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DRUG RECORD

 

TRANSPLANT AGENTS

OVERVIEW
Transplant Agents

 

Solid organ transplantation has been made possible by the development of potent immunosuppressive agents which block cellular rejection adequately for survival of the transplanted organ and induction of at least partial tolerance.  The first regimens that were found to successfully prevent cellular rejection consisted of high doses of corticosteroids and an immunosuppressive antimetabolite such as azathioprine, 6-mercaptopurine or cyclophosphamide.  These combinations allowed for the initial successes in renal, liver, lung and heart transplantation in the 1950s and 1960s.  However, acute and chronic rejection as well as complications of high dose corticosteroid therapy remained major problems.  The subsequent introduction of the calcineurin inhibitors, cyclosporine and tacrolimus in the 1980s placed organ transplantation on a solid basis, leading to its acceptance as the standard of care for end-stage kidney, liver, heart and lung disease.  The further addition of the newer, more specific antiproliferative and immunosuppressive agents–mycophenolate mofetil (1995) and sirolimus (1999)–have further improved the management of patients after solid organ transplantation.  All of these agents are associated with mild liver test abnormalities that occur early during therapy or shortly after transplantation and that resolve rapidly with dose modification.  While these potent immunosuppressive agents all have some degree of liver toxicity, clinically significant injury is rare and has invariably been mild and rapidly reversible with dose modification or switching to another agent.  These agents are often used in patients with underlying liver disease or who are receiving multiple potentially hepatotoxic drugs, so that their role in causing hepatic injury is not always clear.

The following drugs used to prevent transplant rejection are discussed separately.  The references regarding the hepatotoxicity and safety of these agents are given together below.

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REFERENCES
Transplant Agents

 

References updated:  16 December 2013

  1. Zimmerman HJ. Cyclosporine. Oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 697-8.  (Expert review of hepatotoxicity published in 1999; cyclosporine therapy was associated with a high rate of cholestatic liver enzyme elevations ranging from 4-86% and occasional instances of cholestatic hepatitis, some features of which were reproducible in animal models; tacrolimus, sirolimus, and mycophenolate are not discussed).

  2. Reuben A.  Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 569-92.  (Review of hepatotoxicity of immunosuppressive agents mentions that reports of hepatotoxicity of cyclosporine have decreased since the 1980s, perhaps because of monitoring of serum levels and lower doses used; liver injury from tacrolimus, sirolimus and mycophenolate is rare and usually rapidly reversible).

  3. Krensky AM, Bennett WM, Vincenti F.  Immnosuppressants, tolerogens, and immunostimulants.  In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1005-30.  (Textbook of pharmacology and therapeutics).

  4. Calne RY, Rolles K, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs, 32 kidneys, 2 pancreas, and 2 livers. Lancet 1979; 2: 1033-6. PubMed Citation  (Initial experience with cyclosporine in 34 transplant recipients; all but 2 patients had liver test abnormalities early after operation, mostly raised bilirubin and Alk P resolving with lowering dose).

  5. Starzl TE, Klintmalm GB, Weil R 3rd, Porter KA, Iwatsuki S, Schroter GP, Fernandez-Bueno C, et al. Cyclosporin A and steroid therapy in sixty-six cadaver kidney recipients. Surg Gynecol Obstet 1981; 153: 486-94. PubMed Citation  (Early experience in using cyclosporine in 66 renal transplant recipients; two patents were switched to azathioprine because of hepatotoxicity, and liver function abnormalities occurred in 13 patients [20%], but no details given).

  6. Loertscher R, Wenk M, Harder F, Brunner F, Follath F, Thiel G. Hyperbilirubinaemia and cyclosporin A levels in renal transplant patients. Lancet 1981; 2: 635-6. PubMed Citation  (Among 8 patients receiving cyclosporine after renal transplantation, there was only a loose association between bilirubin and cyclosporine levels, serum bilirubin being elevated in 5 patients and decreasing with dose reduction [peak 4.2 mg/dL]).

  7. Laupacis A, Keown PA, Ulan RA, Sinclair NR, Stiller CR. Hyperbilirubinaemia and cyclosporin A levels. Lancet 1981; 2: 1426-7. PubMed Citation  (4 of 21 renal transplant recipients developed elevations in serum bilirubin [1.1-4.5 mg/dL] 4-12 days after transplant, which correlated with higher cyclosporine levels).

