The liver is the largest organ in the body; it has a complex architecture, wide range of functions and unique regenerative capacity. The growing incidence of liver diseases worldwide requires increased numbers of liver transplant and leads to an ongoing shortage of donor livers. To meet the huge demand, various alternative approaches are being investigated including, hepatic cell transplantation, artificial devices and bioprinting of the organ itself. Adult hepatocytes are the preferred cell sources, but they have limited availability, are difficult to isolate, propagate poor and undergo rapid functional deterioration in vitro. There have been efforts to overcome these drawbacks; by improving culture condition for hepatocytes, providing adequate extracellular matrix, co-culturing with extra-parenchymal cells and identifying other cell sources. Differentiation of human stem cells to hepatocytes has become a major interest in the field of stem cell research and has progressed greatly. At the same time, use of decellularized organ matrices and 3 D printing are emerging cutting-edge technologies for tissue engineering, opening up new paths for liver regenerative medicine. This review provides a compact summary of the issues, and the locations of liver support systems and tissue engineering, with an emphasis on reproducible and useful sources of hepatocytes including various candidates formed by differentiation from stem cells.

Cell sources, liver support systems and liver tissue engineering: alternatives to liver transplantation.

Non-biological artificial liver support (ALS) devices aim to remove albumin-bound and water-soluble toxins arising as a result of liver failure. They do not directly improve the liver synthetic capacity. The currently most used devices combine haemodialysis with albumin dialysis (MARS) or plasma separation and filtration (Prometheus). These devices have been used as a treatment for different types of liver failure: acute liver failure, acute-on-chronic liver failure and primary non- or poor-function after liver transplantation. Overall these devices are found to be safe. The following beneficial effects have been documented: improvement of jaundice, amelioration of haemodynamic instability, reduction of portal hypertension, lowering of intracranial pressure and improvement of hepatic encephalopathy. However, recently multicentre controlled trials failed to show a beneficial effect on transplant-free survival. Therefore the use of these devices at present seems only justified as a bridge to liver transplantation.

Artificial liver support devices as treatment option for liver failure

https://www.journal-of-hepatology.eu/article/S0168-8278(15)00196-8/pdf

Efficacy of coupled low-volume plasma exchange with plasma filtration adsorption in treating pigs with acute liver failure: A randomised study

AIM: To identify prognostic factors for survival in patients with liver failure treated with a molecular adsorbent recirculating system (MARS). METHODS: MARS is a liver-assisting device that has been used in the treatment of liver failure to enable native liver recovery, and as a bridge to liver transplantation (LTX). We analyzed the 1-year outcomes of 188 patients treated with MARS, from 2001 to 2007, in an intensive care unit specializing in liver disease. Demographic, clinical and laboratory parameters were recorded before and after each treatment. One-year survival and the number of LTXs were recorded. Logistic regression analysis was performed to determine factors predicting survival. RESULTS: The study included 113 patients with acute liver failure (ALF), 62 with acute-on-chronic liver failure (AOCLF), 11 with graft failure (GF), and six with miscellaneous liver failure. LTX was performed for 29% of patients with ALF, 18% with AOCLF and 55% with GF. The overall 1-year survival rate was 74% for ALF, 27% for AOCLF, and 73% for GF. The poorest survival rate, 6%, was noted in non-transplanted patients with alcohol-related AOCLF and cirrhosis, whereas, patients with enlarged and steatotic liver had 55% survival. The etiology of liver failure was the most important predictor of survival (P < 0.0001). Other prognostic factors were encephalopathy (P = 0.001) in paracetamol-related ALF, coagulation factors (P = 0.049) and encephalopathy (P = 0.064) in non-paracetamol-related toxic ALF, and alanine aminotransferase (P = 0.013) and factor V levels (P = 0.022) in ALF of unknown etiology. CONCLUSION: The etiology of liver disease was the most important prognostic factor. MARS treatment appears to be ineffective in AOCLF with end-stage cirrhosis without an LTX option.

/pdf/survival-predictors-in-patients-treated-with-a-molecular-bw5ru0uvrh.pdf

Survival predictors in patients treated with a molecular adsorbent recirculating system.

