the diagnosis and management of patients Extrapolation from level 1 studies B HLA genotyping may be used to support the diagnosis of DILI due to specific drugs or distinguish DILI from AIH. Further validation of genetic testing is required before routine implementation can be recommended Level 5 D Grade of evidence Grade of recommendation

25. Diagnosis: a stepwise approach *record start and stop dates; † hepatic vascular disease, chronic hepatitis, fibrosis, microvesicular steatosis EASL CPG DILI. J Hepatol 2019;70:1222  61. Discontinue non-essential drugs/HDS treatment Features supporting toxic aetiology Skin involvement, kidney injury, previous DILI episodes Potential pitfalls Lack of information ( eg. dose, duration), several medications, hidden HDS and OTC drug intake Abnormal biochemistry/acute hepatitis DILI suspicion Careful enquiry of exposure to HDS, drugs, OTC drugs* Calculate biochemical pattern of liver injury   Hepatocellular R ≥ 5 Mixed 2 > R < 5 Cholestatic ≤ 2 Search in hepatotoxicity resources (Liver tox)

26. Diagnosis: a stepwise approach *record start and stop dates; † hepatic vascular disease, chronic hepatitis, fibrosis, microvesicular steatosis EASL CPG DILI. J Hepatol 2019;70:1222  61. Discontinue non-essential drugs/HDS treatment Features supporting toxic aetiology Skin involvement, kidney injury, previous DILI episodes Potential pitfalls Lack of information ( eg. dose, duration), several medications, hidden HDS and OTC drug intake Abnormal biochemistry/acute hepatitis DILI suspicion Careful enquiry of exposure to HDS, drugs, OTC drugs* Calculate biochemical pattern of liver injury Search for alternative causes   Hepatocellular R ≥ 5 Mixed 2 > R < 5 Cholestatic ≤ 2 Search in hepatotoxicity resources (Liver tox)

27. Diagnosis: a stepwise approach *record start and stop dates; † hepatic vascular disease, chronic hepatitis, fibrosis, microvesicular steatosis EASL CPG DILI. J Hepatol 2019;70:1222  61. Discontinue non-essential drugs/HDS treatment Features supporting toxic aetiology Skin involvement, kidney injury, previous DILI episodes Potential pitfalls Lack of information ( eg. dose, duration), several medications, hidden HDS and OTC drug intake Viral infections (HAV, HBV, HCV, HEV, EBV, CMV) Alcohol-related liver disease, hepatic ischaemia Autoantibody titres, ↑ IgG Abnormal biochemistry/acute hepatitis DILI suspicion Careful enquiry of exposure to HDS, drugs, OTC drugs* Calculate biochemical pattern of liver injury Search for alternative causes   Hepatocellular R ≥ 5 Mixed 2 > R < 5 Cholestatic ≤ 2 Search in hepatotoxicity resources (Liver tox)

28. Diagnosis: a stepwise approach *record start and stop dates; † hepatic vascular disease, chronic hepatitis, fibrosis, microvesicular steatosis EASL CPG DILI. J Hepatol 2019;70:1222  61. Discontinue non-essential drugs/HDS treatment Features supporting toxic aetiology Skin involvement, kidney injury, previous DILI episodes Potential pitfalls Lack of information ( eg. dose, duration), several medications, hidden HDS and OTC drug intake Viral infections (HAV, HBV, HCV, HEV, EBV, CMV) Alcohol-related liver disease, hepatic ischaemia Autoantibody titres, ↑ IgG Benign/malignant biliary obstruction Primary biliary cholangitis Primary sclerosing cholangitis Abnormal biochemistry/acute hepatitis DILI suspicion Careful enquiry of exposure to HDS, drugs, OTC drugs* Calculate biochemical pattern of liver injury Search for alternative causes   Hepatocellular R ≥ 5 Mixed 2 > R < 5 Cholestatic ≤ 2 Search in hepatotoxicity resources (Liver tox)

29. Diagnosis: a stepwise approach *record start and stop dates; † hepatic vascular disease, chronic hepatitis, fibrosis, microvesicular steatosis EASL CPG DILI. J Hepatol 2019;70:1222  61. Discontinue non-essential drugs/HDS treatment Features supporting toxic aetiology Skin involvement, kidney injury, previous DILI episodes Potential pitfalls Lack of information ( eg. dose, duration), several medications, hidden HDS and OTC drug intake Viral infections (HAV, HBV, HCV, HEV, EBV, CMV) Alcohol-related liver disease, hepatic ischaemia Autoantibody titres, ↑ IgG Benign/malignant biliary obstruction Primary biliary cholangitis Primary sclerosing cholangitis Abnormal biochemistry/acute hepatitis DILI suspicion Careful enquiry of exposure to HDS, drugs, OTC drugs* Calculate biochemical pattern of liver injury Search for alternative causes Consider liver biopsy if Negative or incomplete rechallenge Acute or chronic atypical presentation † Autoimmune hepatitis   Hepatocellular R ≥ 5 Mixed 2 > R < 5 Cholestatic ≤ 2 Search in hepatotoxicity resources (Liver tox)

