Comprehensive Research Journal of Biological Science (CRJBS) Vol.1(1) pp. 001 - 005 December, 2013 Available online http://crjournals.org/CRJBS/Index.

htm Copyright 2013 Comprehensive Research Journals

Review

Hepatotoxicity: mini review

Saim Jamil M1, Akram M*2, Halima Nazar1, Khan Usmanghani1, Asif M. H2, Osama Alam1, Tasneem Qureshi1, Mohiuddin E1
2 1

Faculty of Eastern Medicine and Surgery, Hamdard University Karachi, Pakistan Department of Eastern Medicine and Surgery, Faculty of Medical and Health Sciences, The University of Poonch, Rawalakot, Azad Jammu and Kashmir, Pakistan
Accepted 12 December, 2013

There are limited data regarding the frequency and proportionality of drug-induced hepatotoxicity. We sought to determine the scope of drug-induced hepatitis as seen in a community-based hepatology referral service. The present work constitutes a review of the drug induced hepatitis in literature. We performed PUBMED, EMBASE, and CENTRAL searches for research papers of drug induced hepatitis. Due to lack of reliable markers it is very difficult to diagnose drug-induced liver injury. Similarly it is very difficult to differentiate between drug-induced hepatotoxicity and any idiosyncratic reaction caused by a toxin. Complexity increases by the simultaneous use of multiple drugs. Liver function returns to normal in most of the cases when the offending drug is stopped. The manuscript plays an important role in the field of hepatotoxicity. This is focused review referring different published article on this topic. Keywords: Hepatitis, drug induced hepatitis, literature review

INTRODUCTION Hepatotoxicity implies chemical-driven liver damage. The term also applies to radioactive materials and drugs of synthetic origin which may cause liver damage. The most susceptible organ to toxicity from foreign agents is liver, due to its major role in transforming and clearing chemicals. Certain medicinal agents may injure the liver when taken in therapeutic range. A lot of chemicals used in laboratories, industries, drugs or even herbal remedies can induce hepatotoxicity. Thus chemicals or drugs which have the tendency to induce liver injury are called Hepatotoxins. Medical world faces with the serious problem of the development of safe and effective
Correspondence Author E-mai: makram_0451@hotmail.com Tel: 923343367632

drug in hepatitis. Modern drugs either lose effects or cause one or another side disease of any pathway. Drug-induced liver injury is one of the major concerns pertaining to drug design for curative and preventive health care function. Therefore it creates problem in the liver in its proper function and also poses threat for its injury leading to the manifestation of drug toxicity. Objective of this paper is to review the published papers on cases of hepatotoxicity. Pathophysiology Antituberculosis drug-induced hepatotoxicity is presented by Jaimer and co-workers where in the age greater than 35 years was the target factor for the drug-

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induced hepatitis in patients who were treated with antituberculosis. A study was conducted to determine whether infection with either the hepatitis C virus or human immunodeficiency virus was to be treated with antituberculosis drugs material. The treatment of tuberculosis in patients who were suffering with drug induced liver injury as well as suffering from hepatitis C and HIV. The patients with hepatitis C who were positive and who developed drug-induced hepatitis on repeated reintroducing of the TB drugs were offered a liver biopsy. If inflammation that cause with hepatitis C, the sample was presented for biopsy, treatment with interferon alpha started and was the anti TB drugs. During the 18 month of the study, 22 patients were found having drug induced liver injury. The relative risk of hepatitis C or HIV positive was determined as fivefold and fourfold, (p <0,05). Partially, four patients were treated with alpha-interferon and antiTB resurgence therapy was shown having liver injury (Koziel and Peters, 2007). Although statins are well tolerated medications, recent cases of autoimmune hepatitis (AIH) associated with statins use have been documented (Nasil, 2004). Satoshi Nakayama studied the overlap syndrome of autoimmune hepatitis and primary billiary cirrhosis induced by Fluvastatin. A 59year old man reported with liver damage, which occur 1 month after initiation of therapy with fluvastatin and continued after stopping the drug. Although druginduced liver damage could have a positive antibody test (antinuclear antibody>1/ 1280, anti-mitochondrial antibodies M2 21 price index) point that autoimmune liver disease is generated. Liver biopsy findings were consistent with overlapping autoimmune hepatitis and primary biliary cirrhosis. Treatment with prednisone and ursodeoxycholic acid resulted in a better clinical response. In patient the exhibition of autoimmune hepatitis and primary biliary cirrhosis overlap syndrome was triggered by statin one year later as the onset (Satoshi and Naoya, 2011). Literature review Over the last five years, two drugs have been withdrawn from the market which can cause severe liver damage, potential risks that were not fully recognized during the pre-approval clinical tests. Drug-induced hepatic injury is the most common reason given for withdrawal, representing more than 50 percent of cases of acute liver failure in different countries around the world. The recent endeavor has been directed toward a better understanding of these facts in order to improve results and contain drug induced liver injury (Dienstag, 2008). Acute liver failure is a rare disorder with high mortality and resource cost (William and George, 2010). In the developing countries, viral causes dominated by infection with hepatitis C are recognized as a common

