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Changes in gut microbiota influence both the gut and liver, which are strictly connected by the so-called “gut–liver axis”. The gut microbiota acts as a major determinant of this relationship in the onset and clinical course of liver diseases. According to the results of several studies, gut dysbiosis is linked to viral hepatitis, mainly hepatitis C virus and hepatitis B virus infection. Gut bacteria-derived metabolites and cellular components are key molecules that affect liver function and modulate the pathology of viral hepatitis. Recent studies showed that the gut microbiota produces various molecules, such as peptidoglycans, lipopolysaccharides, DNA, lipoteichoic acid, indole-derivatives, bile acids, and trimethylamine, which are translocated to the liver and interact with liver immune cells causing pathological effects. Therefore, the existence of crosstalk between the gut microbiota and the liver and its implications on host health and pathologic status are essential factors impacting the etiology and therapeutic approach. Concrete mechanisms behind the pathogenic role of gut-derived components on the pathogenesis of viral hepatitis remain unclear and not understood. In this review, we discuss the current findings of research on the bidirectional relationship of the components of gut microbiota and the progression of liver diseases and viral hepatitis and vice versa. Moreover, this paper highlights the current therapeutic and preventive strategies, such as fecal transplantation, used to restore the gut microbiota composition and so improve host health.

Background Most hepatocellular carcinomas (HCCs) are hypervascular, with characteristic features of hepatic arterial supply to the tumor. The factors involved in tumor angiogenesis include angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and vascular endothelial growth factor (VEGF). Aim To investigate the profiles of plasma levels of angiogenesis markers in patients with HCC and evaluate their roles in predicting overall survival (OS) and progression-free survival (PFS). Methods Plasma samples from 240 prospectively enrolled HCC patients in the very early to advanced stages were used to measure the levels of Ang-1, Ang-2, and VEGF. Their associations with clinical characteristics, OS, and PFS were analyzed. Results The median plasma levels of Ang-1, Ang-2, and VEGF were 3216 pg/mL, 1684 pg/mL, and 26.5 pg/mL, respectively. The plasma level of Ang-2 showed a significant increase from early stage [Barcelona clinic liver cancer (BCLC) A] to intermediate (BCLC B) and advanced stage HCC (BCLC C/D), whereas Ang-1, VEGF, and alpha-fetoprotein (AFP) levels in the plasma did not show any such changes. Multivariable analysis, propensity score-matched analysis, and time-dependent receiver operating curve analysis revealed that Ang-2 levels had the highest predictive power for OS and PFS. Neither Ang-1 nor VEGF was significantly associated with OS or PFS. The neutrophil-to-lymphocyte ratio was an independent factor for OS and PFS. Conclusion The plasma levels of Ang-2 correlated with liver function, tumor stage, and tumor invasiveness, showing better performance in predicting OS and PFS than AFP, Ang-1, or VEGF.

Since it was first reported in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has spread rapidly around the world to cause the ongoing pandemic. Although the clinical manifestations of SARS-CoV-2 infection are predominantly in the respiratory system, liver enzyme abnormalities exist in around half of the cases, which indicate liver injury, and raise clinical concern. At present, there is no consensus whether the liver injury is directly caused by viral replication in the liver tissue or indirectly by the systemic inflammatory response. This review aims to summarize the clinical manifestations and to explore the underlying mechanisms of liver dysfunction in patients with SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19) is caused by infection of the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with typical respiratory symptoms. SARS-CoV-2 invades not only the respiratory system, but also other organs expressing the cell surface receptor angiotensin converting enzyme 2. In particular, the digestive system is a susceptible target of SARS-CoV-2. Gastrointestinal symptoms of COVID-19 include anorexia, nausea, vomiting, diarrhea, abdominal pain, and liver damage. Patients with digestive damage have a greater chance of progressing to severe or critical illness, a poorer prognosis, and a higher risk of death. This paper aims to summarize the digestive system symptoms of COVID-19 and discuss fecal-oral contagion of SARS-CoV-2. It also describes the characteristics of inflammatory bowel disease patients with SARS-CoV-2 infection and discusses precautions for preventing SARS-CoV-2 infection during gastrointestinal endoscopy procedures. Improved attention to digestive system abnormalities and gastrointestinal symptoms of COVID-19 patients may aid health care providers in the process of clinical diagnosis, treatment, and epidemic prevention and control.

Background The introduction of direct-acting antiviral drugs into clinical practice has revolutionized the treatment of chronic hepatitis C, making it highly effective and safe for patients. However, few researchers have analyzed the factors causing therapy failure in some patients. Aim To analyze factors influencing the failure of direct antiviral drugs in the large, multicenter EpiTer-2 cohort in a real-world setting. Methods The study cohort consisted of patients with chronic hepatitis C treated at 22 Polish centers from 2016-2020. Data collected from the online EpiTer-2 database included the following: hepatitis C virus (HCV) genotype, stage of fibrosis, hematology and liver function parameters, Child-Turcotte-Pugh and Model for End-stage Liver Disease scores, prior antiviral therapy, concomitant diseases, and drugs used in relation to hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) coinfections. Adverse events observed during the treatment and follow-up period were reported. Both standard and machine learning methods were used for statistical analysis. Results During analysis, 12614 patients with chronic hepatitis C were registered, of which 11938 (mean age: 52 years) had available sustained virologic response (SVR) data [11629 (97%) achieved SVR and 309 (3%) did not]. Most patients (78.1%) were infected with HCV genotype 1b. Liver cirrhosis was diagnosed in 2974 patients, while advanced fibrosis (F3) was diagnosed in 1717 patients. We included patients with features of hepatic failure at baseline [ascites in 142 (1.2%) and encephalopathy in 68 (0.6%) patients]. The most important host factors negatively influencing treatment efficacy were liver cirrhosis, clinical and laboratory features of liver failure, history of hepatocellular carcinoma, and higher body mass index. Among viral factors, genotype 3 and viral load also exerted an influence on treatment efficacy. Classical statistical analysis revealed that treatment ineffectiveness seemed to be influenced by the male sex, which was not confirmed by the multivariate analysis using the machine learning algorithm (random forest). Coinfection with HBV (including patients with on-treatment reactivation of HBV infection) or HIV, extrahepatic manifestations, and renal failure did not significantly affect the treatment efficacy. Conclusion In patients with advanced liver disease, individualized therapy (testing for resistance-associated variants and response-guided treatment) should be considered to maximize the chance of achieving SVR.

The worldwide outbreak of coronavirus disease 2019 (COVID-19) has challenged the priorities of healthcare system in terms of different clinical management and infection transmission, particularly those related to hepatic-disease comorbidities. Epidemiological data evidenced that COVID-19 patients with altered liver function because of hepatitis infection and cholestasis have an adverse prognosis and experience worse health outcomes. COVID-19-associated liver injury is correlated with various liver diseases following a severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) infection that can progress during the treatment of COVID-19 patients with or without pre-existing liver disease. SARS-CoV-2 can induce liver injury in a number of ways including direct cytopathic effect of the virus on cholangiocytes/hepatocytes, immune-mediated damage, hypoxia, and sepsis. Indeed, immediate cytopathogenic effects of SARS-CoV-2 via its potential target, the angiotensin-converting enzyme-2 receptor, which is highly expressed in hepatocytes and cholangiocytes, renders the liver as an extra-respiratory organ with increased susceptibility to pathological outcomes. But, underlying COVID-19-linked liver disease pathogenesis with abnormal liver function tests (LFTs) is incompletely understood. Hence, we collated COVID-19-associated liver injuries with increased LFTs at the nexus of pre-existing liver diseases and COVID-19, and defining a plausible pathophysiological triad of COVID-19, hepatocellular damage, and liver disease. This review summarizes recent findings of the exacerbating role of COVID-19 in pre-existing liver disease and vice versa as well as international guidelines of clinical care, management, and treatment recommendations for COVID-19 patients with liver disease.

Background Cyanidin-3-O-glucoside (cyan) exhibits antioxidant and anticancer properties. The cell cycle proteins and antimitotic drugs might be promising therapeutic targets in hepatocellular carcinoma. Aim To investigate the effect of cyan administration on cell cycle in hepatic precancerous lesion (PCL) induced by diethylnitrosamine/2-acetylaminofluorene (DEN/2-AAF) in Wistar rats. Methods In vivo, DEN/2-AAF-induced hepatic PCL, rats were treated with three doses of cyan (10, 15, and 20 mg/kg/d, for four consecutive days per week for 16 wk). Blood and liver tissue samples were collected for measurement of the followings; alpha fetoprotein (AFP) liver function and RNA panel differential expression was evaluated via real time polymerase chain reaction. Histopathological examination of liver sections stained with H&E and immunohistochemical study using glutathione S-transferase placental (GSTP) and proliferating cell nuclear antigen (PCNA) antibodies were assessed. Results Cyan administration mitigated the effect of DEN/2-AFF induced PCL, decreased AFP levels, and improved liver function. Remarkably, treatment with cyan dose dependently decreased the long non-coding RNA MALAT1 and tubulin gamma 1 mRNA expressions and increased the levels of miR-125b, all of which are involved in cell cycle and mitotic spindle assembly. Of note, cyan decreased GSTP foci percent area and PCNA positively stained nuclei. Conclusion Our results indicated that cyan could be used as a potential therapeutic agent to inhibit liver carcinogenesis in rat model via modulation of cell cycle.

