Nonsteroidal Anti-Inflammatory Drug–Induced Hepatoxicity

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<ul><li><p>Nonsteroidal Anti- InflammatoryDrugInduced Hepatoxicity</p><p>Alberto Unzueta, MDa, Hugo E. Vargas, MDb,*</p><p>INTRODUCTION</p><p>Since recognition of the first cases of nonsteroidal anti-inflammatory drug (NSAIDs)induced hepatotoxicity the incidence has been considered very rare, mainly becauseof the idiosyncratic cause of drug-induced liver injury (DILI). With the more widespreaduse of these prescription and over-the-counter medications, well-described DILI withacute liver failure (ALF) leading to transplantation and death in relationship to theseagents has been reported. However, most of the cases associated with DILI causedby NSAIDs (N-DILI) are asymptomatic or mild, and only in a minority of cases hassevere hepatotoxicity been described.</p><p>vard, Phoenix, AZ85054, USA; b Division of Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ</p><p>lent with some evidence of cross-reactivity among some NSAIDs. A higher incidence ofDILI has been described with diclofenac and sulindac.</p><p> A genetic predisposition to develop DILI has been found with some NSAIDs (diclofenacand lumiracoxib). Pharmacogenomic studies are a promising way to evaluate individualsor populations with predisposition to DILI.</p><p> Use of NSAIDs in patients with coexisting liver or renal disease and who are taking otherpotential hepatotoxic medications must be avoided because this could increase thepotential for severe hepatotoxicity.85054, USA* Corresponding author.E-mail address:</p><p>Clin Liver Dis 17 (2013) 643656a Division of Hospital Internal Medicine, Mayo Clinic, 5777 East Mayo Bouleimportant to detect severe cases of hepatotoxicity.</p><p> Among currently approved NSAIDs the safety profile for severe hepatotoxicity is equiva-KEYWORDS</p><p> Nonsteroidal anti-inflammatory drugs Drug-induced liver injury Acute liver injury Liver transplantation Idiosyncratic hepatotoxicity Hys law Drug safety Drug surveillance</p><p>KEY POINTS</p><p> The mechanism of hepatotoxicity associated with NSAIDs is mainly idiosyncratic and hasa very low incidence compared with the widespread use of NSAIDs worldwide.</p><p> Surveillance and monitoring after approval of new medications and NSAIDs is extremely liver.theclinics.com1089-3261/13/$ see front matter 2013 Elsevier Inc. All rights reserved.</p></li><li><p>Unzueta &amp; Vargas644Several cases of NSAIDs withdrawn from the market (bromfenac, benoxaprofen,and lumiracoxib) illustrate the relevance of postmarketing monitoring to detect severecases of liver injury. The incremental regulations and restrictions applied by somecountries in the use of NSAIDs, such as nimesulide, are relevant to prevent new casesof severe hepatotoxicity. Most of these regulations are based on reports of isolatedcases because epidemiologic studies have not clearly revealed evidence of severehepatotoxicity with most NSAIDs.The development of cyclooxygenase-2 (COX-2) inhibitors opened a promising era</p><p>for NSAIDs because of the significant decrease in gastrointestinal side effects. How-ever, the evidence of severe cardiovascular events led to the withdrawal of rofecoxibin 2004 and significantly limited the use of celecoxib with a boxed warning by theFood and Drug Administration (FDA). DILI is a rare event but currently is the most com-mon cause of ALF in the United States, hence the diagnosis of N-DILI is of clinicalrelevance.</p><p>DRUG-INDUCED LIVER INJURY</p><p>Idiosyncratic DILI is defined as an unexpected hepatic adverse drug reaction of anindividual to the pharmacologic action of a drug. DILI has been recognized as themost common cause of ALF in the United States.1 Acetaminophen is responsiblefor approximately half of cases and nonacetaminophen DILI is implicated in 7% to15% of cases in the United States and Europe.24 The most common drugs associ-ated with DILI are antibiotics, antiepileptic drugs, and NSAIDs.5,6 Hepatotoxicity isalso one of the main reasons for nonapproval of new medications by the FDA. Theincidence of DILI has been calculated in a prospective population study in Franceas 14 cases in 100,000 people with a rate of 6% fatality7; however, the true incidenceis unknown because of underreporting and lack of diagnostic standards. Hospitaliza-tions associated with DILI are rare but the mortality associated with ALF issignificant.8</p><p>Diagnostic Criteria for DILI</p><p>An international DILI Expert Working Group has recently published guidelines forthe diagnosis and classification of DILI.9 One of the following criteria need to bepresent: (1) greater than or equal to 5 Upper Limit of Normal (ULN) level foralanine aminotransferase (ALT); (2) greater than or equal to 2 ULN for alkalinephosphatase (AP); or (3) greater than or equal to 3 ULN for ALT and greaterthan 2 ULN for bilirubin. These criteria aim to guide the standardization ofresearch in DILI and also to help diagnose drug hepatotoxicity.