1. Clinical Practice Guidelines
Drug-induced liver injury

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

5. Outline Methods Background Guidelines Future prospects
Grading evidence and recommendations
Methods
General concepts
Epidemiology
Background
Key recommendations
Guidelines
New biomarkers
Unresolved issues
Unmet needs
Future prospects
EASL CPG DILI. J Hepatol 2019;70:122261.

6. Methods
Grading evidence and recommendations

7. Evidence
Level of evidence based on the Oxford Centre for Evidence-based Medicine1,2
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’
RCT, randomized controlled trial; SR, systematic review
*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
1. Oxford Centre for Evidence Based Medicine. Levels of evidence (March 2009). Available at: Accessed March 2019;
2. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:122261.

8. Evidence
Level of evidence based on the Oxford Centre for Evidence-based Medicine1,2
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’
CDR, clinical decision rule; RCT, randomized controlled trial; SR, systematic review
1. Oxford Centre for Evidence Based Medicine. Levels of evidence (March 2009). Available at: Accessed March 2019;
2. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:122261.

9. Evidence
Level of evidence based on the Oxford Centre for Evidence-based Medicine1,2
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’
CDR, clinical decision rule; SR, systematic review
1. Oxford Centre for Evidence Based Medicine. Levels of evidence (March 2009). Available at: Accessed March 2019;
2. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:122261.
*Absolute SpPin = a diagnostic finding whose Specificity is so high that a Positive result rules-in the diagnosis; Absolute SnNout = a diagnostic finding whose Sensitivity is so high that a Negative result rules-out the diagnosis

10. Evidence
Level of evidence based on the Oxford Centre for Evidence-based Medicine1,2
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’
SR, systematic review
1. Oxford Centre for Evidence Based Medicine. Levels of evidence (March 2009). Available at: Accessed March 2019;
2. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:122261.

11. Grades of recommendation
Grading is adapted from the Oxford Centre for Evidence-based Medicine1,2
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
*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: Accessed March 2019;
2. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15. EASL CPG DILI. J Hepatol 2019;70:122261.

12. Background
General concepts
Epidemiology

13. Idiosyncratic DILI: a complex drug–host interaction1
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
Drug properties
Physicochemical
Pharmacological
Toxicological
Biophysical effects
Possible host factors
Genetic variants
Race/ethnicity
Age
Gender
Reproductive state
Nutrition/alcohol/smoking
Lifestyles
Disease conditions
Medications
Gut flora
Host response to injury insult
DAMP, damage-associated molecular-pattern; ER, endoplasmic reticulum
Immune/inflammation
Repair
Tissue injury
Clinical manifestation and outcome
1. Chen, et al. J Hepatol 2015;63:503–14. EASL CPG DILI. J Hepatol 2019;70:122261.

14. Epidemiology
The incidence of DILI in the general population is not well known
Population-based studies:
France: 14 cases per 100,000 inhabitants per year1
Iceland: 19 cases per 100,000 inhabitants per year2
Korea: 12 cases of hospitalization per 100,000 inhabitants per year3
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 Registry5
DILIN6
LATINDILIN7
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.
*Lower incidence may be due to: use of higher liver enzyme cut-offs vs. previous prospective studies;
limitation of surveillance to subspecialists

15. Most common causative drug classes in large DILI populations
HDS, herbal or dietary supplements; ISD, immunosuppressant drugs; NSAIDs, non-steroidal anti-inflammatory drugs
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
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 biochemistry1
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
ALP, alkaline phosphatase; ALT, alanine aminotransferase; TBL, total bilirubin; ULN, upper limit of normal;
1. Aithal GP, et al. Clin Pharmacol Ther 2011;89:806–15.
EASL CPG DILI. J Hepatol 2019;70:122261.

17. ALT >3x ULN; TBL >2x ULN
Hy’s law: a sensitive and specific predictor of a drug’s potential to cause severe liver injury
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 ULN1
ALT >3x ULN; TBL >2x ULN
R ≥5; TBL >2x ULN
nR ≥5; TBL >2x ULN
Sensitivity, % 90 83
Specificity, % 44 67 63
AUROC
0.67
0.74
0.77
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under receiver operating characteristic; FDA, US Food & Drug Administration; nR, new R ratio; TBL, total bilirubin; ULN, upper limit of normal
*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.

