Drug-Induced Hepatotoxicity

Background

Drugs are an important cause of liver injury. More than 900 drugs, toxins, and herbs have been reported to cause liver injury, and drugs account for 20-40% of all instances of fulminant hepatic failure. Approximately 75% of the idiosyncratic drug reactions result in liver transplantation or death. Drug-induced hepatic injury is the most common reason cited for withdrawal of an approved drug. Physicians must be vigilant in identifying drug-related liver injury because early detection can decrease the severity of hepatotoxicity if the drug is discontinued. The manifestations of drug-induced hepatotoxicity are highly variable, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure. Knowledge of the commonly implicated agents and a high index of suspicion are essential in diagnosis.

Mortality/morbidity

In the United States, approximately 2000 cases of acute liver failure occur annually and drugs account for over 50% of them (39% are due to acetaminophen, 13% are idiosyncratic reactions due to other medications). Drugs account for 2-5% of cases of patients hospitalized with jaundice and approximately 10% of all cases of acute hepatitis.

Internationally, data on the incidence of adverse hepatic drug reactions in the general population remain unknown.

Drugs withdrawn from the market secondary to hepatotoxicity

In the last few years, the US Food and Drug Administration (FDA) has withdrawn 2 drugs from the market for causing severe liver injury: bromfenac and troglitazone. Bromfenac (Duract), a nonsteroidal anti-inflammatory drug (NSAID), was introduced in 1997 as a short-term analgesic for orthopedic patients. Although approved for a dosing period of less than 10 days, patients used it for longer periods. This resulted in more than 50 cases of severe hepatic injury, and the drug had to be withdrawn in 1998. Troglitazone (Rezulin) is a thiazolidinedione and was approved in 1997 as an antidiabetic agent. Over 3 years, more than 90 cases of hepatotoxicity were reported, which resulted in withdrawal of this drug.

Recently, kava kava, an herb used for anxiety, was reported as being hepatotoxic and was withdrawn from the German market. The FDA has also issued a warning in this country. This demonstrates the importance of postmarketing surveillance to identify reactions that are not reported or are underreported in drug trials.

Pemoline (Cylert), used for attention deficit disorder and narcolepsy is no longer available in the United States. The Food and Drug Administration (FDA) concluded that the overall risk of liver toxicity from pemoline outweighs the benefits. In May 2005, Abbott chose to stop sales and marketing of their brand of pemoline (Cylert) in the U.S. In October 2005, all companies that produced generic versions of pemoline also agreed to stop sales and marketing of pemoline.

Other drugs that have significant limitations of use because of their hepatotoxic effects are felbamate (Felbatol), an antiepileptic used for complex partial seizures; zileuton (Zyflo), indicated for asthma; tolcapone (Tasmar), used for Parkinson disease; trovafloxacin (Trovan), an antibiotic; benoxaprofen, an NSAID; and tienilic acid, a diuretic.

Recent warnings issued by the FDA

Severe hepatic injury, including cases of hepatic failure, has been reported in patients taking interferon beta-1a (Avonex) used in treatment of multiple sclerosis. Asymptomatic elevation of hepatic transaminases have also been reported and, in some patients, recurred upon rechallenge. In some cases, these events occurred in the presence of other drugs that have been associated with hepatic injury. The potential risk of Avonex used in combination with known hepatotoxic drugs or other products (eg, alcohol) should be considered prior to Avonex administration or when adding new agents to the regimen of patients already on Avonex.

The US Food and Drug Administration (FDA) recently (January 2006) issued a warning after 3 cases of serious liver toxicity were reported with taking telithromycin. In June 2006, the prescribing information for telithromycin (Ketek) was changed to include a warning describing the drug's association with rare cases of serious liver injury and liver failure. Four of these events resulted in deaths and one resulted in liver transplant. The added warning follows evaluation by the FDA on postmarketing surveillance reports. If clinical hepatitis or liver enzyme elevations combined with other systemic symptoms occur, telithromycin should be permanently discontinued. Telithromycin is an antibiotic of the ketolide class, approved by the FDA in April 2004 for the treatment of respiratory infections in adults. It is marketed and is widely used in several countries including Japan and countries in Europe.

