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Indirect hyperbilirubinemia caused by cyclosporine
622 Brief reports
J AM ACAD DERMATOL OCTOBER 2002
Indirect hyperbilirubinemia caused by cyclosporine Arash Kimyai-Asadi, MD, and Ming H. Jih, MD, PhD New York, New York
From The Ronald O. Perelman Department of Dermatology, The New York University School of Medicine. Funding sources: None. Conflicts of interest: None. Reprints not available from authors. Correspondence: Arash Kimyai-Asadi, MD, 401 E 34th St, S-6N, New York, NY 10016. J Am Acad Dermatol 2002;47:622-3. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 ⫹ 0 16/54/124082 doi:10.1067/mjd.2002.124082
C
yclosporine causes cholestasis resulting from inhibition of bile salt export pumps in 58% of patients.1,2 Elevated indirect bilirubin levels, however, are exceedingly rare, having been reported previously in only 2 patients.3 A 26-year-old 50-kg woman with no personal or family history of jaundice and receiving no medications presented with biopsy-proven psoriatic exfoliative erythroderma. After she began receiving cyclosporine, 3 mg/kg per day, her total bilirubin level
J AM ACAD DERMATOL VOLUME 47, NUMBER 4
rose from a baseline of 0.9 to 1.5 mg/dL (normal, 0.2-1.3 mg/dL). A dose of 4 mg/kg per day resulted in further elevation of the bilirubin level to 2.3 mg/ dL. Although she remained asymptomatic, cyclosporine was discontinued pending further evaluation. Throughout the treatment period, her direct bilirubin level had remained at 0.1 to 0.2 mg/dL (normal, 0-0.2 mg/dL). Serum transaminase, alkaline phosphatase, ␥-glutamyltransferase, creatinine, hemoglobin, and hematocrit values had remained consistently normal and stable. Serum haptoglobin, lactate dehydrogenase, and reticulocyte indices were normal, as were hepatitis A, B, and C serologies. Although the bilirubin level normalized within 1 week of cyclosporine discontinuation, a psoriatic flare necessitated resumption of cyclosporine therapy. Over the ensuing month, her bilirubin level rose to 2.1 mg/dL and subsequently remained stable over the ensuing 4 months (1.9-2.7 mg/dL) (Fig 1). The onset of indirect hyperbilirubinemia promptly after initiation of cyclosporine therapy, its further doseand time-related exacerbations, its rapid resolution with discontinuation of cyclosporine, its prompt recurrence on rechallenge, and the exclusion of other causes strongly suggest that cyclosporine was the culprit. This implies that cyclosporine, like rifampicin and fusidic acid, either inhibits the hepatic uptake or conjugation of bilirubin or competes with bilirubin for albumin-binding.4,5 In this and the previously reported cases, the indirect hyperbilirubinemia was mild, dose related, and readily resolved with drug discontinuation. We recommend monitoring of indirect bilirubin
Brief reports 623
Fig 1. Pattern of total (B tot) and direct (B dir) serum bilirubin levels and cyclosporine dose during 6 months of treatment.
levels in patients receiving cyclosporine and discontinuing cyclosporine only if clinically indicated. Increases in indirect bilirubin levels should be investigated for other potential causes, including Gilbert’s syndrome and hemolysis. REFERENCES 1. Kullak-Ublick GA, Stieger B, Hagenbuch B, Meier PJ. Hepatic transport of bile salts. Semin Liver Dis 2000;20:273-92. 2. Kassianides C, Nussenblatt R, Palestine AG, Mellow SD, Hoofnagle JH. Liver injury from cyclosporine A. Dig Dis Sci 1990;35:693-7. 3. Edefonti A, Ghio L, Bettinelli A, Paterlini G, Giani M, Nebbia G, et al. Unconjugated hyperbilirubinemia due to ciclosporin administration in children with nephritic syndrome. Contrib Nephrol 1988;67: 121-4. 4. Westphal JF, Vetter D, Brogard JM. Hepatic side effects of antibiotics. J Antimicrob Chemother 1994;33:387-401. 5. Brodersen R. Fusidic acid binding to serum albumin and interaction with binding of bilirubin. Acta Pediatr Scand 1985;74:874-80.
