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Table 1 Some of the Drugs That Induce DILI and the Mechanisms Underlying Their Toxicity.54–78

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Table 1 Some of the Drugs That Induce DILI and the Mechanisms Underlying Their Toxicity.54–78 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
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