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Acute vanishing bile duct syndrome after ibuprofen therapy in a child
ACUTE VANISHING BILE DUCT SYNDROME AFTER IBUPROFEN THERAPY IN A CHILD M. TAGHIAN, MD, T. A. TRAN, MD, S. BRESSON-HADNI, MD, PHD, A. MENGET, MD, PHD, S. FELIX, MD, AND E. JACQUEMIN, MD, PHD
We report the case of a 10 year-old girl who had Stevens-Johnson syndrome and cholestasis after ibuprofen therapy. Liver histology was compatible with vanishing bile duct syndrome. She received ursodeoxycholic acid, and liver tests normalized within 7 months. This report confirms that ibuprofen may induce acute vanishing bile duct syndrome. (J Pediatr 2004;145:273-6)
anishing bile duct syndrome (VBDS) represents a group of biliary diseases with different underlying causes but one common feature, progressive loss of intrahepatic interlobular bile ducts, typically in more than 50% of portal tracts.1-4 It has been associated with primary biliary cirrhosis, sclerosing cholangitis, sarcoidosis, viral infections, Hodgkin disease, allograft rejection, graft-versus-host disease, a-1 antitrypsin deficiency, cystic fibrosis, Alagille syndrome, and drugs.1-9 Acute VBDS is often drug-related.1,2,4,6-9 We report a child in whom severe and rapidly progressive cholestatic jaundice associated with VBDS developed 12 days after initiation of ibuprofen therapy at conventional pediatric doses.
V
CASE REPORT A 10-year-old girl had fever during 2 days and rhinopharyngitis; she received ibuprofen at conventional pediatric doses (maximum of 30 mg/kg/day). Eight days later, the fever relapsed, and she received again ibuprofen. Two days later, maculopapular pruriginous rash appeared on the face. Forty-eight hours later, she was hospitalized because of jaundice, dark urine, discolored stools, arthralgia, cheilitis, conjunctivitis, pharyngeal erythema, and extension of maculopapular rash to the whole body with small bullae. The girl was thought to have Stevens-Johnson syndrome and hepatitis.6 Kawasaki disease was ruled out. She had no adenopathy, hepatosplenomegaly, nor stigmata of chronic liver disease or Alagille syndrome. Her medical history reported nickel contact dermatitis and tonsillectomy. She had been treated, on previous occasions, mainly for fever episodes, with Nonsteroidal antiFrom the Pediatric Unit, Vesoul inflammatory drugs (NSAIDs) such as acetylsalicylic acid and niflumic acid. The patient’s Hospital, Vesoul; the Infectious Disease Unit, the Hepatology Unit, the mother said that her daughter has received ibuprofen at least on one previous occasion, but Pediatric Intensive Care Unit, the this information was not registered in the patient health booklet. Pathology Unit, Besanc xon University Hospital, Besanc xon; the Pediatric Initial liver tests were as follows: total bilirubin level, 93 lmol/L (N < 17 lmol/L); Hepatology Unit, Biceˆtre University conjugated bilirubin, 69 lmol/L (N < 4 lmol/L); aspartate aminotransferase, 333 IU/L Hospital, Assistance Publique–Hoˆpi(N < 50 IU/L); alanine aminotransferase, 639 IU/L (N < 39 IU/L); gamma-glutamyl taux de Paris, Le Kremlin-Biceˆtre, Paris, France. transferase, 275 IU/L (N < 25 IU/L); and alkaline phosphatase, 1697 IU/L (N < 720 IU/L). Submitted for publication Dec 11, 2003; Serum albumin, prothrombin time, and clotting factor V level were normal. Abdominal last revision received Apr 20, 2004; Doppler ultrasonographic and computed tomographic scans showed no abnormality of the accepted May 13, 2004. Reprint requests: Prof Emmanuel liver or bile ducts. Serologic tests for viral hepatitis A, B, C, and G, cytomegalovirus, Jacquemin, De´partement de Pe´diatrie, Epstein Barr virus, parvovirus B19, echovirus, Coxsackie virus, herpes simplex virus, herpes He´patologie Pe´diatrique, Centre 6 virus, human immunodeficiency virus, cat scratch disease, mycoplasma, leptospirosis, Hospitalier Universitaire de Biceˆtre, 78, rue du Ge´ne´ral Leclerc, 94275 toxoplasmosis, and echinococcosis were all negative. Antinuclear, antimitochondrial, anti– Le Kremlin Biceˆtre Cedex, France. smooth muscle, anti–liver/kidney microsomal, anti–liver cytosol, and antineutrophil E-mail: emmanuel.jacquemin@bct. ap-hop-paris.fr. cytoplasmic antibodies were all negative. Immunoglobulin, alpha-1 antitrypsin, ferritin, 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. NSAIDs
