Hepatotoxicity and hepatotoxicants: A systematic review

Liver act as metabolic factory of the body and metabolism of virtually every foreign substance. Its functioning is crucial for health and disease. Chemicals that cause liver injury are called hepatotoxicants. More than 950 drugs have been implicating in causing liver injury and were withdrawn from the market. Mechanism of hepatotoxicity induced by drug, immune based and genetic based toxicity. The drug models which are applied to study hepatotoxicity are Paracetamol, CCl4, Galactosamine, Alcohol, Azathioprine, Rantidine and different classof drugs cause acute and chronic liver injury.


Introduction
Liver is the fundamental organ for digestion and metabolism of medicines. 1 Hepatotoxicity alludes to liver dysfunction or liver harm that is related with an over-burden of medications or xenobiotics 2 and some of the time in any event, when presented inside therapeutics ranges, may harm the organ, 3 may result not just from direct poisonous quality of the essential compound yet additionally reaction influencing hepatocytes, biliary epithelial cells and additionally liver vasculature. 2 The synthetics that reason liver damage are called hepatotoxins or hepatotoxicants. 2 Hepatotoxicants are exogenous mixes of clinical significance and may incorporate overdose of certain therapeutic medications, mechanical synthetic concoctions, regular synthetic concoctions like microcystins, home grown cures and dietary supplements, 2 these operators are convert in synthetically receptive metabolites in liver, which can interconnect with cell macromolecules, for example, protein, lipids and nucleic acids, prompting protein brokenness, lipid per oxidation, DNA harm and oxidative stress. 3 An awkwardness among forceful and defensive powers brings about harm to the liver and complex system are associated with such hepatotoxicity actuated by an assortment of ecological and synthetic specialists.

Liver-the target organ
Liver performs in excess of 500 fundamental metabolic capacities. It is associated with the union of items like glucose got from glycogenesis, plasma proteins, thickening variables and urea that are discharged into the circulatory system. It directs blood levels of amino acids. 2 Liver parenchyma fills in as a capacity organ for a few items like glycogen, fat and fat solvent nutrients. 2 It is likewise engaged with the creation of a substance considered bile that is discharged to the intestinal tract. Bile helps in the evacuation of poisonous substances and fills in as a channel that isolates out harmful substance. 2 Simultaneously liver is inclined to numerous ailments like hypersensitivity to nourishment and includes safe framework too. 1 Hepatitis is caused due to infections, toxic substances, autoimmunity and can likewise result from non-alcoholic greasy liver malady associated with stoutness and steatosis. 1 Hepatic encephalopathy is brought about by aggregation of poisons in the circulatory system that are typically expelled by the liver. 1 Liver harm can likewise be brought about by drugs, such as tubercular drugs, general soporifics, paracetamol in moderately high doses and some against drugs used in oncology. Harmful hepatitis is the most extreme antagonistic response to antituberculosis drugs, 1 it generally starts in the initial scarcely any long stretches of treatment alongside liver putrefaction, which may advance to encephalopathy and death. 1 Alcoholic liver sicknesses with cirrhosis brought about by inordinate liquor utilization is a typical event. 1 Liver can now and again be harmed by certain synthetic compounds called hepatotoxins, for example, galactosamine and chloroform. 1 Additionally, steroids, immunizations and antiviral medications which are utilized as treatment for liver ailments, may create unfriendly impacts particularly after constant organization. 1 There are in excess of 900 medications that can prompt hepatotoxicity and is one of the significant explanations behind a portion of the medications pulled back from showcase. 1

