Advanced therapeutic strategies for HBV-related acute-on-chronic liver failure

Changsha, China

Advanced therapeutic strategies for HBV-related acute-on-chronic liver failure

Xin-Yu Liu, Feng Peng, Ya-Jie Pan and Jun Chen

Changsha, China

BACKGROUND: Acute-on-chronic liver failure (ACLF) is increasingly recognized as a distinct clinical entity and is associated with a high short-term mortality. The most common cause of ACLF is chronic hepatitis B worldwide. Currently, there is no standardized approach for the management of ACLF and the efficacy and safety of therapeutic modalities are uncertain.

DATA SOURCES: PubMed and Web of Science were searched for English-language articles. The search criteria focused on clinical trials and observational studies on the treatment of patients with HBV-related ACLF.

RESULTS: Therapeutic approaches for ACLF in patients with chronic hepatitis B included nucleos(t)ide analogues, artificial liver support systems, immune regulatory therapy, stem cell therapy and liver transplantation. All of these therapeutic approaches have shown the potential to improve liver function and increase patients' survival rate, but most of the studies were not randomized or controlled.

CONCLUSION: Substantial challenges for the treatment of HBV-related ACLF remain and further basic research and randomized controlled clinical trials are needed.

(Hepatobiliary Pancreat Dis Int 2015;14:354-360)

chronic hepatitis B; acute-on-chronic liver failure; therapy

Introduction

Hepatitis B virus (HBV) infection is a major cause of liver disease worldwide and continues to be a problem for public health. HBV-related endstage liver disease or hepatocellular carcinoma is responsible for over half million deaths per year, and now accounts for 5%-10% of cases of liver transplantation.[1]Liver related mortality in chronic hepatitis B (CHB) can be classifed into three groups: (i) complications of liver cirrhosis or hepatocellular carcinoma; (ii) gradual hepatic decompensation with liver failure; and (iii) acute decompensation, otherwise known as acute-on-chronic liver failure (ACLF).[2]The term ACLF was frst recommended by the Asian Pacifc Association for the Study of the Liver (APASL) in 2009.[3]ACLF is defned as an acute liver insult manifesting as jaundice and coagulopathy, complicated within four weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease.[3]Recently, the European CANONIC study investigators defned more precisely the clinical entity of ACLF.[4]It was based on the presence of the three major characteristics of the syndrome: acute decompensation (inclusion criterion, present in all patients), organ failure (predefned by the chronic liver failure-sequential organ failure assessment [CLIFSOFA] score), and high 28-day mortality rate (predefned threshold of 15%).[4]Although the exact pathogenesis of ACLF remains to be elucidated, HBV fare and the immune system overreaction to the alteration play an important role. In these complex processes, the infammation and necrosis of hepatocytes lead to liver failure and result in hepatic encephalopathy, hepatorenal syndrome and secondary infection.

In recent years, many therapeutic modalities such as nucleos(t)ide analogues, artifcial liver support systems, immune regulatory therapy, stem cell therapy and liver transplantation are widely used. The therapeutic effcacies of these treatment options are uncertain and the mortality from HBV-related ACLF remains high. Thepresent review focused on recent advances of therapeutic strategies for HBV-related ACLF.