Nonsteroidal anti-inflammatory drugs
VBDS
Vanishing bile duct syndrome
10.1016/j.jpeds.2004.05.027
273
Figure. Evolution of serum liver tests in a child with VBDS appearing after ibuprofen therapy. Total bilirubin level, N < 17 lmol/L; aspartate aminotransferase, N < 50 IU/L; alanine aminotransferase, N < 39 IU/L; gamma-glutamyl transferase, N < 25 IU/L; alkaline phosphatase, N < 720 IU/L; bile acids, N < 15 lmol/L. Figure can be viewed in color online at www.us.elsevierhealth.com/jpeds.
copper, ceruloplasmin, alpha-fetoprotein, and ACE serum levels as well 24-hour urinary copper excretion and sweat test were normal. The search for butterfly-like vertebrae and posterior embryotoxon was negative. All medications were stopped and during the next 2 weeks;, jaundice increased, as did pruritus. A percutaneous liver biopsy including more than 10 portal tracts3 and performed 48 days after stopping ibuprofen therapy showed intrahepatic centrolobular cholestasis with loss of interlobular bile ducts in more than 50% of portal tracts and bile duct injury in the remainder and portal polymorphous infiltrate with numerous eosinophils. There was no portal fibrosis, no granuloma, and no ductular proliferation. These histopathologic features were consistent with the diagnosis of acute VBDS.6 Treatment with ursodeoxycholic acid (600 mg/m2/day or 25 mg/kg/day) and liposoluble vitamins was initiated on hospital day 9. Rifampicin was started on day 45 for persistent pruritus. We observed a favorable outcome with disappearance of pruritus and complete biochemical recovery within 7 months. Evolution of serum liver tests is shown in the Figure. Serum cholesterol level was 4.94 g/L (N: 1.1-2 g/L) at hospital day 9, reached a maximum of 15.94 g/L at hospital day 37, and normalized within 7 months. Skin lesions disappeared within 10 months. Two years later, the child 274
Taghian et al
has a normal activity and physical status and is still receiving ursodeoxycholic acid therapy.
DISCUSSION Acute vanishing bile duct syndrome is a rare cause of prolonged and progressive cholestasis and is often clinically associated to fever, fatigue, upper abdominal pain, and skin rash.2,6 Serum liver tests comprise a generally mild increase in transaminase activities with high total bilirubin concentration, persistently elevated alkaline phosphatase and gammaglutamyl transpeptidase activities, and hypercholesterolemia. The acute symptoms usually subside within days or weeks. Prolonged cholestasis appears thereafter.1,2,6-8 These features were present in the patient reported here. Although it is impossible to prove the cause of the VBDS observed in our patient, it may be reasonably ascribed to ibuprofen because (1) there was no history of liver or biliary tract disease; (2) liver and biliary tract were normal on ultrasonography and computerized scan tomography; (3) the patient had a history of previous treatment with acetylsalicylic acid and niflumic acid (NSAID) a few years ago, and also very likely with ibuprofen; (4) there was a close temporal relation between ibuprofen administration and the appearance of cholestasis; (5) prominent eosinophils The Journal of Pediatrics August 2004
Table. Main characteristics of three cases of acute VBDS associated with ibuprofen use
Age
Sex
Alam et al7
29
M
Asthma Allergic rhinitis Hyposensitization treatment
3 wk
Srivastava et al6
9
F
No known allergy
3d
Stevens-Johnson syndrome
10
F
Nickel contact dermatitis, Tonsillectomy
12 d
Stevens-Johnson syndrome
Present case
Medical history
Interval Between Ibuprofen Intake and VBDS
Authors (ref.)
