Chapter 8 Drug-induced and toxic liver disease

1 Drug-induced liver injury (DILI) accounts for 7% of reported drug adverse effects, 2% of hospitalizations for jaundice, 1% of cases of acute liver failure (ALF), and most cases of hepatitis in patients older than 50 years of age. Ten percent of those with jaundice will die.

2 The spectrum of DILI ranges from subclinical liver disease with mildly elevated liver chemistry test results to subacute liver failure and ALF requiring liver transplantation. DILI can mimic almost every type of acute and chronic liver disease.

3 Many different medications and toxins have been implicated in causing ALF, and the prognosis is poor without liver transplantation.

4 Over-the-counter preparations and herbal medications may have significant hepatotoxicity, and their use should be determined in cases of unexplained acute or chronic liver disease.

5 Early suspicion of DILI is essential because morbidity is greatly increased if the medication is continued after symptoms develop or liver chemistry test abnormalities appear.

6 The main treatment for drug hepatotoxicity is withdrawal of the offending agent. Patients should be counseled regarding signs of DILI, especially with use of agents with well-recognized hepatotoxic potential.

Overview

1. Drug-induced liver injury (DILI) is one of the most common causes of elevated liver chemistry values.

2. Patients with DILI and jaundice at initial presentation experience worse outcomes.

3. The Drug-Induced Liver Injury Network (DILIN) was created by the National Institutes of Health in 2003. Initial DILIN findings showed that 73% of cases resulted from taking a single prescription medication, 9% were attributable to herbal or dietary supplements, and 18% resulted from taking multiple agents.

4. Among patients with DILI caused by a single prescription drug, the major offending agents were antimicrobials (46%), central nervous system agents (15%), immunomodulating agents (5%), analgesics (5%), and lipid-lowering agents (3%).

5. In Asia, most cases of DILI result from taking complementary and alternative medications (CAM).

6. The incidence of DILI is greater in older individuals, probably related to altered pharmacokinetic factors.

7. Polypharmacy may contribute to an increased risk of adverse drug reactions through alterations of cytochrome P-450.

8. Although most DILI cases in children are mild, pediatric patients have the potential to progress to ALF.

9. Children with viral infection have an unusual sensitivity to aspirin (Reye’s syndrome); however, the most common agents causing DILI in children are antiepileptic drugs, such as valproate, and psychotropic agents.

10. Patients with chronic liver disease have an increased incidence of DILI and a worse outcome.

11. DILI is the single most common adverse drug reaction leading to discontinuation during development of new medications, failure of new drugs to obtain regulatory approval, and withdrawal of existing drugs from the market.

Clinical Presentation

1. DILI may occur as an unexpected idiosyncratic reaction to a medication’s therapeutic dose or as an expected consequence of the agent’s intrinsic toxicity.

2. Hepatotoxicity may be the only manifestation of the adverse drug effect, or it may be accompanied by injury to other organ systems or by systemic manifestations.

3. Acute liver injury may develop within days of ingestion of a known hepatotoxin or after several weeks of taking a drug that provokes an immunoallergic reaction. Liver tests may have a necroinflammatory, cholestatic, or a mixed pattern with features of both parenchymal and cholestatic injury.

Aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and lactate dehydrogenase may be elevated 10 to 100 times the upper limit of normal (ULN) in acute hepatocellular injury, whereas alkaline phosphatase levels are usually less than 3 times the ULN.

Cholestatic drug injury resembles obstructive jaundice in its clinical manifestations and biochemical parameters. Serum alkaline phosphatase, gamma glutamyltranspeptidase, and direct bilirubin are variably elevated with or without aminotransferase elevation (usually no higher than five to eight times ULN).

Subclinical hepatic injury reflected only by minor liver enzyme elevation (e.g., AST and ALT in the range of 100 to 250 U/L) is a common phenomenon and may not worsen and may even subside despite continued administration of a medication.

Table 8.1 shows the histopathologic conditions associated with particular hepatotoxic agents.

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.

