Rofecoxib-induced hepatotoxicity: A forgotten complication of the … · 2019. 8. 1. · Rofecoxib is a member of the coxib family of nonsteroidal anti-inflammatory drugs that selectively

Can J Gastroenterol Vol 20 No 5 May 2006 351

Rofecoxib-induced hepatotoxicity: A forgotten complication of the coxibs

Brian Yan MD1, Yvette Leung MD1, Stefan J Urbanski MD2, Robert P Myers MD1

1Liver Unit, Division of Gastroenterology, Department of Medicine; 2Department of Pathology, University of Calgary; Calgary, AlbertaCorrespondence: Dr Robert P Myers, G126, 3330 Hospital Drive North West, Calgary, Alberta T2N 4N1. Telephone 403-210-9837,

fax 403-210-9368, e-mail [email protected] for publication May 1, 2005. Accepted January 9, 2006

B Yan, Y Leung, SJ Urbanski, RP Myers. Rofecoxib-induced

hepatotoxicity: A forgotten complication of the coxibs. Can J

Gastroenterol 2006;20(5):351-355.

Rofecoxib is a member of the coxib family of nonsteroidal anti-inflammatory drugs that selectively inhibit cyclooxygenase-2. Althoughthe coxibs are generally well-tolerated, rofecoxib was recently with-drawn from the market due to concerns regarding cardiovascularsafety. Rare cases of hepatic injury attributable to the coxibs havebeen reported. In the present study, two additional cases of severehepatotoxicity are described in patients with cholestatic symptomsand abnormal liver biochemistry, shortly following the initiation ofrofecoxib for arthritic complaints. In both cases, liver histology wascompatible with drug-induced hepatotoxicity, and rapid clinical andbiochemical improvements were observed following rofecoxibdiscontinuation. With new coxibs and expanding indications on thehorizon, physicians in all areas of practice must be aware of this disorderand consider it in any patient who develops hepatic dysfunction aftertaking a coxib.

Key Words: Adverse effects; Cholestasis; Coxib; Drug toxicity;

Hepatitis; Rofecoxib

L’hépatotoxicité du rofécoxib : complicationoubliée des coxibs

Le rofécoxib fait partie de la famille des coxibs, anti-inflammatoires non

stéroïdiens qui entravent de façon sélective la cyclo-oxygénase-2. Même

si les coxibs se tolèrent généralement bien, le rofécoxib a été retiré

dernièrement du marché pour des raisons de nocuité cardiovasculaire. De

rares cas d’atteinte hépatique, attribuable aux coxibs ont déjà été signalés.

La présente étude fait état de deux autres cas d’hépatotoxicité grave, se

traduisant par des symptômes cholestatiques et des analyses biochimiques

anormales du foie peu après l’amorce d’un traitement au rofécoxib pour

des douleurs arthritiques. Dans les deux cas, l’examen histologique du foie

était compatible avec une réaction hépatotoxique d’origine médica-

menteuse, et l’arrêt du traitement au rofécoxib a été suivi rapidement

d’une amélioration clinique et biochimique. Compte tenu de l’arrivée de

nouveaux coxibs et de la reconnaissance possible de nouvelles indica-

tions, les médecins, quel que soit leur champ de pratique, devraient être

sensibilisés à l’apparition de cette réaction, et celle-ci devrait être envis-

agée chez tous les patients qui présentent des troubles hépatiques après la

prise d’un coxib.

The coxibs are a class of nonsteroidal anti-inflammatorydrugs (NSAIDs) designed to selectively inhibitcyclooxygenase-2 (COX-2) (1). They have gained widespreadpopularity as analgesics, based on their improvedgastrointestinal safety profile compared with nonselectiveNSAIDs (2,3). However, the cardiovascular safety of the coxibshas come under scrutiny. Due to an increased risk of myocardialinfarction and stroke in the Adenomatous Polyp Prevention onVioxx (APPROVE) study, rofecoxib (Vioxx, Merck and Co Inc,Canada) was recently withdrawn by the manufacturer (4,5). For similar reasons, sales of valdecoxib (Bextra, Pfizer Canada Inc)were recently suspended, but celecoxib (Celebrex, Pfizer Canada Inc) remains on the North American market.

Significant hepatotoxicity due to NSAIDs, including thecoxibs, is uncommon. The estimated annual incidence is one to10 cases per 100,000 exposed individuals (6,7). In the CelecoxibLong-term Arthritis Safety Study (CLASS), 0.6% of celecoxib-treated patients experienced an alanine aminotransferase (ALT)elevation; only 0.2% had an elevation greater than three timesthe upper limit of normal (3). In the present report, wedescribe two cases of severe rofecoxib-induced hepatic injurywith the intention of highlighting this potentially seriouscomplication of the coxibs.

