Table 1 Some of the drugs that induce DILI and the mechanisms underlying their toxicity.54–78

Drug Use Possible mechanism of liver injury Liver injury type Abacavir Reverse a. Abacavir can cause clinically rare apparent a. Hepatotoxicity is observed due to transcriptase hepatotoxicity. hypersensitivity syndrome and/or allergy inhibitor, used (fever, rash and fatigue). in the therapy b. Within 1 to 3 months of starting abacavir, b. Hypersensitivity is associated with the of HIV usually mild, transient elevations in serum HLA-B*57:01 haplotype. infection aminotransferase levels (>5 times the upper limit) are observed in up to 6% of patients c. The serum enzyme pattern can be c. Few cases of on hypersensitivity hepatocellular or cholestatic. abacavir induced hepatitis with unknown d. Rapid recovery (within 4 weeks) can be mechanism. observed after stopping therapy. Acetaminophe Analgesic and a. Chronic acetaminophen therapy (4 g/day) a. Acetaminophen is largely converted to n antipyretic leads to transient ~3-fold elevations in serum nontoxic glucuronate or sulfate conjugates medication for aminotransferase levels after 3 to 7 in 39% and later secreted in the urine. mild-to- of persons. Both of these syndromes can be moderate pain life threatening and both may be and fever accompanied by evidence of liver injury. b. Direct hepatoxicity is observed usually b. A minor amount of acetaminophen is after an acute overdose ingestion (e.g. metabolized via the CYP450 system to suicide attempt using 7.5-15 g) within 24 to intermediates that can be toxic, 72 hours. Marked elevations in serum ALT particularly N-acetyl-p- and AST (often to >2000 U/L) are observed. benzoquinoneimine reactive intermediate, After 48 to 96 h several clinical symptoms which is rapidly conjugated to GSH. (jaundice, confusion, hepatic failure, renal insufficiency) in some instances death are observed. c. Severe hypersensitivity reactions, i.e. SJS c. If GSH levels are low or the pathway is and TEN may also be observed. interrupted by high acetaminophen doses, this intermediate accumulates and binds to intracellular macromolecules that can lead to cell injury, usually through caspase- independent apoptosis initiated by activation of PARP-1. Aspirin analgesic and a. Long term, moderate to high dose aspirin a. Aspirin is a direct, intrinsic hepatotoxin. antipyretic therapy cause elevations in serum ALT medication levels, mild increases in AP and bilirubin and usually resolve rapidly after discontinuation of aspirin therapy. b. More dramatic examples of aspirin b. Aspirin has been shown to inhibit hepatotoxicity usually occur with 1,800 to mitochondrial function in the case of Reye 3,200 mg/day (>100 mg/kg) doses. syndrome, and the drug induced mitochondrial dysfunction combination with a systemic viral illness is postulated to underlie the pathogenesis of Reye syndrome. The mitochondrial failure is manifested by LASH. c. High doses symptoms of nausea, anorexia c. While liver biopsy generally shows and abdominal pain and even minimal injury despite the height of the encephalopathy with signs of hepatic enzyme elevations, electron microscopy dysfunction (hyperammonemia and may reveal fat and mitochondrial coagulopathy) can occur. abnormalities. Interferon beta commonly to a. Interferon beta is a well-known cause of a. The cause of hepatic injury from (ß-1a and ß- prevent mild hepatic injury mostly in women and interferon beta is not known. 1b) relapses in rarely can result in severe liver injury with multiple jaundice. sclerosis b. Interferon beta causes transient and mild b. The asymptomatic elevations in serum elevations above 3 times the upper limit in enzymes may be dose-related. The cases serum aminotransferase levels (after ~3 -12 with acute jaundice are occasionally months therapy in 20-40% of patients). associated with autoimmune features and may represent a triggering of an underlying autoimmune disease. c. Serum AP levels are usually normal or minimally elevated, and symptoms and jaundice (<1 in1000, after 2-12 months) or to acute liver failure are rare. Persistent ALT elevations suggest chronic hepatitis and may require discontinuation of treatment in up to 20% of patients. d. Autoimmune features can occur, but may relate more to the underlying multiple sclerosis rather than drug-induced liver disease. Dabigatran Antithrombin a. Chronic therapy is associated with a. The cause of liver injury during anticoagulant moderate ALT elevations (> 3 