Diclofenac-Associated Hepatotoxicity
`
`Simon M. Helfgott, MD; Joanne Sandberg-Cook, RNC, MS; David Zakim, MD; Jeffry Nestler, MD
`
`Diclofenac sodium, a phenylacetic acid\p=m-\derivednonsteroidal anti-inflammatory
`drug (NSAID) recently released in the United States, was associated with the
`development of significant hepatitis in seven patients, with one associated
`death. Signs and symptoms developed within several weeks of initiation of drug
`use and generally resolved 4 to 6 weeks following discontinuation of use of the
`drug. The only patient rechallenged with the drug developed a recurrence of her
`hepatic abnormalities. In one patient, fatal, fulminant hepatitis developed despite
`early withdrawal of the drug. Review of the European literature disclosed three
`additional fatalities associated with diclofenac therapy. It is unclear whether the
`incidence of hepatotoxicity is higher with this drug compared with other nonste-
`roidal anti-inflammatory drugs. Carefulpatient monitoring is advised, and prompt
`discontinuation of the drug is suggested when signs or symptoms of liver disease
`develop.
`
`(JAMA. 1990;264:2660-2662)
`
`DICLOFENAC sodium (Voltaren), a
`nonsteroidal anti-inflammatory drug
`(NSAID) that is a phenylacetic acid de¬
`rivative, has recently been released for
`use in the United States, although it has
`been available in Europe since 1974.
`Borderline elevations of serum amino-
`transferase level have been described in
`approximately 15% of patients taking
`diclofenac,1 yet signs and symptoms of
`liver disease rarely occur. We report
`
`For editorial comment see p 2677.
`
`the development of diclofenac-associ-
`ated hepatitis in seven patients, includ¬
`ing one patient with fatal
`fulminant
`massive hepatic necrosis (Table 1).
`Report of Cases
`Case 1.—A 65-year-old housewife
`with a history of osteoarthritis and os¬
`teoporosis presented with a 1-month
`history ofjaundice, elevations of amino-
`transferase level, and coagulopathy.
`The patient had been well except for
`worsening arthritic pain unresponsive
`to treatment with ibuprofen. Diclofenac
`sodium therapy, 75 mg twice daily, was
`started 2 months prior to admission, and
`use of ibuprofen was discontinued. Liv¬
`er function studies yielded normal re-
`From the Beth Israel and Brigham & Women's Hospi-
`tals and Harvard Medical School (Dr Helfgott), Boston,
`Mass; Braintree Hospital (Ms Sandberg-Cook), Brain\x=req-\
`tree, Mass; and the New York Hospital and Cornell
`Medical College (Drs Nestler and Zakim), New York,
`NY.
`Reprint requests to 85 Seymour St, Hartford, CT
`06106 (Dr Nestler).
`
`suits 3 weeks after initiation of diclo¬
`fenac therapy, but 3 weeks later the
`patient had sudden onset of nausea,
`vomiting, and fatigue. A serum alanine
`transpeptidase (ALT)
`concentration
`was 53 U/L and a serum aspartate
`transpeptidase (AST)
`concentration
`was 40 U/L (normal values: ALT, 0 to
`45 U/L; AST, 0 to 45 U/L). The use of
`diclofenac was discontinued. Her only
`othermedications at the time were long-
`term estrogen and progesterone hor¬
`mone replacement therapy, which was
`stopped. Five days later the patient was
`noted to be jaundiced, with a bilirubin
`level of 291 |j.mol/L (normal level, 2 to
`18 fj-mol/L), an AST of 3740 U/L, and a
`prothrombin time of 17.9 seconds (nor¬
`mal prothrombin time, 9.0 to 12.5 sec¬
`onds). Hepatitis A and B sérologies and
`analysis of antimitochondrial antibody
`and antinuclear antibody yielded nor¬
`mal results. A computed tomographic
`scan of the abdomen revealed hepato¬
`megaly without focal lesions or biliary
`tapering
`duct obstruction. A brief
`course of 60 mg of prednisone per day
`was started without improvement. The
`patient denied alcohol use, blood prod¬
`uct transfusions, foreign travel, intra¬
`venous drug use, or known exposure to
`toxic agents. Medications included furo-
`semide, 20 mg/d; famotidine, 40 mg/d;
`and prednisone, 30 mg/d.