Background Hepatic encephalopathy (HE) remains an enormous challenge in patients who undergo transjugular intrahepatic portosystemic shunt (TIPS) implantation. The preoperative indocyanine green retention rate at 15 min (ICG-R15), as one of the liver function assessment tools, has been developed as a prognostic indicator in patients undergoing surgery, but there are limited data on its role in TIPS. Aim To determine whether the ICG-R15 can be used for prediction of post-TIPS HE in decompensated cirrhosis patients with portal hypertension (PHT) and compare the clinical value of ICG-R15, Child-Pugh score (CPS), and model for end-stage liver disease (MELD) score in predicting post-TIPS HE with PHT. Methods This retrospective study included 195 patients with PHT who underwent elective TIPS at Beijing Shijitan Hospital from January 2018 to June 2019. All patients underwent the ICG-R15 test, CPS evaluation, and MELD scoring 1 wk before TIPS. According to whether they developed HE or not, the patients were divided into two groups: HE group and non-HE group. The prediction of one-year post-TIPS HE by ICG-R15, CPS and MELD score was evaluated by the areas under the receiver operating characteristic curves (AUCs). Results A total of 195 patients with portal hypertension were included and 23% (45/195) of the patients developed post-TIPS HE. The ICG-R15 was identified as an independent predictor of post-TIPS HE. The AUCs for the ICG-R15, CPS, and MELD score for predicting post-TIPS HE were 0.664 (95% confidence interval [CI]: 0.557-0.743, P = 0.0046), 0.596 (95%CI: 0.508-0.679, P = 0.087), and 0.641 (95%CI: 0.554-0.721, P = 0.021), respectively. The non-parametric approach (Delong-Delong & Clarke-Pearson) showed that there was statistical significance in pairwise comparison between AUCs of ICG-R15 and MELD score (P = 0.0229). Conclusion The ICG-R15 has appreciated clinical value for predicting the occurrence of post-TIPS HE and is a choice for evaluating the prognosis of patients undergoing TIPS.

BACKGROUND Vitamin D is an essential fat-soluble secosteroid hydroxylated by the liver to form the intermediate metabolite calcidiol {25-hydroxy vitamin D [25(OH)D]}, which is a reliable indicator to investigate individual vitamin D status. Vitamin-D-binding protein (VDBP) is a multifunctional glycoprotein mainly synthesized in the liver and the major transport protein for vitamin D and its metabolites. Serum vitamin D and VDBP are both associated with hepatitis B. However, few studies have reported the relationship and clinical significance of vitamin D and VDBP with hepatitis B virus (HBV) replication and hepatic fibrosis in children with chronic hepatitis B (CHB). AIM To explore vitamin D and VDBP serum levels in children with CHB and the association of vitamin D and VDBP with HBV replication and hepatic fibrosis. METHODS We enrolled 204 children with CHB admitted to Hunan Children’ Hospital in summer and autumn between 2018 and 2019 and 170 healthy controls. CHB patients included: 164 hepatitis B e antigen (HBeAg) positive and 40 HBeAg negative; 193 hepatitis B surface antigen (HBsAg) positive and 11 HBsAg negative; 164 with detectable HBV deoxyribonucleic acid (DNA) and 40 with undetectable HBV DNA; 131 with HBV genotype B and 23 with HBV genotype C; and 27 without hepatic fibrosis and 97 with hepatic fibrosis. Serum levels of 25(OH)D, VDBP, liver function markers, and other clinical parameters were collected to analyze their association with vitamin D and VDBP. Mann-Whitney U test, Kruskal-Wallis H test, or t test was used to analyze serum 25(OH)D and VDBP levels in different groups. Spearman rank correlation test was utilized to analyze the correlation of 25(OH)D and VDBP with other markers. Statistically significant factors determined by univariate analysis were further analyzed by binary multivariate logistic regression analysis. P < 0.05 was considered statistically significant. RESULTS Children with CHB had lower serum 25(OH)D (56.64 ± 17.89 nmoL/L) and VDBP [122.40 (70.74-262.84 μg/L)] levels than healthy controls had (P < 0.001). Serum 25(OH)D and VDBP levels were significantly different among the different grades of hepatic fibrosis (P < 0.05). VDBP levels in children with HBV genotype C, HBsAg, HBeAg, and detectable HBV DNA were significantly lower than those in children with HBV genotype B, no HBsAg, no HBeAg, and undetectable HBV DNA (P < 0.05). Serum 25(OH)D level was negatively correlated with age and serum total bilirubin level (r = -0.396 and -0.280, respectively, P < 0.001). Serum VDBP level was negatively correlated with HBV DNA (log10 IU/mL) (r = -0.272, P < 0.001). Serum 25(OH)D level was not correlated with VDBP level (P > 0.05). Univariate (P < 0.05) and multivariate logistic regression analysis showed that low level of 25(OH)D (odds ratio = 0.951, 95% confidence interval: 0.918-0.985) and high level of HBV DNA (odds ratio = 1.445, 95% confidence interval: 1.163-1.794) were independently correlated with hepatic fibrosis (P < 0.01). CONCLUSION Serum levels of 25(OH)D and VDBP are decreased in children with CHB. Serum VDBP level is negatively correlated with HBV replication. Low level of 25(OH)D is independently associated with hepatic fibrosis in children with CHB. There is no significant association between serum levels of 25(OH)D and VDBP.

BACKGROUND The infusion of triolein emulsion (TE) induced increased vascular permeability and a negligible and temporary decrease in liver function without specific histopathological damage. AIM To assess changes in doxorubicin concentration according to the percentage of TE infused via a hepatic artery to study the vascular permeability in the rabbit liver. METHODS Thirty-nine healthy rabbits were divided into five groups according to the concentration of emulsified triolein infused into the hepatic arteries: Group 0, saline infusion (control group, n = 5); group 1, 0.3% TE (n = 13); group 2, 0.6% TE (n = 6); group 3, 0.9% TE (n = 8); and group 4, 1.5% TE (n = 6). Doxorubicin (2.4 mg/kg) was infused immediately after TE injection via the hepatic arteries. After 2 h, the livers were harvested, and doxorubicin concentrations were calculated fluorometrically. The doxorubicin concentrations were compared between TE groups and the control group, and the optimal concentrations within the TE groups were calculated. Statistical analysis was performed using the nonparametric Mann-Whitney U test and Kruskal–Wallis test. P < 0.05 were considered statistically significant. RESULTS In the liver, doxorubicin concentrations were 2.06, 2.07, 2.16 and 1.66 times higher in groups 1 through 4, respectively, and significantly higher in the TE groups than in the control group (all P < 0.05). However, there were no significant differences in the mean doxorubicin concentrations between the four TE groups (P = 0.642). In the lungs, the mean doxorubicin concentrations were not significantly different between the control and TE groups (P > 0.05). CONCLUSION TE infusion into the hepatic arteries significantly increased the doxorubicin concentration approximately twofold but was not different between the TE groups. These findings suggest that TE infusion might be a useful adjuvant treatment of liver cancers.

BACKGROUND Studies suggested that remote ischemic preconditioning (RIPC) may effectively lessen the harmful effects of ischemia reperfusion injury during organ transplantation surgery. AIM To investigate the protective effects of RIPC on living liver donors and recipients following pediatric liver transplantation. METHODS From January 2016 to January 2019 at Renji Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, 208 donors were recruited and randomly assigned to four groups: S-RIPC group (no intervention; n = 55), D-RIPC group (donors received RIPC; n = 51), R-RIPC group (recipients received RIPC, n = 51) and DR-RIPC group (both donors and recipients received RIPC; n = 51). We primarily evaluated postoperative liver function among donors and recipients and incidences of early allograft dysfunction, primary nonfunction and postoperative complications among recipients. RESULTS RIPC did not significantly improve alanine transaminase and aspartate aminotransferase levels among donors and recipients or decrease the incidences of early allograft dysfunction, primary nonfunction, and postoperative complications among recipients. Limited protective effects were observed, including a lower creatinine level in the D-RIPC group than in the S-RIPC group on postoperative day 0 (P < 0.05). However, no significant improvements were found in donors who received RIPC. Furthermore, RIPC had no effects on the overall survival of recipients. CONCLUSION The protective effects of RIPC were limited for recipients who received living liver transplantation, and no significant improvement of the prognosis was observed in recipients.

Background Extrahepatic biliary duct injury (BDI) remains a complicated issue for surgeons. Although several approaches have been explored to address this problem, the high incidence of complications affects postoperative recovery. As a nonimmunogenic scaffold, an animal-derived artificial bile duct (ada-BD) could replace the defect, providing good physiological conditions for the regeneration of autologous bile duct structures without changing the original anatomical and physiologic conditions. Aim To evaluate the long-term feasibility of a novel heterogenous ada-BD for treating extrahepatic BDI in pigs. Methods Eight pigs were randomly divided into two groups in the study. The animal injury model was developed with an approximately 2 cm segmental defect of various parts of the common bile duct (CBD) for all pigs. A 2 cm long novel heterogenous animal-derived bile duct was used to repair this segmental defect (group A, ada-BD-to-duodenum anastomosis to repair the distal CBD defect; group B, ada-BD-to-CBD anastomosis to repair the intermedial CBD defect). The endpoint for observation was 6 mo (group A) and 12 mo (group B) after the operation. Liver function was regularly tested. Animals were euthanized at the above endpoints. Histological analysis was carried out to assess the efficacy of the repair. Results The median operative time was 2.45 h (2-3 h), with a median anastomosis time of 60.5 min (55-73 min). All experimental animals survived until the endpoints for observation. The liver function was almost regular. Histologic analysis indicated a marked biliary epithelial layer covering the neo-bile duct and regeneration of the submucosal connective tissue and smooth muscle without significant signs of immune rejection. In comparison, the submucosal connective tissue was more regular and thicker in group B than in group A, and there was superior integrity of the regeneration of the biliary epithelial layer. Despite the advantages of the regeneration of the bile duct smooth muscle observed in group A, the effect on the patency of the ada-BD grafts in group B was not confirmed by macroscopic assessment and cholangiography. Conclusion This approach appears to be feasible for repairing a CBD defect with an ada-BD. A large sample study is needed to confirm the durability and safety of these preliminary results.

