Editorial
Copyright ©2007 Baishideng Publishing Group Co.
World J Gastroenterol. Jan 21, 2007; 13(3): 329-340
Published online Jan 21, 2007. doi: 10.3748/wjg.v13.i3.329
Table 1 Medications, herbal products and illicit drugs related to the hepatocellular-type of damage
CompoundOther injuryComments
AcarboseFHF
AllopurinolGranulomaHypersensitivity
AmiodaronePhospholipidosis, cirrhosis
Amoxicillin, Ampicillin
Anti-HIV: (Didanosine, Zidovudine, protease inhibitors)
NSAIDs (AAS, Ibuprofen, Diclofenac, Piroxicam, Indometacin)Nimesulide; withdrawn
AsparaginaseSteatosis
BentazepamChronic hepatitis
ChlormethizoleCholestatic hepatitisFHF
Cocaine, Ecstasy and amphetamine derivativesFHF
DiphenytoinHypersensitivity
DisulfiramFHF
EbrotidineCirrhosisFHF
Fluoxetine, ParoxetineChronic hepatitis
FlutamideFHF
Halothane
Hypolipemics; Lovastatin, Pravastatin, Simvastatin, Atorvastatin
IsoniazidGranuloma, chronic hepatitisFHF
Ketoconazole, Mebendazole, Albendazole, PentamidineFHF
MesalazineChronic hepatitisAutoimmune features
MethotrexateSteatosis, fibrosis, cirrhosis
MinocyclineChronic hepatitis, steatosisAutoimmune features
NitrofurantoinChronic hepatitis
NefazodoneFHF, withdrawn
Omeprazole
Penicillin GProlonged cholestasis
Pyrazinamide
Herbal remediesFHF
Germander (Teucrium chamaedrys), senna
Pennyroyal oil, kava-kava
Camellia sinnensis (green tea); Chinese herbal medicines
Risperidone
Ritodrine
SulfasalazineHypersensitivity
Telithromycin
TerbinafineCholestatic hepatitisFHF
TetracyclineMicro-steatosisFHF
TolcaponeFHF, withdrawn
Topiramate
TrazodoneChronic hepatitis
TrovafloxacinFHF, withdrawn in Europe
Valproic acidMicro-steatosis
Venlafaxine
VerapamilGranuloma
Vitamin AFibrosis, cirrhosis
XimelagatranFHF, discontinued
Table 2 Medications associated with the cholestatic-type damage
CompoundOther injuryComment
Cholestasis without hepatitis (canalicular/bland/pure jaundice)
Estrogens, contraceptive steroids and anabolic-steroids (Budd-Chiari, adenoma, carcinoma, peliosis hepatitis, adenoma, carcinoma)
Cholestatis with hepatitis (hepatocanalicular jaundice)
Amoxicillin-clavulanic acidChronic cholestasisVBDS
AtorvastatinChronic cholestasis
AzathioprineChronic cholestasis
Benoxaprofen (withdrawn)
BupropionChronic cholestasis
Captopril, enalapril, fosinopril
CarbamazepineChronic cholestasisVBDS
Carbimazole
Cloxacillin, dicloxacillin, flucloxacillin
ClindamycinChronic cholestasis
Ciprofloxacin, norfloxacin
CyproheptadineChronic cholestasisVBDS
Diazepam, nitrazepam
ErythromycinsChronic cholestasisVBDS
Gold compounds, penicillamine
Herbal remedies:
Chaparral leaf (Larrea tridentate); Glycyrrhizin, greater celandine (Chelidonium majus)
IrbesartanChronic cholestasis
Lipid lowering agents (“statins”)
Macrolide antibiotics
Mianserin
MirtazapineChronic cholestasis
Phenotiazines (chlorpromazine)Chronic cholestasis
Robecoxib, celecoxib
Rosiglitazone, oioglitazone
RoxithromycinChronic cholestasis
Sulfamethoxazole-trimethoprimChronic cholestasisVBDS
SulfonamidesChronic cholestasis
Sulfonylureas (Glibenclamide, Chlorpropamide)
Sulindac, piroxicam, diclofenac, ibuprofen
TerbinafineChronic cholestasisVBDS
TamoxifenHepatocellular, peliosis Chronic cholestasis
TetracyclineChronic cholestasis
Ticlopidine & ClopidogrelChronic cholestasis
ThiabendazoleVBDS
Tricyclic antidepressants (Amitriptyline, Imipramine)Chronic cholestasisVBDS
Sclerosing cholangitis-likeFloxuridine (intra-arterial)
Cholangiodestructive (primary biliary cirrhosis)Chlorpromazine, ajmaline
Table 3 Autoantibodies specific to drug-induced hepatotoxicity
AutoantibodyExample
Anti-mitochondrial (anti-M6) autoantibodyIproniazid
Anti-liver kidney microsomal 2 antibody (anti-LKM2)Tienilic acid
Anti CYP 1A2Dihydralazine
Anti CYP 2E1Halothane
Anti-liver microsomal autoantibodyCarbamazepine
Anti-microsomal epoxide hydrolaseGermander
Table 4 Clinical work-up to identify other possible causes of liver disease
TestConditionCommentary
Viral serologyViral hepatitisLess frequent in older patients, especially Hepatitis A, search for epidemiologic risk factors, outcome may be similar to that of DILI following de-challenge.
