Review article: drug hepatotoxicity

Background Drug toxicity is the leading cause of acute liver failure in the United States. Further understanding of hepatotoxicity is becoming increasingly important as more drugs come to market. Aims (i) To provide an update on recent advances in our understanding of hepatotoxicity of select commonly used drug classes. (ii) To assess the safety of these medications in patients with pre‐existing liver disease and in the post‐liver transplant setting. (iii) To review relevant advances in toxicogenomics which contribute to the current understanding of hepatotoxic drugs. Methods A Medline search was performed to identify relevant literature using search terms including ‘drug toxicity, hepatotoxicity, statins, thiazolidinediones, antibiotics, antiretroviral drugs and toxicogenomics’. Results Amoxicillin‐clavulanic acid is one of the most frequently implicated causes of drug‐induced liver injury worldwide. Statins rarely cause clinically significant liver injury, even in patients with underlying liver disease. Newer thiazolidinediones are not associated with the degree of liver toxicity observed with troglitazone. Careful monitoring for liver toxicity is warranted in patients who are taking antiretrovirals, especially patients who are co‐infected with hepatitis B and C. Genetic polymorphisms among enzymes involved in drug metabolism and HLA types may account for some of the differences in individual susceptibility to drug hepatotoxicity. Conclusions Drug‐induced hepatotoxicity will remain a problem that carries both clinical and regulatory significance as long as new drugs continue to enter the market. Future results from ongoing multicentre collaborative efforts may help contribute to our current understanding of hepatotoxicity associated with drugs.     

Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

The advances in the drug development that allowed the replacement of many potentially hepatotoxic agents by safer alternatives have been out-weighed by the vast expansion of the total number of agents now available for use. Now, rare adverse reactions to several commonly prescribed medications contribute to the total burden of drug-induced liver injury. Studies involving well-characterised patients with diclofenac-induced hepatotoxicity indicate that multiple steps are involved in the development of liver injury. Individual susceptibility to idiosyncratic hepatotoxicity is determined by the interaction of metabolic and immunological factors. Immunomodulatory and anti-inflammatory cytokines, such as IL-10, may have a protective role in reducing drug-induced liver injury. Understanding the mechanisms of idiosyncratic hepatotoxicity may increase our ability to identify susceptible individuals and hence, prevent serious adverse reactions.     

Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

The advances in the drug development that allowed the replacement of many potentially hepatotoxic agents by safer alternatives have been out-weighed by the vast expansion of the total number of agents now available for use. Now, rare adverse reactions to several commonly prescribed medications contribute to the total burden of drug-induced liver injury. Studies involving well-characterised patients with diclofenac-induced hepatotoxicity indicate that multiple steps are involved in the development of liver injury. Individual susceptibility to idiosyncratic hepatotoxicity is determined by the interaction of metabolic and immunological factors. Immunomodulatory and anti-inflammatory cytokines, such as IL-10, may have a protective role in reducing drug-induced liver injury. Understanding the mechanisms of idiosyncratic hepatotoxicity may increase our ability to identify susceptible individuals and hence, prevent serious adverse reactions.     

Drug-induced hepatotoxicity in cancer patients - implication for treatment

ABSTRACT

Introduction: All anticancer drugs can cause idiosyncratic liver injury. Therefore, hepatoprotective agents assume particular importance to preserve liver function. Hepatic injury represents 10% of cases of acute hepatitis in adults; drug-related damage is still misjudged because of relative clinical underestimation and difficult differential diagnosis. Chemotherapeutic agents can produce liver toxicity through different pathways, resulting in different categories of liver injuries, but these drugs are not homogeneously hepatotoxic. Frequently, anticancer-induced hepatotoxicity is idiosyncratic and influenced by multiple factors.

Areas covered: The aim of this paper is to perform a review of the literature regarding anticancer-induced liver toxicity. We described hepatotoxicity mechanisms of principal anticancer agents and respective dose reductions. Furthermore, we reviewed studies on hepatoprotectors and their optimal use. Tiopronin, magnesium isoglycyrrhizinate and S-Adenosylmethionine (AdoMet) demonstrated, in some small studies, a potential hepatoprotective activity.