</p><p>Clinical Patterns of DILI</p><p>Three types of liver damage based on ALT, AP, and bilirubin levels are currentlyconsidered. Hepatocellular is the most common followed by mixed and cholestatic.Liver biopsy is not necessary for diagnosis in most cases because there are notspecific histologic criteria for diagnosis of DILI. The pattern of liver injury is definedby R value, where R 5 (ALT/ULN)(ALP/ULN), hepatocellular pattern: R 5, mixedpattern: R &gt;2 and </p></li><li><p>hand. In June 1998, the manufacturer voluntarily withdrew bromfenac less than 1 year</p><p>NSAIDs Hepatotoxicity 645after its approval after reports of four deaths and eight cases of ALF necessitating livertransplantation.21</p><p>The bromfenac case illustrates nonallergic, idiosyncratic drug-related hepatotoxic-ity.22 Hepatocyte necrosis was associated with cumulative doses of this NSAID.23 Inthe preapproval trials, one case of possible hepatocellular injury associated with jaun-dice was detected, leading to a projected incidence of ALF of 1 per 10,000 (Hyslaw).21 In hindsight, questions arose about whether the detection of even one casethat invoked Hys law (severe hepatocellular jaundice) and the presence of symptom-atic hepatitis in other cases might have prevented approval of the drug and the sub-sequent postapproval morbidity and mortality.24 It is also relevant that severehepatotoxicity developed in most patients who took the medication for a longertime than the FDA guidelines and that labeling instructions for short-term use werenot followed by physicians or patients.12 Because the incidence of idiosyncratic se-vere hepatotoxicity with NSAIDs is rare, the number of afflicted subjects required inthe preapproval process to trigger concerns of severe hepatotoxicity is an importantfact to consider.The relevance of surveillance and monitoring programs, and the report of single</p><p>cases by physicians (FDA MEDWATCH), is crucial in the evaluation of drugs withHys case consists of hepatocellular damage with increase in bilirubin and clinicaljaundice with minimal elevation of AP (elevations of aminotransferases &gt;3 ULNand serum bilirubin &gt;2 ULN). This has been associated with ALF and approxi-mately 10% mortality or need for liver transplantation.5 It is considered a safetybiomarker by the FDA that identifies a subgroup of patients with high risk of liverinjury.14 The grading of the severity of DILI has been recently proposed as mild,moderate, severe, and fatal or transplantation based on common laboratory valuesthat assess liver disease.9</p><p>Clinical Resources</p><p>Liver tox ( is a comprehensive World Wide Webbased resourcecreated in 2012 by the DILI network that provides current clinical information regardingapproximately 600 drugs currently approved by the FDA in the United States. It pro-vides illustrative clinical cases and can also generate causality assessment scoresof individual cases based on RUCAM diagnostic instrument.15 A compilation of drugsthat have been associated with ALF reported to major registries and other databaseshas been created.16</p><p>SEVERE HEPATOTOXICITY ASSOCIATED WITH NSAIDSThe Bromfenac, Benoxaprofen, and Lumiracoxib Cases</p><p>The history of bromfenac illustrates the challenges involved in detecting N-DILI. Brom-fenac, a phenylaceticacid-derivative NSAID, was approved by the FDA in 1997 for themanagement of acute orthopedic pain, with recommended use of no more than10 days. During the 4 months after its approval, numerous individual reports andcase series were published that documented resultant ALF requiring liver transplanta-tion or causing death.1720 A systematic review of NSAIDs withdrawn from the US andUK market (bromfenac, ibufenac, and benoxaprofen) found no published clinical trialsof bromfenac before its approval.21 The preapproval public FDA database includedthree clinical trials with 1195 subjects. Transaminase elevations greater than 3XULN were detected in 2.8% of subjects, most of whom had flu-like symptoms before-potentially severe hepatotoxicity. This is exemplified by a cautionary footnote from</p></li><li><p>Unzueta &amp; Vargas646the editors of the British Medical Journal in a letter to the editor reporting two cases ofbenoxaprofen-related fatal cholestatic jaundice25:</p><p>We have received several other letters describing side effects of benoxaprofen butfor reasons of space we suggest that further case reports should be forwarded tothe Committee on Safety of Medicines.25</p><p>ED, BMJ</p><p>A previous report of five elderly women with cholestatic jaundice and ALF associ-ated with benoxaprofen had been published by the journal.26 Benoxaprofen is anNSAID that was approved in the United States in April 1982 and was withdrawnfrom the market 4 months later, after numerous reports of severe hepatotoxicity inthe United States and United Kingdom. Although there were no case reports publishedin the United States, the FDA received numerous reports of liver injury associated withbenoxaprofen.27</p><p>Lumiracoxib is a selective COX-2 inhibitor structurally related to diclofenac. It is thelatest NSAID withdrawn from the market because of association with severe DILI. Itwas never approved for use in the United States. Lumiracoxib illustrates, as