Drug-Induced Hepatotoxicity

Updated: Dec 08, 2016
  • Author: Nilesh Mehta, MD; Chief Editor: Michael R Pinsky, MD, CM, Dr(HC), FCCP, MCCM  more...
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Overview

Overview

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.

For patient education resources, visit the First Aid and Injuries Center. Also, see the patient education articles Acetaminophen (Tylenol) Poisoning, FDA Overview, Pain Medications, and Alcoholism.

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Drugs withdrawn from the market secondary to hepatotoxicity

In the last few years, the US Food and Drug Administration (FDA) has withdrawn 2 drugs from the market for causing severe liver injury: bromfenac and troglitazone.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 This resulted in more than 50 cases of severe hepatic injury, and the drug had to be withdrawn in 1998.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.

Kava kava, an herb used for anxiety, was reported as being hepatotoxic and was withdrawn from the German market. [1] 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.

Warnings issued by the FDA

In April 2010, the FDA had added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for propylthiouracil. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that propylthiouracil should be reserved for use in those who cannot tolerate other treatments such as methimazole, radioactive iodine, or surgery.

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

In 2009, the FDA issued guidelines to assist the pharmaceutical industry and other investigators who are conducting new drug development in assessing the potential for a drug to cause severe liver injury (ie, irreversible liver failure that is fatal or requires liver transplantation). In particular, the guidance addresses how laboratory measurements that signal the potential for such drug-induced liver injury can be obtained and evaluated during drug development. [2]

In June 2009, the FDA issued a report that identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with propylthiouracil (PTU). Of the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver transplants occurred. PTU is indicated for hyperthyroidism due to Graves disease.

These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death). PTU is considered as a second-line drug therapy, except in patients who are allergic or intolerant to methimazole, or for women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy.

The FDA recommends the following criteria be considered for prescribing PTU:

  • Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole.
  • Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.
  • For suspected liver injury, promptly discontinue PTU therapy and evaluate for evidence of liver injury and provide supportive care.
  • PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole, and no other treatment options are available.
  • Counsel patients to promptly contact their health care provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

For more information, see the FDA Safety Alert.

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.

In January 2006, the US Food and Drug Administration (FDA) 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 [3, 4]

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 [3]

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

Preexisting liver disease has not been thought to make patients more susceptible to drug-induced liver injury, [5, 6] but it may be that a diminished liver reserve or the ability to recover could make the consequences of injury worse. Although the total cytochrome P-450 is reduced in chronic liver disease, 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 [7]

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. [8]

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

Factors that may enhance susceptibility to drugs, possibly inducing liver disease, are as follows:

  • 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 two major groups, (1) drugs that directly affect the liver and (2) drugs that mediate an immune response, as follows:

  • 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. Regarding hypersensitivity reactions, 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. A metabolic-idiosyncratic 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).
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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 the P-450 enzymes are as follows:

  • Phenobarbital
  • Phenytoin
  • Carbamazepine
  • Primidone
  • Ethanol
  • Glucocorticoids
  • Rifampin
  • Griseofulvin
  • Quinine
  • Omeprazole - Induces P-450 1A2

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

  • Amiodarone
  • Cimetidine
  • Erythromycin
  • Grape fruit
  • Isoniazid
  • Ketoconazole
  • Metronidazole
  • Sulfonamides
  • Quinidine
  • Omeprazole - Inhibits P-450 2C8
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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. [9] 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 two 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. [10]

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, as follows:

  • 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. [11]

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, [12] and on long-term treatment for inflammatory bowel disease. Alcohol, excess vitamin A, floxuridine, [13] 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
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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 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. The onset is usually within 5-90 days of starting the drug. Excluding other causes of liver injury is essential.

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.

Previously documented reactions to a drug aid in diagnosis.

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.

Differential diagnoses are as follows:

  • Acute viral hepatitis
  • Autoimmune hepatitis
  • Nonalcoholic steatohepatitis (NASH)
  • Shock liver/cardiovascular causes, especially right-sided heart failure
  • Cholecystitis
  • Cholangitis
  • Budd-Chiari syndrome
  • Alcoholic liver disease
  • Cholestatic liver disease
  • Pregnancy-related conditions of liver
  • Malignancy
  • Wilson disease
  • Hemochromatosis
  • Coagulation disorders
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Workup

Laboratory studies

Performing laboratory tests to assess and diagnose the effects of the suspected medication is essential.

