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.

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

o Female - Halothane, nitrofurantoin, sulindaco Male - Amoxicillin-clavulanic acid (Augmentin)o Old age - Acetaminophen, halothane, INH, amoxicillin-clavulanic acido Young age - Salicylates, valproic acido Fasting or malnutrition - Acetaminopheno Large body mass index/obesity - Halothaneo Diabetes mellitus - Methotrexate, niacino Renal failure - Tetracycline, allopurinolo AIDS - Dapsone, trimethoprim-sulfamethoxazoleo Hepatitis C - Ibuprofen, ritonavir, flutamideo 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:

o 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.

o 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.

o 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.

o 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.

o 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.

o 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.

o 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.

o 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 DrugsThe 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 o Phenobarbitalo Phenytoino Carbamazepineo Primidoneo Ethanolo Glucocorticoidso Rifampino Griseofulvino Quinineo Omeprazole - Induces P-450 1A2

Inhibitors o Amiodaroneo Cimetidineo Erythromycino Grape fruito Isoniazido Ketoconazoleo Metronidazoleo Sulfonamideso Quinidineo Omeprazole - Inhibits P-450 2C8

Clinical and Pathological ManifestationsDrug 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.

o 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.

o 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.

o 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.

o Other drugs include sulfonamides, salicylates, sulfonylureas, and quinidine.o 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

o 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.

o 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.

o 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.

o 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:

o Chlorpromazine, phenylbutazone, halogenated anesthetic agents, sulindac - Fever, rash, eosinophilia

o Dapsone - Sulfone syndrome (ie, fever, rash, anemia, jaundice)o INH, halothane - Acute viral hepatitiso Chlorpromazine, erythromycin, amoxicillin-clavulanic acid - Obstructive jaundiceo Phenytoin, carbamazepine, phenobarbital, primidone - Anticonvulsant

hypersensitivity syndrome (ie, triad of fever, rash, and liver injury) o Para-amino salicylate, phenytoin, sulfonamides - Serum sickness syndromeo Clofibrate - Muscular syndrome (ie, myalgia, stiffness, weakness, elevated

creatine kinase level)o Procainamide - Antinuclear antibodies (ANAs)o Gold salts, propylthiouracil, chlorpromazine, chloramphenicol - Marrow injuryo Amiodarone, nitrofurantoin - Associated pulmonary injuryo Gold salts, methoxyflurane, penicillamine, paraquat - Associated renal injuryo Tetracycline - Fatty liver of pregnancyo Contraceptive and anabolic steroids, rifampin - Bland jaundiceo Aspirin - Reye syndromeo Sodium valproate - Reyelike syndrome

Pathological manifestations

Pathological manifestations of drug-induced hepatotoxicity are as follows:

o Acute hepatocellular injuryo Acute viral hepatitis–like picture - INH, halothane, diclofenac, troglitazoneo Mononucleosis like picture - Phenytoin, sulfonamides, dapsoneo Chronic hepatocellular injury - Pemoline, methyldopao Massive necrosis - Acetaminophen, halothane, diclofenaco Steatosiso Macrovesicular steatosis - Alcohol, methotrexate, corticosteroids, minocycline,

nifedipine, TPN

o Microvesicular steatosis - Alcohol, valproic acid, tetracycline, piroxicamo Steatohepatitis - Amiodarone, nifedipine, synthetic estrogens, didanosineo Pseudoalcoholic injury - Amiodaroneo Acute cholestasis - Amoxicillin-clavulanic acid, erythromycin, sulindaco Chronic cholestasis - Chlorpromazine, sulfamethoxazole-trimethoprim,

tetracycline, ibuprofeno Granulomatous hepatitis - Carbamazepine, allopurinol, hydralazineo Vascular injury - Steroidso Neoplasia - Contraceptives, anabolic steroidso Adenoma - Steroidso Angiosarcoma - Vinyl chlorideo Hepatocellular carcinoma - Anabolic steroids, aflatoxin, arsenic, vinyl chloride

DiagnosisWhen 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.

o Onset: The onset is usually within 5-90 days of starting the drug.o 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.

Workup

Laboratory studies

Performing laboratory tests to assess and diagnose the effects of the suspected medication is essential. These include complete blood cell count, basic metabolic profile, 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: 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: 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: 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

Liver biopsy: 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.

Specific Agents and Their Effects on the LiverMost 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 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 o 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.

o 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 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 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. 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 o 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.

o 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.

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

o Chaparral is used for a variety of conditions, including weight loss, cancer, and skin conditions. It may cause jaundice and fulminant hepatic failure.[2]

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

Recreational drugs o Ecstasy is an amphetamine used as a stimulant and may cause hepatitis and

cirrhosis.o Cocaine abuse has been associated with acute elevation of hepatic enzymes. Liver

histology shows necrosis and microvascular changes.

Treatment & ManagementEarly recognition of drug-induced liver reactions is essential to minimizing injury. 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.

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:

o pH less than 7.3 (irrespective of grade of encephalopathy)o Prothrombin time (PT) greater than 100 seconds or international normalized ratio

greater than 7.7o 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: o PT greater than 100 seconds (irrespective of grade of encephalopathy) oro Any 3 of the following criteria:

Age younger than 10 years or older than 40 years Etiology of non-A/non-B hepatitis, halothane hepatitis, or idiosyncratic

drug reactions Duration of jaundice of more than 7 days before onset of encephalopathy PT greater than 50 seconds 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.