CASE PRESENTATIONSCase 1A 44-year-old Caucasian man presented with a four-day historyof painless jaundice, nausea and malaise two weeks afterbeginning rofecoxib 25 mg daily for osteoarthritis of the knees.The patient had taken rofecoxib on several occasions over thepreceding three years, but only for a few days at a time. Thepatient’s past medical history included noninsulin-dependentdiabetes mellitus, psoriasis and a cutaneous follicular lymphomaof the cheek resected six months before presentation. Long-standing medications included insulin and a corticosteroidointment for psoriasis. The patient denied other recent changesin his medications, ingestion of potential hepatotoxins,significant alcohol consumption or allergies. There were no riskfactors for viral hepatitis or a family history of liver disease.

On examination, the patient was markedly jaundiced; how-ever, there was no sign of chronic liver disease or organomegaly.The patient was afebrile and there was no lymphadenopathy orcutaneous recurrence of lymphoma. Laboratory investigationsrevealed a normal blood count (including absence ofeosinophilia), ALT 1826 U/L (normal less than 60 U/L),alkaline phosphatase (ALP) 741 U/L (normal less than 145 U/L),gamma-glutamyltransferase 897 U/L (normal less than 60 U/L),

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total bilirubin 242 µmol/L (normal less than 17 µmol/L), albumin30 g/L and an international normalized ratio of 1.1. Serum bileacids were markedly elevated (279 µmol/L; normal less than8.2 µmol/L). Antinuclear (ANA) and smooth muscle antibodies,as well as serology for hepatitis A, B, C, Epstein-Barr virus andcytomegalovirus, were negative. Computed tomography of theabdomen revealed two lymph nodes measuring 1 cm in thecardiophrenic and aortocaval regions, and multiple smallperiportal and ileocolic mesenteric lymph nodes. Biliary tractdilation and hepatic space-occupying lesions were excluded. A liver biopsy revealed mononuclear infiltration within the portaltriads and perivenular areas, mild hepatocellular necrosis (Figure 1) and moderate interface hepatitis. Isolated eosinophilswere present (Figure 2). Histologically, cholestasis was notevident. The bile ductular epithelium was normal and there wasno fibrosis or evidence of a lymphoproliferative disorder.

A diagnosis of rofecoxib-induced cholestatic hepatitis wasmade. Rofecoxib was discontinued and ursodeoxycholic acid1500 mg/day was introduced. Within one month, the patient’sbilirubin had fallen to 75 µmol/L, ALP to 212 U/L and ALT to893 U/L. Within two months, the patient’s liver biochemistrynormalized and his symptoms resolved. Six months later, thepatient was asymptomatic, had normal liver biochemistry and hadreceived adjuvant radiotherapy for his lymphoma.

Case 2A 44-year-old Asian woman presented with a two-week history ofanorexia, fatigue, choluria, pruritus and jaundice. The patientbecame unwell 10 weeks before presentation when she developedmigratory arthralgias affecting her wrists, shoulders, knees andtoes with morning stiffness and joint redness. Associatedsymptoms included sore throat, fatigue, myalgias, a 3 kg weightloss and a fluctuating macular rash over her torso and thighs. Shedenied oral ulceration, facial rash, alopecia or other symptomssuggestive of connective tissue disease. Approximately eight weeksbefore presentation (two weeks into her illness), she startedrofecoxib 12.5 mg daily for arthralgia. Within two to three weeks,her arthralgia improved and she continued rofecoxib therapy.

The patient’s medical history included asthma,multinodular goiter and beta-thalassemia trait. Her othermedications included bronchodilators and an oralcontraceptive which was long-standing. She denied ingestion of

alcohol or other potential hepatotoxins. There was no familyhistory of liver disease or risk factors for viral hepatitis.