In general, an increase of serum alanine transaminase (ALT) to greater than 3 times the upper limits of normal should be followed by repeat testing (hepatic function panel) within 72 hours to confirm the abnormalities and to determine if they are increasing or decreasing. There also should be inquiry made about symptoms. Serum ALT may rise and fall quite rapidly, and waiting a week or two before obtaining confirmation of elevations may lead to a false conclusion that the initially observed abnormality was spurious. Of greater concern, delay in retesting may allow progression to severe worsening if the initial abnormality was the herald of a severe reaction to follow. The need for prompt repeat testing is especially great if the ALT is much greater than 3 times the upper limits of normal and/or total bilirubin level is greater than 2 times the upper limit of normal.

Initial testing should include complete blood cell count, basic metabolic profile, hepatic function panel and urinalysis. Patients with a hepatocellular process generally have a disproportionate elevation in serum aminotransferase levels compared with alkaline phosphatase levels, while those with cholestasis have the opposite findings. Hepatitis B serology (hepatitis B surface antigen, anti–hepatitis B surface antibody, anti–hepatitis B core antibody, hepatitis C serology) and hepatitis A serology (anti–hepatitis A virus antibody) should be performed to exclude an infectious etiology.

ANA testing may help in cases of possible autoimmune hepatitis. Positive ANA and ASMA findings may add to the diagnostic evaluation but are usually confusing and hence not used. The presence of antibodies to specific forms of CYP has been associated with hypersensitivity to some drugs. For example, some antibodies and the associated drugs involved are as follows: CYP 1A2, dihydralazine; CYP 3A1, anticonvulsants; and CPY 2E1, halothane. Their role in pathophysiology is uncertain but may help in diagnosis. Lymphocyte transformation to test drugs may be observed for drugs acting through immunologic reactions, but this is not commonly used.

Hepatic function tests and their interpretations are as follows:

  • Bilirubin (total) - To diagnose jaundice and assess severity
  • Bilirubin (unconjugated) - To assess for hemolysis
  • Alkaline phosphatase - To diagnose cholestasis and infiltrative disease
  • AST/serum glutamic oxaloacetic transaminase (SGOT) - To diagnose hepatocellular disease and assess progression of disease
  • ALT/serum glutamate pyruvate transaminase (SGPT) - ALT relatively lower than AST in persons with alcoholism
  • Albumin - To assess severity of liver injury (HIV infection and malnutrition may confound this.)
  • Gamma globulin - Large elevations suggestive of autoimmune hepatitis, other typical increase observed in persons with cirrhosis
  • Prothrombin time after vitamin K - To assess severity of liver disease
  • Antimitochondrial antibody - To diagnose primary biliary cirrhosis
  • ASMA - To diagnose primary sclerosing cholangitis

Imaging studies

Imaging studies are used to exclude causes of liver pathology, after which a diagnosis can be made.

Ultrasonography is inexpensive compared with CT scanning and MRI and is performed in only a few minutes. Ultrasonography is effective to evaluate the gall bladder, bile ducts, and hepatic tumors.

CT scanning can help detect focal hepatic lesions 1 cm or larger and some diffuse conditions. It can also be used to visualize adjacent structures in the abdomen.

MRI provides excellent contrast resolution. It can be used to detect cysts, hemangiomas, and primary and secondary tumors. The portal vein, hepatic veins, and biliary tract can be visualized without contrast injections.

Procedures

Histopathologic evaluation remains an important tool in diagnosis. A liver biopsy is not essential in every case, but a morphologic pattern consistent with the expected pattern provides supportive evidence.

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Specific Agents and Their Effects on the Liver

Hepatocellular injury can be caused by drugs that rarely, if ever, cause severe liver injury (eg, aspirin, tacrine, [9, 14] statins, heparin), as well as by drugs that do cause such injury. [2, 15]

Most drugs have a signature effect, which is a pattern of liver injury, although some drugs such as rifampin can cause all types of liver injury, including hepatocellular injury, cholestasis, or even isolated hyperbilirubinemia. However, knowledge of the most commonly implicated agents and a high index of suspicion are essential in diagnosis.

Acetaminophen

Hepatotoxicity from acetaminophen is due to the toxic metabolite NAPQI. This metabolite is generated by cytochrome P-450-2E1. Alcohol and other drugs induce cytochrome P-450-2E1 and may result in enhanced toxicity. In adults, a dose of 7.5-10 g produces hepatic necrosis, but the dose is difficult to assess because of early vomiting and unreliable history. Nonetheless, doses as low as 4-8 g/d may produce liver injury in persons with alcoholism and people with underlying liver disease. For details about acetaminophen toxicity, refer to Toxicity, Acetaminophen.

Amoxicillin

Amoxicillin causes a moderate rise in SGOT levels, SGPT levels, or both, but the significance of this finding is unknown. Hepatic dysfunction, including jaundice, hepatic cholestasis, and acute cytolytic hepatitis, have been reported.