J AM ACAD DERMATOL OCTOBER 2002
Indirect hyperbilirubinemia caused by cyclosporine Arash Kimyai-Asadi, MD, and Ming H. Jih, MD, PhD New York, New York
From The Ronald O. Perelman Department of Dermatology, The New York University School of Medicine. Funding sources: None. Conflicts of interest: None. Reprints not available from authors. Correspondence: Arash Kimyai-Asadi, MD, 401 E 34th St, S-6N, New York, NY 10016. J Am Acad Dermatol 2002;47:622-3. Copyright © 2002 by the American Academy of Dermatology, Inc. 0190-9622/2002/$35.00 ⫹ 0 16/54/124082 doi:10.1067/mjd.2002.124082
C
yclosporine causes cholestasis resulting from inhibition of bile salt export pumps in 58% of patients.1,2 Elevated indirect bilirubin levels, however, are exceedingly rare, having been reported previously in only 2 patients.3 A 26-year-old 50-kg woman with no personal or family history of jaundice and receiving no medications presented with biopsy-proven psoriatic exfoliative erythroderma. After she began receiving cyclosporine, 3 mg/kg per day, her total bilirubin level
J AM ACAD DERMATOL VOLUME 47, NUMBER 4
rose from a baseline of 0.9 to 1.5 mg/dL (normal, 0.2-1.3 mg/dL). A dose of 4 mg/kg per day resulted in further elevation of the bilirubin level to 2.3 mg/ dL. Although she remained asymptomatic, cyclosporine was discontinued pending further evaluation. Throughout the treatment period, her direct bilirubin level had remained at 0.1 to 0.2 mg/dL (normal, 0-0.2 mg/dL). Serum transaminase, alkaline phosphatase, ␥-glutamyltransferase, creatinine, hemoglobin, and hematocrit values had remained consistently normal and stable. Serum haptoglobin, lactate dehydrogenase, and reticulocyte indices were normal, as were hepatitis A, B, and C serologies. Although the bilirubin level normalized within 1 week of cyclosporine discontinuation, a psoriatic flare necessitated resumption of cyclosporine therapy. Over the ensuing month, her bilirubin level rose to 2.1 mg/dL and subsequently remained stable over the ensuing 4 months (1.9-2.7 mg/dL) (Fig 1). The onset of indirect hyperbilirubinemia promptly after initiation of cyclosporine therapy, its further doseand time-related exacerbations, its rapid resolution with discontinuation of cyclosporine, its prompt recurrence on rechallenge, and the exclusion of other causes strongly suggest that cyclosporine was the culprit. This implies that cyclosporine, like rifampicin and fusidic acid, either inhibits the hepatic uptake or conjugation of bilirubin or competes with bilirubin for albumin-binding.4,5 In this and the previously reported cases, the indirect hyperbilirubinemia was mild, dose related, and readily resolved with drug discontinuation. We recommend monitoring of indirect bilirubin
Brief reports 623
Fig 1. Pattern of total (B tot) and direct (B dir) serum bilirubin levels and cyclosporine dose during 6 months of treatment.
levels in patients receiving cyclosporine and discontinuing cyclosporine only if clinically indicated. Increases in indirect bilirubin levels should be investigated for other potential causes, including Gilbert’s syndrome and hemolysis. REFERENCES 1. Kullak-Ublick GA, Stieger B, Hagenbuch B, Meier PJ. Hepatic transport of bile salts. Semin Liver Dis 2000;20:273-92. 2. Kassianides C, Nussenblatt R, Palestine AG, Mellow SD, Hoofnagle JH. Liver injury from cyclosporine A. Dig Dis Sci 1990;35:693-7. 3. Edefonti A, Ghio L, Bettinelli A, Paterlini G, Giani M, Nebbia G, et al. Unconjugated hyperbilirubinemia due to ciclosporin administration in children with nephritic syndrome. Contrib Nephrol 1988;67: 121-4. 4. Westphal JF, Vetter D, Brogard JM. Hepatic side effects of antibiotics. J Antimicrob Chemother 1994;33:387-401. 5. Brodersen R. Fusidic acid binding to serum albumin and interaction with binding of bilirubin. Acta Pediatr Scand 1985;74:874-80.