were present on liver biopsy; and (6) other potential causes of VBDS were excluded including drugs known to induce cholestasis. Ibuprofen has been reported to be responsible for VBDS in a 29-year-old man7 and a 9-year-old girl who had, as in our patient, Stevens-Johnson syndrome.6 In these two cases, a chronic course developed with evidence of cirrhosis, and both patients were referred for liver transplantation (Table). The hepatotoxicity of NSAIDs is being increasingly recognized.6-8,10 Ibuprofen, a member of the propionic acid class of NSAIDs, appears to have a low incidence of hepatic injury.7,8,10-12 The mechanism of interlobular bile duct loss is not fully understood. Toxic and immune causes have been suggested.1,2,6,8,13 The potential of ibuprofen to trigger an immunoallergic reaction is strongly suggested by the association with Stevens-Johnson syndrome.6 Ibuprofen, inhibits cyclo-oxygenase/prostaglandin synthesis.14 When metabolized in the liver, it may form covalent, hapten-like associations with host proteins, leading to a loss of tolerance and destruction of small bile ducts.2,11 In this view, it might be possible that niflumic acid or another NSAID acts as a sensitizer and thus fosters the ibuprofen hepatotoxicity.15 Indeed, StevensJohnson syndrome and cholestasis has been reported in a 19-year-old woman after ketorolac and ibuprofen therapy.16 The prognosis of acute drug-induced VBDS is unpredictable and might be related to the ability of small bile ducts to regenerate.2 Sometimes, secondary biliary cirrhosis may occur with the ultimate development of portal hypertension and decompensated hepatic function.6,7 Treatment for druginduced VBDS includes withdrawal of the causal agent and supportive care by ursodeoxycholic acid, which may correct the impaired hepatocellular excretory capacity for potentially toxic cholephils and protect against injury of the biliary tree induced by hydrophobic bile acids.6,7,17,18 Ursodeoxycholic acid may Acute Vanishing Bile Duct Syndrome After Ibuprofen Therapy in a Child
Associated signs
Medical treatment
Positive CMV-IgM antibodies
Prednisone Antihistaminics Cholestyramine Lovastatin Ursodeoxycholic acid Ursodeoxycholic acid Prednisone Tacrolimus Betamethasone Antihistaminics Ursodeoxycholic acid Rifampicin
Evolution Persistence of jaundice and pruritus >12 mo after onset, patient referred for liver transplantation Persistence of jaundice and pruritus >4 mo after onset, patient referred for liver transplantation Complete clinical and biochemical recovery within 7 mo
have also some immunomodulating properties such as reduction of hepatic aberrant HLA class I expression.17 Although there is no proof of the efficiency of ursodeoxycholic acid treatment in this condition, it could be proposed to continue treatment when effective.18 Reintroduction of ibuprofen as well as other NSAID is strictly proscribed. Ibuprofen-associated VBDS has been exceptionally reported in the pediatric age group.2,6-8 Because this drug is currently widely prescribed in the pediatric population and has potentially very severe adverse events, even in the absence of overdose, it should remain a second-line treatment for fever and pain, after paracetamol.10,12,19 Occurrence of jaundice after ibuprofen must evoke the diagnosis of ibuprofen-induced acute VBDS and lead to discontinuation of ibuprofen therapy and may justify early ursodeoxycholic acid treatment. We are grateful to Drs O. Bernard, N. Khayat, J. M. Estavoyer, B. Hoen, P. Colin, J. P. Carbillet, B. Coupe, P. Thierry, J. M. Jacquet, and N. Haghiri for taking care of the patients and for helpful comments.