30. Therapy EASL CPG DILI. J Hepatol 2019;70:1222  61. Toxic liver damage is still an orphan hepatic disease with respect to therapy Most important initial step in terms of management of suspected DILI is to discontinue the implicated agent Recommendations Specific therapies Cholestyramine: a short administration may be used to decrease the course of hepatotoxicity induced by very selected drugs, such as leflunomide and terbinafine Level 4 C Carnitine may be used to decrease the course of valproate hepatotoxicity Level 4 C The efficacy of NAC to improve the severity of liver injury from drugs other than paracetamol may not be significantly substantiated Inconclusive Level 4 D The efficacy of UDCA to reduce the severity of liver injury may not be significantly substantiated Inconclusive Level 4 D Grade of evidence Grade of recommendation

31. Management of drug-induced acute liver failure 1. Ostapowitz G, et al. Ann Intern Med 2002;137:947–54; 2. Wei G, et al. J Intern Med 2007;262:393–401. EASL CPG DILI. J Hepatol 2019;70:1222  61. DILI is the most common cause of acute liver failure in western countries 1,2 Recommendations In case of drug-induced ALF, liver transplantation should be considered as a therapeutic option Consistent level 2 studies B Adults with idiosyncratic drug-induced ALF should receive NAC early in the course (coma grade I–II) Extrapolation from level 1b study B In idiosyncratic DILI, routine use of corticosteroid treatment may not be substantiated Level 4 studies C Grade of evidence Grade of recommendation

32. Preventing DILI EASL CPG DILI. J Hepatol 2019;70:1222  61. Pre- and post-marketing surveillance of drugs using liver biochemistry is warranted to decrease the incidence of DILI Recommendations Systematic monitoring of liver tests can be necessary for drugs with known DILI liability in clinical development. In the postmarketing setting, drugs with a relevant risk may have a boxed warning for hepatotoxicity, in which case intensified monitoring and surveillance of liver function is indicated Inconclusive level 2b studies D Hy’s law should be considered to identify patients at risk of progressing to severe DILI in the setting of clinical trials. Thresholds for interrupting or stopping treatment with a study drug as recommended by the FDA are intended as guidelines for studies in drug development and may be adapted depending on individual risk-benefit assessment. Consistent level 2b studies B Grade of evidence Grade of recommendation

33. Specific phenotypes: AIH EASL CPG DILI. J Hepatol 2019;70:1222  61. A number of drugs have been associated with drug-induced AIH A syndrome that shares many features of idiopathic AIH In cohorts of cases with the diagnosis of AIH, 2  9% were considered to be drug-induced Conversely, drug-induced AIH accounts for 9% of all DILI Recommendations Suspected drug-induced AIH should be evaluated in detail including causality assessment, serology, genetic tests and liver biopsy whenever possible Extrapolation from level 2 studies B In patients with suspected drug-induced AIH and treated with corticosteroids, withdrawal of therapy once the liver injury has resolved should be accompanied by close monitoring Level 2a studies B Grade of evidence Grade of recommendation

34. Specific phenotypes: Cancer immunotherapy-induced DILI EASL CPG DILI. J Hepatol 2019;70:1222  61. Immune checkpoint inhibitors act by increasing anti-tumour immune response supressed in cancer The break in tumour tolerance is associated with inflammatory side effects and an increase in immune-related adverse events, including hepatotoxicity Recommendations It is suggested that decisions regarding corticosteroid treatment of immune mediated hepatitis associated with immune checkpoint inhibitors are made by a multidisciplinary team involving hepatologists if DILI is sufficiently severe based on clinical and histological assessment Level 2 studies C Grade of evidence Grade of recommendation Statement Immune checkpoint inhibitors can induce immune related hepatotoxicity in a substantial proportion of patients, with CTLA-4 inhibitors (ipilimumab) being more hepatotoxic than PD-L1 agents (nivolumab), and combination treatments carrying a greater risk Level 1a studies

35. Specific phenotypes: Secondary sclerosing cholangitis 1. Gudnason HO, et al. Dig Liver Dis 2015;47:502–7. EASL CPG DILI. J Hepatol 2019;70:1222  61. Strictures of the bile tract may result from ischaemia or drug toxicity 1 Recommendations Diagnosis of drug-induced secondary sclerosing cholangitis can be considered in patients with a cholestatic pattern of DILI with slow resolution of liver injury and characteristic changes in the biliary system demonstrated on MRCP or ERCP Extrapolation from level 2 studies C Grade of evidence Grade of recommendation

36. Specific phenotypes: Granulomatous hepatitis 1. Drebber U, et al. Liver Int 2008;28:828–34. EASL CPG DILI. J Hepatol 2019;70:1222  61. Hepatic granulomas are reported in 2–15% of liver biopsies 1 Of those with granulomatous hepatitis, 2.5% are considered drug-related Recommendations Diagnosis of drug-related granulomatous hepatitis is suggested to involve expert evaluation of liver histology as well as exclusion of specific infections, inflammatory and immunological conditions that are well recognized causes of hepatic granulomata Level 5 D Grade of evidence Grade of recommendation