Nucleos(t)ide analogues

The introduction of nucleos(t)ide analogues therapy over the last 15 years has dramatically improved the treatment outcomes in patients with CHB. Nucleos(t)ide analogues markedly suppress HBV replication leading to the improvement of liver function and a reduction in the incidence of fbrosis, cirrhosis and hepatocellular carcinoma.[1]In recent years, nucleos(t)ide analogues were widely used in patients with HBV-related ACLF, especially in Asia. Whether these patients will still beneft from antiviral treatment is not known, but is now attracting attention for clinical research. A report from China compared patients receiving entecavir (n=33), lamivudine (n=34) or no nucleos(t)ide analogues (n=37). After three months of treatment, signifcant virus suppression was observed in both nucleos(t)ide analogues groups, but no change in survival rates was reported.[5]A Japanese study[6]also compared lamivudine treated patients with historical controls. Although there was a reduction in viral load in lamivudine treated patients, there was no difference in the incidence of three month mortality rate. In our previous retrospective study,[7]55 patients with chronic severe hepatitis B were treated with entecavir and 74 nontreated patients served as controls. The results showed no difference in short-term survival between the two groups, despite potent suppression of HBV viral load by entecavir. An earlier study[8]reported lamivudine (150 mg/day) in the treatment of 60 consecutive patients with severe acute exacerbations of CHB. As a historical control, another 31 CHB patients with acute exacerbation resulting in decompensated liver hospitalized in an immediate past 6-month period were enrolled for comparison. The results showed that lamivudine may prevent mortality in patients with CHB and hepatic decompensation, but only if the treatment was started early enough or before serum bilirubin levels rose over 20 mg/dL. Minimal beneft was documented for patients with serum bilirubin levels higher than 20 mg/dL. From these published data, we conclude that treatment with nucleos(t)ide analogues confers little beneft for patients with ACLF unless treatment is initiated early in the course of disease.

A recent study[9]reported the safety and effcacy of entecavir in 36 patients with CHB who developed an acute spontaneous exacerbation of hepatitis B. A total of 117 patients treated by lamivudine served as historical controls. By week 48, mortality in the entecavir treated group reached 19% in contrast to only 4% in the lamivudine treated patients (P=0.010). Furthermore, despite a lower prevalence of cirrhosis and the faster and more effcient suppression of viral load, the entecavir treated group had a higher liver related mortality associated with prolonged bilirubinemia, hepatic encephalopathy and ascites. Another retrospective study[10]from China compared the effect of entecavir and lamivudine in the shortterm treatment (30 days) of patients with severe acute exacerbation of CHB. The results suggested that shortterm treatment with lamivudine markedly reduced the bilirubin levels in patients with severe acute exacerbation of CHB and there was no signifcant difference in the deterioration rate between patients treated by the two types of medication. There was one report in 2009 of severe lactic acidosis occurring in 5 of 16 patients with liver cirrhosis and CHB who received entecavir treatment.[11]These fndings suggested that the safety of entecavir needs further evaluation.

Furthermore, recent studies have shown contradictory fndings. In a multicenter double-blind phase II clinical trial,[12]112 patients with HBV associated decompensated liver disease were randomized to receive the treatment with tenofovir disoproxil fumarate (TDF), emtricitabine/ TDF or entecavir. The results showed that the patients tolerated all the treatments well and improved virological, biochemical and clinical parameters. However, this study was just related to the treatment of decompensated chronic HBV-related liver disease and did not include patients with HBV fare. Another prospective study[13]from India showed that tenofovir improved three month survival rate for patients with HBV-related ACLF. A retrospective report[14]from China compared patients treated with entecavir (n=42), lamivudine (n=30) or no nucleos(t)ide analogues (n=34). During the frst three months of treatment, the mortality in patients treated with nucleos(t)ide analogues was signifcantly lower than that in those untreated controls.

In summary, currently available evidence for nucleos(t)ide analogues therapy is inconsistent (Table). Only two of the studies were randomized and controlled, whilst others were retrospective. Furthermore, all the studies contained small sample sizes. Consequently, these factors may account for the inconsistent results reported for effcacy and safety of nucleos(t)ide analogues. More reliable clinical data from larger randomized controlled trials (RCTs) are needed. At present, nucleos(t)ide analogues therapy is still recommended for the prevention of further liver injury, including the long-term risk of hepatocellular carcinoma and complications of cirrhosis.[1-3]Moreover, among patients who develop liver failure and require liver transplantation, suppression of HBV DNA can reduce the risk of viral recurrence after surgery.[1-3]

Table. Clinical trials of nucleo(t)side analogues therapy in patients with HBV-related ACLF

Artificial liver support systems

In recent years, considerable research has been conducted to develop effective liver support devices to improve liver function in patients with liver failure. In many developed countries, plasmapheresis therapy and/or plasma exchange are widely used in liver support devices. During the procedure, plasma is removed by fltration and replaced with fresh-frozen plasma.[15,16]Plasma exchange can correct coagulopathy and remove hepatotoxins, but the main disadvantage is non-selective removal of benefcial substances.[17]

