Systematic review: Preventive and therapeutic applications of metformin in liver disease

Metformin, a biguanide derivative, is the most commonly prescribed medication in the treatment of type 2 diabetes mellitus. More recently, the use of metformin has shown potential as a preventive and therapeutic agent for a broad spectrum of conditions, including liver disease and hepatic malignancies. In this systematic review,we critically analyze the literature behind the potential use of metformin across the spectrum of liver disease and malignancies. The Pub Med and Ovid MEDLINE databases were searched from 2000 to March 2015, using a combination of relevant text words and MeS H terms: metformin and mammalian target of rapamycin, hepatitis B virus(HBV), hepatitis B virus(HCV), nonalcoholic fatty liver disease(NAFLD), hepatocellular carcinoma(HCC) or cholangiocarcinoma. The search results were evaluated for pertinence to the issue of metformin in liver disease as well as for quality of study design. Metformin has a number of biochemical effects that would suggest a benefit in treating chronic liver diseases, particularly in the context of insulin resistance and inflammation. However, the literature thus far does not support any independent therapeutic role in NAFLD or HCV. Nonetheless, there is Level Ⅲ evidence for a chemopreventive role in patients with diabetes and chronic liver disease, with decreased incidence of HCC and cholangiocarcinoma. The use of metformin seems to be safe in patients with cirrhosis, and provides a survival benefit. Once hepatic malignancies are already established, metformin does not offer any therapeutic potential. In conclusion, there is insufficient evidence to recommend use of metformin in the adjunctive treatment of chronic liver diseases, including NAFLD and HCV. However, there is good evidence for a chemopreventive role against HCC among patients with diabetes and chronic liver disease, and metformin should be continued in patients even with cirrhosis to provide this benefit.

Metformin does not improve survival in patients with hepatocellular carcinoma

AIM:To assess whether metformin,which has a chemopreventive effect in chronic liver disease,has any chemotherapeutic effect in hepatocellular carcinoma.METHODS:This was a retrospective study of 701 patients with newly diagnosed hepatocellular carcinoma(HCC)seen between January 2005 and June 2011 at Mayo Clinic,Rochester,Minnesota.This patient cohort was a part of the global HCC BRIDGE study,which is a large longitudinal study of HCC determining the realworld experience of HCC characteristics,management and patient outcomes.We defined significant metformin exposure as continuation of this agent at least 90d beyond diagnosis of HCC,and compared survival of diabetic patients on metformin to diabetic patients not on metformin and non-diabetics.RESULTS:Our cohort was 72.9%male,with a mean±SD age of 62.6±12.3 years.The most common etiologies of liver disease were hepatitis C(34%),alcoholic liver disease(29%),fatty liver disease(15%)and hepatitis B(9%).By univariate analysis,using diabetics not on metformin as the reference group,diabetic patients with HCC on metformin had no survival advantage,with a HR(95%CI)of 1.0(0.8-1.3).Non-diabetic HCC patients also did not appear to have a survival advantage as compared to diabetic HCC patients not on metformin,as demonstrated by a HR(95%CI)of1.1(0.7-1.7).Diabetics on metformin beyond 90 d after HCC diagnosis had a longer median survival at 34.2 mo,as compared to 25.5 mo among diabetic patients who were not on metformin or had discontinued metformin within 90 d after HCC diagnosis.This finding was likely due to potential survival bias among those who lived long enough to receive metformin.CONCLUSION:Although the literature suggests a chemotherapeutic effect in other malignancies,our study demonstrates no survival benefit to the use of metformin in diabetic patients with HCC.

