Liver Support System and Transplant-Free Survival Patients with Liver Failure: an Evidence-Based Case Report

Background: The mortality rate in patients with acute liver failure (ALF) and acute on chronic liver failure (ACLF) is still very high. Currently, liver support systems are an alternative therapy in bridging liver transplantation. However, its effectiveness in reducing mortality is still controversial when compared to standard medical therapy (SMT). Our study aims to review the efficacy of liver support system compared to standard medical therapy (SMT) among acute liver failure patients without liver transplantation. Method: We conducted systematic literature searching using PubMed/MEDLINE, EBSCO-CINAHL, ProQuest, and Cochrane databases. Selected articles were examined for duplicates and were screened by abstract and title. Then, we appraised the articles based on the critical appraisal tools from Centre for Evidence-Based Medicine (CEBM) University of Results: One systematic review and meta-analysis of randomized control trials study was extracted after thorough research. Alhamshi et al showed that extracorporeal liver support has significantly reduced mortality in both ALF and ACLF patients as the primary outcome. Other main findings about adverse events including hepatic encephalopathy, thrombocytopenia, bleeding, and infection were still unclear. Conclusion: The use of liver support system demonstrated better outcome in reducing mortality to standard medical therapy in transplant free patients with liver failure, but best modality recommendation was inconclusive.


INTRODUCTION
Acute liver failure (ALF) and acute on chronic liver failure (ACLF), regardless of the underlying cause, are manifested by severe encephalopathy, coagulopathy, and subsequent multi-system organ failure resulting in a high mortality rate. [1][2][3] In the CANONIC study, the kidney was the most frequently affected organ (55.8% of patients), followed by liver (43.6% of patients), coagulation (27.7% of patients), brain (24.1% of patients), circulation (16.8% of patients) and lungs (9.2% of patients). 4 In the NACSELD study, 55.7% had grade III-IV hepatic encephalopathy (HE), 17.6% of patients had shock, 15.1% of patients required renal replacement therapy and 15.8% of patients required mechanical ventilation. 5 Until recent times, liver transplantation is still considered as the main therapeutic modality in acute liver failure with a one-year long-term survival rate exceeding 88%. However, many obstacles are encountered in its application, both the availability of donors and supporting facilities. 6,7 In addition to standard medical therapy (SMT), currently liver support systems are one of the therapeutic options for patients who have not received a liver transplant yet. 8,9 Extracorporeal liver support systems, in particular albumin dialysis and/or plasma exchange, have been proposed as a new therapeutic option that can be used as a bridge for liver transplantation in patients with acute liver failure with efforts to improve clinical, neurological, and biological parameters. 4,6,9,11 The most studied liver support systems include the adsorbent molecular circulation system (MARS) and the plasma separation and absorption system (Prometheus), which are based on the principle of albumin dialysis. 12,13,15 Prospective trials have demonstrated that MARS can improve cholestasis, hepatic, and renal function and hemodynamic in patients with decompensated cirrhosis; however, the effect on survival is not conclusive. 9,16

CASE ILLUSTRATION
A 57-years-old male patient came to the ER brought by his family with complaints of confusion, disoriented and somnolent, he had a history of nausea, looked yellow with tea-coloured urine. The patient has had cirrhosis on chronic hepatitis B with a history of regular alcohol consumption. On examination, grade II hepatic encephalopathy, jaundice, ascites with elevated transaminase enzymes (ALT 4375; AST 1593) hyperbilirubinemia (up to 39.53 mg/dL) coagulopathy with INR prolongation 2.8x, reactive HBsAg and HBV DNA increase 5.97 x 106 units (log 6.78) 3.47x10 7 were found. The patient has been routinely consulted to physician and previously treated with tenofovir disoproxil fumarate, he has been suggested for a liver transplant option but constrained by donor availability. The patient's condition was assessed as acute on chronic liver failure. During treatment, the patient underwent liver support therapy by using plasmapheresis method.
Clinical question: In patients with acute liver failure, are liver support systems more effective in reducing mortality risk than standard medical therapy (SMT)?
Liver Support System and Transplant-Free Survival Patients with Liver Failure: an Evidence-Based Case Report

METHOD
The selected articles met the eligibility criteria using a systematic review, meta-analysis, and clinical trial method. The inclusion criteria included: clinical trial or meta-analysis study, research subjects were humans with a population of acute liver failure patients, including acute liver failure in chronic liver disease, with intervention of liver supportive therapy in any method compared to standard medical therapy with mortality outcome. The exclusion criteria used were paediatric patients, and had undergone liver transplantation, as well as literature in the form of guidelines and article reviews. We do not limit the selection of articles by year of publication or language.
The literature search was carried out on 11-15 November 2021 in five databases, including MEDLINE, PROQUEST, EBSCO, and Cochrane. The keywords are "acute liver failure" and "liver support" with related terminology ( Table 1). The search strategy based on exclusion and inclusion criteria described above (Figure 1). The literature obtained was then screened for titles and abstracts, removed duplications in different databases, and in-depth screening of each intact text was carried out based on the suitability of the clinical question. After literature selection, a critical assessment was carried out by consensus of all authors to assess validity, study results, and clinical application based on the Centre of Evidence-Based Medicine, University of Oxford for both systematic review and meta-analysis studies.

RESULTS
Based on the literature search strategy, one article met the eligibility criteria based on clinical questions. The summary of the article and its method presented in Table 2. The article is a systematic review or metaanalysis of randomized control trials with level of evidence 1a.

DISCUSSION
The study conducted by Alhamshi et al has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) study protocol. Based on the literature, there was a significant mortality reduction, in both ALF and ACLF patients receiving liver support therapy with various modalities compared to SMT. 6 Heterogeneity based on the Cochran Q-test was not statistically significant for the mortality outcome. 6 In addition, there was a secondary outcome of hepatic encephalopathy that was more common in patients with liver support systems than those with SMT, but with significant heterogeneity. Another secondary outcome is the accompanying side effects, either bleeding, infection, or thrombocytopenia, the results of which are still unclear. 6 The subject population was highly broad, included acute liver failure and acute conditions in chronic liver disease, as well as various underlying etiologies affected the potential risk, severity, as well as the different treatment history in each patient. 6 Variations in survival time in various studies also affected heterogeneity. 6 In subgroup analysis, not all subjects could be analysed. 6 Therefore, although this study provides an overview of the benefits of using liver support systems in patients with liver failure in general, its application in daily practice still requires further studies regarding comorbid side effects and the choice of the most superior modality. 6 Careful consideration is needed between the magnitude of the benefits compared to the prognosis of individuals with specific comorbidities considering the costs and facilities are greater than the use of SMT. 6