Pituitary stalk interruption syndrome (PSIS) is a rare congenital abnormality characterized by thinning or disappearance of the pituitary stalk, hypoplasia of the anterior pituitary and an ectopic posterior pituitary. Although the etiology of PSIS is still unclear, gene changes and perinatal adverse events such as breech delivery may play important roles in the pathogenesis of PSIS. PSIS can cause multiple hormone deficiencies, such as growth hormone, which then cause a series of changes in the human body. On the one hand, hormone changes affect growth and development, and on the other hand, they could affect human metabolism and subsequently the liver resulting in nonalcoholic fatty liver disease (NAFLD). Under the synergistic effect of multiple mechanisms, the progression of NAFLD caused by PSIS is faster than that due to other causes. Therefore, in addition to early identification of PSIS, timely hormone replacement therapy and monitoring of relevant hormone levels, clinicians should routinely assess the liver function while managing PSIS.

Background Liver fibrosis is a common health problem worldwide and there is still a lack of effective medicines. The Chinese herbal medicine, Gan Shen Fu Fang (GSFF) is composed of salvianolic acid B and diammonium glycyrrhizinate. In this study, we observed the effects of GSFF on liver fibrosis in vivo and in vitro in an attempt to provide some hope for the treatment. Aim To observe the effects of GSFF on liver fibrosis in vivo and in vitro and investigate the mechanism from the perspective of the inflammatory response and extracellular signal-regulated kinase (ERK) phosphorylation. Methods Common bile duct-ligated rats were used for in vivo experiments. Hepatic stellate cells-T6 (HSC-T6) cells were used for in vitro experiments. Hematoxylin and eosin staining and Masson staining, biochemical assays, hydroxyproline (Hyp) assays, enzyme-linked immunoasorbent assay and western blotting were performed to evaluate the degree of liver fibrosis, liver function, the inflammatory response and ERK phosphorylation. The CCK8 assay, immunofluorescence and western blotting were applied to test the effect of GSFF on HSC-T6 cell activation and determine whether GSFF had an effect on ERK phosphorylation in HSC-T6 cells. Results GSFF improved liver function and inhibited liver fibrosis in common bile duct-ligated rats after 3 wk of treatment, as demonstrated by histological changes, hydroxyproline assays and collagen I concentrations. GSFF alleviated inflammatory cell infiltration and reduced the synthesis of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α) and interlukin-1β] and NF-κB. In addition, GSFF decreased ERK phosphorylation. In vitro, GSFF inhibited the viability of HSC-T6 cells with and without transforming growth factor β1 (TGF-β1) stimulation and decreased the synthesis of collagen I. GSFF had the greatest effect at a concentration of 0.5 μmol/L. GSFF inhibited the expression of α-smooth muscle actin (α-SMA), a marker of HSC activation, in HSC-T6 cells. Consistent with the in vivo results, GSFF also inhibited the phosphorylation of ERK and downregulated the expression of NF-κB. Conclusion GSFF inhibited liver fibrosis progression in vivo and HSC-T6 cell activation in vitro. These effects may be related to an alleviated inflammatory response and downregulated ERK phosphorylation.

Background Postoperative liver failure is the most severe complication in cirrhotic patients with hepatocellular carcinoma (HCC) after major hepatectomy. Current available clinical indexes predicting postoperative residual liver function are not sufficiently accurate. Aim To determine a radiomics model based on preoperative gadoxetic acid-enhanced magnetic resonance imaging for predicting liver failure in cirrhotic patients with HCC after major hepatectomy. Methods For this retrospective study, a radiomics-based model was developed based on preoperative hepatobiliary phase gadoxetic acid-enhanced magnetic resonance images in 101 patients with HCC between June 2012 and June 2018. Sixty-one radiomic features were extracted from hepatobiliary phase images and selected by the least absolute shrinkage and selection operator method to construct a radiomics signature. A clinical prediction model, and radiomics-based model incorporating significant clinical indexes and radiomics signature were built using multivariable logistic regression analysis. The integrated radiomics-based model was presented as a radiomics nomogram. The performances of clinical prediction model, radiomics signature, and radiomics-based model for predicting post-operative liver failure were determined using receiver operating characteristics curve, calibration curve, and decision curve analyses. Results Five radiomics features from hepatobiliary phase images were selected to construct the radiomics signature. The clinical prediction model, radiomics signature, and radiomics-based model incorporating indocyanine green clearance rate at 15 min and radiomics signature showed favorable performance for predicting postoperative liver failure (area under the curve: 0.809-0.894). The radiomics-based model achieved the highest performance for predicting liver failure (area under the curve: 0.894; 95%CI: 0.823-0.964). The integrated discrimination improvement analysis showed a significant improvement in the accuracy of liver failure prediction when radiomics signature was added to the clinical prediction model (integrated discrimination improvement = 0.117, P = 0.002). The calibration curve and an insignificant Hosmer-Lemeshow test statistic (P = 0.841) demonstrated good calibration of the radiomics-based model. The decision curve analysis showed that patients would benefit more from a radiomics-based prediction model than from a clinical prediction model and radiomics signature alone. Conclusion A radiomics-based model of preoperative gadoxetic acid-enhanced MRI can be used to predict liver failure in cirrhotic patients with HCC after major hepatectomy.

BACKGROUND Liver resection is an effective treatment for benign and malignant liver tumors. However, a method for preoperative evaluation of hepatic reserve has not yet been established. Previously reported assessments of preoperative hepatic reserve focused only on liver failure in the early postoperative period and did not consider the long-term recovery of hepatic reserve. When determining eligibility for hepatectomy, the underlying pathophysiology needs to be considered to determine if the functional hepatic reserve can withstand both surgery and any postoperative therapy. AIM To identify pre-hepatectomy factors associated with both early postoperative liver failure and long-term postoperative liver function recovery. METHODS This study was a retrospective cohort study. We retrospectively investigated 215 patients who underwent hepatectomy at our hospital between May 2013 and December 2016. Early post-hepatectomy liver failure (PHLF) was defined using the International Study Group of Liver Surgery’s definition of PHLF. Long-term postoperative recovery of liver function was defined as the time taken for serum total bilirubin and albumin levels to return to levels of < 2 mg/dL and > 2.8 g/dL, respectively, and the time taken for Child-Pugh score to return to Child-Pugh class A. RESULTS Preoperative type IV collagen 7S was identified as a significant independent factor associated with both PHLF and postoperative long-term recovery of liver function. Further analysis revealed that the time taken for the recovery of Child-Pugh scores and serum total bilirubin and albumin levels was significantly shorter in patients with type IV collagen 7S ≤ 6 ng/mL than in those with type IV collagen 7S > 6 ng/mL. In additional analyses, similar results were observed in patients without chronic viral hepatitis associated with fibrosis. CONCLUSION Preoperative type IV collagen 7S is a preoperative predictor of PHLF and long-term postoperative liver function recovery. It can also be used in patients without chronic hepatitis virus.

BACKGROUND Acute liver failure (ALF) is a significant and complex hepatic insult that may rapidly progress to life-threatening conditions. Recently, menstrual blood stem cells (MenSCs) have been identified as a group of easily accessible mesenchymal stem cells with the advantages of non-invasive acquisition, low immunogenicity, a greater capacity of self-renewal and multi-lineage differentiation, making them promising candidates for stem cell-based therapy to revolutionize the treatment strategies for liver failure. AIM To investigate the therapeutic potential of MenSCs for treating ALF in pigs and to dynamically trace the biodistribution of transplanted cells. METHODS MenSCs were labeled in vitro with PKH26, a lipophilic fluorescent dye. The treatment group received immediate transplantation of PKH26-labelled MenSCs (2.5 × 106/kg) via the portal vein after D-galactosamine injection, and the control group underwent sham operation. The survival time, liver function, and hepatic pathological changes were compared between the two groups. Three major organs (liver, lungs and spleen) were extracted from animals and imaged directly with the In vivo Imaging System (IVIS) at the predetermined time points. The regions of interest were drawn to quantify the cell uptake in different organs. RESULTS The labelling procedure did not affect the morphology, viability or multipotential differentiation of MenSCs. Biochemical analysis showed that the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and prothrombin time (PT) measured at selected time points 24 h after transplantation were significantly decreased in the treatment group (P < 0.05). The survival time of ALF animals was prolonged in the treatment group compared with the control group (75.75 ± 5.11 h vs 53.75 ± 2.37 h, log rank, P < 0.001). The liver pathological tissue in the MenSC treatment group showed obviously increased numbers of remaining hepatocytes and a comparatively slight necrotic degree and area. In addition, the IVIS imaging revealed that PKH26-positive MenSCs were clearly retained in the liver initially and then diffused through the systemic circulation. Interestingly, the signal intensity in the liver increased obviously at 36 h, which corresponded to the biochemical result that liver function deteriorated most rapidly at 24 - 36 h. CONCLUSION Our study demonstrates the therapeutic efficacy and homing ability of transplanted MenSCs in a large animal model of ALF and suggests that MenSC transplantation could be a promising strategy for treating ALF.