REFERENCES 1. Degott C, Feldman G, Larrey D, Durand-Schneider AM, Grange D, Machayekhi JP, et al. Drug-induced prolonged cholestasis in adults: a histological semi-quantitative study demonstrating progressive ductopenia. Hepatology 1992;15:244-51. 2. Geubel AP, Sempoux C, Rahier J. Bile duct disorders. Clin Liver Dis 2003;7:295-309. 3. Hadchouel M. Paucity of interlobular bile ducts. Semin Diagn Pathol 1992;9:24-30. 4. Ludwig J. Vanishing bile duct syndrome. In: Bircher J, Benhamou JP, McIntyre N, et al, editors. Oxford textbook of clinical hepatology. 2nd ed. Oxford: Oxford University Press; 1999. p. 1131-3. 5. Furuya KN, Roberts EA, Canny GJ, Phillips MJ. Neonatal hepatitis syndrome with paucity of interlobular bile ducts in cystic fibrosis. J Pediatr Gastroenterol Nutr 1991;12:127-30.
275
6. Srivastava M, Perez-Atayde A, Jonas MM. Drug associated acute-onset vanishing bile duct and Stevens-Johnson Syndrome in a child. Gastroenterology 1998;115:743-6. 7. Alam I, Ferrell LD, Bass NM. Vanishing bile duct syndrome temporally associated with ibuprofen use. Am J Gastroenterol 1996;91: 1626-30. 8. Chitturi S, Farrell GC. Drug-induced cholestasis. Semin Gastrointest Dis 2001;12:113-24. 9. Dousset B, Conti F, Houssin D, Calmus Y. Acute vanishing bile duct syndrome after interferon therapy for recurrent HCV infection in liver-transplant recipients. N Engl J Med 1994;330:1160-1. 10. Stempel DA, Miller JJ III Lymphopenia and hepatic toxicity with ibuprofen. J Pediatr 1997;90:657-8. 11. Boelslerli UA, Zimmerman HJ, Kretz-Rommel A. Idiosyncratic liver toxicity of non-steroidal anti-inflammatory drugs: molecular mechanisms and pathology. Crit Rev Toxicol 1995;25:207-35. 12. Halpern SM, Fitzpatrick R, Volans GN. Ibuprofen toxicity: a review of adverse reactions and overdose. Adverse Drug React Toxicol Rev 1993;12: 107-28.
276
Taghian et al
13. Batts KP, Moore SB, Perkins JD, Wiesner RH, Grambsch PM, Krom RA. Influence of positive lymphocyte crossmatch and HLA mismatching on vanishing bile duct syndrome in human liver allografts. Transplantation 1988; 45:376-9. 14. Fiorucci S, Antonelli E. Cyclo-oxygenase isoenzymes: structural basis for selective inhibition of cyclo-oxygenases by anti-inflammatory agents. Dig Liver Dis 2001;33:S2-7. 15. Menniti-Ippolito F, Sagliocca L, Da Cas R, Saggiomo G, Di Nardo R, Traversa G, et al. Niflumic acid and cutaneous reactions in children. Arch Dis Child 2001;84:430-1. 16. Morelli MS, O’Brien FX. Stevens-Johnson syndrome and cholestatic hepatitis. Dig Dis Sci 2001;46:2385-8. 17. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 2002; 36:525-31. 18. O’Brien CB, Shields DS, Saul SH, Reddy KR. Drug-induced vanishing bile duct syndrome: response to ursodiol. Am J Gastroenterol 1996;91:1456-7. 19. Cranswick N, Coghlan D. Paracetamol efficacy and safety in children: the first 40 years. Am J Ther 2000;7:135-41.
