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Acute liver damage following intravenous glucocorticoid treatment for Graves’ ophthalmopathy

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Abstract

Purpose

Over the last years, there have been several reports on the occurrence of acute liver damage (ALD) in patients affected with Graves’ ophthalmopathy (GO) receiving intravenous glucocorticoids (ivGCs). This article is aimed at reviewing the literature on this specific topic and reporting two new cases of ALD occurring in GO patients while on ivGCs.

Methods

The terms “glucocorticoid therapy” and “Graves’ Ophthalmopathy”/“Graves’ Orbitopathy”/”Thyroid eye disease” were used both separately and in conjunction with the terms “liver disease,” “liver damage,” “hepatotoxicity,” “liver failure,” to search MEDLINE for articles published since the first report of ALD in 2000 and up to 2015.

Results

ALD [defined as an increase in alanine aminotransferase (ALT) >300 U/L] during or after completion of ivGCs has been so far reported in 17 fully documented cases. Overall, one-half of those patients were diagnosed as having autoimmune hepatitis (AIH) and in the vast majority of the remaining cases a diagnosis of methylprednisolone(MP)-induced hepatotoxicity was suspected. The clinical course of liver injury varied from asymptomatic hypertransaminasemia in the vast majority of patients to fatal hepatic failure in four patients receiving higher (>8 g) cumulative doses of MP.

Conclusions

The overall risk of ALD is relatively low (~1 %), and seems higher using a single dose >0.5 g and a cumulative dose >8.5 g MP. Whenever ivGC treatment is required, serum liver enzymes, viral hepatitis markers, and autoantibodies related to AIH should be obtained prior to ivGC administration. Liver function should be monitored during ivGC and up to 6 months after the end of treatment. Prolonging observation after 6 months is likely unnecessary, since all cases of ALD so far reported always occurred well within this term.

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References

  1. P. Perros, G.E. Krassas, Graves’ orbitopathy: a perspective. Nat. Rev. Endocrinol. 5, 312–318 (2009)

    Article  PubMed  Google Scholar 

  2. L. Bartalena, V. Fatourechi, Extrathyroidal manifestations of Graves’ disease: a 2014 update. J. Endocrinol. Invest. 37, 691–700 (2014)

    Article  CAS  PubMed  Google Scholar 

  3. E. Piantanida, M.L. Tanda, A. Lai, L. Sassi, L. Bartalena, Prevalence and natural history of Graves’ orbitopathy in the XXI century. J. Endocrinol. Invest. 36, 444–449 (2013)

    CAS  PubMed  Google Scholar 

  4. F. Menconi, M.A. Profilo, M. Leo, E. Sisti, M.A. Altea, R. Rocchi, F. Latrofa, M. Nardi, P. Vitti, C. Marcocci, M. Marinò, Spontaneous improvement of untreated mild Graves’ ophthalmopathy: rundle’s curve revisited. Thyroid 24, 60–66 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. W.M. Wiersinga, Management of Graves’ ophthalmopathy. Nat. Clin. Pract. Endocrinol. Metab. 3, 396–404 (2007)

    Article  CAS  PubMed  Google Scholar 

  6. L. Bartalena, Diagnosis and management of Graves’ disease: a global overview. Nat. Rev. Endocrinol. 9, 724–734 (2013)

    Article  CAS  PubMed  Google Scholar 

  7. L. Bartalena, L. Baldeschi, A.J. Dickinson, A. Eckstein, P. Kendall-Taylor, C. Marcocci, M.P. Mourits, P. Perros, K. Boboridis, A. Boschi, N. Currò, C. Daumerie, G.J. Kahaly, G. Krassas, C.M. Lane, J.H. Lazarus, M. Marino, M. Nardi, C. Neoh, J. Orgiazzi, S. Pearce, A. Pinchera, S. Pitz, M. Salvi, P. Sivelli, M. Stahl, G. von Arx, W.M. Wiersinga, Consensus statement of the European group on Graves’ orbitopathy (EUGOGO) on management of Graves’ orbitopathy. Thyroid 18, 333–346 (2008)