`On examination the patient was le¬
`thargic and jaundiced. The liver was not
`enlarged. There was some ascites and
`bilateral pitting edema. Marked aster-
`ixis was present. Bilirubin value
`was 616 punol/L; AST, 177 U/L; ALT,
`
`and prothrombin time,
`140 U/L;
`15.8 seconds. Abdominal ultrasound ex¬
`amination revealed a small
`liver with
`patent hepatic veins and no biliary ob¬
`struction. On the seventh hospital day
`the patient suffered a cardiopulmonary
`arrest. She was resuscitated but contin¬
`ued to deteriorate and died 1 week later.
`At autopsy the liver was markedly re¬
`duced in size, weighing 800 g, with a
`yellow-green, wrinkled appearance.
`Microscopic examination revealed mas¬
`sive hepatocellular necrosis with evi¬
`dence of bridging necrosis and marked
`intrahepatic cholestasis (Figure). There
`was a mild nonspecific inflammatory in¬
`filtrate in the portal triads and some
`regenerating nodules.
`Immunohisto-
`chemical stains for hepatitis B core and
`surface antigen were normal.
`Case 2. —A 46-year-old female nurse
`with a history of fibrositis started tak¬
`ing diclofenac sodium, 75 mg twice a
`day. Other medications included ami-
`triptyline hydrochloride, 100 mg every
`night; ranitidine, 300 mg every night;
`nadolol, 40 mg/d; and furosemide, 40
`mg/d. Findings from pretreatment liver
`function studies were normal. Four and
`one-half months later she developed
`mild anorexia and nausea. The ALT
`concentration measured 149 U/L and
`AST, 110 U/L. The use of diclofenac was
`discontinued, and her symptoms re¬
`solved. Results of liver function studies
`normalized over the next 8 weeks. Her
`musculoskeletal symptoms had wors¬
`ened in the interval, and she restarted
`diclofenac sodium therapy at 50 mg
`twice daily. Six weeks later she devel¬
`oped nausea, anorexia, malaise, and
`right upper quadrant pain. On examina¬
`tion there was tenderness in the right
`upper quadrant and a slightly palpable,
`but not enlarged, liver. The ALT level
`measured 363 U/L and AST, 252 U/L.
`Hepatitis A and B sérologies were nor¬
`mal. Use of diclofenac was discontin¬
`ued, her symptoms resolved, and the
`results of the liver function studies nor¬
`malized 5 weeks later.
`Case 3.—A 54-year-old housewife
`with rheumatoid arthritis, treated with
`biweekly parenteral gold salt
`injec¬
`tions, started a regimen of diclofenac
`sodium, 75 mg twice daily. Pretreat¬
`ment liver function studies yielded nor-
`
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`
`

`
`Table 1.—Clinical Characteristics of Patients With Diclofenac-lnduced Hepatotoxicity (Present Series)*
`
`Peak Liver Function Studies
`Dose of
` -'-'
`Diclofenac
`Onset of
`Aminotransferase:
`Symptoms
`Diagnosis
`Sex
`Sodium
`Age, y
`AST/ALTf
`Hepatotoxicity, d
`AP/Alb/Bili$
`65_F Qsteoarthritis_75 mg bid_42_Nausea_3740/2409_55/34/693
`46
`Flbrositls
`F
`Nausea, malaise,
`75 mg bid
`186/40/17
`139
`363/252
`RUQ pain
`Acute RUQ pain,
`nausea, anorexia
`F
`75 mg bid
`Trazodone, estrogen,
`Anorexia, nausea,
`472/254
`88/48/17
`weight loss
`progesterone
`45_M Qsteoarthritis_75 mg bid_VU_Asymptomatic_922/492_213/43/15 None_
`F
`75 mg bid
`54
`Osteoarthritis
`RUQ pain, nausea,
`763/442
`186/38/17
`41
`None
`anorexia
`Nausea,
`abdominal pain
`
`54
`
`55
`
`F
`
`Rheumatoid arthritis
`
`75 mg bid
`
`Flbrositls
`
`69
`
`F
`
`Osteoarthritis
`
`25mgtid
`
`82
`
`131
`
`35
`
`Concomitant Drugs
`Estrogen, progesterone
`Amitriptyllne, furosemide,
`ranitidine, nadolol
`Parenteral gold salts
`
`389/327
`
`360/30/50
`
`217/notdone
`
`225/35/99
`
`None
`
`•AST indicates aspartate transpeptidase; ALT, alanlne transpeptidase; AR alkaline phosphatase; Alb, albumin; Bill, bilirubin; bid, twice a day; tld, three times daily; and RUQ,
`right upper quadrant.
