Joong Ho Bae, et al. Fatal HBV reactivation during long-term very low-dose steroid treatment Not surprisingly, most of these reports have come from the fields of oncology and transplantation, but there have been a growing number of cases reported in patients with rheumatic disease un- dergoing immunosuppressive therapy as well.11-13 Among the factors that have been shown to precipitate acute flares of chronic HBV infection is the administration of immuno- suppressive drugs. In vitro and in vivo studies clearly indicated that immunosuppression leads to increased HBV replication, assessed by different methods (serum HBV DNA, HBsAg, and HBV DNA polymerase titers). This enhanced replication is attributed to a number of mechanisms, one of which is related to a direct stimula- tory effect of these agents on HBV replication. This is particularly the case for corticosteroids, because a corticosteroid responsive element is present in HBV genome and is responsible for increased HBV DNA transcriptional activity and viremia in patients receiving corticosteroids.14 Glucocorticoid is implicated as an important predisposing factor for HBV reactivation. In patients with chronic hepatitis B, long- term prednisolone treatment increases levels of HBsAg, HBcAg, and HBV DNA in hepatocytes,15 as well as decreases T-cell func- tion. Immunosuppression is thought to enhance viral replication with a subsequent spread in hepatocyte infection. In addition, glucocorticoids may cause a direct reactivation of the latent HBV infection.16 The findings of a glucocorticoid responsive element in HBV genome and the demonstration that glucocorticoids specifi- cally activate HBV gene expression in cultured human hepato- cellular carcinoma cells lend support to the direct reactivation theory.16 Despite these findings, limited information is available on the effect of the different immunosuppressive regimens given for longer periods of time in lower doses in patients with chronic HBV infection. Data from the long term administration of immunosup- pressive drugs in HBsAg positive renal transplant recipients have shown a high incidence of hepatitis and liver related mortality (10- 30%).17 There is a paucity of information for other diseases where long term administration of immunosuppression is required-for example, patients with inflammatory bowel diseases,18 severe asthma, and various different rheumatic diseases including rheu- matoid arthritis.11-13 Although there have been some case reports of acute flare-up of HBV after high dose steroid therapy, only a few patients with rheumatic disease and HBV reactivation associated with both non-biological and biological immunosuppressive therapies have been reported. In addition, all of the previously reported HBV reactivation cases with low dose steroid administration have co- administered methotrexate in some degree (varying from 4 mg/ week to 15 mg/week), with no reported case of low dose steroid administration alone. It is also worthy to note that the steroid dose administered in the present case was possibly the lowest dose applicable (2.5 mg/day). To the best of our knowledge, there has been no previous report of hepatitis B virus reactivation with acute severe flare-up in an inactive hepatitis B virus carrier, es- pecially while taking continuous low dose oral steroid as long as 4-years for maintenance treatment of rheumatoid arthritis. The clinical spectrum of the HBV reactivation can vary from an asymp- tomatic to acute flare-up and fulminant course. HBV reactivation leading to a fulminant course is a serious condition and results in death or transplantation in most cases. In this situation, the goals of aggressive antiviral therapy prevent the need for liver transplan- tation, decrease post-transplantation HBV recurrence, and sustain viral suppression and viral activity reduction.19 The patient was not a candidate for transplantation, and we immediately decided to initiate antiviral treatment. Although the patient underwent prompt antiviral treatment with clevudine, and despite some response toward the viral activ- ity, the liver function gradually failed, ultimately leading to multi- organ failure and death. The limitation of this case could be that spontaneous reacti- vation of HBV cannot be wholly excluded. Moreover, since the patient was visiting only the department of rheumatology at a regular base, the viral markers and HBV DNA which represents the activity of the HBV were not recorded as often as it should have been. However, since the incidence of such spontaneous reactiva- tion of HBV is very rare in an old-aged patient such as in this case, and the fact that viral load of the patient surged dramatically, it suggests that the etiology of HBV reactivation may be long-term steroid administration. It is also true to say that the possibility of inactive cirrhosis cannot be fully excluded, in which steroid admin- istration might have caused a fatal HBV reactivation. Our case suggests that even an administration of non-combina- tion, minimal dosage of single oral steroid can cause reactivation of indolent, inactive HBV. Since a vast number of patients are at some point in need of low-dose steroid administration, including most rheumatologic diseases such as rheumatoid arthritis, this will be of important concerns in the sectors where low dose steroid is an essential part of prescription. In conclusion, in an inactive HBV carrier, if a long-term admin- istration of steroid is planned, an adequate evaluation of the liver function and disease status should be evaluated by specialists. Once steroid has been administered, regular HBV DNA monitoring is mandatory, and early antiviral therapy is required if the serum http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2012.18.2.225 227