Table 1 Some of the drugs that induce DILI and the mechanisms underlying their toxicity

Transcription

1 Table 1 Some of the drugs that induce DILI and the mechanisms underlying their toxicity Drug Use Possible mechanism of liver injury Liver injury type Abacavir Acetaminophe n Aspirin Interferon beta (ß-1a and ß- 1b) Reverse transcriptase inhibitor, used in the therapy of HIV infection Analgesic and antipyretic medication for mild-tomoderate pain and fever analgesic and antipyretic medication commonly to prevent relapses in multiple sclerosis a. Abacavir can cause clinically rare apparent hepatotoxicity. b. Within 1 to 3 months of starting abacavir, usually mild, transient elevations in serum aminotransferase levels (>5 times the upper limit) are observed in up to 6% of patients c. The serum enzyme pattern can be hepatocellular or cholestatic. d. Rapid recovery (within 4 weeks) can be observed after stopping therapy. a. Chronic acetaminophen therapy (4 g/day) leads to transient ~3-fold elevations in serum aminotransferase levels after 3 to 7 in 39% of persons. Both of these syndromes can be life threatening and both may be accompanied by evidence of liver injury. b. Direct hepatoxicity is observed usually after an acute overdose ingestion (e.g. suicide attempt using g) within 24 to 72 hours. Marked elevations in serum ALT and AST (often to >2000 U/L) are observed. After 48 to 96 h several clinical symptoms (jaundice, confusion, hepatic failure, renal insufficiency) in some instances death are observed. c. Severe hypersensitivity reactions, i.e. SJS and TEN may also be observed. a. Long term, moderate to high dose aspirin therapy cause elevations in serum ALT levels, mild increases in AP and bilirubin and usually resolve rapidly after discontinuation of aspirin therapy. b. More dramatic examples of aspirin hepatotoxicity usually occur with 1,800 to 3,200 mg/day (>100 mg/kg) doses. c. High doses symptoms of nausea, anorexia and abdominal pain and even encephalopathy with signs of hepatic dysfunction (hyperammonemia and coagulopathy) can occur. a. Interferon beta is a well-known cause of mild hepatic injury mostly in women and rarely can result in severe liver injury with jaundice. a. Hepatotoxicity is observed due to hypersensitivity syndrome and/or allergy (fever, rash and fatigue). b. Hypersensitivity is associated with the HLA-B*57:01 haplotype. c. Few cases of on hypersensitivity abacavir induced hepatitis with unknown mechanism. a. Acetaminophen is largely converted to nontoxic glucuronate or sulfate conjugates and later secreted in the urine. b. A minor amount of acetaminophen is metabolized via the CYP450 system to intermediates that can be toxic, particularly N-acetyl-pbenzoquinoneimine reactive intermediate, which is rapidly conjugated to GSH. c. If GSH levels are low or the pathway is interrupted by high acetaminophen doses, this intermediate accumulates and binds to intracellular macromolecules that can lead to cell injury, usually through caspaseindependent apoptosis initiated by activation of PARP-1. a. Aspirin is a direct, intrinsic hepatotoxin. b. Aspirin has been shown to inhibit mitochondrial function in the case of Reye 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. While liver biopsy generally shows minimal injury despite the height of the enzyme elevations, electron microscopy may reveal fat and mitochondrial abnormalities. a. The cause of hepatic injury from interferon beta is not known. b. Interferon beta causes transient and mild b. The asymptomatic elevations in serum