Expert Opinion: Actually, in the literature only small experiences are reported. Even though hepatoprotective agents seem to be useful in the oncologic setting, the lack of well-designed prospective Phase III randomized controlled trials is a major limit in the introduction of hepatoprotectors in cancer patients and these kind of studies are warranted to support their use and to give further recommendations for the clinical practice.     

Looking beyond highly active antiretroviral therapy: drug-related hepatotoxicity in patients with human immunodeficiency virus infection

Management of human immunodeficiency virus (HIV) has become increasingly complex since the introduction of highly active antiretroviral therapy (HAART). Patients with HIV have become exposed to an increasing array of drugs to treat HIV, prevent opportunistic infections and immune dysfunction, and manage comorbid illnesses and therapeutic complications. Hepatic complications have become common and may lead to discontinuation of treatment and significant morbidity. Up to 90% of patients with acquired immunodeficiency syndrome (AIDS) receive at least one drug that can cause hepatotoxicity. Clinicians treating patients with HIV frequently face difficulty distinguishing abnormal liver transaminase levels and toxicities in patients receiving several drugs. Some potential causes of hepatic dysfunction are viral infections, alcohol and substance abuse, and hepatotoxic drugs such as HAART. Recent reports have focused on the hepatotoxicity of HAART and the role of hepatitis viruses to the exclusion of many other agents prescribed for patients with HIV. Many of the common antibiotics, antifungals, antivirals, and ancillary agents prescribed for patients with HIV are independently associated with hepatotoxicity. Clinicians should be aware of the potential non-antiretroviral hepatotoxic agents that are frequently administered in HIV management.     

Oxidative stress mediates drug-induced hepatotoxicity in rats: a possible role of DNA fragmentation

Sodium diethyldithiocarbamate, diclofenac and ketoconazol are three important chemotherapeutic agents that are commonly associated with hepatotoxicity. This study was undertaken to provide a better understanding of the mechanism through which these drugs induce hepatotoxicity. Some of the possible mechanisms underlying such modulation were investigated. The hepatotoxic activity of sodium diethyldithiocarbamate (800 mg kg(-1)); diclofenac (200 mg kg(-1)) and ketoconazol (100 mg kg(-1)) were investigated in vivo through the assessment of liver functions, lipid peroxidation and histopathological examination. It was found that all drugs have induced severe hepatic damage as evidenced by the elevation serum aminotransferase activities and confirmed by histological changes of liver. In addition, the drug-induced hepatotoxicity was also associated with massive liver DNA fragmentation and an increase in lipid peroxidation. These results strongly suggest a positive correlation between hepatotoxicity and DNA fragmentation. Moreover, this study also implicates calcium as a potential mediator of the drug-induced oxidative stress associated with hepatotoxicity.     

Evaluation of hepatotoxic potential of drugs by inhibition of bile-acid transport in cultured primary human hepatocytes and intact rats.

Inhibition of canalicular bile acid efflux by medications is associated with clinical liver toxicity, sometimes in the absence of major liver effects in experimental species. To predict the hepatotoxic potential of compounds in vitro and in vivo, we investigated the effect of clinical cholestatic agents on [3H]taurocholic acid transport in regular and collagen-sandwich cultured human hepatocytes. Hepatocytes established a well-developed canalicular network with bile acid accumulating in the canalicular lumen within 15 min of addition to cells. Removing Ca2+ and Mg2+ from the incubation buffer destroyed canalicular junctions, resulting in bile acid efflux into the incubation buffer. Canalicular transport was calculated based on the difference between the amount of bile acid effluxed into the Ca/Mg2+-free and regular buffers with linear efflux up to 10 min. Hepatocytes cultured in the nonsandwich configuration also transported taurocholic acid, but at 50% the rate in sandwiched cultures. Cyclosporin A, bosentan, CI-1034, glyburide, erythromycin estolate, and troleandomycin inhibited efflux in a concentration-dependent manner. In contrast, new generation macrolide antibiotics with lower incidence of clinical hepatotoxicity were much less potent inhibitors of efflux. An in vivo study was conducted whereby glyburide or CI-1034, administered iv to male rats, produced a 2.4-fold increase in rat total serum bile acids. A synergistic 6.8-fold increase in serum total bile acids was found when both drugs were delivered together. These results provide methods to evaluate inhibitory effects of potentially cholestatic compounds on bile-acid transport, and to rank compounds according to their hepatotoxic potential.     