In February 2007, the FDA took further action and removed 2 of the 3 indications: acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis. Following comprehensive scientific analysis, the FDA determined that the balance of benefits and risks no longer supports the approval of the drug for these indications. Telithromycin is now indicated for treatment of mild-to-moderate community-acquired pneumonia.

In October 2005, the manufactures of duloxetine (an anti-depressant) reported postmarketing cases of hepatitis and cholestatic jaundice. The new package insert now states, “Cymbalta should not be administered to patients with substantial alcohol use or any hepatic insufficiency."

Risk factors for drug-induced liver injury

• Race: Some drugs appear to have different toxicities based on race. For example, blacks and Hispanics may be more susceptible to isoniazid (INH) toxicity. The rate of metabolism is under the control of P-450 enzymes and can vary from individual to individual.
• Age: Apart from accidental exposure, hepatic drug reactions are rare in children. Elderly persons are at increased risk of hepatic injury because of decreased clearance, drug-to-drug interactions, reduced hepatic blood flow, variation in drug binding, and lower hepatic volume. In addition, poor diet, infections, and multiple hospitalizations are important reasons for drug-induced hepatotoxicity.
• Sex: Although the reasons are unknown, hepatic drug reactions are more common in females.
• Alcohol ingestion: Alcoholic persons are susceptible to drug toxicity because alcohol induces liver injury and cirrhotic changes that alter drug metabolism. Alcohol causes depletion of glutathione (hepatoprotective) stores that make the person more susceptible to toxicity by drugs.
• Liver disease: In general, patients with chronic liver disease are not uniformly at increased risk of hepatic injury. Although the total cytochrome P-450 is reduced, some may be affected more than others. The modification of doses in persons with liver disease should be based on the knowledge of the specific enzyme involved in the metabolism. Patients with HIV infection who are co-infected with hepatitis B or C virus are at increased risk for hepatotoxic effects when treated with antiretroviral therapy. Similarly, patients with cirrhosis are at increased risk of decompensation by toxic drugs.
• Genetic factors: A unique gene encodes each P-450 protein. Genetic differences in the P-450 enzymes can result in abnormal reactions to drugs, including idiosyncratic reactions. Debrisoquine is an antiarrhythmic drug that undergoes poor metabolism because of abnormal expression of P-450-II-D6. This can be identified by polymerase chain reaction amplification of mutant genes. This has led to the possibility of future detection of persons who can have abnormal reactions to a drug.
• Other comorbidities: Persons with AIDS, persons who are malnourished, and persons who are fasting may be susceptible to drug reactions because of low glutathione stores.
• Drug formulation: Long-acting drugs may cause more injury than shorter-acting drugs.

• Host factors that may enhance susceptibility to drugs, possibly inducing liver disease
  • Female - Halothane, nitrofurantoin, sulindac
  • Male - Amoxicillin-clavulanic acid (Augmentin)
  • Old age - Acetaminophen, halothane, INH, amoxicillin-clavulanic acid
  • Young age - Salicylates, valproic acid
  • Fasting or malnutrition - Acetaminophen
  • Large body mass index/obesity - Halothane
  • Diabetes mellitus - Methotrexate, niacin
  • Renal failure - Tetracycline, allopurinol
  • AIDS - Dapsone, trimethoprim-sulfamethoxazole
  • Hepatitis C - Ibuprofen, ritonavir, flutamide
  • Preexisting liver disease - Niacin, tetracycline, methotrexate