On examination, the patient was jaundiced, but wasafebrile and had no sign of chronic liver disease,organomegaly or abdominal tenderness. The thyroid wasslightly enlarged and symmetrical with no palpable nodules.Musculoskeletal examination was normal. There was a diffuse,erythematous, macular rash on her face, arms, back and upperthighs. Laboratory investigations included mild microcyticanemia (hemoglobin 117 g/L; mean corpuscular volume69 fL), but normal platelet and white blood cell counts. Theliver biochemistry was as follows: ALT 995 U/L; ALP 243 U/L;gamma-glutamyltransferase 99 U/L; total bilirubin 207 µmol/L;albumin 27 g/L and an international normalized ratio of 1.1.Serology for acute hepatitis A, B and C, and parvovirus B19 wasnegative. The ANA was positive (1:320 in a speckled pattern)but rheumatoid factor and antibodies to smooth muscle, mito-chondria, liver/kidney microsome type I and extractable nuclearantigens (including Jo-1, ribonucleoprotein, Sclero-70, Sm, SS-A/Ro, SS-B/La and chromatin) were negative. Serumimmunoglobulin (Ig) G was slightly elevated (20.75 g/L;normal less than 18.0 g/L) but IgA, IgM and ceruloplasminwere normal. An abdominal ultrasound revealed anechogenic liver. Histologically, mild macrovesicular steatosisand established fibrosis of both portal and perivenular distri-bution was identified (Figure 3), suggestive of a chronicprocess. A mononuclear inflammatory infiltrate in a portal andlobular distribution was also observed (Figure 4). No eosinophilswere present and the bile ducts were normal.

These findings were interpreted as indicative of an acutedrug-induced hepatotoxicity superimposed on previouslysubclinical liver injury of uncertain etiology. Rofecoxib wasdiscontinued and within one week her hepatic symptomsresolved. The liver biochemistry normalized over theensuing month. The patient’s liver profile remains normaland she is clinically well, although she has had intermittentrash and arthralgias of unclear etiology.

DISCUSSIONDue to their improved gastrointestinal safety profile, the coxibshave dominated the global market for prescription NSAIDs.Before its recent withdrawal by the manufacturer, approximately

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Can J Gastroenterol Vol 20 No 5 May 2006352

Figure 1) Expansion of the periportal and perivenular spaces due toinflammation with focal hepatocellular necrosis (periodic acid-Schiffstain, original magnification ×100)

Figure 2) Perivenular inflammatory infiltrate composed of mononu-clear cells and prominent eosinophils (arrows) (hematoxylin and eosinstain, original magnification ×200)

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80 million patients had received rofecoxib and annual salesexceeded $2.5 billion (4). In the present report, we describetwo cases of severe hepatotoxicity due to rofecoxib to highlightthis potentially serious complication of the coxibs. Becauseanother medication of this class (celecoxib) remains on theNorth American market, and others (etoricoxib and lumira-coxib) are awaiting approval, it is imperative that physiciansrecognize the potential for significant hepatic injury attributableto these medications.

Hepatotoxicity is a well-recognized, albeit uncommon,complication of NSAID therapy. Significant liver injuryattributable to the coxibs is less frequent than with nonselectiveNSAIDs (6,7). In the CLASS, an ALT elevation greater thanthree times the upper limit of normal was observed in 0.2%of celecoxib-treated patients compared with 1.7% of thosereceiving diclofenac or ibuprofen (3). In a review of 14 con-trolled trials (8), the frequency of hepatic dysfunction was notsignificantly different between celecoxib (0.8%) and placebo(0.9%). In clinical trials of rofecoxib and valdecoxib, 0.3% to0.5% of patients experienced significant ALT elevations butno cases of severe hepatotoxicity were reported (9,10).However, since the approval of the coxibs, 11 other cases ofsevere hepatic injury have been reported in the Englishliterature (four with rofecoxib [11-14], seven with celecoxib[15-21] and none with valdecoxib). This finding emphasizesthe critical role of postmarketing surveillance in detectingthese rare but serious adverse events that may escapedetection in preclinical testing.

We are confident that a causal relationship exists betweenrofecoxib therapy and liver dysfunction in the cases described(22,23). Both cases were highly probable of drug-inducedliver injury according to the Council for InternationalOrganizations of Medical Sciences scale for causality assessmentin drug hepatotoxicity (24,25). The temporal association wasappropriate (symptoms within two to six weeks of drug initiation)and clinical and biochemical improvements were observedrapidly upon rofecoxib discontinuation. Moreover, we werecareful to exclude other causes of liver injury including viralhepatitis, hepatotoxicity due to other toxins and autoimmunehepatitis. In this regard, our first patient had previouslyreceived rofexocib on several brief occasions without apparenthepatotoxicity. We speculate that the patient was sensitized to

rofecoxib by repeated use and hepatotoxicity only becameapparent on prolonged exposure.