Mechanism of hepatotoxicity
Medication related hepatotoxicity can't be seen as a solitary sickness. A wide range of components lead to hepatotoxicity, including disruption of the cell membrane and cell death resulting from covalent binding of the drug to cell proteins, which creates new adducts that serve as immune targets, in this way actuating an immunologic response hindrance of cell pathways of medication digestion, strange bile stream coming about because of interruption of subcellular actin fibers or interference of Indian Journal of Pharmacy and Pharmacology, October-December, 2019;6(4):107-112 trans-port siphons, prompting cholestasis and jaundice, in some cases with negligible cell damage modified cell demise (apoptosis), happening through tumor-corruption factor and Fas pathways; and restraint of mitochondrial work, with amassing of receptive oxygen species and lipid peroxidation, fat aggregation, and cell passing. 4 Drug induced hepatotoxicity In the most essential sense, the reason for medicate digestion is to encourage discharge of a less polar medication through the arrangement of progressively polar metabolites. 5 The subsequent water solvent compound can be discharged from the body by the kidneys. Much of the time Phase I digestion through oxidation, decrease or hydrolysis by CYP450 catalysts delivers the polar metabolites that are then made water dissolvable and accessible for discharge by Phase II digestion by means of glucuronidation or sulphation. 5 Be that as it may, we can't disregard the way that exercises of hepatic medication processing catalysts might be influenced by articulation of qualities related with these proteins notwithstanding adjustments in blood stream to the liver in typical and pathogenic states. 5 At times, a medication or its metabolite may initiate hepatotoxicity legitimately by accessing proximally found defenseless hepatocytes. 5 Acetaminophen or paracetamol is the most-very much examined medication that is accepted to utilize this component. 5 Direct hepatotoxicity of acetaminophen is portion related that pursues possibly one huge single portion or an enormous combined portion of acetaminophen. 5 The last pathway of hepatocyte damage is by means of authoritative of a dangerous CYP2E1-inferred metabolite, N-acetyl-p-benzoquinone imine (NAPQI), to subcellular organelles that initiates putrefaction or apoptosis. 5 A few different medications are additionally fit for actuating portion related hepatotoxicity that takes numerous structures. 5 Direct hepatotoxicity from hepatocyte rot can happen following bromfenac, cyclophosphamide (direct damage to hepatic sinusoidal cells) or methotrexate. 5 Ischemic rot can be actuated by cocaine, phencyclidine or niacin. Steatohepatitis can be actuated by amiodarone. 5 Hereditary based drug induced hepatotoxicity Before genome-wide affiliation thinks about, hereditary qualities was accepted to have a job in sedate initiated lethality. 5 Seat analysts and doctors thinking about patients searched for HLA haplotypes or other hereditary markers that could help distinguish people in danger for poisonous quality after specific medications. 5 Remarkable affiliations, for example, female sex and expanded weight had been watched while singular changeability in sedate impact recommended contrasts in Phase I and Phase II chemical articulation that could clarify a few parts of hepatotoxicity. 5 Epigenetic reactions had likewise been additionally involved in hepatotoxic reactions to drugs. 5 This area will audit current proof for the hereditary premise of medication hepatotoxicity, perceiving that notwithstanding the conspicuous job in recognizing HLA haplotypes, hereditary qualities could have a job in the statement of Phase I and Phase II compounds, cytokine articulation or any chemical framework that has a job in the advancement of hepatotoxicity in light of drugs. 5 Immune based Drug induced Hepatotoxicity Medications related with an insusceptible premise of medication poisonous quality are normally kept in the immuno-unfavorably susceptible or immune system class. 5 Insusceptible cells, cytokines and chemokines have all been researched as go between of medication hepatotoxicity. 5 This area will survey contemplates that address these segments regarding commencement or enactment of the resistant reaction as for what is thought about medication hepatotoxicity. 5 Concerning inception, it is commonly concurred this happens through antigen acknowledgment by assistant T cells working together with key cytokines. 5 Resistant cells whose essential job is to assault attacking life forms or non-self, for example, microorganisms and potentially infections, would then assault self. The following invulnerable reactions would prompt an insusceptible intervened hepatitis, antibodies to sedate haptens just as autoantibodies to self-proteins. 5 Curiously, preceding this insusceptible move in the perspective encompassing medication hepatotoxicity, most examinations tons of hepatotoxicity activated by incidental organization of unnecessary measures of the prompting drug. 5 Acetaminophen and halothane unequivocally recommended that covalent alteration of self by responsive medication haptens set off the loss of self-recognition. 5 Hepatotoxicants A. Models of hepatotoxicity 1. CCl4 induced hepatotoxicity Carbon tetrachloride (CCl4) is a xenobiotic mechanical dissolvable that is utilized to initiate synthetic hepatitis and liver wounds in trial creatures. Carbon tetrachlorideprompted liver wounds are the most widely recognized trial model for observing the hepatoprotective action of specific medications. 6 A solitary presentation to CCl4 just like a solid hepatotoxic xenobiotic straightforwardly prompts serious liver corruption and steatosis. Unthinking contemplates offer proof that digestion of CCl4 by means of CYP2E1 to emphatically receptive free extreme metabolites assumes a urgent job in the proposed method of activity. 6 The significant metabolites, trichloromethyl (CCl3 ) and trichloromethylperoxy (CCl3O2⋅) free radicals, are very receptive and are equipped for covalent tie to cell macromolecules, inclining toward unsaturated fats of the layer phospholipids. 6 The free radicals actuate cell layer lipid peroxidation by means of dis-rupting polyunsaturated unsaturated fats inside these films, starting a successive free extreme chain response. 6 CCl4 ⇒ CCl3O-✚ O-

