TABLE 12-1

CLASSIFICATION OF ACUTE DRUG-INDUCED INJURY

Serum Aminotransferases Serum Alkaline Phosphatase Serum Cholesterol Corresponding Histologic Patterns

Hepatocellular Injury

 5 to 500X ­ 1 to 2X ­ normal or ­ acute hepatitis confluent necrosis fatty change

Cholestatic Injury

       

Canalicular

 1 to 5X ­ 1 to 3X ­ normal or ­ pure cholestasis

Hepatocanalicular

 1 to 8X ­ 3 to 10X ­ ­ cholestatic hepatitis

Mixed Hepatocellular- Cholestatic Injury

 8 to 100X ­ 1 to 10X ­ normal or ­ cholestatic hepatitis acute hepatitis (with prominent cholestasis)
 

Table 12-2

HISTOLOGIC PATTERNS IN DRUG-INDUCED INJURY

Hepatitis
Acute
Chronic
Confluent Necrosis
Zonal
Multilobular
Cholestasis
Acute
Chronic
Fatty change
Macrovesicular
Microvesicular
Granulomas
Fibrosis and Cirrhosis
Vascular Disorders
Budd-Chiari syndrome
Hepatoportal sclerosis
Peliosis hepatis
Sinusoidal dilatation
Veno-occlusive disease
Neoplasms
Hepatocellular adenoma
Hepatocellular carcinoma
Angiosarcoma
Cholangiocarcinoma

Chapter 12 Appendix
Drugs and toxins associated with hepatic injury

DRUGS AND TOXINS ASSOCIATED WITH HEPATIC INJURY

Hepatitis Confluent Necrosis Cholestasis Fatty Change Granulomas Fibrosis/ Cirrhosis Vascular Disorders Neoplasms Other Changes References
  Acute Chronic   Pure Cholestatic Hepatitis Chronic              

Acetaminophen

   X X   X X X   X       23,76,128, 230,340

Acetohexamide

         X       X       89,240

Ajmaline

         X X             152

Albendazole

 X   X                   289

Allopurinol

 X   X   X     X       acute cholangitis fibrin-ring granulomas 3,291,298, 318

Amanita

mushrooms

     X       X           139,326

Amiodarone

 X   X   X   X X X     steatohepatitis phospholipidosis microvesicular fatty change 97,129,133, 158,159,247

Amitriptyline

 X   X   X X             50,148

Amodiaquine

 X   X   X   X           289

Androgens

       X X X       peliosis HCA HCC   111,117,199

Aprindine

 X     X X               106,288

Arsenicals

                 X HPS VOD AngioSa   146,190

L-Asparaginase

 X           X           217

Aspirin

 X X         X X       microvesicular fatty change in fatal intoxication 180,266,284, 340

Azathioprine

     X   X       X SD peliosis VOD   NRH 54,57,77, 137,241,286

Captopril

 X X X X X               15,238

Carbamazepine

X   X   X     X       acute cholangitis 151,157,185, 331

Carbenicillin

 X                       333

Carbimazole

 X       X   X X         26,210

Carbon

tetrachloride

     X       X           229

Cephalosporins

X       X     X         4,180,289

Chenodeoxycholic

acid

 X                       71

hlorambucil

 X   X   X               217,341

Chloramphenicol

         X               289

Chlordiazepoxide

     X   X               1

Chlorinated

hydrocarbons

     X       X           229,342

Chlorpromazine

   X X   X X   X X       113,259,323

Chlorzoxazone

 X   X                   289

Chlorpropamide

     X X X     X         264,289

Cimetidine

 X   X   X               168,258,317

Cisplatin

 X       X   X           289,342

Clavulanic acid

(combined with

amoxicillin)

       X X   X X       acute cholangitis 242,295,320

Clofibrate

         X     X       NRH 189,289

Clometacin

 X X     X   X X X     giant multinucleated hepatocytes 220

Cloxacillin

         X               66

Cocaine

 X   X       X         microvesicular fatty change 134,216,324

Corticosteroids

             X     peliosis   NRH 296,301

Cromolyn sodium

           X             289

Cyanamide

   X     X       X     ground-glass inclusions in hepatocytes 33,34

Cyclosporin

      X X               131,136,140

Cytosine arabinoside

 X   X             VOD     217,225,341

Dacarbazine (DTIC)

     X   X         BCS VOD     42,93

Danazol

 X     X           peliosis HCA HCC   69,132,205, 325

Dantrolene

 X X X   X   X   X       312,332

Dapsone

 X   X   X     X       mononucleosis-like acute hepatitis 75,124,126

Diazepam

     X   X X   X         180,302

Diclofenac

 X X X   X               121,265

Dihydralazine

   X X   X             acute cholangitis 213

Diltiazem

         X     X         262,307

Disulfiram

 X   X   X             ground-glass inclusions in hepatocytes 13,204,319

Enflurane

 X   X                   65,162,327

Erythromycin

   X X X X     X         59,81,248, 338

Estrogens

(including oral

contraceptives)

       X     X X   SD peliosis BCS HCA steatohepatitis 111,186,268

Ethionamide

     X   X               289

Etoposide

(VP-16)

 X                       127,311

Etretinate

 X X     X   X           39,85

Flucloxacillin

         X     X         322

Fluphenazine

         X               279

Flurazepam

         X   X           245

Floxuridine

(FUDR)