Background. Hepatitis B virus-associated acute-on-chronic liver failure (HBV-ALCF) is a complicated syndrome with extremely high short-term mortality. The artificial liver support system (ALSS) may improve the liver function for patients with HBV-ACLF, but the data on its short-term outcomes are insufficient in China. Methods. We recruited HBV-ACLF patients in this nationwide, multicenter, retrospective study. Patients with HBV-ACLF were diagnosed by the COSSH-ACLF criteria. Propensity score matching (PSM) analysis was used to generate compared pairs. The short-term (28/90 days) survival rates between the standard medical therapy (SMT) group and ALSS group were calculated using a Kaplan–Meier graph. Result. In total, 790 patients with HBV-ACLF were included in this retrospective study; 412 patients received SMT only (SMT group), and 378 patients received SMT and ALSS treatment (ALSS group). PSM generated 310 pairs and eliminated the baseline differences between the two groups ( for all baseline variables). The probabilities of survival on day 28 were 65.2% (205/310) in the ALSS group and 59.0% (185/310) in the SMT group; on day 90, they were 51.0% (163/310) and 42.3% (136/310). The short-term (28/90 days) survival rates of the ALSS group were significantly higher than those of the SMT group ( and , respectively). Compared to receiving SMT alone, treatment with ALSS was associated with a significant reduction in serum bilirubin levels and the model for end-stage liver disease (MELD) scores at day 7 and day 28. Multivariate logistic regression analysis revealed that older age, high total bilirubin (T-Bil), low albumin, high ALT, high MELD scores, and high COSSH-ACLF grade were independent baseline factors associated with poor prognosis. Conclusions. This retrospective study found that compared to SMT, the ALSS improved the short-term (28/90 days) survival rates and laboratory parameters in HBV-ACLF patients. The ALSS had a better therapeutic effect than SMT for patients with HBV-ACLF in China.

/pdf/artificial-liver-support-system-improves-short-term-outcomes-35vkamj9uc.pdf

Artificial Liver Support System Improves Short-Term Outcomes of Patients with HBV-Associated Acute-on-Chronic Liver Failure: A Propensity Score Analysis

220 predictive factors of transplant free survival in patients with fulminant and subfulminant hepatic failure: results from a randomized controlled multicenter trial

Introduction Chez les patients atteints d’une insuffisance hepatique aigue, le systeme de dialyse hepatique a l’albumine MARS®, tel qu’il a ete rapporte dans de nombreuses etudes non controlees, a permis une amelioration de l’encephalopathie hepatique, de l’ammoniemie et de la perfusion cerebrale. But de l’etude Survie des patients a 6 mois avec ou sans transplantation. Patients et Methodes Etude prospective, controlee, randomisee, 16 centres. Les patients atteints d’une hepatite fulminante ou subfulminante etaient randomises des qu’ils presentaient les criteres d’indications a la transplantation hepatique (criteres de Clichy ou du King's College), soit dans un bras conventionnel (CONV) ou un traitement par le MARS® combine au traitement CONV dans l’attente d’un greffon. Les patients etaient stratifies selon l’etiologie liee ou non au paracetamol. Le traitement par le MARS® devait debuter dans les 12 heures suivant la randomisation. Des seances de 8 heures devaient etres realisees jusqu’a la disponibilite d’un greffon hepatique. Resultats D’aout 2004 a decembre 2007, 110 patients ont ete randomises, 8 ont ete exclus pour violation majeure du protocole (cirrhose alcoolique decompensee, 3pts, et absence de consentement, 5pts). 102 patients (49 CONV, 53 MARS ; 57 % femmes) avec une moyenne d’âge de 40,4 ± 13 ans (extremes 18-70 ans), ont ete inclus dans l’analyse en intention de traiter (ITT). La cause principale de l’HF etait une intoxication au paracetamol (38 %, 19 CONV, 20 MARS). A l’inclusion, 32 patients etaient sous ventilation mecanique (13 CONV, 19 MARS), le stade de l’encephalopathie et les valeurs moyennes des ALAT : 4 455 ± 4 862 UI/L, bilirubine totale : 191 ± 181 μmol/L, INR : 8,3 ± 4,1, facteur V : 17,8 ± 10,8 % et de la creatininemie : 210 ± 175 μmol/L n’etaient pas significativement differents entre les 2 groupes. L’analyse en per-protocole (PP) a exclu les patients randomises dans le groupe MARS, mais qui n’ont pas ete traites par le MARS (7pts) ou qui ont eu une seance  Il y avait une amelioration mais non significative de la survie a 6 mois dans le groupe MARS a la fois dans l’analyse en ITT (84,9 % vs 75,5 %) et PP (82,1 % vs 75,5 %), et particulierement dans le groupe d’HF due au paracetamol (85 % vs 68,5 %). Au total, 66/102 patients ont ete transplantes (79,4 % dans le bras non-paracetamol et 41 % dans le bras paracetamol ; p  Conclusion Il s’agit d’une premiere etude randomisee multicentrique realisee sur un support hepatique artificiel demontrant sa bonne tolerance avec une tendance a une amelioration de la survie des patients atteints d’une hepatite fulminante ou subfulminante.

CO.88 Étude prospective, randomisée, multicentrique, évaluant l’efficacité et la tolérance du système de dialyse hépatique à l’albumine MARS ® chez les patients atteints d’une hépatite fulminante en attente de transplantation

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220 predictive factors of transplant free survival in patients with fulminant and subfulminant hepatic failure: results from a randomized controlled multicenter trial

CO.88 Étude prospective, randomisée, multicentrique, évaluant l’efficacité et la tolérance du système de dialyse hépatique à l’albumine MARS ® chez les patients atteints d’une hépatite fulminante en attente de transplantation