Our second patient was prescribed rofecoxib for arthriticsymptoms in association with a rash, sore throat, fatigue,myalgias, weight loss and ANA positivity. One might argue thatthe acute hepatitis in this patient was attributable to anonhepatotrophic viral infection, autoimmune hepatitis or asystemic inflammatory disorder. Although possible, thehistological findings and abrupt improvement with rofecoxibdiscontinuation were more consistent with drug toxicity.Moreover, the patient has continued to have intermittentarthralgias and rash despite the absence of hepatic symptoms orabnormal liver biochemistry. We speculate that she has anundefined connective tissue disorder that is unrelated to heracute hepatitis. Nonhepatotrophic viruses (eg, parvovirus B19,Epstein-Barr virus, cytomegalovirus and human herpesvirus-6)may cause a similar constellation of symptoms and a role hasbeen proposed in the promotion of drug-induced hypersensi-tivity (26,27). We excluded parvovirus B19 infection in thiscase, but cannot definitively discount infection with anothervirus, either as the sole explanation for her symptoms or as apredisposing factor for drug-related hepatotoxicity.Interestingly, established fibrosis was demonstrated histolog-ically in this patient, suggesting a pre-existing liver disorder.Although lacking metabolic risk factors for nonalcoholicfatty liver disease (NAFLD), this diagnosis would besupported by the histological findings of macrovesicularsteatosis, hepatic echogenicity on ultrasound and ANApositivity (seen in approximately one-third of NAFLDpatients) (28). Whether underlying NAFLD may havepredisposed to rofecoxib-induced hepatoxicity in thispatient, as reported in other causes of drug-induced liverinjury (eg, methotrexate), is unclear (29).

The two cases described in the present report illustrate thevariability in presentation of rofecoxib-induced hepatic injury.Although both patients had cholestatic symptoms, their liverbiochemistry and histology differed substantially. The firstpatient presented with a biochemical pattern of mixed hepato-cellular and cholestatic injury (ie, cholestatic hepatitis). A liverbiopsy demonstrated predominantly zone 1 injury with hepato-cellular damage. On the other hand, the second patient had asignificant ALT elevation (with only a minimal rise in ALP

Rofecoxib-induced hepatotoxicity


Figure 3) Established perivenular and periportal fibrosis associatedwith an inflammatory infiltrate and mild steatosis (periodic acid-Schiffstain, original magnification ×40)

Figure 4) Area of perivenular fibrosis uniformly inflamed withmononuclear cells without eosinophils (hematoxylin and eosin stain,original magnification ×200)

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levels) and a liver biopsy demonstrating mild zone 1 and zone 3injury. In the four previously reported cases of rofecoxib-inducedhepatotoxicity (11-14), the clinical presentations were primarilycholestatic (Table 1), although cases of predominantly hepato-cellular injury have been reported with celecoxib (15,17,18).

Our cases also appeared to differ in their speed of resolutionfollowing dechallenge. As observed commonly in drug-inducedhepatotoxicity, complete biochemical normalization was slowerin our patient with cholestatic hepatitis (24,25). This patienthas not developed a vanishing bile duct syndrome, although thiscomplication is suspected in a case with persistently cholestaticliver enzymes more than two years following discontinuation ofrofecoxib (13). None of the patients described in the literaturedeveloped evidence of acute liver failure perhaps due to rapidwithdrawal of the offending medication. With the exception ofbromfenac, which was recently withdrawn from the market dueto hepatotoxicity, acute liver failure appears to be an uncommoncomplication of NSAIDs (30). Finally, none of our patientsdemonstrated signs of a hypersensitivity reaction (eg, fever, rashand eosinophilia) attributable to rofecoxib therapy.Hypersensitivity has been reported in the setting of celecoxib-induced hepatotoxity; however, this patient was allergic tosulfonamides, a known contraindication to celecoxib (16).

Management of coxib-induced hepatic injury is empirical,but consists of drug withdrawal and supportive therapy.Corticosteroids (13) and ursodeoxycholic acid (11,13,14) havebeen used (including in one of our patients) but their efficacy isunclear in the absence of controlled data. In one case (11), extra-corporeal albumin dialysis (molecular adsorbent recycling system)

appeared beneficial for cholestasis resistant to conventionaltherapy.

To our knowledge, the molecular mechanisms underlyingcoxib-induced hepatic injury have not been established. In contrast, the etiology of hepatotoxicity attributable to non-selective NSAIDs has been extensively investigated (7).Experimental evidence suggests that at least three mechanismslikely play a role:

• mitochondrial injury (31);

• induction of cholestasis (eg, via competition forhepatobiliary transmembrane transporters) (32,33); and

• formation of reactive metabolites that covalently modifyproteins and produce oxidative stress (33).