Pathophysiology and mechanisms of drug-induced liver injury

• Pathophysiologic mechanisms: The pathophysiologic mechanisms of hepatotoxicity are still being explored and include both hepatocellular and extracellular mechanisms. The following are some of the mechanisms that have been described:
  • Disruption of the hepatocyte: Covalent binding of the drug to intracellular proteins can cause a decrease in ATP levels, leading to actin disruption. Disassembly of actin fibrils at the surface of the hepatocyte causes blebs and rupture of the membrane.
  • Disruption of the transport proteins: Drugs that affect transport proteins at the canalicular membrane can interrupt bile flow. Loss of villous processes and interruption of transport pumps such as multidrug resistance–associated protein 3 prevent the excretion of bilirubin, causing cholestasis.
  • Cytolytic T-cell activation: Covalent binding of a drug to the P-450 enzyme acts as an immunogen, activating T cells and cytokines and stimulating a multifaceted immune response.
  • Apoptosis of hepatocytes: Activation of the apoptotic pathways by the tumor necrosis factor-alpha receptor of Fas may trigger the cascade of intercellular caspases, which results in programmed cell death.
  • Mitochondrial disruption: Certain drugs inhibit mitochondrial function by a dual effect on both beta-oxidation energy production by inhibiting the synthesis of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, resulting in decreased ATP production.
  • Bile duct injury: Toxic metabolites excreted in bile may cause injury to the bile duct epithelium.

• Drug toxicity mechanisms: The classic division of drug reactions is into at least 2 major groups, (1) drugs that directly affect the liver and (2) drugs that mediate an immune response.
  • Intrinsic or predictable drug reactions: Drugs that fall into this category cause reproducible injuries in animals, and the injury is dose related. The injury can be due to the drug itself or to a metabolite. Acetaminophen is a classic example of a known intrinsic or predictable hepatotoxin at supertherapeutic doses. Another classic example is carbon tetrachloride.
  • Idiosyncratic drug reactions: Idiosyncratic drug reactions can be subdivided into those that are classified as hypersensitivity or immunoallergic and those that are metabolic-idiosyncratic.
    • Hypersensitivity: Phenytoin is a classic, if not common, cause of hypersensitivity reactions. The response is characterized by fever, rash, and eosinophilia and is an immune-related response with a typical short latency period of 1-4 weeks.
    • Metabolic-idiosyncratic: This type of reaction occurs through an indirect metabolite of the offending drug. Unlike intrinsic hepatotoxins, the response rate is variable and can occur within a week or up to one year later. It occurs in a minority of patients taking the drug, and no clinical manifestations of hypersensitivity are noted. INH toxicity is considered to fall into this class. Not all drugs fall neatly into one of these categories, and overlapping mechanisms may occur with some drugs (eg, halothane).

METABOLISM OF DRUGS
The liver metabolizes virtually every drug or toxin introduced in the body. Most drugs are lipophilic (fat soluble), enabling easy absorption across cell membranes. In the body, they are rendered hydrophilic (water soluble) by biochemical processes in the hepatocyte to enable inactivation and easy excretion. Metabolism of drugs occurs in 2 phases. In the phase 1 reaction, the drug is made polar by oxidation or hydroxylation. All drugs may not undergo this step, and some may directly undergo the phase 2 reaction.

The cytochrome P-450 enzymes catalyze phase 1 reactions. Most of these intermediate products are transient and highly reactive. These reactions may result in the formation of metabolites that are far more toxic than the parent substrate and may result in liver injury. As an example, the metabolite of acetaminophen is N-acetyl-p-benzoquinone-imine (NAPQI) and is produced with ingestion of high doses. NAPQI is responsible for the liver injury in cases of toxicity. Cytochrome P-450 enzymes are hemoproteins located in the smooth endoplasmic reticulum of the liver. At least 50 enzymes have been identified, and based on structure, they are categorized into 10 groups, with groups 1, 2, and 3 being the most important in drug metabolism. Each P-450 enzyme can metabolize many drugs. Drugs that share the same P-450 specificity for biotransformation may competitively inhibit each other, resulting in drug interactions. Several drugs can induce and inhibit the P-450 enzyme (see below).

Phase 2 reactions may occur within or outside the liver. They involve conjugation with a moiety (ie, acetate, amino acid, sulfate, glutathione, glucuronic acid) that further increases solubility. Subsequently, drugs with high molecular weight may be excreted in bile, while the kidneys excrete the smaller molecules.

