Practical guidelines for diagnosis and early management of drug-induced liver injury

Table 1 Common causative agents of drug-induced liver injury with fatalities fatalities

Drug	n (%)
Acetaminophen	305 (16.9)
Anti-HIV1
Stavudine, didanosine, nevirapine, zidovudine	303 (16.8)
Troglitazone	211 (11.7)
Anticonvulsants (valproate, phenytoin)	187 (10.3)
Anti-cancer	223 (12.3)
Flutamide	59 (3.3)
Cyclophosphamide	56 (3.1)
Methotrexate	55 (3.0)
Cytarabine	53 (2.9)
Antibiotics	158 (8.7)
Trovafloxacin	57 (3.2)
Sulfa/trimethoprim	52 (2.9)
Clarithromycin	51 (2.8)
Anesthetic
Halothane	85 (4.8)
Anti-tuberculosis
Isoniazid	57 (3.2)
Diclofenac	56 (3.1)
Oxycodone	56 (3.1)

¹human immunodeficiency virus.

Table 2 Drugs suspected of being responsible for at least two cases of drug-induced liver injury and the types of liver injury reported in recent literature

Use	Drugs	Hepatocellular	Cholestatic	Mixed
Anti-microbial	Amoxicillin-clavulanate	28	26	23
	Azithromycin	0	8	0
	Trovafloxacin	5	0	1
	Erythromycin	2	4	3
	Clindamycin	2	0	0
	Nitrofurantoin	1	1	0
	Levofloxacin	0	0	1
	Ciprofloxacin	2	1	1
	Flucloxacillin	0	7	1
	Sulfasalazine	1	0	1
	INH + RIP + PIZ	24	6	32
	HAART	4	1	1
	Dapsone	2	0	0
Anti-inflammatory	Acetaminophen	40	0	0
	Diclofenac	18	8	3
	Nimesulide	7	2	0
	Ibuprofen	8	3	9
Anti-convulsant	Carbamazepine	6	1	3
	Valproic acid	4	1	3
	Bentazepam	5	0	2
Psychiatric	Paroxetine	4	1	2
	Disulfiram	2	0	0
	Tetrabamate	6	1	0
Anti-cancer	Flutamide	12	1	5
	Methotrexate	3	0	0
Lipid-lowering	Atorvastatin	6	2	2
	Fenofibrate	1	0	2
Gastrointestinal	Ebrotidine	23	0	2
For circulation	Captopril	1	0	1
Anti-coagulant	Ticlopidine	8	5	1
For endocrine	Thiamazole	1	4	0
Immunosuppressant	Azathioprine	5	4	2
Others	Medical herbs	26	3	2
	OTC health supplements	3	0	0

INH: Isoniazid; RIP: Rifampicin; PIZ: Pirazinamide. HAART: Highly active antiretroviral therapy. 40 cases from United States of America between 1998 and 2006; 28 cases from Spain between 1995-2005; 88 cases from Switzerland between 1996 and 2000; 461 cases from Spain between 1994 and 2004; 29 cases from United States of America between 1999 and 2003; 34 cases from France between 1997 and 2000; 77 cases from Sweden between 1995 and 2005; 31 cases from Asia between 2004 and 2006.

Table 3 Axes and scores of four representative scales utilized for diagnosis of drug-induced liver injury

