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Chronic hepatitis C, ibuprofen, and liver damage
1854
Letters to the Editor
AJG – Vol. 97, No. 7, 2002
was admitted to hospital. Physical examination findings were normal except for jaundice. Serum chemistry showed total bilirubin of 28.45 mg/dl (normal ⫽ 0.3–1.3); conjugated bilirubin, 20.6 mg/dl (normal ⫽ 0 – 0.4); ALP, 249 U/L (normal ⫽ 35–120); AST, 37 U/L (normal ⫽ 5– 40), and ALT, 58 U/L (normal ⫽ 5– 40). Abdominal ultrasonography, CT scan, and cholangiography magnetic resonance were normal and ruled out obstruction of the bile ducts. Serology excluded viral causes. Screening for autoantibodies and metabolic diseases was negative. A liver biopsy specimen showed predominantly casts in canaliculi and mild portal inflammatory infiltrates with lymphocytes and eosinophils. Results of liver tests became normal during the subsequent 2 months. Trovafloxacin, another new quinolone, has been withdrawn from the market in Europe and limited to life-threatening conditions in the United States because of hepatic toxicity (3– 6). This is, to our knowledge, the first published report of liver injury due to moxifloxacin. Other causes of liver injury were ruled out. The histological picture was consistent with drug-induced hepatic injury. It is noteworthy that there was a delay of 3 wk between the end of the treatment and the onset of jaundice that may hinder the diagnosis. Santiago Soto, Leopoldo Lo´ pez-Rose´ s, Susana A´ vila, A´ ngel Lancho, Abel Gonza´ lez, Eva Santos, Begon˜ a Urraca,
M.D. M.D. M.D. M.D. M.D. M.D. M.D.
Digestive Diseases Unit Hospital Xeral de Lugo Lugo, Spain
REFERENCES 1. Culley CM, Lacy MK, Klutman N, et al. Moxifloxacin: Clinical efficacy and safety. Am J Health Syst Pharm 2001;58:379 – 88. 2. Landen H, Moller M, Tillotson GS, et al. Clinical experience in Germany of treating community acquired respiratory infections with the new 8-methoxyfluoroquinolone, moxyfloxacin. J Int Med Res 2001;29:51– 60. 3. Bertino J Jr, Fish D. The safety profile of the fluoroquinolones. Clin Ther 2000;22:798 – 817. 4. Chen HJL, Bloch KJ, MacLean JA. Acute eosinophilic hepatitis from trovafloxacin. N Engl J Med 2000;342:359 – 60. 5. Ball P. Future of the quinolones. Semin Respir Infect 2001;16: 215–24. 6. Zhanel GG, Ennis K, Vercaigne L, et al. A critical review of the fluoroquinolones: Focus on respiratory infections. Drugs 2002; 62:13–59. Reprint requests and correspondence: Santiago Soto Iglesias, M.D., “Unidad de Endoscopias,” Hospital Xeral de Lugo, Ru´ a Severo Ochoa s.n., 27004 Lugo (Galicia), Spain. Received Feb. 4, 2002; accepted Feb. 18, 2002.
Chronic Hepatitis C, Ibuprofen, and Liver Damage TO THE EDITOR: Riley and Smith reported in 1998 (1) three patients with chronic hepatitis C who developed marked elevations in liver transaminases after taking ibuprofen. No other cases have been reported thereafter, and the plausibility of such an association has recently been questioned (2, 3). We describe an additional patient with chronic hepatitis C who experienced an increase in liver tests in the range of acute hepatitis during a course of ibuprofen. A 57-yr-old active homosexual man was diagnosed as having chronic hepatitis C (HCV antibody positive by the second generation ELISA assay) in 1996 during a routine evaluation to discard HIV infection. Confirmatory analysis included HCV RNA by reverse transcription polymerase chain reaction (1,390,000 copies/ml). Baseline liver chemistry was abnormal for an AST of 99 IU/L and for an ALT of 130 IU/L. A liver biopsy showed chronic active hepatitis with bridging fibrosis. He was intolerant to interferon alfa-2b (3 MU three times weekly) started in early 1997, and routine liver tests performed every 6 months thereafter showed values similar to baseline. In late 2000 he was prescribed ibuprofen (600 mg b.i.d.) for painful abdominal hernia. Liver transaminases 30 days after initiation of ibuprofen were as