MOJ ISSN: 2379-6294MOJT

Toxicology
Research Article
Volume 1 Issue 5 - 2015
Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms
Pinar Erkekoglu1*, Asim Elnour2, Belma Kocer-GümüÅŸel1, Akshaya Srikanth Bhagavathula3 and Abdulla Shehab4
1Department of Toxicology, Faculty of Pharmacy, Hacettepe University, Turkey
2Department of Pharmacology, College of Medicine and Health Sciences, UAE University, UAE
3Department of Clinical Pharmacy, College of Medicine and Health Sciences, University of Gondar, Ethiopia
4Department of Internal Medicine, College of Medicine and Health Sciences, UAE University, UAE
Received: November 18, 2015 | Published: November 27, 2015
*Corresponding author: Pinar Erkekoglu, Department of Toxicology, Faculty of Pharmacy, Hacettepe University, Turkey, Tel: 00903123052178; Fax: 00903123114777; Email:
Citation: Erkekoglu P, Elnour A, Kocer-GümüÅŸel B, Bhagavathula AS, Shehab A (2015) Cellular and Molecular Aspects of Drug-Induced Liver Toxicity: Recent Prominent Mechanisms. MOJ Toxicol 1(5): 00023. DOI: 10.15406/mojt.2015.01.00023

Abstract

Despite recent advances in drug development technologies, some drugs continue to be withdrawn from the market because of their late hepatotoxic effects. Drugs can cause liver toxicity through several molecular mechanisms, most of which need to be clarified by further research. Newly found drug-induced liver injury (DILI)-mechanisms like endoplasmic reticulum stress should also be considered while evaluating drug toxicity. New drugs launched in the market should be tested particularly for hepatotoxicity by using hepatic cell cultures and animal models continuously. Future research should target patients in the post-marketing phase in order to provide more evidence grounds to the clinical safety of potential drugs of high propensity of DILI. This review aims to draw the attention to the issue of cellular and molecular aspects of liver toxicity induced by drugs and address DILI as a potential clinical problem that needs further investigation.

Keywords: Drug-induced liver injury; Hepatotoxic drugs; Molecular mechanisms; Endoplasmic reticulum stress

Abbreviations

ALT: Alanine Transaminase; AP: Alkaline Phosphatase; CYP450: Cytochrome P450; DILI: Drug Ä°nduced Liver Ä°njury; GSH: Glutathione; HIV: Human Ä°mmunodeficiency Virus; LASH: Lactic Acidosis, Acute Microvesicular Steatosis and Hepatic Dysfunction; NAFLD: Non Alcoholic Fatty Liver Disease; PARP-1: Poly (Adenosine Diphosphate-ADP-Ribose) Polymerase; SJS: Stevens Johnson Syndrome; TEN: Toxic Epidermal Necrolysis; UL: Upper Limit

Introduction

The liver is a vital organ for all higher organisms. It has a wide range of functions, ranging from the biotransformation (particularly detoxification) of various chemicals to protein synthesis (i.e., plasma proteins); from glycogen storage and lipogenesis to bile production [1]. Drug-induced liver diseases are particularly caused by prescribed medications, as well as over-the-counter medications, vitamins, hormones, herbs, illicit ("recreational") drugs, and environmental toxins. While the liver is exposed to many xenobiotics (including several drugs), its injury is inevitable when successful regeneration is not possible. Drugs continue to be withdrawn from the market because of late discovery of their hepatotoxic effects [1].

This review aims to draw the attention to the issue of “drug-induced liver injury (DILI)” as a potential clinical problem that needs further exploration. In this framework, the newly discovered underlying mechanisms of DILI are being addressed and literature is reviewed through relevant articles that address DILI.

