Author Affiliations: Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China (Xu YT, Meng FY, Li GB and Liu J); Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan 250012, China (Liu DJ)

Corresponding Author: Jun Liu, MD, Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China (Tel: 86-531-87925615; Email: xyt@mail.sdu.edu.cn)

 

© 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(14)60256-3

 

Contributors: LJ proposed the study. XYT and LDJ designed the study, collected and analyzed the data, and wrote the first draft. LGB contributed to the critical revision of the manuscript. MFY contributed to the design and interpretation of the study. XYT and LDJ contributed equally to this work. LJ is the guarantor.

Funding: None.

Ethical approval: The study was approved by the Ethics Committee of Shandong Provincial Hospital Affilliated to Shandong University.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

ABSTRACT: Liver transplantation for autoimmune hepatitis (AIH) is usually successful with excellent long-term outcomes, but primary disease may recur. The recurrence of AIH is a significant cause of graft loss. This study was to analyze the effect of splenectomy in preventing AIH relapse. The clinical courses of 12 patients who had transplantation for AIH were analyzed retrospectively. All patients were subjected to transplantation for end-stage liver disease caused by chronic AIH. Based on the duration of immunosuppressive treatment before liver transplantation, simultaneous splenectomy was performed in ten patients. Two patients underwent liver transplantation without splenectomy, one of them developed recurrent AIH and died from graft failure caused by AIH relapse. However, no episode of AIH recurrence was observed in patients who had undergone simultaneous splenectomy. Splenectomy might be an option to prevent AIH relapse in some patients with high risk factors.

 

(Hepatobiliary Pancreat Dis Int 2014;13:328-331)

 

KEY WORDS: autoimmune hepatitis; liver transplantation; recurrence; splenectomy

Autoimmune hepatitis (AIH) is a generally progressive, chronic necroinflammatory liver disease of unknown etiology.^[1] Aberrant T cell-mediated autoimmune reactions against liver antigens not adequately controlled by appropriate regulatory T cells are believed to play an important role in the pathogenesis of AIH.^{[2, 3]} Multiple pathogenic factors have been implicated in the loss of autoimmune tolerance, including genetic predispositions and environmental triggers.^[1] Although AIH has diverse clinical phenotypes, ranging from an asymptomatic presentation to an acute severe disease, AIH generally responds to immunosuppressive treatment.^{[4, 5]}

 

Liver transplantation (LT) is required in patients who are refractory to conventional and alternative immunosuppressive therapy and in whom end-stage liver disease develops. However, AIH recurrence occurs after LT despite the use of immunosuppressive drugs.^{[6, 7]} The mechanism of AIH relapse remains obscure. Auto-immunologic abnormalities in patients with AIH that can not be corrected by LT may be of major relevance to the primary disease recurrence.^[6]

 

Recurrent AIH often responds to steroid-based immunosuppressive therapy, but some patients may progress to graft failure,^[8-10] and patients having retransplantation for recurrence are at particularly a high risk of recurrence again.^[11] Hence, further effective treatments are warranted to reduce AIH recurrence. Splenomegaly can be seen in AIH patients with end-stage liver disease. Although splenectomy combined with LT is performed for preemptive anti-HCV therapy, for ABO-incompatible grafts, and for small-for-size syndrome,^[12] the role of splenectomy in preventing AIH recurrence after LT, especially in AIH patients with steroid resistance, has not been elucidated. The present study aimed to determine the role of LT combined with simultaneous splenectomy in the prevention of AIH recurrence.

 

 

Twelve adult patients with chronic AIH at the end-stage who had undergone LT at our center from March 2004 to December 2013 were analyzed retrospectively. The clinical features included ascites, jaundice, low albuminemia, low prothrombin level, liver cirrhosis and hypersplenism. All of the patients had no history of exposure to hepatotoxic drugs or alcohol abuse, anti-nuclear antibodies (ANA) were positive, and anti-smooth muscle antibodies (ASMA), anti-liver-kidney microsome type 1 antibodies (ALKM1), alpha-fetoprotein (AFP) and virological markers for hepatitis B, C and HIV were negative. All of the patients were subjected to immunosuppressive treatment with corticosteroids before LT.