follows: AST, 355 IU/L; ALT, 1,093 IU/L; and ␥-glutamyltranspeptidase 355 IU/L. He drank alcohol occasionally in the past, but denied current intake as well as the use of any other medication or herbal remedies. Screenings for viral hepatitis A and B, cytomegalovirus, herpesvirus, and Epstein-Barr virus were negative, as was repeated testing for HIV infection. Ibuprofen was stopped and 3 months later the AST level was 52 IU/L; ALT, 119 IU/L; and ␥-glutamyltranspeptidase, 41 IU/L. No new elevations in liver enzymes have been noted in the follow-up. The patient discussed here had a flare of ALT markedly exceeding those usually seen in the natural outcome of chronic hepatitis C. In fact, this prompted us to search for a superimposed factor. A drug-induced etiology should always be kept in mind, especially when other common causes of acute hepatitis have been ruled out. This patient had been taking ibuprofen several days before symptoms appeared. Assessment of this case by the Council for International Organizations of Medical Sciences (CIOMS) scale yields a score of 9 points for ibuprofen, which falls into the category of highly probable (4). As in the cases previously reported (1), the pattern of hepatic injury was hepatocellular. In addition, the absence of the hallmarks of hypersensitivity (fever, rash, and eosinophilia) does not support an immunological idiosyncrasy. Ibuprofen is thought to be far less hepatotoxic than other nonsteroidal anti-inflammatory drugs (NSAIDs), with an estimated incidence of acute liver injury of 1.6/100,000 users (5). No other instances of ibuprofen-associated hepatotoxicity in patients with chronic liver disease unrelated to
AJG – July, 2002
Letters to the Editor
hepatitis C virus have been reported, suggesting that the possible susceptibility of patients with hepatitis C to this adverse effect of ibuprofen is dependent rather on specific etiology of the liver disease than on the type and degree of histological damage. On the contrary, no other NSAIDs have been involved in increased hepatotoxicity of patients with chronic hepatitis C, suggesting that this phenomenon is drug specific. The incidence of acute liver injury in patients with chronic hepatitis C exposed to ibuprofen remains to be determined. We did not find any other similar case among the 421 patients with chronic hepatitis C observed in our liver clinic since 1992. However, this could be due in part to the fact that our policy is to strongly discourage the use of NSAIDs by patients with chronic hepatitis C. In conclusion, our report provides further evidence for the predisposition of patients with chronic hepatitis C to the hepatotoxicity of ibuprofen. A warning for the use of ibuprofen in this subset of patients should probably be considered. Rau´ l J. Andrade, Marı´a Isabel Lucena, Miren Garcı´a-Corte´ s, Elena Garcı´a-Ruiz, Eva Ferna´ ndez-Bonilla, Luis Va´ zquez,
M.D. M.D. M.D. M.D. M.D. M.D.
Liver Unit, Department of Gastroenterology, and Clinical Pharmacology Service University Hospital and School of Medicine of Ma´ laga Ma´ laga, Spain
REFERENCES 1. Riley TR, Smith JP. Ibuprofen-induced hepatotoxicity in patients with chronic hepatitis C: A case series. Am J Gastroenterol 1998;93:1563–5. 2. Lewis JH. Drug-induced liver disease. Med Clin North Am 2000;84:1275–311. 3. Mariano G, Lewis JH. Drug-induced liver disease. Curr Opin Gastroenterol 2001;17:232– 41. 4. Danan G, Be´ nichou C. Causality assessment of adverse reactions to drugs I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries. J Clin Epidemiol 1993;46:1323–30. 5. Manoukian AV, Carson JL. Nonsteroidal anti-inflammatory drug-induced hepatic disorders. Incidence and prevention. Drug Saf 1996;15:64 –71. Reprint requests and correspondence: Rau´ l J. Andrade, M.D., Unidad de Hepatologia, Departamento de Medicina, Facultad de Medicina, Campus Universitario de Teatinos s/n, 29071-Ma´ laga, Spain. Received Feb. 4, 2002; accepted Feb. 18, 2002.