Currently, the mainstream devices are the molecular adsorbent recirculating system (MARS), the single-pass albumin dialysis (SPAD) and the Prometheus FPSA system.[18-21]All of these systems remove large quantities of hepatotoxins and most of them have good safety and tolerability profles. The bioartifcial liver support systems have been developed synchronously with artifcial liver support systems. In contrast to artifcial liver support devices which can only replace some of the liver detoxifcation functions, the bioartifcial liver support systems attempt to provide liver-specifc functions, including synthetic, regulatory, immunological and biotransformation. Bioartifcial liver support systems use porcine or human hepatocytes in hollow-fber bioreactors that are perfused with patient's blood or plasma. These devices include the Hepat Assist device, extracorporeal liver assist device (ELAD), modular extracorporeal liver support (MELS), bioartifcial liver support system (BLSS) and Amsterdam Medical Center-bioartifcal liver (AMC-BAL).[22-25]

A total of 74 clinical studies including 17 RCTs were found in the literature on the extracorporeal liver support (ELS), including 198 patients with acute liver failure and 157 patients with ACLF. The results showed that ELS systems appear to improve survival of patients with acute liver failure, but not of those with ACLF (risk ratio: 0.87; P=0.37).[26]Another review by Hassanein et al[27]also concluded that ELS systems were safe and well tolerated for patients with ACLF, but RCTs failed to show improvement in survival. Vaid et al[28]recently conducted a meta-analysis to examine the effcacy of MARS in the treatment of patients with acute, acute-on-chronic, and hyper-acute liver failure. The results suggested that MARS signifcantly decreased total bilirubin levels and improved hepatic encephalopathy, but did not improve survival. Mao et al[29]found that plasma exchange improved the 30-day survival rate in patients with ACLF and limited MELD score of 20-30 (50.0% versus 31.7%, P＜0.05); but plasma exchange had no effect on the 30-day survival of patients with MELD scores of more than 30 (8.3% versus 0%, P＞0.05).[29]In a systematic review, Zhao et al[30]analyzed major obstacles in the development of BLSSs. They found that extracorporeal BLSSs are restricted by fawed bioreactors and incompetent cell sources. Therefore, more studies on hepatocyte differentiation and liver microstructure formation are required to facilitate the development of this technology. Recently, an international multicenter study[31]randomized 189 patients with ACLF to MARS (n=95) or standard therapy (n=94). The results revealed that MARS therapy did not improve the survival rate.

In general, most studies indicated that the liver support devices can not effectively improve the survival rate of patients with ACLF, whereas plasma exchange and MARS may improve survival under certain conditions. More advanced biologic devices that incorporate hepatocytes in bioreactors and large-scale RCTs are required to further assess the therapeutic outcome of liver support systems.