18. In an independent population cohort
Hy’s law: a sensitive and specific predictor of a drug’s potential to cause severe liver injury
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 ULN1
In an independent population cohort
new R ratio for Hy’s law better identified risk for death compared with the original Hy’s law2
ALT >3x ULN; TBL >2x ULN
R ≥5; TBL >2x ULN
nR ≥5; TBL >2x ULN
Sensitivity, % 90 83
Specificity, % 44 67 63
AUROC
0.67
0.74
0.77
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under receiver operating characteristic; FDA, US Food & Drug Administration; nR, new R ratio; TBL, total bilirubin; ULN, upper limit of normal
*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.

19. Guidelines
Key recommendations

20. Click on a topic to skip to that section
Topics
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
EASL CPG DILI. J Hepatol 2019;70:122261.

21. Definition and classification of liver injury
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
Grade of evidence
Grade of recommendation
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; TBL, total bilirubin
EASL CPG DILI. J Hepatol 2019;70:122261.

22. Extrapolation from level 2 studies
Diagnosis of DILI relies largely on exclusion of alternative causes of liver damage
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
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
Grade of evidence
Grade of recommendation
AIH, autoimmune hepatitis; HCV hepatitis C virus; HEV, hepatitis E virus
EASL CPG DILI. J Hepatol 2019;70:122261.

23. Diagnosis: determining causality
Causality assessment may increase objectivity in the evaluation of suspected DILI
‘Positive’ rechallenge with suspected drug is strong proof of causality1
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
CIOMS, Council for International Organizations of Medical Sciences
1. Andrade RJ, et al. Expert Opin Drug Saf 2009;8:709–14.
EASL CPG DILI. J Hepatol 2019;70:122261.

24. Extrapolation from level 1 studies
Genetic testing
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
AIH, autoimmune hepatitis; GWAS, genome-wide association study; HLA, human leukocyte antigen
EASL CPG DILI. J Hepatol 2019;70:122261.

25. Diagnosis: a stepwise approach
Abnormal biochemistry/acute hepatitis
DILI suspicion
Features supporting toxic aetiology
Skin involvement, kidney injury, previous DILI episodes
Careful enquiry of exposure to HDS, drugs, OTC drugs*
Potential pitfalls
Lack of information (eg. dose, duration), several medications, hidden HDS and OTC drug intake
Discontinue non-essential drugs/HDS treatment
Search in hepatotoxicity resources (Liver tox)
Calculate biochemical pattern of liver injury
𝐀𝐋𝐓/𝐔𝐋𝐍 𝐀𝐋𝐏/𝐔𝐋𝐍 (𝐑)
Hepatocellular
R ≥ 5
Mixed
2 > R < 5
Cholestatic
≤ 2
ALP, alkaline phosphatase; ALT, alanine aminotransferase; Chol, cholestatic injury pattern; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDS, herbal and dietary supplements; Hep, hepatocellular injury pattern; HEV, hepatitis E virus; IgG, immunoglobulin G; Mix, mixed injury pattern; OTC, over-the-counter drugs; ULN, upper limit of normal
*record start and stop dates; †hepatic vascular disease, chronic hepatitis, fibrosis, microvesicular steatosis EASL CPG DILI. J Hepatol 2019;70:122261.

26. Diagnosis: a stepwise approach
Abnormal biochemistry/acute hepatitis
DILI suspicion
Features supporting toxic aetiology
Skin involvement, kidney injury, previous DILI episodes
Careful enquiry of exposure to HDS, drugs, OTC drugs*
Potential pitfalls
Lack of information (eg. dose, duration), several medications, hidden HDS and OTC drug intake
Discontinue non-essential drugs/HDS treatment
Search in hepatotoxicity resources (Liver tox)
Calculate biochemical pattern of liver injury
𝐀𝐋𝐓/𝐔𝐋𝐍 𝐀𝐋𝐏/𝐔𝐋𝐍 (𝐑)
Hepatocellular
R ≥ 5
Mixed
2 > R < 5
Cholestatic
≤ 2
ALP, alkaline phosphatase; ALT, alanine aminotransferase; Chol, cholestatic injury pattern; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDS, herbal and dietary supplements; Hep, hepatocellular injury pattern; HEV, hepatitis E virus; IgG, immunoglobulin G; Mix, mixed injury pattern; OTC, over-the-counter drugs; ULN, upper limit of normal
Search for alternative causes
*record start and stop dates; †hepatic vascular disease, chronic hepatitis, fibrosis, microvesicular steatosis EASL CPG DILI. J Hepatol 2019;70:122261.