Epidemiology of Drug-Induced Liver Injury (DILI)

The estimated annual incidence of DILI is 10-15 per 10.000 to 100.000 persons who are taking prescripted medications [2]. In addition, DILI accounts for approximately 10% of acute hepatitis cases annually and it is the most common cause of acute liver failure in the United States [3-5]. DILI is also one of the most common causes of medication withdrawal from the market [4,6,7]. DILI may not be detected prior to drug approval as Phase III trials are performed on <3000 people. Therefore, cases of DILI with an incidence of 1 in 10,000 may be missed and this will determine the future of the drug on the market. It has been estimated that in a clinical trial, for every 10 cases of alanine amino transferase elevation (>10 times the upper limit of normal), there will be one case of severe liver injury [8,9]. Different factors such as gender, age, ethnicity/race, nutritional status (malnutrition, high fat consumption), other pathological conditions (renal dysfunction, liver disease, obesity, diabetes mellitus, infections, inflammatory diseases), addictions (high alcohol consumption, smoking) and pregnancy might also affect the emergence of DILI. Besides, drug-related factors (duration, dosage, dosage form, usage of other drugs and drug interactions) and metabolic and enzymatic profile (genetic polymorphisms) can also be the underlying factor for DILI. The pathophysiology of DILI varies depending on the drug and, in many cases, is not entirely understood. DILI mechanisms include covalent binding of the drug to cellular proteins resulting in immune injury, direct cytotoxicity, inhibition of cell metabolic pathways, blockage of cellular transport pumps, induction of apoptosis, and interference with mitochondrial function [10].

The Mechanism of Drug-Induced Liver Injury

Cytotoxicity
Cytotoxicity is one of the main mechanisms that may lead to acute or chronic liver injury. Cytotoxicity can be caused by several factors, including oxidative stress. Changes in the expression of antioxidant enzymes and in the synthesis or degradation of cellular thiols, increases in lipid peroxidation and protein oxidation are good markers of cellular oxidation [11,12]. On the other hand, disruption of thiol synthesis or oxidation of cellular thiols, particularly high oxidation of glutathione (GSH), may also be an underlying factor for cellular toxicity [11,12]. Cytotoxicity may be followed by cell death, by either apoptosis or necrosis.

Apoptosis
Apoptosis is a form of programmed cell death and activation of caspase pathways (intrinsic or extrinsic). Chemicals and drugs usually activate extrinsic caspase pathway, leading to increase in caspase 3 and later caspase 8 activities, and to poly (adenosine diphosphate-ADP-ribose) polymerase (PARP) cleavage. It has been suggested that the mode of death for acetaminophen’s liver toxicity is caspase-independent apoptosis, initiated by activation of PARP-1 [13-15]. The widely used antidepressant, sertraline was shown to cause to apoptosis and mitochondrial dysfunction in primary rat hepatocytes and human HepG2 cells [16].

Necrosis
Necrosis, on the other hand, is a form of cell injury that results in the premature death of cells in living tissue by autolysis. On a cellular basis, it is suggested that hepatic necrosis is the result of overwhelming or deregulated apoptosis [17]. Besides, exaggerated mitochondrial dysfunction or lysosomal permeabilization can result in cell death (by either apoptosis or necrosis) [17,18]. However, regeneration of hepatocytes lost by necrotic and apoptotic cell death may mask detection of DILI [19,20].

Zonal necrosis is the most common type of necrosis that is induced by drugs. In this specific pathological condition, the injury largely remains limited to a particular zone of a liver lobule leading to a very high level of ALT, severe disturbance of liver function and finally to acute liver failure [21]. Acetaminophen, valproic acid and carbon tetrachloride can lead to zonal necrosis if taken in high doses [22].

Endoplasmic Reticulum (ER) Stress
The endoplasmic reticulum (ER) is an organelle in the eukaryotic cells. It plays a vital role in many cellular processes such as protein synthesis, folding, assembly, trafficking and post-modulation. Besides, it provides quality control of both secretory and membrane proteins, lipid synthesis, and regulation of intracellular calcium hemostasis. ER stress is an exciting area of research in liver injury, although available data mostly comes from other experimental systems. The stressed ER exhibits an imbalance between unfolded proteins and mature proteins, activating a series of compensatory responses, collectively termed as “unfolded protein response” [23-25]. Three ER membrane-localized proteins are considered as ‘sensors’ of ER stress: inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase RNA-activated (PKR)-like ER kinase (PERK) [26]. ER stress may occur before apoptotic cell death and glutathione (GSH) depletion. Excessive and prolonged ER stress finally leads to apoptosis or necrotic cell death [27]. However, ER stress may also occur after a cascade of events, such as GSH depletion and oxidative stress [28].