2 Dabigatran Estrogens /Oral contraceptives Sulfonyl ureas (glyburide gliclazide, glipizide, and Antithrombin anticoagulant (for prevention of stroke and venous embolism) oral contraceptive and in estrogen replacement therapy antidiabetic agents elevations above 3 times the upper limit in serum aminotransferase levels (after ~3-12 months therapy in 20-40% of patients). 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. a. Chronic therapy is associated with moderate ALT elevations (> 3 times the upper limit, in 1.5% to 3% of patients) and very rare apparent liver injury with jaundice. b. Liver injury with jaundice and a mixed pattern of serum enzyme elevations can arise ~4 weeks of starting dabigatran and resolved rapidly with its discontinuation. a. Estrogens and oral contraceptives are associated with several liver-related complications (i.e. intrahepatic cholestasis, sinusoidal dilatation, peliosis hepatitis, 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 cause mild inhibition of bilirubin excretion leading to jaundice (especially in patients who have genetically impaired bilirubin metabolism, such as the Dubin Johnson syndrome). c. After first few cycles of therapy, estrogens and oral contraceptives can induce an apparent cholestatic liver injury (with symptoms like fatigue, pruritus, nausea, dark urine) particularly in women with idiopathic 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. a. These agents are infrequent causes of clinically apparent liver injury. b. Clinically apparent liver injury from the sulfonyl ureas is rare (minor enzyme enzymes may be dose-related. The cases with acute jaundice are occasionally associated with autoimmune features and may represent a triggering of an underlying autoimmune disease. a. The cause of liver injury during dabigatran oral anticoagulant therapy is likely to be idiosyncratic and perhaps immunologic. a. Estrogens affect the orphan nuclear receptors that modulate bile acid and bilirubin metabolism and cholestasis occurs. b. Genetically impaired biluribun metabolism may be the cause of estrogenrelated hepatic disease. c. Women with cholestasis often have a history of cholestasis of pregnancy (with jaundice and/or pruritus) and genetic variations in bile acid transporter genes (ABC B4, B11 and C2) are frequent. a. The mechanism of liver injury might be due to hypersensitivity. b. Cross reactivity to reactions to sulfonamides can occur, however,

3 glimepiride) Ketoconazole Lovastatin Methimazole Methylphenida te An imidazole fungicidal agent with a very broad spectrum of activity commonly used cholesterol lowering agent (statin) an antithyroid medication used in the hyperthyroidis m and Graves disease Used as a central nervous system stimulant used for the therapy elevations in less than 1% of patients), usually appears after 3 to 12 weeks with symptoms of fatigue, nausea and abdominal discomfort, dark urine and jaundice. Resolution is rapid after medication is stopped. c. Rare instances of hepatic injury arising after many months or years of therapy have been reported, particularly soon after an increase in dosage. 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. a. Ketoconazole-related clinically apparent acute DILI (mostly acute hepatitis) is welldocumented after usually 1 to 6 months of therapy(1:2,000 to 1:15,000 users). Recovery takes 1 to 3 months after stopping the therapy. b. Mild and transient elevations in liver enzymes occur in 4% to 20% of patients on oral ketaconazole. c. While most cases present with a hepatocellular injury, cholestatic forms was also described. 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. a. Lovastatin can cause mild and asymptomatic serum ALT (in 3 to 5% of patients, 3 times above UL) elevations and it rarely is the underlying factor of clinically apparent acute liver injury. b. The onset of clinical injury (usually cholestatic, but can be hepatocellular) can vary from weeks to years. a. Methimazole has been linked to clinically apparent serum aminotransferase elevations, cholestatic injury and idiosyncratic liver injury within 2 to 12 weeks. However, these elevations can resolve with the discontinuation of the therapy. a. Methylphenidate has been linked to a low rate of mild-to-moderate serum aminotransferase elevations and acute hepatocellular injury during therapy and to rare instances of acute, clinically apparent liver injury (mostly after i.v. abuse sulfonylurea-associated hepatic injury is not actually quite like the immuno allergic pattern of sulfonamides. c. The sulfonyl ureas should be used with caution in patients with sulfonamide hypersensitivity or sulfonamide-related hepatotoxicity. a. The cause of clinically apparent hepatotoxicity from ketoconazole is unknown; however, it may correlate with the ability of ketoconazole to inhibit mammalian sterol synthesis. b. Acute liver injury is clearly idiosyncratic. c. Ketoconazole is a potent inhibitor of human CYP 3A4 and can alter the serum levels of many drugs that are metabolized via the P450 system, increasing the toxicity of these agents. a. The underlying event of hepatic damage caused by lovastatin is unknown. b. Lovastatin is largely metabolized by CYP 3A4 and metabolites are excreted in bile. The mild ALT elevations are likely due to a toxic metabolite. a. The mechanism by which methimazole causes acute liver injury is unknown, but is likely due to an immunological reaction to a metabolic product of its metabolism. a. The mechanism by which methylphenidate might cause liver injury is unknown, but the injury occurring after intravenous use is likely due to direct toxicity. Methylphenidate is extensively metabolized in the liver and has many