Since its introduction in 2012, associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) has significantly expanded the pool of candidates for liver resection. It offers patients with insufficient liver function a chance of a cure. ALPPS is most controversial when its high morbidity and mortality is concerned. Operative mortality is usually a result of post-hepatectomy liver failure and can be minimized with careful patient selection. Elderly patients have limited reserve for tolerating the demanding operation. Patients with colorectal liver metastasis have normal liver and are ideal candidates. ALPPS for cholangiocarcinoma is technically challenging and associated with fair outcomes. Patients with hepatocellular carcinoma have chronic liver disease and limited parenchymal hypertrophy. However, in selected patients with limited hepatic fibrosis satisfactory outcomes have been produced. During the inter-stage period, serum bilirubin and creatinine level and presence of surgical complication predict mortality after stage II. Kinetic growth rate and hepatobiliary scintigraphy also guide the decision whether to postpone or omit stage II surgery. The outcomes of ALPPS have been improved by a combination of technical modifications. In patients with challenging anatomy, partial ALPPS potentially reduces morbidity, but remnant hypertrophy may compare unfavorably to a complete split. When compared to conventional two-stage hepatectomy with portal vein embolization or portal vein ligation, ALPPS offers a higher resection rate for colorectal liver metastasis without increased morbidity or mortality. While ALPPS has obvious theoretical oncological advantages over two-stage hepatectomy, the long-term outcomes are yet to be determined.

BACKGROUND Researchers have investigated the diagnostic value of protein induced by vitamin K absence or antagonist II (PIVKA-II) and alpha-fetoprotein (AFP) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), and obtained abundant clinical diagnostic data. However, PIVKA-II and AFP have unsatisfactory specificity and sensitivity in the diagnosis of early-stage HBV-related HCC. Gamma-glutamyltransferase (γ-GT) and aspartate aminotransferase (AST) are common biomarkers for evaluating liver function, and we hypothesized that the γ-GT/AST ratio in combination with PIVKA-II and AFP would improve the diagnosis of early-stage HBV-related HCC. AIM To evaluate the diagnostic value of γ-GT/AST ratio alone or in combination with PIVKA-II and AFP in HBV-related HCC. METHODS Serum levels of γ-GT, AST, PIVKA-II, and AFP were detected and analysed in 176 patients with HBV-related HCC and in 359 patients with chronic hepatitis B. According to tumour size and serum level of HBV DNA, HBV-related HCC patients were divided into the following categories: Early-stage HCC patients, HCC patients, HBV DNA positive (HBV DNA+) HCC patients, and HBV DNA negative (HBV DNA-) HCC patients. Receiver-operating characteristic (ROC) curves were used to analyse and compare the diagnostic value of the single and combined detection of various biomarkers in different types of HBV-related HCC. RESULTS Tumour size was positively correlated with serum levels of PIVKA-II and AFP in HCC patients (r = 0.529, aP < 0.001 and r = 0.270, bP < 0.001, respectively), but there was no correlation between tumour size and the γ-GT/AST ratio (r = 0.073, P = 0.336). The areas under the receiver-operating characteristic curves (AUROCs) of the γ-GT/AST ratio in early-stage HCC patients, HBV DNA+ HCC patients and HBV DNA- HCC patients were not significantly different from that in the total HCC patients (0.754, 0.802, and 0.705 vs 0.779, respectively; P > 0.05). When PIVKA-II was combined with the γ-GT/AST ratio in the diagnosis of early-stage HCC, HCC, and HBV DNA+ HCC, the AUROCs of PIVKA-II increased, with values of 0.857 vs 0.835, 0.925 vs 0.913, and 0.958 vs 0.954, respectively. When AFP was combined with the γ-GT/AST ratio in the diagnosis of early-stage HCC, HCC, HBV DNA+ HCC, and HBV DNA- HCC, the AUROCs of AFP increased, with values of 0.757 vs 0.621, 0.837 vs 0.744, 0.868 vs 0.757, and 0.840 vs 0.828, respectively. CONCLUSION The γ-GT/AST ratio may be better than PIVKA-II and AFP in the diagnosis of early-stage HBV-related HCC, and its combination with PIVKA-II and AFP can improve the diagnostic value for HBV-related HCC.

© The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved. BACKGROUND Cirrhosis is a chronic late stage liver disease associated with hepatitis viruses, alcoholism, and metabolic disorders, such as Wilson disease (WD). There are no clear markers or clinical features that define cirrhosis originating from these disparate origins. We hypothesized that cirrhosis is not one disease and cirrhosis of different etiology may have differential clinical hepatic features. AIM To delineate the liver features between WD-associated cirrhosis and hepatitis Bassociated cirrhosis in the Chinese population. METHODS In this observational study, we reviewed the medical data of consecutive inpatients who had WD-associated cirrhosis or hepatitis B-associated cirrhosis from January 2010 to August 2018, and excluded patients who had carcinoma, severe heart or pulmonary diseases, or other liver diseases. According to the etiology of cirrhosis, patients were divided into two groups: WD-associated cirrhosis group (60 patients) and hepatitis B-associated cirrhosis group (56 patients). The liver fibrosis degree, liver function indices, and portal hypertension features of these patients were compared between the two groups. RESULTS No inter-group differences were observed in the diagnostic liver fibrosis markers, however, clinical features clearly defined the origin of cirrhosis. WD-associated cirrhosis patients (16-29 years) had lower levels of alanine transaminase, aspartate transaminase, and bilirubin, lower prothrombin time, lower incidence of hepatic encephalopathy, and lower portal vein diameter (P < 0.05), compared to cirrhosis resulting from hepatitis B in older patients (45-62 years). Importantly, they had decreased risks of progression from Child-Pugh grade A to B (odds ratio = 0.046, 95% confidence interval: 0.006-0.387, P = 0.005) and of ascites (odds ratio = 0.08, 95% confidence interval: 0.01-0.48, P = 0.005). Conversely, WDassociated cirrhosis patients had a higher risk of splenomegaly (odds ratio = 4.15, 95% confidence interval: 1.38-12.45, P = 0.011). CONCLUSION WD-associated cirrhosis presents a higher risk of splenomegaly associated with leukopenia and thrombocytopenia, although revealing milder liver dysfunction and portal hypertension symptoms, which recommends WD patients to be monitored for associated complications.

BACKGROUND Exposure to high sustained +Gz (head-to-foot inertial load) is known to have harmful effects on pilots’ body in flight. Although clinical data have shown that liver dysfunction occurs in pilots, the precise cause has not been well defined. AIM To investigate rat liver function changes in response to repeated +Gz exposure. METHODS Ninety male Wistar rats were randomly divided into a blank control group (BC group, n = 30), a +6 Gz/5 min stress group (6GS group, n = 30), and a +10 Gz/5min stress group (10GS group, n = 30). The 6GS and 10GS groups were exposed to +6 Gz and +10 Gz, respectively, in an animal centrifuge. The onset rate of +Gz was 0.5 G/s. The sustained time at peak +Gz was 5 min for each exposure (for 5 exposures, and 5-min intervals between exposures for a total exposure and non-exposure time of 50 min). We assessed liver injury by measuring the portal venous flow volume, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), liver tissue malondialdehyde (MDA), Na+-K+-ATPase, and changes in liver histology. These parameters were recorded at 0 h, 6 h, and 24 h after repeated +Gz exposures. RESULTS After repeated +Gz exposures in the 6GS and the 10GS groups, the velocity and flow signal in the portal vein (PV) were significantly decreased as compared to the BC group at 0 h after exposure. Meanwhile, we found that the PV diameter did not change significantly. However, rats in the 6GS group had a much higher portal venous flow volume than the 10GS group at 0 h after exposure. The 6GS group had significantly lower ALT, AST, and MDA values than the 10GS group 0 h and 6 h post exposure. The Na+-K+-ATPase activity in the 6GS group was significantly higher than that in the 10GS group 0 h and 6 h post exposure. Hepatocyte injury, determined pathologically, was significantly lower in the 6GS group than in the 10GS group. CONCLUSION Repeated +Gz exposures transiently cause hepatocyte injury and affect liver metabolism and morphological structure.