A wide range of human diseases, have been associated with ER stress. These diseases include, but are not limited to, neurological (Alzheimer’s disease, Parkinson’s disease), kidney, lung, and cardiovascular diseases, diabetes, obesity/metabolic syndrome, inflammatory diseases and cancer [23]. In addition, environmental toxicants as well as drugs were related to ER stress in the last reports. In liver, ER stress can be induced by several factors, including drugs, UV radiation, and insulin resistance. ER stress can regulate both the intrinsic and extrinsic cell death machinery. Studies in the last decade have shown that non-steroidal anti-inflammatory drugs (NSAIDs, such as indomethacin, diclofenac), benzodiazepines, lithium and sodium valproate were shown to induce ER stress both in vitro or in vivo [25]. The HIV-protease inhibitors, atazanavir and ritonavir were shown to induce both ER stress and apoptosis. Moreover, the mechanisms involved in the liver toxicity of anti-diabetic drug troglitazone, include mitochondrial dysfunction, apoptosis, disruption of calcium hemostasis, oxidative stress, and ER stress [23]. Although the most important mechanism for sertaline-induced liver toxicity is mitochondrial dysfunction and apoptosis, ER stress was found to contribute to its liver toxicity [29]. Interestingly, certain antioxidants (butylated hydroxyanisole (BHA), TM2002, and Baicalein) were also shown to cause ER stress in liver [30].

Mitochondrial Dysfunction
Mitochondria are the key organelles for intracellular energy generation. They are involved in several metabolic pathways including cellular respiration. These organelles are highly organized, have high metabolic capacity and act through various signaling networks. Mitochondria are directly or indirectly involved in the activation of intracellular stress cascades, apoptosis, and necrosis or death receptor-mediated pathways [31]. High intracellular ROS levels accompanied by GSH depletion, lipid peroxidation, protein oxidation/alkylation and respiratory complex changes are associated with mitochondrial dysfunction. These events may be the critical underlying factors for many types of chronic liver diseases and for DILI [32]. Moreover, the formation of reactive metabolites, after the biotransformation of drug with Phase I or Phase II enzymes, can trigger hepatitis through direct toxicity or immune reactions. These reactions might also cause mitochondrial membrane disruption [33]. On the other hand, parent drug can also lead to mitochondrial dysfunction through different mechanisms [33-35]:

  1. Direct inhibition of mitochondrial functions
  2. Inhibition of mitochondrial DNA synthesis (acetaminophen, alcohol, ganciclovir, tamoxifen, troglitazone, zidovudine)
  3. Impairment of mitochondrial DNA synthesis (fialuridine, ciprofloxacin, nalidixic acid)
  4. Disruption in mitochondrial DNA protein synthesis (chloramphenicol, erythromycin, thiamphenicol)
  5. Decrease mitochondrial transcripts (interferon-α)
  6. Impairment in oxidative phosphorylation and secondarily inhibition ß-oxidation leading to steatosis, cell death, mostly necrosis (e.g. amineptine, amiodarone, aspirin, chloroquine, perhexiline, tetracyclines and tianeptine)
  7. Disruption in pyruvate catabolism, leading to lactic acidosis
  8. Decreased gluconeogenesis
  9. Accumulation of free fatty acids and lipid peroxidation products, leading to the impairment of energy production

Types of Drug Induced Liver Toxicity
Several different medications have been linked to the development of DILI. Drug induced liver injury (DILI) can be predictable (occurs shortly after exposure, dose-related) or unpredictable (develops after a period of latency, dose-independent). Subclinical DILI may be underreported [36].
DILI can be classified as follows:
Idiosyncratic DILI: DILI is mostly observed as an idiosyncratic reaction that may or may not be dose-related. It is unpredictable, and usually occurs after a latent period [37]. It is a rare cause of severe liver disease.
Intrinsic DILI:It is a dose dependent (i.e. acetaminophen-induced) and predictable event. There is a threshold dose for each chemical, above which individuals respond with liver toxicity that becomes more severe with increasing dose [38].
Chronic DILI:If there is chronic exposure to a hepatotoxic drug, DILI proceeds. There becomes a failure of return of liver enzymes or bilirubin to pre-DILI baseline. Later, other signs or symptoms of ongoing liver disease (e.g., Ascites, encephalopathy, portal hypertension, and coagulopathy) may be observed in 6 months. As liver has a high reserve of albumin, a decrease of the content of albumin tends to be associated with chronic DILI. Chronic DILI predisposes to acute liver failure, acute jaundice, cirrhosis and finally death [39].