Genetic and/or acquired patient factors may contribute tohepatotoxicity by either augmenting the pathways leading tohepatic toxicity or impeding protective and detoxifying path-ways (7). For example, a potential role of polymorphisms inhuman UDP-glucuronosyltransferases (UG2B7 and UG2B15)responsible for rofecoxib metabolism (34) has been proposed butnot investigated (12). Moreover, recent evidence suggests thatCOX-2 inhibition by NSAIDs may play a role in liver injurythrough effects on prostaglandins (PGs), notably PGE2.Inhibition of PGE2 may downregulate the antiapoptoticmitochondrial protein Bcl-2, which protects against bile acid-induced apoptosis (35). Indeed, a recent study (36) of a murinemodel of acetaminophen-induced hepatotoxicity demonstratedincreased susceptibility to liver injury in COX-2-deficient mice,

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Can J Gastroenterol Vol 20 No 5 May 2006354

TABLE 1Clinical characteristics of six patients with severe rofecoxib-induced hepatotoxicity

Reference, Patient Dose and Liver Normalization of liveryear (age/sex) duration Symptoms biochemistry* Liver histology enzymes (treatment)

Huster et al (11) 52 F 25 mg/day Jaundice, pruritus, malaise ALT 228 U/L Hepatocellular/canalicular cholestasis 2.5 months

2002 3 months ALP 1314 U/L Portal inflammation (eosinophils) (MARS and UDCA )

Bili 420 µmol/L

Harsch et al (12) 73 F 25 mg/day Jaundice ALT 440 U/L Hepatocellular/canalicular cholestasis 2 months

2003 10 days ALP 435 U/L Portal inflammation (lymphocytes

Bili 170 µmol/L and eosinophils)

Bile duct destruction

Focal hepatocyte necrosis

Papachristou et al (14) 76 F 25 mg/day Jaundice, pruritus, ALT 239 U/L Hepatocellular/canalicular cholestasis 3 months (UDCA)

2004 22 months choluria, acholic stool ALP 314 U/L Portal inflammation (lymphocytes)

Bili 95 µmol/L Bile duct destruction

Linares et al (13) 74 F 12.5 mg/day Jaundice, fatigue, vomiting, ALT 31 U/L Centrilobular cholestasis >2 years†

2004 2 months choluria, bloody ALP 2968 U/L (UDCA and prednisone)

diarrhea, renal failure Bili 205 µmol/L

Yan et al (present study) 44 M 25 mg/day Jaundice, nausea, malaise ALT 1826 U/L Portal and perivenular inflammation 2 months (UDCA)

2006 (case 1) 2 weeks ALP 741 U/L (lymphocytes, eosinophils)

Bili 242 µmol/L Moderate interface hepatitis

Focal hepatocyte necrosis

Yan et al (present study) 44 F 12.5 mg/day Jaundice, pruritus, ALT 995 U/L Mild portal and lobular 1 month

2006 (case 2) 8 weeks choluria, fatigue, ALP 243 U/L inflammation (lymphocytes)

anorexia Bili 207 µmol/L Mild macrovesicular steatosis

Portal and perivenular fibrosis

*Different reference ranges among laboratories where bilirubin was reported in mg/dL, conversion made using 1 mg/dL = 17.1 µmol/L; †Mild abnormalities of alka-line phosphatase (ALP) and gamma-glutamyltransferase persist after more than two years, vanishing bile duct syndrome is suspected but not histologically proven.ALT Alanine aminotransferase; Bili Total bilirubin; F Female; M Male; MARS Molecular adsorbent recycling system; UDCA Ursodeoxycholic acid

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an effect that was reproduced by celecoxib treatment in wild-type mice. It appears that this effect is mediated by a reductionin PGE2 and PGD2 in COX-2-deficient mice that leads to animpairment in the ability to induce expression of hepatoprotec-tive heat shock proteins.

Hepatotoxicity is a potentially serious, but uncommon,complication of coxib therapy. Although rofecoxib has nowbeen withdrawn from the market, previous cases of hepatic

injury attributable to celecoxib suggest that this may be aclass effect. With new coxibs and expanding indications onthe horizon (eg, chemoprevention of cancer [37]),physicians in all areas of practice must be aware of thisdisorder and consider it in any patient who develops hepaticdysfunction after taking a coxib. Management consists of immediate withdrawal of the coxib and supportive therapy.

Rofecoxib-induced hepatotoxicity


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Rofecoxib-induced hepatotoxicity: A forgotten complication of the … · 2019. 8. 1. · Rofecoxib is a member of the coxib family of nonsteroidal anti-inflammatory drugs that selectively