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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
1Faculty of Eastern Medicine and Surgery, Hamdard University Karachi, Pakistan 2Department of Eastern Medicine and Surgery, Faculty of Medical and Health Sciences, The University of Poonch, Rawalakot, Azad Jammu and Kashmir, Pakistan 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.
drug in hepatitis. Modern drugs either lose effects or The term also applies to radioactive materials and drugs cause one or another side disease of any pathway. of synthetic origin which may cause liver damage. The Drug-induced liver injury is one of the major concerns most susceptible organ to toxicity from foreign agents is pertaining to drug design for curative and preventive liver, due to its major role in transforming and clearing health care function. Therefore it creates problem in the chemicals. Certain medicinal agents may injure the liver liver in its proper function and also poses threat for its when taken in therapeutic range. A lot of chemicals used injury leading to the manifestation of drug toxicity. in laboratories, industries, drugs or even herbal Objective of this paper is to review the published papers 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 Pathophysiology
Correspondence Author E-mai: makram_0451@hotmail.com presented by Jaimer and co-workers where in the age greater than 35 years was the target factor for the drug- induced hepatitis in patients who were treated with cause in many countries. In the developed countries, the antituberculosis. A study was conducted to determine incidence of virally induced disease has declined whether infection with either the hepatitis C virus or significantly in recent years, with most cases now arising human immunodeficiency virus was to be treated with antituberculosis drugs material. The treatment of paracetamol. However, results have clearly showed that tuberculosis in patients who were suffering with drug use of liver transplantation emergency (William, 2003). induced liver injury as well as suffering from hepatitis C A study on Ceftriaxone induces toxic hepatitis actively and HIV. The patients with hepatitis C who were positive in the liver system. Toxic hepatitis or drug-induced liver and who developed drug-induced hepatitis on repeated injury include manifestation of clinical illness which range reintroducing of the TB drugs were offered a liver biopsy. from mild to moderate as well as biochemical If inflammation that cause with hepatitis C, the sample abnormalities in acute liver failure. There is advantage of was presented for biopsy, treatment with interferon alpha a long half life, wide spectrum, high tissue penetration as started and was the anti TB drugs. During the 18 month well as a good safety profile of ceftriaxone which is of the study, 22 patients were found having drug induced regarded as third generation cephalosporin. The choice for the treatment of childhood infections which is The relative risk of hepatitis C or HIV positive was regarded in previous studies have shown that few cases determined as fivefold and fourfold, (p <0,05). Partially, of high aspartate and alanine aminotransferases, with four patients were treated with alpha-interferon and anti- three cases of hepatitis have been caused by TB resurgence therapy was shown having liver injury ceftriaxone. It has been brought to the notice to cite a (Koziel and Peters, 2007). Although statins are well case of drug-induced toxic hepatitis in a patient who was tolerated medications, recent cases of autoimmune treated with ceftriaxone for acute tonsillitis (Erdal and hepatitis (AIH) associated with statins use have been documented (Nasil, 2004). Satoshi Nakayama studied the overlap syndrome of autoimmune hepatitis and hepatotoxicity as of paramount importance. Clinical and primary billiary cirrhosis induced by Fluvastatin. A 59- laboratory action of non-steroidal anti-inflammatory year old man reported with liver damage, which occur 1 drugs are mentioned in great detail in text. month after initiation of therapy with fluvastatin and Hepatotoxicity is one of the rare side effects of aspirin, continued after stopping the drug. Although drug- indomethacin, naproxen, phenylbutazone, sulindac and induced liver damage could have a positive antibody test other drugs. Diclofenac sodium is a potent and widely used non-steroidal anti-inflammatory and analgesic antibodies M2 21 price index) point that autoimmune composite. It ranks among the strongest of this type of liver disease is generated. Liver biopsy findings were medications while among the better tolerated diclofenac consistent with overlapping autoimmune hepatitis and metabolites excreted in urine and into bile. Experiments primary biliary cirrhosis. Treatment with prednisone and displayed that the main route of drug life is different in ursodeoxycholic acid resulted in a better clinical different species, urinary excretion is most important to response. In patient the exhibition of autoimmune humans. The lack of enterohepatic in human being hepatitis and primary biliary cirrhosis overlap syndrome accounts for the reduced gastrointestinal toxicity of this was triggered by statin one year later as the onset 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 Literature review