Concerning the type of liver damage, DILI can cause the damages listed below [40-42]:

Hepatocellular damage

This type of injury can result from drugs such as acetaminophen and isoniazid.
Symptoms:

  1. Malaise
  2. Right upper quadrant abdominal pain
  3. Marked elevation in amino transferase levels (ALT, AST, or both)
  4. Hyperbilirubinemia (with jaundice, impaired hepatic synthesis, and encephalopathy)
Cholestatic Damage

Substances known to lead to this type of injury include amoxicillin/clavulanate and chlorpromazine. This type of injury is usually less serious than severe hepatocellular damage.
Symptoms:

  1. Development of pruritus and jaundice
  2. Marked elevation of serum alkaline phosphatase (AP) levels.
  3. Vanishing bile duct syndrome (rarely).
Mixed damage: Drugs such as phenytoin can cause this type of injury. Neither aminotransferase nor AP elevations are clearly predominant. Symptoms may also be mixed.

Clinical Significance of Drug-Induced Liver Injury

Many drugs, medicinal herbs, plants, and nutritional supplements can induce liver injury in acute or chronic use [43]. The term DILI may be used to express clinically significant liver injury or asymptomatic liver injury. The most specific predictor for a drug’s potential for severe hepatotoxicity, however, is the aminotransferase elevations, which can be accompanied by increase in serum total bilirubin (TBL) [30]. Hyperbilirubinemia leads to hepatocellular jaundice and, according to Hy’s law, is associated with mortality rates as high as 50%. Drugs most commonly cause asymptomatic elevation of hepatic enzymes (aspartate amino transferase (AST), alanine amino transferase (ALT), which is more specific, and AP). Although the finding of a higher rate of such elevations in subjects using drugs than in a control group is a sensitive signal of a potential to cause severe DILI, it is not specific signal. A more specific signal of such potential is a higher rate of more marked peak ALT elevations (10x, 15x upper limit of normal-ULN), with cases of increases to >1,000 U/L causing more concerns [44].

Increased plasma prothrombin (PT) time, or its international normalized ratio (INR) because of reduced hepatic production of Vitamin K-dependent clotting factors, is another potentially useful measure of liver function that might suggest DILI [44]. However, clinically significant liver injury (e.g. jaundice, abdominal pain, or pruritus) or impaired liver function, resulting in deficient protein synthesis (with prolonged PT or with hypo albuminemia) is rare. DILI includes injury caused by medicinal herbs, plants, and nutritional supplements as well as drugs [43,44].

 

Drug

 

Use

 

Possible Mechanism of Liver Injury

 

Liver Injury Type

Abacavir

Reverse transcriptase inhibitor, used in the therapy of HIV infection

  • Abacavir can cause clinically rare apparent hepatotoxicity.
  • 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
  • The serum enzyme pattern can be hepatocellular or cholestatic.
  • Rapid recovery (within 4 weeks) can be observed after stopping therapy.
  • Hepatotoxicity is observed due to hypersensitivity syndrome and/or allergy (fever, rash and fatigue).
  • Hypersensitivity is associated with the HLA-B*57:01 haplotype.
  • Few cases of on hypersensitivity abacavir induced hepatitis with unknown mechanism.

Acetaminophen

Analgesic and antipyretic medication for mild-to-moderate pain and fever

  • 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.
  • Direct hepatoxicity is observed usually after an acute overdose ingestion (e.g. suicide attempt using 7.5-15 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.
  • Severe hypersensitivity reactions, i.e. SJS and TEN may also be observed.
  • Acetaminophen is largely converted to nontoxic glucuronate or sulfate conjugates and later secreted in the urine.
  • A minor amount of acetaminophen is metabolized via the CYP450 system to intermediates that can be toxic, particularly N-acetyl-p-benzoquinoneimine reactive intermediate, which is rapidly conjugated to GSH.
  • 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 caspase-independent apoptosis initiated by activation of PARP-1.