Amiodarone

Amiodarone [16, 17, 18, 19, 20] causes abnormal liver function test results in 15-50% of patients. The spectrum of liver injury is wide, ranging from isolated asymptomatic transaminase elevations to a fulminant disorder. Hepatotoxicity usually develops more than 1 year after starting therapy, but it can occur in 1 month. It is usually predictable, dose dependent, and has a direct hepatotoxic effect. Some patients with elevated aminotransferase levels have detectable hepatomegaly, and clinically important liver disease develops in less than 5% of patients. In rare cases, amiodarone toxicity manifests as alcoholic liver disease. Hepatic granulomas are rare. Importantly, amiodarone has a very long half-life and therefore may be present in the liver for several months after withdrawal of therapy. Amiodarone is iodinated, and this results in increased density on CT scans, which does not correlate with hepatic injury.

Chlorpromazine

Chlorpromazine liver injury resembles that of infectious hepatitis with laboratory features of obstructive jaundice rather than those of parenchymal damage. The overall incidence of jaundice is low regardless of dose or indication of the drug. Most cases occur 2-4 weeks after therapy. Any surgical intervention should be withheld until extrahepatic obstruction is confirmed. It is usually promptly reversible upon withdrawal of the medication; however chronic jaundice has been reported. Chlorpromazine should be administered with caution to persons with liver disease.

Ciprofloxacin

Cholestatic jaundice has been reported with repeated use of quinolones. Approximately 1.9% of patients taking ciprofloxacin show elevated SGPT levels, 1.7% have elevated SGOT levels, 0.8% have increased alkaline phosphatase levels, and 0.3% have elevated bilirubin levels. Jaundice is transient, and enzyme levels return to the reference range.

Diclofenac

Elderly females are more susceptible to diclofenac-induced liver injury. Elevations of one or more liver test results may occur. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline or greater elevations of transaminase levels occur in approximately 15% of patients treated with diclofenac. Of the hepatic enzymes, ALT is recommended for monitoring liver injury. Meaningful (>3 times the upper limit of the reference range) elevations of ALT or AST occur in approximately 2% of patients during the first 2 months of treatment. In patients receiving long-term therapy, transaminase levels should be measured periodically within 4-8 weeks of initiating treatment. Some may also have positive ANA findings. In addition to the elevation of ALT and AST levels, cases of liver necrosis, jaundice, and fulminant hepatitis with and without jaundice have occurred.

Erythromycin

Erythromycin may cause hepatic dysfunction, including increased liver enzyme levels and hepatocellular and/or cholestatic hepatitis with or without jaundice. A cholestatic reaction is the most common adverse effect and usually begins within 2-3 weeks of therapy. The liver principally excretes erythromycin; exercise caution when this drug is administered to patients with impaired liver function. The use of erythromycin in patients concurrently taking drugs metabolized by the P-450 system may be associated with elevations in the serum levels of other drugs.

Fluconazole

The spectrum of hepatic reactions ranges from mild transient elevations in transaminase levels to hepatitis, cholestasis, and fulminant hepatic failure. In fluconazole-associated hepatotoxicity, hepatotoxicity is not obviously related to the total daily dose, duration of therapy, or sex or age of the patient. Fatal reactions occur in patients with serious underlying medical illness. Fluconazole-associated hepatotoxicity is usually, but not always, reversible upon discontinuation of therapy.

Isoniazid

Severe and fatal hepatitis has been reported with INH therapy. The risk of developing hepatitis is age related, with an incidence of 8 cases per 1000 persons older than 65 years. In addition, the risk of hepatitis is increased with daily consumption of alcohol. Mild hepatic dysfunction evidenced by a transient elevation of serum transaminase levels occurs in 10-20% of patients taking INH. This abnormality usually appears in the first 3 months of treatment, but it may occur anytime during therapy. In most instances, enzyme levels return to the reference range, with no need to discontinue the medication. Occasionally, progressive liver damage can occur.

Patients administered INH should be carefully monitored and interviewed at monthly intervals. For persons aged 35 years and older, hepatic enzymes should be measured prior to starting INH and periodically throughout treatment. If SGOT values exceed 3-5 times the upper limit of the reference range, discontinuation of the drug should be strongly considered. Patients should be instructed to immediately report any symptoms, specifically unexplained anorexia, nausea, vomiting, dark urine, icterus, rash, persistent paresthesias of the hand and feet, persistent fatigue, weakness or fever of greater than 3 days' duration, and/or abdominal tenderness, especially right quadrant discomfort. In such cases, INH should be discontinued because continued use can lead to severe liver damage.