cause in many countries. In the developed countries, the incidence of virally induced disease has declined significantly in recent years, with most cases now arising from drug-induced liver damage, often from paracetamol. However, results have clearly showed that use of liver transplantation emergency (William, 2003). A study on Ceftriaxone induces toxic hepatitis actively in the liver system. Toxic hepatitis or drug-induced liver injury include manifestation of clinical illness which range from mild to moderate as well as biochemical abnormalities in acute liver failure. There is advantage of a long half life, wide spectrum, high tissue penetration as well as a good safety profile of ceftriaxone which is regarded as third generation cephalosporin. The choice for the treatment of childhood infections which is regarded in previous studies have shown that few cases of high aspartate and alanine aminotransferases, with three cases of hepatitis have been caused by ceftriaxone. It has been brought to the notice to cite a case of drug-induced toxic hepatitis in a patient who was treated with ceftriaxone for acute tonsillitis (Erdal and Eren 2009). Schapira (1986) cited the diclofenac-induced hepatotoxicity as of paramount importance. Clinical and laboratory action of non-steroidal anti-inflammatory drugs are mentioned in great detail in text. Hepatotoxicity is one of the rare side effects of aspirin, indomethacin, naproxen, phenylbutazone, sulindac and other drugs. Diclofenac sodium is a potent and widely used non-steroidal anti-inflammatory and analgesic composite. It ranks among the strongest of this type of medications while among the better tolerated diclofenac metabolites excreted in urine and into bile. Experiments displayed that the main route of drug life is different in different species, urinary excretion is most important to humans. The lack of enterohepatic in human being accounts for the reduced gastrointestinal toxicity of this drug. Side effects of liver function are very rare. Seaman et al. has reported and these has also been verified in experimental and are extensively cited in medical literature. In one study, two patients developed acute hepatotoxicity soon after initiating treatment with diclofenac sodium. Furthermore, HLA association of amoxicillin clavulanate-induced hepatitis has been pinpointed. Drug-induced hepatitis immune allergic effects of patients are caused by the drug in clinical settings of adverse stage of development. This could be due to metabolic or immunologic idiosyncrasy. The presence of an immunologic idiosyncrasy may be thought due to HLA associated. An investigation was conducted where in 35 patients with biopsy-documented amoxicillinclavulanate-induced hepatitis were clinically and biochemically monitored. HLA-A and B were typed using alloantisera along with 300 controls. Amoxicillinclavulanate-induced hepatitis associated with DRB1* 1501-DRB5 * 0101-DQB1 * 0602 haplotype yielded

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results that temper immune-mediated HLA class II antigens, is found to exert its activity on the pathogenesis of drug-induced hepatitis immunoallergic (Marc, 1996). Minocycline as a cause of drug-induced autoimmune hepatitis reported by (Neal and Naseer, 2000) where in clinical and liver biopsy morphological characteristics of four patients described with minocycline autoimmune hepatitis (group 1). Serum laboratory values were compared with liver biopsy findings from group 1 with those from 10 patients with sporadic autoimmune hepatitis (group 2). All patients in group 1 were assessed having positive serum antinuclear antibodies, but no one observed having positive serum anti-smooth muscle antibodies. The morphological determination of the biopsy group 1 was the response with those of autoimmune hepatitis in all 4 patients. However, 1 of these biopsy specimens shown scattered eosinophils, in comparison with autoimmune hepatitis. The mean histological activity index scores for patients in Groups 1 and 2 was respectively, 6.7 and 5.4 and not patient in group 1 mark bridging fibrosis or cirrhosis, compared with 4 of 10 patients in group 2. Minocycline clinical prevention with autoimmune hepatitis is alike autoimmune hepatitis. The absence of eosinophils cannot be predicted as an attribute the possibility a minocycline cause. If the drug is unmasking latent autoimmune hepatitis then morphological differentiation cannot be considered as diagnostic approach. Acute liver failure with concurrent Bupropion and Carbimazole treatment plan has been communicated. Bupropion is an antidepressant and has been in use as an aid for smoking cessation. It also inhibits dopamine neurons and norepinephrine and enhances the effect of norepinephrine and dopamine, with no appreciable effect on monoamine oxidase activity. Till date the studies given in the literature reveal that bupropion is found connected with hepatotoxicity. However case reports are available where in the patients made a smooth recovery during 8 weeks period after the initial presentation by the patients. The hepatotoxicity of carbimazole has been quite amply proved in which acute liver failure showed concurrent treatment with carbimazole and bupropion (Khoo and Tham, 2003). Horng and Chia, (2011), detailed delineation on the hepatic insufficiency by using Itraconazole as compared with Corticosteroids treatment. Itraconazole have shown risk of hepatotoxicity because of its low affinity for human P-450 enzyme. Although, hepatic failure caused by itraconazole is rather rare. The case of a 46-year old woman was investigated who developed liver failure with itraconazole that was administered for the treatment of onychomycosis. Treatment with corticosteroids found effective for itraconazole-induced hepatitis, especially in those patients not responding to conventional treatment. A study conducted based on Halothane-induced hepatitis in developing countries shows that Halothane