NADRPS		CIOMS/RUCAM		M&V		DDW-J
Axis	Score	Axis	Score	Axis	Score	Axis	Score
Chronological criteria		Chronological criteria		Chronological criteria		Chronological criteria
Illegibility in onset	-1 to +2	From drug intake until onset	+1 to +2	From drug intake until onset	+1 to +3	From drug intake until onset	+1 to +2
		From drug withdrawal until onset	0 to +1	From drug withdrawal until onset	-3 to +3	From drug withdrawal until onset	0 to +1
Course of the reaction
	0 to +1	Course of the reaction	-2 to +3	Course of the reaction	-3 to +3	Course of the reaction	-2 to +3
		Risk factors Age	0 to +1			Risk factors
		Alcohol (or Pregnancy)1	0 to +1			Alcohol (or Pregnancy)1	0 to +1
		Concomitant therapy	-3 to 0
Exclusion of other causes	-1 to +2	Exclusion of other causes	-3 to +2	Exclusion of other causes	-3 to +3	Exclusion of other causes	-3 to +2
		Previous information	0 to +2	Previous information	0 to +2	Previous information	0 to +1
Rechallenge	-1 to +2	Rechallenge	-2 to +3	Rechallenge	0 to +3	Rechallenge	0 to +3
Placebo response	0 to +1
Drug concentration and monitoring	0 to +1			Extrahepatic manifestations rash, fever, arthralgia, eosinophilia, cytopenia	0 to +3	Extrahepatic manifestations eosinophilia	0 to +1
Dose relationship	0 to +1
Previous exposure and cross-reactivity	0 to +1
Any objective evidence	0 to +1					DLST	0 to +2
≥ 9 Definitive		> 8 Definitive		≥ 18 Definitive		≥ 5 Definitive
5 to 8 Probable		6 to 8 Probable		14 to 17 Probable		3 to 4 Probable
1 to 4 Possible		3 to 5 Possible		10 to 13 Possible		≤ 2 Unlikely
≤ 0 Unlikely		1 to 2 Unlikely		6 to 9 Unlikely
		≤ 0 Excluded		≤ 5 Excluded

¹Cholestatic/Mixed cases; DLST: Drug lymphocyte stimulation test.

Table 4 Diagnostic methods used for diagnosis of drug-induced liver injury during the last decade

Drug	Type2	Criteria	Country	Yr
Acetoaminophen1	H	None	Italy	2008
Dexketoprofen trometamol	H	None	Spain	2008
Anabolic-androgenic steroids	C	None	Mexico	2008
Quizalofop-p-ethyl	M	CIOMS/RUCAM	Greece	2007
Amoxicillin/clavulanate	M	None	USA	2007
Fenofibrate	H	None	Poland	2007
INH/RMP/PZA	M	None	USA	2007
Risperidone, Quetiapine	C	NADRPS	USA	2007
Clindamycin	C	NADRPS	Turkey	2007
Bupropion	M	CIOMS/RUCAM, M&V	USA	2007
Flutamide, Cyproterone	H	CIOMS/RUCAM	Spain	2007
Levothyroxine	H	DDW-J	Japan	2007
5-Fluorouracil1	H, M	NADRPS	New Zealand	2007
Sairei-to	H	LMT3	Japan	2007
Terbinafine	H	NADRPS, CIOMS/RUCAM	USA	2007
Ezetimide	H	None	USA	2007
Terbinafine	M	None	USA	2007
Infliximab1	H, C	None	Colombia	2007
Methylenedioxymethamphetamine	M	None	Canada	2006
Methylprednisolone	H	NADRPS	Turkey	2006
Shen-min	H	CIOMS/RUCAM	China	2006
Nimesulide	H	None	Italy	2006
Nevirapine	H	None	France	2006
Sirolimus	H	None	Poland	2005
Amiodarone	H	None	Japan	2005
Proguanil, Chloroquine	M	CIOMS/RUCAM	France	2005
Sulpyrine, Clarithromycin	H	None	Japan	2005
Glimepiride	C	None	Greece	2005
Flucloxacillin	M	None	Australia	2005
Sulbactam/ampicillin	C	NADRPS	Turkey	2004
Hydrochlorothiazide	M	NADRPS	Israel	2004
Ketoconazole	M	Original criteria	Korea	2003
Nimesulide	M	None	Turkey	2003
Ramipril	C	None	Canada	2003
Gemcitabine	M	None	USA	2003
Amoxicillin/clavulanate, Ciprofloxacin	H	Medline	USA	2003
Bupropion, Carbimazole	H	NADRPS	Singapole	2003
Ciprofloxacin	H	CIOMS/RUCAM	Germany	2003
6-Thioguanine	H	None	USA	2003
Terfenadine, Oxatomide	M	None	Japan	2002
Pioglitazone	M	None	USA	2002
Danazol	H	None	Japan	2001
Levofloxacin	H	None	USA	2001
Captopril1	M	None	Israel	2001
Pioglitazone	H	None	Japan	2001
Celecoxib	M	None	USA	2001
Nimesulide	M	WHO database	Switzerlamd	2001
Flutamide1	H	CIOMS/RUCAM, M&V	Spain	2001
Risperidone	C	None	Germany	2001
Zafirlukast	H	None	USA	2000
Troglitazone	H	None	USA	2000
Stavudine1	H	None	USA	2000
Bentazepam1	M	None	Spain	2000
Rosiglitazone	H	None	USA	2000
Nitrofurantoin	M	Non	Israel	1999
Nimesulide1	H, M	CIOMS/RUCAM	Belgium	1998
Omeprazole	H	WHO database	Switzerlamd	1998
Troglitazone	M	None	USA	1998
Acarbose1	H	None	Japan	1998
Benzylpenicillin	H	CIOMS/RUCAM	Switzerland	1997
Terbinafine	M	None	France	1997