`tAST and ALT are measured in units per liter.
`t-AP is measured in units per tlter; Alb, in grams per liter; and Bili, in mlcromoles per liter.
`
`mal results. Ten weeks later she devel¬
`right
`oped
`acute,
`severe
`upper
`quadrant and epigastric pain that neces¬
`sitated admission to a hospital. The
`ALT level measured 389 U/L; AST, 327
`U/L; alkaline phosphatase, 360 U/L
`(normal level, 50 to 136 U/L); total bili¬
`rubin, 50 u-mol/L; direct bilirubin, 39
`jxmol/L; and amylase, 41 U/L; hepatitis
`A and B sérologies yielded normal re¬
`sults. An abdominal computed tomo-
`graphic scan revealed mild gallbladder
`distention without an obstructive le¬
`sion; an ultrasound examination of the
`gallbladder displayed minimally dilated
`extrahepatic ducts (8 to 9 mm) without
`obstruction. Results of a radionuclide
`hepatic biliary and a double-contrast
`upper gastrointestinal tract series were
`normal except for a hiatus hernia. Diclo¬
`fenac use was discontinued, and 5 weeks
`later the results of her liver function
`studies returned to normal.
`Case 4.—A 55-year-old waitress
`with a history offibrositis started a regi¬
`men of diclofenac sodium, 75 mg twice a
`day. Results of pretreatment liver func¬
`tion studies were normal. Six months
`later she developed nausea, anorexia,
`and weight loss. Other medications in¬
`cluded trazodone hydrochloride, 150 mg
`every night;
`conjugated estrogens,
`0.625 mg/d with cyclic progesterone, 10
`mg 10 days per month. The ALT con¬
`centration measured 472 U/L; AST, 254
`U/L; and total bilirubin, 27 u.mol/L.
`Hepatitis A and B sérologies yielded
`normal results. Results of an upper gas¬
`trointestinal tract series and abdominal
`ultrasound examination were within
`normal limits. The use of diclofenac was
`discontinued, and 1 month later her
`symptoms resolved and the results of
`her liver function studies normalized.
`Case 5.—A 45-year-old male steel-
`worker with osteoarthritis of the hip
`started a regimen of diclofenac sodium,
`
`Low-power photomicrograph of collapsed hepatic parenchyma with nearly complete loss of hepatocytes and
`approximation of portal areas (case 1 ) (magnification x 100).
`
`75 mg twice a day. Whereas pretreat-
`ment liver function studies yielded nor¬
`mal results, 3V2 months later the ALT
`level measured 922 U/L; AST, 492 U/L;
`alkaline phosphatase, 213 U/L; and total
`bilirubin, 15 jimol/L. Results of hepati¬
`tis sérologies were normal. The patient
`denied any gastrointestinal symptoms.
`He admitted increasing his dose ofdiclo¬
`fenac sodium intermittently to 225
`mg/d, as well as drinking an average of8
`to 12 cans of beer per week. The use of
`diclofenac was stopped, and 6 weeks lat¬
`er the results of his liver function stud¬
`ies returned to normal.
`Case
`6.—A 54-year-old
`female
`housekeeper with osteoarthritis of the
`knees started a regimen of diclofenac
`sodium, 75 mg twice a day. The results
`of pretreatment liver function studies
`
`were normal. Six weeks later she devel¬
`oped an asymptomatic elevation of the
`ALT level to 248 U/L and AST to 148
`U/L. Because her arthritis symptoms
`had improved with use ofdiclofenac, she
`continued to take the drug. Two months
`later she complained of anorexia, nau¬
`sea, and abdominal pain. The ALT con¬
`centration measured 763 U/L and AST,
`442 U/L. The results of hepatitis A and
`B sérologies were normal. Diclofenac
`therapy was discontinued. Four weeks
`later her symptoms resolved and the
`results of her liver function studies
`normalized.
`Case 7.—A 69-year-old housewife
`with generalized osteoarthritis started
`taking 75 mg of diclofenac sodium per
`day, her only medication. Five weeks
`later she developed severe nausea,
`
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`
`Table 2.—Clinical Characteristics of Patients With Diclofenac-lnduced Hepatotoxicity: European Literature
`Review*
`
`...
