Efficacy of Granulocyte Colony-Stimulating Factor in Acute on Chronic Liver Failure: A Systematic Review and Survival Meta-Analysis.

BACKGROUND: Acute-on-chronic liver failure (ACLF) mostly occurs when there is an acute insult to the liver in patients with pre-existing liver disease, and it is characterized by a high mortality rate. Various therapeutic approaches have been used thus far, with orthotopic liver transplantation being the only definitive cure. Clinical trials and meta-analyses have investigated the use of granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow-derived stem cells. Some studies have suggested that G-CSF may have a significant role in the management and survival of patients with ACLF. However, the results are conflicting, and the efficacy of G-CSF still needs to be confirmed. AIM: The aim was to assess the efficacy of G-CSF in patients with ACLF. METHODS: Electronic databases were searched until May 2023 for randomized controlled trials investigating the use of G-CSF in adult patients with ACLF. Outcome measures were the effects of G-CSF on overall survival, changes in liver disease severity scores, complications of cirrhosis, other G-CSF-related adverse effects, and all-cause mortality. The study's protocol has been registered with Prospero (CRD42023420273). RESULTS: Five double-blind randomized controlled trials involving a total of 421 participants met the inclusion criteria. The use of G-CSF demonstrated a significant effect on overall survival (HR 0.63, 95% CI 0.41 to 0.95, and I2 48%), leading to a decreased mortality (LogOR-0.97, 95% CI -1.57 to -0.37, and I2 37.6%) and improved Model for End-Stage Liver Disease (MELD) scores (SMD -0.87, 95% CI -1.62 to -0.13, and I2 87.3%). There was no correlation between the improvement of the Child-Pugh score and the use of G-CSF(SMD -2.47, 95% CI -5.78 to 0.83, and I2 98.1%). The incidence of complications of cirrhosis did not decrease significantly with G-CSF treatment (rate ratio 0.51, 95% CI 0.26 to 1.01, and I2 90%). A qualitative synthesis showed that the use of G-CSF is safe. CONCLUSIONS: The administration of G-CSF has demonstrated a positive impact on overall survival, liver function, and the MELD score. The presence of heterogeneity in the included studies prohibits conclusive recommendations.

Adipopenia in body composition analysis: a promising imaging biomarker and potential predictive factor for patients undergoing transjugular intrahepatic portosystemic shunt placement.

OBJECTIVE: Body tissue composition plays a crucial role in the multisystemic processes of advanced liver disease and has been shown to be influenced by transjugular intrahepatic portosystemic shunt (TIPS). A differentiated analysis of the various tissue compartments has not been performed until now. The purpose of this study was to evaluate the value of imaging biomarkers derived from automated body composition analysis (BCA) to predict clinical and functional outcome. METHODS: A retrospective analysis of 56 patients undergoing TIPS procedure between 2013 and 2021 was performed. BCA on the base of pre-interventional CT examination was used to determine quantitative data as well as ratios of bone, muscle and fat masses. Furthermore, a BCA-derived sarcopenia marker was investigated. Regarding potential correlations between BCA imaging biomarkers and the occurrence of hepatic encephalopathy (HE) as well as 1-year survival, an exploratory analysis was conducted. RESULTS: No BCA imaging biomarker was associated with the occurrence of HE after TIPS placement. However, there were significant differences in alive and deceased patients regarding the BCA-derived sarcopenia marker (alive: 1.60, deceased: 1.83, p = 0.046), ratios of intra- and intermuscular fat/skeletal volume (alive: 0.53, deceased: 0.31, p = 0.015) and intra- and intermuscular fat/muscle volume (alive: 0.21, deceased: 0.14, p = 0.031). CONCLUSION: A lower amount of intra- and intermuscular adipose tissue might have protective effects regarding liver derived complications and survival. ADVANCES IN KNOWLEDGE: Precise characterization of body tissue components with automated BCA might provide prognostic information in patients with advanced liver disease undergoing TIPS procedure.

Implications of anaemia and response to anaemia treatment on outcomes in patients with cirrhosis.

