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)

Corresponding Author: 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.

doi: 10.1016/S1499-3872(15)60338-1

Published online January 19, 2015.

 

 

Contributors: CJ proposed the study. LXY and CJ wrote the first 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 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.

 

 

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)

 

KEY WORDS: chronic hepatitis B; acute-on-chronic liver failure; therapy

 

Hepatitis B virus (HBV) infection is a major cause of liver disease worldwide and continues to be a problem for public health. HBV-related end-stage 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 classified 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 first recommended by the Asian Pacific Association for the Study of the Liver (APASL) in 2009.^[3] ACLF is defined 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 defined 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 (predefined by the chronic liver failure-sequential organ failure assessment [CLIF-SOFA] score), and high 28-day mortality rate (predefined threshold of 15%).^[4] Although the exact pathogenesis of ACLF remains to be elucidated, HBV flare and the immune system overreaction to the alteration play an important role. In these complex processes, the inflammation 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, artificial liver support systems, immune regulatory therapy, stem cell therapy and liver transplantation are widely used. The therapeutic efficacies of these treatment options are uncertain and the mortality from HBV-related ACLF remains high. The present review focused on recent advances of therapeutic strategies for HBV-related ACLF.

 

 

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 fibrosis, 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 benefit 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, significant 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 non-treated 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 benefit 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 benefit for patients with ACLF unless treatment is initiated early in the course of disease.

 

A recent study^[9] reported the safety and efficacy 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 efficient 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 short-term treatment (30 days) of patients with severe acute exacerbation of CHB. The results suggested that short-term treatment with lamivudine markedly reduced the bilirubin levels in patients with severe acute exacerbation of CHB and there was no significant 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 findings suggested that the safety of entecavir needs further evaluation.

 

Furthermore, recent studies have shown contradictory findings. 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 flare. 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 first three months of treatment, the mortality in patients treated with nucleos(t)ide analogues was significantly 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 efficacy 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]

 

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 filtration 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 beneficial 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 profiles. The bioartificial liver support systems have been developed synchronously with artificial liver support systems. In contrast to artificial liver support devices which can only replace some of the liver detoxification functions, the bioartificial liver support systems attempt to provide liver-specific functions, including synthetic, regulatory, immunological and biotransformation. Bioartificial liver support systems use porcine or human hepatocytes in hollow-fiber 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), bioartificial liver support system (BLSS) and Amsterdam Medical Center-bioartifical 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 efficacy of MARS in the treatment of patients with acute, acute-on-chronic, and hyper-acute liver failure. The results suggested that MARS significantly 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 flawed 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.

 

 

In the natural history of CHB, early-stage ACLF is associated with a vigorous immune response leading to excessive hepatic necroinflammation and activation of inflammatory 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 inflammatory 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 confirmed 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 significantly 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 short-term 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 efficacy 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 significantly decreased (8.9% versus 70.2%) and its survival rate was significantly elevated (96.4% versus 52.6%). A study from China^[43] also revealed that glucocorticoid treatment exhibited significantly 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.

 

 

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 significant hepatic stellate cells activation compared with acute hepatitis and other chronic liver diseases. The significant 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 significantly reduced MELD scores, and increased serum albumin, cholinesterase, and platelet counts. Serum alanine aminotransferase and total bilirubin levels were significantly decreased. There was also obvious improvement in survival rates in patients with ACLF treated by UC-MSC. No significant 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] assessed 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 significantly 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 efficacy of G-CSF therapy in patients with HBV-associated ACLF. Fifty-five 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.

 

 

During the progression of ACLF in CHB, hepatocytes usually undergo massive necrosis and dysfunction and are difficult to completely recover by conservative treatment. Consequently, liver transplantation is widely considered as the irreplaceable and definitive 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 insufficient. A study^[52] found that at a median follow-up 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 artificial 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 artificial 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 ALSS-LT and LT groups were 79.2% and 83.0%, 69.7% and 78.6%, respectively. But there was no significant difference in survival rates between the two groups. The data mentioned above indicated that artificial liver support systems establish a bridge to liver transplantation for the ACLF patients on the waiting list.

 

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

 

 

At present, the most important therapeutic approaches for ACLF in CHB include nucleos(t)ide analogues, artificial 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 insufficient 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.

 

 

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