Immune regulatory therapy

In the natural history of CHB, early-stage ACLF is associated with a vigorous immune response leading to excessive hepatic necroinfammation and activation ofinfammatory cells including CD4+and CD8+T cells.[32]The progression of ACLF involves immune dysregulation such as the activation of innate immunologic cells and cytokine released from these infammatory cells. Many different cell types, including T lymphocytes, monocytes and dendritic cells, are primed in ACLF, and these are believed to play a pivotal role in the pathogenesis of this disease.[32-37]Treating CHB patients with corticosteroids to inhibit an excessive immune response and prevent cytolysis of infected hepatocytes would be a logical step assuming HBV could be controlled. Corticosteroids have been used to treat active CHB since the 1970s. In recent years, however, their advantage has not been confrmed in controlled studies. Furthermore, corticosteroids have serious side effects such as secondary infection, acute peptic ulceration and bleeding, and all of these limit their use for the routine management of CHB. In 2005, Japanese researchers reported that the combination of corticosteroids and nucleos(t)ide analogue signifcantly reversed deterioration in patients with life-threatening exacerbations of CHB compared with historical controls, when used in the early-stage of their disease. Additionally, corticosteroid treatment for more than a few weeks is better than conventional pulsed therapy for a short period.[38-40]Matsumoto et al[41]also reported two patients with severe exacerbation of CHB who received shortterm corticosteroids together with continuous entecavir. This study suggested that entecavir treatment effectively reduced serum HBV DNA levels and corticosteroids suppressed the excessive host immune response, the combination was useful for stopping progressive deterioration. Zhang et al[42]evaluated the effcacy of short-term dexamethasone therapy in acute-on-chronic pre-liver failure. A total of 170 patients were treated with dexamethasone and the control group comprised 114 patiants. Compared to the control group, the incidence of ACLF in the dexamethasone group was signifcantly decreased (8.9% versus 70.2%) and its survival rate was signifcantly elevated (96.4% versus 52.6%). A study from China[43]also revealed that glucocorticoid treatment exhibited signifcantly greater improvement of liver function compared with control group in patients with HBV-related ACLF. Patients in the control group (n=44) received lamivudine and routine integrated treatment, and those in the treatment group (n=43) were treated with additional short-term low-dose glucocorticoids. In a study by Zhao et al,[44]patients with HBV-related ACLF were treated with methylprednisolone. A total of 30 patients received methylprednisolone treatment at 10-day intervals; 26 patients received conservative medical treatment and acted as the control group. The results strongly suggested that higher myeloid dendritic cells numbers at baseline and the recovery of myeloid dendritic cells numbers at the end of treatment, may represent a prognostic marker for a favorable response to corticosteroid treatment in patients with HBV-related ACLF. These reports suggested that corticosteroid or glucocorticoid may improve the clinical prognosis, but the type of patients, their treatment, and the duration of the treatment need further investigation.

Stem cell therapy

Liver transplantation is often the only available treatment for many end-stage liver diseases, but is limited by donor shortage, a requirement for lifelong immunosuppressive treatment and high cost. Hepatic stem/progenitor cell transplantation is increasingly recognized as a promising strategy. In recent years, a series of animal models transplanted with human hepatic stem cells have been established and several clinical trials have been reported. The most novel breakthrough is the use of human fetal liver and endothelial cells engrafted into naturally derived scaffolds to create a liver like tissue in vitro.[45]

A recent study[46]investigated the number of activated hepatic stellate cells and their relationship with hepatic stem/progenitor cells in patients with ACLF. Comparisons were made of patients with acute and chronic stages of other liver diseases. The results showed that ACLF was associated with signifcant hepatic stellate cells activation compared with acute hepatitis and other chronic liver diseases. The signifcant relationship between hepatic stellate cells and hepatic stem/progenitor cells indicate that hepatic stellate cells may contribute to liver regeneration and pathobiology of ACLF. Wan et al[47]recently demonstrated that ACLF led to mobilization of CD34+cells that was associated with hepatic differentiation potential. Mesenchymal stem cells (MSCs) are multipotent cells that have self-renewing abilities and the potential to differentiate into various types of cells including hepatocytes. Clinically, Shi et al[48]administered umbilical cord-derived mesenchymal stem cells (UC-MSCs) to patients with HBV-related ACLF. A total of 24 patients with ACLF were treated with UC-MSCs and 19 controls with saline. UC-MSCs transfusion signifcantly reduced MELD scores, and increased serum albumin, cholinesterase, and platelet counts. Serum alanine aminotransferase and total bilirubin levels were signifcantly decreased. There was also obvious improvement in survival rates in patients with ACLF treated by UC-MSC. No signifcant adverse events were observed during the trial. These results suggest that UC-MSC transfusions may serve as a novel therapeutic approach for patients with HBV-associated ACLF. Garg et al[49]as-sessed granulocyte-colony stimulating factor (G-CSF) in 23 patients with ACLF compared with 24 patients treated with placebo. Compared to the control group, G-CSF signifcantly reduced MELD, Child-Turcotte-Pugh and Sequential Organ Failure Assessment (SOFA) scores, and prevented the secondary infection, hepatorenal syndrome and hepatic encephalopathy. Thus, G-CSF effectively increased the two-month survival rate in patients with ACLF. Recently, a randomized, controlled, and double-blinded study[50]from China evaluated the safety and effcacy of G-CSF therapy in patients with HBV-associated ACLF. Fifty-fve patients with HBV-associated ACLF were randomized into two groups: a treatment group and a control group. The result indicated that G-CSF therapy promoted CD34+cell mobilization, and improved the liver function and the survival rate of these patients.

