Copyright ©The Author(s) 2017.
World J Hepatol. Apr 8, 2017; 9(10): 491-502
Published online Apr 8, 2017. doi: 10.4254/wjh.v9.i10.491
Table 1 Summary of drug-induced liver injury guidelines by the American College of Gastroenterology[7,69]
Elements necessary for the diagnostic evaluation of DILI
Known duration of exposure
Concomitant medications and diseases
Response to dechallenge (and rechallenge if performed)
Presence or absence of symptoms, rash, eosinophilia
Performing sufficient exclusionary tests (viral serology, imaging, etc.) to reflect the injury pattern and acuteness of liver function tests (e.g., acute viral serology for A, B and C and autoimmune hepatitis when presenting with acute hepatocellular injury; routine testing for hepatitis E virus not recommended because of the problems with current commercial assays; Epstein-Barr virus, cytomegalovirus, and other viral serology if lymphadenopathy, atypical lymphocytosis present)
Sufficient time to determine clinical outcome - did the event resolve or become chronic?
Use of liver biopsy
Often not required if the acute injury resolves
Helpful in confirming clinical suspicion of DILI but rarely pathognomonic
Useful to differentiate between Drug-Induced autoimmune hepatitis and idiopathic autoimmune hepatitis
Useful to rule out underlying chronic viral hepatitis, non-alcoholic fatty liver disease, alcoholic liver disease, or other chronic liver disease
Used to exclude DILI where re-exposure or ongoing use of an agent is expected
Rechallenge: Generally best avoided, unless there is no alternative treatment
Use of Causality Assessment Methods
Roussel Uclaf Causality Assessment Method is best considered an adjunct to expert opinion (it should not be the sole diagnostic method)
Consensus opinion
Expert consultation
For patients with chronic viral hepatitis, DILI requires a high index of suspicion, knowledge of a stable clinical course before the new medication, and monitoring of viral loads to rule out flares of the underlying disease
Assigning causality to herbal compounds and dietary supplements can be especially difficult; require knowledge of all ingredients and their purity
Table 2 The most common individual drugs and classes responsible for idiosyncratic drug-induced liver injury according to various Global Registries
Iceland[78], n = 96India[79], n = 313Spain[76], n = 446Sweden[77], n = 784United States DILIN[72], n = 899
Individual drugs (%)
Amoxicillin-clavulanate 22.9INH + anti-TB 57.8Amoxicillin-clavulanate 13.2Flucloxacillin 16.5Amoxicillin-clavulanate 10%
Diclofenac 6.3Phenytoin 6.7INH + anti-TB 6.9Erythromycin 5.4INH 5.3%
Nitrofurantoin 4.2Dapsone 5.4Ebrotidine 4.9Disulfiram 3.4Nitrofurantoin 4.7%
Infliximab 4.2Olanzapine 5.4Ibuprofen 4TMP-SMX 2.7SMX-TMP 3.4%
Azathioprine 4.2Carbamazine 2.9Flutamide 3.8Diclofenac 2.6Minocycline 3.1%
Isotretinoin 3.1Cotrimoxazole 2.2Ticlopidine 2.9Carbamazepine 2.2Cefazolin 2.2%
Atorvastatin 2.1Atorvastatin 1.6Diclofenac 2.7Halothane 1.9Azithromycin 2%
Doxycycline 2.1Leflunamide 1.3Nimesulide 2Naproxen 1.4Ciprofloxacin 1.8%
Ayurvedic 1.3Carbamazepine 1.8Ranitidine 1.3Levofloxacin 1.4%
Drug classes (%)
Table 3 R values[105]
Calculation of R value
ALT/AST value divided by its ULN = fold elevation/fold elevation above ULN for alkaline phosphatise
Hepatocellular injury = R > 5
Cholestatic injury = R < 2
Mixed injury = R > 2 < 5
Table 4 Classic Clinical Syndromes of drug-induced liver injury and the drugs most commonly associated[6,7,117]
Acute viral hepatitis-like: e.g., INH: Absence of hypersensitivity symptoms; present with malaise, fatigue, anorexia, nausea, vomiting, right upper quadrant pain
Hypersensitivity syndrome: Fever, rash, and/or eosinophilia seen in 25%-30% of DILI cases, usually with short latency and prompt rechallenge response (e.g., amoxicillin-clavulanate, phenytoin, carbamazepine, SMX-TMP, halothane)
Sulfone syndrome: e.g., dapsone: Fever, exfoliative dermatitis, lymphadenopathy, atypical lymphocytosis, eosinophilia, hemolytic anemia, methemoglobinemia
Pseudomononucleosis syndrome: e.g., phenytoin, dapsone, sulfonamides: Hypersensitivity syndrome with atypical lymphocytosis, lymphadenopathy, and splenomegaly
DILI associated with severe skin injury: Stevens-Johnson syndrome, toxic epidermal necrolysis, e.g., beta-lactam antibiotics, allopurinol, carbamazepine
Autoimmune hepatitis associated with positive autoantibodies: e.g., nitrofurantoin, minocycline, methyldopa
Immune-mediated colitis with autoimmune hepatitis: e.g., ipilimumab
Acute cholecystitis-like: e.g., erythromycin estolate
Reye syndrome-like: e.g., valproic acid: Hepatocellular injury, acidosis, hyperammonemia, encephalopathy, abdominal pain, nausea, vomiting, paradoxical worsening of seizure activity, microvesicular steatosis on biopsy
Table 5 Drug-induced liver injury network scoring criteria[59,118]
Causal relationshipPercentage of likelihoodDefinition
Unlikely< 25Clear evidence that an etiology other than the drug is responsible
Possible25-49Evidence for the drug is present but equivocal
Probable50-75Preponderance of the evidence links the drug to the injury
Highly likely75-95Evidence for the drug causing injury is clear and convincing but not definite
Definite< 95Evidence of the drug being causal is beyond any reasonable doubt