`
`Dose of
`Concomitant
`Onset of
`Diclofenac
`Sodium
`Drugs
`Reference
`Outcome
`Symptoms, d
`Age, y
`Sex
`Death
`7
`56
`M
`75 mg qd
`Indomethicin
`47
`68_F 50 mg bid_14, 7t_._^_Normalized_8
`Normalized
`75 mg bid
`8
`F
`5
`70
`120, 35t_ _Normalized_9
`52_M Not available
`42_F 75 mg bid_7, 2t_.„_Normalized_10
`Death
`11
`Not available
`Glafenlne
`F
`35
`45
`F
`Death
`12
`Oxazepam,
`21
`50mgbid
`55
`clomipramlne,
`Noctadiol.t- Atrlum§
`Nltrazepam, promethazine,
`amilorlde,
`hydrochlorothlazide
`Nadoxolol
`chlorhydrate
`
`60
`
`72
`
`F
`
`F
`
`75mgbid
`
`50mgbld
`
`150
`
`107
`
`Normalized
`
`Normalized
`
`13
`
`14
`
`*qd Indicates every day; and bid, twice a day.
`fRechallenge with diclofenac.
`ÍNoctadiol Is composed of amobarbital, secobarbital, and meprobamate.
`§Atrium Is composed of febarbamate, dlfebarbamate, and phénobarbital.
`
`right upper quadrant pain, and jaun¬
`dice. She denied alcohol intake. Liver
`function studies revealed a peak total
`bilirubin level of 99 u.mol/L, an alkaline
`phosphatase level of 225 U/L, and an
`AST level of 217 U/L. Hepatitis A and B
`sérologies yielded normal results. The
`results of an abdominal ultrasound ex¬
`amination and endoscopie retrograde
`cannulation of the pancreas and com¬
`mon bile duct were normal. Diclofenac
`use was discontinued, followed by reso¬
`lution of symptoms and normalization of
`liver function.
`
`Comment
`
`Following NSAID therapy, hepato-
`cellular and cholestatic liver disease
`have been reported, with both seen
`in association with phenylbutazone-in-
`duced hepatitis.2 High doses of salicy-
`lates, notably in children, can induce a
`mild, reversible hepatocellular injury.3
`Although propionic acid derivatives
`rarely cause hepatic injury, benoxapro-
`fen was withdrawn from the market pri¬
`marily because of a relatively high
`incidence of cholestaticjaundice.4 Diclo-
`fenac-induced hepatotoxicity most com¬
`monly results in an asymptomatic, mild,
`reversible elevation in the serum ami-
`notransferase levels that occurs in up to
`15% of patients using the drug.1'5 Fifty-
`one patients of 5700 developed marked
`rises (ie, at least 8 x the upper limits of
`normal) in the aminotransferase levels,
`yet signs and symptoms of liver disease
`occurred in only three cases, and one
`patient developed jaundice.1 A large,
`retrospective Danish study revealed a
`very low incidence of hepatotoxicity
`with diclofenac.6 Nevertheless, nine
`
`case reports have documented severe
`hepatitis associated with diclofenac
`therapy,6'14 including three fatalities.
`These cases are summarized in Table 2.
`Features common to the European
`cases and this series include a striking
`female preponderance (6:1), a mean age
`in the mid-50s, and an underlying diag¬
`nosis of osteoarthritis. These character¬
`istics may reflect the population taking
`NSAIDs. The onset of hepatic symp¬
`toms usually occurred within several
`weeks of drug initiation. Discontinua¬
`tion of the use of the drug did not al¬
`ways result in a return of normal liver
`function, as noted in our first case and
`three previously reported European
`cases.71112 Concomitant drug use,
`in¬
`cluding corticosteroids in our patient
`and other potential hepatotoxins in the
`European patients, may have contrib¬
`uted to their death. Two of our patients
`(cases 1 and 4) were using conjugated
`estrogens and one patient (case 5) ad¬
`mitted to regular alcohol consumption.
`Sérologies for hepatitis types A and B
`in all our patients. Al¬
`were normal
`though sporadic hepatitis C cannot be
`ruled out with absolute certainty, none
`of our patients had risk factors for this
`condition.