Methyldopa

Methyldopa [21] is an antihypertensive that is contraindicated in patients with active liver disease. Periodic determination of hepatic function should be performed during the first 6-12 weeks of therapy. Occasionally, fever may occur within 3 weeks of methyldopa therapy, which may be associated with abnormalities in liver function test results or eosinophilia, necessitating discontinuation. In some patients, findings are consistent with those of cholestasis and hepatocellular injury. Rarely, fatal hepatic necrosis has been reported after use of methyldopa, which may represent a hypersensitivity reaction.

Oral contraceptives

Oral contraceptives [22, 23] can lead to intrahepatic cholestasis with pruritus and jaundice in a small number of patients. Patients with recurrent idiopathic jaundice of pregnancy, severe pruritus of pregnancy, or a family history of these disorders are more susceptible to hepatic injury. Oral contraceptives are contraindicated in patients with a history of recurrent jaundice of pregnancy. Benign neoplasm, rarely malignant neoplasm of the liver, and hepatic vein occlusion have also been associated with oral contraceptive therapy.

Statins/HMG-CoA reductase inhibitors (package insert)

The use of statins is associated with biochemical abnormalities of liver function. [24, 25, 26] Moderate elevations of serum transaminase levels (< 3 times the upper limit of the reference range) have been reported following initiation of therapy and are often transient. Elevations are not accompanied by any symptoms and do not require interruption of treatment. Persistent increases in serum transaminase levels (>3 times the upper limit of the reference range) occur in approximately 1% of patients, and these patients should be monitored until liver function returns to normal after drug withdrawal. Active liver disease or unexplained transaminase elevations are contraindications to use of these drugs. Exercise caution in patients with a recent history of liver disease or in persons who drink alcohol regularly and in large quantities. Statins are among the most widely prescribed medications in the western world. Currently, 6 statins are available for use in the United States. Due to the information contained in package inserts, physicians tend to be concerned while administering statins to patients with deranged liver function tests. Although no concrete evidence shows that statins cause more harm in patients with elevated liver enzymes (recent data), prescribing them in consultation with a specialist may be prudent.

Rifampin

Rifampin is usually administered with INH. On its own, rifampin may cause mild hepatitis, but this is usually in the context of a general hypersensitivity reaction. Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking rifampin with other hepatotoxic agents. Careful monitoring of liver function (especially SGPT/SGOT) should be performed prior to therapy and then every 2-4 weeks during therapy. In some cases, hyperbilirubinemia resulting from competition between rifampin and bilirubin for excretory pathways of the liver can occur in the early days of treatment. Isolated cholestasis also may occur. An isolated report showing a moderate rise in bilirubin and/or transaminase levels is not in itself an indication for interrupting treatment. Rather, the decision should be based on repeated test results and trends in conjunction with the patient's clinical condition.

Valproic acid and divalproex sodium

Microvesicular steatosis is observed with alcohol, aspirin, valproic acid, amiodarone, piroxicam, stavudine, didanosine, nevirapine, and high doses of tetracycline. Prolonged therapy with methotrexate, INH, ticrynafen, perhexiline, enalapril, and valproic acid may lead to cirrhosis. Valproic acid typically causes microsteatosis. This drug should not be administered to patients with hepatic disease; exercise caution in patients with a prior history of hepatic disease. Those at particular risk include children younger than 2 years, those with congenital metabolic disorders or organic brain disease, and those with seizure disorders treated with multiple anticonvulsants.

Hepatic failures resulting in fatalities have occurred in patients receiving valproic acid. These incidents usually occur during the first 6 months of treatment and are preceded by nonspecific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, vomiting, and even loss of seizure control. Liver function tests should be performed prior to therapy and at frequent intervals, especially in the first 6 months. Physicians should not rely totally on laboratory results; they should also consider findings from the medical history and physical examination.

Herbs

The increasing use of alternative medicines has led to many reports of toxicity. The spectrum of liver disease is wide with these medicines. [27, 28, 29]

Senecio/crotalaria (Bush teas) can cause venoocclusive disease.

Germander in teas is used for its anticholinergic and antiseptic properties. Jaundice with high transaminase levels may occur after 2 months of use, but it disappears after stopping the drug. [30, 31]

Chaparral is used for a variety of conditions, including weight loss, cancer, and skin conditions. It may cause jaundice and fulminant hepatic failure. [32, 33, 34]

Chinese herbs (eg, Jin bu huan [Lycopodium serratum], Inchin-ko-to [TJ-135], Ma-huang [Ephedra equisetina]) have been associated with hepatotoxicity. [28, 29]

Recreational drugs

Ecstasy is an amphetamine used as a stimulant and may cause hepatitis and cirrhosis.