  8. Klintmalm GB, Iwatsuki S, Starzl TE. Cyclosporin A hepatotoxicity in 66 renal allograft recipients. Transplantation 1981; 32:4 88-9. PubMed Citation  (Among 66 renal transplant recipients on cyclosporine, 13 [17%] had rise of bilirubin above 2.0 [range 2.1-4.5] mg/dL, with minimal or no change in ALT or Alk P, and all episodes were mild and easily managed by dose reduction).

  9. Ferguson RM, Rynasiewicz JJ, Sutherland DE, Simmons RL, Najarian JS. Cyclosporin A in renal transplantation: a prospective randomized trial. Surgery 1982; 92: 175-82. PubMed Citation  (Controlled trial of cyclosporine and prednisone vs azathioprine, prednisone and antilymphocyte globulin in 100 renal transplant patients, hepatotoxicity was uncommon and mild; 3 of 48 patients on cyclosporine had mild bilirubin elevations [1.6-2.5 mg/dL], which were rapidly reversible with dose adjustment).

  10. Rodger S, Turney JH, Haynes I, McMaster P, Michael J, Adu D. Normal liver function in renal allograft recipients treated with cyclosporine. Transplantation 1983; 36: 451-2. PubMed Citation  (Among 35 renal transplant recipients, liver test abnormalities arose in 8 including 4 of 21 on cyclosporine, but other causes were found to be the cause in all eight [infection or heart failure]).

  11. European Multicentre Trial Group. Cyclosporine in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet 1983; 2: 986-9. PubMed Citation  (Controlled trial of cyclosporine vs azathioprine and corticosteroids in 232 transplant recipients showing improved graft survival with cyclosporine; "mild, clinically insignificant degrees of hepatic functional impairment were observed in some cyclosporine-treated patients").

  12. Canadian Multicenter Transplant Study Group. A randomized clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med 1983; 309: 809-15. PubMed Citation  (Controlled trial of cyclosporine vs azathioprine and corticosteroids in 209 transplant recipients showing improved graft survival; 4 instances of hepatotoxicity occurred in cyclosporine recipients usually associated with high plasma levels).

  13. Najarian JS, Strand M, Fryd DS, Ferguson RM, Simmons RL, Ascher NL, Sutherland DER. Comparison of cyclosporine versus azathioprine-antilymphocyte globulin in renal transplantation. Transplant Proc 1983; 15 (4 Suppl 1): 2463-8. Not in PubMed.

  14. Schade RR, Guglielmi A, van Thiel DH, Thompson ME, Warty V, Griffith B, Sanghvi A, et al. Cholestasis in heart transplant recipients treated with cyclosporine. Transplant Proc 1983; 15 (4 Suppl 1): 2757-60. Not in PubMed.

  15. Atkinson K, Biggs J, Dodds A, Concannon A. Cyclosporine-associated hepatotoxicity after allogeneic marrow transplantation in man: differentiation from other causes of posttransplant liver disease. Transplant Proc 1983; 15 (4 Suppl 1): 2761-7. Not in PubMed.

  16. Cohen DJ, Loertscher R, Rubin MF, Tilney NL, Carpenter CB, Strom TB. Cyclosporine: a new immunosuppressive agent for organ transplantation. Ann Intern Med 1984; 101: 667-82. PubMed Citation  (Review of mechanism of action, clinical experience and side effects of cyclosporine; elevations in serum bilirubin reported in 20% of patients on cyclosporine after transplant, enzyme elevations were uncommon and "clinically, hepatotoxicty has been of little significance").

  17. Palestine AG, Nussenblatt RB, Chan CC. Side effects of systemic cyclosporine in patients not undergoing transplantation. Am J Med 1984; 77: 652-6. PubMed Citation  (Among 22 patients with autoimmune uveitis treated with cyclosporine, side effects were fewer and less severe than after transplantation; only one patient had elevations in serum bilirubin [peak 1.6 mg/dL] and aminotransferase elevations did not occur).

  18. Welz A, Reichart B, Uberfuhr P, Kemkes B, Klinner W. Cyclosporine as the main immunosuppressant in clinical heart transplantation: correlation of hepatotoxicity and nephrotoxicity. Transplant Proc 1984; 16: 1212-3. PubMed Citation  (Among 10 patients undergoing heart transplantation and receiving cyclosporine, five with preexisting hepatic congestion had higher cyclosporine levels and higher serum bilirubin levels than the 5 without preexisting liver abnormalities [mean peak 5.8 vs 1.3 mg/dL]).