Background Given the shortage of suitable liver grafts for liver transplantation, proper use of hepatitis B core antibody-positive livers might be a possible way to enlarge the donor pool and to save patients with end-stage liver diseases. However, the safety of hepatitis B virus core antibody positive (HBcAb+) donors has been controversial. Initial studies were mainly conducted overseas with relatively small numbers of HBcAb+ liver recipients, and there are few relevant reports in the population of mainland China. We hypothesized that the safety of HBcAb+ liver grafts is not suboptimal. Aim To evaluate the safety of using hepatitis B virus (HBV) core antibody-positive donors for liver transplantation in Chinese patients. Methods We conducted a retrospective study enrolling 1071 patients who underwent liver transplantation consecutively from 2005 to 2016 at West China Hospital Liver Transplantation Center. Given the imbalance in several baseline variables, propensity score matching was used, and the outcomes of all recipients were reviewed in this study. Results In the whole population, 230 patients received HBcAb+ and 841 patients received HBcAb negative (HBcAb-) liver grafts. The 1-, 3- and 5-year survival rates in patients and grafts between the two groups were similar (patient survival: 85.8% vs 87.2%, 77.4% vs 81.1%, 72.4% vs 76.7%, log-rank test, P = 0.16; graft survival: 83.2% vs 83.6%, 73.8% vs 75.9%, 70.8% vs 74.4%, log-rank test, P = 0.19). After propensity score matching, 210 pairs of patients were generated. The corresponding 1-, 3- and 5-year patient and graft survival rates showed no significant differences. Further studies illustrated that the post-transplant major complication rates and liver function recovery after surgery were also similar. In addition, multivariate regression analysis in the original cohort and propensity score-matched Cox analysis demonstrated that receiving HBcAb+ liver grafts was not a significant risk factor for long-term survival. These findings were consistent in both HBV surface antigen-positive (HBsAg+) and HBsAg negative (HBsAg-) patients.Newly diagnosed HBV infection had a relatively higher incidence in HBsAg- patients with HBcAb+ liver grafts (13.23%), in which HBV naive recipients suffered most (31.82%), although this difference did not affect patient and graft survival (P = 0.50 and P = 0.49, respectively). Recipients with a high HBV surface antibody (anti-HBs) titer (more than 100 IU/L) before transplantation and antiviral prophylaxis with nucleos(t)ide antiviral agents post-operation, such as nucleos(t)ide antiviral agents, had lower de novo HBV infection risks. Conclusion HBcAb+ liver grafts do not affect the long-term outcome of the recipients. Combined with proper postoperative antiviral prophylaxis, utilization of HBcAb+ grafts is rational and feasible.

Liver transplantation for critically ill cirrhotic patients with acute deterioration of liver function associated with extrahepatic organ failures is controversial. While transplantation has been shown to be beneficial on an individual basis, the potentially poorer post-transplant outcome of these patients taken as a group can be held as an argument against allocating livers to them. Although this issue concerns only a minority of liver transplants, it calls into question the very heart of the allocation paradigms in place. Indeed, most allocation algorithms have been centered on prioritizing the sickest patients by using the model for end-stage liver disease score. This has led to allocating increasing numbers of livers to increasingly critically ill patients without setting objective or consensual limits on how sick patients can be when they receive an organ. Today, finding robust criteria to deem certain cirrhotic patients too sick to be transplanted seems urgent in order to ensure the fairness of our organ allocation protocols. This review starts by fleshing out the argument that finding such criteria is essential. It examines five types of difficulties that have hindered the progress of recent literature on this issue and identifies various strategies that could be followed to move forward on this topic, taking into account the recent discussion on acute on chronic liver failure. We move on to review the literature along four axes that could guide clinicians in their decision-making process regarding transplantation of critically ill cirrhotic patients.

BACKGROUND: Various liver and gastrointestinal involvements occur in patients with coronavirus disease 2019 (COVID-19) at variable prevalence. Most studies report mild liver function disturbances correlated with COVID-19 severity, though liver failure is unusual. AIM: To study liver and gastrointestinal dysfunctions in Egyptian patients with COVID-19 and their relation to disease outcomes. METHODS: This multicentre cohort study was conducted on 547 Egyptian patients from April 15, 2020 to July 29, 2020. Consecutive polymerase chain reaction-confirmed COVID-19 cases were included from four quarantine hospitals affiliated to the Egyptian ministry of health. Demographic information, laboratory characteristics, treatments, fibrosis-4 (FIB-4) index, COVID-19 severity, and outcomes were recorded and compared according to the degree of liver enzyme elevation and the presence of gastrointestinal symptoms. Follow-ups were conducted until discharge or death. Regression analyses were performed to determine the independent factors affecting mortality. RESULTS: This study included 547 patients, of whom 53 (9.68%) died during hospitalization and 1 was discharged upon his request. Patients' mean age was 45.04 ± 17.61 years, and 21.98% had severe or critical COVID-19. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were available for 430 and 428 patients, respectively. In total, 26% and 32% of patients had elevated ALT and AST, respectively. Significant liver injury with ALT or AST elevation exceeding 3-fold was recorded in 21 (4.91%) and 16 (3.73%) patients, respectively. Male gender, smoking, hypertension, chronic hepatitis C, and lung involvement were associated with elevated AST or ALT. AST was elevated in 50% of patients over 60-years-old. FIB-4 was significantly higher in patients admitted to the intensive care unit (ICU), those with more severe COVID-19, and non-survivors. The independent variables affecting outcome were supplementary vitamin C intake (1 g daily capsules) [odds ratio (OR): 0.05, 95% confidence interval (CI): 0.008-0.337]; lung consolidation (OR: 4.540, 95%CI: 1.155-17.840); ICU admission (OR: 25.032, 95%CI: 7.110-88.128); and FIB-4 score > 3.25 (OR: 10.393, 95%CI: 2.459-43.925). Among 60 (13.98%) patients with gastrointestinal symptoms, 52 (86.67%) had diarrhoea. Patients with gastrointestinal symptoms were predominantly females with higher body mass index, and 50 (83.40%) patients had non-severe COVID-19. CONCLUSION: Few Egyptian patients with COVID-19 developed a significant liver injury. The independent variables affecting mortality were supplementary vitamin C intake, lung consolidation, ICU admission, and FIB-4 score.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered the causative pathogen of coronavirus disease 2019 (COVID-19) and has become an international danger to human health. Although respiratory transmission and symptoms are still the essential manifestations of COVID-19, the digestive system could be an unconventional or supplementary route for COVID-19 to be transmitted and manifested, most likely due to the presence of angiotensin-converting enzyme 2 (ACE2) in the gastrointestinal tract. In addition, SARS-CoV-2 can trigger hepatic injury via direct binding to the ACE2 receptor in cholangiocytes, antibody-dependent enhancement of infection, systemic inflammatory response syndrome, inflammatory cytokine storms, ischemia/reperfusion injury, and adverse events of treatment drugs. Gastrointestinal symptoms, including anorexia, nausea, vomiting, and diarrhea, which are unusual in patients with COVID-19, and some digestive signs may occur without other respiratory symptoms. Furthermore, SARS-CoV-2 can be found in infected patients' stool, demonstrating the likelihood of transmission through the fecal-oral route. In addition, liver function should be monitored during COVID-19, particularly in more severe cases. This review summarizes the evidence for extra-pulmonary manifestations, mechanisms, and management of COVID-19, particularly those related to the gastrointestinal tract and liver.

Although multiple drugs are accessible for recovering liver function in patients, none are considered efficient. Liver transplantation is the mainstay therapy for end-stage liver fibrosis. However, the worldwide shortage of healthy liver donors, organ rejection, complex surgery, and high costs are prompting researchers to develop novel approaches to deal with the overwhelming liver fibrosis cases. Mesenchymal stem cell (MSC) therapy is an emerging alternative method for treating patients with liver fibrosis. However, many aspects of this therapy remain unclear, such as the efficiency compared to conventional treatment, the ideal MSC sources, and the most effective way to use it. Because bone marrow (BM) is the largest source for MSCs, this paper used a systematic review approach to study the therapeutic efficiency of MSCs against liver fibrosis and related factors. We systematically searched multiple published articles to identify studies involving liver fibrosis and BM-MSC-based therapy. Analyzing the selected studies showed that compared with conventional treatment BM-MSC therapy may be more efficient for liver fibrosis in some cases. In contrast, the cotreatment presented a more efficient way. Nevertheless, BM-MSCs are lacking as a therapy for liver fibrosis; thus, this paper also reviews factors that affect BM-MSC efficiency, such as the implementation routes and strategies employed to enhance the potential in alleviating liver fibrosis. Ultimately, our review summarizes the recent advances in the BM-MSC therapy for liver fibrosis. It is grounded in recent developments underlying the efficiency of BM-MSCs as therapy, focusing on the preclinical in vivo experiments, and comparing to other treatments or sources and the strategies used to enhance its potential while mentioning the research gaps.

BACKGROUND The expression of macrophage inhibitory factor-1 (MIC-1) is increased in peripheral blood of patients with chronic hepatitis and liver cirrhosis. However, whether MIC-1 gene polymorphism is correlated with relevant diseases is not yet reported. AIM To explore the correlation between gene polymorphism in MIC-1 exon region and chronic hepatitis C virus (HCV) infection. METHODS This case-control study enrolled 178 patients with chronic hepatitis C (CHC) in the case group, and 82 healthy subjects from the same region who had passed the screening examination comprised the control group. The genotypes of rs1059369 and rs1059519 loci in the MIC-1 gene exon were detected by DNA sequencing. Also, the MIC-1 level, liver function metrics, liver fibrosis metrics, and HCV RNA load were determined. Univariate analysis was used to compare the differences and correlations between the two groups with respect to these parameters. Multivariate logistic regression was used to analyze the independent relevant factors of CHC. RESULTS The plasma MIC-1 level in the CHC group was higher than that in the control group (P < 0.05), and it was significantly positively correlated with alanine aminotransferase, aspartate aminotransferase (AST), type III procollagen N-terminal peptide (known as PIIINP), type IV collagen, and HCV RNA (P < 0.05), whereas negatively correlated with total protein and albumin (P < 0.05). The genotype and allele frequency distribution at the rs1059519 locus differed between the two groups (P < 0.05). The allele frequency maintained significant difference after Bonferroni correction (Pc < 0.05). Logistic multiple regression showed that AST, PIIINP, MIC-1, and genotype GG at the rs1059519 locus were independent relevant factors of CHC (P < 0.05). Linkage disequilibrium (LD) was found between rs1059369 and rs1059519 loci, and significant difference was detected in the distribution of haplotype A-C between the CHC and control groups (P < 0.05). Meanwhile, we found the MIC-1 level trend to increase among rs1059519 genotypes (P = 0.006) and the level of MIC-1 in GG genotype to be significantly higher than CC genotype (P = 0.009, after Bonferroni correction). CONCLUSION Plasma MIC-1 level was increased in CHC patients and correlated with liver cell damage, liver fibrosis metrics, and viral load. The polymorphism at the MIC-1 gene rs1059519 locus was correlated with HCV infection, and associated with the plasma MIC-1 level. G allele and GG genotype may be an important susceptible factor for CHC.