Galactosamine induced Hepatotoxicity
Galactosamine produces diffuse sort of liver damage reenacting viral hepatitis. It probably disturbs the union of fundamental uridylate nucleotides bringing about organelle damage and at last cell passing. 7 Exhaustion of those nucleotides would block the ordinary combination of RNA and subsequently would create a decrease in protein amalgamation. 7 This system of lethality realizes an expansion in cell layer penetrability prompting compound spillage and in the long run cell demise. The cholestasis brought about by galactosamine might be from its harming impacts on bile conduits or ductules or canalicular film of hepatocytes Galactosamine decline the bile stream and it's substance for example bile salts, cholic corrosive and deoxycholic acid. 7

Paracetamol induced hepatotoxicity
Acetaminophen hepatotoxicity is a strong model sister have accomplished a striking level of achievement in con-of the "harmful metabolite speculation" When huge overdose with this medication happens, an arylating metabolite of the medication, created in the liver cell, overpowers the hepatocytes protection systems and makes the cell pass on. 8 The paracetamol is separated to sulfate and glucuronide conjugates after that it's utilized to responsive middle of the road. It's depolluted by conjugation with glutathione. 1 The covalent authoritative of N-acetyl-P-benzoquinoneimine, an oxidative result of paracetamol to sulphydryl gatherings of protein, bring about lipid per oxidative debasement of glutathione and causes cell corruption in the liver. 1

Alcohol induced hepatotoxicity
Liver is among the organs generally helpless to the harmful impacts of ethanol. Liquor utilization is known to cause greasy invasion, hepatitis and cirrhosis. 7 Oxidative stress may assume a significant job in the ethanol-interceded hepatotoxicity. It prompts cytochrome P450 which advances digestion of ethanol itself, acetaminophen and others. Ethanol digestion yields acetaldehyde which adds to glutathione exhaustion, protein conjugation, free extreme age and lipid peroxidation. 2 Alcohol can instigate invivo changes in film phospholipid synthesis and smoothness, on account of an expansion in hepatic lipid peroxidation which may in the long run influence cell capacities brings about loss of layer structure and respectability. 7 The impacts of ethanol can upgraded age of oxyfree radicals during its oxidation in liver. 7 This outcomes in raised degrees of glutamyltranspeptidase, a film bound chemical in serum. 7 Ethanol represses glutathione peroxidase, decline the action of catalase, superoxide dismutase, alongside increment in levels of glutathione in liver. 7 The reduction in action of cancer prevention agent catalysts superoxide dismutase, glutathione peroxidase are theorized to be because of the harming impacts of free radicals created following ethanol introduction or then again could be because of an immediate impact of acetaldehyde, framed by oxidation of ethanol. 7 Thioacetamide  is  an  organosulfar compound. Thioacetamide, a specific hepatotoxicity inside a brief timeframe after the organization of the medication. 3 It encounters an expansion digestion to acetamide and thioacetamide s-oside by the blended capacity oxidase framework while thioacetamide s-oxide is additionally processed to cytochrome P-450 monooxygenase to sulfene. 3 Component of thioacetamide harmfulness is because of the development of thioacetamide s-oxide which is answerable for the change in cell porousness and the grouping of Ca++ increments intracellular in atomic volume and furthermore impedes mitochondrial action which signs to cell passing. 3