Mechanisms and outcomes of drug- and toxicant-induced liver toxicity in diabetes

Increase dincidences of hepatotoxicity have been observed in diabetic patients receiving drug therapies. Neither the mechanisms nor the predisposing factors underlying hepatotoxicity in diabetics are clearly understood. Animal studies designed to examine the mechanisms of diabetes-modulated hepatotoxicity have traditionally focused only on bioactivation/detoxification of drugs and toxicants. It is becoming clear that once injury is initiated, additional events determine the final outcome of liver injury. Foremost among them are two leading mechanisms: first, biochemical mechanisms that lead to progression or regression of injury; and second, whether or not timely and adequate liver tissue repair occurs to mitigate injury and restore liver function. The liver has a remarkable ability to repair and restore its structure and function after physical or chemical-induced damage. The dynamic interaction between biotransformation-based liver injury and compensatory tissue repair plays a pivotal role in determining the ultimate outcome of hepatotoxicity initiated by drugs or toxicants. In this review, mechanisms underlying altered hepatotoxicity in diabetes with emphasis on both altered bioactivation and liver tissue repair are discussed. Animal models of both marked sensitivity (diabetic rats) and equally marked protection (diabetic mice) from drug-induced hepatotoxicity are described. These examples represent a remarkable species difference. Availability of the rodent diabetic models offers a unique opportunity to uncover mechanisms of clinical interest in averting human diabetic sensitivity to drug-induced hepatotoxicities. While the rat diabetic models appear to be suitable, the diabetic mouse models might not be suitable in preclinical testing for potential hepatotoxic effects of drugs or toxicants, because regardless of type 1 or type2 diabetes, mice are resistant to acute drug-or toxicant-induced toxicities.     

Thalidomide-induced severe hepatotoxicity

Thalidomide is a relatively safe and efficacious form of therapy in the treatment of advanced, refractory multiple myeloma. Hepatotoxicity is listed as an extremely rare adverse effect associated with its use. We describe a 76-year-old woman with multiple myeloma who was treated with dexamethasone and thalidomide. By week 6 of therapy, she had developed acute increases in her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to more than 50 times the upper limit of normal. Her liver function test results had been within the normal ranges before and immediately after the start of therapy, and the patient had no known history of underlying liver disease. A liver biopsy specimen demonstrated evidence of acute injury with chronic changes of underlying steatosis and bridging fibrosis due to previously undiagnosed nonalcoholic steatohepatitis. Immediately after discontinuing thalidomide, her liver function test results began trending downward. Seven days later, her AST and ALT levels had improved to 86 and 165 U/L, respectively. This case and a limited number of other reports demonstrate severe hepatotoxicity as a rare but potentially serious adverse effect of thalidomide therapy. With the expanding use of thalidomide as a therapeutic agent, clinicians must recognize severe hepatotoxicity as a potential complication. Whether patients with preexisting liver disease are at increased risk when receiving thalidomide remains to be seen.     