Drugs that induce and inhibit the P-450 enzymes are as follows:

• Inducers
  • Phenobarbital
  • Phenytoin
  • Carbamazepine
  • Primidone
  • Ethanol
  • Glucocorticoids
  • Rifampin
  • Griseofulvin
  • Quinine
  • Omeprazole - Induces P-450 1A2
• Inhibitors
  • Amiodarone
  • Cimetidine
  • Erythromycin
  • Grape fruit
  • Isoniazid
  • Ketoconazole
  • Metronidazole
  • Sulfonamides
  • Quinidine
  • Omeprazole - Inhibits P-450 2C8

CLINICAL AND PATHOLOGICAL MANIFESTATIONS OF DRUG-INDUCED LIVER DISEASE
Drug hepatotoxicity manifests with clinical signs and symptoms caused by an underlying pathological injury. The clinical presentation may or may not suggest the underlying liver injury, and therefore, the types of injuries are sometimes described separately. Some drugs usually cause one clinical and pathologic injury and other drugs can cause a variety of injuries, often making the diagnosis more challenging.

Clinical manifestations

The manifestations of drug-induced hepatotoxicity are highly variable, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure. The injury may suggest a hepatocellular injury, with elevation of aminotransferase levels as the predominant symptom, or a cholestatic injury, with elevated alkaline phosphatase levels (with or without hyperbilirubinemia) being the main feature. In addition, drugs that cause mild aminotransferase elevations with subsequent adaptation are differentiated from those that result in true toxicity that require discontinuation.