    Article  PubMed  Google Scholar 

  8. S. Zang, K.A. Ponto, G.J. Kahaly, Clinical review: intravenous glucocorticoids for Graves’ orbitopathy: efficacy and morbidity. J. Clin. Endocrinol. Metab. 96, 320–332 (2011)

    Article  CAS  PubMed  Google Scholar 

  9. M. Riedl, E. Kolbe, E. Kampmann, I. Kramer, G.J. Kahaly, Prospectively recorded and MedDRA-coded safety data of intravenous methylprednisolone therapy in Graves’ orbitopathy. J. Endocrinol. Invest. 38, 177–182 (2015)

    Article  CAS  PubMed  Google Scholar 

  10. G. Gao, J. Dai, Y. Qian, F. Ma, Meta-analysis of methylprednisolone pulse therapy for Graves’ ophthalmopathy. Clin. Exp. Ophthalmol. 42, 769–777 (2014)

    Article  PubMed  Google Scholar 

  11. C. Marcocci, T. Watt, M.A. Altea, A.K. Rasmussen, U. Feldt-Rasmussen, J. Orgiazzi, L. Bartalena, Fatal and non-fatal adverse events of glucocorticoid therapy for Graves’ orbitopathy: a questionnaire survey among members of the European Thyroid Association. Eur. J. Endocrinol. 166, 247–253 (2012)

    Article  CAS  PubMed  Google Scholar 

  12. L. Bartalena, G.E. Krassas, W. Wiersinga, C. Marcocci, M. Salvi, C. Daumerie, C. Bournaud, M. Stahl, L. Sassi, G. Veronesi, C. Azzolini, K.G. Boboridis, M.P. Mourits, M.R. Soeters, L. Baldeschi, M. Nardi, N. Curro, A. Boschi, M. Bernard, G. von Arx, Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 97, 4454–4463 (2012)

    Article  CAS  PubMed  Google Scholar 

  13. M. Weissel, W. Hauff, Fatal liver failure after high-dose glucocorticoid pulse therapy in a patient with severe thyroid eye disease. Thyroid 10, 521 (2000)

    CAS  PubMed  Google Scholar 

  14. M. Marino, E. Morabito, M.R. Brunetto, L. Bartalena, A. Pinchera, C. Marcocci, Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy. Thyroid 14, 403–406 (2004)

    Article  PubMed  Google Scholar 

  15. M. Salvi, G. Vannucchi, F. Sbrozzi, A.B. Del Castello, A. Carnevali, S. Fargion, P. Beck-Peccoz, Onset of autoimmune hepatitis during intravenous steroid therapy for thyroid-associated ophthalmopathy in a patient with Hashimoto’s thyroiditis: case report. Thyroid 14, 631–634 (2004)

    Article  PubMed  Google Scholar 

  16. M. Marino, E. Morabito, M.A. Altea, E. Ambrogini, F. Oliveri, M.R. Brunetto, L.E. Pollina, D. Campani, P. Vitti, L. Bartalena, A. Pinchera, C. Marcocci, Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves’ ophthalmopathy treated successfully with glucocorticoids themselves. J. Endocrinol. Invest. 28, 280–284 (2005)

    Article  CAS  PubMed  Google Scholar 

  17. B. Melamud, Y. Lurie, E. Goldin, I. Levi, Y. Esayag, Methylprednisolone-induced liver injury: a diagnostic challenge. Isr. Med. Assoc. J. 16, 180–181 (2014)

    PubMed  Google Scholar 

  18. E. Sisti, B. Coco, F. Menconi, M. Leo, R. Rocchi, F. Latrofa, B. Mazzi, E. Albano, P. Vitti, C. Marcocci, M. Brunetto, M. Marino, Intravenous glucocorticoid therapy for Graves’ ophthalmopathy and acute liver damage: an epidemiological study. Eur. J. Endocrinol. 172, 269–276 (2015)

