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`Brief Case Reports • (cid:9)
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`2299
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`sucrase-isomaltase deficiency. It is tempting to postulate
`that it represents a genetically determined condition, which
`was unmasked by an episode of gastroenteritis. The alter-
`native that it may represent a truly acquired condition pos-
`sibly, precipitated by an enteric infection, has also to be
`considered.
`
`ACKNOWLEDGMENT
`
`We thank the Department of Gastroenterology, University
`College Hospital, Galway, for their assistance with this case.
`
`Reprint requests and correspondence: Professor F. Gleeson,
`James Connolly Memorial Hospital, Blanchardstown, Dublin 15,
`Ireland.
`Received June 27. 1997; accepted Jan. 11, 1999.
`
`REFERENCES
`
`I. Weijers HA, Van De Kamer JH, Mosel DAA, et al. Diarrhoea
`caused by deficiency of sugar splitting enzymes. Lancet 1960;
`2:296.
`2. Auricchio S, Rubino A, Prade A, et al. Intestinal glycosidase
`activities in congenital malabsorption of disaccharides. J Pe-
`diatr 1965;66:555.
`3. Sonntag WM, Brill ML, Troyer ME, et al. Sucrase-isomaltase
`malabsorption in an adult woman. Gastroenterology 1964;47:
`18.
`4. Neale G, Clark M, Levin B. Intestinal sucrase deficiency
`presenting as sucrose intolerance in adult life. Br Med J
`1965;2:1223.
`5. Santagelo WC, Dueno MI, Krejs GJ. Pseudopancreatic cholera
`syndrome: Effect of a synthetic Somatostatin analogue. SMS
`201-995. Am J Med 1987;82(suppl 58):84.
`6. Stevens F, Lloyd R, Geraghty S, et al. Schizophrenia and
`coeliac disease-The nature of the relationship. Psychol Med
`1977;7:259-63.
`7. Cooper BT, Scott J, Hopkins J, et al. Adult onset sucrase-
`isomaltase deficiency with secondary disaccharidase defi-
`ciency resulting from severe dietary carbohydrate restriction.
`Dig Dis Sci 1983;28:473.
`8. Ringrose RE, Preiser H, Welsh JD. Sucrase-isomaltase (Pala-
`tinase) deficiency diagnosed during adulthood. Dig Dis Sci
`1980;25:384.
`9. Gudmand-Hoyer E. Sucrase malabsorption in children: A re-
`port of thirty one Greenlanders. J Pediatr Gastroenterol Nutr
`1985;4:873.
`10. Gray GM, Conklin KA, Townley RR. Sucrase-isomaltase de-
`ficiency. N Engl J Med 1976;294:750-3.
`11. Prader A, Aurrichio S. Defects of intestinal disaccharide ab-
`sorption. Annu Rev Med 1965;13:345.
`12. Smith MW, Phillips AD, Walker-Smith JA. Selective inhibi-
`tion of brush border hydrolase development in coeliac disease
`and cows milk protein intolerance. Paediatr Res 1986;20:693
`(abstract).
`13. Lifshitz F. Perspectives of carbohydrate intolerance in infants
`with diarrhoea. In: Lifshitz F, ed. Carbohydrate intolerance in
`infancy. New York: Marcel Dekker, 1982:3.
`14. Dahlqvist A. Assay of intestinal disaccharidases. Anal Bio-
`chem 1968;22:99-107.
`
`Bromfenac(Duract)-Associated
`Hepatic Failure Requiring
`Liver Transplantation
`
`Philip E. Johnston, Pharm.D.,
`Ellen B. Hunter, M. (cid:9)
`• • (cid:9)
`Gordon Tanner, M.D., C. •• (cid:9)
`Joseph A. Awad, M.D.
`Departments of Medicine, Surgery, and Pharmacology,
`Divisions of Gastroenterology, Clinical Pharmacology, and
`Hepatobiliary Surgery and Liver Transplantation, Vanderbilt
`University, Nashville, Tennessee
`
`., and
`
`ABSTRACT
`Bromfenac sodium (Duract) is a phenylacetic acid-derived
`nonsteroidal anti-inflammatory agent introduced in the
`United States in 1997 and withdrawn in 1998. We describe
`the first case of fulminant hepatic failure associated with this
`agent treated successfully with liver transplantation. Simi-
`larities to hepatotoxicity with related agents is discussed.
`(Am J Gastroenterol 1999;94:2299-2301. © 1999 by Am.