Azathioprine induced hepatic putrefaction
AZA is a significant medication utilized in the treatment of immune system issue and in forestalling unite dismissal. 7 The nitro-conjugated twofold obligation of imidazole ring of AZA is a Michael acceptor. 7 AZA is severed in vitro to 6-MP non enzymatically by a nucleophilic assault of sulfhydryl bunches fundamentally GSH, on the β carbon in the actuated twofold security AZA lethality to rodent hepatocytes was gone before by exhaustion of GSH. Earlier GSH exhaustion improved harmfulness while supplemental GSH was defensive. 7 In hepatocytes GSH is devoured during digestion of AZA to 6-MP. The system of AZA poisonous quality to hepatocytes includes exhaustion of GSH prompting mitochondrial damage with significant consumption of ATP and cell demise by putrefaction. 7 Lipid peroxidations just as changed degrees of some endogenous scroungers are taken as backhanded in vivo dependable records for the commitment of free extreme age and thus oxidative stress. 7

Ranitidine initiated hepatotoxicity
The damage delivered by ranitidine happens because of the nearness of its metabolites that reason oxidative harm in liver or start resistant unfavorably susceptible response. It additionally makes a response as reflected by penetration of hepatocytes with ranitidine (portion of either 50 mg/kg or 30 mg/kg). 1 After noticeable centrilobular and crossing over rot radical fiery changes with development of collagenous septa. 1 In parenchyma there happens central liver cell rot with some amassing of histocytic components and slight steatosis and cholestasis. 1 It prompts fibrosis, bile conduit expansion, and invasion of lymphocytes, plasma cells, polymorphs, and eosinophils. 1 Hepatic harm is grouped as far as ascend in serum aminotransferases, unassuming hepatic penetration by the two lymphocytes and eosinophils and slight central hepatocellular corruption. 1 Ranitidine likewise instigates liver cholestasis related with raise in plasma bilirubin and basic phosphatase. 1

B. Medications cause hepatotoxicity a. Anticonvulsants or Antiepileptic drugs
A portion of the anticonvulsants may offer ascent to hepatotoxicity. Clonazepam, diazepam, primidone and sultiame are not considered to initiate genuine liver ailment. 2 Sodium valproate is a compelling anticonvulsant including less danger of hepatotoxicity. 9 Valproate is changed to valproyl adenosine monophosphate and valproyl coenzyme An in the mitochondrial network. 9 The valproate prompted consumption of coenzyme An influences the intramitochondrial pool of this cofactor and in this way impedes mitochondrial proteins associated with β-oxidation of greasy acids. 9 Patients who take phenytoin regularly have transaminase height up to multiple times the maximum furthest reaches of ordinary [ULN] yet liver biopsies don't uncover critical pathology. 2 The utilization of felbamate was notably diminished as a result of its relationship with aplastic sickliness and hepatotoxicity in some patients. 2 Phenobarbital is once in a while known to cause hepatic harm including hepatocellular and cholestatic liver damage and furthermore excessive touchiness reaction. 2

b. Anti thyroid drugs
The antithyroidthionamide drugs, propylthiouracil (PTU), methimazole (MMI) and carbimazole (CBZ), stay one of the backbones of treatment for Graves' disease worldwide and can likewise be utilized for the treatment of different reasons for hyperthyroidism, for example, harmful nodular goiter. The general occurrence of hepatotoxicity with any antithyroid prescription is < 0.5%, yet distributed proof currently shows an expanded danger of genuine liver damage related with one of the thionamides. 10 The accurate instrument behind PTU instigated hepatotoxicity isn't clear. 10 Different instruments have been proposed including restraint of glucoronyltransferase, decreased bile corrosive amalgamation and expanded oxygen utilization by hepatocytes. 10 Liver biopsy and after death assessments have uncovered different degrees of irritation and liver corruption. 10 Methimazole cause rise of transaminase and have high poisonous quality contrast with PTU. 10 c. Antituberculosis drugs Antituberculosis sedate actuated hepatotoxicity [ATDH] is a significant issue and primary driver of treatment interference and change in treatment routine during tuberculosis treatment course. 2 ATDH causes generous dismalness and mortality. Asymptomatic transaminase heights are normal during against tuberculosis treatment however hepatotoxicity can be deadly when not perceived early and when treatment isn't hindered in time. 2 Hostile to tuberculosis drugs like isoniazid, rifampicin and pyrazinamide have been seen as conceivably hepatotoxic. 2 There has been a report of ethambutol-actuated liver cholestatic jaundice, with misty conditions. 2 The danger of hostile to tuberculosis medicate actuated hepatotoxicity has been found to increment by different components like high liquor admission, more seasoned age, prior constant liver ailment, ceaseless viral contamination, propelled TB, female sex, concominant organization of hepatotoxic medications, improper utilization of medications and wholesome status. 2 INH is used to monoacetyl hydrazine, which is additionally utilized to a harmful item by cytochrome P 450 prompting hepatotoxicity. 11 Patients on simultaneous rifampicin treatment have an expanded rate of hepatitis. 11 This has been proposed due to rifampicin-actuated cytochrome P 450 catalyst acceptance, causing an expanded creation of the poisonous metabolites from acetyl hydrazine (AcHz). 11 Rifampicin likewise expands the digestion of INH to isonicotinic corrosive and hydrazine, the two of which are hepatotoxic. 11 The plasma half existence of AcHz (metabolite of INH) is abbreviated by rifampicin and AcHz is immediately changed over to its dynamic metabolites by expanding the oxidative end pace of AcHz, which is identified with the higher frequency of liver rot brought about by INH and rifampicin in mix. 11 Rifampicin instigates hydrolysis pathway of INH digestion into the hepatotoxic metabolite hydrazine.