Aspirin

analgesic and antipyretic medication

  • 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.
  • More dramatic examples of aspirin hepatotoxicity usually occur with 1,800 to 3,200 mg/day (>100 mg/kg) doses.
  • High doses symptoms of nausea, anorexia and abdominal pain and even encephalopathy with signs of hepatic dysfunction (hyperammonemia and coagulopathy) can occur.
  • Aspirin is a direct, intrinsic hepatotoxin.
  • 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.
  • While liver biopsy generally shows minimal injury despite the height of the enzyme elevations, electron microscopy may reveal fat and mitochondrial abnormalities.

Interferon beta (ß-1a and ß-1b)

commonly to prevent relapses in multiple sclerosis

  • Interferon beta is a well-known cause of mild hepatic injury mostly in women and rarely can result in severe liver injury with jaundice.
  • Interferon beta causes transient and mild elevations above 3 times the upper limit in serum aminotransferase levels (after ~3 -12 months therapy in 20-40% of patients).
  • 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.
  • Autoimmune features can occur, but may relate more to the underlying multiple sclerosis rather than drug-induced liver disease.
  • The cause of hepatic injury from interferon beta is not known.
  • The asymptomatic elevations in serum 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.

 

Dabigatran

Antithrombin anticoagulant (for prevention of stroke and venous embolism)

  • 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.
  • 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.
  • The cause of liver injury during dabigatran oral anticoagulant therapy is likely to be idiosyncratic and perhaps immunologic.

 

Estrogens /Oral contraceptives

oral contraceptive and in estrogen replacement therapy

  • 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.
  • 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).
  • 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.
  • 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.

 

  • Estrogens affect the orphan nuclear receptors that modulate bile acid and bilirubin metabolism and cholestasis occurs.
  • Genetically impaired biluribun metabolism may be the cause of estrogen-related hepatic disease.
  • 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.

 

Sulfonyl ureas (glyburide gliclazide, glipizide, and glimepiride)

 

antidiabetic agents

  • These agents are infrequent causes of clinically apparent liver injury.
  • Clinically apparent liver injury from the sulfonyl ureas is rare (minor enzyme 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.
  • Rare instances of hepatic injury arising after many months or years of therapy have been reported, particularly soon after an increase in dosage.
  • Hepatocellular, cholestatic and mixed injuries have been described with sulfonylurea-induced liver injury.
  • 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.
  • The mechanism of liver injury might be due to hypersensitivity.
  • Cross reactivity to reactions to sulfonamides can occur, however, sulfonylurea-associated hepatic injury is not actually quite like the immuno allergic pattern of sulfonamides.
  • The sulfonyl ureas should be used with caution in patients with sulfonamide hypersensitivity or sulfonamide-related hepatotoxicity.

 

Ketoconazole

An imidazole fungicidal agent with a very broad spectrum of activity

  • Ketoconazole-related clinically apparent acute DILI (mostly acute hepatitis) is well- documented 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.
  • Mild and transient elevations in liver enzymes occur in 4% to 20% of patients on oral ketaconazole.
  • While most cases present with a hepatocellular injury, cholestatic forms was also described.
  • Rash, fever and eosinophilia are rare as is autoantibody formation.
  • Severe cases with acute liver failure (need for emergency liver transplantation) and even death have also been described.
  • The cause of clinically apparent hepatotoxicity from ketoconazole is unknown; however, it may correlate with the ability of ketoconazole to inhibit mammalian sterol synthesis.
  • Acute liver injury is clearly idiosyncratic.
  • 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.

Lovastatin

commonly used cholesterol lowering agent (statin)

  • 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.
  • The onset of clinical injury (usually cholestatic, but can be hepatocellular) can vary from weeks to years.
  • The underlying event of hepatic damage caused by lovastatin is unknown.
  • Lovastatin is largely metabolized by CYP 3A4 and metabolites are excreted in bile. The mild ALT elevations are likely due to a toxic metabolite.