• Asymptomatic elevations in aminotransferase: Some drugs cause asymptomatic elevations of liver enzymes that do not progress despite continued use of the drug.
  • As many as 50% of patients receiving tacrine for Alzheimer disease have elevated enzyme levels. Alkaline phosphatase and bilirubin levels are rarely elevated, and severe injury is rare. Rechallenging a patient with this medication may even be appropriate, and in more than 80% of cases, the alanine aminotransferase (ALT) abnormalities resolve or do not reoccur.
  • This tolerance is also observed in 25-50% of the patients taking drugs such as methyldopa or phenytoin, and it is especially well described with INH.
  • 5-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are also associated with a mild elevation in enzyme levels in less than 5% of cases.
  • Other drugs include sulfonamides, salicylates, sulfonylureas, and quinidine.
  • If the clinician is not familiar with the drug or if any question remains about the safety of continuing a drug, consultation with a hepatologist should be considered.
• Elevated aminotransferase levels with acute hepatocellular injury: Drug-induced liver injury is designated hepatocellular if the ALT levels are increased to more than twice the upper limit of the reference range, with alkaline phosphatase levels that are within the reference range or are minimally elevated. Elevation of aspartate aminotransferase (AST) greater than ALT, especially if more than 2 times greater, suggests alcoholic hepatitis. Elevation of AST less than ALT is usually observed in persons with viral hepatitis. In viral and drug-induced hepatitis, the AST and ALT levels steadily increase and peak in the low thousands range within 7-14 days. Many medications can cause increases in AST, such as acetaminophen, NSAIDs, ACE inhibitors, nicotinic acid, INH, sulfonamides, erythromycin, and antifungal agents such as griseofulvin and fluconazole. In acetaminophen overdose, transaminase levels greater than 10,000 IU/L are also noted.
• Elevated aminotransferase and bilirubin levels suggestive of subfulminant or fulminant necrosis
  • With increasing hepatocellular injury, bilirubin levels are invariably increased, suggesting a worse prognosis. Normally, the total bilirubin level is less than 1.1 mg/dL and approximately 70% is indirect (unconjugated) bilirubin. Unconjugated hyperbilirubinemia (>80% of the total bilirubin is indirect) suggests hemolysis or Gilbert syndrome. Conjugated hyperbilirubinemia (>50% of the total bilirubin is direct) suggests hepatocellular dysfunction or cholestasis. When the bilirubin level is above 25-30 mg/dL, extrahepatic cholestasis is an unlikely diagnosis; because the predominantly conjugated bilirubin is water soluble, it is easily excreted by the kidney in extrahepatic cholestasis.
  • Subfulminant hepatic failure most commonly results from acetaminophen, halothane, methoxyflurane, enflurane, trovafloxacin, troglitazone, ketoconazole, dihydralazine, tacrine, mushroom poisoning, ferrous sulfate poisoning, phosphorus poisoning, and cocaine toxicity. Drugs that result in massive necrosis are propylthiouracil, INH, phenytoin, phenelzine, sertraline, naproxen, diclofenac, kava kava, and ecstasy.
• Elevated alkaline phosphatase (acute cholestatic injury) levels: Acute intrahepatic cholestasis is divisible into 2 broad categories, (1) cholestasis without hepatocellular injury (bland jaundice or pure cholestasis) and (2) cholestasis with variable hepatocyte injury.
  • The most common biochemical abnormality is elevation of the alkaline phosphate level, usually without hyperbilirubinemia. Men and older patients are more prone to these adverse effects. The interval of developments is usually less than 4 weeks and may be as long as 8 weeks. Fever, rash, and eosinophilia may be observed in as many as 30% of individuals, but these findings do not define the disorder.
  • Some common drugs associated with cholestatic injury include chlorpromazine, ciprofloxacin, ofloxacin, cimetidine, phenytoin, naproxen, captopril, erythromycin, azithromycin, and dicloxacillin. Amoxicillin-clavulanic acid is also an important cause of cholestatic jaundice. Extrahepatic cholestasis secondary to biliary sludge or calculi is caused by sulindac or octreotide.
• Extrahepatic manifestations: Some drugs cause systemic reactions associated with hepatic injury. Extrahepatic manifestations of drug-induced hepatotoxicity are as follows:
  • Chlorpromazine, phenylbutazone, halogenated anesthetic agents, sulindac - Fever, rash, eosinophilia
  • Dapsone - Sulfone syndrome (ie, fever, rash, anemia, jaundice)
  • INH, halothane - Acute viral hepatitis
  • Chlorpromazine, erythromycin, amoxicillin-clavulanic acid - Obstructive jaundice
  • Phenytoin, carbamazepine, phenobarbital, primidone - Anticonvulsant hypersensitivity syndrome (ie, triad of fever, rash, and liver injury)
  • Para-amino salicylate, phenytoin, sulfonamides - Serum sickness syndrome
  • Clofibrate - Muscular syndrome (ie, myalgia, stiffness, weakness, elevated creatine kinase level)
  • Procainamide - Antinuclear antibodies (ANAs)
  • Gold salts, propylthiouracil, chlorpromazine, chloramphenicol - Marrow injury
  • Amiodarone, nitrofurantoin - Associated pulmonary injury
  • Gold salts, methoxyflurane, penicillamine, paraquat - Associated renal injury
  • Tetracycline - Fatty liver of pregnancy
  • Contraceptive and anabolic steroids, rifampin - Bland jaundice
  • Aspirin - Reye syndrome
  • Sodium valproate - Reyelike syndrome

Pathological manifestations

Besides the use of clinical and laboratory data, the pattern of liver histology may be classified into categories as described below.