Background & Aims: Anaemia is frequently observed in patients with cirrhosis and was identified as a predictor of adverse outcomes, such as increased mortality and occurrence of acute-on-chronic liver failure. To date, the possible effects of iron supplementation on these adverse outcomes are not well described. We therefore aimed to assess the role of iron supplementation in patients with cirrhosis and its capability to improve prognosis. Methods: Laboratory diagnostics were performed in consecutive outpatients with cirrhosis admitted between July 2018 and December 2019 to the University Hospital Essen. Associations with transplant-free survival were assessed in regression models. Results: A total of 317 outpatients with cirrhosis were included, of whom 61 received a liver transplant (n = 19) or died (n = 42). In multivariate Cox regression analysis, male sex (hazard ratio [HR] = 3.33, 95% CI [1.59, 6.99], p = 0.001), model for end-stage liver disease score (HR = 1.19, 95% CI [1.11, 1.27], p <0.001) and the increase of haemoglobin levels within 6 months (ΔHb6) (HR = 0.72, 95% CI [0.63, 0.83], p <0.001) were associated with transplant-free survival. Regarding the prediction of haemoglobin increase, intake of rifaximin (beta = 0.50, SD beta = 0.19, p = 0.007) and iron supplementation (beta = 0.79, SD beta = 0.26, p = 0.003) were significant predictors in multivariate analysis. Conclusions: An increase of haemoglobin levels is associated with improvement of transplant-free survival in patients with cirrhosis. Because the prediction of haemoglobin increase significantly depends on rifaximin and iron supplementation, application of these two medications can have an important impact on the outcome of these patients. Impact and implications: Anaemia is very common in patients with cirrhosis and is known to be a predictor of negative outcomes, but little is known about the effect of iron substitution in these individuals. In our cohort, increase of haemoglobin levels improved transplant-free survival of patients with cirrhosis. The increase of haemoglobin levels was mainly induced by iron supplementation and was even stronger in the case of concomitant use of iron and rifaximin. Clinical trial registration: UME-ID-10042.

Fibrosis in Chronic Liver Disease: An Update on Diagnostic and Treatment Modalities.

Fibrosis is a common outcome of most chronic inflammatory diseases, characterized by the accumulation of excessive extracellular matrix components. Individuals with progressive liver fibrosis develop cirrhosis, are at risk of developing liver cancer, and may succumb to liver failure. Although a number of specific therapies for different diseases have been developed and successfully used, for example, direct antiviral agents in treatment for hepatitis C, effective and specific antifibrotic therapies are still not available. Liver biopsy remains the gold standard of staging liver fibrosis. However, transient elastography is increasingly being used in clinical trials and in hepatology clinics as part of standard-of-care evaluation because it is easy to use. Magnetic resonance (MR)-elastography is most accurate in evaluating fibrosis stage but is costly and time consuming and thus not readily available. Recent advances, however, have been made in areas of diagnostic and therapeutic modalities, with an increasing number of potential drugs currently in phase II and III trials, particularly in the field of non-alcoholic steatohepatitis-related liver fibrosis. These new drugs target multiple pathways involved in the pathogenesis of chronic liver disease, and we anticipate that some of them may soon be approved for use in patients.

Gfi1b: a key player in the genesis and maintenance of acute myeloid leukemia and myelodysplastic syndrome.

Differentiation of hematopoietic stem cells is regulated by a concert of different transcription factors. Disturbed transcription factor function can be the basis of (pre)malignancies such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Growth factor independence 1b (Gfi1b) is a repressing transcription factor regulating quiescence of hematopoietic stem cells and differentiation of erythrocytes and platelets. Here, we show that low expression of Gfi1b in blast cells is associated with an inferior prognosis of MDS and AML patients. Using different models of human MDS or AML, we demonstrate that AML development was accelerated with heterozygous loss of Gfi1b, and latency was further decreased when Gfi1b was conditionally deleted. Loss of Gfi1b significantly increased the number of leukemic stem cells with upregulation of genes involved in leukemia development. On a molecular level, we found that loss of Gfi1b led to epigenetic changes, increased levels of reactive oxygen species, as well as alteration in the p38/Akt/FoXO pathways. These results demonstrate that Gfi1b functions as an oncosuppressor in MDS and AML development.