 

LT was performed with an ABO blood group-compatible liver graft in all patients. After a long-term immunosuppressive treatment before LT (≥1 year), 10 patients (cases 1-10) underwent a simultaneous splenectomy. Two patients (cases 11 and 12) received a short period of immunosuppressive treatment (<1 year) and liver transplantation with no simultaneous splenectomy.

 

After discharge from the hospital, the patients were followed up monthly for the first six months, every other month for another six months, every 3 months in the second year and every 3-6 months afterwards according to their clinical and laboratory data. Follow-up examinations consisted of physical examination, routine blood test, liver and kidney function tests, test of gamma globulin, detection of auto-antibodies, measurement of whole blood tacrolimus, and Doppler ultrasonography of the allograft. We did not perform routine biopsies in view of the risk of biopsy complications. However, post-operative tissues were examined whenever the abnormal liver function was detected. Auto-antibodies were titrated with fluorescence isothiocyanate (FITC)-conjugated goat anti-human secondary antibodies. The positive cut-off values for ANA, ASMA, and ALKM1 were expressed as a titer >1:100.

 

The diagnosis of AIH relapse was depended on the reappearance of clinical symptoms and signs, the presence of auto-antibodies, interface hepatitis based on histologic analysis, the increased levels of transaminases and immunoglobulin G, response to prednisone and azathioprine, and exclusion of other causes of graft dysfunction.^{[6, 13, 14]}

 

All patients received a triple immunosuppressive regimen including tacrolimus (FK506), mycophenolate mofetil (MMF) and corticosteroids with higher doses and more prolonged courses of corticosteroids compared to those used in patients who received transplantation for other benign liver diseases. Tacrolimus doses were individualized to maintain a target whole-blood trough level of 10-15 ng/mL in the first three months immediately after liver transplantation, 8-10 ng/mL in the following three months, and 5-8 ng/mL subsequently. Intravenous methylprednisolone was administered immediately before perfusion of the graft portal vein at a initial dose of 1000 mg per day, and progressively tapered to a daily dose of 40 mg by 7 days. Then intravenous methylprednisolone was changed to oral prednisone which was maintained at a dose of 20 mg per day in the following three months and then gradually tapered to a daily maintenance dose of 10 mg. The maintenance dose of prednisone was reduced cautiously, while monitoring liver function one year after transplantation. Because inadequate maintenance immunosuppression, especially discontinued use of corticosteroids, was a risk factor for the recurrence of AIH.^{[13, 15, 16]} MMF was administered at a dose of 1000 mg per day and it was discontinued 3 months after transplantation. The treatment of recurrent AIH was empiric and similar to that of classical AIH. The principal immunosuppressive regimen was to increase the dose of corticosteroids.

 

 

All patients were female with a median age of 54.1 years (range 25 to 67). LT was successfully performed in all these patients. Clinical characteristics of the 12 patients are shown in Table 1. Three months after operation, liver function tests were normal or near normal in all patients. The 12 patients were followed up for a mean of 49.4 months (range 6 to 117). Case 1 developed superior mesenteric venous thrombosis 19 days after LT and was cured with anticoagulation and thrombolysis. Case 7 developed pulmonary infection 6 months after LT and died of respiratory failure. Other recipients had an uneventful recovery. None of the 12 patients underwent retransplantation. Hypergammaglobulinemia rapidly decreased to the normal level after LT in all patients. Auto-antibodies disappeared slowly in 3 patients, however, persisted at a lower titer than before operation and were of the same type before and after LT in the rest 9 patients. Case 11 underwent LT and had relapse of AIH 26 months after transplantation. She developed severe osteoporosis due to a high dose of corticosteroids and eventually died of graft failure 99 months after transplantation. No AIH recurrence was observed in patients who underwent simultaneous splenectomy (Table 2).