Implication of the intestinal microbiome in complications of cirrhosis

The intestinal microbiome(IM) is altered in patients with cirrhosis,and emerging literature suggests that this impacts on the development of complications.The Pub Med database was searched from January 2000 to May 2015 for studies and review articles on the composition,pathophysiologic effects and therapeutic modulation of the IM in cirrhosis.The following combination of relevant text words and MeS H terms were used,namely intestinal microbiome,microbiota,or dysbiosis,and cirrhosis,encephalopathy,spontaneous bacterial peritonitis,hepatorenal syndrome,variceal bleeding,hepatopulmonary syndrome,portopulmonary hypertension and hepatocellular carcinoma.The search results were evaluated for pertinence to the subject of IM and cirrhosis,as well as for quality of study design.The IM in cirrhosis is characterized by a decreased proportion of Bacteroides and Lactobacilli,and an increased proportion of Enterobacteriaceae compared to healthy controls.Except for alcoholic cirrhosis,the composition of the IM in cirrhosis is not affected by the etiology of the liver disease.The percentage of Enterobacteriaceae increases with worsening liver disease severity and decompensation and is associated with bacteremia,spontaneous bacterial peritonitis and hepatic encephalopathy.Lactulose,rifaximin and Lactobacillus-containing probiotics have been shown to partial y reverse the cirrhosis associated enteric dysbiosis,in conjunction with improvement in encephalopathy.The IM is altered in cirrhosis,and this may contribute to the development of complications associated with end-stage liver disease.Therapies such as lactulose,rifaximin and probiotics may,at least partially,reverse the cirrhosisassociated changes in the IM.This,in turn,may prevent or alleviate the severity of complications.

Epigenetic basis of hepatocellular carcinoma: A network-based integrative meta-analysis

AIM To identify the key epigenetically modulated genes and pathways in HCC by performing an integrative meta-analysis of all major, well-annotated and publicly available methylation datasets using tools of network analysis.METHODS Pub Med and Gene Expression Omnibus were searched for genome-wide DNA methylation datasets. Patient clinical and demographic characteristics were obtained. DNA methylation data were integrated using the Ingenuity Pathway Analysis, a software package for visualizing and analyzing biological networks. Pathway enrichment analysis was performed using IPA, which also provides literature-driven and computationallypredicted annotations for significant association of genes to curated molecular pathways.RESULTS From an initial 928 potential abstracts, we identified and analyzed 11 eligible high-throughput methylation datasets representing 354 patients. A significant proportion of studies did not provide concomitant clinical data. In the promoter region, HIST1H2AJ and SPDYA were the most commonly methylated, whereas HRNBP3 gene was the most commonly hypomethylated. ESR1 and ERK were central genes in the principal networks. The pathways most associated with the frequently methylated genes were G-protein coupled receptor and c AMP-mediated signalling. CONCLUSION Using an integrative network-based analysis approach of genome-wide DNA methylation data of both the promoter and body of genes, we identified G-protein coupled receptor signalling as the most highly associated with HCC. This encompasses a diverse range of cancer pathways, such as the PI3 K/Akt/m TOR and Ras/Raf/MAPK pathways, and is therefore supportive of previous literature on gene expression in HCC. However, there are novel targetable genes such as HIST1H2 AJ that are epigenetically modified, suggesting their potential as biomarkers and for therapeutic targeting of the HCC epigenome.

Divergent trajectories of lean vs obese non-alcoholic steatohepatitis patients from listing to post-transplant:A retrospective cohort study

BACKGROUND Non-alcoholic steatohepatitis(NASH)cirrhosis is the second most common indication for liver transplantation(LT).The role of body mass index(BMI)on outcomes of NASH cirrhosis has been conflicting.AIM To compare the longitudinal trajectories of patients with lean vs obese NASH cirrhosis,from listing up to post-transplant,having adjusted their BMI for ascites.METHODS We retrospectively reviewed all adult NASH patients listed for LT in our program from 2012 to 2019.Fine-Gray Competing Risk analyses and Cox Proportional-Hazard Models were performed to examine the cumulative incidence of transplant and survival outcomes respectively.RESULTS Out of 265 NASH cirrhosis listed patients,176 were included.Median age was 61.0 years;46%were females.111 patients underwent LT.Obese robust patients had better waitlist survival[hazard ratio(HR):0.12;95%CI:0.05–0.29,P<0.0001]with higher instantaneous rate of transplant(HR:5.71;95%CI:1.26–25.9,P=0.02).Lean NASH patients had a substantially higher risk of graft loss within 90 d post-LT(1.2%vs 13.8%,P=0.032)and death post-LT(2.4%vs 17.2%,P=0.029).1-3-and 5-year graft survival was poor for lean NASH(78.6%,77.3%and 41.7%vs 98.6%,96%and 85%respectively).Overall patient survival post-LT was significantly worse in lean NASH(HR:0.17;95%CI:0.03–0.86,P=0.0142)with 83%lower instantaneous rate of death in obese group.CONCLUSION Although lean NASH is considered to be more benign than obese NASH,our study suggests a paradoxical correlation of lean NASH with waitlist outcomes,and graft and patient survival post-LT.