27. Diagnosis: a stepwise approach
Abnormal biochemistry/acute hepatitis
DILI suspicion
Features supporting toxic aetiology
Skin involvement, kidney injury, previous DILI episodes
Careful enquiry of exposure to HDS, drugs, OTC drugs*
Potential pitfalls
Lack of information (eg. dose, duration), several medications, hidden HDS and OTC drug intake
Discontinue non-essential drugs/HDS treatment
Search in hepatotoxicity resources (Liver tox)
Calculate biochemical pattern of liver injury
𝐀𝐋𝐓/𝐔𝐋𝐍 𝐀𝐋𝐏/𝐔𝐋𝐍 (𝐑)
Hepatocellular
R ≥ 5
Mixed
2 > R < 5
Cholestatic
≤ 2
ALP, alkaline phosphatase; ALT, alanine aminotransferase; Chol, cholestatic injury pattern; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDS, herbal and dietary supplements; Hep, hepatocellular injury pattern; HEV, hepatitis E virus; IgG, immunoglobulin G; Mix, mixed injury pattern; OTC, over-the-counter drugs; ULN, upper limit of normal
Search for alternative causes
Viral infections (HAV, HBV, HCV, HEV, EBV, CMV)
Alcohol-related liver disease, hepatic ischaemia
Autoantibody titres, ↑ IgG
*record start and stop dates; †hepatic vascular disease, chronic hepatitis, fibrosis, microvesicular steatosis EASL CPG DILI. J Hepatol 2019;70:122261.

28. Diagnosis: a stepwise approach
Abnormal biochemistry/acute hepatitis
DILI suspicion
Features supporting toxic aetiology
Skin involvement, kidney injury, previous DILI episodes
Careful enquiry of exposure to HDS, drugs, OTC drugs*
Potential pitfalls
Lack of information (eg. dose, duration), several medications, hidden HDS and OTC drug intake
Discontinue non-essential drugs/HDS treatment
Search in hepatotoxicity resources (Liver tox)
Calculate biochemical pattern of liver injury
𝐀𝐋𝐓/𝐔𝐋𝐍 𝐀𝐋𝐏/𝐔𝐋𝐍 (𝐑)
Hepatocellular
R ≥ 5
Mixed
2 > R < 5
Cholestatic
≤ 2
ALP, alkaline phosphatase; ALT, alanine aminotransferase; Chol, cholestatic injury pattern; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDS, herbal and dietary supplements; Hep, hepatocellular injury pattern; HEV, hepatitis E virus; IgG, immunoglobulin G; Mix, mixed injury pattern; OTC, over-the-counter drugs; ULN, upper limit of normal
Search for alternative causes
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
*record start and stop dates; †hepatic vascular disease, chronic hepatitis, fibrosis, microvesicular steatosis EASL CPG DILI. J Hepatol 2019;70:122261.

29. Diagnosis: a stepwise approach
Abnormal biochemistry/acute hepatitis
DILI suspicion
Features supporting toxic aetiology
Skin involvement, kidney injury, previous DILI episodes
Careful enquiry of exposure to HDS, drugs, OTC drugs*
Potential pitfalls
Lack of information (eg. dose, duration), several medications, hidden HDS and OTC drug intake
Discontinue non-essential drugs/HDS treatment
Search in hepatotoxicity resources (Liver tox)
Calculate biochemical pattern of liver injury
𝐀𝐋𝐓/𝐔𝐋𝐍 𝐀𝐋𝐏/𝐔𝐋𝐍 (𝐑)
Hepatocellular
R ≥ 5
Mixed
2 > R < 5
Cholestatic
≤ 2
ALP, alkaline phosphatase; ALT, alanine aminotransferase; Chol, cholestatic injury pattern; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDS, herbal and dietary supplements; Hep, hepatocellular injury pattern; HEV, hepatitis E virus; IgG, immunoglobulin G; Mix, mixed injury pattern; OTC, over-the-counter drugs; ULN, upper limit of normal
Search for alternative causes
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
Consider liver biopsy if
Negative or incomplete rechallenge
Acute or chronic atypical presentation†
Autoimmune hepatitis
*record start and stop dates; †hepatic vascular disease, chronic hepatitis, fibrosis, microvesicular steatosis EASL CPG DILI. J Hepatol 2019;70:122261.