in thecase with bromfenac and benoxaprofen, the importance of postmarketing monitoringto detect severe cases of N-DILI that were not expected in preapproval clinicaltrials.28 The Therapeutic Arthritis Research and Gastrointestinal Event Trial, a ran-domized clinical trial comparing lumiracoxib with naproxen and ibuprofen, found ele-vations of aminotransferases greater than three times ULN that was significantbetween lumiracoxib (2.57%; N 5 230) and NSAIDs (0.63%; N 5 56); odds ratio,3.97 (confidence interval [CI], 2.965.32). Six cases of clinical hepatitis were detectedin the lumiracoxib group; all of them improved after the drug was stopped and no re-ports of liver failure were seen.29,30 During clinical trials lumiracoxib showed a prom-ising cardiovascular and gastrointestinal safety profile. However, the drug waswithdrawn in Europe and Australia (2007) because of reports of approximately 20cases of severe hepatotoxicity that included 14 cases with ALF with two deathsand three liver transplants.28,31,32 A genome-wide association study found anincreased risk for DILI in lumiracoxib users with the HLA-DQA1*0102 allele.33 Thereis an increasing number of drugs that have been linked to human leukocyte antigengenotypes.34 In the future, the use of pharmacogenetic studies could play a meaning-ful role in the evaluation of the hepatotoxicity of drugs by the identification of geneticrisk factors for susceptible populations.35</p><p>Nimesulide: A Case of Incremental Regulation to Prevent Hepatotoxicity</p><p>Nimesulide is an NSAID that belongs to the class of the sulphonanilides (the onlyNSAID in this group). It was initially approved in Italy in 1985 and is available inmore than 50 countries.36 Some countries, such as the United States, Canada,England, Japan, Australia, and New Zealand, never approved its use. Several otherEuropean countries, such as Finland, Spain, Ireland, Portugal, and a handful in otherparts of the world (Argentina, Uruguay, and Singapore) withdrew the medication sec-ondary to concerns of severe hepatotoxicity based on published reports.36,37 Nimesu-lide has continued to be prescribed widely and is commonly used in Italy and othercountries.38 Epidemiologic population-based reports have not confirmed an increasedrisk of severe hepatotoxicity compared with other commonly used NSAIDs.39 AConsensus Report Group on nimesulide in 2005 found a positive risk-benefit ratio interms of gastrointestinal side effects and hepatotoxicity.40 However, in 2007, theEuropean Medicines Agency issued restrictions for prescription of nimesulide as a</p><p>second-line therapy. In 2011, new European restrictions limited nimesulide for use</p></li><li><p>Among nongenetic factors age, gender, use of other hepatotoxic drugs, and other</p><p>NSAIDs Hepatotoxicity 647conditions, such as chronic liver diseases, OA, RA, or human immunodeficiency infec-tion, have been implicated.49,50 A predisposition of N-DILI in patients with metabolicsyndrome and steatosis has been proposed.51 Genetic factors of N-DILI have beenin acute pain and primary dysmenorrhea because of concerns that long-term use willincrease the risk of liver injury.41</p><p>EPIDEMIOLOGY OF NSAID-INDUCED HEPATOTOXICITY</p><p>In part because of the heterogeneity of this drug class and the relative safety of theseagents, the incidence of N-DILI in several population-based studies has been esti-mated to be low and ranging from 0.29 to 9 per 100,000 patient-years.42</p><p>A prospective double-blind trial of diclofenac (N 5 17,289 patients) versus etori-coxib (N 5 17,412 patients) for rheumatoid arthritis (RA) or osteoarthritis (OA) with amean follow-up of 18 months found no increased incidence in hospitalizations or mor-tality associated with either NSAID.43 There were four cases of liver injury (0.023%)and two cases of severe hepatocellular jaundice (0.012%), but no cases of liver failure,transplantation, or death. Patients with preexisting liver disease or alcohol abuse wereexcluded from the study.A postmarketing surveillance study from the reimbursement database of National</p><p>Health Insurance in Taiwan reported 4519 hospitalizations associated with acute hep-atitis (viral and other hepatobiliary pathology excluded). This led the investigators toconclude that there was an increased incidence of hospitalizations associated withN-DILI (acute/subacute necrosis, toxic hepatitis) from 2001 to 2004.44 The odds ratiosfor nimesulide-, diclofenac-, ibuprofen-, and celecoxib-related DILI were considerablyincreased.A case/noncase study that analyzed the databases of the US FDA and the World</p><p>Health Organization for the proportion of reports of events associated with N-DILIfound an increased rate of hepatotoxicity associated with nimesulide (16.7% vs14.4%), bromfenac (12% vs 20.7%), diclofenac (8.1% vs 4.7%), and sulindac (6.1%vs 9.9%), compared with that of other NSAIDs.45</p><p>A comparison of pharmacovigilance databases from Spain and France from 1982 to2001 using a case/noncase method revealed differences in NSAID hepatotoxi...</p></li></ul>


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