Therapy For Liver Disease Research Articles

Strategies to improve the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicle (MSC-EV): a promising cell-free therapy for liver disease.

Liver disease has emerged as a significant worldwide health challenge due to its diverse causative factors and therapeutic complexities. The majority of liver diseases ultimately progress to end-stage liver disease and liver transplantation remains the only effective therapy with the limitations of donor organ shortage, lifelong immunosuppressants and expensive treatment costs. Numerous pre-clinical studies have revealed that extracellular vesicles released by mesenchymal stem cells (MSC-EV) exhibited considerable potential in treating liver diseases. Although natural MSC-EV has many potential advantages, some characteristics of MSC-EV, such as heterogeneity, uneven therapeutic effect, and rapid clearance in vivo constrain its clinical translation. In recent years, researchers have explored plenty of ways to improve the therapeutic efficacy and rotation rate of MSC-EV in the treatment of liver disease. In this review, we summarized current strategies to enhance the therapeutic potency of MSC-EV, mainly including optimization culture conditions in MSC or modifications of MSC-EV, aiming to facilitate the development and clinical application of MSC-EV in treating liver disease.

Recent Advances in Mesenchymal Stem/Stromal Cell-Based Therapy for Alcohol-Associated Liver Disease and Non-alcoholic Fatty Liver Disease.

Alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) represent pathological conditions that include many distinct stages, potentially leading to the final stage of cirrhotic liver. To date, liver transplantation is the sole successful treatment with concomitant limitations related to donor organ shortage and the need of life-long immunosuppressive therapy. Recently, cell-based therapies for ALD and NAFLD have been proposed with mesenchymal stem/stromal cells (MSCs) as promising effectors. MSC therapeutic applications offer hepatoprotection, regulation of the inflammatory process and angiogenesis particularly in ALD and NAFLD pre-clinical disease models. Recent studies suggested that hepatospecific MSC-based therapies could benefit liver diseases by restoring liver function and decreasing inflammation and fibrosis. Similarly to solid-organ transplantation, limitations in MSC approaches include donor availability exacerbated by high number of cells and cell trapping into lungs. Herein, based on recent advances, we discuss the use of MSCs as a therapeutic approach for ALD and NAFLD and we provide the available information for the establishment of a framework toward a potential clinical application.

Microbiome and Genetic Factors in the Pathogenesis of Liver Diseases

Our genetic background has not changed over the past century, but chronic diseases are on the rise globally. In addition to the genetic component, among the critical factors for many diseases are inhabitants of our intestines (gut microbiota) as a crucial environmental factor. Dysbiosis has been described in liver diseases with different etiologies like non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ALD), viral hepatitis, autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), cirrhosis, hepatocellular carcinoma (HCC). On the other hand, new technologies have increased our understanding of liver disease genetics and treatment options. Genome-wide association studies (GWAS) identify unknown genetic risk factors, positional cloning of unknown genes associated with different diseases, gene tests for single nucleotide variations (SNVs), and next-generation sequencing (NGS) of selected genes or the complete genome. NGS also allowed studying the microbiome and its role in various liver diseases has begun. These genes have proven their effect on microbiome composition in host genome–microbiome association studies. We focus on altering the intestinal microbiota, and supplementing some bacterial metabolites could be considered a potential therapeutic strategy. The literature data promote probiotics/synbiotics role in reducing proinflammatory cytokines such as TNF-α and the interleukins (IL-1, IL-6, IL-8), therefore improving transaminase levels, hepatic steatosis, and NAFLD activity score. However, even though microbial therapy appears to be risk-free, evaluating side effects related to probiotics or synbiotics is imperative. In addition, safety profiles for long-term usage should be researched. Thus, this review focuses on the human microbiome and liver diseases, recent GWASs on liver disease, the gut-liver axis, and the associations with the microbiome and microbiome during/after liver disease therapy.