  19. McKenzie FN, Moses GC, Henderson AR. Routine "cardiac" and "hepatic" serum enzyme profiles in cardiac transplant patients treated with cyclosporine A: operative and postoperative findings. Clin Chem 1985; 31: 822-5. PubMed Citation  (Prospective study of liver test abnormalities in 20 heart transplant recipients receiving cyclosporine found that transient elevations in ALT and AST were common during the 2 weeks after transplant).

  20. Jensen CW, Flechner SM, Van Buren CT, Frazier OH, Cooley DA, Lorber MI, Kahan BD. Exacerbation of cyclosporine toxicity by concomitant administration of erythromycin. Transplantation 1987; 43: 263-70. PubMed Citation  (Concurrent erythromycin led to elevations in cyclosporine levels and more toxicity in 9 transplant recipients, median serum bilirubin levels being 1.2 before, 2.1 during and 0.8 mg/dL after a course of the macrolide antibiotic).

  21. Stone BG, Udani M, Sanghvi A, Warty V, Plocki K, Bedetti CD, Van Thiel DH. Cyclosporin A-induced cholestasis. The mechanism in a rat model. Gastroenterology 1987; 93: 344-51. PubMed Citation  (In rats, cyclosporine led to decrease in bile flow [35%] and rise in serum bile acid levels without change in ALT or bilirubin).

  22. Kahan BD, Flechner SM, Lorber MI, Golden D, Conley S, Van Buren CT. Complications of cyclosporine-prednisone immunosuppression in 402 renal allograft recipients exclusively followed at a single center for from one to five years. Transplantation 1987; 43: 197-204. PubMed Citation  (Retrospective analysis of complications of cyclosporine in 402 renal transplant recipients; 50% had at least one liver test abnormality in first month, 20% at one year and 10% at 3 years; no details given).

  23. Lorber MI, Van Buren CT, Flechner SM, Williams C, Kahan BD. Hepatobiliary and pancreatic complications of cyclosporine therapy in 466 renal transplant recipients. Transplantation 1987; 43: 35-40. PubMed Citation  (Among 466 patients undergoing renal transplantation, 49% developed liver test abnormalities after transplant [bilirubin in 48%, ALT 73%, Alk P 59%], but abnormalities were usually early [<90 days], mild and self-limiting; among 32 with persistent abnormalities, 11 had cholelithiasis).

  24. Gulbis B, Adler M, Ooms HA, Desmet JM, Leclerc JL, Primo G. Liver-function studies in heart-transplant recipients treated with cyclosporin A. Clin Chem 1988; 34: 1772-4. PubMed Citation  (Prospective study of liver tests in 17 heart transplant recipients found rises in bile acid and GGT levels only, which occurred only in those with preexisting liver injury).

  25. Cadranel JF, Grippon P, Mattei MF, Lunel F, Pauwels A, Rossant P, Karkouche B, et al. Prevalence and causes of long-lasting hepatic dysfunction after heart transplantation: a series of 80 patients. Artif Organs 1988; 12: 234-8. PubMed Citation  (Among 80 heart transplant recipients, 62% had persistent liver test abnormalities, usually due to heart failure [9%], hepatitis B [26%], non-A, non-B hepatitis [28%] and drug [not cyclosporine]-induced liver injury [14%]).

  26. Kassianides C, Nussenblatt R, Palestine AG, Mellow SD, Hoofnagle JH. Liver injury from cyclosporine A. Dig Dis Sci 1990; 35: 693-7. PubMed Citation  (Retrospective analysis of liver test abnormalities arising in 59 patients with autoimmune uveitis being treated with cyclosporine; persistent biochemical evidence of mild cholestasis [Alk P and bilirubin elevations] occurred in 32% of patients, but was usually self-limited and asymptomatic, improving spontaneously or with dose modification in all cases).

  27. Rush DN. Cyclosporine toxicity to organs other than the kidney. Clin Biochem 1991; 24: 101-5. PubMed Citation  (Review of mechanism of toxicity of cyclosporine; hyperbilirubinemia may be caused by inhibition of bile flow).

  28. Wisecarver JL, Earl RA, Haven MC, Timmins PW, Shaw BW Jr, Stratta RJ, Langnas AN, et al. Histologic changes in liver allograft biopsies associated with elevated whole blood and tissue cyclosporine concentrations. Mod Pathol 1992; 5: 611-6. PubMed Citation  (Among 16 patients on cyclosporine after liver transplantation, histology of liver showed minor abnormalities of bile duct epithelium).