The Journal of Pediatrics August 2004
We report the case of a 10 year-old girl who had Stevens-Johnson syndrome and cholestasis after ibuprofen therapy. Liver histology was compatible with vanishing bile duct syndrome. She received ursodeoxycholic acid, and liver tests normalized within 7 months. This report confirms that ibuprofen may induce acute vanishing bile duct syndrome. (J Pediatr 2004;145:273-6)
anishing bile duct syndrome (VBDS) represents a group of biliary diseases with different underlying causes but one common feature, progressive loss of intrahepatic interlobular bile ducts, typically in more than 50% of portal tracts.1-4 It has been associated with primary biliary cirrhosis, sclerosing cholangitis, sarcoidosis, viral infections, Hodgkin disease, allograft rejection, graft-versus-host disease, a-1 antitrypsin deficiency, cystic fibrosis, Alagille syndrome, and drugs.1-9 Acute VBDS is often drug-related.1,2,4,6-9 We report a child in whom severe and rapidly progressive cholestatic jaundice associated with VBDS developed 12 days after initiation of ibuprofen therapy at conventional pediatric doses.
V
CASE REPORT A 10-year-old girl had fever during 2 days and rhinopharyngitis; she received ibuprofen at conventional pediatric doses (maximum of 30 mg/kg/day). Eight days later, the fever relapsed, and she received again ibuprofen. Two days later, maculopapular pruriginous rash appeared on the face. Forty-eight hours later, she was hospitalized because of jaundice, dark urine, discolored stools, arthralgia, cheilitis, conjunctivitis, pharyngeal erythema, and extension of maculopapular rash to the whole body with small bullae. The girl was thought to have Stevens-Johnson syndrome and hepatitis.6 Kawasaki disease was ruled out. She had no adenopathy, hepatosplenomegaly, nor stigmata of chronic liver disease or Alagille syndrome. Her medical history reported nickel contact dermatitis and tonsillectomy. She had been treated, on previous occasions, mainly for fever episodes, with Nonsteroidal antiFrom the Pediatric Unit, Vesoul inflammatory drugs (NSAIDs) such as acetylsalicylic acid and niflumic acid. The patient’s Hospital, Vesoul; the Infectious Disease Unit, the Hepatology Unit, the mother said that her daughter has received ibuprofen at least on one previous occasion, but Pediatric Intensive Care Unit, the this information was not registered in the patient health booklet. Pathology Unit, Besanc xon University Hospital, Besanc xon; the Pediatric Initial liver tests were as follows: total bilirubin level, 93 lmol/L (N < 17 lmol/L); Hepatology Unit, Biceˆtre University conjugated bilirubin, 69 lmol/L (N < 4 lmol/L); aspartate aminotransferase, 333 IU/L Hospital, Assistance Publique–Hoˆpi(N < 50 IU/L); alanine aminotransferase, 639 IU/L (N < 39 IU/L); gamma-glutamyl taux de Paris, Le Kremlin-Biceˆtre, Paris, France. transferase, 275 IU/L (N < 25 IU/L); and alkaline phosphatase, 1697 IU/L (N < 720 IU/L). Submitted for publication Dec 11, 2003; Serum albumin, prothrombin time, and clotting factor V level were normal. Abdominal last revision received Apr 20, 2004; Doppler ultrasonographic and computed tomographic scans showed no abnormality of the accepted May 13, 2004. Reprint requests: Prof Emmanuel liver or bile ducts. Serologic tests for viral hepatitis A, B, C, and G, cytomegalovirus, Jacquemin, De´partement de Pe´diatrie, Epstein Barr virus, parvovirus B19, echovirus, Coxsackie virus, herpes simplex virus, herpes He´patologie Pe´diatrique, Centre 6 virus, human immunodeficiency virus, cat scratch disease, mycoplasma, leptospirosis, Hospitalier Universitaire de Biceˆtre, 78, rue du Ge´ne´ral Leclerc, 94275 toxoplasmosis, and echinococcosis were all negative. Antinuclear, antimitochondrial, anti– Le Kremlin Biceˆtre Cedex, France. smooth muscle, anti–liver/kidney microsomal, anti–liver cytosol, and antineutrophil E-mail: emmanuel.jacquemin@bct. ap-hop-paris.fr. cytoplasmic antibodies were all negative. Immunoglobulin, alpha-1 antitrypsin, ferritin, 0022-3476/$ - see front matter Copyright ª 2004 Elsevier Inc. All rights reserved. NSAIDs
