Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists

Table 1 Medications, herbal products and illicit drugs related to the hepatocellular-type of damage

Compound	Other injury	Comments
Acarbose		FHF
Allopurinol	Granuloma	Hypersensitivity
Amiodarone	Phospholipidosis, cirrhosis
Amoxicillin, Ampicillin
Anti-HIV: (Didanosine, Zidovudine, protease inhibitors)
NSAIDs (AAS, Ibuprofen, Diclofenac, Piroxicam, Indometacin)		Nimesulide; withdrawn
Asparaginase	Steatosis
Bentazepam	Chronic hepatitis
Chlormethizole	Cholestatic hepatitis	FHF
Cocaine, Ecstasy and amphetamine derivatives		FHF
Diphenytoin		Hypersensitivity
Disulfiram		FHF
Ebrotidine	Cirrhosis	FHF
Fluoxetine, Paroxetine	Chronic hepatitis
Flutamide		FHF
Halothane
Hypolipemics; Lovastatin, Pravastatin, Simvastatin, Atorvastatin
Isoniazid	Granuloma, chronic hepatitis	FHF
Ketoconazole, Mebendazole, Albendazole, Pentamidine		FHF
Mesalazine	Chronic hepatitis	Autoimmune features
Methotrexate	Steatosis, fibrosis, cirrhosis
Minocycline	Chronic hepatitis, steatosis	Autoimmune features
Nitrofurantoin	Chronic hepatitis
Nefazodone		FHF, withdrawn
Omeprazole
Penicillin G	Prolonged cholestasis
Pyrazinamide
Herbal remedies		FHF
Germander (Teucrium chamaedrys), senna
Pennyroyal oil, kava-kava
Camellia sinnensis (green tea); Chinese herbal medicines
Risperidone
Ritodrine
Sulfasalazine		Hypersensitivity
Telithromycin
Terbinafine	Cholestatic hepatitis	FHF
Tetracycline	Micro-steatosis	FHF
Tolcapone		FHF, withdrawn
Topiramate
Trazodone	Chronic hepatitis
Trovafloxacin		FHF, withdrawn in Europe
Valproic acid	Micro-steatosis
Venlafaxine
Verapamil	Granuloma
Vitamin A	Fibrosis, cirrhosis
Ximelagatran		FHF, discontinued

Features of hypersensitivity include fever, rash and eosinophilia; FHF: Fulminant hepatic failure.

Table 2 Medications associated with the cholestatic-type damage

Compound	Other injury	Comment
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 acid	Chronic cholestasis	VBDS
Atorvastatin	Chronic cholestasis
Azathioprine	Chronic cholestasis
Benoxaprofen (withdrawn)
Bupropion	Chronic cholestasis
Captopril, enalapril, fosinopril
Carbamazepine	Chronic cholestasis	VBDS
Carbimazole
Cloxacillin, dicloxacillin, flucloxacillin
Clindamycin	Chronic cholestasis
Ciprofloxacin, norfloxacin
Cyproheptadine	Chronic cholestasis	VBDS
Diazepam, nitrazepam
Erythromycins	Chronic cholestasis	VBDS
Gold compounds, penicillamine
Herbal remedies:
Chaparral leaf (Larrea tridentate); Glycyrrhizin, greater celandine (Chelidonium majus)
Irbesartan	Chronic cholestasis
Lipid lowering agents (“statins”)
Macrolide antibiotics
Mianserin
Mirtazapine	Chronic cholestasis
Phenotiazines (chlorpromazine)	Chronic cholestasis
Robecoxib, celecoxib
Rosiglitazone, oioglitazone
Roxithromycin	Chronic cholestasis
Sulfamethoxazole-trimethoprim	Chronic cholestasis	VBDS
Sulfonamides	Chronic cholestasis
Sulfonylureas (Glibenclamide, Chlorpropamide)
Sulindac, piroxicam, diclofenac, ibuprofen
Terbinafine	Chronic cholestasis	VBDS
Tamoxifen	Hepatocellular, peliosis Chronic cholestasis
Tetracycline	Chronic cholestasis
Ticlopidine & Clopidogrel	Chronic cholestasis
Thiabendazole		VBDS
Tricyclic antidepressants (Amitriptyline, Imipramine)	Chronic cholestasis	VBDS
Sclerosing cholangitis-like	Floxuridine (intra-arterial)
Cholangiodestructive (primary biliary cirrhosis)	Chlorpromazine, ajmaline

VBDS: Vanishing bile duct syndrome.