 

 

AIH is a relatively rare indication for LT, accounting for 4% of LTs in Europe and the United States.^[17] The frequency of AIH recurrence may be institution-specific because of the different management policies and diagnostic criteria and increases with time. It has been reported that AIH occurs in 8%-12% of patients at 1 year and 36%-68% after 5 years.^[18]

 

Multiple risk factors are associated with AIH relapse. AIH sometimes recurred, particularly in chronic versus fulminant AIH patients and in those who had already received retransplantation for recurrence. It was suggested that patients with chronic AIH who required LT continued to have a propensity for immunosuppression resistance, just as they had done before transplantation, whereas patients with fulminant AIH, naive to immunosuppressive therapy, were likely to respond to the immunosuppressive treatment.^[11] In addition, incomplete suppression of AIH activity prior to LT was also a high risk factor for AIH recurrence, suggesting that AIH resisted to treatment was more likely to relapse after LT.^{[14, 19]}

 

Our patients achieved good long-term outcomes after LT. Simultaneous splenectomy was performed in AIH patients with long-term immunosuppressive treatment before LT who had a propensity for immunosuppression resistance. Auto-antibodies disappeared in 3 patients probably because autoimmune disorder was inhibited by postoperative immunosuppressive therapy and removal of the target organ. However, auto-antibodies persisted in most patients after LT, indicating that the underlying autoimmune disorder could not be corrected by LT. Long-term steroid therapy was needed to prevent primary disease recurrence. No AIH relapse occurred in patients receiving simultaneous splenectomy in this study. AIH recurrence in case 11 might be related to incomplete suppression of primary disease activity as reflected by high serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and immunoglobulin G (IgG) before transplantation. However, although many patients receiving simultaneous splenectomy also had high pretransplant serum levels of AST, ALT and IgG, they did not develop recurrent AIH. Hence, we assume that splenectomy might prevent AIH recurrence after LT in patients with a propensity for immunosuppression resistance or severe AIH. Furthermore, it is also interesting to explore whether patients having simultaneous splenectomy might require a lower maintenance dose of corticosteroids, which could be helpful to reduce side-effects of steroids.

 

An animal study^[20] showed that dysregulated follicular helper T cells in the spleen could directly migrate into the liver and were responsible for the induction of fatal AIH. Moreover, follicular helper T cells in the spleen were responsible not only for the development of AIH but also for relapse after discontinuing treatment with corticosteroids. The splenectomy overcame this insufficiency, suppressed the development of AIH and prolonged the effects of corticosteroids in mouse models of AIH.^[21] The similar mechanisms might be involved in AIH recurrence after LT in humans.

 

Splenectomy increases the risk of post-transplant infection^[22] and the incidence of portal vein thrombosis.^[23] In addition, simultaneous splenectomy in patients with preoperative prothrombin time of more than 5 seconds, thrombosis of the portal vein, or serious inflammation of the spleen is at a higher perioperative risk.^[24] In series, case 1 developed superior mesenteric venous thrombosis and case 7 died of pulmonary infection after LT. Therefore, simultaneous splenectomy should be carefully assessed.

 

Statistical analysis was not performed in the present study because of the limited number of patients. Further studies are needed to validate the effect of splenectomy in LT for patients with AIH.

 

In conclusion, splenectomy might be a considerable option to prevent AIH recurrence in some high-risk patients with a propensity for immunosuppression resistance or incomplete suppression of AIH activity before LT. 

 

 

1 Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, et al. Diagnosis and management of autoimmune hepatitis. Hepatology 2010;51:2193-2213. PMID: 20513004

2 Ferri S, Longhi MS, De Molo C, Lalanne C, Muratori P, Granito A, et al. A multifaceted imbalance of T cells with regulatory function characterizes type 1 autoimmune hepatitis. Hepatology 2010;52:999-1007. PMID: 20683931

3 Liberal R, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: a comprehensive review. J Autoimmun 2013;41:126-139. PMID: 23218932

4 Czaja AJ, Freese DK; American Association for the Study of Liver Disease. Diagnosis and treatment of autoimmune hepatitis. Hepatology 2002;36:479-497. PMID: 12143059

5 Czaja AJ, Carpenter HA. Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol 2004;40:646-652. PMID: 15030981

6 Ratziu V, Samuel D, Sebagh M, Farges O, Saliba F, Ichai P, et al. Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease. J Hepatol 1999;30:131-141. PMID: 9927160