Spontaneous porto-systemic shunts (SPSS) are frequent in liver cirrhosis and their prevalence increases as liver function deteriorates, probably as a consequence of worsening portal hypertension, but without achieving an effective protection against cirrhosis' complications. Several types of SPSS have been described in the literature, each one associated with different clinical manifestations. In particular, recurrent or persistent hepatic encephalopathy is more frequent in patients with splenorenal shunt, while the presence of gastric varices and consequently the incidence of variceal bleeding is more common in gastrorenal shunt. In the advanced stage, the presence of large SPSS can lead to the so called "portosystemic shunt syndrome", characterized by a progressive deterioration of hepatic function, hepatic encephalopathy and, sometimes, portal vein thrombosis. The detection of SPSS in patients with liver cirrhosis is recommended in order to prevent or treat recurrent hepatic encephalopathy or variceal bleeding.

BACKGROUND Treatments for hepatic sinusoidal obstruction syndrome (HSOS) are limited. AIM To evaluate transjugular intrahepatic portosystemic shunting (TIPS) as a treatment for pyrrolidine alkaloid-related HSOS (PA-HSOS). METHODS This retrospective analysis included patients with PA-HSOS admitted to the First Affiliated Hospital of the University of Science and Technology of China (June 2015 to January 2019). Baseline clinical characteristics and follow-up data were extracted from the medical records. All patients included in this study experienced failure of initial therapy. Patients were divided into the TIPS and conservative treatment groups according to the therapy they received. Liver function, maximal ascites depth, imaging characteristics, pathology findings, and survival were compared between groups. RESULTS The TIPS group included 37 patients (28 males), and the conservative treatment group included 17 patients (11 males). Baseline characteristics were similar between groups. There were two deaths in the TIPS group and seven deaths in the conservative treatment group during follow-up (3-48 mo). The 3-, 6-, 12- and 24-mo survival rates were 94.6%, 94.6%, 94.6% and 94.6%, respectively, in the TIPS group and 70.6%, 57.8%, 57.8% and 57.8%, respectively, in the conservative treatment group. Kaplan-Meier analysis revealed significantly longer survival for the TIPS group than for the conservative treatment group (P = 0.001). Compared with the pre-treatment value, maximal ascites depth was significantly lower at 1 wk, 2 wk, 1 mo, and 3 mo for the TIPS group (all P < 0.05) but not in the conservative treatment group. Contrast-enhanced computed tomography demonstrated the disappearance of patchy liver enhancement after TIPS. Pathology showed that liver congestion and hepatocyte swelling improved with time after TIPS placement. CONCLUSION TIPS may achieve better outcomes than conventional symptomatic treatment in patients with PA-HSOS.

Aim To study the influence of different doses of tacrolimus (FK506) on gut microbiota after liver transplantation (LT) in rats. Methods Specific pathogen-free Brown Norway (BN) rats and Lewis rats were separated into five groups: (1) Tolerance group (BN-BN LT, n = 8); (2) rejection group (Lewis-BN LT, n = 8); (3) high dosage FK506 (FK506-H) group (Lewis-BN LT, n = 8); (4) middle dosage FK506 (FK506-M) group (Lewis-BN LT, n = 8); and (5) low dosage FK506 (FK506-L) group (Lewis-BN LT, n = 8). FK506 was administered to recipients at a dose of 1.0 mg/kg, 0.5 mg/kg, and 0.1 mg/kg body weight for 29 d after LT to the FK506-H, FK506-M, and FK506-L groups, respectively. On the 30th day after LT, all rats were sampled and euthanized. Blood samples were harvested for liver function and plasma endotoxin testing. Hepatic graft and ileocecal tissues were collected for histopathology observation. Ileocecal contents were used for DNA extraction, Real-time quantitative polymerase chain reaction (RT-PCR) and digital processing of denaturing gradient gel electrophoresis (DGGE) profiles and analysis. Results Compared to the FK506-H and FK506-L groups, FK506-M was optimal for maintaining immunosuppression and inducing normal graft function; the FK506-M maintained gut barrier integrity and low plasma endotoxin levels; furthermore, DGGE results showed that FK506-M induced stable gut microbiota. Diversity analysis indicated that FK506-M increased species richness and rare species abundance, and cluster analysis confirmed the stable gut microbiota induced by FK506-M. Phylogenetic tree analysis identified crucial bacteria associated with FK506-M; seven of the nine bacteria that were decreased corresponded to Bacteroidetes, while increased bacteria were of the Bifidobacterium species. FK506-M increased Faecalibacterium prausnitzii and Bifidobacterium spp. and decreased Bacteroides-Prevotella and Enterobacteriaceae, as assessed by RT-PCR, which confirmed the crucial bacterial alterations identified through DGGE. Conclusion Compared to the low or high dosage of FK506, an optimal dosage of FK506 induced immunosuppression, normal graft function and stable gut microbiota following LT in rats. The stable gut microbiota presented increased probiotics and decreased potential pathogenic endotoxin-producing bacteria. These findings provide a novel strategy based on gut microbiota for immunosuppressive dosage assessment for recipients following LT.

AIM To assess the accuracy of Look-Locker on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for staging liver fibrosis in chronic hepatitis B/C (CHB/C). METHODS We prospectively included 109 patients with CHB or CHC who underwent a 3.0-Tesla MRI examination, including T1-weighted and Look-Locker sequences for T1 mapping. Hepatocyte fractions (HeF) and relaxation time reduction rate (RE) were measured for staging liver fibrosis. A receiver operating characteristic analysis using the area under the receiver operating characteristic curve (AUC) was used to compare the diagnostic performance in predicting liver fibrosis between HeF and RE. RESULTS A total of 73 patients had both pathological results and MRI information. The number of patients in each fibrosis stage was evaluated semiquantitatively according to the METAVIR scoring system: F0, n = 23 (31.5%); F1, n = 19 (26.0%); F2, n = 13 (17.8%); F3, n = 6 (8.2%), and F4, n = 12 (16.4%). HeF by EOB enhancement imaging was significantly correlated with fibrosis stage (r = -0.808, P < 0.05). AUC values for diagnosis of any (≥ F1), significant (≥ F2) or advanced (≥ F3) fibrosis, and cirrhosis (F4) using HeF were 0.837 (0.733-0.913), 0.890 (0.795-0.951), 0.957 (0.881-0.990), and 0.957 (0.882-0.991), respectively. HeF measurement was more accurate than use of RE in establishing liver fibrosis staging, suggesting that calculation of HeF is a superior noninvasive liver fibrosis staging method. CONCLUSION A T1 mapping-based HeF method is an efficient diagnostic tool for the staging of liver fibrosis.

AIM To investigate novel predictors of survival in hepatocellular carcinoma (HCC) patients following transarterial chemoembolization (TACE). METHODS One hundred sixty seven patients with un-resectable HCC were retrospectively analyzed to identify factors that might contribute to their HCC biology and aggressiveness. We correlated routine laboratory results (total bilirubin, AST, ALKP, GGTP, albumin etc.) to maximum tumor diameter, number of tumor nodules, portal vein thrombosis and blood alpha-fetoprotein levels. These 4 parameters were previously combined to form an aggressiveness index (AgI). We used The Wilcoxon rank-sum (Mann-Whitney), to test the correlation between the AgI categories and liver function parameters. The Cox proportional hazards model was applied to evaluate the categories of AgI associated with overall survival. RESULTS The AgI was strongly correlated with survival in this novel patient population. Three year survival probability for AgI > or < 4 was 42.4% vs 61.8%; P < 0.0863 respectively. Several factors independently correlated with AgI using univariate multiple logistic regression of AgI with 8 laboratory parameters. Lower albumin levels had an OR of 2.56 (95%CI: 1.120-5.863 P < 0.026), elevated Alkaline phosphatase and gamma glutamyl transpeptidase (GGTP) had ORs of 1.01 (95%CI: 1.003-1.026, P < 0.017) and 0.99 (95%CI: 0.99-1.00, P < 0.053) respectively. In a Cox proportional hazard model combining mortality for AgI score and liver function parameters, only GGTP levels and the AgI were independently associated with survival. An AgI > 4 had HR for mortality of 2.18 (95%CI: 1.108-4.310, P < 0.024). GGTP’s single unit change had a HR for mortality of 1.003 (95%CI: 1.001-1.006, P < 0.016). These were considered in the final multivariate model with the total cohort. An AgI > 4 had a HR for mortality of 2.26 (95%CI: 1.184-4.327, P < 0.016). GGTP had a HR of 1.003 (95%CI: 1.001-1.004, P < 0.001). CONCLUSION Our study validates the AgI in a new population with un-resectable HCC patients undergoing TACE. The analysis establishes a correlation between GGTP and the AgI.