Insulin-like growth factor-1 short-period therapy improves Non-Alcoholic Fatty Liver Disease (NAFLD) in obese mice

This study seeks to evaluate Insulin-like Growth Factor 1 (IGF-1) short-period therapy in Non-Alcoholic Fatty Liver Disease (NAFLD) as it relates to western diet-induced obesity. For this purpose, 21-day-old male Swiss mice were divided into a control group (CG, N=8), which was fed a standard diet, and an obese group (GO, N=16), which was fed a western diet, rich in saturated fat and simple carbohydrates, for 12 weeks. In the 11th week, part of the animals in the obese group (N=8) received a daily subcutaneous injection of recombinant human IGF-1 (100µg/kg/day) during seven consecutive days (GO+IGF-1). Biometric and metabolic parameters, intraperitoneal glucose tolerance test (IGTT), quantitative analysis of liver steatosis, quantitative analysis of collagen in liver and expression of immunoperoxidase of alpha-smooth muscle actin (a-SMA) were analyzed. Our data demonstrated that IGF-1 short-term treatment was able to improve obesity-related biometric and metabolic parameters. In addition, it promoted the recovery of liver parenchyma, thereby reducing steatosis and fibrosis, thus demonstrating an important hepatoprotective action.

The essential role of O-GlcNAcylation in hepatic differentiation.

O-GlcNAcylation is a post-translational modification catalyzed by the enzyme O-GlcNAc transferase, which transfers a single N-acetylglucosamine sugar from UDP-GlcNAc to the protein on serine and threonine residues on proteins. Another enzyme, O-GlcNAcase (OGA), removes this modification. O-GlcNAcylation plays an important role in pathophysiology. Here, we report that O-GlcNAcylation is essential for hepatocyte differentiation, and chronic loss results in fibrosis and HCC. Single-cell RNA-sequencing (RNA-seq) was used to investigate hepatocyte differentiation in hepatocyte-specific O-GlcNAc transferase-knockout (OGT-KO) mice with decreased hepatic O-GlcNAcylation and in O-GlcNAcase-KO mice with increased O-GlcNAcylation in hepatocytes. Patients HCC samples and the diethylnitrosamine-induced HCC model were used to investigate the effect of modulation of O-GlcNAcylation on the development of liver cancer. Loss of hepatic O-GlcNAcylation resulted in disruption of liver zonation. Periportal hepatocytes were the most affected by loss of differentiation, characterized by dysregulation of glycogen storage and glucose production. O-GlcNAc transferase-KO mice exacerbated diethylnitrosamine-induced HCC development with increased inflammation, fibrosis, and YAP signaling. Consistently, O-GlcNAcase -KO mice with increased hepatic O-GlcNAcylation inhibited diethylnitrosamine-induced HCC. A progressive loss of O-GlcNAcylation was observed in patients with HCC. Our study shows that O-GlcNAcylation is a critical regulator of hepatic differentiation, and loss of O-GlcNAcylation promotes hepatocarcinogenesis. These data highlight increasing O-GlcNAcylation as a potential therapy in chronic liver diseases, including HCC.

Fecal Microbiota Transplantation in Liver Cirrhosis.

The human gastrointestinal tract houses a diverse array of probiotic and pathogenic bacteria and any alterations in this microbial composition can exert a significant influence on an individual's well-being. It is well-established that imbalances in the gut microbiota play a pivotal role in the development of liver diseases. In light of this, a new adjuvant therapy for liver diseases could be regulating the intestinal microbiota. Through fecal microbiota transplantation, patients whose microbiomes are compromised are treated with stool from healthy donors in an attempt to restore a normal microbiome and alleviate their symptoms. A review of cross-sectional studies and case reports suggests that fecal microbiota transplants may offer effective treatment for chronic liver diseases. Adding to the potential of this emerging therapy, recent research has indicated that fecal microbiota transplantation holds promise as a therapeutic approach specifically for liver cirrhosis. By introducing a diverse range of beneficial microorganisms into the gut, this innovative treatment aims to address the microbial imbalances often observed in cirrhotic patients. While further validation is still required, these preliminary findings highlight the potential impact of fecal microbiota transplantation as a novel and targeted method for managing liver cirrhosis. We aimed to summarize the current state of understanding regarding this procedure, as a new therapeutic method for liver cirrhosis, as well as to explain its clinical application and future potential.