`Coll. of Gastroenterology)
`
`INTRODUCTION
`
`Bromfenac sodium (Duract) is a phenylacetic acid-derived,
`nonsteroidal anti-inflammatory agent (NSAID). It was ap-
`proved by the United States Food and Drug Administration
`(FDA) July 15, 1997, and withdrawn by the manufacturer
`June 22, 1998, after drug-associated severe hepatic injury
`resulted in death or liver transplantation. We describe the
`first case of fulminant hepatic failure associated with brom-
`fenac sodium reported to the FDA that was treated success-
`fully with liver transplantation, and discuss the similarities
`of this case to liver dysfunction reported with other mem-
`bers of this class of NSAIDs.
`
`CASE REPORT
`
`A 36-yr-old man was transferred to Vanderbilt University
`Hospital with severe hepatic dysfunction. Past medical his-
`tory was significant only for osteoarthritis treated with
`bromfenac sodium 50 mg t.i.d. for 3 months. He was ad-
`mitted to a local hospital 8 days before transfer with jaun-
`dice and epigastric pain. Bromfenac was discontinued at that
`time. His serum bilirubin was 11.4 mg/dl, alkaline phospha-
`tase 130 U/L, AST 1805 U/L, ALT 1451 U/L, prothrombin
`time 5 s prolonged, and albumin 3.0 mg/dl. Computed
`tomography of the abdomen was notable for edema and
`thickening of the gallbladder wall. Endoscopic retrograde
`cholangiography was normal. Hepatitis B surface antigen,
`and IgM antibodies to hepatitis B core antigen and hepatitis
`A were not detected. Antibodies to hepatitis B surface
`antigen and hepatitis C (ELISA II) were also not detected.
`Continued nausea and vomiting, development of grade I-II
`
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`AJG - Vol. 94, No. 8, 1999
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`encephalopathy, and scrum glucoses <55 nig/di prompted
`transfer of the patient.
`The patient denied a history of significant alcohol use,
`injection drug use, blood transfusion, mushroom ingestion,
`or toxin exposure. He had no personal or family history of
`liver disease. Vital signs were within normal limits with no
`recorded fever. He was jaundiced, but without tattoos, cu-
`taneous stigmata of chronic liver disease, or hypersensitivity
`reaction. Kaiser-Fleischer rings were absent and cardiopul-
`monary examination was within normal limits. The liver
`was palpable just below the costal margin, but the spleen
`was not. The patient was somnolent with asterixis. The
`serum bilirubin had increased to 29 mg/dl and prothrombin
`time was 12 s prolonged. The AST was 892 U/L, ALT 1480
`U/L, and alkaline phosphatase 144 U/L. Factor V activity
`was 26%. Hematocrit was 44% with a reticulocyte count of
`2.4%, and creatinine was 0.7 mg/dl.
`The FDA was contacted November 25, 1997, and a Med-
`Watch report was subsequently filed because of concern
`regarding hepatic failure related to bromfenac. At that point,
`no similar reports had been filed. The patient's condition
`continued to deteriorate and he underwent orthotopic liver
`transplantation December 17, 1997, 31 days after presentation.
`Pretransplant evaluation at our facility revealed no other
`cause of liver disease, although repeat serological testing for
`viral hepatitis was confusing. Hepatitis B surface antigen
`and hepatitis C ELISA II testing were both positive at low
`levels despite the absence of all other serological markers of
`hepatitis B, negative DNA testing for hepatitis B (<5 pg/
`ml), and negative RNA detection for hepatitis C (qualitative
`polymerase chain reaction). Antinuclear and antismooth
`muscle antibodies were absent. Histological examination of
`the explanted liver showed hepatic necrosis and parenchy-
`mal collapse with only scant fibrous tissue within the bridg-
`ing necrosis consistent with severe acute injury. There was
`marked subacute inflammation, cholangiolar proliferation,
`and extensive bile ductular stasis with plugging. An orcein
`stain was negative. One year posttransplant, the patient has
`normal allograft function. Hepatitis B surface antigen and core
`antibody remain negative. Testing for hepatitis C by ELISA II
`and polymerase chain reaction also remain negative.