Methimazole

an antithyroid medication used in the therapy of hyperthyroidism and Graves disease

  • 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.
  • 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.

Methylphenidate

Used as a central nervous system stimulant used for the therapy of attention deficit disorder and narcolepsy.

  • 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 particularly in hepatitis C patients), which might unfortunately lead to death.
  • 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 drug-drug interactions.

Olanzapine

 

an atypical antipsychotic
used currently in the treatment of schizophrenia and bipolar illness

  • 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.
  • 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.
  • Allergic symptoms (rash, fever, and eosinophilia) and autoimmune markers are uncommon.
  • Cases with significant weight gain (1 kg/month, as much as 20 to 30 kg, in 25% of the patients, within 1-2 years) may lead to NAFLD.
  • The mechanism underlying the hepatotoxicity of olanzapine is not known.
  • Some instances of ALT elevations occurring on olanzapine therapy may be due to NAFLD caused by weight gain.
  • 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

a barbiturate derivative, widely used as a sedative and an antiseizure medication

  • 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.
  • Prospective studies suggest that less than develop elevations in serum aminotransferase levels during long term Phenobarbital therapy
  • 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.
  • The mechanism of Phenobarbital hepatotoxicity is thought to be hypersensitivity or an immunological response to a metabolically generated drug-protein complex.

Phenytoin

commonly used major anticonvulsant agent

  • 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.
  • A high proportion of patients taking phenytoin have transient serum aminotransferase (>3 fold) elevations, which are usually not associated with liver histological abnormalities.
  • The serum enzyme elevations can be mostly hepatocellular; however rarely mixed and cholestatic patterns are also observed.

 

  • DILI caused by phenytoin (common in blacks than whites) appears to be due to a hypersensitivity reaction, mostly typical cases of immunoallergic hepatotoxicity.
  • Phenytoin is metabolized by CYP450 system to arene oxide, which may result in toxic or immunogenic metabolite formation.
  • In some populations, the risk of injury correlates with the presence of HLA-B*1502.

Quinine

used for the prevention and therapy of malaria, also used for idiopathic muscle cramps

  • Quinine therapy has been linked to rare instances of hypersensitivity reactions, which can observed with hepatitis, and mild jaundice.
  • There is little data showing that chronic quinine therapy is related to elevations in serum aminotransferases.
  • 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)
  • The pattern of serum enzymes elevations is typically cholestatic or mixed.

The hepatotoxicity of quinine is due to a hypersensitivity reaction (mostly attributed to genetic predisposition) and there is no evidence for a direct hepatotoxic effect.

 

Quinidine

Used as antiarrhythmic for the treatment of atrial and ventricular arrhythmias.

  • 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.
  • 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.

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.

Isotretinoin

a vitamin A derivative used in the treatment of severe acne and some forms of skin, head and neck cancer

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%).

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.

Rifampin (Rifampicin)

a macrocyclic antibiotic with major activity against mycobacteria, commonly used in combination with other agents as therapy of tuberculosis

  • 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.
  • 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 injury.
  • The mechanism of rifampin hepatotoxicity is not well known.
  • The drug is extensively metabolized by the liver and directly induces CYP3A4 and ABC C2 (MRP2).
  • The cause of injury is likely to be due to toxic metabolic products that directly induce an immunologic reaction.
  • 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 cirrhosis are particularly likely to develop jaundice on rifampin therapy.

Tacrolimus

a calcineurin inhibitor and potent immuno suppressive agent used largely as a means of prophylaxis against organ rejection after transplantation

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.

  • Tacrolimus undergoes extensive hepatic metabolism by CYP3A4.
  • 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.

 

 

 

 

Valproate or valproic acid

used as therapy of epilepsy, bipolar disorders and migraine headaches

  • 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.
  • During long term of therapy, patients (5% to 10%) develop asymptomatic ALT elevations, which can usually resolve after the continuation of drug.
  • 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.
  • 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.
  • Valproate is rarely associated with anticonvulsant hypersensitivity syndrome and generally a safe alternative for patients who can develop this syndrome with aromatic anticonvulsants.
  • Valproate lowers tissue carnitine levels, which can lead to inhibition of beta-oxidation and loss of mitochondrial function, hyperammonemia and microvesicular steatosis.
  • Valproate is extensively metabolized by the liver and excreted in urine.
  • 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.
  • 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.