Caroli’s Syndrome in Two Siblings TO THE EDITOR: Caroli’s syndrome is characterized by multiple segmental cystic or saccular dilations of intrahepatic bile ducts associated with congenital hepatic fibrosis. Polycystic renal disease, medullary sponge kidney, or pancreatic cysts
1855
may be associated (1). Portal hypertension due to congenital hepatic fibrosis is the common complication (2). Although this entity seems to be inherited as an autosomally recessive disease, a few reports have it in siblings (3, 4). Here we report Caroli’s syndrome presented during childhood in two siblings. Two siblings, a 6-yr-old girl and a 3-yr-old boy, were admitted to our hospital with abdominal distention. The parents are nonconsanguineous, and the siblings had two healthy sisters. On admission their physical findings were almost similar. Weights and heights were below the 10th percentile, the abdomen was distended, and the liver was palpable 5 and 3 cm below the costal margin and 10 and 6 cm below the xiphoid, respectively. Their spleens were 2 cm palpable. Laboratory investigations revealed that they had mild anemia, and white blood cell and thrombocyte counts were normal. Serum transaminases, bilirubin, electrolytes, urea, creatinine, glucose, total protein, and albumin were within normal limits. Abdominal ultrasonography revealed cystic dilations of intrahepatic bile ducts compatible with Caroli’s disease. The girl had renal cysts and the boy had medullary nephrocalsinosis on abdominal ultrasonography. Liver biopsies showed enhanced fibrous bands connecting portal tracts, abnormal ductal structure, and bile duct dilation compatible with congenital hepatic fibrosis. During a 10-yr follow-up, they developed hypersplenism with anemia, leukopenia, and thrombocytopenia. Complications due to portal hypertension were not detected. The disease presented during early childhood in our patients, similar to Pinto and colleagues’ study (5). Two siblings showed similar symptoms and laboratory and histopathological features except renal findings on ultrasonography. Their clinical courses were also identical. The left lobe was more affected in our patients, as mentioned previously (2, 5). Common complications such as cholangitis and cholelithiasis did not develop during the follow-up period. Ultrasonography is informative in the diagnosis of Caroli’s syndrome. Intra- or extrahepatic cysts can easily be detected by ultrasonography, whereas congenital hepatic fibrosis is a histopathological diagnosis. Progressive renal failure may develop in patients with kidney involvement. Therefore, renal functions of the siblings were monitored. The inheritance of the disease seems to be autosomally recessive; therefore, genetic counseling for the family may be important. Aysel Yu¨ ce, Nurten Koc¸ ak, Okan Akhan, Figen Gu¨ rakan, Hasan Ozen,
M.D. M.D. M.D. M.D. M.D.
Gastroenterology Unit Department of Pediatrics Hacettepe University Ihsan Dog˘ ramacı Children’s Hospital Ankara, Turkey
Letters to the Editor
AJG – Vol. 97, No. 7, 2002
was admitted to hospital. Physical examination findings were normal except for jaundice. Serum chemistry showed total bilirubin of 28.45 mg/dl (normal ⫽ 0.3–1.3); conjugated bilirubin, 20.6 mg/dl (normal ⫽ 0 – 0.4); ALP, 249 U/L (normal ⫽ 35–120); AST, 37 U/L (normal ⫽ 5– 40), and ALT, 58 U/L (normal ⫽ 5– 40). Abdominal ultrasonography, CT scan, and cholangiography magnetic resonance were normal and ruled out obstruction of the bile ducts. Serology excluded viral causes. Screening for autoantibodies and metabolic diseases was negative. A liver biopsy specimen showed predominantly casts in canaliculi and mild portal inflammatory infiltrates with lymphocytes and eosinophils. Results of liver tests became normal during the subsequent 2 months. Trovafloxacin, another new quinolone, has been withdrawn from the market in Europe and limited to life-threatening conditions in the United States because of hepatic toxicity (3– 6). This is, to our knowledge, the first published report of liver injury due to moxifloxacin. Other causes of liver injury were ruled out. The histological picture was consistent with drug-induced hepatic injury. It is noteworthy that there was a delay of 3 wk between the end of the treatment and the onset of jaundice that may hinder the diagnosis. Santiago Soto, Leopoldo Lo´ pez-Rose´ s, Susana A´ vila, A´ ngel Lancho, Abel Gonza´ lez, Eva Santos, Begon˜ a Urraca,
M.D. M.D. M.D. M.D. M.D. M.D. M.D.