Table 3 Autoantibodies specific to drug-induced hepatotoxicity

Autoantibody	Example
Anti-mitochondrial (anti-M6) autoantibody	Iproniazid
Anti-liver kidney microsomal 2 antibody (anti-LKM2)	Tienilic acid
Anti CYP 1A2	Dihydralazine
Anti CYP 2E1	Halothane
Anti-liver microsomal autoantibody	Carbamazepine
Anti-microsomal epoxide hydrolase	Germander

CYP: Cytochrome P450.

Table 4 Clinical work-up to identify other possible causes of liver disease

Test	Condition	Commentary
Viral serology	Viral hepatitis	Less 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, Coxiella	Bacterial hepatitis	If persistent fever and/or diarrhea
Serology for syphilis	Secondary syphilis	Multiple sexual partners. Disproportionately high serum AP levels.
Autoimmunity (ANA, ANCA, AMA, ASMA, anti-LKM-1)	Autoimmune hepatitis, Primary biliary cirrhosis	Women, ambiguous course following de-challenge. Other autoimmunity features.
AST/ALT ratio > 2	Alcoholic hepatitis	Alcohol abuse. Moderate increase in transaminases despite severity at presentation
Ceruloplasmine, urine cooper	Wilson’s disease	Patients < 40 yr
Alfa-1 antitrypsin	Deficit of α-1 antitrypsin	Pulmonary disease
Transferrin saturation	Hemochromatosis	In anicteric hepatocellular damage. Middle-aged men and older women.
Brilliant eco texture of the Liver.	Non-alcoholic steatohepatitis	In anicteric hepatocellular damage. Obesity, Metabolic syndrome.
Transaminase levels markedly high	Ischemic hepatitis	Disproportionately 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 obstruction	Colic abdominal pain, cholestatic/mixed pattern.

ALT: alanine aminotransferase; AP: alkaline phosphatase; AST: aspartate aminotransferase; AU: abdominal ultrasound examination; Anti-HAV: Hepatitis A antibody; Anti-HBc: Hepatitis B core antibody; Anti-HCV: Hepatitis C antibody; anti-LKM-1: Liver-kidney microsomal antibody type 1; AMA: antimitochondrial antibody; ANA: antinuclear antibody; ANCA: perinuclear antineutrophil cytoplasmic antibody; ASMA: antismooth muscle antibody; BPC: Biliary primary cirrhosis; CMV: cytomegalovirus; CT: computed tomography; EBV: Epstein-Barr virus; ERCP: Endoscopic retrograde cholangiography; MRCP: Magnetic resonance cholangiography.

Table 5 Rationale for performing liver biopsy in a case suspected of having drug-induced hepatotoxicity

Clinical setting	Presentation
Any clinical context	Putative drugs not previously incriminated in liver toxicity
Acute or chronic liver disease	Female, autoantibody sero-positive
	High serum gammaglobulin and immunoglobulin G levels at presentation
	Incomplete or ambiguous de-challenge
Chronic alcoholism	Acute 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 criteria	Score	Maria & Victorino criteria	Score
Chronology criterion		Chronology criterion
From drug intake until event onset	+2 to +1	From drug intake until event onset	+1 to +3
From drug withdrawal until event onset	+1 to 0	From drug withdrawal until event onset	-3 to +3
Time-course of the reaction	-2 to +3	Time-course of the reaction	0 to +3
Risk factors		Exclusion of alternative causes	-3 to +3
Age	+1 to 0
Alcohol	+1 to 0	Extra-hepatic manifestations	0 to +3
Concomitant therapy	-3 to 0	Literature data	-3 to +2
Exclusion of non-drug-related causes	-3 to +2	Re-challenge	0 to +3
Literature data	0 to +2
Re-challenge	-2 to +3