`
`DISCUSSION
`
`Bromfenac sodium (Duract) is a phenylacetic acid NSAID
`related to diclofenac sodium (Voltaren) approved by the
`FDA July 15, 1997, and withdrawn voluntarily by the man-
`ufacturer June 22, 1998, after >2.5 million prescriptions for
`the drug were written (1). Bromfenac sodium was approved
`only for short term treatment of pain (cid:9)
`days). The
`package insert reported a 15% rate of AST or ALT elevation
`of up to three times the upper limit of normal (ULN) in short
`term clinical trials of bromfenac including 926 patients.
`Transaminase elevations of more than three times the ULN
`were noted in 2.7% of patients, and elevations more than
`eight times the ULN were seen in 0.4% of patients in short
`
`and longer term trials. The package insert advised monitor-
`ing hepatic biochemistries of patients treated for >4 wk (2).
`NSAIDs are among the most commonly used medications
`worldwide. Liver injury does not appear to be common, but
`severe hepatic injury and death have been reported sporad-
`ically with many agents representing a variety of chemical
`classes (3, 4). However, at least two other phenylacetic acid
`derivatives, diclofenac sodium and ibufenac, cause hepatic
`biochemical abnormalities in >10% of patients, and ibufe-
`nac was abandoned in the late 1960s (3). Diclofenac sodium
`received attention because of reports of severe hepatic in-
`jury shortly after its introduction in the United States (5, 6).
`The pattern of liver injury in our patient was similar to that
`described in most patients with diclofenac-induced hepato-
`toxicity. He presented with severe hepatitis that progressed
`to fulminant hepatic failure without signs of hypersensitiv-
`ity, had no history or histological evidence of chronic liver
`disease, and no other recognizable cause of hepatitis was
`identified. The common occurrence of hepatic biochemical
`abnormalities after treatment with phenylacetic NSAIDs
`suggests a definable mechanism of injury in some patients
`that may result in hepatic failure in a rare patient.
`This is the first case of fulminant hepatic failure in a
`patient treated with bromfenac sodium after its approval by
`the FDA. Reporting of this and other cases to the MedWatch
`program caused issuance of a letter by Wyeth-Ayerst Lab-
`oratories in February 1998, informing health care providers
`of revised product labeling including a new boxed warning
`of severe hepatitis and liver failure in patients taking brom-
`fenac sodium (7). On June 22, 1998 bromfenac sodium was
`withdrawn voluntarily from the market by the manufacturer
`because of four liver failure-related deaths and eight liver
`transplantations of patients using bromfenac sodium, most
`for longer than the recommended length of time (1).
`We believe that this case illustrates why health care
`providers should exercise caution when prescribing new
`medications, especially if the drug has recognized organ
`toxicity and there are efficacious alternatives. This case also
`emphasizes the need for gastroenterologists to be vigilant
`for cases of gastrointestinal and hepatic injury that may be
`related to new medications, and the importance of reporting
`these cases to the MedWatch program.
`
`Reprint requests and correspondence: Joseph A. Awad, M.D..
`Division of Gastroenterology, Vanderbilt University, MCN/C-
`2104, Nashville, TN 37232-2279.
`Received July 14, /998; accepted Jan. 26, 1999.
`
`REFERENCES
`
`I. Dear Health Professional Letter-Duract. Philadelphia, PA:
`Wyeth Laboratories Inc., June 22, 1998.
`2. Package insert, Duract (bromfenac sodium capsules). Philadel-
`phia, PA: Wyeth Laboratories Inc., May 16, 1997.
`3. Rabinowitz M, Van Thiel DH. Hepalotoxicity of nonsteroidal
`anti-inflammatory drugs. Am J Gastroenterol 1992;87:1696-
`1704.
`
`Page 2
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`AJG - August, 1999 (cid:9)
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`Brief Case Reports (cid:9)
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`2301
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`4. Boerlstcrli UA, Zimmerman HJ, Kretz-Rommel A. Idiosyn-
`cratic liver toxicity of nonsteroidal antiinllammatory drugs:
`Molecular mechanisms and pathology. Crit Rev Toxicol 1995;
`25:207-35.
`5. Helfgott SM, Sandberg-Cook J, Zakim D, et al. Diclofenac-
`associated hepatotoxicity. JAMA 1990;264:2660-2.
`6. Scully LJ, Clarke D, Barr RJ. Diclofcnac induced hepatitis: 3
`Cases with features of autoimmunc chronic active hepatitis. Dig
`Dis Sci [993;38:744-51.
`7. Dear Health Professional Letter-Duract. Philadelphia, PA:
`Wyeth Laboratories Inc., February 1998.
`
`Pancreatitis Associated With Crohn's
`Disease: A Premalignant State for
`Cystadenocarcinoma of Pancreas?