Development of a cell-based assay system considering drug metabolism and immune- and inflammatory-related factors for the risk assessment of drug-induced liver injury

Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical pharmacotherapy. However, prediction of DILI is difficult because the underlying mechanisms are not fully understood. To establish a novel cell-based screening system to suggest drugs with hepatotoxic potential in preclinical drug development, comprehensive gene expression analyses during in vivo DILI are necessary. Using in vivo mouse DILI models and 4 sets of hepatotoxic positive and non-hepatotoxic drugs, we found that the hepatic mRNA levels of S100A8; S100A9; “NATCH, LRR, and pyrin domain-containing protein 3” (NALP3); interleukin (IL)-1β; and the receptor for advanced glycation endproducts (RAGE) were commonly increased in hepatotoxic drug-administered mice compared to non-hepatotoxic drug-administered mice. To clarify whether these 5 in vivo biomarkers can be applied to a cell-based screening system, we adapted human liver microsomes (HLM) in the presence of NADPH to assess the metabolic activation reaction, and we also adapted human monocytic leukemia cells HL-60, K562, KG-1 and THP-1 to assess the effects on mRNA expression of immune- and inflammatory-related factors. We investigated 30 clinical drugs with different safety profiles with regard to DILI and found that the total sum score of gene expression levels of S100A8, S100A9, RAGE, NALP3 and IL-1β mRNA in HL-60 or K562 cells incubated with HLM, could identify drugs at high risk for hepatotoxicity. We proposed the use of the total sum score of gene expression level for assessing metabolic activation by drug-metabolizing enzymes and immune- and inflammatory-related factors for the risk assessment of DILI in preclinical drug development.     

Hepatotoxic profile of catecholOmethyltranferase inhibitors in Parkinson’s disease

Entacapone and tolcapone are selective catechol-O-methyltransferase (COMT) inhibitors developed recently as adjuncts to levodopa for the treatment of Parkinson’s disease (PD). They extend the duration of action of levodopa. As a result, they increase ‘on’ time, decrease ‘off’ time and improve motor scores in patients with motor fluctuations. Both benefits and main side effects are related to increased dopaminergic activity. This paper reviews the use of those COMT inhibitors in PD with particular focus on the issue of hepatotoxicity. Neither tolcapone nor entacapone caused hepatotoxicity in preclinical studies. However, in 1998, four patients who were using tolcapone presented with serious liver dysfunction; three of them died due to acute liver failure. Tolcapone is now known to have the potential to cause hepatotoxicity in clinical use and experimental studies. It is now recommended that tolcapone be administered only in patients with motor fluctuations who are no longer satisfactorily treated with other medications for PD. Routine liver monitoring is now mandatory with this agent. Entacapone has been described as a well-tolerated and safe drug in recent experimental studies, human clinical trials and postmarketing surveillance. It can be offered to any patient with motor fluctuations and routine liver monitoring is not required.     

216例药物性肝炎的临床分析

目的：提高对药物性肝炎的认识。方法：对216例药物性肝炎的发病规律及临床特征进行分析。结果：药物性肝炎多发生于长期、联合使用有肝毒性的药物而又无肝功监测的患者，多见于农民及工人。多发生于服药后十天至一个月。有HBsAg阳性者更易发生药物性肝炎及重症肝炎，且病死亡率高。结论：影响药物性肝炎的因素有患者的文化程度、药物的种类、用药时间、联合用药、HBsAg阳性、肝功能的监测等。     

Hepatotoxic profile of catechol-O-methyltransferase inhibitors in Parkinson's disease

Entacapone and tolcapone are selective catechol-O-methyltransferase (COMT) inhibitors developed recently as adjuncts to levodopa for the treatment of Parkinson's disease (PD). They extend the duration of action of levodopa. As a result, they increase 'on' time, decrease 'off' time and improve motor scores in patients with motor fluctuations. Both benefits and main side effects are related to increased dopaminergic activity. This paper reviews the use of those COMT inhibitors in PD with particular focus on the issue of hepatotoxicity. Neither tolcapone nor entacapone caused hepatotoxicity in preclinical studies. However, in 1998, four patients who were using tolcapone presented with serious liver dysfunction; three of them died due to acute liver failure. Tolcapone is now known to have the potential to cause hepatotoxicity in clinical use and experimental studies. It is now recommended that tolcapone be administered only in patients with motor fluctuations who are no longer satisfactorily treated with other medications for PD. Routine liver monitoring is now mandatory with this agent. Entacapone has been described as a well-tolerated and safe drug in recent experimental studies, human clinical trials and postmarketing surveillance. It can be offered to any patient with motor fluctuations and routine liver monitoring is not required.     