times the dabigatran oral anticoagulant therapy is (for prevention upper limit, in 1.5% to 3% of patients) and likely to be idiosyncratic and perhaps of stroke and very rare apparent liver injury with jaundice. immunologic. venous b. Liver injury with jaundice and a mixed embolism) pattern of serum enzyme elevations can arise ~4 weeks of starting dabigatran and resolved rapidly with its discontinuation. Estrogens oral a. Estrogens and oral contraceptives are a. Estrogens affect the orphan nuclear /Oral contraceptive associated with several liver-related receptors that modulate bile acid and contraceptives and in estrogen complications (i.e. intrahepatic cholestasis, bilirubin metabolism and cholestasis replacement sinusoidal dilatation, peliosis hepatitis, occurs. therapy hepatic adenomas with big liver mass or rupture with hemoperitoneum , hepatocellular carcinoma, hepatic venous thrombosis and an increase risk of gallbladder disease and gallstones), particularly at high doses. b. Estrogens and oral contraceptives can b. Genetically impaired biluribun cause mild inhibition of bilirubin excretion metabolism may be the cause of estrogen- leading to jaundice (especially in patients related hepatic disease. who have genetically impaired bilirubin metabolism, such as the Dubin Johnson syndrome). c. After first few cycles of therapy, estrogens c. Women with cholestasis often have a and oral contraceptives can induce an history of cholestasis of pregnancy (with apparent cholestatic liver injury (with jaundice and/or pruritus) and genetic symptoms like fatigue, pruritus, nausea, dark variations in bile acid transporter genes urine) particularly in women with idiopathic (ABC B4, B11 and C2) are frequent. cholestasis of pregnancy, and rarely after the six months. Serum enzyme elevations are usually mixed or cholestatic, although very early during the injury, ALT levels can be markedly elevated upto 5- to 20-fold. Resolution may be delayed. d. Use of oral contraceptives has also been linked to an increase in venous thrombosis and cases of hepatic venous thrombosis. Portal vein thrombosis has also been reported with oral contraceptive use. Sulfonyl ureas antidiabetic a. These agents are infrequent causes of a. The mechanism of liver injury might be (glyburide agents clinically apparent liver injury. due to hypersensitivity. gliclazide, b. Clinically apparent liver injury from the b. Cross reactivity to reactions to glipizide, and sulfonyl ureas is rare (minor enzyme sulfonamides can occur, however, glimepiride) elevations in less than 1% of patients), sulfonylurea-associated hepatic injury is usually appears after 3 to 12 weeks with not actually quite like the immuno allergic symptoms of fatigue, nausea and abdominal pattern of sulfonamides. discomfort, dark urine and jaundice. Resolution is rapid after medication is stopped. c. Rare instances of hepatic injury arising c. The sulfonyl ureas should be used with after many months or years of therapy have caution in patients with sulfonamide been reported, particularly soon after an hypersensitivity or sulfonamide-related increase in dosage. hepatotoxicity. d. Hepatocellular, cholestatic and mixed injuries have been described with sulfonylurea-induced liver injury. e. As sulfonyl ureas may be given in combination with other hypoglycemic agents, many of which also cause liver injury, it can be difficult to determine which agent is responsible for the injury. Ketoconazole An imidazole a. Ketoconazole-related clinically apparent a. The cause of clinically apparent fungicidal acute DILI (mostly acute hepatitis) is well- hepatotoxicity from ketoconazole is agent with a documented after usually 1 to 6 months of unknown; however, it may correlate with very broad therapy(1:2,000 to 1:15,000 users). Recovery the ability of ketoconazole to inhibit spectrum of takes 1 to 3 months after stopping the mammalian sterol synthesis. activity therapy. b. Mild and transient elevations in liver b. Acute liver injury is clearly enzymes occur in 4% to 20% of patients on idiosyncratic. oral ketaconazole. c. While most cases present with a c. Ketoconazole is a potent inhibitor of hepatocellular injury, cholestatic forms was human CYP 3A4 and can alter the serum also described. levels of many drugs that are metabolized via the P450 system, increasing the toxicity of these agents. d. Rash, fever and eosinophilia are rare as is autoantibody formation. e. Severe cases with acute liver failure (need for