Digestive Diseases Unit Hospital Xeral de Lugo Lugo, Spain
REFERENCES 1. Culley CM, Lacy MK, Klutman N, et al. Moxifloxacin: Clinical efficacy and safety. Am J Health Syst Pharm 2001;58:379 – 88. 2. Landen H, Moller M, Tillotson GS, et al. Clinical experience in Germany of treating community acquired respiratory infections with the new 8-methoxyfluoroquinolone, moxyfloxacin. J Int Med Res 2001;29:51– 60. 3. Bertino J Jr, Fish D. The safety profile of the fluoroquinolones. Clin Ther 2000;22:798 – 817. 4. Chen HJL, Bloch KJ, MacLean JA. Acute eosinophilic hepatitis from trovafloxacin. N Engl J Med 2000;342:359 – 60. 5. Ball P. Future of the quinolones. Semin Respir Infect 2001;16: 215–24. 6. Zhanel GG, Ennis K, Vercaigne L, et al. A critical review of the fluoroquinolones: Focus on respiratory infections. Drugs 2002; 62:13–59. Reprint requests and correspondence: Santiago Soto Iglesias, M.D., “Unidad de Endoscopias,” Hospital Xeral de Lugo, Ru´ a Severo Ochoa s.n., 27004 Lugo (Galicia), Spain. Received Feb. 4, 2002; accepted Feb. 18, 2002.
Chronic Hepatitis C, Ibuprofen, and Liver Damage TO THE EDITOR: Riley and Smith reported in 1998 (1) three patients with chronic hepatitis C who developed marked elevations in liver transaminases after taking ibuprofen. No other cases have been reported thereafter, and the plausibility of such an association has recently been questioned (2, 3). We describe an additional patient with chronic hepatitis C who experienced an increase in liver tests in the range of acute hepatitis during a course of ibuprofen. A 57-yr-old active homosexual man was diagnosed as having chronic hepatitis C (HCV antibody positive by the second generation ELISA assay) in 1996 during a routine evaluation to discard HIV infection. Confirmatory analysis included HCV RNA by reverse transcription polymerase chain reaction (1,390,000 copies/ml). Baseline liver chemistry was abnormal for an AST of 99 IU/L and for an ALT of 130 IU/L. A liver biopsy showed chronic active hepatitis with bridging fibrosis. He was intolerant to interferon alfa-2b (3 MU three times weekly) started in early 1997, and routine liver tests performed every 6 months thereafter showed values similar to baseline. In late 2000 he was prescribed ibuprofen (600 mg b.i.d.) for painful abdominal hernia. Liver transaminases 30 days after initiation of ibuprofen were as follows: AST, 355 IU/L; ALT, 1,093 IU/L; and ␥-glutamyltranspeptidase 355 IU/L. He drank alcohol occasionally in the past, but denied current intake as well as the use of any other medication or herbal remedies. Screenings for viral hepatitis A and B, cytomegalovirus, herpesvirus, and Epstein-Barr virus were negative, as was repeated testing for HIV infection. Ibuprofen was stopped and 3 months later the AST level was 52 IU/L; ALT, 119 IU/L; and ␥-glutamyltranspeptidase, 41 IU/L. No new elevations in liver enzymes have been noted in the follow-up. The patient discussed here had a flare of ALT markedly exceeding those usually seen in the natural outcome of chronic hepatitis C. In fact, this prompted us to search for a superimposed factor. A drug-induced etiology should always be kept in mind, especially when other common causes of acute hepatitis have been ruled out. This patient had been taking ibuprofen several days before symptoms appeared. Assessment of this case by the Council for International Organizations of Medical Sciences (CIOMS) scale yields a score of 9 points for ibuprofen, which falls into the category of highly probable (4). As in the cases previously reported (1), the pattern of hepatic injury was hepatocellular. In addition, the absence of the hallmarks of hypersensitivity (fever, rash, and eosinophilia) does not support an immunological idiosyncrasy. Ibuprofen is thought to be far less hepatotoxic than other nonsteroidal anti-inflammatory drugs (NSAIDs), with an estimated incidence of acute liver injury of 1.6/100,000 users (5). No other instances of ibuprofen-associated hepatotoxicity in patients with chronic liver disease unrelated to
AJG – July, 2002
Letters to the Editor
hepatitis C virus have been reported, suggesting that the possible susceptibility of patients with hepatitis C to this adverse effect of ibuprofen is dependent rather on specific etiology of the liver disease than on the type and degree of histological damage. On the contrary, no other NSAIDs have been involved in increased hepatotoxicity of patients with chronic hepatitis C, suggesting that this phenomenon is drug specific. The incidence of acute liver injury in patients with chronic hepatitis C exposed to ibuprofen remains to be determined. We did not find any other similar case among the 421 patients with chronic hepatitis C observed in our liver clinic since 1992. However, this could be due in part to the fact that our policy is to strongly discourage the use of NSAIDs by patients with chronic hepatitis C. In conclusion, our report provides further evidence for the predisposition of patients with chronic hepatitis C to the hepatotoxicity of ibuprofen. A warning for the use of ibuprofen in this subset of patients should probably be considered. Rau´ l J. Andrade, Marı´a Isabel Lucena, Miren Garcı´a-Corte´ s, Elena Garcı´a-Ruiz, Eva Ferna´ ndez-Bonilla, Luis Va´ zquez,
M.D. M.D. M.D. M.D. M.D. M.D.