Characterization of Drug-Induced Liver Injury

Intrinsic Hepatotoxicity

This is almost always dose dependent and reproducible in laboratory animals. Examples of agents include acetaminophen, carbon tetrachloride, and alcohol.

Idiosyncratic Hepatotoxicity

1. This occurs unpredictably in a small number of recipients of a medication and accounts for most cases of DILI. Some dose dependency exists, and toxicity is not reliably reproduced in laboratory animals. Examples of agents include isoniazid (INH), sulfonamides, valproate, and phenytoin.

2. Liver injury may manifest after latent periods of varying duration.

3. Susceptibility results from an interplay among factors such as the toxic potential of the drug, environmental and host genetic risk factors that determine drug disposition, and metabolism and tissue susceptibility to toxicity.

4. Immunologically mediated injury can be accompanied by a mononucleosis-like illness and extrahepatic hallmarks of generalized hypersensitivity such as fever, rash, and eosinophilia; these features usually develop after a sensitization period of several weeks.

5. Symptoms recur if the agent is used again.

Mitochondrial Hepatotoxicity

This decreases fatty acid oxidation and/or energy production and leads to cell death. Examples of agents include diclofenac, amiodarone, tacrine, troglitazone, and topoisomerases.

Pathophysiology

1. The liver is exposed to high concentrations of ingested drugs, particularly those with a high first-pass metabolism.

2. Hepatic uptake of drugs may occur by specific transport mechanisms; most drugs are lipophilic and diffuse across the hepatocellular sinusoids.

3. Many of the mechanisms in the pathophysiology of DILI at the molecular level are shown in Table 8.2.

4. Normally, the liver metabolizes drugs to more polar forms, thus facilitating their excretion in aqueous fluids. Sometimes these metabolites may be toxic (e.g., in acetaminophen overdose), but they are generally converted to less toxic compounds by detoxification enzymes.

5. Individual susceptibility to drug hepatotoxicity is influenced by multiple variables that affect the biotransformation of drugs, and usually more than one of these is involved in any one patient (Table 8.3).

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

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.

Phase 1 Reactions

1. These are mediated by cytochrome P-450, are primarily oxidative, and yield active intermediate metabolites that may be responsible for liver injury. The cytochrome P-450 family of isoenzymes found primarily within the endoplasmic reticulum results in aliphatic and aromatic hydroxylation, dealkylation, or dehydrogenation. Products of these reactions may sometimes undergo further metabolism through phase 2 reactions.

2. Many medications may alter cytochrome P-450 activity and thus promote drug toxicity. Cytochrome P-450 enzymes catalyze the rate-limiting steps in the elimination of many drugs.

Phase 2 Reactions

1. These are mainly conjugative, converting the active metabolite to nontoxic, more hydrophilic products by linkage with glutathione, sulfate, or glucuronide. This is the only step required for the hepatic metabolism of some compounds; however, most drugs first undergo cytochrome P-450 metabolism.

2. Phase 1 reactions may thus be regarded as “toxification” and phase 2 as “detoxification.” Drug injury may result from toxification (increased active metabolites) or inadequate detoxification.

Phase 3 Reactions

These involve excretion and transport. Substances formed from drug detoxification become substrates for the export pump of the multidrug resistance protein family that mediates adenosine triphosphate–dependent secretion across the canalicular membrane into bile.

Diagnosis of Drug-induced Liver Injury

1. A detailed drug history, including dosage, duration of therapy, and other concomitantly administered drugs, is essential.

2. Other causes of liver disease must be excluded by careful assessment of clinical, radiologic, histologic, biochemical, and serologic findings.

3. The possibility of drug injury superimposed on preexisting liver disease must be considered.

4. Elevation of serum lactate dehydrogenase levels is more indicative of toxic liver injury than of viral-related disease, although this finding is nonspecific.

5. Nonspecific histologic lesions suggestive of drug injury include granulomas (Fig. 8.1), eosinophils within an inflammatory infiltrate (Fig. 8.2), a sharp zone of demarcation between necrosis and unaffected parenchyma, and a disproportionately severe degree of damage in relation to the patient’s condition and the extent of liver chemistry test abnormalities.