  29. Demetris AJ, Fung JJ, Todo S, McCauley J, Jain A, Takaya S, Alessiani M, et al. Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy - a clinicopathologic study of 96 patients. Transplantation 1992; 53: 1056-62. PubMed Citation  (Switching patients from cyclosporine to tacrolimus often improved acute rejection, but rarely improved chronic liver injury or suspected hepatotoxicity).

  30. Mor E, Sheiner PA, Schwartz ME, Emre S, Guy S, Miller CM. Reversal of severe FK506 side effects by conversion to cyclosporine-based immunosuppression. Transplantation 1994; 58: 380-2. PubMed Citation  (Severe side effects of tacrolimus therapy requiring dose modification or switching to cyclosporine occurred in 15 of 90 patients [17%] including nephropathy, diabetes, and neuropathy, but not hepatotoxicity).

  31. Jazzar A, Fagiuoli S, Caraceni P, Deal S, Wright HI, Sisson S, Gavaler J, et al. Incidence and etiology of hepatic dysfunction in heart transplant recipients receiving a cyclosporine-based triple immunosuppressive therapy. Transplant Proc 1994; 26: 2654. PubMed Citation  (Among 100 heart transplant recipients, 52 had abnormal liver tests, causes being viral hepatitis in 27%, azathioprine in 54%, unknown in 23% which were usually mild and spontaneously reversible).

  32. Fisher A, Mor E, Hytiroglou P, Emre S, Boccagni P, Chodoff L, Sheiner P, et al. FK506 hepatotoxicity in liver allograft recipients. Transplantation 1995; 59: 1631-2. PubMed Citation  (Among 50 liver transplant recipients treated with tacrolimus, 6 had liver test abnormalities not explained by rejection or hepatitis, which resolved or improved on lowering dose or switching rejection therapy [bilirubin levels not given, ALT 121-744 U/L, Alk P 68-1293 U/L], biopsies showed centrolobular dropout).

  33. Kowdley KV, Keeffe EB. Hepatotoxicity of transplant immunosuppressive agents. Gastroenterol Clin North Am 1995; 24: 991-1001. PubMed Citation  (Review of reports of hepatotoxicity from cyclosporine in form of mild hyperbilirubinemia, mild to moderate serum enzyme elevations and biliary sludge and stones).

  34. Moore RA, Greenberg E, Tangen L. Cyclosporine-induced worsening of hepatic dysfunction in a patient with Crohn's disease and enterocutaneous fistula. South Med J 1995; 88: 843-4. PubMed Citation  (44 year old man with severe Crohn disease on total parenteral nutrition [TPN] developed marked bilirubin rises after starting cyclosporine [from 4.7 to 17.5 mg/dL], which resolved upon stopping both cyclosporine and TPN).

  35. Simmons WD, Rayhill SC, Sollinger HW. Preliminary risk-benefit assessment of mycophenolate mofetil in transplant rejection. Drug Saf 1997; 17: 75-92. PubMed Citation  (Review of mechanism of action, pharmacology, clinical efficacy and toxicity of mycophenolate for transplant rejection; gastrointestinal intolerance was the most common side effect, no mention of effect on ALT levels or hepatotoxicity).

  36. Ertöter ME, Payda. S, Sagliker Y. Hyperbilirubinemia in a renal transplant patient due to cyclosporin A therapy. Nephron 1997; 76: 368. PubMed Citation  (50 year old male renal transplant recipient developed jaundice and fever [bilirubin 6.0 mg/dL, ALT 20 U/L, Alk P 263 U/L], resolving on stopping cyclosporine and recurring 3 months after restarting [bilirubin 3.4 mg/dL, ALT 72 U/L, Alk P 400 U/L], resolving within 2 weeks of stopping).

  37. Tsamandas AC, Jain AB, Felekouras ES, Fung JJ, Demetris AJ, Lee RG. Central venulitis in the allograft liver: a clinicopathologic study. Transplantation 1997; 64: 252-7. PubMed Citation  (Among 27 patients with central venulitis receiving cyclosporine or tacrolimus, there was no association with drug levels and the histological lesion was attributed to rejection rather than drug induced liver injury).