 X       X   X   X VOD sclerosing cholangitis 61,107,224

Glafenine

   X X   X       X       292

Glyburide

 X       X             acute cholangitis 90

Gold compounds

 X   X X X   X X       brown granular deposits in Kupffer cells 80,102

Griseofulvin

         X               43

Haloperidol

 X X     X X             60

Halothane

 X X X   X   X X X       16,145,269, 310

Hycanthone

 X   X   X               46

Hydralazine

 X   X   X     X       acute cholangitis 120,180,198

Ibuprofen

 X       X   X           236

Imipramine

     X   X X             35,109

Indomethacin

 X   X   X   X           236

Iodipamide

     X   X               289

Iopanoic acid

     X                   289

Iprindole

       X                 2

Iproclozide

     X   X               221

Isoniazid

 X X X   X   X X X       24,170,184, 285

Ketoconazole

 X X X X X               18,161,293

Labetalol

 X X X                   44

Lergotrile

 X                       303

Mebendazole

 X                       289

Mercaptopurine

 X   X   X       X VOD     217,341

Methimazole

 X       X     X         208

Methotrexate

     X       X   X       144,160,309

Methoxyflurane

 X   X                   130

Methyldopa

 X X X   X   X X X       7,38,249, 342

Methylenedianiline

("Epping jaundice')

         X               178

Mithramycin

     X                   341

Mitomycin C

     X       X     VOD     92,341

Naproxen

 X   X       X           82,236,321

Nicotinic acid

 X X X   X               67,195,237

Nifedipine

         X   X         steatohepatitis 8,272

Nitroaromatic compounds

     X                   229

Nitrofurantoin

 X X X X X   X X X       271,278,294

Nitrosoureas

 X   X   X         VOD     179,217,341

Oxacillin

 X X     X     X         32

Oxyphenisatin

 X X                     342

Papaverine

 X X     X     X X       215,228

Para-aminosalicylic

acid

 X X     X             mononucleosis-like acute hepatitis 289

Paraquat

         X X           degenerated bile ducts 193,299

Penicillamine

       X X               196

Penicillin

 X X     X     X         289,330

Perhexiline

maleate

 X           X   X     steatohepatitis phospholipidosis 212,219,232

Phenazopyridine

 X                       87

Phenobarbital

 X   X   X             ground-glass inclusions 187,211,270

Phenylbutazone

 X X X   X X   X X       17,114,315

Phenytoin

X X X   X     X   vasculitis   mononucleosis-like acute hepatitis 74,192,256, 282

Phosphorus (yellow)

     X       X         periportal necrosis 342

Piperazine

         X               99

Piroxicam

     X X X X             37,105,154, 226

Practolol

           X             31

Prajmaline

 X X X   X   X X X       254

Probenecid

     X         X         289

Procainamide

 X X           X         255,289

Prochlorperazine

     X X X X             113

Propoxyphene

         X             acute cholangitis 14

Propylthiouracil

 X X X         X         101,163,165

Pyrimethamine/

sulfadoxine

     X   X     X         346

Pyrrolizidine

alkaloids

                 X VOD     352

Quinidine

 X     X X     X         29,141

Quinine

         X   X X         174,234

Rifampin

 X   X   X   X           263,285

Spironolactone

 X           X           276

Streptokinase

 X                     hepatic hemorrhage and rupture 261

Sulfasalazine

 X   X   X     X         70,203,246

Sulfonamides

 X X X X X     X       mononucleosis-like acute hepatitis 289,342

Sulindac

 X   X   X   X         acute cholangitis 58,156,214, 329

Tamoxifen

       X X         peliosis     25,167

Tetracyclines

         X   X         microvesicular fatty change 223,289,342

hiabendazole

         X X     X       172,243,257

6-Thioguanine

     X             peliosis VOD HPS   NRH 52,84,341

Thiopental

         X               289

Thioridazine

         X               289,342

Thorium dioxide

(thorotrast)

                 X peliosis VOD HCC CCa AngioSa grey-brown granular material 56,118

Ticrynafen

   X X           X       345

Tolazamide

   X X   X       X       30,201

Tolbutamide

         X X   X         94

Total parenteral

nutrition

       X X   X   X     steatohepatitis phospholipidosis 10,11,48, 235

Toxic rapeseed oil

(toxic oil syndrome)

   X     X       X     steatohepatitis NRH 218,282

Tranylcypromine

 X       X               289

Triazolam

         X               45,153

Trifluoperazine

         X               289,342

Trimethoprim/

sulfmethoxazole

X   X X X   X X       microvesicular fatty change, phospholipidosis 143,197,200, 305

Troleandomycin

         X               289

Valproic acid

     X   X   X   X SD   microvesicular fatty change 297,337,343

Verapamil

 X       X               36,95,103

Vinyl chloride

                 X HPS HCC, AngioSa   306,342

Vitamin A

             X   X peliosis VOD HPS   Ito cell hyperplasia 20,78,182

Warfarin

       X               hepatic hemorrhage and rupture 289
  AngioSa = angiosarcomaHCC = hepatocellular carcinoma BCS = Budd-Chiari syndromeNRH = nodular regenerative hyperplasia CCa = cholangiocarcinomaSD = sinusoidal dilatation HPS = hepatoportal sclerosisVOD = veno-occlusive disease HCA = hepatocellular adenoma