emergency liver transplantation) and even death have also been described. Lovastatin commonly a. Lovastatin can cause mild and a. The underlying event of hepatic damage used asymptomatic serum ALT (in 3 to 5% of caused by lovastatin is unknown. cholesterol patients, 3 times above UL) elevations and it lowering agent rarely is the underlying factor of clinically (statin) apparent acute liver injury. b. The onset of clinical injury (usually b. Lovastatin is largely metabolized by cholestatic, but can be hepatocellular) can CYP 3A4 and metabolites are excreted in vary from weeks to years. bile. The mild ALT elevations are likely due to a toxic metabolite. Methimazole an antithyroid a. Methimazole has been linked to clinically a. The mechanism by which methimazole medication apparent serum aminotransferase elevations, causes acute liver injury is unknown, but used in the cholestatic injury and idiosyncratic liver is likely due to an immunological reaction therapy of injury within 2 to 12 weeks. However, these to a metabolic product of its metabolism. hyperthyroidis elevations can resolve with the m and Graves discontinuation of the therapy. disease Methylphenida Used as a a. Methylphenidate has been linked to a low a. The mechanism by which te central rate of mild-to-moderate serum methylphenidate might cause liver injury nervous aminotransferase elevations and acute is unknown, but the injury occurring after system hepatocellular injury during therapy and to intravenous use is likely due to direct stimulant used rare instances of acute, clinically apparent toxicity. Methylphenidate is extensively for the therapy liver injury (mostly after i.v. abuse metabolized in the liver and has many of attention particularly in hepatitis C patients), which drug-drug interactions. deficit disorder might unfortunately lead to death. and narcolepsy. Olanzapine an atypical a. Mild, transient liver test alterations have a. The mechanism underlying the antipsychotic been reported to occur frequently in 10% to hepatotoxicity of olanzapine is not known. used currently 50% of patients from a few weeks to a year in the of olanzapine therapy. treatment of b. However in some cases, of more marked b. Some instances of ALT elevations schizophrenia elevations in serum aminotransferase levels occurring on olanzapine therapy may be and bipolar and clinically apparent hepatitis with due to NAFLD caused by weight gain. illness jaundice were also reported with the pattern of hepatocellular, mixed and even cholestatic injury. c. Allergic symptoms (rash, fever, and c. Olanzapine has extensive hepatic eosinophilia) and autoimmune markers are metabolism, partially by CYP450 uncommon. enzymes and some cases of clinically apparent hepatotoxicity may be due to production of a toxic metabolite. d. Cases with significant weight gain (1 kg/month, as much as 20 to 30kg, in 25% of the patients, within 1-2 years) may lead to NAFLD. Phenobarbital a barbiturate a. Phenobarbital has been linked to rare (1% a. The mechanism of Phenobarbital derivative, of subjects) instances of severe idiosyncratic hepatotoxicity is thought to be widely used as liver injury (usually mixed, but can be hypersensitivity or an immunological a sedative and hepatocellular or cholestatic) that can be response to a metabolically generated an antiseizure fatal. drug-protein complex. medication b. Prospective studies suggest that less than develop elevations in serum aminotransferase levels during long term Phenobarbital therapy c. Besides, hypersensitivity (with fever, rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia) with mostly liver involvement (elevations in serum aminotransferase levels, jaundice and signs of hepatic failure) can also be observed. Phenytoin commonly a. Phenytoin is a rare (1 per 1000 to 1 per a. DILI caused by phenytoin (common in used major 10,000) but well-known cause of severe and blacks than whites) appears to be due to a anticonvulsant even fatal acute idiosyncratic DILI (with hypersensitivity reaction, mostly typical agent fever, rash, facial edema and cases of immunoallergic hepatotoxicity. lymphadenopathy, followed in a few days by jaundice and dark urine), usually after 2 to 8 weeks of therapy. These cases may mostly resolve within 1 to 2 months of stopping phenytoin intake. b. A high proportion of patients taking b. Phenytoin is metabolized by CYP450 phenytoin have transient serum system to arene oxide, which may result aminotransferase (>3 