`The mechanism of hepatotoxicity
`with diclofenac remains unclear. Reac¬
`tive metabolites have been reported to
`play a role in benoxaprofen- and other
`NSAID-induced hepatitis.16 In some
`cases a hypersensitivity reaction ap¬
`peared to play a key role7,9; however,
`none of our patients displayed the typi¬
`features of drug hypersensitivity,
`cal
`including fever, rash, or eosinophilia.
`The temporal relationship between di¬
`clofenac administration and the subse¬
`quent development of liver disease as
`well as recurrence of the illness with
`
`drug rechallenge (case 2) implies a drug-
`disease association. Four of six patients
`restarted the use of NSAIDs, including
`naproxen, piroxicam, and flurbiprofen,
`without adverse effects.
`These cases represent the first de¬
`this complication in the
`scription of
`United States since approval of this
`drug by the Food and Drug Administra¬
`tion. It is unclear whether this repre¬
`sents a higher incidence of hepatotoxic¬
`ity than with other NSAIDs, but we
`would strongly encourage careful moni¬
`toring16 of all patients using this agent
`and prompt discontinuation of the drug
`therapy when signs or symptoms of liv¬
`er disease develop.
`
`We thank Richard Herrmann, MD, and Judith
`Feldman, MD, for kindly referring patients 1 and 7,
`respectively; Tom Goodwin, MD, for reviewing the
`histopathology; and Grace LeFort for expert secre¬
`tarial assistance.
`
`References
`1. Package insert, Voltaren (diclofenac sodium).
`Ardsley, NY: Geigy Pharmaceuticals Division of
`Ciba-Geigy Corp; October 1988.
`2. Fowler PD, Woolfe D, Alexander S. Phenylbu-
`tazone and hepatitis. Rheumatol Rehab. 1975;14:
`71-75.
`3. Zimmerman HJ. Aspirin-induced hepatic inju-
`ry. Ann Intern Med. 1974;80:103-105.
`4. Fowler PD. Major toxic reactions associated
`with NSAIDs. In: Dudley Hart F, Klinenberg JR,
`eds. Choosing NSAID Therapy. Auckland, New
`Zealand: ADIS Press; 1985:41-57.
`5. Ciccuolunghi SN. Report on a long-term toler-
`ability study of up to two years with diclofenac
`sodium. Scand J Rheumatol. 1978;22:86-96.
`6. Kromaann-Anderson H, Pedersen A. Reported
`adverse reactions to and consumption of nonsteroi-
`dal anti-inflammatory drugs in Denmark over a 17\x=req-\
`year period. Danish Med Bull. 1988;35:187-192.
`7. Breen E, McNicholl J, Cosgrove E, McCabe J,
`Stevens F. Fatal hepatitis associated with diclo-
`fenac. Gut. 1986;27:1390-1393.
`8. Schapira D, Bassan L, Nahir A, Scharf A. Diclo-
`fenac-induced hepatotoxicity. Postgrad Med J.
`1986;62:63-65.
`9. Dunk A, Walt R, Jenkins W, Sherlock S. Diclo-
`fenac hepatitis. BMJ. 1982;289:1605-1606.
`10. Masana P, Rojas G, Diego V, Leal S. Hepatitis
`aquid
`sodico. Rev Clin Esp.
`y diclofenac
`1986;179:476.
`11. Babany G, Bernau J, Danaw G, Rueff B, Ben-
`hamou J. Fulminating hepatitis in a woman taking
`glafenine and diclofenac. Gastroenterol Clin Biol.
`1985;9:185.
`12. Lasgar G, Grippon P, Levy V. Acute fatal hep-
`atitis during treatment with diclofenac. Gastroen-
`terol Clin Biol. 1984:8:881-882.
`13. Babany G, Passayre D, Benhamou J. Hepatitis
`caused by diclofenac. Gastroenterol Clin Biol.
`1983;7:316.
`14. Deshayes P, Leloet X, Bercoff E, Fouin-Forti-
`net H. Diclofenac hepatitis. Presse Med. 1984;
`13:1847.
`15. Mitchell MC, Lietman PS. Evidence for the
`role of reactive metabolites in hepatotoxicity of
`benoxaprofen and other NSAIDs. Hepatology.
`1983;3:808. Abstract.
`16. Campbell PM, Wilske K. Drug monitoring. In:
`Weaver AL, ed. Guidelinesfor Reviewers ofRheu-
`matic Disease Care. 2nd ed. Atlanta, Ga: Council of
`Rheumatologic Care of the American College of
`Rheumatology; 1989:23-24.
`
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