Drug-induced liver injury: Do we know everything?

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

DILI: Drug-induced liver injury.

Table 2 The most common individual drugs and classes responsible for idiosyncratic drug-induced liver injury according to various Global Registries

	Iceland[78], n = 96	India[79], n = 313	Spain[76], n = 446	Sweden[77], n = 784	United States DILIN[72], n = 899
Individual drugs (%)
	Amoxicillin-clavulanate 22.9	INH + anti-TB 57.8	Amoxicillin-clavulanate 13.2	Flucloxacillin 16.5	Amoxicillin-clavulanate 10%
	Diclofenac 6.3	Phenytoin 6.7	INH + anti-TB 6.9	Erythromycin 5.4	INH 5.3%
	Nitrofurantoin 4.2	Dapsone 5.4	Ebrotidine 4.9	Disulfiram 3.4	Nitrofurantoin 4.7%
	Infliximab 4.2	Olanzapine 5.4	Ibuprofen 4	TMP-SMX 2.7	SMX-TMP 3.4%
	Azathioprine 4.2	Carbamazine 2.9	Flutamide 3.8	Diclofenac 2.6	Minocycline 3.1%
	Isotretinoin 3.1	Cotrimoxazole 2.2	Ticlopidine 2.9	Carbamazepine 2.2	Cefazolin 2.2%
	Atorvastatin 2.1	Atorvastatin 1.6	Diclofenac 2.7	Halothane 1.9	Azithromycin 2%
	Doxycycline 2.1	Leflunamide 1.3	Nimesulide 2	Naproxen 1.4	Ciprofloxacin 1.8%
		Ayurvedic 1.3	Carbamazepine 1.8	Ranitidine 1.3	Levofloxacin 1.4%
Drug classes (%)
Antibiotics	37	65	32	27	45.4
HDS	16	1.3	2	NS	16.1
CNS	7	12	17	3	9.8
Hypolipidemic	3.1	1.6	5	1	3.7
Others	37	20	44	69	25.7

United States DILIN: United States Drug-Induced Liver Injury Network; INH: Isoniazid; SMX: Sulfamethoxazole; TMP: Trimethoprim; TB: Tuberculosis; HDS: Herbal and dietary supplements; CNS: Central nervous system; NS: Not specified.

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

Definitions

Hepatocellular injury = R > 5

Cholestatic injury = R < 2

Mixed injury = R > 2 < 5

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ULN: Upper limit of normal.

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

INH: Isoniazid; SMX: Sulfamethoxazole; TMP: Trimethoprim; DILI: Drug-induced liver injury.

Table 5 Drug-induced liver injury network scoring criteria[59,118]

Causal relationship	Percentage of likelihood	Definition
Unlikely	< 25	Clear evidence that an etiology other than the drug is responsible
Possible	25-49	Evidence for the drug is present but equivocal
Probable	50-75	Preponderance of the evidence links the drug to the injury
Highly likely	75-95	Evidence for the drug causing injury is clear and convincing but not definite
Definite	< 95	Evidence of the drug being causal is beyond any reasonable doubt