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
P. Perros, G.E. Krassas, Graves’ orbitopathy: a perspective. Nat. Rev. Endocrinol. 5, 312–318 (2009)
L. Bartalena, V. Fatourechi, Extrathyroidal manifestations of Graves’ disease: a 2014 update. J. Endocrinol. Invest. 37, 691–700 (2014)
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)
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)
W.M. Wiersinga, Management of Graves’ ophthalmopathy. Nat. Clin. Pract. Endocrinol. Metab. 3, 396–404 (2007)
L. Bartalena, Diagnosis and management of Graves’ disease: a global overview. Nat. Rev. Endocrinol. 9, 724–734 (2013)
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)
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)
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)
G. Gao, J. Dai, Y. Qian, F. Ma, Meta-analysis of methylprednisolone pulse therapy for Graves’ ophthalmopathy. Clin. Exp. Ophthalmol. 42, 769–777 (2014)
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)
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)
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)
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)
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)
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)
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)
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)
M.A. Henegan, A.D. Yeoman, S. Verma, A.D. Smith, M.S. Longhi, Autoimmune hepatitis. Lancet 382, 1433–1444 (2013)
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)
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)
F. Menconi, M. Leo, P. Vitti, C. Marcocci, M. Marinò, Total thyroid ablation in Graves’ orbitopathy. J. Endocrinol. Invest. 38, 809–815 (2015)
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)
G. Danan, Consensus meetings on: causality assessment of drug-induced liver injury. J. Hepatol. 7, 132–136 (1988)
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)
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)
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)
B.K. Gunawan, N. Kaplowitz, 2007 Mechanisms of drug-induced liver disease. Clin. Liver Dis. 11, 459–475 (2011)
T. Nanki, R. Koike, N. Miyasaka, Subacute severe steatohepatitis during prednisolone therapy for systemic lupus erythematosis. Am. J. Gastroenterol. 94, 3379 (1999)
S.P. Dourakis, V.A. Sevastianos, P. Kaliopi, Acute severe steatohepatitis related to prednisolone therapy. Am. J. Gastroenterol. 97, 1074–1075 (2002)
J.H. Hoofnagle, Reactivation of hepatitis B. Hepatology 49(5 Suppl), S156–S165 (2009)
H. Wichary, T. Gasinska, Methylprednisolone and hepatotoxicity in Graves’ ophthalmopathy. Thyroid 22, 64–69 (2011)
R. Bahn, 2012 High-Dose Intravenous Glucocorticoid Therapy for Graves’ Ophthalmopathy: where Are We Now? Thyroid 22, 1–2 (2011)
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)
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)
H.M. Hofstee, P.W. Nanayakkara, C.D. Stehouwer, Acute hepatitis related to prednisolone. Eur. J. Intern. Med. 16, 209–210 (2005)
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)
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)
F. Topal, E. Ozaslan, S. Akbulut, M. Küçükazman, O. Yüksel, E. Altiparmak, Methylprednisolone-induced toxic hepatitis. Ann. Pharmacother. 40, 1868–1871 (2006)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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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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DOI: https://doi.org/10.1007/s12020-016-0928-3