Orlistat

an inhibitor of pancreatic and gastric lipase; a commonly used weight loss agent

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.

  • The mechanism by which Orlistat causes liver injury is not known.
  • 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 receptor antagonist who is widely used for the prophylaxis and chronic treatment of asthma.

  • 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.
  • 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.
  • The mechanism of hepatic injury is clearly idiosyncratic.
  • The extensive hepatic metabolism of zafirlukast by CYP2C9 system suggests that injury may be a result of a hepatotoxic or metabolite.

Table 1: Some of the drugs that induce DILI and the mechanisms underlying their toxicity [54-78].

Management of Drug-Induced Liver Injury

Early drug withdrawal usually results in recovery. In severe cases, consultation with a specialist is indicated, especially if patients have hepatocellular jaundice and impaired liver function, because liver transplantation may be required [45,46]. Antidotes for DILI are available for only a few hepatotoxins; such as N -acetylcysteine for acetaminophen [47].

Prevention of Drug-Induced Liver Injury

The preventive strategies to prevent DILI are always taken seriously and initiated during the drug development process; however, such efforts may not ensure the drug safety in Phase IV (post-marketing) due to a larger population exposure. The post-marketing surveillance, now increasingly controlled by Food and Drug Agency (FDA) in United States, may enhance the awareness to potentially hepatotoxic drugs [44]. Many countries, including Turkey, have their own pharmacovigilance systems and these systems provide a high rate of observation of drug-related injuries, including DILI.

In United States, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has established the Drug-Induced Liver Injury Network (DILIN) to collect and analyze cases of severe liver injury induced by prescribed drugs, over-the-counter (OTC) drugs, and alternative medicines, such as herbal products and dietary supplements [48]. Besides, The National Institutes of Health (NIH) has created a database named “LIVERTOX” for drugs that may lead to the development of DILI. It has been suggested that the use of pharmacogenomics in the near future may allow tailoring of drug use and avoidance of potential toxicities in susceptible individuals, like children, elderly and pregnant [49].

Discussion

Drugs cause liver injury by many different mechanisms. DILI can be predictable, dose-related or unpredictable, unrelated to the dose of the drug on question. DILI can exist as hepatocellular damage, cholestatic damage (usually less serious than hepatocellular), or mixed damage [50]. The risk factors associated with DILI include age (<18 or >65years), obesity, pregnancy, concomitant alcohol consumption, and certain genetic polymorphisms (such as cytochrome P450 polymorphisms). It has been suggested that susceptible populations should not be subjective to re-challenge with drugs suspected of causing DILI [49,50-53]. These injuries resemble almost all known liver diseases and there are no pathognomonic findings, even upon liver biopsy, that clarify the diagnosis of DILI. Therefore, when the clinician suspects of DILI, it is essential to gather additional clinical and laboratory information necessary for differential diagnosis of the cause. The most important key point is to exclude other causes of liver disease (existence of acute/chronic hepatitis, nonalcoholic steatohepatitis [NASH], biliary tract diseases (stones, sand), obesity/metabolic syndrome, circulatory problems, congestive heart failure, concomitant exposure to other hepatotoxic drugs, alcohol or hepatotoxins) [51-53]. Some of the drugs that induce DILI and the mechanisms underlying their toxicity are summarized in Table 1 [54-78].

There are several molecular mechanisms induced by drugs that can be suggested for liver toxicity, most of which need to be clarified by further research. New drugs launched in the market should be tested especially for hepatotoxicity by using hepatic cell cultures and animal models. The pharmaceutical companies and researchers should particularly focus on late hepatotoxicity as it is sneaky and most dangerous effect, which can lead to high morbidity. Moreover, newly found toxicity mechanisms like ER stress should also be considered while evaluating drug toxicity. Future research should target patients in the post-marketing phase in order to provide more evidence grounds to the clinical safety of potential drugs of high propensity to DILI.

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