Abstract

Hepatitis B flares are associated with hepatitis B virus reactivation, which may be asymptomatic or symptomatic, and may result in rapid hepatic decompensation and death. The case was a 69-year-old female with rheumatoid arthritis using immunosuppressive therapies (methotrexate and methylprednisolone), finally suffered from fulminant hepatic failure due to hepatitis B virus flare-up. The case report indicates that examinations, such as HBsAg, anti-HBc and/or hepatitis B virus DNA, and prophylactic antiviral therapy are important for rheumatoid arthritis patients with hepatitis B carriers before immunosuppressive therapy.

Key Words: immunosuppression, hepatitis B, hepatitis flare, methotrexate

Introduction

Administration or discontinuation of steroid or immunosuppressants sometimes inducing fulminant hepatitis has been reported in the practice of rheumatology.¹ The hepatitis flare-up refers to a patient with underlying chronic liver disease who has an abrupt increase in aminotransferase（AST or ALT）levels with or without hepatitis symptoms. One proposed definition was an abrupt increase in serum ALT to five times greater than the upper limit of normal or to three times greater than baseline level, whichever was higher.² Because many hepatitis flare-up are transient, the detection of fulminant hepatitis need to be monitored more frequently. Hepatitis B flares are usually preceded by an increase in serum HBV DNA levels and can also be associated with an increase in alpha fetoprotein levels（AFP）Some hepatitis flares are accompanied by hepatitis symptoms such as fatigue, anorexia, and nausea. Occasionally, fulminant hepatitis may be accompanied by jaundice, ascites, prolonged prothrombin time or coagulopathy, hepatic decompensation, and even death. Severe outcomes are more likely when flares develop in patients who have underlying cirrhosis.²

Hepatitis B virus（HBV）infection is the most common chronic viral infection affecting the liver in the world, and it is the leading cause of cirrhosis and hepatocellular carcinoma. Reactivation of HBV replication in patients undergoing immunosuppressive therapy is frequently reported and is a considered clinical important complication.^3,4 HBV-induced liver inflammation is predominantly immune mediated.^5,6 The basic hypothesis is HBV replication via activation of corticosteroid responsive element（GRE）particularly in the case for corticosteroids and expression of viral epitopes in infected hepatocytes which is followed by a variable host immune response, and may lead to acute or chronic liver necroinflammation.⁷

A reviewing article that reviewed five published case reports of HBV reactivation in patients with rheumatic disease treated with immunosuppressive drugs, all cases were taking methotraxate weekly doses ranging from 4 to 15 mg and prednisolon or prednisone daily doses ranging from 5 to 7.5 mg. Based on the conclusion to the article, “Four of the five reports HBV reactivation was seen briefly（15–60 days）after decrease or interruption of the immunosuppressive regimen, while in one report reactivation was noted during chronic therapy. The outcome was severe with three patients dying and one requiring liver transplantation. The other one patient was helped with antiviral therapy.”⁸

This case report encourages healthcare providers to review researches on immunosuppressive therapy（methotrexate and methylprednisolone）and hepatitis flares to identify the risks and preventions of fulminant hepatic failure due to hepatitis B flares in HBV carriers with immunosuppressive drugs.