d. Corticosteroids or glucocorticoids and anabolic
androgenic steroids Glucocorticoids advance glycogen stockpiling in the liver. 2 An amplified liver is an uncommon symptom of long haul steroid use in youngsters. 2 Steatosis might be watched both in grown-up and kids upon delayed use. 2 Anabolic androgenic steroids being advertised as dietary enhancements are a cause for genuine hepatotoxicity. 2 e. Arthritis medications It isn't viewed as normal however when it happens it tends to be possibly genuine. 2 In patients treated for rheumatoid joint pain with methotrexate(MTX), infinitesimal proof of liver damage has been found for any transaminase rise over the ULN (upper limit of normal). 2 MTX can harm typical cells thus either enormous portions or delayed utilization of MTX can be went with hepatotoxicity, lung poisonous quality or nephrotoxicity. 12 In spite of the fact that The unmistakable instrument of MTX initiated hepatotoxicity isn't yet totally cleared, oxidative pressure and irritation are professed to be partaken in pathogenesis of MTX-prompted hepatotoxicity. 12 MTX has been accounted for to cause mitochondrial damage and upset the oxidant/cancer prevention agent balance through discharging overabundance receptive oxygen species(ROS) that devour the normally accessible cell reinforcements, for example, diminished glutathione (GSH), superoxide dismutase(SOD) and catalase (CAT). 12 f. Antimalarial drugs Antimalarial drugs like amodiaquine can make hepatotoxicity in people by oxidation a receptive metabolite, iminoquinone, by liver microsomes and peroxidases. 2 The receptive metabolites can irreversibly tie to proteins which lead to coordinate poisonous quality by upsetting the cell function. 2 g. Chemotherapy Chemotherapy utilizes dangerous synthetic compounds or medications like tyrosine kinase inhibitors, alkylating operators, antimetabolites, antitumor anti-infection agents, platinums, biologic reaction modifiers and androgens to obliterate disease cells. 2 Be that as it may, during treatment, if the poisons develop in the body quicker than the liver can process them, hepatotoxicity may happen. 2 Chemotherapeutic specialists alone or in mix may cause excessive touchiness responses or direct hepatic toxicity. 2