fold) elevations, which in toxic or immunogenic metabolite are usually not associated with liver formation. histological abnormalities. c. The serum enzyme elevations can be c. In some populations, the risk of injury mostly hepatocellular; however rarely mixed correlates with the presence of HLA- and cholestatic patterns are also observed. B*1502. Quinine used for the a. Quinine therapy has been linked to rare The hepatotoxicity of quinine is due to a prevention and instances of hypersensitivity reactions, which hypersensitivity reaction (mostly therapy of can observed with hepatitis, and mild attributed to genetic predisposition) and malaria, also jaundice. there is no evidence for a direct used for b. There is little data showing that chronic hepatotoxic effect. idiopathic quinine therapy is related to elevations in muscle cramps serum aminotransferases. c. There have been several reports of acute hypersensitivity reactions (fatigue, nausea, vomiting, diffuse muscle aches, arthralgias, high fever, elevations in serum aminotransferase and alkaline phosphatase levels as well as mild jaundice) to quinine that include hepatic involvement. The liver toxicity usually arises usually after 1 to 2 weeks (but can occur as early as 24 hours) d. The pattern of serum enzymes elevations is typically cholestatic or mixed. Quinidine Used as a.Quinidine has been related to clinically The hepatotoxicity of quinidine is due to a antiarrhythmic apparent cholestatic or mixed liver injury hypersensitivity reaction (mostly for the (with fever, mild jaundice, increases in attributed to genetic predisposition) and treatment of serum aminotransferase and alkaline there is no evidence for a direct atrial and phosphatase levels) in up to 2% of treated hepatotoxic effect. ventricular patients, which can get worse for a few days arrhythmias. even after stopping quinidine. b.There have also been many reports of acute hypersensitivity reactions (within 24 hours or after 1 to 2 weeks, rash, fatigue, nausea, vomiting, diffuse muscle aches, arthralgias and high fever) to quinidine that involve hepatic toxicity. Isotretinoin a vitamin A Asymptomatic and transient liver test The mechanism by which isotretinoin derivative used abnormalities that resolve even with causes serum aminotransferase elevations in the continuing therapy occur in up to 15% of are not known. The drug may be causing treatment of patients on isotretinoin. However, marked direct liver toxicity; which can be more severe acne elevations above three times the UL of frequent with higher dose therapy. and some normal or requiring drug discontinuation are forms of skin, rare (<1%). head and neck cancer Rifampin a macrocyclic a. Rifampin is associated with transient and a. The mechanism of rifampin (Rifampicin) antibiotic with asymptomatic elevations in serum hepatotoxicity is not well known. major activity aminotransferase (in 10% to 20% of the against patients) and bilirubin (both total and mycobacteria, indirect) levels. Mutations in the hepatic commonly canalicular protein known as ABC C2 or used in MRP2, which is responsible for transport of combination conjugated bilirubin from the hepatocyte into with other the bile canalicus, can cause these increases agents as in bilirubin levels. Serum bilirubin levels therapy of usually decrease to below baseline after a tuberculosis short period. b. The drug is a well-known cause of b. The drug is extensively metabolized by clinically apparent (within 1 to 6 weeks), the liver and directly induces CYP3A4 acute liver disease (hepatocellular at the and ABC C2 (MRP2). onset, but can also be cholestatic and mixed) c. The cause of injury is likely to be due to that can be severe and even fatal. As toxic metabolic products that directly rifampin is usually given in combination induce an immunologic reaction. with isoniazid and/or pyrazinamide, which d. The elevation in direct and total are also other known hepatotoxic agents, the bilirubin in rare patients receiving cause of the acute liver injury in patients on rifampin may be related to gene mutations rifampin may be difficult to relate to a single of MRP2 (ABC C2), the major bilirubin agent. Research suggests that the glucuronide transporter in hepatocytes. combination therapy is more likely to cause Patients with preexisting liver disease and injury. cirrhosis are particularly likely to develop jaundice on rifampin therapy. Tacrolimus a calcineurin Tacrolimus therapy is often associated with a. Tacrolimus