Although studies assessing hepatic stem cells in patients with ACLF are few, they do suggest that hepatic stem cells play a possible role in liver regeneration and pathobiology of ACLF and hepatic stem cells treatment might be an effective therapy for patients with ACLF. Further evidence is required before hepatic stem cells can be widely used in clinical practice.

Liver transplantation

During the progression of ACLF in CHB, hepatocytes usually undergo massive necrosis and dysfunction and are diffcult to completely recover by conservative treatment. Consequently, liver transplantation is widely considered as the irreplaceable and defnitive treatment for ACLF, particularly for the patients who do not improve with supportive measures to sustain life. In recent decades, the improvement of survival rate with liver transplant (1- and 5-year survival of 83% and 75%, respectively) has made liver transplantation as a doable therapy for all types of end-stage liver disease.[51]

The data on liver transplant in patients with ACLF is insuffcient. A study[52]found that at a median followup of 23 months, the survival rates of patients and grafts were 88%. They concluded that living donor liver transplantation using the right lobe is an effective therapeutic option for patients with ACLF in CHB. The survival rates were comparable with those in patients undergoing living donor liver transplantation for elective conditions. A retrospective study from Hong Kong analyzed 103 patients who received living donor liver grafts and 46 patients who received deceased donor liver grafts. The 5-year survival rate was 93.2% for patients with acute exacerbation of CHB and 90.5% for cirrhotic patients with acute deterioration. These results suggested that liver transplantation is a life-saving therapy for ACLF.[53]

However, the shortage of donors limits liver transplantation. Finkenstedt et al[54]investigated the feasibility of liver transplantation and determined the postoperative outcomes of patients with ACLF. The study concluded that liver transplantation remains the only therapeutic option for considerable patients with ACLF. However, liver transplantation was feasible in less than one fourth of the patients with a 5-year survival rate greater than 80%, and the mortality of the patients on the wait list is quite high (54%). The widening gap between needy recipients and available organ donors indicates that temporary liver support to patients with ACLF is necessary. A recent study[55]evaluated the experience in an artifcial liver support system combined with liver transplantation in the treatment of ACLF. A total of 171 patients with HBV-related ACLF undergoing liver transplantation were divided into two groups: 115 received treatment of a plasma exchange-centered artifcial liver support system before liver transplantation (ALSS-LT group) and the other 56 received emergency liver transplantation (LT group). The 1- and 5-year survival rates in the ALSSLT and LT groups were 79.2% and 83.0%, 69.7% and 78.6%, respectively. But there was no signifcant difference in survival rates between the two groups. The data mentioned above indicated that artifcial liver support systems establish a bridge to liver transplantation for the ACLF patients on the waiting list.

In summary, liver transplantation is undoubtedly a signifcant defnitive treatment for ACLF. However, organ shortage limits liver transplantation.

Conclusions

At present, the most important therapeutic approaches for ACLF in CHB include nucleos(t)ide analogues, artifcial liver support systems, immune regulatory therapy, stem cells therapy and liver transplantation. Generally, the former three therapies improve liver function of HBV-related ACLF patients to certain extent. However, these therapies lack substantial evidence with regard to the improvement of the survival rate. Apart from liver transplantation, current evidence indicates that stem cell therapy may be a novel effective approach for facilitating liver regeneration as well as improving the survival rate of the patients. We believe that stem cell therapy will play a more important role in the treatment of ACLF. Since studies are insuffcient and many challenges remain for the treatment of HBV-related ACLF, laboratory research into pathogenesis and progression factors of ACLF, multi-center and large sample size RCTs and new treatment strategies are required.

Contributors:CJ proposed the study. LXY and CJ wrote the frst draft; PF wrote the part of immune regulatory therapy; PYJ wrote the part of stem cells therapy. All authors contributed to the design and interpretation of the study and to further drafts. CJ is the guarantor.