hepatotoxicity soon after initiating treatment with Over the last five years, two drugs have been withdrawn from the market which can cause severe liver clavulanate-induced hepatitis has been pinpointed. damage, potential risks that were not fully recognized Drug-induced hepatitis immune allergic effects of during the pre-approval clinical tests. Drug-induced patients are caused by the drug in clinical settings of hepatic injury is the most common reason given for adverse stage of development. This could be due to withdrawal, representing more than 50 percent of cases metabolic or immunologic idiosyncrasy. The presence of of acute liver failure in different countries around the an immunologic idiosyncrasy may be thought due to world. The recent endeavor has been directed toward a HLA associated. An investigation was conducted where better understanding of these facts in order to improve in 35 patients with biopsy-documented amoxicillin- results and contain drug induced liver injury (Dienstag, 2008). Acute liver failure is a rare disorder with high biochemically monitored. HLA-A and B were typed mortality and resource cost (William and George, 2010). using alloantisera along with 300 controls. Amoxicillin- In the developing countries, viral causes dominated by clavulanate-induced hepatitis associated with DRB1* infection with hepatitis C are recognized as a common 1501-DRB5 * 0101-DQB1 * 0602 haplotype yielded results that temper immune-mediated HLA class II as an anesthetic was introduced in 1950 and thus antigens, is found to exert its activity on the proved its effectiveness in surgery. Two types of pathogenesis of drug-induced hepatitis immunoallergic halothane associated hepatotoxicity have been cited: (Marc, 1996). Minocycline as a cause of drug-induced type 1, or mild hepatitis, related with elevated autoimmune hepatitis reported by (Neal and Naseer, transminase levels and self-limiting symptoms and type 2000) where in clinical and liver biopsy morphological 2 or severe hepatotoxicity connected with acute fatal liver failure and its fatality in many cases. Hepatotoxicity minocycline autoimmune hepatitis (group 1). Serum is most likely found with the immune system, based on laboratory values were compared with liver biopsy many elements. The free radicals generated by findings from group 1 with those from 10 patients with metabolism of halothane in the liver may alter cellular sporadic autoimmune hepatitis (group 2). All patients in proteins and introduce neo-antigens to the immune group 1 were assessed having positive serum system. These neo-antigens produce a more severe antinuclear antibodies, but no one observed having reaction after multiple exposures. Majority cases of positive serum anti-smooth muscle antibodies. The hepatitis type 2 occur after repeated contact. It is morphological determination of the biopsy group 1 was interesting to note here that new halogenated the response with those of autoimmune hepatitis in all 4 anesthetics such as enflouranio, and desflurane are not patients. However, 1 of these biopsy specimens shown metabolized in the liver that led to the concern (Pieman scattered eosinophils, in comparison with autoimmune and Nastran, 2011). Raquel and co-workers have hepatitis. The mean histological activity index scores for worked on the genetic polymorphism of NAT2, CYP2E1 patients in Groups 1 and 2 was respectively, 6.7 and 5.4 and not patient in group 1 mark bridging fibrosis or antituberculosis drug-induced hepatitis in tuberculosis cirrhosis, compared with 4 of 10 patients in group 2. patients. The drug used was isoniazid which is used in antituberculosis treatment plan is also the drug hepatitis is alike autoimmune hepatitis. The absence of implicated in hepatotoxicity. The differences in INH- eosinophils cannot be predicted as an attribute the induced toxicity have been attributed to genetic possibility a minocycline cause. If the drug is unmasking variability more posts as NAT2, CYP2E1, GSTM1 and GSTT1, that code for enzymes that metabolize drugs. differentiation cannot be considered as diagnostic The polymorphism was studied in these enzymes as susceptibility factors in anti-TB drug-induced hepatitis Acute liver failure with concurrent Bupropion and suffering patients. In a case control having active Carbimazole treatment plan has been communicated. tuberculosis participated in this clinical trial. Patients with Bupropion is an antidepressant and has been in use as a history of anti-TB drug-induced acute hepatitis (cases an aid for smoking cessation. It also inhibits dopamine with up to 3 times the upper limit of normal serum neurons and norepinephrine and enhances the effect of transaminases and symptoms of hepatitis) and patients norepinephrine and dopamine, with no appreciable effect without evidence of TB effects liver function (controls) on monoamine oxidase activity. Till date the studies were genotyped for NAT2, CYP2E1, GSTM1 and given in the literature reveal that bupropion is found GSTT1 polymorphism. With slow onset having a higher connected with hepatotoxicity. However case reports incidence of hepatitis from intermediate/rapid acetylators are available where in the patients made a smooth [22% (18/82) versus 9,8% (6/61), odds ratio (OR),2,86, recovery during 8 weeks period after the initial 95% confidence interval (CI), 1,06 – 7,68, p= 0,04). presentation by the patients. The hepatotoxicity of Logistic regression showed that the slow acetylation carbimazole has been quite amply proved in which acute status was the independent risk factor (OR 3.59, 95% CI, 2,53 4, 64, p=0,02) for the appearance of anti- carbimazole and bupropion (Khoo and Tham, 2003). tuberculosis drug-induced hepatitis during treatment for Horng and Chia, (2011), detailed delineation on the TB with INH systems containing patients (Raquel and hepatic insufficiency by using Itraconazole as compared Renata, 2011). Ashima (2010), have put forward a study with Corticosteroids treatment. Itraconazole have shown to deal with autoimmune hepatitis diagnosis and risk of hepatotoxicity because of its low affinity for treatment in order to make it easy for the health officials human P-450 enzyme. Although, hepatic failure caused to differentiate between autoimmune or drug-induced by itraconazole is rather rare. The case of a 46-year old hepatitis. Autoimmune hepatitis is an acute inflammatory woman was investigated who developed liver failure with natured position by inflammation around the gate, itraconazole that was administered for the treatment of onychomycosis. Treatment with corticosteroids found response to immunosuppressant. One environmental effective for itraconazole-induced hepatitis, especially in factor (tropical) is assumed to cause immune-mediated those