    Article  CAS  PubMed  Google Scholar 

  19. M.A. Henegan, A.D. Yeoman, S. Verma, A.D. Smith, M.S. Longhi, Autoimmune hepatitis. Lancet 382, 1433–1444 (2013)

    Article  Google Scholar 

  20. G.N. Dalekos, K. Zachou, C. Liaskos, N. Gatselis, Autoantibodies and defined target autoantigens in autoimmune hepatitis: an overview. Eur. J. Intern. Med. 13, 293–303 (2002)

    Article  CAS  PubMed  Google Scholar 

  21. M. Moleti, M.A. Violi, D. Montanini, C. Trombetta, B. Di Bella, G. Sturniolo, S. Presti, A. Alibrandi, A. Campennì, S. Baldari, F. Trimarchi, F. Vermiglio, Radioiodine ablation of postsurgical thyroid remnants after treatment with recombinant human TSH (rhTSH) in patients with moderate-to-severe graves’ orbitopathy (GO): a prospective, randomized, single-blind clinical trial. J. Clin. Endocrinol. Metab. 99, 1783–1789 (2014)

    Article  CAS  PubMed  Google Scholar 

  22. F. Menconi, M. Leo, P. Vitti, C. Marcocci, M. Marinò, Total thyroid ablation in Graves’ orbitopathy. J. Endocrinol. Invest. 38, 809–815 (2015)

    Article  CAS  PubMed  Google Scholar 

  23. L. Bartalena, P.E. Macchia, C. Marcocci, M. Salvi, F. Vermiglio, Effects of treatment modalities for Graves’ hyperthyroidism on Graves’ orbitopathy: a 2015 Italian Society of Endocrinology Consensus Statement. J. Endocrinol. Invest. 38, 481–487 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. G. Danan, Consensus meetings on: causality assessment of drug-induced liver injury. J. Hepatol. 7, 132–136 (1988)

    Article  CAS  PubMed  Google Scholar 

  25. N.P. Chalasani, P.A. Hayashi, H.L. Bonkovsky, V.J. Navarro, W.M. Lee, R.J. Fontana, On behalf of the Practice Committee of the American College of Gastroenterology, ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induces liver injury. Am. J. Gastroenterol. 109, 1–17 (2014)

    Article  Google Scholar 

  26. A. Loraschi, P. Banfi, M. Mauri, F. Sessa, G. Bono, M. Cosentino, Hepatotoxicity after high-dose methylprednisolone for demyelinating disease. Clin. Neuropharm. 33, 52–54 (2010)

    Article  CAS  Google Scholar 

  27. K. Gutkowski, A. Chwist, M. Hartleb, Liver injury induced by high-dose methylprednisolone therapy: a case report and brief review of the literature. Hepat. Mon. 11, 656–661 (2011)

    Article  PubMed  PubMed Central  Google Scholar 

  28. B.K. Gunawan, N. Kaplowitz, 2007 Mechanisms of drug-induced liver disease. Clin. Liver Dis. 11, 459–475 (2011)

    Article  Google Scholar 

  29. T. Nanki, R. Koike, N. Miyasaka, Subacute severe steatohepatitis during prednisolone therapy for systemic lupus erythematosis. Am. J. Gastroenterol. 94, 3379 (1999)

    Article  CAS  PubMed  Google Scholar 

  30. S.P. Dourakis, V.A. Sevastianos, P. Kaliopi, Acute severe steatohepatitis related to prednisolone therapy. Am. J. Gastroenterol. 97, 1074–1075 (2002)

    Article  CAS  PubMed  Google Scholar 

  31. J.H. Hoofnagle, Reactivation of hepatitis B. Hepatology 49(5 Suppl), S156–S165 (2009)

    Article  CAS  PubMed  Google Scholar 

  32. H. Wichary, T. Gasinska, Methylprednisolone and hepatotoxicity in Graves’ ophthalmopathy. Thyroid 22, 64–69 (2011)

    Article  PubMed  Google Scholar 

  33. R. Bahn, 2012 High-Dose Intravenous Glucocorticoid Therapy for Graves’ Ophthalmopathy: where Are We Now? Thyroid 22, 1–2 (2011)