Funding:None.

Ethical approval:Not needed.

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

1 European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-185.

2 Seto WK, Lai CL, Yuen MF. Acute-on-chronic liver failure in chronic hepatitis B. J Gastroenterol Hepatol 2012;27:662-669.

3 Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacifc Association for the study of the liver (APASL). Hepatol Int 2009;3:269-282.

4 Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426-1437.

5 Cui YL, Yan F, Wang YB, Song XQ, Liu L, Lei XZ, et al. Nucleoside analogue can improve the long-term prognosis of patients with hepatitis B virus infection-associated acute on chronic liver failure. Dig Dis Sci 2010;55:2373-2380.

6 Tsubota A, Arase Y, Suzuki Y, Suzuki F, Sezaki H, Hosaka T, et al. Lamivudine monotherapy for spontaneous severe acute exacerbation of chronic hepatitis B. J Gastroenterol Hepatol 2005;20:426-432.

7 Chen J, Han JH, Liu C, Yu RH, Li FZ, Li QF, et al. Short-term entecavir therapy of chronic severe hepatitis B. Hepatobiliary Pancreat Dis Int 2009;8:261-266.

8 Chien RN, Lin CH, Liaw YF. The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B. J Hepatol 2003;38:322-327.

9 Wong VW, Wong GL, Yiu KK, Chim AM, Chu SH, Chan HY, et al. Entecavir treatment in patients with severe acute exacerbation of chronic hepatitis B. J Hepatol 2011;54:236-242.

10 Liu C, Ye J, Jia H, Zhang M, Han H, Chen F, et al. Entecavir and lamivudine therapy for severe acute chronic hepatitis B. Exp Ther Med 2013;5:545-548.

11 Lange CM, Bojunga J, Hofmann WP, Wunder K, Mihm U, Zeuzem S, et al. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology 2009;50:2001-2006.

12 Liaw YF, Sheen IS, Lee CM, Akarca US, Papatheodoridis GV, Suet-Hing Wong F, et al. Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology 2011;53:62-72.

13 Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A. Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. Hepatology 2011;53:774-780.

14 Chen T, He Y, Liu X, Yan Z, Wang K, Liu H, et al. Nucleoside analogues improve the short-term and long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure. Clin Exp Med 2012;12:159-164.

15 Sabin S, Merritt JA. Treatment of hepatic coma in cirrhosis by plasmapheresis and plasma infusion (plasma exchange). Ann Intern Med 1968;68:1-7.

16 Yamazaki Z, Kanai F, Idezuki Y, Inoue N. Extracorporeal methods of liver failure treatment. Biomater Artif Cells Artif Organs 1987-1988;15:667-675.

17 Abe T, Kobata H, Hanba Y, Kitabata Y, Narukawa N, Hasegawa H, et al. Study of plasma exchange for liver failure: benefcial and harmful effects. Ther Apher Dial 2004;8:180-184.

18 Stange J, Ramlow W, Mitzner S, Schmidt R, Klinkmann H. Dialysis against a recycled albumin solution enables the removal of albumin-bound toxins. Artif Organs 1993;17:809-813.

19 Sauer IM, Goetz M, Steffen I, Walter G, Kehr DC, Schwartlander R, et al. In vitro comparison of the molecular adsorbent recirculation system (MARS) and single-pass albumin dialysis (SPAD). Hepatology 2004;39:1408-1414.

20 Falkenhagen D, Strobl W, Vogt G, Schref A, Linsberger I, Gerner FJ, et al. Fractionated plasma separation and adsorption system: a novel system for blood purifcation to remove albumin bound substances. Artif Organs 1999;23:81-86.

21 Rozga J. Liver support technology--an update. Xenotransplantation 2006;13:380-389.

22 Sussman NL, Chong MG, Koussayer T, He DE, Shang TA, Whisennand HH, et al. Reversal of fulminant hepatic failure using an extracorporeal liver assist device. Hepatology 1992;16:60-65.