• Acute hepatocellular injury: Manifestations of acute liver injury may range from spotty necrosis to fulminant liver failure. Spotty necrosis resembles classic viral hepatitis and involves all acinar zones. Hepatocellular injury consists of ballooning degeneration or apoptosis with eosinophils, especially in cases of peripheral eosinophilia. Drugs that can cause this type of injury are INH, halothane, phenylbutazone, indomethacin, and disulfiram. Submassive necrosis, as the name suggests, may affect zone 1 (periportal) or zone 3 (central necrosis). Periportal changes occur with ferrous sulfate poisoning, phosphorus poisoning, and cocaine toxicity. Central necrosis occurs with acetaminophen, halothane, methoxyflurane, trovafloxacin, ketoconazole, dihydralazine, tacrine, and mushroom poisoning. Massive necrosis is an extension of submassive necrosis and manifests as fulminant failure.
• Chronic hepatocellular injury: Drug-induced chronic changes manifest many forms.
  • Pigment accumulation: Lipofuscin pigment storage in the liver cells has been reported with phenothiazines, phenacetin, aminopyrine, and cascara sagrada. Hemosiderin accumulation in the liver cells may result from excessive iron ingestion or parenteral iron therapy in patients undergoing hemodialysis.
  • Steatosis, steatohepatitis, and phospholipidosis: Steatosis secondary to drug toxicity may be in the form of medium-sized and large droplets (macrovesicular) or small droplets (microvesicular). Microvesicular steatosis is observed with alcohol, aspirin, valproic acid, amiodarone, piroxicam, stavudine, didanosine, nevirapine, and high doses of tetracycline. Drugs that can cause macrovesicular steatosis include alcohol, corticosteroids, methotrexate, minocycline, nifedipine, parenteral nutrition, and perhexiline maleate. Steatohepatitis has been reported with amiodarone, nifedipine, synthetic estrogens, and didanosine. Phospholipidosis results from lysosomal phospholipid storage secondary to inactivation of lysosomal phospholipases by drugs. Common causes are perhexiline maleate, amiodarone, total parenteral nutrition (TPN), trimethoprim-sulfamethoxazole, and chloroquine.
  • Hepatic fibrosis and cirrhosis: Most hepatic drug reactions of minimal-to-moderate severity are followed by recovery and no significant fibrosis. Any drug causing submassive hepatocellular injury may be followed by fibrosis, nodular regeneration, and cirrhosis. However, some agents produce an increase in collagen deposition, with minimal or absent features of necrosis or inflammation. Drugs leading to fibrosis include methotrexate, hypervitaminosis A, vinyl chloride, thorotrast, and heroin. Prolonged therapy with methotrexate, INH, ticrynafen, perhexiline, enalapril, and valproic acid may lead to cirrhosis.
• Acute cholestasis: Cholestasis is defined as a reduction in bile flow resulting from reduced secretion or obstruction of the biliary tree. If any evidence indicates hepatocellular injury, it is called cholestatic hepatitis. Histology shows apoptotic bodies, small foci of necrosis, and, less often, ballooning with or without zone 3 necrosis. Bile accumulates in the cytoplasm of the liver cells, canaliculi, and Kupffer cells. Drugs that lead to a pure cholestatic reaction include anabolic steroids (eg, methyl testosterone, oxymetholone, fluoxymesterone) and contraceptive steroids. Drugs that can cause cholestatic hepatitis include erythromycin, azithromycin, ciprofloxacin, ofloxacin, ranitidine, cimetidine, phenytoin, gold salts, and terbinafine. Intrahepatic cholestasis may be accompanied by acute cholangitis and is observed in patients taking chlorpromazine, allopurinol, chlorpropamide, and hydralazine.
• Chronic cholestasis: Histology shows chronic portal inflammation and degeneration of the bile duct referred to as progressive ductopenia or vanishing bile duct syndrome. Most cases of drug-induced cholestasis are followed by rapid clinical and biochemical recovery upon withdrawal of the drug. However, approximately 1% of patients may continue to have abnormal liver test results and some may progress to a condition resembling primary biliary cirrhosis. Causes of intrahepatic cholestasis include chlorpropamide, amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, carbamazepine, and TPN. Floxuridine causes intrahepatic and extrahepatic cholestasis.