Hepatotoxicity in patients with liver disease.

The biochemical and physiological disturbances caused by liver disease may enhance the toxicity of drugs. Besides alterations in liver blood flow and drug binding, a decreased rate of drug metabolism is an important phenomenon. Studies with phenazone, a model drug, demonstrates that the rate of microsomal drug metabolism is related to the degree of metabolic hepatic impairment. Individual dosage adjustments in patients with liver disease are complicated for many drugs, because of the counteracting influences of a decreased hepatic blood clearance and an increased free fraction of drug which may enhance drug metabolism and drug action. Moreover, many drugs owe part of their pharmacological action to active metabolites formed in the liver. Finally, little is known about altered receptor sensitivity in patients with liver disease. Non-predictable hepatotoxic reactions appear not to occur more frequently in patients with liver disease than in other patients. However, hepatotoxicity may be masked by the liver disease or by the intake of ethanol.     

Hepatotoxicity and metabolism of trabectedin: a literature review.

Trabectedin is a promising anticancer drug currently undergoing phase II evaluation. In preclinical studies, trabectedin was found to cause hepatotoxicity and in patients it reversibly increases plasma levels of liver enzymes. On the basis of preclinical work, it was suggested that metabolism of trabectedin contributed to the pharmacological effects of trabectedin, including hepatotoxicity in rats and increases in liver enzymes in humans. Our aim was to review the current literature on the metabolism of trabectedin and its role in the increases in liver enzymes and hepatotoxicity. We conclude that the trabectedin metabolic profile appears to predict the reversible nature of hepatotoxicity. The rat may not be the best species to investigate trabectedin hepatotoxicity because both trabectedin metabolic profile and reversibility of hepatotoxicity differs from humans. Humans and monkeys display a similar metabolic profile of trabectedin and in both species hepatotoxicity is reversible. Trabectedin is a drug with predictable hepatotoxic effects. Monitoring of plasma levels of liver enzymes ensures safe use of trabectedin in the clinic. Future investigations must be aimed at elucidating the mechanism of trabectedin hepatotoxicity.     

Leflunomide for the treatment of rheumatoid arthritis in clinical practice: incidence and severity of hepatotoxicity.

OBJECTIVE: Leflunomide is a novel disease modifying antirheumatic drug (DMARD). Because of reports on possible hepatotoxicity and adaptations in the recommendations for monitoring liver function during leflunomide treatment, we conducted a study to evaluate the incidence and severity of hepatotoxicity. METHODS: We included consecutive rheumatoid arthritis patients starting treatment with leflunomide in the region of Friesland (The Netherlands) between January 2000 and January 2002. During follow-up patient characteristics, disease characteristics, and clinical and laboratory data on liver functions were registered. Severity of hepatotoxicity was categorised using the National Cancer Institute Common Toxicity Criteria, as moderate (grade 2), severe (grade 3) or life threatening (grade 4). RESULTS: One hundred and one patients were followed for a median period of 10 months (range 0.5-12). Grade 2 or 3 elevations in any liver function blood test were recorded in a total of nine patients (8.9%). No grade 4 elevations were recorded. Four patients (4%) showed grade 2-3 aminotransferase elevations. Due to grade 2 hepatotoxicity one patient (1%) was withdrawn from leflunomide treatment, and one patient continued leflunomide at a reduced dose. In eight of nine patients with grade 2-3 liver function blood tests, these elevated liver function tests occurred within 6 months after starting leflunomide. None of the patients with grade 2 or 3 toxicity had a history of hepatic disease, eight patients concomitantly used potential hepatotoxic co-medication. Eight (8%) patients used leflunomide in combination with methotrexate, and one of these patients developed hepatotoxicity. No clinical signs of serious hepatotoxicity were recorded during follow-up. DISCUSSION: In 8.9% of the patients, grade 2 or 3 hepatotoxicity was recorded within the first year after the start of leflunomide therapy based on liver enzyme determinations. In the majority of the patients liver enzyme elevations occurred within the first 6 months of therapy and resolved during continued follow-up. None of the patients showed clinical signs of hepatotoxicity. CONCLUSION: Under continued monitoring of liver functions hepatotoxicity during leflunomide use does not seem to be a major problem in our population.     