Impact of immunosuppression on incidence of post-transplant diabetes mellitus in solid organ transplant recipients:Systematic review and meta-analysis

BACKGROUND Solid organ transplantation is a life-saving intervention for end-stage organ disease.Post-transplant diabetes mellitus(PTDM)is a common complication in solid organ transplant recipients,and significantly compromises long-term survival beyond a year.AIM To perform a systematic review and meta-analysis to estimate incidence of PTDM and compare the effects of the 3 major immunosuppressants on incidence of PTDM.METHODS Two hundred and six eligible studies identified 75595 patients on Tacrolimus,51242 on Cyclosporine and 3020 on Sirolimus.Random effects meta-analyses was used to calculate incidence.RESULTS Network meta-analysis estimated the overall risk of developing PTDM was higher with tacrolimus(OR=1.495%CI:1.0–2.0)and sirolimus(OR=1.8;95%CI:1.5–2.2)than with Cyclosporine.The overall incidence of PTDM at years 2-3 was 17%for kidney,19%for liver and 22%for heart.The risk factors for PTDM most frequently identified in the primary studies were age,body mass index,hepatitis C,and African American descent.CONCLUSION Tacrolimus tends to exhibit higher diabetogenicity in the short-term(2-3 years post-transplant),whereas sirolimus exhibits higher diabetogenicity in the longterm(5-10 years post-transplant).This study will aid clinicians in recognition of risk factors for PTDM and encourage careful evaluation of the risk/benefit of different immunosuppressant regimens in transplant recipients.

Integrative analysis of layers of data in hepatocellular carcinoma reveals pathway dependencies

BACKGROUND The broader use of high-throughput technologies has led to improved molecular characterization of hepatocellular carcinoma(HCC).AIM To comprehensively analyze and characterize all publicly available genomic,gene expression,methylation,miRNA and proteomic data in HCC,covering 85 studies and 3355 patient sample profiles,to identify the key dysregulated genes and pathways they affect.METHODS We collected and curated all well-annotated and publicly available highthroughput datasets from PubMed and Gene Expression Omnibus derived from human HCC tissue.Comprehensive pathway enrichment analysis was performed using pathDIP for each data type(genomic,gene expression,methylation,miRNA and proteomic),and the overlap of pathways was assessed to elucidate pathway dependencies in HCC.RESULTS We identified a total of 8733 abstracts retrieved by the search on PubMed on HCC for the different layers of data on human HCC samples,published until December 2016.The common key dysregulated pathways in HCC tissue across different layers of data included epidermal growth factor(EGFR)andβ1-integrin pathways.Genes along these pathways were significantly and consistently dysregulated across the different types of high-throughput data and had prognostic value with respect to overall survival.Using CTD database,estradiol would best modulate and revert these genes appropriately.CONCLUSION By analyzing and integrating all available high-throughput genomic,transcriptomic,miRNA,methylation and proteomic data from human HCC tissue,we identified EGFR,β1-integrin and axon guidance as pathway dependencies in HCC.These are master regulators of key pathways in HCC,such as the mTOR,Ras/Raf/MAPK and p53 pathways.The genes implicated in these pathways had prognostic value in HCC,with Netrin and Slit3 being novel proteins of prognostic importance to HCC.Based on this integrative analysis,EGFR,andβ1-integrin are master regulators that could serve as potential therapeutic targets in HCC.