  38. Ngo MD, Hagè H, Rosa I, Cartier VA, Lons T, Gordin J, Chousterman M. [Acute hepatitis in the course of cyclosporine therapy of Crohn's disease]. Presse Med 1999; 28: 1873-5. French. PubMed Citation  (26 year old woman with Crohn's disease on total parenteral nutrition developed marked rises in ALT [30 times ULN] and minimal increase in Alk P and bilirubin 1 week after starting cyclosporine, resolving within 2 weeks of stopping; multiple other drugs given).

  39. Yuan QS, Zheng FL, Sun Y, Yu Y, Li Y. Rescue therapy with tacrolimus in renal graft patients with cyclosporine A-induced hepatotoxicity: a preliminary study. Transplant Proc 2000; 32:1694-5. PubMed Citation  (7 renal transplant recipients with suspected cyclosporine hepatotoxicity were switched to tacrolimus, ALT levels decreased from 28-119 to 24-43 U/L; no mention of bilirubin, Alk P or symptoms).

  40. Emre S, Genyk Y, Schluger LK, Fishbein TM, Guy SR, Sheiner PA, Schwartz ME, et al. Treatment of tacrolimus-related adverse effects by conversion to cyclosporine in liver transplant recipients. Transpl Int 2000; 13: 73-8. PubMed Citation  (Among 388 liver transplant recipients treated with tacrolimus, 70 required conversion to cyclosporine because of side effects, including 6 for late hepatotoxicity, often for steatohepatitis or recurrent autoimmune hepatitis, with improvement in 4).

  41. Basara N, Fauser AA. Safety profile of mycophenolate mofetil. Bone Marrow Transplant 2000; 26: 1362-3. PubMed Citation  (Letter stressing the good safety profile of mycophenolate and that severe liver injury after bone marrow transplantation is more likely due to graft-vs-host disease than drug induced liver injury).

  42. Kahan BD. Sirolimus: a comprehensive review. Expert Opin Pharmacother 2001; 2: 1903-17. PubMed Citation  (Review of chemical structure, pharmacology, mechanism of action, clinical efficacy and safety of sirolimus; most serious adverse effects are hyperlipidemia and myelosuppression; no mention of hepatotoxicity or ALT levels).

  43. Corrieri-Baizeau C, Dumortier J, Scoazec JY, Poncet G, Choucair A, Vial T, Boillot O. [Mycophenolate mofetil induced acute hepatitis]. Gastroenterol Clin Biol 2002; 26: 300-1. French. PubMed Citation  (36 year old liver transplant recipient developed ALT elevations 5 times ULN 2 weeks after starting mycophenolate [bilirubin normal, Alk P 1.5 times ULN], biopsy not showing rejection and tests returning to normal 6 weeks after stopping mycophenolate).

  44. Sen HN, Suhler EB, Al-Khatib SQ, Djalilian AR, Nussenblatt RB, Buggage RR. Mycophenolate mofetil for the treatment of scleritis. Ophthalmology 2003; 110: 1750-5. PubMed Citation  (One of 8 patients with scleritis treated with mycophenolate developed liver test abnormalities, but patient was also receiving methotrexate).

  45. Dunkelberg JC, Trotter JF, Wachs M, Bak T, Kugelmas M, Steinberg T, Everson GT, et al. Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications. Liver Transpl 2003; 9: 463-8. PubMed Citation  (Retrospective analysis of outcome of 170 patients undergoing liver transplantation and treatment with sirolimus found no increase in hepatic artery complications in comparison to historic controls).

  46. Montalbano M, Neff GW, Yamashiki N, Meyer D, Bettiol M, Slapak-Green G, Ruiz P, et al. A retrospective review of liver transplant patients treated with sirolimus from a single center: an analysis of sirolimus-related complications. Transplantation 2004; 78: 264-8. PubMed Citation  (Retrospective analysis of complications among 91 liver transplant recipients treated with sirolimus; common side effects were edema, oral ulcers and dermatitis; 12 developed liver test abnormalities that resolved only with stopping drug, and 2 cases of hepatic artery thrombosis).

  47. Neff GW, Ruiz P, Madariaga JR, Nishida S, Montalbano M, Meyer D, Levi DM, et al. Sirolimus-associated hepatotoxicity in liver transplantation. Ann Pharmacother 2004; 38: 1593-6. PubMed Citation  (Among 210 liver transplant recipients who received sirolimus, 10 had evidence of hepatotoxicity but 6 had chronic hepatitis C and others rejection as primary or contributing cause).

  48. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. PubMed Citation  (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, 124 for acetaminophen and 137 for other drugs or toxins, but none for agents used to prevent transplant rejection).