4 Olanzapine of attention deficit disorder and narcolepsy. an atypical antipsychotic used currently in the schizophrenia and bipolar illness particularly in hepatitis C patients), which might unfortunately lead to death. a. Mild, transient liver test alterations have been reported to occur frequently in 10% to 50% of patients from a few weeks to a year of olanzapine therapy. b. However in some cases, of more marked elevations in serum aminotransferase levels and clinically apparent hepatitis with jaundice were also reported with the pattern of hepatocellular, mixed and even cholestatic injury. c. Allergic symptoms (rash, fever, and eosinophilia) and autoimmune markers are uncommon. 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. drug-drug interactions. a. The mechanism underlying the hepatotoxicity of olanzapine is not known. b. Some instances of ALT elevations occurring on olanzapine therapy may be due to NAFLD caused by weight gain. c. Olanzapine has extensive hepatic metabolism, partially by CYP450 enzymes and some cases of clinically apparent hepatotoxicity may be due to production of a toxic metabolite. Phenobarbital Phenytoin Quinine a barbiturate derivative, widely used as a sedative and an antiseizure medication commonly used major anticonvulsant agent used for the prevention and malaria, also a. Phenobarbital has been linked to rare (1% of subjects) instances of severe idiosyncratic liver injury (usually mixed, but can be hepatocellular or cholestatic) that can be fatal. 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. a. Phenytoin is a rare (1 per 1000 to 1 per 10,000) but well-known cause of severe and even fatal acute idiosyncratic DILI (with fever, rash, facial edema and 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 phenytoin have transient serum aminotransferase (>3 fold) elevations, which are usually not associated with liver histological abnormalities. c. The serum enzyme elevations can be mostly hepatocellular; however rarely mixed and cholestatic patterns are also observed. a. Quinine therapy has been linked to rare instances of hypersensitivity reactions, which can observed with hepatitis, and mild jaundice. a. The mechanism of Phenobarbital hepatotoxicity is thought to be hypersensitivity or an immunological response to a metabolically generated drug-protein complex. a. DILI caused by phenytoin (common in blacks than whites) appears to be due to a hypersensitivity reaction, mostly typical cases of immunoallergic hepatotoxicity. b. Phenytoin is metabolized by CYP450 system to arene oxide, which may result in toxic or immunogenic metabolite formation. c. In some populations, the risk of injury correlates with the presence of HLA- B*1502. The hepatotoxicity of quinine is due to a hypersensitivity reaction (mostly attributed to genetic predisposition) and there is no evidence for a direct

5 Quinidine Isotretinoin Rifampin (Rifampicin) used for idiopathic muscle cramps Used as antiarrhythmic for the atrial and ventricular arrhythmias. a vitamin A derivative used in the severe acne and some forms of skin, head and neck cancer a macrocyclic antibiotic with major activity against mycobacteria, commonly used in combination with other agents as tuberculosis b. There is little data showing that chronic quinine therapy is related to elevations in 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. a.quinidine has been related to clinically apparent cholestatic or mixed liver injury (with fever, mild jaundice, increases in serum aminotransferase and alkaline phosphatase levels) in up to 2% of treated patients, which can get worse for a few days 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. Asymptomatic and transient liver test abnormalities that resolve even with continuing therapy occur in up to 15% of patients on isotretinoin. However, marked elevations above three times the UL of normal or requiring drug discontinuation are rare (<1%). a. Rifampin is associated with transient and asymptomatic elevations in serum aminotransferase (in 10% to 20% of the patients) and bilirubin (both total and indirect) levels. Mutations in the hepatic canalicular protein known as ABC C2 or MRP2, which is responsible for transport of conjugated bilirubin from the hepatocyte into the bile canalicus, can cause these increases in bilirubin levels. Serum bilirubin levels usually decrease to below baseline after a short period. b. The drug is a well-known cause of clinically apparent (within 1 to 6 weeks), acute liver disease (hepatocellular at the onset, but can also be cholestatic and mixed) that can be severe and even fatal. As rifampin is usually given in combination with isoniazid and/or pyrazinamide, which are also other known hepatotoxic agents, the cause of the acute liver injury in patients on rifampin may be difficult to relate to a single agent. Research suggests that the combination therapy is more likely to cause hepatotoxic effect. The hepatotoxicity of quinidine is due to a hypersensitivity reaction (mostly attributed to genetic predisposition) and there is no evidence for a direct hepatotoxic effect. The mechanism by which isotretinoin causes serum aminotransferase elevations are not known. The drug may be causing direct liver toxicity; which can be more frequent with higher dose therapy. a. The mechanism of rifampin hepatotoxicity is not well known. b. The drug is extensively metabolized by the liver and directly induces CYP3A4 and ABC C2 (MRP2). c. The cause of injury is likely to be due to toxic metabolic products that directly induce an immunologic reaction. d. The elevation in direct and total bilirubin in rare patients receiving rifampin may be related to gene mutations of MRP2 (ABC C2), the major bilirubin glucuronide transporter in hepatocytes. Patients with preexisting liver disease and