patients not responding to conventional treatment. attack against liver antigens in genetically predisposed A study conducted based on Halothane-induced individuals. A variety of clinical presentations have been hepatitis in developing countries shows that Halothane observed ranging from chronic indolent disease to fulminant hepatic failure, and diagnosis requires the detoxification of foreign material but also become a exclusion of other causes of liver disease. Treatment target for toxicity. More than 1000 drugs are utilized with with corticosteroids should be executed promptly. idiosyncratic hepatotoxocoty and drug-induced liver Treatment decision is usually complicated by the diverse injury. This has created an awareness as well as point clinical manifestations and its clinical efficacy plan for for removing viable drugs from the market. Drug-induced multitude immunosuppressive agents. Achieving normal hepatotoxicity involved in half of cases of acute liver liver test and tissue is the ideal indicator for treatment failure, with paracetamol as the main factor responsible point. Compensated patients may benefit from liver for the violation. The liver damage caused by the drug in transplantation. Long-term prognosis is excellent, with 2.3% of patients hospitalized for jaundice. However, early and aggressive initiation of therapy. The research drugs used in drug-induced toxicity could not be figured work carried out on autoimmune hepatitis gives detailed out because of the difficulty in diagnosis and the low frequency of furnishing the data on pharmacovigilance. pathogenesis, diagnostic parameter, treatment with in Therefore drug-induced toxicity represents a clinical pregnancy, and long term effects on cirrhosis and challenge due to the large number of reported hepato-cellular carcinoma in patients (Jou and Muir, hepatotoxic drugs in use, the wide range of liver damage because of absence of clinical findings and the diagnosis hepatitis, drug-induced autoimmunity or classical on the effect on liver. Therefore the assessment of drug- autoimmune hepatitis was the subject that was induced liver injury should be the first priority while presented by Altintas et al. It was the subject of the developing dosage form design (Ryder, 2008). Drug-induced liver injury is a growing problem along progesterone for women has been utilized in with complication of drugs prescribed, because the liver gynecological complaints and disorders. But the is for the metabolic disposal of drugs and foreign material. Although drugs are supposed to metabolize dydrogesterone-induced hemolytic anemia has been without damage, the liver damage has been constantly dealt extensively in literature findings. The authors have observed an adverse event. Drugs produce metabolites proposed a case of hepatitis and warm antibody causing liver damage in a single dose fashion. Most drug hemolytic anemia due to dydrogestrone and given its material is a toxic byproduct only in rare individuals. assessment for the possible differentiation in the Injury to hepatocytes results either directly by the diagnosis of hepatitis induction and drug induced disruption of intracellular function or membrane integrity or indirectly by immune-mediated membrane damage. Kazuto (2008), have cited a default study and Genetic alterations in enzymes harmful metabolite furnished the practical guidelines to combat drug- competition in drugs, and depletion of substrates induced liver injury. The range of the drug induced liver required to detoxify the metabolite in the liver so that it injury is both diverse and complex in its onset on liver can be prevented. Drug-induced hepatotoxicity clearly function. Neil Kaplawitz has given detailed description on spelled out the withdrawal of many drugs that produced drug-induced liver injury. The predominant clinical severe liver damage, a potential risk that was not picture is acute hepatitis or cholestasis with clinical recognized in the pre-approval clinical trials. Drug- pathological parameter of acute or chronic liver disease induced liver injury is the leading cause for more than 50 percent of cases of acute liver failure. More than 75 pathogenesis of drug-induced liver disease involves the percent of cases of idiosyncratic drug reactions have participation of the parent drug or metabolite that either given way to option for liver transplantation that has lead directly affects the biochemistry of cells or to elicit an to death in some cases. In order to improve the drug not immune response. Each hepatotoxin is associated with a to resort to drug-induced liver damage the pathogenesis distinctive signature on the pattern of loss and latency. of drug-induced liver damage, common adverse drug Unpredictable, low frequency, reactions occur in the reactions is to be understood in a better experimental background by a higher rate of mild asymptomatic liver and clinical findings and this should be monitored injury and these are difficult to detect by monitoring exclusively to check the types of malaise (William, investigation on development in toxicogenomics and Mechanism of drug-induced liver injury is the choice of proteomics could improve the determination of risk research in many findings and has depicted the factors and exploration of idiosyncratic hepatotoxicity idiosyncratic nature and poor prognosis of drug-induced liver damage exhibit drug reaction and safety and the The recent view of research undertaken on drug- cause of withdrawal of drugs. Drug-induced toxicity is induced liver injury describe that liver metabolizes generated by direct hepatotoxic effects of a drug or its foreign substances and also functionally insert between metabolites. Parenchymal cell damage create the site of absorption and systemic circulation (Tainin, activation of innate and / or adaptive immune cells, 2008). These parameters fulfill the liver with the which combat inflammatory and tissue hepatotoxic mediators and propel immune responses against drug- REFERENCES
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