Nonsteroidal anti-inflammatory drugs
VBDS
Vanishing bile duct syndrome
10.1016/j.jpeds.2004.05.027
273
Figure. Evolution of serum liver tests in a child with VBDS appearing after ibuprofen therapy. Total bilirubin level, N < 17 lmol/L; aspartate aminotransferase, N < 50 IU/L; alanine aminotransferase, N < 39 IU/L; gamma-glutamyl transferase, N < 25 IU/L; alkaline phosphatase, N < 720 IU/L; bile acids, N < 15 lmol/L. Figure can be viewed in color online at www.us.elsevierhealth.com/jpeds.
copper, ceruloplasmin, alpha-fetoprotein, and ACE serum levels as well 24-hour urinary copper excretion and sweat test were normal. The search for butterfly-like vertebrae and posterior embryotoxon was negative. All medications were stopped and during the next 2 weeks;, jaundice increased, as did pruritus. A percutaneous liver biopsy including more than 10 portal tracts3 and performed 48 days after stopping ibuprofen therapy showed intrahepatic centrolobular cholestasis with loss of interlobular bile ducts in more than 50% of portal tracts and bile duct injury in the remainder and portal polymorphous infiltrate with numerous eosinophils. There was no portal fibrosis, no granuloma, and no ductular proliferation. These histopathologic features were consistent with the diagnosis of acute VBDS.6 Treatment with ursodeoxycholic acid (600 mg/m2/day or 25 mg/kg/day) and liposoluble vitamins was initiated on hospital day 9. Rifampicin was started on day 45 for persistent pruritus. We observed a favorable outcome with disappearance of pruritus and complete biochemical recovery within 7 months. Evolution of serum liver tests is shown in the Figure. Serum cholesterol level was 4.94 g/L (N: 1.1-2 g/L) at hospital day 9, reached a maximum of 15.94 g/L at hospital day 37, and normalized within 7 months. Skin lesions disappeared within 10 months. Two years later, the child 274
Taghian et al
has a normal activity and physical status and is still receiving ursodeoxycholic acid therapy.
DISCUSSION Acute vanishing bile duct syndrome is a rare cause of prolonged and progressive cholestasis and is often clinically associated to fever, fatigue, upper abdominal pain, and skin rash.2,6 Serum liver tests comprise a generally mild increase in transaminase activities with high total bilirubin concentration, persistently elevated alkaline phosphatase and gammaglutamyl transpeptidase activities, and hypercholesterolemia. The acute symptoms usually subside within days or weeks. Prolonged cholestasis appears thereafter.1,2,6-8 These features were present in the patient reported here. Although it is impossible to prove the cause of the VBDS observed in our patient, it may be reasonably ascribed to ibuprofen because (1) there was no history of liver or biliary tract disease; (2) liver and biliary tract were normal on ultrasonography and computerized scan tomography; (3) the patient had a history of previous treatment with acetylsalicylic acid and niflumic acid (NSAID) a few years ago, and also very likely with ibuprofen; (4) there was a close temporal relation between ibuprofen administration and the appearance of cholestasis; (5) prominent eosinophils The Journal of Pediatrics August 2004
Table. Main characteristics of three cases of acute VBDS associated with ibuprofen use
Age
Sex
Alam et al7
29
M
Asthma Allergic rhinitis Hyposensitization treatment
3 wk
Srivastava et al6
9
F
No known allergy
3d
Stevens-Johnson syndrome
10
F
Nickel contact dermatitis, Tonsillectomy
12 d
Stevens-Johnson syndrome
Present case
Medical history
Interval Between Ibuprofen Intake and VBDS
Authors (ref.)