Cocaine abuse has been associated with acute elevation of hepatic enzymes. Liver histology shows necrosis and microvascular changes.

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Treatment & Management

Early recognition of drug-induced liver reactions is essential to minimizing injury. [35] Monitoring hepatic enzyme levels is appropriate and necessary with a number of agents, especially with those that lead to overt injury. For drugs that produce liver injury unpredictably, biochemical monitoring is less useful. ALT values are more specific than AST values. ALT values that are within the reference range at baseline and rise 2- to 3-fold should lead to enhanced vigilance in terms of more frequent monitoring. ALT values 4-5 times higher than the reference range should lead to prompt discontinuation of the drug.

The general recommendations for evaluating and monitoring potential drug-induced hepatotoxicity may not be suitable for all situations and should be modified for special populations, such as people with preexisting liver disease or malignancies, and in light of accumulating data.

No specific treatment is indicated for drug-induced hepatic disease. Treatment is largely supportive and based on symptomatology. The first step is to discontinue the suspected drug. Specific therapy against drug-induced liver injury is limited to the use of N -acetylcysteine in the early phases of acetaminophen toxicity. L-carnitine is potentially valuable in cases of valproate toxicity. In general, corticosteroids have no definitive role in treatment. They may suppress the systemic features associated with hypersensitivity or allergic reactions. Management of protracted drug-induced cholestasis is similar to that for primary biliary cirrhosis. Cholestyramine may be used for alleviation of pruritus. Ursodeoxycholic acid may be used. Lastly, consulting a hepatologist is also helpful.

Referral to liver transplantation center/surgical care

No specific antidote is available for the vast majority of hepatotoxic agents. Emergency liver transplantation has increasing utility in the setting of drug-induced fulminant hepatic injury. Considering early liver transplantation is important. The Model for End-Stage Liver Disease score can be used to evaluate short-term survival in an adult with end-stage liver disease. This can help stratify candidates for liver transplantation. The parameters used are serum creatinine, total bilirubin, international normalized ratio, and the cause of the cirrhosis. Another criterion commonly used for liver transplantation is the Kings College criteria.

Kings College criteria for liver transplantation in cases of acetaminophen toxicity are as follows:

  • pH less than 7.3 (irrespective of grade of encephalopathy)
  • Prothrombin time (PT) greater than 100 seconds or international normalized ratio greater than 7.7
  • Serum creatinine level greater than 3.4 mg/dL in patients with grade III or IV encephalopathy

Measurement of lactate levels at 4 and 12 hours also helps in early identification of patients who require liver transplantation.

Kings College criteria for liver transplantation in other cases of drug-induced liver failure are as follows:

  • PT greater than 100 seconds (irrespective of grade of encephalopathy) or
  • Any three of the following criteria: (1) Age younger than 10 years or older than 40 years; (2) etiology of non-A/non-B hepatitis, halothane hepatitis, or idiosyncratic drug reactions; (3) duration of jaundice of more than 7 days before onset of encephalopathy; (4) PT greater than 50 seconds; (5) serum bilirubin level greater than 17 mg/dL

Prognosis

The prognosis is highly variable depending on the patient's presentation and stage of liver damage. In a prospective study conducted in the United States from 1998-2001, the overall survival rate of patients (including those who received a liver transplant) was 72%. The outcome of acute liver failure is determined by etiology, the degree of hepatic encephalopathy present upon admission, and complications such as infections.

Reporting of adverse drug reactions

Reporting every life-threatening drug complication (including hepatic complications) to the MedWatch Program of the FDA is essential. Drug complications may be reported to the FDA at MedWatch or by calling 1-800-FDA-1088.

The DILIN network

The Drug-Induced Liver Injury Network (DILIN) was established in 2003 with the aim of studying the problem of hepatotoxicity. Supported by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) and the National Institutes of Health, the goals of the network are 1) to establish a registry of well-characterized patients who have experienced drug-induced hepatic injury and 2) to provide to the scientific community genomic DNA, serum, and immortalized lymphocytes for research purposes.

The 5 DILIN centers are located in North Carolina, Indiana, San Francisco, Michigan, and Connecticut. At present, DILIN has developed protocols for both retrospective and prospective studies of drug-induced liver disease. The retrospective study will establish a registry of patients who have taken one of 4 specific drugs since 1994 and developed liver injury later. The 4 drugs are isoniazid, phenytoin, valproic acid, and clavulanic acid/amoxicillin. These drugs were chosen because they are widely prescribed and have definite clinical presentation.

DILIN may eventually help advance our understanding of drug-induced liver injury.

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