IgM anti-HAV
IgM anti-HBc
Anti-HCV, RNA-HCV (RT-PCR)
IgM-CMV
IgM-EBV
Herpes virus
Bacterial serology: Salmonella, Campylobacter, Listeria, CoxiellaBacterial hepatitisIf persistent fever and/or diarrhea
Serology for syphilisSecondary syphilisMultiple sexual partners. Disproportionately high serum AP levels.
Autoimmunity (ANA, ANCA, AMA, ASMA, anti-LKM-1)Autoimmune hepatitis, Primary biliary cirrhosisWomen, ambiguous course following de-challenge. Other autoimmunity features.
AST/ALT ratio > 2Alcoholic hepatitisAlcohol abuse. Moderate increase in transaminases despite severity at presentation
Ceruloplasmine, urine cooperWilson’s diseasePatients < 40 yr
Alfa-1 antitrypsinDeficit of α-1 antitrypsinPulmonary disease
Transferrin saturationHemochromatosisIn anicteric hepatocellular damage. Middle-aged men and older women.
Brilliant eco texture of the Liver.Non-alcoholic steatohepatitisIn anicteric hepatocellular damage. Obesity, Metabolic syndrome.
Transaminase levels markedly highIschemic hepatitisDisproportionately high AST levels. Hypotension, shock, recent surgery, heart failure, antecedent vascular disease, elderly
Dilated bile ducts by image procedures (AU, CT, MRCP and ERCP)Biliary obstructionColic abdominal pain, cholestatic/mixed pattern.
Table 5 Rationale for performing liver biopsy in a case suspected of having drug-induced hepatotoxicity
Clinical settingPresentation
Any clinical contextPutative drugs not previously incriminated in liver toxicity
Acute or chronic liver diseaseFemale, autoantibody sero-positive
High serum gammaglobulin and immunoglobulin G levels at presentation
Incomplete or ambiguous de-challenge
Chronic alcoholismAcute deterioration during aversive therapy (disulfiram, carbimide calcium)
Any acute liver deterioration in a patient with cirrhosis or chronic hepatitis C.e.g. worsening of liver function in a patient with primary biliary cirrhosis receiving rifampicin or a chronic hepatitis C patient receiving ibuprofen
Chronic impairment in liver tests in non-jaundiced patients.Especially if constitutional symptoms and/or clinical signs of portal hypertension are disclosed.
Young patients with sero-negative acute hepatitis or chronic liver disease.Moderate decrease in ceruloplasmin levels or slight increases in urinary copper excretion.
Table 6 Comparison of the scores for individual axes of the CIOMS and Maria & Victorino diagnostic scales
CIOMS criteriaScoreMaria & Victorino criteriaScore
Chronology criterionChronology criterion
From drug intake until event onset+2 to +1From drug intake until event onset+1 to +3
From drug withdrawal until event onset+1 to 0From drug withdrawal until event onset-3 to +3
Time-course of the reaction-2 to +3Time-course of the reaction0 to +3
Risk factorsExclusion of alternative causes-3 to +3
Age+1 to 0
Alcohol+1 to 0Extra-hepatic manifestations0 to +3
Concomitant therapy-3 to 0Literature data-3 to +2
Exclusion of non-drug-related causes-3 to +2Re-challenge0 to +3
Literature data  0 to +2
Re-challenge-2 to +3