    Article  Google Scholar 

  34. A. Shigematsu, K. Okada, N. Abe, S. Ota, N. Kato, K. Kondo, S. Hige, J. Tanaka, M. Asaka, M. Imamura, Non-alcoholic steatohepatitis occurring in a patient with T-lymphoblastic lymphoma during chemotherapy including prednisolone. Leuk. Lymphoma 47, 1397–1399 (2006)

    Article  PubMed  Google Scholar 

  35. Y. Koga, R. Kumashiro, K. Yasumoto, S. Shakado, N. Ono, H. Noguchi, K. Nagata, M. Sata, H. Abe, N. Kaku, K. Tanikawa, Two fatal cases of hepatitis B virus carriers after corticosteroid therapy for bronchial asthma. Intern. Med. 31, 208–213 (1992)

    Article  CAS  PubMed  Google Scholar 

  36. H.M. Hofstee, P.W. Nanayakkara, C.D. Stehouwer, Acute hepatitis related to prednisolone. Eur. J. Intern. Med. 16, 209–210 (2005)

    Article  PubMed  Google Scholar 

  37. A. Takahashi, Y. Kanno, Y. Takahashi, N. Sakamoto, K. Monoe, H. Saito, K. Abe, J. Yokokawa, A. Irisawa, H. Ohira, Development of autoimmune hepatitis type 1 after pulsed methylprednisolone therapy for multiple sclerosis: a case report. World J. Gastroenterol. 14, 5474–5477 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. R. Reuβ, K. Retzlaff, S. Vogel, F.E. Franke, P. Oschmann, Autoimmune hepatitis after high-dose intravenous methylprednisolone pulse in RR-MS. CEJMed 2, 356–359 (2007)

    Google Scholar 

  39. F. Topal, E. Ozaslan, S. Akbulut, M. Küçükazman, O. Yüksel, E. Altiparmak, Methylprednisolone-induced toxic hepatitis. Ann. Pharmacother. 40, 1868–1871 (2006)

    Article  CAS  PubMed  Google Scholar 

  40. R. Gerolami, P. Mambrini, M. Barthet, M.J. Jean-Pastor, J. Salducci, J.C. Grimaud, Acute hepatitis caused by Solupred in a patient with Crohn disease. Gastroenterol. Clin. Biol. 21, 236–237 (1997)

    CAS  PubMed  Google Scholar 

  41. F.M. Rivero, J.M. Riesco, V.F. Moreira, A. Moreno, S.R.A. Lopez, G. Arranz, D.A.L. Ruiz, Recurrent acute liver toxicity from intravenous methylprednisolone. Rev. Esp. Enferm. Dig. 100, 720–723 (2008)

    Google Scholar 

  42. D. Covelli, G. Vannucchi, I. Campi, N. Currò, R. D’Ambrosio, M. Maggioni, U. Gianelli, P. Beck-Peccoz, M. Salvi, Statins may increase the risk of liver dysfunction in patients treated with steroids for active Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 100, 1731–1737 (2015)

    Article  CAS  PubMed  Google Scholar 

  43. H. Eguchi, J. Tani, S. Hirao, M. Tsuruta, I. Tokubuchi, K. Yamada, M. Kasaoka, Y. Teshima, T. Kakuma, Y. Hiromatsu, Liver dysfunction associated with intravenous methylprednisolone pulse therapy in patients with Graves’ orbitopathy. Int. J. Endocrinol. 2015, 835979 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  44. R. Le Moli, L. Baldeschi, P. Saeed, N. Regensburg, M.P. Mourits, W.M. Wiersinga, Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves’ ophthalmopathy. Thyroid 17, 357–362 (2007)

    Article  PubMed  Google Scholar 

  45. C. Marcocci, L. Bartalena, M.L. Tanda, L. Manetti, E. Dell’Unto, R. Rocchi, G. Barbesino, B. Mazzi, M.P. Bartolomei, P. Lepri, F. Cartei, M. Nardi, A. Pinchera, Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J. Clin. Endocrinol. Metab. 86, 3562–3567 (2001)