23 Mazariegos GV, Patzer JF 2nd, Lopez RC, Giraldo M, Devera ME, Grogan TA, et al. First clinical use of a novel bioartifcial liver support system (BLSS). Am J Transplant 2002;2:260-266.

24 Morsiani E, Pazzi P, Puviani AC, Brogli M, Valieri L, Gorini P, et al. Early experiences with a porcine hepatocyte-based bioartifcial liver in acute hepatic failure patients. Int J Artif Organs 2002;25:192-202.

25 van de Kerkhove MP, Di Florio E, Scuderi V, Mancini A, Belli A, Bracco A, et al. Phase I clinical trial with the AMC-bioartifcial liver. Int J Artif Organs 2002;25:950-959.

26 Stutchfeld BM, Simpson K, Wigmore SJ. Systematic review and meta-analysis of survival following extracorporeal liver support. Br J Surg 2011;98:623-631.

27 Hassanein TI, Schade RR, Hepburn IS. Acute-on-chronic liver failure: extracorporeal liver assist devices. Curr Opin Crit Care 2011;17:195-203.

28 Vaid A, Chweich H, Balk EM, Jaber BL. Molecular adsorbent recirculating system as artifcial support therapy for liver failure: a meta-analysis. ASAIO J 2012;58:51-59.

29 Mao W, Ye B, Lin S, Fu Y, Chen Y, Chen Y. Prediction value of model for end-stage liver disease scoring system on prognosis in the acute on chronic liver failure patients with plasma exchange treatment. ASAIO J 2010;56:475-478.

30 Zhao LF, Pan XP, Li LJ. Key challenges to the development of extracorporeal bioartifcial liver support systems. Hepatobiliary Pancreat Dis Int 2012;11:243-249.

31 Bañares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M, et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 2013;57:1153-1162.

32 Xu D, Fu J, Jin L, Zhang H, Zhou C, Zou Z, et al. Circulating and liver resident CD4+CD25+ regulatory T cells actively infuence the antiviral immune response and disease progressionin patients with hepatitis B. J Immunol 2006;177:739-747.

33 Zou Z, Li B, Xu D, Zhang Z, Zhao JM, Zhou G, et al. Imbalanced intrahepatic cytokine expression of interferon-gamma, tumor necrosis factor-alpha, and interleukin-10 in patients with acute-on-chronic liver failure associated with hepatitis B virus infection. J Clin Gastroenterol 2009;43:182-190.

34 Zou Z, Xu D, Li B, Xin S, Zhang Z, Huang L, et al. Compartmentalization and its implication for peripheral immunologically-competent cells to the liver in patients with HBV-related acute-on-chronic liver failure. Hepatol Res 2009;39:1198-1207.

35 Zhang JY, Zhang Z, Lin F, Zou ZS, Xu RN, Jin L, et al. Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B. Hepatology 2010;51:81-91.

36 Zhang JY, Zou ZS, Huang A, Zhang Z, Fu JL, Xu XS, et al. Hyper-activated pro-infammatory CD16 monocytes correlate with the severity of liver injury and fbrosis in patients with chronic hepatitis B. PLoS One 2011;6:e17484.

37 Shi F, Zhang JY, Zeng Z, Tien P, Wang FS. Skewed ratios between CD3(+) T cells and monocytes are associated with poor prognosis in patients with HBV-related acute-on-chronic liver failure. Biochem Biophys Res Commun 2010;402:30-36.

38 Fujiwara K, Yokosuka O, Kojima H, Kanda T, Saisho H, Hirasawa H, et al. Importance of adequate immunosuppressive therapy for the recovery of patients with "life-threatening" severe exacerbation of chronic hepatitis B. World J Gastroenterol 2005;11:1109-1114.

39 Fujiwara K, Yasui S, Yonemitsu Y, Fukai K, Arai M, Imazeki F, et al. Effcacy of combination therapy of antiviral and immunosuppressive drugs for the treatment of severe acute exacerbation of chronic hepatitis B. J Gastroenterol 2008;43:711-719.