Development of Technology of Phytosubstantiation of <i>Silybum marianum</i> L. Fruits as a Component of Complex Therapy of Liver Diseases

Development of Technology of Phytosubstantiation of <i>Silybum marianum</i> L. Fruits as a Component of Complex Therapy of Liver Diseases

Practical Aspects of Clinical Manifestations, Pathogenesis and Therapy of Alcoholic Liver Disease and Non-alcoholic Fatty Liver Disease: Expert Opinion

Aim: to present the results of an expert discussion of modern aspects of the clinical manifestations, pathogenesis and treatment of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD).Key points. ALD and NAFLD are characterized by high prevalence and have a significant impact on public health. For the diagnosis of liver pathology, it is important to determine the stage of fibrosis and the severity of the exacerbation of the disease. In the treatment of ALD, it is recommended to achieve abstinence, proper nutrition, the appointment of B vitamins, drugs with cytoprotective activity. In severe hepatitis, corticosteroids may be prescribed. In the treatment of NAFLD, diet and lifestyle modification, weight loss, the use of insulin sensitizers, vitamin E, statins (in the presence of hyperlipidemia) and drugs with metabolic activity are effective.Currently, a point of view is being actively expressed about the synergism of the action of alcohol and the metabolic syndrome on the development of fibrosis, cirrhosis, and hepatocellular carcinoma. The current international consensus recommends a change in the nomenclature of NAFLD and ALD and proposes the terms “metabolically associated steatotic liver disease” and “metabolically associated alcoholic liver disease”.Conclusion. The closeness of the clinical manifestations and pathogenesis of NAFLD and ALD justifies attention to drugs with metabolic activity, which are recommended by the Russian Gastroenterological Association and Russian Scientific Liver Society for the treatment of these diseases. The experts support the suggestion to quantify alcohol consumption in patients with NAFLD in order to change the management of patients, if necessary.

PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish

Despite the robust regenerative capacity of the liver, prolonged and severe liver damage impairs liver regeneration, leading to liver failure. Since the liver co-opts the differentiation of liver progenitor cells (LPCs) into hepatocytes to restore functional hepatocytes, augmenting LPC-mediated liver regeneration may be beneficial to patients with chronic liver diseases. However, the molecular mechanisms underlying LPC-to-hepatocyte differentiation have remained largely unknown. Using the zebrafish model of LPC-mediated liver regeneration, Tg(fabp10a:pt-β-catenin), we present that peroxisome proliferator-activated receptor-alpha (PPARα) activation augments LPC-to-hepatocyte differentiation. We found that treating Tg(fabp10a:pt-β-catenin) larvae with GW7647, a potent PPARα agonist, enhanced the expression of hepatocyte markers and simultaneously reduced the expression of biliary epithelial cell (BEC)/LPC markers in the regenerating livers, indicating enhanced LPC-to-hepatocyte differentiation. Mechanistically, PPARα activation augments the differentiation by suppressing YAP signaling. The differentiation phenotypes resulting from GW7647 treatment were rescued by expressing a constitutively active form of Yap1. Moreover, we found that suppression of YAP signaling was sufficient to promote LPC-to-hepatocyte differentiation. Treating Tg(fabp10a:pt-β-catenin) larvae with the TEAD inhibitor K-975, which suppresses YAP signaling, phenocopied the effect of GW7647 on LPC differentiation. Altogether, our findings provide insights into augmenting LPC-mediated liver regeneration as a regenerative therapy for chronic liver diseases.

Potential Therapeutic Strategies in the Treatment of Metabolic-Associated Fatty Liver Disease.

Metabolic-associated Fatty Liver Disease is one of the outstanding challenges in gastroenterology. The increasing incidence of the disease is undoubtedly connected with the ongoing obesity pandemic. The lack of specific symptoms in the early phases and the grave complications of the disease require an active approach to prompt diagnosis and treatment. Therapeutic lifestyle changes should be introduced in a great majority of patients; but, in many cases, the adherence is not satisfactory. There is a great need for an effective pharmacological therapy for Metabolic-Associated Fatty Liver Disease, especially before the onset of steatohepatitis. Currently, there are no specific recommendations on the selection of drugs to treat liver steatosis and prevent patients from progression toward more advanced stages (steatohepatitis, cirrhosis, and cancer). Therefore, in this Review, we provide data on the clinical efficacy of therapeutic interventions that might improve the course of Metabolic-Associated Fatty Liver Disease. These include the drugs used in the treatment of obesity and hyperlipidemias, as well as affecting the gut microbiota and endocrine system, and other experimental approaches, including functional foods. Finally, we provide advice on the selection of drugs for patients with concomitant Metabolic-Associated Fatty Liver Disease.

Higher need for polycystic liver disease therapy in female patients: Sex-specific association between liver volume and need for therapy.