Liver Unit, Department of Gastroenterology, and Clinical Pharmacology Service University Hospital and School of Medicine of Ma´ laga Ma´ laga, Spain
REFERENCES 1. Riley TR, Smith JP. Ibuprofen-induced hepatotoxicity in patients with chronic hepatitis C: A case series. Am J Gastroenterol 1998;93:1563–5. 2. Lewis JH. Drug-induced liver disease. Med Clin North Am 2000;84:1275–311. 3. Mariano G, Lewis JH. Drug-induced liver disease. Curr Opin Gastroenterol 2001;17:232– 41. 4. Danan G, Be´ nichou C. Causality assessment of adverse reactions to drugs I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries. J Clin Epidemiol 1993;46:1323–30. 5. Manoukian AV, Carson JL. Nonsteroidal anti-inflammatory drug-induced hepatic disorders. Incidence and prevention. Drug Saf 1996;15:64 –71. Reprint requests and correspondence: Rau´ l J. Andrade, M.D., Unidad de Hepatologia, Departamento de Medicina, Facultad de Medicina, Campus Universitario de Teatinos s/n, 29071-Ma´ laga, Spain. Received Feb. 4, 2002; accepted Feb. 18, 2002.
Caroli’s Syndrome in Two Siblings TO THE EDITOR: Caroli’s syndrome is characterized by multiple segmental cystic or saccular dilations of intrahepatic bile ducts associated with congenital hepatic fibrosis. Polycystic renal disease, medullary sponge kidney, or pancreatic cysts
1855
may be associated (1). Portal hypertension due to congenital hepatic fibrosis is the common complication (2). Although this entity seems to be inherited as an autosomally recessive disease, a few reports have it in siblings (3, 4). Here we report Caroli’s syndrome presented during childhood in two siblings. Two siblings, a 6-yr-old girl and a 3-yr-old boy, were admitted to our hospital with abdominal distention. The parents are nonconsanguineous, and the siblings had two healthy sisters. On admission their physical findings were almost similar. Weights and heights were below the 10th percentile, the abdomen was distended, and the liver was palpable 5 and 3 cm below the costal margin and 10 and 6 cm below the xiphoid, respectively. Their spleens were 2 cm palpable. Laboratory investigations revealed that they had mild anemia, and white blood cell and thrombocyte counts were normal. Serum transaminases, bilirubin, electrolytes, urea, creatinine, glucose, total protein, and albumin were within normal limits. Abdominal ultrasonography revealed cystic dilations of intrahepatic bile ducts compatible with Caroli’s disease. The girl had renal cysts and the boy had medullary nephrocalsinosis on abdominal ultrasonography. Liver biopsies showed enhanced fibrous bands connecting portal tracts, abnormal ductal structure, and bile duct dilation compatible with congenital hepatic fibrosis. During a 10-yr follow-up, they developed hypersplenism with anemia, leukopenia, and thrombocytopenia. Complications due to portal hypertension were not detected. The disease presented during early childhood in our patients, similar to Pinto and colleagues’ study (5). Two siblings showed similar symptoms and laboratory and histopathological features except renal findings on ultrasonography. Their clinical courses were also identical. The left lobe was more affected in our patients, as mentioned previously (2, 5). Common complications such as cholangitis and cholelithiasis did not develop during the follow-up period. Ultrasonography is informative in the diagnosis of Caroli’s syndrome. Intra- or extrahepatic cysts can easily be detected by ultrasonography, whereas congenital hepatic fibrosis is a histopathological diagnosis. Progressive renal failure may develop in patients with kidney involvement. Therefore, renal functions of the siblings were monitored. The inheritance of the disease seems to be autosomally recessive; therefore, genetic counseling for the family may be important. Aysel Yu¨ ce, Nurten Koc¸ ak, Okan Akhan, Figen Gu¨ rakan, Hasan Ozen,
M.D. M.D. M.D. M.D. M.D.
Gastroenterology Unit Department of Pediatrics Hacettepe University Ihsan Dog˘ ramacı Children’s Hospital Ankara, Turkey