Case Report

The 69 year-old female patient visited ER on April 30 and complained of anorexia, nausea, malaise, jaundice and tea color urine rapidly since one week ago. Her past medical histories were RA with methylprednisolone and methotraxate for one year, and recurrent duodenal ulcer bleeding for years. Prior to her admission to our ER, she had shown elevated AST, ALT, α-fetoprotein（AFP）and positive HBsAg at the local clinic. Under the impression of suspect HCC or HBV with acute exacerbation, she was admitted to our hospital for further evaluation and management. Patient's current medication were listed from other local hospital on April 13, which included folic acid 5mg oral daily, methylprednisolone 4 mg oral daily, methoterexate 10 mg oral weekly, mosapride 5 mg oral three times a day, esomeprazole 40 mg oral daily, hydroxychloroquine 400 mg oral daily, and celecoxib 200 mg oral daily. On May 1, she received abdominal echography due to the elevated AFP（450 ng/mL）and was diagnosed with parenchymal liver disease of score 6. Since admission, she received ursodeoxycholic acid, mosapride and esomeprazole treatment, but methotraxate and methylprednisolone were discontinued. On May 2, patient still felt fatigue, poor appetite with jaundice. Entecavir 0.5 mg oral daily was then prescribed, plus vitamin K1 10 mg intravenous daily for prolonged prothrombin time（PT）.HBV DNA ﹥ 100,000,000 copies/ml, GOT: 754 U/L, GPT: 588 U/L, and total bilirubin （TBIL）:14.31 mg/dL were noted. On May 8, patient's consciousness became drowsy and elevated ammonia level 218 μg/dL and she was treated with lactulose enema every 8 hours. Her overall liver function tests were summarized on Table 1. On May 9, patient's consciousness was unclear and hepatorenal syndrome was developed. Serum creatinine level was elevated to 3.0 mg/dL, TBIL: 17.17 mg/dL, Prothrombin Time: 38.8 sec. Liver transplant was a relative contraindication for this patient due to the old age after general surgery（GS）consulting. Unfortunately, patient expired due to fulminant hepatic failure on May 9.

 

Discussion

The 69-year-old female patient developed fulminant hepatitis with elevated levels of hepatitis B virus（HBV）DNA and subsequently died due to fulminant hepatic failure. Based on our case's clinical laboratory data and symptoms, we may conclude the development of fulminant hepatitis in a HBV carrier was due to taking immunosuppressants（methotrexate and methylprednisolone）without giving any prophylactic antiviral therapy.

The 2009 practice guidelines for treatment of chronic hepatitis B provided by the American Association for the Study of Liver Diseases（AASLD）,⁹which recommend prophylactic antiviral therapy for HBV carriers at the onset of finite course of immunosuppressive therapy. One recommendation is giving lamivudine or telbivudine if the anticipated duration of the immunosuppressive treatment is less than 12 months and baseline serum HBV DNA is not detectable. One other recommendation is giving adefovir or entecavir if longer duration of immunosuppression is anticipated. In a small number of patients with rheumatic disease who had reactivation of HBV during an immunosuppressive regimen, HBV replication was successfully suppressed by lamivudine.^10,11 The longer course of lamivudine prophylactic treatment may potentially be associated with emergence of lamivudine resistant HBV strains. The benefit versus risk of prophylactic antiviral therapy to prevent HBV flares is still less certain in those patients who are requiring an extended course of immunosuppressive therapy. Therefore, this is a particular concern in rheumatic disorder population who may need longer immunosuppressive regimens including corticosteroids.

In addition to the prophylactic antiviral therapy for HBV carriers, AASLD practice guidelines⁹ also recommend that patients at high risk of HBV should undergo testing for HBsAg and anti-HBc before immunosuppressive therapy. While no antiviral prophylactic treatment is given in HBsAg negative, anti-HBs, and/or anti-HBc positive patients, the periodic follow up of ALT and HBV DNA will be recommended to identify the HBV flares in an early asymptomatic stage; while the HBV flare has been identified, treatment of HBV can be started before the onset of jaundice or liver failure.

According to studies, the risk of a flare-up of hepatitis after withdrawal of immunosuppressive therapy may appear between 20% and 50%¹². Withdrawal of immunosuppresants is not always safe for patients, because of the immune and clinical rebound which can be extremely severe and finally lead to submassive or massive hepatic necrosis and failure¹³. One review article that reviewed four cases on severe/fulminant HBV hepatitis after withdrawal of low-dose MTX for RA. They indicates that “the mutations in the core promoter and the precore regions of HBV-DNA and the immunosuppressive effect of low-dose MTX may have led to widespread HBV infection to hepatocytes. Thus, after withdrawal of the drug several weeks later, the restoration of immunocompetency could lead to a rigorous immunologic attack against the infected hepatocytes.”¹⁴ Three of four died and one was rescued by liver transplant. In our case, elevated HBV DNA （﹥ 100,000,000 copies/ml）was detected three days after discontinuation of methotraxate and no test had been done for checking the mutations of HBV DNA. Based on the information above, we may exclude the reason for developing fulminant hepatic failure in this case was associated with discontinuation of the low-dose methotraxate therapy.