Prognostic tools or biomarkers are urgently needed in polycystic liver disease (PLD) to monitor disease progression and evaluate treatment outcomes. Total liver volume (TLV) is currently used to assess cross-sectional disease severity, and female patients typically have larger livers than males. Therefore, this study explores the sex-specific association between TLV and volume-reducing therapy (VRT). In this prospective cohort study, we included patients with PLD from European treatment centers. We explored sex-specific differences in the association between baseline TLV and initiation of volume-reducing therapy and determined the cumulative incidence rates of volume-reducing therapy in our cohort.We included 358 patients, of whom 157 (43.9%) received treatment. Treated patients had a higher baseline TLV (median TLV 2.16 vs. 4.34 liter, p < 0.001), were more frequently female (69.7% vs. 89.8%, p < 0.001), and had a higher risk of liver events (HR 4.381, p < 0.001). The cumulative volume-reducing therapy rate at 1 year of follow-up was 21.0% for females compared to 9.1% for males. Baseline TLV was associated with volume-reducing therapy, and there was an interaction with sex (HR females 1.202, p < 0.001; HR males 1.790, p < 0.001; at 1.5l). Baseline TLV is strongly associated with volume-reducing therapy initiation at follow-up in patients with PLD, with sex-specific differences in this association. Disease staging systems should use TLV to predict the need for future volume-reducing therapy in PLD separately for males and females.

Fibroblast growth factor 21 ameliorates cholestatic liver injury via a hepatic FGFR4-JNK pathway

Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequently leads to liver injury, inflammation, fibrosis, and liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver-secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury caused by α-naphthylisothiocyanate (ANIT) treatment and Mdr2 deficiency. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.

Identification and Characterization of a Novel Nanobody Against Human CTGF to Reveal Its Antifibrotic Effect in an in vitro Model of Liver Fibrosis.

No agents are currently available for the treatment or reversal of liver fibrosis. Novel antifibrotic therapies for chronic liver diseases are thus urgently needed. Connective tissue growth factor (CTGF) has been shown to contributes profoundly to liver fibrogenesis, which makes CTGF as a promising target for developing antifibrotic agents. In this study, we identified a novel nanobody (Nb) against human CTGF (anti-CTGF Nb) by phage display using an immunized camel, which showed high affinity and specificity in vitro. LX-2 cells, the immortalized human hepatic stellate cells, were induced by transforming growth factor beta1 (TGFβ1) as an in vitro model of liver fibrosis to verify the antifibrotic activity of the anti-CTGF Nb. Our data demonstrated that anti-CTGF Nb effectively alleviated TGFβ1-induced LX-2 cell proliferation, activation, and migration, and promoted the apoptosis of activated LX-2 cells in response to TGFβ1. Moreover, the anti-CTGF Nb remarkably reduced the levels of TGFβ1, Smad2, and Smad3 expression in LX-2 stellate cells stimulated by TGFβ1. Taken together, we successfully identified a novel Nb against human CTGF, which exhibited antifibrotic effects in vitro by regulating the biological functions of human stellate cells LX-2.

Liver Injury and Regeneration: Current Understanding, New Approaches, and Future Perspectives.

The liver is a complex organ with the ability to regenerate itself in response to injury. However, several factors can contribute to liver damage beyond repair. Liver injury can be caused by viral infections, alcoholic liver disease, non-alcoholic steatohepatitis, and drug-induced liver injury. Understanding the cellular and molecular mechanisms involved in liver injury and regeneration is critical to developing effective therapies for liver diseases. Liver regeneration is a complex process that involves the interplay of various signaling pathways, cell types, and extracellular matrix components. The activation of quiescent hepatocytes that proliferate and restore the liver mass by upregulating genes involved in cell-cycle progression, DNA repair, and mitochondrial function; the proliferation and differentiation of progenitor cells, also known as oval cells, into hepatocytes that contribute to liver regeneration; and the recruitment of immune cells to release cytokines and angiogenic factors that promote or inhibit cell proliferation are some examples of the regenerative processes. Recent advances in the fields of gene editing, tissue engineering, stem cell differentiation, small interfering RNA-based therapies, and single-cell transcriptomics have paved a roadmap for future research into liver regeneration as well as for the identification of previously unknown cell types and gene expression patterns. In summary, liver injury and regeneration is a complex and dynamic process. A better understanding of the cellular and molecular mechanisms driving this phenomenon could lead to the development of new therapies for liver diseases and improve patient outcomes.