h. Psychotropic Drugs
Antipsychotics neuroleptics including phenothiazines, butyrophenones, and clozapine. Hepatotoxicity of psychotropic medications happens in a variable yet little extent of clients and thusly can be viewed as eccentric or quirky. 13 Intense plain responses to drugs will in general have clinicopathological highlights of hepatitis (annihilation of liver parenchyma), cholestasis (impeded bile emission), or both. 13 Moreover, likewise with most hepatolethal medications, individual psychotropic medications have a characteristic example of damage, i.e., cholestatic for a few (e.g., chlorpromazine, haloperidol, tricyclics). 13 Phenothiazines, albeit no longer in wide spread use, various medications related with liver damage. 13 Chlorpromazine has been the most widely considered and the clinical highlights seem, by all accounts, to be represented by a blend of extreme touchiness response and metabolite poisonous quality, The bile ductule might be a significant objective, and a ductopenic disorder is the most severe. 13
Tricyclics Most tricyclic antidepressants are conceivably hepatotoxic. 13 Amineptine-initiated liver sickness is essentially cholestatic, albeit moderate rot might be seen. 13 An immunoallergic component is proposed by the event of fever, rash, eosinophilia, and positive rechallenge. 13 Amineptine is changed over by microsomes into an epoxide that is detoxified by GSH. 13 Albeit poor hydroxylators are at diminished hazard, 90% of whites are fast hydroxylators (CYP2D6). 13 In this way, hydroxylator status is certainly not a helpful indicator of danger, in spite of the fact that it focuses to the job of receptive metabolites equipped for evoking an invulnerable reaction. 13 MAO Inhibitors MAO inhibitors, which get from hydrazine, are altogether potential hepatotoxins. 13 The involvement in one, iproniazid, was sad: unmistakable hepatitis happened in 1% with case fatalities moving toward 20%, and the medication was pulled back. 13 Hydrazines can be utilized by P450 to dangerous intermediates. Their digestion and component look like that of isoniazid, likewise a hydrazine. One substituted hydrazine MAO inhibitor stays accessible, in particular phenelzine; there have been case reports of hepatitis. 13 Different Antidepressants Trazodone has been involved as the reason for an injury with components of both hepatitis and cholestasis; the issue has all the earmarks of being uncommon. 13 j. Non-steroidal anti inflammatory drugs(NSAID`S) NSAIDS prompted hepatotoxicity by portion reliant and peculiar responses have been seen. 2 Two principle components are viewed as liable for damage, extreme touchiness and metabolic deviation. Excessive touchiness responses o en have signi cant against atomic factor or hostile to smooth muscle counter acting agent titres, lymphadenopathy and eosinophilia. 2 Metabolic abnormalities can happen as hereditary polymorphisms and change weakness to a wide scope of medications. Ibuprofen, sulindac, piroxicam, diclofenac and indomethacin are related with particular response. 2 Headache medicine and phenylbutazone are related with inborn hepatotoxicity. 2 Diclofenac hepatotoxicity disability of ATP combination by mitochondria, and to creation of dynamic metabolites, especially N,5-dihydroxydiclofenac, which causes direct cytotoxicity. 2 Mitochondrial penetrability progress [MPT] has likewise been demonstrated to be significant in diclofenacprompted liver damage, bringing about age of responsive oxygen species, mitochondrial expanding and oxidation of NADP and protein thiols. 2 Nimesulide actuated hepatotoxicity with serious, and even deadly, instances of liver damage have been accounted for in patients who got nimesulide treatment. 14 15 Fluconazole has been accounted for to cause hepatitic or cholestatic liver damage by hindrance of cytochrome P450 proteins in the internal mitochondrial layer and smooth endoplasmic reticulum which prompts hepatocyte mitochondrial illness and flavin containing monooxygenase (FMO) digestion of the azole antifungal medications in the liver, was liable for the azole-incited hepatotoxicity. 15 n. Antihyperlipidemic drugs The example of damage from antihyperlipidemics is commonly hepatocellular or blended in nature with uncommon occasions of unadulterated cholestatic hepatitis. 2 Provastatin has been accounted for to cause intense intrahepatic cholestasis. 2 Atorvastatin and lovastatin-related hepatotoxicity has been related with a blended example of liver damage ordinarily happening a while after the commencement of the prescription. 2 Simvastatin hepatotoxicity is theorized to happen because of medication tranquilize associations. 2 Fenofibrate may seldom incite an immune system hepatitis type response particularly when taken in blend with statin prescriptions. 2

o. Herbal and dietary suppliments
Herbal contaminated with over the top measure of prohibited pesticides, microbial contaminants, overwhelming metals, concoction poisons contaminated with manufactured drugs. 2 The liver damage from home grown cures has run from gentle heights of hepatic compounds to fulminant liver disappointment requiring liver transplantation. 2 Complete nonattendance of potential peculiar responses in any home grown treatment can't be ensured. 2 Admission of home grown enhancements can cause unfavorable impact on livers of individuals with ordinary working livers and no history of earlier liver malady. 2 New examples of liver damage keep on developing among known home grown hepatotoxins. 2 The shifted appearances of liver damage incorporate steatosis, intense and interminable hepatitis, hepatic fibrosis, zonal or diffuse hepatic corruption, bile channel damage, venoocclusive malady, intense liver disappointment requiring liver transplantation and carcinogenesis. 2

Conclusion
Armamentarium of drugs lead to damage of liver hepatocytes which may not be reversed leading to fatal consequences. Therefore dose titration, pharmacogenetic evaluation and existing disease are important factors to be considered.