Conclusions: During the case report, we suggest that the use of steroids, MTX and other immunosuppressants should be avoided for RA patients with chronic infection with HBV, even when the hepatitis seems to be inactive. If steroids or immunosuppressants must be used for treatment, the periodic follow up of ALT and HBV DNA should be closely monitored. Administration of antiviral is recommended to prevent serious complications.

Reference:

1. Ito S, Nakazono K, Murasawa A, et al: Development of fulminant hepatitis B (precore variant mutant type)after the discontinuation of low-dose methotrexate therapy in a rheumatoid arthritis patient. Arthritis Rheum 2001; 44(2): 339-42.

2. Lok Anna SF, Bonis Peter AL: Hepatitis B virus reactivation associated with immunosuppression. UpToDate, Accessed by December 12, 2009.

3. Perrillo RP: Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology 2001; 120: 1009-22.

4. Vento S, Cainelli F, Longhi MS: Reactivation of replication of hepatitis B and C viruses after immunosuppressive therapy: an unresolved issue. Lancet Oncol 2002; 3: 333-40.

5. Chisari FV, Ferrari C: Hepatitis B virus immunopathogenesis. Annu Rev Immunol 1995; 13: 29-60.

6. Rehermann B, Nascimbeni M: Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005; 5: 215-29.

7. Hadziyannis SJ, Vassilopoulos D: Hepatitis B e antigen-negative chronichepatitis B. Hepatology 2001; 34: 617-24.

8. Calabrese LH, Zein NN, Vassilopoulos D: Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis 2006; 65: 983-989.

9. Lok AS, McMahon BJ: Chronic hepatitis B: Update 2009. Hepatology 2009; 50: 661.

10. Calabrese LH, Zein N, Vassilopoulos D: Safety of antitumour necrosis factor (anti-TNF) therapy in patients with chronic viral infections: hepatitis C, hepatitis B, and HIV infection. Ann Rheum Dis 2004; 63 (suppl 2): ii18-24.

11. Wendling D, Auge B, Bettinger D, et al: Reactivation of a latent precore mutant hepatitis B virus related chronic hepatitis during infliximab treatment for severe spondyloarthropathy. Ann Rheum Dis 2005; 64: 788-9.

12. Lueg E, Heathcote J: Dangers of immunosuppressive therapy in hepatitis B virus carriers. CMAJ 1992; 147(8): 1155-8.

13. Liaw YF: Hepatitis viruses under immunosuppressive agents. J Gastroenterol Hepatol 1998; 13(1): 14-20.

14. Hagiyama H, Kubota T, Komano Y, et al: Fulminant hepatitis in an asymptomatic chronic carrier of hepatitis B virus mutant after withdrawal of low-dose methotrexate therapy for rheumatoid arthritis. Clin Exp Rheumatol 2004; 22: 375.

摘要

猛爆性肝炎發作與B型肝炎病毒被活化相關，在發病時可能伴隨無症狀或有症狀發生，最終可能導致肝臟代償不全及死亡。

本病例報告為69歲婦人患有風濕性關節炎並且以免疫抑制劑（methotrexate and methylprednisolone）進行治療，最終由於引起B型肝炎病毒被活化而導致病患猛爆性肝衰竭。

藉由此案例報告指出風濕性關節炎病患且為B肝帶原在給予免疫抑制劑治療前須進行一些重要的檢查，例如HBsAg, anti-HBc及/或Hepatitis B virus DNA，以及在給予免疫抑制劑治療之前建議先投予預防性抗病毒藥物來預防猛爆性肝炎的發生。

作者

義大醫院藥劑部藥師 謝坤屏、黃意文、蔡斌智

義大醫院醫師 許筌淵