as an anesthetic was introduced in 1950 and thus proved its effectiveness in surgery. Two types of halothane associated hepatotoxicity have been cited: type 1, or mild hepatitis, related with elevated transminase levels and self-limiting symptoms and type 2 or severe hepatotoxicity connected with acute fatal liver failure and its fatality in many cases. Hepatotoxicity is most likely found with the immune system, based on many elements. The free radicals generated by metabolism of halothane in the liver may alter cellular proteins and introduce neo-antigens to the immune system. These neo-antigens produce a more severe reaction after multiple exposures. Majority cases of hepatitis type 2 occur after repeated contact. It is interesting to note here that new halogenated anesthetics such as enflouranio, and desflurane are not metabolized in the liver that led to the concern (Pieman and Nastran, 2011). Raquel and co-workers have worked on the genetic polymorphism of NAT2, CYP2E1 and GST enzymes and the appearance of antituberculosis drug-induced hepatitis in tuberculosis patients. The drug used was isoniazid which is used in antituberculosis treatment plan is also the drug implicated in hepatotoxicity. The differences in INHinduced toxicity have been attributed to genetic variability more posts as NAT2, CYP2E1, GSTM1 and GSTT1, that code for enzymes that metabolize drugs. The polymorphism was studied in these enzymes as susceptibility factors in anti-TB drug-induced hepatitis suffering patients. In a case control having active tuberculosis participated in this clinical trial. Patients with a history of anti-TB drug-induced acute hepatitis (cases with up to 3 times the upper limit of normal serum transaminases and symptoms of hepatitis) and patients without evidence of TB effects liver function (controls) were genotyped for NAT2, CYP2E1, GSTM1 and GSTT1 polymorphism. With slow onset having a higher incidence of hepatitis from intermediate/rapid acetylators [22% (18/82) versus 9,8% (6/61), odds ratio (OR),2,86, 95% confidence interval (CI), 1,06 7,68, p= 0,04). Logistic regression showed that the slow acetylation status was the independent risk factor (OR 3.59, 95% CI, 2,53 4, 64, p=0,02) for the appearance of antituberculosis drug-induced hepatitis during treatment for TB with INH systems containing patients (Raquel and Renata, 2011). Ashima (2010), have put forward a study to deal with autoimmune hepatitis diagnosis and treatment in order to make it easy for the health officials to differentiate between autoimmune or drug-induced hepatitis. Autoimmune hepatitis is an acute inflammatory natured position by inflammation around the gate, elevated immunoglobulins, auto-antibodies, and response to immunosuppressant. One environmental factor (tropical) is assumed to cause immune-mediated attack against liver antigens in genetically predisposed individuals. A variety of clinical presentations have been observed ranging from chronic indolent disease to

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fulminant hepatic failure, and diagnosis requires the exclusion of other causes of liver disease. Treatment with corticosteroids should be executed promptly. Treatment decision is usually complicated by the diverse clinical manifestations and its clinical efficacy plan for multitude immunosuppressive agents. Achieving normal liver test and tissue is the ideal indicator for treatment point. Compensated patients may benefit from liver transplantation. Long-term prognosis is excellent, with early and aggressive initiation of therapy. The research work carried out on autoimmune hepatitis gives detailed clinical findings of the risk factors, immunepathogenesis, diagnostic parameter, treatment with in pregnancy, and long term effects on cirrhosis and hepato-cellular carcinoma in patients (Jou and Muir, 2008). The differentiation between drug-induced hepatitis, drug-induced autoimmunity or classical autoimmune hepatitis was the subject that was presented by Altintas et al. It was the subject of the debate that Dydrogesterone which is natural progesterone for women has been utilized in gynecological complaints and disorders. But the dydrogesterone-induced hepatotoxicity and dydrogesterone-induced hemolytic anemia has been dealt extensively in literature findings. The authors have proposed a case of hepatitis and warm antibody hemolytic anemia due to dydrogestrone and given its assessment for the possible differentiation in the diagnosis of hepatitis induction and drug induced immunity (Altintas, 2004). Kazuto (2008), have cited a default study and furnished the practical guidelines to combat druginduced liver injury. The range of the drug induced liver injury is both diverse and complex in its onset on liver function. Neil Kaplawitz has given detailed description on drug-induced liver injury. The predominant clinical picture is acute hepatitis or cholestasis with clinical pathological parameter of acute or chronic liver disease appears as a core commitant outcome. The pathogenesis of drug-induced liver disease involves the participation of the parent drug or metabolite that either directly affects the biochemistry of cells or to elicit an immune response. Each hepatotoxin is associated with a distinctive signature on the pattern of loss and latency. Unpredictable, low frequency, reactions occur in the background by a higher rate of mild asymptomatic liver injury and these are difficult to detect by monitoring serum alanine aminotransferase levels. The investigation on development in toxicogenomics and proteomics could improve the determination of risk factors and exploration of idiosyncratic hepatotoxicity (Neil, 2011). The recent view of research undertaken on druginduced liver injury describe that liver metabolizes foreign substances and also functionally insert between site of absorption and systemic circulation (Tainin, 2008). These parameters fulfill the liver with the