  49. Balal M, Demir E, Paydas S, Sertdemir Y, Erken U. Uncommon side effect of MMF in renal transplant recipients. Ren Fail 2005; 27: 591-4. PubMed Citation  (Among 79 renal transplant recipients receiving mycophenolate, 11 had serum ALT elevations [51-508 U/L] 4-70 days after transplant and resolving with lowering dose or stopping mycophenolate).

  50. Niemczyk M, Wyzga. J, Perkowska A, Porowski D, Paczek L. Sirolimus-associated hepatotoxicity in the kidney graft recipient. Transpl Int 2005; 18: 1302-3. PubMed Citation  (30 year old man developed persistent ALT elevations 16 months after renal transplant, resolving only when sirolimus was stopped at 24 months).

  51. Ganschow R, Albani J, Grabhorn E, Richter A, Burdelski M. Tacrolimus-induced cholestatic syndrome following pediatric liver transplantation and steroid-resistant graft rejection. Pediatr Transplant 2006; 10: 220-4. PubMed Citation  (Among 112 children undergoing liver transplantation and switched from cyclosporine to tacrolimus because of steroid resistant rejection, 6 [5.4%] developed a cholestatic syndrome within 2 weeks of change of medications).

  52. Shah S, Budev M, Blazey H, Fairbanks K, Mehta A. Hepatic veno-occlusive disease due to tacrolimus in a single-lung transplant patient. Eur Respir J 2006; 27: 1066-8. PubMed Citation  (60 year old woman developed sinusoidal obstruction syndrome 18 months after lung transplant, which the authors attributed to tacrolimus therapy).

  53. Loupy A, Anglicheau D, Mamzer-Bruneel MF, Martinez F, Thervet E, Legendre C, Serpaggi J, et al. Mycophenolate sodium-induced hepatotoxicity: first report. Transplantation 2006; 82: 581. PubMed Citation  (42 year old renal transplant recipient with chronic hepatitis C developed rash and jaundice 17 days after switching from sirolimus to mycophenolate [bilirubin 11.1 mg/dL, ALT 140 U/L], with no change in HCV RNA levels and resolution upon stopping mycophenolate).

  54. Jakab SS, West AB, Meighan DM, Brown RS Jr, Hale WB. Mycophenolate mofetil for drug-induced vanishing bile duct syndrome. World J Gastroenterol 2007; 13: 6087-9. PubMed Citation  (69 year old man developed jaundice followed by vanishing bile duct syndrome 3 weeks after a course of amoxicillin/clavulanate, which appeared to improve upon corticosteroid and then mycophenolate therapy).

  55. Dourakis SP, Boki K, Soultati A, Cherouvim E, Delladetsima I. Acute hepatitis following mycophenolate mofetil administration for ANCA-positive vasculitis. Scand J Rheumatol 2007; 36: 237-9. PubMed Citation  (73 year old man with systemic vasculitis developed abnormal liver tests 5 months after starting mycophenolate [bilirubin 1 mg/dL, ALT 750 U/L, Alk P 500 U/L], resolving 12 weeks after stopping).

  56. Taniai N, Akimaru K, Ishikawa Y, Kanada T, Kakinuma D, Mizuguchi Y, Mamada Y, et al. Hepatotoxicity caused by both tacrolimus and cyclosporine after living donor liver transplantation. J Nippon Med Sch 2008; 75: 187-91. PubMed Citation  (56 year old liver transplant recipient developed fluctuating ALT elevations [averaging 200-300 U/L] and bilirubin elevations [peak 11 mg/dL] that were not explained by rejection or infection and appeared to respond transiently to changing from tacrolimus to cyclosporine and then recurring, ultimately treated with lower doses of tacrolimus and mycophenolate).

  57. Jacques J, Dickson Z, Carrier P, Essig M, Guillaudeau A, Lacour C, Bocquentin F, et al. Severe sirolimus-induced acute hepatitis in a renal transplant recipient. Transpl Int 2010; 23: 967-70. PubMed Citation  (54 year old man developed fatigue 1-2 months after switching from cyclosporine to sirolimus after renal transplantation [bilirubin 5.3 mg/dL, ALT 609 U/L, GGT 1043 U/L], resolving within 2 months of switching back to cyclosporine).

  58. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, none were attributed to cyclosporine, tacrolimus, sirolimus or mycophenolate).

  59. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none to an agent used to prevent transplant rejection).

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