¹Cases reported in multiple numbers, not in a single case, are summarized.

²Type of liver injury. H: hepatocellular; C: cholestatic; M: mixed.

³LMT, Lymphocyte migration test.

Table 5 Examinations that should be performed in a patient with suspected DILI

Test	Subjects that can be evaluated
Hematological test1	Determination of the type of liver injury (the ratio of ALT and ALP)
Blood count (including eosinophils)
Biochemical test1
Aspartate aminotransferase (AST)	Possibility (e.g. Increase in eosinophil count, the existence of mixed type liver injury without any biliary disorders on imaging studies, High IgG level (> 2 g/dL) is suspicious of autoimmune hepatitis. Antibodies against hepatitis virus may be false-negative especially in the early phase of infection. Instead, measurement of viral RNA or DNA may be useful for the diagnosis. HDV (requires concomitant HBV infection) and HEV are relatively rare in advanced countries. Although, liver injury caused by EBV or CMV is also relatively rare, young patients with possible DILI should be checked for EBV or CMV).
Alanine aminotransferase (ALT)
Lactate dehydrogenase
γ-glutamyl transpeptidase (γ-GTP)
Alkaline phosphatase (ALP)
Total bilirubin (including direct and indirect bilirubin)
Albumin
Choline esterase (ChE)
Total cholesterol (Cho)
Coagulation test1
Prothrombin time international ratio (PT-INR)
Serological test1
IgG, IgA, IgM	Severity (Marked increase or decrease in white blood cell count, decrease in platelet count. Increase in bilirubin level, decrease in albumin, ChE or Cho levels. Decrease in the ratio of direct/total bilirubin (< 0.67). Prolongation of PT-INR).
Anti-nuclear antibody (ANA)
Anti-mitochondrial antibody (AMA or M2)
Viral serology
IgM anti-HA1
HBsAg1, IgM-HBc1, anti-HBc, HBV-DNA
HCV-Ab1, HCV-RNA
HDV-Ab, HDV-DNA
HEV-Ab, HEV-RNA
IgM-EBV
IgM-CMV
Imaging study
Ultrasonography (US)1

¹Tests which should be carried out first. Ig: Immunoglobulin; HA: Hepatitis A; HBsAg: Hepatitis B surface antigen; HBc: Hepatitis B core; HBV: Hepatitis B virus; HCV: Hepatitis C virus; Ab: Antibody; HDV: Hepatitis D virus; HEV: Hepatitis E virus; EBV: Epstein-Barr virus; CMV: Cytomegalovirus.