were present on liver biopsy; and (6) other potential causes of VBDS were excluded including drugs known to induce cholestasis. Ibuprofen has been reported to be responsible for VBDS in a 29-year-old man7 and a 9-year-old girl who had, as in our patient, Stevens-Johnson syndrome.6 In these two cases, a chronic course developed with evidence of cirrhosis, and both patients were referred for liver transplantation (Table). The hepatotoxicity of NSAIDs is being increasingly recognized.6-8,10 Ibuprofen, a member of the propionic acid class of NSAIDs, appears to have a low incidence of hepatic injury.7,8,10-12 The mechanism of interlobular bile duct loss is not fully understood. Toxic and immune causes have been suggested.1,2,6,8,13 The potential of ibuprofen to trigger an immunoallergic reaction is strongly suggested by the association with Stevens-Johnson syndrome.6 Ibuprofen, inhibits cyclo-oxygenase/prostaglandin synthesis.14 When metabolized in the liver, it may form covalent, hapten-like associations with host proteins, leading to a loss of tolerance and destruction of small bile ducts.2,11 In this view, it might be possible that niflumic acid or another NSAID acts as a sensitizer and thus fosters the ibuprofen hepatotoxicity.15 Indeed, StevensJohnson syndrome and cholestasis has been reported in a 19-year-old woman after ketorolac and ibuprofen therapy.16 The prognosis of acute drug-induced VBDS is unpredictable and might be related to the ability of small bile ducts to regenerate.2 Sometimes, secondary biliary cirrhosis may occur with the ultimate development of portal hypertension and decompensated hepatic function.6,7 Treatment for druginduced VBDS includes withdrawal of the causal agent and supportive care by ursodeoxycholic acid, which may correct the impaired hepatocellular excretory capacity for potentially toxic cholephils and protect against injury of the biliary tree induced by hydrophobic bile acids.6,7,17,18 Ursodeoxycholic acid may Acute Vanishing Bile Duct Syndrome After Ibuprofen Therapy in a Child
Associated signs
Medical treatment
Positive CMV-IgM antibodies
Prednisone Antihistaminics Cholestyramine Lovastatin Ursodeoxycholic acid Ursodeoxycholic acid Prednisone Tacrolimus Betamethasone Antihistaminics Ursodeoxycholic acid Rifampicin
Evolution Persistence of jaundice and pruritus >12 mo after onset, patient referred for liver transplantation Persistence of jaundice and pruritus >4 mo after onset, patient referred for liver transplantation Complete clinical and biochemical recovery within 7 mo
have also some immunomodulating properties such as reduction of hepatic aberrant HLA class I expression.17 Although there is no proof of the efficiency of ursodeoxycholic acid treatment in this condition, it could be proposed to continue treatment when effective.18 Reintroduction of ibuprofen as well as other NSAID is strictly proscribed. Ibuprofen-associated VBDS has been exceptionally reported in the pediatric age group.2,6-8 Because this drug is currently widely prescribed in the pediatric population and has potentially very severe adverse events, even in the absence of overdose, it should remain a second-line treatment for fever and pain, after paracetamol.10,12,19 Occurrence of jaundice after ibuprofen must evoke the diagnosis of ibuprofen-induced acute VBDS and lead to discontinuation of ibuprofen therapy and may justify early ursodeoxycholic acid treatment. We are grateful to Drs O. Bernard, N. Khayat, J. M. Estavoyer, B. Hoen, P. Colin, J. P. Carbillet, B. Coupe, P. Thierry, J. M. Jacquet, and N. Haghiri for taking care of the patients and for helpful comments.