Adult 10-year survivors after liver transplantation: a single-institution experience over 40 years

Liver transplantation (LT) represents the best cure for several acute and chronic liver diseases. Several studies reported excellent mid-term survivals after LT. However, lesser evidence has been reported on very long (10- and 20-year) follow-up results. This study aims to analyze the monocentric LT experience of the Sapienza University of Rome to identify the pre-operatively available parameters limiting a 10-year post-transplant survival. A total of 491 patients transplanted between 1982 and 2012 were enrolled. The cohort was split into two groups, namely the Short Surviving Group (< 10 years; n = 228, 46.4%) and the Long Surviving Group (≥ 10 years; n = 263, 53.6%). Several differences were reported between the two groups regarding initial liver function, surgical techniques adopted, and immunosuppression. Four variables emerged as statistically relevant as independent risk factors for not reaching at least 10 years of follow-up: recipient age (OR = 1.02; P = 0.01), donor age (OR = 1.01; P = 0.03), being transplanted during the eighties (OR = 6.46; P < 0.0001) and nineties (OR = 2.63; P < 0.0001), and the UNOS status 1-2A (OR = 2.62; P < 0.0001). LT confirms to be an extraordinary therapy for several severe liver diseases, consenting to reach in half of the transplanted cases even more than 20 years of follow-up. The initial liver function and the donor and recipient ages are relevant in impacting long-term survival after transplantation. A broad commitment from many professional groups, including surgeons, hepatologists, and anesthesiologists, is necessary. The achievement of excellent results in terms of long-term survival is proof of the effectiveness of this multidisciplinary collaboration.

Hypoimmunogenic Human Pluripotent Stem Cells as a Powerful Tool for Liver Regenerative Medicine.

Induced pluripotent stem cells (iPSC) have huge potential as cell therapy for various diseases, given their potential for unlimited self-renewal and capability to differentiate into a wide range of cell types. Although autologous iPSCs represents the ideal source for patient-tailored regenerative medicine, the high costs of the extensive and time-consuming production process and the impracticability for treating acute conditions hinder their use for broad applications. An allogeneic iPSC-based strategy may overcome these issues, but it carries the risk of triggering an immune response. So far, several approaches based on genome-editing techniques to silence human leukocyte antigen class I (HLA-I) or II (HLA-II) expression have been explored to overcome the immune rejection of allogeneic iPSCs. In this study, we employed the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9) system to delete the β2-Microglobulin (B2M) and the Class II Major Histocompatibility Complex Transactivator (CIITA) genes, essential for the correct surface expression of HLA-I and HLA-II proteins. The resulting hypoimmunogenic iPSC line has a normal karyotype, expresses the pluripotency stem cell markers, and is capable of differentiating into the three embryonic germ layers. Furthermore, we showed that it specifically retains the ability to differentiate towards different liver cells, such as endothelial-like cells, hepatocyte-like cells, and hepatic stellate-like cells. Our results indicate that hypoimmunogenic iPSCs could give a new cost-effective and off-the-shelf opportunity for cell therapy in liver diseases.

Pharmaceutical Strategies to Improve Druggability of Potential Drug Candidates in Nonalcoholic Fatty Liver Disease Therapy.

Nonalcoholic fatty liver disease (NAFLD) has become globally prevalent and is the leading cause of chronic liver disease. Although NAFLD is reversible without medical intervention in the early stage, the condition could be sequentially worsened to nonalcoholic steatohepatitis (NASH) and, eventually, cirrhosis and hepatic cancer. The progression of NAFLD is related to various factors such as genetics, pre-disposed metabolic disorders, and immunologic factors. Thankfully, to date, there have been accumulating research efforts and, as a result, different classes of potent drug candidates have been discovered. In addition, there have also been various attempts to explore pharmaceutical strategies to improve the druggability of drug candidates. In this review, we provided a brief overview of the drug candidates that have undergone clinical trials. In the latter part, strategies for developing better drugs are discussed.

Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages

Hepatic insulin resistance is recognized as a driver of type 2 diabetes and fatty liver disease but specific therapies are lacking. Here we explore the potential of human induced pluripotent stem cells (iPSCs) for modeling hepatic insulin resistance in vitro, with a focus on resolving the controversy about the impact of inflammation in the absence of steatosis. For this, we establish the complex insulin signaling cascade and the multiple inter-dependent functions constituting hepatic glucose metabolism in iPSC-derived hepatocytes (iPSC-Heps). Co-culture of these insulin-sensitive iPSC-Heps with isogenic iPSC-derived pro-inflammatory macrophages induces glucose output by preventing insulin from inhibiting gluconeogenesis and glycogenolysis and activating glycolysis. Screening identifies TNFα and IL1β as the mediators of insulin resistance in iPSC-Heps. Neutralizing these cytokines together restores insulin sensitivity in iPSC-Heps more effectively than individual inhibition, reflecting specific effects on insulin signaling and glucose metabolism mediated by NF-κB or JNK. These results show that inflammation is sufficient to induce hepatic insulin resistance and establish a human iPSC-based in vitro model to mechanistically dissect and therapeutically target this metabolic disease driver.

Suppression of endoplasmic reticulum stress reverses hindlimb unloading-induced hepatic cellular processes in mice

BackgroundThe Hindlimb unloaded mouse, an animal model of simulated microgravity demonstrates significant metabolic and hepatic derangements. However, cellular and molecular mechanisms driving liver dysfunction in Hindlimb unloaded mice are poorly characterized. MethodsWe investigated the possible contribution of dysregulated protein homeostasis by endoplasmic reticulum, endoplasmic reticulum stress, to liver dysfunction during HU. C57BL/6j male mice were grouped into ground-based controls or Hindlimb unloaded groups treated daily with vehicle or 4-phenylbutyrate (4-PBA), a potent inhibitor of endoplasmic reticulum stress. Following three weeks of HU, mice were sacrificed, and liver tissues were dissected for further analysis. ResultsHindlimb unloaded was associated with hepatic atrophy and elevated endoplasmic reticulum stress, which was restored by 4-PBA treatment. The Gene Ontology analysis revealed the downregulation of genes primarily involved in liver metabolic and Wingless-related integration site (WNT) signaling pathways, while those related to cytochrome P450, and liver fibrosis were upregulated. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed downregulation of several genes involved in metabolic pathways following treatment with 4-PBA, induced by HU. ConclusionsWe report several differential and uniquely expressed genes associated with microgravity-induced elevated ER stress and liver injury. Our data has translational potential in unraveling novel molecular targets for pharmaceutical therapies of liver diseases. General significanceOur novel findings show a pathogenic role for elevated ER stress in liver injury in microgravity conditions.

Questionnaire PLD-complaint-specific assessment identifies need for therapy in polycystic liver disease: A multi-centric prospective study.

Polycystic liver disease (PLD) can lead to extensive hepatomegaly. Symptom relief is the primary goal of the treatment. The role of the recently developed disease-specific questionnaires for identification of the thresholds and the assessment of therapy needs further investigation. A five-year prospective multi-centric observational study in 21 hospitals in Belgium gathered a study population of 198 symptomatic PLD-patients of whom the disease-specific symptom questionnaire PLD-complaint-specific assessment (POLCA) scores were calculated. The thresholds of the POLCA score for the need for volume reduction therapy were analyzed. The study group consisted of mostly (82.8%) women with baseline mean age of 54.4years ±11.2, median liver volume expressed as height-adjusted total liver volume(htLV) of 1994mL (interquartile range [IQR] 1275; 3150) and median growth of the liver of +74mL/year (IQR +3; +230). Volume reduction therapy was needed in 71 patients (35.9%). A POLCA severity score (SPI)≥14 predicted the need for therapy both in the derivation (n=63) and the validation cohort (n=126). The thresholds to start somatostatin analogues (n=55) or to consider liver transplantation (n=18) were SPI scores of ≥14 and≥18 and the corresponding mean htLVs were 2902mL (IQR 1908; 3964) and 3607mL (IQR 2901; 4337), respectively. Somatostatin analogues treatment resulted in a decrease in the SPI score -6.0 versus+4.5 in patients without somatostatin analogues (p<0.01). Changes in the SPI score were significantly different between the liver transplantation group and no liver transplantation group, +4.3±7.1 versus -1.6±4.9, respectively, (p<0.01). A polycystic liver disease-specific questionnaire can be used as a guide on when to start a volume reduction therapy and to assess the effect of treatment.