Since the advent of direct acting antiviral (DAA) agents, chronic hepatitis C virus (HCV) treatment has evolved at a rapid pace. In contrast to prior regimen involving ribavirin and pegylated interferon, these newer agents are highly effective, well-tolerated, have shorter course of therapy and safer essentially in all HCV patients including those with advanced liver disease and following liver transplantation. Clinicians caring for HCV-infected patients on the liver transplant (LT) waitlist are often faced with a dilemma whether to treat HCV infection before or after liver transplantation. Sustained virological response (SVR) rates following HCV treatment may improve hepatic function sufficiently enough to negate the need for LT in certain patients. On the other hand, the decrease in MELD without improvement in quality of life in certain patients may lead to delay or dropout from potentially curative LT surgery list. In this context, our review focuses on the approach to and optimal timing of DAA-based treatment of HCV infection in LT candidates in the peri-transplant period.

AIM To investigate the value of the gamma-glutamyltraspeptidase (GGT)-to-platelet (PLT) ratio (GPR) in the diagnosis of hepatic fibrosis in patients with chronic hepatitis B (CHB). METHODS We included 390 untreated CHB patients in this study. The GPR, aspartate aminotransferase (AST)-to-PLT ratio index (APRI), and fibrosis-4 (FIB-4) of all patients were analysed to determine if these parameter were correlated with age, gender, medical history, liver function [total bilirubin (TBil), alanine aminotransferase (ALT), and AST], GGT, PLT count, or hepatic fibrosis stage. The GPR, APRI, and FIB-4, as well as the combination of the GPR and APRI or the GPR and FIB-4 were assessed in different cirrhosis stages using receiver operating characteristic (ROC) curve analysis to evaluate their value in diagnosing hepatic fibrosis in CHB patients. RESULTS The GPR, APRI, and FIB-4 were not correlated with CHB patients’ age, gender, or disease duration (P > 0.05), but all of these parameters were positively correlated with serum ALT, AST, GGT, and PLT count (P < 0.01). Additionally, the GPR, APRI, and FIB-4 were positively correlated with hepatic fibrosis (P < 0.01); the areas under the ROC curve for the GPR in F1, F2, F3, and F4 stages were 0.723, 0.741, 0.826, and 0.833, respectively, which were significantly higher than the respective values for the FIB-4 and APRI (F1: 0.581, 0.612; F2: 0.706, 0.711; F3: 0.73, 0.751; and F4: 0.799, 0.778). The respective diagnostic cut-off points for each stage were 0.402, 0.448, 0.548, and 0.833, respectively. The diagnostic sensitivity and specificity were, respectively, 88.8% and 87.5% in F1, 72.7% and 89.7% in F2, 81.3% and 98.6% in F3, and 80% and 97.4% in F4 when the GPR and APRI were connected in parallel; 86.6% and 90.2%, 78.4% and 96%, 78.6% and 97.4%, and 73.2% and 97.9%, respectively, when the GPR and APRI were connected in series; 80.2% and 89%, 65% and 89%, 70.3% and 98.5%, and 78.8% and 96.8%, respectively, when the GPR and FIB-4 were connected in parallel; and 83.6% and 87.9%, 76.8% and 96.6%, 72.7% and 98%, and 74.4% and 97.7%, respectively, when the GPR and FIB-4 were connected in series. CONCLUSION The GPR, as a serum diagnostic index of liver fibrosis, is more accurate, sensitive, and easy to use than the FIB-4 and APRI, and the GPR can significantly improve the sensitivity and specificity of hepatic fibrosis diagnosis in CHB when combined with the FIB-4 or APRI.

We report a case of double domino liver transplantation in a 32-year-old woman who was diagnosed with familial amyloid polyneuropathy (FAP) and liver dysfunction. A two-stage surgical plan was designed, and one domino graft was implanted during each stage. During the first stage, an auxiliary domino liver transplantation was conducted using a domino graft from a 4-year-old female child with Wilson's disease. After removing the right lobe of the FAP patient's liver, the graft was rotated 90 degrees counterclockwise and placed along the right side of the inferior vena cava (IVC). The orifices of the left, middle, and right hepatic veins were reconstructed using an iliac vein patch and then anastomosed to the right side of the IVC. Thirty days later, a second domino liver graft was implanted. The second domino graft was from a 3-year-old female child with an ornithine carbamyl enzyme defect, and it replaced the residual native liver (left lobe). To balance the function and blood flow between the two grafts, a percutaneous transcatheter selective portal vein embolization was performed, and "the left portal vein" of the first graft was blocked 9 mo after the second transplantation. The liver function indices, blood ammonia, and 24-h urinary copper levels were normal at the end of a 3-year follow-up. These two domino donor grafts from donors with different metabolic disorders restored normal liver function. Our experience demonstrated a new approach for resolving metabolic disorders with domino grafts and utilizing explanted livers from children.

Aim To examine the effects of aspirin and enoxaparin on liver function, coagulation index and histopathology in a rat model of liver fibrosis. METHODS Forty-five male Sprague-Dawley rats were randomly divided into the control group (n = 5) and model group (n = 40). Thioacetamide (TAA) was used to induce liver fibrosis in the model group. TAA-induced fibrotic rats received TAA continuously (n = 9), TAA + low-dose aspirin (n = 9), TAA + high-dose aspirin (n = 9) or TAA + enoxaparin (n = 9) for 4 wk. All rats were euthanized after 4 wk, and both hematoxylin-eosin and Masson staining were performed to observe pathological changes in liver tissue. Results Liver fibrosis was assessed according to the METAVIR score. Compared with untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the low-dose aspirin, high-dose aspirin and enoxaparin treated groups, especially in the high-dose aspirin treated group. Alanine aminotransferase and total bilirubin were higher, albumin was lower and both prothrombin time and international normalized ratio were prolonged in the four treatment groups compared to controls. No significant differences among the four groups were observed. Conclusion Aspirin and enoxaparin can alleviate liver fibrosis in this rat model.

AIM To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI). METHODS Rats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined. RESULTS Histological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham vs CTL, P < 0.0001; CTL vs DMF, P < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L vs CTL 10592 ± 1152 U/L, P = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L vs CTL 26.0 ± 1.0 μmol/L, P = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg vs CTL 18.3 ± 0.6 nmol/mg, P = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL vs CTL 6.0 ± 0.5 mU/mL, P = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold vs 0.17 ± 0.06-fold, P = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group. CONCLUSION DMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI.

Although viral hepatitis treatments have evolved over the years, the resultant liver cirrhosis still does not completely heal. Platelets contain proteins required for hemostasis, as well as many growth factors required for organ development, tissue regeneration and repair. Thrombocytopenia, which is frequently observed in patients with chronic liver disease (CLD) and cirrhosis, can manifest from decreased thrombopoietin production and accelerated platelet destruction caused by hypersplenism; however, the relationship between thrombocytopenia and hepatic pathogenesis, as well as the role of platelets in CLD, is poorly understood. In this paper, experimental evidence of platelets improving liver fibrosis and accelerating liver regeneration is summarized and addressed based on studies conducted in our laboratory and current progress reports from other investigators. In addition, we describe our current perspective based on the results of these studies. Platelets improve liver fibrosis by inactivating hepatic stellate cells, which decreases collagen production. The regenerative effect of platelets in the liver involves a direct effect on hepatocytes, a cooperative effect with liver sinusoidal endothelial cells, and a collaborative effect with Kupffer cells. Based on these observations, we ascertained the direct effect of platelet transfusion on improving several indicators of liver function in patients with CLD and liver cirrhosis. However, unlike the results of our previous clinical study, the smaller incremental changes in liver function in patients with CLD who received eltrombopag for 6 mo were due to patient selection from a heterogeneous population. We highlight the current knowledge concerning the role of platelets in CLD and cancer and anticipate a novel application of platelet-based clinical therapies to treat liver disease.