REFERENCES 1. Degott C, Feldman G, Larrey D, Durand-Schneider AM, Grange D, Machayekhi JP, et al. Drug-induced prolonged cholestasis in adults: a histological semi-quantitative study demonstrating progressive ductopenia. Hepatology 1992;15:244-51. 2. Geubel AP, Sempoux C, Rahier J. Bile duct disorders. Clin Liver Dis 2003;7:295-309. 3. Hadchouel M. Paucity of interlobular bile ducts. Semin Diagn Pathol 1992;9:24-30. 4. Ludwig J. Vanishing bile duct syndrome. In: Bircher J, Benhamou JP, McIntyre N, et al, editors. Oxford textbook of clinical hepatology. 2nd ed. Oxford: Oxford University Press; 1999. p. 1131-3. 5. Furuya KN, Roberts EA, Canny GJ, Phillips MJ. Neonatal hepatitis syndrome with paucity of interlobular bile ducts in cystic fibrosis. J Pediatr Gastroenterol Nutr 1991;12:127-30.
275
6. Srivastava M, Perez-Atayde A, Jonas MM. Drug associated acute-onset vanishing bile duct and Stevens-Johnson Syndrome in a child. Gastroenterology 1998;115:743-6. 7. Alam I, Ferrell LD, Bass NM. Vanishing bile duct syndrome temporally associated with ibuprofen use. Am J Gastroenterol 1996;91: 1626-30. 8. Chitturi S, Farrell GC. Drug-induced cholestasis. Semin Gastrointest Dis 2001;12:113-24. 9. Dousset B, Conti F, Houssin D, Calmus Y. Acute vanishing bile duct syndrome after interferon therapy for recurrent HCV infection in liver-transplant recipients. N Engl J Med 1994;330:1160-1. 10. Stempel DA, Miller JJ III Lymphopenia and hepatic toxicity with ibuprofen. J Pediatr 1997;90:657-8. 11. Boelslerli UA, Zimmerman HJ, Kretz-Rommel A. Idiosyncratic liver toxicity of non-steroidal anti-inflammatory drugs: molecular mechanisms and pathology. Crit Rev Toxicol 1995;25:207-35. 12. Halpern SM, Fitzpatrick R, Volans GN. Ibuprofen toxicity: a review of adverse reactions and overdose. Adverse Drug React Toxicol Rev 1993;12: 107-28.
276
Taghian et al
13. Batts KP, Moore SB, Perkins JD, Wiesner RH, Grambsch PM, Krom RA. Influence of positive lymphocyte crossmatch and HLA mismatching on vanishing bile duct syndrome in human liver allografts. Transplantation 1988; 45:376-9. 14. Fiorucci S, Antonelli E. Cyclo-oxygenase isoenzymes: structural basis for selective inhibition of cyclo-oxygenases by anti-inflammatory agents. Dig Liver Dis 2001;33:S2-7. 15. Menniti-Ippolito F, Sagliocca L, Da Cas R, Saggiomo G, Di Nardo R, Traversa G, et al. Niflumic acid and cutaneous reactions in children. Arch Dis Child 2001;84:430-1. 16. Morelli MS, O’Brien FX. Stevens-Johnson syndrome and cholestatic hepatitis. Dig Dis Sci 2001;46:2385-8. 17. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 2002; 36:525-31. 18. O’Brien CB, Shields DS, Saul SH, Reddy KR. Drug-induced vanishing bile duct syndrome: response to ursodiol. Am J Gastroenterol 1996;91:1456-7. 19. Cranswick N, Coghlan D. Paracetamol efficacy and safety in children: the first 40 years. Am J Ther 2000;7:135-41.
The Journal of Pediatrics August 2004