• Granulomatous hepatitis: Most of these reactions consist of noncaseating epithelioid granulomas located in periportal or portal areas. This injury is usually transient and causes no sequelae. Drugs implicated include sulfonamide, sulfonylurea, phenytoin, quinidine, and hydralazine. Long-term use of mineral oil for constipation can cause lipogranulomas. Allopurinol is known to cause granulomas with a fibrin ring, whereas gold salts may lead to the formation of lipogranulomas with black pigment. Carbamazepine is a common cause of granulomatous hepatitis.
• Autoimmune hepatitis: Histology reveals active necroinflammatory lesions with prominent plasma cells. Females are affected more often than males. Autoimmune hepatitis manifests insidiously as fatigue, anorexia, weight loss, jaundice, ascites, portal hypertension, hepatomegaly, and splenomegaly. The serology may be positive for ANA, anti–smooth muscle antibody (ASMA), or lupus erythematosus factor with elevated gamma globulin levels. Examples of commonly implicated drugs include methyldopa, minocycline, nitrofurantoin, dihydralazine, lisinopril, sulfonamides, and trazodone.
• Vascular lesions/venoocclusive disease: Drugs can injure any component of the liver, including the sinusoids, hepatic veins, and hepatic arteries. Azathioprine has been associated with hepatic venoocclusive disease in patients with a renal transplant, bone marrow transplant, and on long-term treatment for inflammatory bowel disease. Alcohol, excess vitamin A, floxuridine, and dacarbazine may lead to venoocclusive disease with or without acinar zone 3 necrosis. Herbal tea preparations (alkaloids) may cause acute ascites, rapid weight gain, abdominal pain, and hepatomegaly, which are reversible but sometimes fatal. Oral contraceptives can cause focal sinusoidal dilatations. Both contraceptives and anabolic steroids may lead to peliosis hepatis, ie, extrasinusoidal blood-filled spaces.
• Neoplastic lesions: Focal nodular hyperplasia and hepatocellular adenomas have been well described since the advent of oral contraceptive steroids. Many agents are linked to malignant hepatic neoplasms, including angiosarcoma from vinyl chloride and thorium dioxide.
• Summary: Pathological manifestations of drug-induced hepatotoxicity are as follows:
  • Acute hepatocellular injury
  • Acute viral hepatitis–like picture - INH, halothane, diclofenac, troglitazone
  • Mononucleosis like picture - Phenytoin, sulfonamides, dapsone
  • Chronic hepatocellular injury - Pemoline, methyldopa
  • Massive necrosis - Acetaminophen, halothane, diclofenac
  • Steatosis
  • Macrovesicular steatosis - Alcohol, methotrexate, corticosteroids, minocycline, nifedipine, TPN
  • Microvesicular steatosis - Alcohol, valproic acid, tetracycline, piroxicam
  • Steatohepatitis - Amiodarone, nifedipine, synthetic estrogens, didanosine
  • Pseudoalcoholic injury - Amiodarone
  • Acute cholestasis - Amoxicillin-clavulanic acid, erythromycin, sulindac
  • Chronic cholestasis - Chlorpromazine, sulfamethoxazole-trimethoprim, tetracycline, ibuprofen
  • Granulomatous hepatitis - Carbamazepine, allopurinol, hydralazine
  • Vascular injury - Steroids
  • Neoplasia - Contraceptives, anabolic steroids
  • Adenoma - Steroids
  • Angiosarcoma - Vinyl chloride
  • Hepatocellular carcinoma - Anabolic steroids, aflatoxin, arsenic, vinyl chloride

DIAGNOSIS
When a single agent is involved, the diagnosis may be relatively simple, but with multiple agents, implicating a specific agent as the cause is difficult. To facilitate the diagnosis of drug-induced hepatic injury, several clinical tools for causality assessment have been developed to assist the clinician.

• History: History must include dose, route of administration, duration, previous administration, and use of any concomitant drugs, including over-the-counter medications and herbs. Knowing whether the patient was exposed to the same drug before may be helpful. The latency period of idiosyncratic drug reactions is highly variable; hence, obtaining a history of every drug ingested in the past 3 months is essential.
  • Onset: The onset is usually within 5-90 days of starting the drug.
  • Exclusion of other causes of liver injury/cholestasis: Excluding other causes of liver injury is essential.
• Dechallenge: A positive dechallenge is a 50% fall in serum transaminase levels within 8 days of stopping the drug. A positive dechallenge is very helpful in cases of use of multiple medications.
• Track record of the drug: Previously documented reactions to a drug aid in diagnosis.
• Rechallenge: Deliberate rechallenge in clinical situations is unethical and should not be attempted; however, inadvertent rechallenge in the past has provided valuable evidence that the drug was indeed hepatotoxic.