6 Tacrolimus Valproate or valproic acid Orlistat a calcineurin inhibitor and potent immuno suppressive agent used largely as a means of prophylaxis against organ rejection after transplantation used as epilepsy, bipolar disorders and migraine headaches an inhibitor of pancreatic and gastric lipase; a commonly used weight loss agent injury. Tacrolimus therapy is often associated with mild, asymptomatic and self-limited serum enzyme elevations in 5% to 10% of patients and is linked to rare clinically apparent cholestatic hepatitis. a. Valproic acid is a well-known cause of several distinctive forms of acute and chronic distinctive hepatocellular injury (microvesicular steatosis with central lobular necrosis, mild to moderate inflammation, fibrosis, bile duct proliferation and 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% to 10%) develop asymptomatic ALT elevations, which can usually resolve after the continuation of drug. c. However, if hyperammonemia develops within a few weeks, it can cause a serious concern. Hyperrammonemia can lead to progressive and episodic confusion followed by obtundation and coma. It can resolve within a few days of stopping the drug or may reverse with carnitidine supplementation or hemodialysis more rapidly. d. Valproate can also cause a Reye-like syndrome in children who are suggested to have viral (influenza or varicella) iinfection. The symptoms are fever, lethargy, confusion, stupor and coma, metabolic acidosis, with raised ammonia levels, significant ALT elevations but normal or minimally elevated bilirubin levels. This syndrome can be 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. Since 2010, Orlistat has been linked to rare instances of acute hepatocellular injury after 2 to 12 weeks, with hepatic failure and serum liver test abnormalities. Some cases have been severe; some progressed to death or some needed liver transplantation. cirrhosis are particularly likely to develop jaundice on rifampin therapy. a. Tacrolimus undergoes extensive hepatic metabolism by CYP3A4. b. Liver test abnormalities can be a result of direct hepatotoxicity, or its effects on levels of other medications (drug-drug interaction), or on the immune system. a. Valproate lowers tissue carnitine levels, which can lead to inhibition of betaoxidation and loss of mitochondrial function, hyperammonemia and microvesicular steatosis. b. Valproate is extensively metabolized by the liver and excreted in urine. c. Genetic factors also appear to be important, as valproate hepatotoxicity is more common in patients who are heterozygous for mutations in gamma polymerase, which is the enzyme responsible for mitochondrial DNA replication and the predominant DNA polymerase found in mitochondria. d. Children with these mutations have Alpers-Huttenlocher syndrome (progressive cerebral degeneration, seizures) and are at very high risk of developing fatal valproate hepatotoxicity. Therefore, valproate is contraindicated in children with known or suspected Alpers- Huttenlocher syndrome. a. The mechanism by which Orlistat causes liver injury is not known. b. As only small amounts of Orlistat (1-3

7 Zafirlukast Aleukotriene receptor antagonist who is widely used for the prophylaxis and chronic asthma. a. Zafirlukast has been linked to rare but occasionally severe cases of acute liver injury (fatigue, nausea, and right upper quadrant pain followed by dark urine, jaundice, eosinophilia and pruritus), leading to hepatic failure, need for liver transplantation or death, usually within 2 to 6 months. The pattern of liver enzyme elevation is usually hepatocellular and resembles acute viral hepatitis. b. Prospective studies have shown that ALT elevations occur in 1.5% of patients receiving zafirlukast, most of which are mild, asymptomatic and self-limited even with continuing therapy. %) are absorbed, hypersensitivity is likely to be the cause of liver injury. However, typical features of hypersensitivity have not been prominent in case reports. a. The mechanism of hepatic injury is clearly idiosyncratic. b. The extensive hepatic metabolism of zafirlukast by CYP2C9 system suggests that injury may be a result of a hepatotoxic or metabolite.