detoxification of foreign material but also become a target for toxicity. More than 1000 drugs are utilized with idiosyncratic hepatotoxocoty and drug-induced liver injury. This has created an awareness as well as point for removing viable drugs from the market. Drug-induced hepatotoxicity involved in half of cases of acute liver failure, with paracetamol as the main factor responsible for the violation. The liver damage caused by the drug in 2.3% of patients hospitalized for jaundice. However, drugs used in drug-induced toxicity could not be figured out because of the difficulty in diagnosis and the low frequency of furnishing the data on pharmacovigilance. Therefore drug-induced toxicity represents a clinical challenge due to the large number of reported hepatotoxic drugs in use, the wide range of liver damage because of absence of clinical findings and the diagnosis on the effect on liver. Therefore the assessment of druginduced liver injury should be the first priority while developing dosage form design (Ryder, 2008). Drug-induced liver injury is a growing problem along with complication of drugs prescribed, because the liver is for the metabolic disposal of drugs and foreign material. Although drugs are supposed to metabolize without damage, the liver damage has been constantly observed an adverse event. Drugs produce metabolites causing liver damage in a single dose fashion. Most drug material is a toxic byproduct only in rare individuals. Injury to hepatocytes results either directly by the disruption of intracellular function or membrane integrity or indirectly by immune-mediated membrane damage. Genetic alterations in enzymes harmful metabolite competition in drugs, and depletion of substrates required to detoxify the metabolite in the liver so that it can be prevented. Drug-induced hepatotoxicity clearly spelled out the withdrawal of many drugs that produced severe liver damage, a potential risk that was not recognized in the pre-approval clinical trials. Druginduced liver injury is the leading cause for more than 50 percent of cases of acute liver failure. More than 75 percent of cases of idiosyncratic drug reactions have given way to option for liver transplantation that has lead to death in some cases. In order to improve the drug not to resort to drug-induced liver damage the pathogenesis of drug-induced liver damage, common adverse drug reactions is to be understood in a better experimental and clinical findings and this should be monitored exclusively to check the types of malaise (William, 1995). Mechanism of drug-induced liver injury is the choice of research in many findings and has depicted the idiosyncratic nature and poor prognosis of drug-induced liver damage exhibit drug reaction and safety and the cause of withdrawal of drugs. Drug-induced toxicity is generated by direct hepatotoxic effects of a drug or its metabolites. Parenchymal cell damage create the activation of innate and / or adaptive immune cells, which combat inflammatory and tissue hepatotoxic

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mediators and propel immune responses against drugrelated antigens. Understanding the molecular and cellular components with different mechanisms can identify risk factors and eventually develop of a working methodology to predict and prevent drug-induced liver injury (Michael and Cynthia, 2006). Diagnosis The first step in diagnosis of drug-induced liver injury is a suspicion based on careful consideration of recent comprehensive reports on the disease. There are some cases where the suspicion of drug-induced liver injury is particularly strong. Exclusion of other possible causes, according to the model of the liver injury is necessary for diagnosis. Management Early management of drug-induced liver injury will mean immediate removal of the used drug suspected to be responsible, in accordance with serum level of Alanine aminotransferase, Alkaline phosphates, and total Bilirubin (Sjogren and Cheatham, 2010). CONCLUSION Fulminant liver failure by drug-induced hepatotoxicity may require liver transplant. Drugs mostly associated with drug-induced liver injury include paracetamol, nonsteroidal anti-inflammatory drugs, antibiotics, immunosuppressants and psychiatric drugs. Articles used in this study showed that the major cause of druginduced hepatotoxicity was due to paracetamol, drug induced toxicity required liver transplants or withdrawal from the drug known to have caused the effects. Conflict of interest declaration There is no conflict of among authors

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