`Amnon Gotian, M.D., and
`Seymour Katz, M.D., F.A.C.G., F.A.C.P.
`Department of Medicine, North Shore University Hospital,
`Manhasset, New York; and New York University School of
`Medicine, New York, New York
`
`ABSTRACT
`We report a 74-yr-old woman with Crohn's disease and
`acute pancreatitis who, 3 yr after resolution of the latter,
`developed cystadenocarcinoma of the pancreas. No drug,
`toxin, or other etiologies including contiguous duodenal
`involvement were identified as responsible for the pancre-
`atitis, suggesting that pancreatitis was an extraintestinal
`manifestation of her Crohn's disease. Could Crohn's-asso-
`ciated pancreatitis be a premalignant state for cystadenocar-
`cinoma of the pancreas? (Am J Gastroenterol 1999;94:
`1999 by Am. Coll. of Gastroenterology)
`2301-2302. (cid:9)
`
`INTRODUCTION
`
`The association between pancreatitis and Crohn's disease
`has been increasingly recognized (1-3). In several studies,
`pancreatitis as an extraluminal manifestation of Crohn's
`disease itself was the only explanation. We report the first
`case of Crohn's-related pancreatitis without contiguous du-
`odenal involvement and with subsequent development of
`cystadenocarcinoma of the pancreas.
`
`CASE REPORT
`
`A 74-yr-old white woman of Hungarian descent was admit-
`ted in 1987 to the hospital with intermittent melena and
`black stool. Her past medical history included mitral valve
`prolapse, uterine prolapse, chronic urinary tract infections,
`bilateral carotid disease, and bilateral subtotal thyroidec-
`tomy for benign nodules, and 15 years of "irritable bowel
`syndrome." Esophagogastroscopy, sigmoidoscopy, and sub-
`sequent colonoscopy were all negative. Enteroclysis showed
`extensive ileitis, ulcerations, and pseudopolyposis consis-
`tent with Crohn's disease.
`
`In March 1988 she was readmitted for anemia, weakness,
`and fatigue. Biopsies of colonic mucosa were negative for
`inflammation. Subsequent CT of the abdomen and pelvis
`demonstrated a thickened wall and narrowed lumen of the
`terminal ileum consistent with inflammatory bowel disease.
`A small focal abnormality was found in the liver consistent
`with a small hcmangioma. The pancreas was normal.
`In June 1988, the patient underwent a resection of 31 cm
`of the terminal ileum with a 5-cm-long segment of attached
`cecum because of persistent debility. The pathology report
`described extensive ulcerations and pseudopolyp formation
`with a small fistula into the mesentery. A follow-up small
`bowel series in October 1989 showed no evidence of recur-
`rence. A colonoscopy performed in July 1991 revealed
`normal colonic mucosa. The patient remained asymptomatic
`and off all medications.
`In March of 1994, while not taking any medications, the
`patient developed abdominal pain and underwent ultra-
`sonography of the abdomen. A focal lesion on right lobe of
`liver was found to be consistent with small hemangioma and
`dilatation of the pancreatic duct with no discrete mass in the
`pancreas. The pancreatic body was slightly heterogeneous,
`consistent with pancreatitis. Her amylase level was 1188
`(24-97 normal), her white blood cells 13,600 with 90%
`polymorphonuclears, hemoglobin 12.7, hematocrit 38.0,
`and platelets 231. Serum amylase fell to 346 (normal 34 —
`122), lipase 130 (normal < 60), total bilirubin 0.8, albumin
`3.3, alkaline phosphatase 58, AST 18, ALT 18, CPK 45,
`LDH 154, and calcium 8.8.
`A computed tomography scan of the abdomen and pelvis
`was consistent with the clinical history of pancreatitis. No
`biliary tract stones or disease were identified. A suggestion
`of possible duodenal wall thickening was believed to be
`secondary to the surrounding peripancreatic inflammation.
`The pancreatitis resolved shortly afterward, and the patient
`was discharged 6 days later with an amylase level of 44. The
`patient continued to remain asymptomatic with normal amy-
`lase levels until June 1997, when she noted weight loss and
`
`kV :20
`mil 260
`
`Large
`5.0 ora/1.0:3 (cid:9)
`
`L (cid:9)
`
`
`
`Figure 1. CT scan of abdomen demonstrating 6 X 3-cm mass on
`the head of the pancreas.
`
`Page 3