Drug-induced and toxic liver disease

Chapter 8 Drug-induced and toxic liver disease





Overview















Clinical Presentation






TABLE 8.1 Clinicopathologic patterns of drug-induced liver injury
































































































Disorder Hepatotoxic agents
Acute
Hepatitis-like syndromes (acute necroinflammation) Dapsone, disulfiram, isoniazid, carbamazepine NSAIDs, allopurinol, bupropion, lisinopril, losartan, paroxetine, phenytoin, sulfonamides, statins, trazodone, pyrazinamide, HAART, valproic acid
Fulminant hepatic failure Acetaminophen, fialuridine (FIAU), halothane, isoniazid, sustained-release niacin, nitrofurantoin, propylthiouracil, valproic acid, flutamide
Cholestasis Ampicillin, chlorpromazine, prochlorperazine, cimetidine, ranitidine, estrogens, cytarabine, trimethoprim–sulfamethoxazole, thiabendazole, tolbutamide, anabolic steroids, erythromycins
Mixed necroinflammatory and cholestatic Carbimazole, chlorpropamide, dicloxacillin, methimazole, azathioprine, naproxen, phenylbutazone, sulindac, phenytoin, thioridazine, captopril, cyproheptadine, enalapril, fosinopril, irbesartan, terbinafine, phenobarbital
Granulomatous hepatitis Allopurinol, dapsone, diazepam, diltiazem, hydralazine, penicillin, phenylbutazone, phenytoin, quinidine, procainamide, clopidogrel, sulfonamides
Macrovesicular steatosis Alcohol, corticosteroids, L-asparaginase, methotrexate, nifedipine, tamoxifen
Microvesicular steatosis Alcohol, amiodarone, aspirin, zidovudine, didanosine, piroxicam, tetracyclines, tolmetin, valproic acid
Budd–Chiari syndrome Estrogens
Ischemic necrosis Cocaine, sustained-release niacin, methylenedioxyamphetamine
Chronic
Chronic active hepatitis Alpha-methyldopa, nitrofurantoin, oxyphenisatin
Fibrosis/cirrhosis Alcohol, alpha-methyldopa, isoniazid, methotrexate
Peliosis hepatis Anabolic/androgenic steroids, azathioprine, hydroxyurea, oral contraceptives, tamoxifen
Phospholipidosis Amiodarone, perhexiline, diltiazem, nifedipine
Primary biliary cirrhosis Chlorpromazine, haloperidol, prochlorperazine
Sclerosing cholangitis Floxuridine (FUDR) by hepatic artery infusion
Steatohepatitis Amiodarone, diethylstilbestrol, tamoxifen, irinotecan
Sinusoidal obstruction syndrome Azathioprine, busulfan, cyclophosphamide, daunorubicin, oxaliplatin, pyrrolizidine alkaloids, 6-thioguanine
Autoimmune hepatitis Minocycline, statins
Hepatoportal sclerosis Didanosine
Nodular regenerative hyperplasia Didanosine, azathioprine, 6-thioguanine, 6-mercaptopurine
Vanishing bile duct syndrome Azithromycin, amoxicillin-clavulanic acid, anabolic steroids, allopurinol
Oncogenic
Cholangiocarcinoma Thorotrast
Focal nodular hyperplasia Estrogens, oral contraceptives
Hepatic adenoma Estrogens, oral contraceptives
Hepatocellular carcinoma Alcohol, anabolic/androgenic steroids
Hepatoblastoma Estrogens
Angiosarcoma Arsenic, vinyl chloride, Thorotrast
Inflammatory pseudotumor Anabolic steroids

HAART, highly active antiretroviral therapy; NSAIDs, nonsteroidal anti-inflammatory drugs.


This list is not meant to be comprehensive.




Pathophysiology








TABLE 8.2 Mechanisms of drug-induced liver injury occurring at the molecular level





























Peroxidation of lipids
Denaturation of protein
Adenosine triphosphate depletion
Mitochondrial dysfunction
Free radical generation
Electrophilic radical generation and hapten formation
Biotransformation through cytochrome P-450
Binding of active metabolites to nuclear or cytoplasmic molecules
Binding or blockage of transfer RNA
Binding or blockage of bile transporters
Attachment to membrane receptors
Disruption of calcium homeostasis
Disruption of the hepatocellular cytoskeleton

TABLE 8.3 Factors influencing an individual’s susceptibility to drug-induced liver injury































Age
Long-term alcohol use
Drug–drug interactions
Duration of use and total dose of drug
Enzyme induction
Enzyme polymorphism
Ethnic and racial factors
Gender
Human leukocyte antigen (HLA) type
Nutritional status
Pregnancy
Renal function
Systemic disease
Underlying liver disease


Biotransformation


This is a process by which therapeutic agents are rendered more hydrophilic, thus facilitating their excretion from the body. Biotransformation takes place in several steps, classified as phase 1, phase 2, and phase 3 reactions.







Hepatotoxicity of Specific Medications


More than 1000 drugs have been implicated in causing acute or chronic liver injury, ranging from subclinical elevation of liver chemistry tests to ALF. The following is a summary of some of the more frequently used medications having hepatotoxic potential and those with the best-characterized mechanisms of injury.



Acetaminophen (Paracetamol, Tylenol)











Jun 4, 2016 | Posted by in GASTROENTEROLOGY | Comments Off on Drug-induced and toxic liver disease

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