40 Fujiwara K, Yasui S, Okitsu K, Yonemitsu Y, Oda S, Yokosuka O. The requirement for a suffcient period of corticosteroid treatment in combination with nucleoside analogue for severe acute exacerbation of chronic hepatitis B. J Gastroenterol 2010;45:1255-1262.

41 Matsumoto K, Miyake Y, Miyatake H, Takahara M, Imada T, Yagi S, et al. A combination treatment of entecavir and earlyphase corticosteroid in severe exacerbation of chronic hepatitis B. World J Gastroenterol 2009;15:1650-1652.

42 Zhang XQ, Jiang L, You JP, Liu YY, Peng J, Zhang HY, et al. Effcacy of short-term dexamethasone therapy in acute-onchronic pre-liver failure. Hepatol Res 2011;41:46-53.

43 Wu JY, Li M, Zhang H. Effect of glucocorticoid treatment on the clinical outcome of patients with early-stage liver failure. Nan Fang Yi Ke Da Xue Xue Bao 2011;31:554-556.

44 Zhao J, Zhang JY, Yu HW, He YL, Zhao JJ, Li J, et al. Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy. Cell Mol Immunol 2012;9:417-422.

45 Baptista PM, Siddiqui MM, Lozier G, Rodriguez SR, Atala A, Soker S. The use of whole organ decellularization for the generation of a vascularized liver organoid. Hepatology 2011;53: 604-617.

46 Rastogi A, Bihari C, Maiwall R, Ahuja A, Sharma MK, Kumar A, et al. Hepatic stellate cells are involved in the pathogenesis of acute-on-chronic liver failure (ACLF). Virchows Arch 2012;461:393-398.

47 Wan Z, You S, Rong Y, Zhu B, Zhang A, Zang H, et al. CD34+ hematopoietic stem cells mobilization, paralleled with multiple cytokines elevated in patients with HBV-related acute-onchronic liver failure. Dig Dis Sci 2013;58:448-457.

48 Shi M, Zhang Z, Xu R, Lin H, Fu J, Zou Z, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med 2012;1:725-731.

49 Garg V, Garg H, Khan A, Trehanpati N, Kumar A, Sharma BC, et al. Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acuteon-chronic liver failure. Gastroenterology 2012;142:505-512.

50 Duan XZ, Liu FF, Tong JJ, Yang HZ, Chen J, Liu XY, et al. Granulocyte-colony stimulating factor therapy improves survival in patients with hepatitis B virus-associated acute-on-chronic liver failure. World J Gastroenterol 2013;19:1104-1110.

51 Adam R, Hoti E. Liver transplantation: the current situation. Semin Liver Dis 2009;29:3-18.

52 Liu CL, Fan ST, Lo CM, Wei WI, Yong BH, Lai CL, et al. Livedonor liver transplantation for acute-on-chronic hepatitis B liver failure. Transplantation 2003;76:1174-1179.

53 Chan AC, Fan ST, Lo CM, Liu CL, Chan SC, Ng KK, et al. Liver transplantation for acute-on-chronic liver failure. Hepatol Int 2009;3:571-581.

54 Finkenstedt A, Nachbaur K, Zoller H, Joannidis M, Pratschke J, Graziadei IW, et al. Acute-on-chronic liver failure: excellent outcomes after liver transplantation but high mortality on the wait list. Liver Transpl 2013;19:879-886.

55 Xu X, Liu X, Ling Q, Wei Q, Liu Z, Xu X, et al. Artifcial liver support system combined with liver transplantation in the treatment of patients with acute-on-chronic liver failure. PLoS One 2013;8:e58738.

Received March 24, 2014

Accepted after revision October 13, 2014

Author Affiliations: Liver Diseases Center, Second Xiangya Hospital, Central South University, Changsha 410011, China (Liu XY, Peng F, Pan YJ and Chen J); Department of Infectious Diseases, Third Xiangya Hospital, Central South University, Changsha 410013, China (Liu XY)

Jun Chen, MD, PhD, Liver Diseases Center, Second Xiangya Hospital, Central South University, Changsha 410011, China (Tel/ Fax: +86-731-85292105; Email: drchenjun@163.com)

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(15)60338-1

Published online January 19, 2015.