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has become a major cause of chronic liver disease. The Chinese herbal medicine (CHM) Dachaihu decoction (DCHD) has been proved to treat NAFLD with good efficacy in previous studies. Based on the TCM principle of formula formation, we divided DCHD into soothing liver part, invigorating spleen part, and dredging intestine part. Marshall officially proposed the concept of “intestinal-hepatic axis”, which systematically explains the interactions between the intestine and liver. We hypothesized that the effect of CHM on NAFLD is achieved by regulating the liver and intestine. Thus, we aimed to investigate the possible effect of a CHM formula on NAFLD in a rat model. AIM To investigate the effects of a CHM formula (a decoction of Chinese thorowax root, scutellaria root, and white peony root) on NAFLD and its regulatory effect on the “intestinal-liver” axis. METHODS Sixty rats were randomly divided into control, model, pioglitazone hydrochloride (PH), and CHM (a decoction of Chinese thorowax root, scutellaria root, and white peony root) groups. An NAFLD rat model was established using a high-fat high-fructose diet for 16 wk. From the 13th week, rats were administered with PH or a decoction of Chinese thorowax, scutellaria, and white peony root (CHM group) for 4 wk. Rats in the control group and model group were administered with an equal volume of distilled water. At the end of the study, blood was collected via the abdominal aorta. Liver tissues were harvested and any morphological changes were observed by hematoxylin-eosin (HE) staining, Oil red O staining, and Masson staining. In addition, blood lipids, liver function markers, and triglyceride (TG) in liver tissues were analyzed. The levels of transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α), Toll-like receptor-4 (TLR4), and nuclear factor-kappa B (NF-кB) in liver tissues and secreted immunoglobulin A (sIgA) in intestinal tissues were analyzed by ELISA, and protein and mRNA expression of occludin and zonula occludens-1 (ZO-1) in the intestine were measured using Western blot and reverse transcription-quantitative polymerase chain reaction, respectively. The endotoxin level in plasma was detected by endpoint chromogenic assay. RESULTS Compared to the normal control group, the liver coefficient, serum TG, total cholesterol (TC), low density lipoprotein (LDL), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), blood glucose, plasma endotoxin, and the levels of TG, TNF-α, TGF-β, NF-kB, and TLR4 in liver tissues increased significantly in the model group, while serum high density lipoprotein (HDL), intestinal sIgA, and protein and mRNA expression of occludin and ZO-1 decreased significantly in the model group (P < 0.01). PH and CHM attenuated the elevated liver coefficient, serum TG, TC, LDL, AST, and ALT, blood glucose, plasma endotoxin, and the levels of TG, TNF-α, TGF-β, NF-kB, and TLR4 in liver tissues and increased serum HDL levels compared to the model group (P < 0.01). Intestinal sIgA and the protein and mRNA expression of intestinal occludin and ZO-1 were significantly increased in the PH group compared to the model and CHM groups (P < 0.01). CONCLUSION The decoction of Chinese thorowax root, scutellaria root, and white peony root is beneficial in regulating lipid metabolism and liver function, which indicates that it has a good effect on the liver. To a certain extent, this CHM formula can affect both the liver and intestine, while its effect on the liver is superior to that on the intestine.

Hepatocyte nuclear factor 4-alpha (HNF4α) is a highly conserved member of nuclear receptor superfamily of ligand-dependent transcription factors that is expressed in liver and gastrointestinal organs (pancreas, stomach, and intestine). In liver, HNF4α is best known for its role as a master regulator of liver-specific gene expression and essential for adult and fetal liver function. Dysregulation of HNF4α expression has been associated with many human diseases such as ulcerative colitis, colon cancer, maturity-onset diabetes of the young, liver cirrhosis, and hepatocellular carcinoma. However, the precise role of HNF4α in the etiology of these human pathogenesis is not well understood. Limited information is known about the role of HNF4α isoforms in liver and gastrointestinal disease progression. There is, therefore, a critical need to know how disruption of the expression of these isoforms may impact on disease progression and phenotypes. In this review, we will update our current understanding on the role of HNF4α in human liver and gastrointestinal diseases. We further provide additional information on possible use of HNF4α as a target for potential therapeutic approaches.

This is the first report of living donor liver transplantation (LDLT) for congenital hepatic fibrosis (CHF) using a mother's graft with von Meyenburg complex. A 6-year-old girl with CHF, who suffered from recurrent gastrointestinal bleeding, was referred to our hospital for liver transplantation. Her 38-year-old mother was investigated as a living donor and multiple biliary hamartoma were seen on her computed tomography and magnetic resonance imaging scan. The mother's liver function tests were normal and she did not have any organ abnormality, including polycystic kidney disease. LDLT using the left lateral segment (LLS) graft from the donor was performed. The donor LLS graft weighed 250 g; the graft recipient weight ratio was 1.19%. The operation and post-operative course of the donor were uneventful and she was discharged on post-operative day (POD) 8. The graft liver function was good, and the recipient was discharged on POD 31. LDLT using a graft with von Meyenburg complex is safe and useful. Long-term follow-up is needed with respect to graft liver function and screening malignant tumors.

Progressive familial intrahepatic cholestasis type 3 is caused by a mutation in the ATP-binding cassette, subfamily B, member 4 (ABCB4) gene encoding multidrug resistance protein 3. A 32-year-old woman with a history of acute hepatitis at age 9 years was found to have jaundice during pregnancy in 2008, and was diagnosed as having intrahepatic cholestasis of pregnancy. In 2009, she underwent cholecystectomy for gallstones and chronic cholecystitis. However, itching and jaundice did not resolve postoperatively. She was admitted to our hospital with fatigue, jaundice, and a recently elevated γ-glutamyl transpeptidase level. Liver biopsy led to the diagnosis of biliary cirrhosis with ductopenia. Genetic testing revealed a pathogenic heterozygous mutation, ex13 c.1531G > A (p.A511T), in the ABCB4 gene. Her father did not carry the mutation, but her mother's brother carried the heterozygous mutation. We made a definitive diagnosis of familial intrahepatic cholestasis type 3. Her symptoms and liver function improved after 3 mo of treatment with ursodeoxycholic acid.

The risk of developing hepatocellular carcinoma (HCC) is strongly associated with hepatitis B virus infection. Hepatic angiomyolipoma (AML), a rare benign tumor, is composed of a heterogeneous mixture of adipose cells, smooth muscle cells and blood vessels. Here, we report the case of a 44-year-old man who developed HCC with a concomitant hepatic AML and a cavernous hemangioma, in the absence of cirrhosis. To our knowledge, based on an extensive literature search using the www.pubmed.gov website, this is the first report of an HCC case with both concomitant AML and cavernous hemangioma at the same position in the liver. The presence of the hepatitis B surface antigen was detected, but the liver function was normal. Clinical and pathological data were collected before and during the treatment. Hepatic AML was diagnosed based on the typical histological characteristics and immunohistochemical staining, which revealed, a positive staining with a melanocytic cell-specific monoclonal antibody. There was no evidence of tuberous sclerosis complex in this patient. Although the HCC was poor- to moderately-differentiated, the characteristics of the AML and the cavernous hemangioma in this patient did not match any criteria for malignancy. Hepatectomy followed by transarterial chemoembolization treatment were effective therapeutic methods for the adjacent lesions in this patient. This case is an interesting coincidence.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world and is associated with a high risk of recurrence. The development of a wide range of new therapies is therefore essential. In this study, from the perspective of supportive therapy for the prevention of HCC recurrence and preservation of liver function in HCC patients, we surveyed a variety of different therapeutic agents. We show that branched chain amino acids (BCAA) supplementation and late evening snack with BCAA, strategies that address issues of protein-energy malnutrition, are important for liver cirrhotic patients with HCC. For chemoprevention of HCC recurrence, we show that viral control after radical treatment is important. We also reviewed the therapeutic potential of antiviral drugs, sorafenib, peretinoin, iron chelators. Sorafenib is a kinase inhibitor and a standard therapy in the treatment of advanced HCC. Peretinoin is a vitamin A-like molecule that targets the retinoid nuclear receptor to induce apoptosis and inhibit tumor growth in HCC cells. Iron chelators, such as deferoxamine and deferasirox, act to prevent cancer cell growth. These chelators may have potential as combination therapies in conjunction with peretinoin. Finally, we review the potential inhibitory effect of bone marrow cells on hepatocarcinogenesis.

Liver transplantation represents a fundamental therapeutic solution to end-stage liver disease. The need for liver allografts has extended the set of criteria for organ acceptability, increasing the risk of adverse outcomes. Little is known about the early postoperative parameters that can be used as valid predictive indices for early graft function, retransplantation or surgical reintervention, secondary complications, long intensive care unit stay or death. In this review, we present state-of-the-art knowledge regarding the early post-transplantation tests and scores that can be applied during the first postoperative week to predict liver allograft function and patient outcome, thereby guiding the therapeutic and surgical decisions of the medical staff. Post-transplant clinical and biochemical assessment of patients through laboratory tests (platelet count, transaminase and bilirubin levels, INR, factor V, lactates, and Insulin Growth Factor 1) and scores (model for end-stage liver disease, acute physiology and chronic health evaluation, sequential organ failure assessment and model of early allograft function) have been reported to have good performance, but they only allow late evaluation of patient status and graft function, requiring days to be quantified. The indocyanine green plasma disappearance rate has long been used as a liver function assessment technique and has produced interesting, although not univocal, results when performed between the 1(th) and the 5(th) day after transplantation. The liver maximal function capacity test is a promising method of metabolic liver activity assessment, but its use is limited by economic cost and extrahepatic factors. To date, a consensual definition of early allograft dysfunction and the integration and validation of the above-mentioned techniques, through the development of numerically consistent multicentric prospective randomised trials, are necessary. The medical and surgical management of transplanted patients could be greatly improved by using clinically reliable tools to predict early graft function.

The age of liver donors has been increasing in the past several years because of a donor shortage. In the United States, 33% of donors are age 50 years or older, as are more than 50% in some European countries. The impact of donor age on liver transplantation (LT) has been analyzed in several studies with contradictory conclusions. Nevertheless, recent analyses of the largest databases demonstrate that having an older donor is a risk factor for graft failure. Donor age is included as a risk factor in the more relevant graft survival scores, such as the Donor Risk Index, donor age and Model for End-stage Liver Disease, Survival Outcomes Following Liver Transplantation, and the Balance of Risk. The use of old donors is related to an increased rate of biliary complications and hepatitis C virus-related graft failure. Although liver function does not seem to be significantly affected by age, the incidence of several liver diseases increases with age, and the capacity of the liver to manage or overcome liver diseases or external injuries decreases. In this paper, the importance of age in LT outcomes, the role of donor age as a risk factor, and the influence of aging on liver regeneration are reviewed.