Drug Induced Liver Disease Thomas S. Foster, Pharm.D. Integrated Therapeutics PHR 961
Introduction Drug-induced liver disease encompasses a broad spectrum of hepatic lesions, including both acute and chronic disorders. Liver injury may occur as a consequence of the direct, intrinsic hepatotoxicity of a drug taken in sufficiently large doses to induce injury. In other instances drug-induced liver injury reflects an idiosyncratic, unanticipated reaction. Certain drugs are associated with cholestasis and others with chronic liver disease. Alcohol-induced liver injury includes a variety of acute and chronic lesions, including fatty
Drug Induced Liver Disease There are 800 million chemical compounds. Increasing with the rate of 7,000/week in common use. 11,000 of them are food ingredients and drugs. 55,000 of chemical compound: potential environmental pollution
Criteria for Disorders Time to apparent onset suggestive 5-90 days compatible <5 or>90 days Course of reaction after cessation of drug <15 days after cessation for hepatocellular and <month for cholestatic Reaction after readministration 1-15 days for hepatocellular 1-90days for cholestatic
Mechanisms of Drug Toxicity Type A Dose Dependent Gen. Predictable Known from Tox Studies acetaminophen CCL4 Type B Idiosyncratic Unpredictable Immunoallergeric Halothane ACE Inhib Metabolic Valproic Acid Isoniazid
Incidence of Drug Induced Liver Disease Incidence: Differ by the method used for estimation. Account for about 2 % of hospitalized patients with jaundice. More in elderly individuals. Account for 25 % of acute liver failure patients. Account for 25 % of chronic active hepatitis patients.
Classification Predictable --- dose related Unpredictable --- dose unrelated, idiosyncrasy
Predictable It can be reproduced in animals and damages particular site of hepatic lobules. It is a kind of direct hepatotoxicity. Frequently induced by drug metabolites, and not caused by the toxicity of the drug itself.
Predictable Drugs Predictable drugs: Acetaminophen, Tetracycline, Anabolic hormones/steroids
Unpredictable Induce massive liver cell necrosis and cholestatic inflammatory reaction. Can not be reproduced in animals. Usually, related to the immune reaction of liver cells. * Drug-induced liver disease occurs unrelated to the pre-existing liver diseases.
Unpredictable Drugs Erythromycin, INH, Halothane, Chlorpromazine
Farell's Classification of Drug-induced Liver Problem/Representative Drugs
Reference Farwell GC:The clinicopathological spectrum of drug-induced liver diseases. Drug-induced liver disease, ed by GC Farewell, Churchill Livingstone, London, p:101,1994)
1. Impaired Liver Function 1.1 Microsomal enzyme induction Phenytoin, Warfarin 1.2 Hyperbilirubinemia Novobiocin, Rifampcin
2. Acute Hepatocyte Necrosis 2.1 Focal necrosis Isoniazid, Cloxacillin, Halothane 2.2 Bridging necrosis Isoniazid, Alphamethyldopa, Phosphorus 2.3 Zonal necrosis Paracetamol, Halothane, Phosphorus 2.4 Massive necrosis Halothane, Valproic acid, NSAID
3. Fatty liver 3.1 Acute fatty change Tetracycline, Valproic acid, NSAID, Corticosteroid, L- asparaginase 3.2 Steatohepatitis Perhexiline maleate, Amidodarone
4. Granulomatous Change Granulomatous change: Hydralazine, Allopurinol, Carbamazepine
5. Acute cholestatic type 5.1 Without hepatitis OCS, Anabolic androgen 5.2 With hepatitis Chlorpromazine, Erythromycin, Flucloxacillin 5.3 With bile duct injury Flucloxacillin, Chlorpromazine, 4,4'- diaminodiphenylmethane
6. Cholestatic type 6.1 Vanishing bile duct syndrome Chlorpromazine, Flucloxacillin, Amitriptyline 6.2 Sclerosing cholangitis Intraarterial 5-fluorodeoxyuridine
7. Chronic parenchymal injury 7.1Chronic active hepatitis Alphamethyldopa, Nitrofurantoin, Dantrolene 7.2 Fibrosis and necrosis Methotrexate, Hypervitaminosis A
8. Vascular change 8.1 Sinusoid widening OCS 8.2 Peliosis hepatis Anabolic androgen 8.3 Non-cirrhotic portal hypertension Vinyl chloride, Hypervitaninosis A, Azathioprine 8.4 Hepatic venous outflow obstruction 6-thioguanine, OCS, Pyrrolizidine alkaloid 8.5 Nodular regenerative hyperplasia Azathioprine, Actinomycin D 8.6 Other vascular lesions OCS
9. Liver tumor 9.1 Hemangioma OCS 9.2 Focal nodualr hyperplsia OCS 9.3 Hepatic adenoma OCS, Androgen 9.4 Hepatocellualr carcinoma OCS, Androgen 9.5 Rare carcinoma Hepatoblastoma, OCS Chlangiocarcinoma, Carcinosarcome 9.6 Hemoangiosarcoma Arsenioc, Vinyl chloride, Thorium dioxide 9.7 Epithelioid hemoangioendothelioma