7 Manns MP, Bahr MJ. Recurrent autoimmune hepatitis after liver transplantation-when non-self becomes self. Hepatology 2000;32:868-870. PMID: 11003637

8 Mottershead M, Neuberger J. Transplantation in autoimmune liver diseases. World J Gastroenterol 2008;14:3388-3395. PMID: 18528936

9 Rowe IA, Webb K, Gunson BK, Mehta N, Haque S, Neuberger J. The impact of disease recurrence on graft survival following liver transplantation: a single centre experience. Transpl Int 2008;21:459-465. PMID: 18225996

10 Tripathi D, Neuberger J. Autoimmune hepatitis and liver transplantation: indications, results, and management of recurrent disease. Semin Liver Dis 2009;29:286-296. PMID: 19676001

11 Reich DJ, Fiel I, Guarrera JV, Emre S, Guy SR, Schwartz ME, et al. Liver transplantation for autoimmune hepatitis. Hepatology 2000;32:693-700. PMID: 11003612

12 Jeng LB, Lee CC, Chiang HC, Chen TH, Hsu CH, Cheng HT, et al. Indication for splenectomy in the era of living-donor liver transplantation. Transplant Proc 2008;40:2531-2533. PMID: 18929791

13 Liberal R, Longhi MS, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis after liver transplantation. Clin Gastroenterol Hepatol 2012;10:346-353. PMID: 22056300

14 Ayata G, Gordon FD, Lewis WD, Pomfret E, Pomposelli JJ, Jenkins RL, et al. Liver transplantation for autoimmune hepatitis: a long-term pathologic study. Hepatology 2000;32:185-192. PMID: 10915722

15 Ilyas JA, O'Mahony CA, Vierling JM. Liver transplantation in autoimmune liver diseases. Best Pract Res Clin Gastroenterol 2011;25:765-782. PMID: 22117641

16 Hübscher SG. Recurrent autoimmune hepatitis after liver transplantation: diagnostic criteria, risk factors, and outcome. Liver Transpl 2001;7:285-291. PMID: 11303286

17 Manns MP. Autoimmune hepatitis: the dilemma of rare diseases. Gastroenterology 2011;140:1874-1876. PMID: 21524652

18 Czaja AJ. Diagnosis, pathogenesis, and treatment of autoimmune hepatitis after liver transplantation. Dig Dis Sci 2012;57:2248-2266. PMID: 22562533

19 Montano-Loza AJ, Mason AL, Ma M, Bastiampillai RJ, Bain VG, Tandon P. Risk factors for recurrence of autoimmune hepatitis after liver transplantation. Liver Transpl 2009;15:1254-1261. PMID: 19790153

20 Aoki N, Kido M, Iwamoto S, Nishiura H, Maruoka R, Tanaka J, et al. Dysregulated generation of follicular helper T cells in the spleen triggers fatal autoimmune hepatitis in mice. Gastroenterology 2011;140:1322-1333. PMID: 21237169

21 Maruoka R, Aoki N, Kido M, Iwamoto S, Nishiura H, Ikeda A, et al. Splenectomy prolongs the effects of corticosteroids in mouse models of autoimmune hepatitis. Gastroenterology 2013;145:209-220. PMID: 23523671

22 Samimi F, Irish WD, Eghtesad B, Demetris AJ, Starzl TE, Fung JJ. Role of splenectomy in human liver transplantation under modern-day immunosuppression. Dig Dis Sci 1998;43:1931-1937. PMID: 9753254

23 Nonami T, Yokoyama I, Iwatsuki S, Starzl TE. The incidence of portal vein thrombosis at liver transplantation. Hepatology 1992;16:1195-1198. PMID: 1427658

24 Li DW, Du CY, Fan B, Huang P, Luo SQ, He Q. Impact of simultaneous splenectomy and orthotopic liver transplantation in patients with end-stage liver diseases and splenic hyperfunction. Hepatobiliary Pancreat Dis Int 2012;11:489-493. PMID: 23060393