    CAS  PubMed  Google Scholar 

  46. P.E. Macchia, M. Bagattini, G. Lupoli, M. Vitale, G. Vitale, G. Fenzi, High-dose intravenous corticosteroid therapy for Graves’ ophthalmopathy. J. Endocrinol. Invest. 24, 152–158 (2001)

    Article  CAS  PubMed  Google Scholar 

  47. G.J. Kahaly, S. Pitz, G. Hommel, M. Dittmar, Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 90, 5234–5240 (2005)

    Article  CAS  PubMed  Google Scholar 

  48. S. Aktaran, E. Akarsu, I. Erbaðci, M. Araz, S. Okumuþ, M. Kartal, Comparison of intravenous methylprednisolone therapy vs. oral methylprednisolone therapy in patients with Graves’ ophthalmopathy. Int. J. Clin. Pract. 61, 45–51 (2007)

    Article  CAS  PubMed  Google Scholar 

  49. F. Menconi, M. Marino, A. Pinchera, R. Rocchi, B. Mazzi, M. Nardi, L. Bartalena, C. Marcocci, Effects of total thyroid ablation versus near-total thyroidectomy alone on mild to moderate Graves’ orbitopathy treated with intravenous glucocorticoids. J. Clin. Endocrinol. Metab. 92, 1653–1658 (2007)

    Article  CAS  PubMed  Google Scholar 

  50. R.J. van Geest, I.V. Sasim, H.P. Koppeschaar, R. Kalmann, S.N. Stravers, W.R. Bijlsma, M.P. Mourits, Methylprednisolone pulse therapy for patients with moderately severe Graves’ orbitopathy: a prospective, randomized, placebo-controlled study. Eur. J. Endocrinol. 158, 229–237 (2008)

    Article  PubMed  Google Scholar 

  51. R. Sanchez-Ortiga, O. Moreno-Perez, V.G. Sanchez, N.A. Mendoza, M.M. Dot, R.A. Guerra, A.L. Macia, A.P. Alfonso, Treatment of Graves’ ophthalmopathy with highdose intravenous methylprednisolone: a comparison of two dosing regimens. Endocrinol. Nutr. 56, 118–122 (2009)

    Article  PubMed  Google Scholar 

  52. B.N. Beleslin, J. Ciric, M. Zarkovic, M. Stojkovic, S. Savic, M. Knezevic, B. Stankovic, B. Trbojevic, B. Trbojevic, Efficacy and safety of combined parenteral and oral steroid therapy in Graves’ orbitopathy. Hormones (Athens) 13, 222–228 (2014)

    Google Scholar 

  53. W. Zhu, L. Ye, L. Shen, Q. Jiao, F. Huang, R. Han, X. Zhang, S. Wang, W. Wang, G. Ning, A prospective, randomized trial of intravenous glucocorticoids therapy with different protocols for patients with Graves’ ophthalmopathy. J. Clin. Endocrinol. Metab. 99, 1999–2007 (2014)

    Article  CAS  PubMed  Google Scholar 

  54. E. Sisti, B. Coco, F. Menconi, M. Leo, R. Rocchi, F. Latrofa, M.A. Profilo, B. Mazzi, P. Vitti, C. Marcocci, M. Brunetto, M. Marinò, Age and dose are major risk factors for liver damage associated with intravenous glucocorticoid pulse therapy for Graves’ orbitopathy. Thyroid 25, 846–850 (2015)

    Article  CAS  PubMed  Google Scholar 

  55. V. Di Marco, V. Calvaruso, A. Iacò, F. Bronte, L. Biasi, K. Prestini, P. Sacchi, G. Amaddeo, G. Squadrito, R. Bruno, M. Puoti, A. Craxì, Liver stiffness measurement by transient elastography predicts early recovery from acute hepatitis. Gut 60, 1023 (2011)

    Article  PubMed  Google Scholar 

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Moleti, M., Giuffrida, G., Sturniolo, G. et al. Acute liver damage following intravenous glucocorticoid treatment for Graves’ ophthalmopathy. Endocrine 54, 259–268 (2016). https://doi.org/10.1007/s12020-016-0928-3

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