A zebrafish phenotypic assay for assessing drug-induced hepatotoxicity

IntroductionNumerous studies have confirmed that zebrafish and mammalian toxicity profiles are strikingly similar and the transparency of larval zebrafish permits direct in vivo assessment of drug toxicity including hepatotoxicity in zebrafish.MethodsHepatotoxicity of 6 known mammalian hepatotoxic drugs (acetaminophen [APAP], aspirin, tetracycline HCl, sodium valproate, cyclophosphamide and erythromycin) and 2 non-hepatotoxic compounds (sucrose and biotin) were quantitatively assessed in larval zebrafish using three specific phenotypic endpoints of hepatotoxicity: liver degeneration, changes in liver size and yolk sac retention. Zebrafish liver degeneration was originally screened visually, quantified using an image-based morphometric analysis and confirmed by histopathology.ResultsAll the tested mammalian hepatotoxic drugs induced liver degeneration, reduced liver size and delayed yolk sac absorption in larval zebrafish, whereas the non-hepatotoxic compounds did not have observable adverse effect on zebrafish liver. The overall prediction success rate for hepatotoxic drugs and non-hepatotoxic compounds in zebrafish was 100% (8/8) as compared with mammalian results, suggesting that hepatotoxic drugs in mammals also caused similar hepatotoxicity in zebrafish.DiscussionLarval zebrafish phenotypic assay is a highly predictive animal model for rapidly in vivo assessment of compound hepatotoxicity. This convenient, reproducible animal model saves time and money for drug discovery and can serve as an intermediate step between cell-based evaluation and conventional animal testing of hepatotoxicity.     

Drug-induced liver injury: results from the hospital-based Berlin Case–Control Surveillance Study

Aim

Drug-induced liver injury (DILI) is often responsible for acute liver failure, drug withdrawal, boxed warnings or drug non-approval. Therefore, we conducted a case–control study to determine the hepatotoxic risk of a wide range of drugs.

Methods

The Berlin Case–Control Surveillance Study FAKOS included all 51 Berlin hospitals in a hospital network. Between 2002 and 2011, 198 patients with acute idiopathic hepatitis, 377 inpatient controls and 708 outpatient controls were ascertained. Case patients were thoroughly validated using anamnestic, clinical, laboratory and histological data. Drug exposure was obtained in a face-to-face interview. A possible drug aetiology was assessed in individual patients by applying the updated Council for International Organizations of Medical Sciences (CIOMS) scale. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case–control design with unconditional logistic regression analysis. Drug intake in the last 28 days before index date was considered for the analysis.

Results

The study corroborated hepatotoxic risks for a number of drugs, including phenprocoumon (OR 3.3, 95% CI 1.5, 6.7), amiodarone (OR 5.5, 95% CI 1.3, 21.2), clozapine (OR 34.6, 95% CI 2.8, 824.9) and flupirtine (OR 40.2, 95% CI 5.5, 856.9). Increased risks were also suggested for less commonly reported substances such as angiotensin II receptor blockers, atypical antipsychotics and for biperiden, a drug never before reported to be hepatotoxic.

Conclusions

Our study identified a large number of drugs as possible causes of hepatotoxicity. The observed risk for seldom reported substances highlights the need for further post-authorization safety studies not exclusively focusing on drugs already labelled as potentially hepatotoxic.