Direct Intrinsic Toxic Injury Occurs predictably Dose-dependent Short latent period Characteristic/reproducible morphologic pattern Offending agent is intrinsic toxin or converted to toxic substances in the liver
Idiosyncratic Reactions Infrequent/unpredictable Not dose-dependent Occurs 1-5 weeks after exposure (hypersensitivity reaction) or weeks to months after exposure (metabolic idiosyncrasy) Variable morphologic picture (hepatitis or cholestasis or both) Mechanisms: immunological (hypersensitivity) or metabolic
Acetaminophen-Direct Heptatotoxicity Acute liver injury seen in overdoses ( > 10g) Hepatotoxicity is enhanced by chronic alcoholism Centrilobular necrosis is typical pattern Peak liver injury on day 3-4 after overdose Most acetaminophen is glucuronidated or sulfated and excreted in urine; a toxic intermediate if formed via cytochrome P-450 and this product is conjugated with glutathione. If glutathione is depleted, the toxic metabolite binds to tissue macromolecules. Patients seen early (within 12 hours of overdose) are treated with N- acetylcysteine which may replete hepatocyte glutathione Chronic hepatitis seen in some individuals
Risks for Acetaminophen Toxicity Alcohol >60G/Day Fasting Cardiopulmonary and/or renal insufficiency Chronic Liver Disease--per se is NOT a risk factor
Halothane-Idiosyncratic Hypersensitivity Incidence 1:10,000 halothane exposures Increased incidence with multiple exposures Obese women, over age 40 at greatest risk Fever, leukocytosis, eosinophilia in week after exposure Jaundice 7-10 days after exposure, earlier in previously exposed individuals Resembles viral hepatitis or massive hepatic necrosis
Isoniazid-Idiosyncratic/ Metabolic Reaction 10% of isoniazid (INH) recipients develop mild increases in aminotransferases during first few weeks of treatment; subsides despite continued treatment, non-predictive 1% incidence of clinical hepatitis, higher (2%) in older ( > 50 years of age) and uncommon in children Hepatitis observed after 2nd month of treatment in 50%; as long as 12 months after beginning INH treatment Hepatitis unrelated to acetylator status
Isoniazid-(cont) Case fatality rate 10% Rifampin may decrease latent period or increase severity of INH hepatitis Allergic manifestations rare INH converted to acetyl-inh which in turn is converted to acetylhydrazine (?the precursor of the toxic metabolite) In some patients chronic hepatitis and cirrhosis consequence of INH hepatotoxicity
Chronic Liver Disease Induced by Drugs A. Chronic active hepatitis: isoniazid, alpha-methyldopa, Sulfonamides, nitrofurantoin, acetaminophen, etc. B. Cirrhosis: methotrexate, isoniazid; resembling primary biliary cirrhosis: chlorpromazine, tolbutamide C. Granulomas/granulomatous hepatitis: quinidine, phenylbutazone, allopurinol, immunotherapy with BCG, etc.
Chronic Liver Dx/Drugs(cont) D. Fatty Liver: alcohol, corticosteroids, high-dose intravenous tetracycline, valproic acid E. Portal hvpertension without cirrhosis or portal vein occlusion: Vitamin A overdose, arsenic poisoning, Thorotrast, vinyl chloride F. Budd-Chiari syndrome and veno-occlusive disease: oral contraceptives,
Chronic Liver Dx/Drugs(cont) G. Hepatic adenoma and hepatocellular carcinoma: oral contraceptives H. Angiosarcoma of the liver: vinyl chloride, arsenic, Thorotrast I. Peliosis hepatis:anabolic androgens, oral contraceptives
Alcoholic Hepatitis Alcoholic hepatitis: a clinical, biochemical, and morphologic entity which appears to be a precursor or accompaniment of alcoholic cirrhosis. Similar lesions have been seen in patients on certain drugs, e.g., amiodarone, following jejunal-ileal bypass for massive obesity, and in some diabetic individuals. In alcoholic subjects there history of excessive alcohol ingestion > 70g per day for more than 10 years); in women the critical threshold may be 35g of ethanol daily. Adequate nutrition will not modify the
Alcoholic Hepatitis Clinical Features: a spectrum of illness (asymptomatic to fatal cases); some patients have fever, abdominal pain, and jaundice. Hepatomegaly is common, splenomegaly may be detected. Laboratory Features: the AST (SGOT) is usually 50-300, rarely in excess of 500 u; the ALT (SGPT) may be normal or minimally increased; hypoalbuminemia and hypoprothrombinemia are common: the latter correlates with the prognosis; leukocytosis or leukopenia, anemia and thrombocytopenia may be found.
Summary-Drug Induced Liver Disease Can mimick other liver diseases History, Lab and Liver Biopsy Critical Consider Environmental and Genetic factors Elderly patients-- Inc risk Withdrawl of offending agent-- IMPORTANT and Probably MOST CRITICAL