37. Specific phenotypes: Acute fatty liver EASL CPG DILI. J Hepatol 2019;70:1222  61. Rare form of acute hepatotoxicity related to microvesicular steatosis Manifested with hypoglycaemia, lactic acidosis, hyperammonaemia and cerebral oedema Dramatically rapid development of organ failure precedes clinical syndrome With an acute rise in liver enzymes and jaundice An index of suspicion is crucial in identifying the drug aetiology when approaching a patient with ‘anicteric hepatic encephalopathy’ Recommendations Acute drug-induced fatty liver can be recognized based on its distinct clinicopathological characteristics in people exposed to drugs such as valproate that are known to interfere with mitochondrial function Level 2 Studies C Grade of evidence Grade of recommendation

38. Specific phenotypes: Drug-associated fatty liver disease (DAFLD) EASL CPG DILI. J Hepatol 2019;70:1222  61. NAFLD is associated with accumulation of fat in >5% of hepatocytes With or without inflammation and fibrosis In those with moderate or lower alcohol consumption <21 units in men and <14 units in women, per week Certain drugs may be one of the aetiologies behind a proportion of ‘secondary’ NAFLD Cases not associated with characteristic features of metabolic syndrome Where no risk factors are obvious Recommendations Particular drugs such as amiodarone , methotrexate and tamoxifen and the chemotherapeutic agents 5-fluorouracil and irinotecan, should be considered as risk factors for fatty liver disease and decisions to continue or withdraw the medication relies upon the benefits of the treatment against the risk of progressive liver disease Extrapolation from level 1 studies B Grade of evidence Grade of recommendation

39. Specific phenotypes: Nodular regenerative hyperplasia 1. Vernier- Massouille G, et al. Gut 2007;56:1404–9. EASL CPG DILI. J Hepatol 2019;70:1222  61. Drugs can injure endothelial cells of sinusoids and portal venules 1 Wide spread vascular changes lead to diffuse nodularity within the hepatic parenchyma Withdrawal of associated medication has been shown to lead to histological resolution Otherwise, management is focused on surveillance and prevention of manifestations of portal hypertension Recommendations Drugs may be considered as risk factors for nodular regenerative hyperplasia and when possible it is suggested that the specific drug that has been associated is withdrawn Extrapolation level 4 studies D Grade of evidence Grade of recommendation

40. Specific phenotypes: Liver tumours EASL CPG DILI. J Hepatol 2019;70:1222  61. Causal association between hormonal therapy and liver tumours is supported by epidemiological data Statements Oral contraceptives may be considered risk factors for the development of liver tumours Consistent level 2 studies Androgens and androgenic steroids particularly in the context of treating bone marrow failure, may be considered risk factors for the development of liver tumours Level 5 Recommendations Withdrawal of medications is suggested where possible with continued monitoring until regression of adenoma or definitive treatment Inconsistent level 4 evidence D Grade of evidence Grade of recommendation

41. Future prospects New biomarkers Unresolved issues Unmet needs

42. Beyond serum ALT: Exploratory circulating biomarkers for DILI Kullak-Ublick G. DILI Conference XVII, 2017; Session IV. EASL CPG DILI. J Hepatol 2019;70:1222  61. Hepatocyte Immune cell Necrosis Keratin-18 (CC) Apoptosis GLDH Mitochondrial dysfunction mIr-122 Hepatocyte injury Keratin-18 (FL) HMGB1 ALT HMGB1 HMGB1-acetyl Immune cell activation M-CSF1 Regeneration

43. SAFE-T’s new liver safety biomarkers Kullak-Ublick G. DILI Conference XVII, 2017; Session IV. EASL CPG DILI. J Hepatol 2019;70:1222  61. Nine new liver safety biomarkers supported by the EMA and/or FDA for exploratory use in clinical drug development: Marker Application Total HMGB1 Mechanism (necrosis), prognosis Hyperacetylated HMGB1 Mechanism (immune activation), prognosis Osteopontin P rognosis Total keratin 18 Mechanism (necrosis), prognosis Caspase-cleaved keratin 18 Mechanism (apoptosis), prognosis M-CSFR1  Mechanism (immune activation), prognosis miR-122 Detection, mechanism (hepatocyte leakage) GLDH Detection, mechanism (mitochondrial injury) SDH Detection

44. Unresolved issues and unmet needs EASL CPG DILI. J Hepatol 2019;70:1222  61. Epidemiology Big data analysis Estimates of socioeconomic burden of DILI and its impact on quality of life Robust case-control or population-based cohort studies to evaluate the risk of HDS- related liver injury, botanical identification and chemical analysis Pathogenesis Identify the factors that unmask or prevent liver injury as well as the determinants of severity of DILI in subjects otherwise genetically predisposed Diagnosis and outcome Discovery, evaluation and validation of biomarkers, which can distinguish self-resolving elevation of liver enzymes related to drugs from those with a potential to evolve into symptomatic DILI Better prediction of DILI subjects at risk of ALF, including prognostic biomarkers Therapy Randomized controlled trials to evaluate the effect of specific interventions on the clinical outcomes of DILI Prediction Algorithms that reliably predict the DILI liability considering drug–host factors