undergoes extensive hepatic inhibitor and mild, asymptomatic and self-limited serum metabolism by CYP3A4. potent immuno enzyme elevations in 5% to 10% of patients b. Liver test abnormalities can be a result suppressive and is linked to rare clinically apparent of direct hepatotoxicity, or its effects on agent used cholestatic hepatitis. levels of other medications (drug-drug largely as a interaction), or on the immune system. means of prophylaxis against organ rejection after transplantation Valproate or used as a. Valproic acid is a well-known cause of a. Valproate lowers tissue carnitine levels, valproic acid therapy of several distinctive forms of acute and which can lead to inhibition of beta- epilepsy, chronic distinctive hepatocellular injury oxidation and loss of mitochondrial bipolar (microvesicular steatosis with central lobular function, hyperammonemia and disorders and necrosis, mild to moderate inflammation, microvesicular steatosis. migraine fibrosis, bile duct proliferation and headaches regenerative nodules and cholestasis), with hepatocellular or mixed pattern of enzyme elevations within 1 to 6 months of starting valproate. >100 fatal cases of acute or chronic liver injury have been reported in the literature. Carnitidine (i.v.) therapy may be beneficial if given soon. b. During long term of therapy, patients (5% b. Valproate is extensively metabolized by to 10%) develop asymptomatic ALT the liver and excreted in urine. elevations, which can usually resolve after the continuation of drug. c. However, if hyperammonemia develops c. Genetic factors also appear to be within a few weeks, it can cause a serious important, as valproate hepatotoxicity is concern. Hyperrammonemia can lead to more common in patients who are progressive and episodic confusion followed heterozygous for mutations in gamma by obtundation and coma. It can resolve polymerase, which is the enzyme within a few days of stopping the drug or responsible for mitochondrial DNA may reverse with carnitidine replication and the predominant DNA supplementation or hemodialysis more polymerase found in mitochondria. rapidly. d. Valproate can also cause a Reye-like d. Children with these mutations have syndrome in children who are suggested to Alpers-Huttenlocher syndrome have viral (influenza or varicella) iinfection. (progressive cerebral degeneration, The symptoms are fever, lethargy, confusion, seizures) and are at very high risk of stupor and coma, metabolic acidosis, with developing fatal valproate hepatotoxicity. raised ammonia levels, significant ALT Therefore, valproate is contraindicated in elevations but normal or minimally elevated children with known or suspected Alpers- bilirubin levels. This syndrome can be Huttenlocher syndrome. rapidly fatal. e. Valproate is rarely associated with anticonvulsant hypersensitivity syndrome and generally a safe alternative for patients who can develop this syndrome with aromatic anticonvulsants. Orlistat an inhibitor of Since 2010, Orlistat has been linked to rare a. The mechanism by which Orlistat pancreatic and instances of acute hepatocellular injury after causes liver injury is not known. gastric lipase; 2 to 12 weeks, with hepatic failure and serum a commonly liver test abnormalities. Some cases have used weight been severe; some progressed to death or loss agent some needed liver transplantation. b. As only small amounts of Orlistat (1-3 %) are absorbed, hypersensitivity is likely to be the cause of liver injury. However, typical features of hypersensitivity have not been prominent in case reports. Zafirlukast Aleukotriene a. Zafirlukast has been linked to rare but a. The mechanism of hepatic injury is receptor occasionally severe cases of acute liver clearly idiosyncratic. antagonist who injury (fatigue, nausea, and right upper is widely used quadrant pain followed by dark urine, for the jaundice, eosinophilia and pruritus), leading prophylaxis to hepatic failure, need for liver and chronic transplantation or death, usually within 2 to 6 treatment of months. The pattern of liver enzyme asthma. elevation is usually hepatocellular and resembles acute viral hepatitis. b. Prospective studies have shown that ALT b. The extensive hepatic metabolism of elevations occur in 1.5% of patients zafirlukast by CYP2C9 system suggests receiving zafirlukast, most of which are that injury may be a result of a mild, asymptomatic and self-limited even hepatotoxic or metabolite. with continuing therapy.