30. Therapy
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
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
Grade of evidence
Grade of recommendation
NAC, N-acetylcysteine; UDCA, ursodeoxycholic acid
EASL CPG DILI. J Hepatol 2019;70:122261.

31. Management of drug-induced acute liver failure
DILI is the most common cause of acute liver failure in western countries1,2
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
In idiosyncratic DILI, routine use of corticosteroid treatment may not be substantiated
Level 4 studies C
Grade of evidence
Grade of recommendation
ALF acute liver failure; NAC, N-acetylcysteine
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.

32. Preventing DILI
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
FDA, US Food & Drug Administration
EASL CPG DILI. J Hepatol 2019;70:122261.

33. Specific phenotypes: AIH
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
Grade of evidence
Grade of recommendation
AIH, autoimmune hepatitis
EASL CPG DILI. J Hepatol 2019;70:122261.

34. Specific phenotypes: Cancer immunotherapy-induced DILI
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
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
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
CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-L1, programmed death-ligand 1
EASL CPG DILI. J Hepatol 2019;70:122261.

35. Specific phenotypes: Secondary sclerosing cholangitis
Strictures of the bile tract may result from ischaemia or drug toxicity1
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
ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography
1. Gudnason HO, et al. Dig Liver Dis 2015;47:502–7.
EASL CPG DILI. J Hepatol 2019;70:122261.

36. Specific phenotypes: Granulomatous hepatitis
Hepatic granulomas are reported in 2–15% of liver biopsies1
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
1. Drebber U, et al. Liver Int 2008;28:828–34.
EASL CPG DILI. J Hepatol 2019;70:122261.

37. Specific phenotypes: Acute fatty liver
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
EASL CPG DILI. J Hepatol 2019;70:122261.

38. Specific phenotypes: Drug-associated fatty liver disease (DAFLD)
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
NAFLD, nonalcoholic fatty liver disease
EASL CPG DILI. J Hepatol 2019;70:122261.

39. Specific phenotypes: Nodular regenerative hyperplasia
Drugs can injure endothelial cells of sinusoids and portal venules1
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
1. Vernier-Massouille G, et al. Gut 2007;56:1404–9. EASL CPG DILI. J Hepatol 2019;70:122261.

40. Specific phenotypes: Liver tumours
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
EASL CPG DILI. J Hepatol 2019;70:122261.

41. Future prospects
New biomarkers
Unresolved issues
Unmet needs

42. Beyond serum ALT: Exploratory circulating biomarkers for DILI
Immune cell
Necrosis
Hepatocyte
HMGB1
HMGB1
ALT
Hepatocyte injury
mIr-122
Keratin-18 (FL)
M-CSF1
Keratin-18 (CC)
GLDH
Regeneration
HMGB1-acetyl
ALT, alanine aminotransferase; GLDH, glutamate dehydrogenase; HMGB1, high mobility group box 1; M-CSF1, macrophage colony-stimulating factor 1
Apoptosis
Mitochondrial dysfunction
Immune cell activation
Kullak-Ublick G. DILI Conference XVII, 2017; Session IV. EASL CPG DILI. J Hepatol 2019;70:122261.

43. SAFE-T’s new liver safety biomarkers
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
Prognosis
Total keratin 18
Caspase-cleaved keratin 18
Mechanism (apoptosis), prognosis
M-CSFR1 
miR-122
Detection, mechanism (hepatocyte leakage)
GLDH
Detection, mechanism (mitochondrial injury)
SDH
Detection
EMA, European Medicines Agency; FDA, US Food & Drug Administration; GLDH, glutamate dehydrogenase; HMGB1, high mobility group box 1; M-CSFR, macrophage colony-stimulating factor; receptor SAFE-T, Safer And Faster Evidence-based Translation consortium; SDH, succinate dehydrogenase
Kullak-Ublick G. DILI Conference XVII, 2017; Session IV. EASL CPG DILI. J Hepatol 2019;70:122261.

44. Unresolved issues and unmet needs
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
ALF, acute liver failure; HDS, herbal or dietary supplements
EASL CPG DILI. J Hepatol 2019;70:122261.