The impact of endotrophin on the progression of chronic liver disease

Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. The fibrotic liver is characterized by the pathological accumulation of extracellular matrix (ECM) proteins. Type VI collagen alpha3 (Col6a3) is a biomarker of hepatic fibrosis, and its cleaved form, endotrophin (ETP), plays a critical role in adipose tissue dysfunction, insulin resistance, and breast cancer development. Here, we studied the effects of the Col6a3-derived peptide ETP on the progression of chronic liver diseases, such as NASH and liver cancer. We used a doxycycline (Dox)-inducible liver-specific ETP-overexpressing mouse model on a NAFLD-prone (liver-specific SREBP1a transgenic) background. For this, we evaluated the consequences of local ETP expression in the liver and its effect on hepatic inflammation, fibrosis, and insulin resistance. Accumulation of ETP in the liver induced hepatic inflammation and the development of fibrosis with associated insulin resistance. Surprisingly, ETP overexpression also led to the emergence of liver cancer within 10 months in the SREBP1a transgenic background. Our data revealed that ETP can act as a “second hit” during the progression of NAFLD and can play an important role in the development of NASH and hepatocellular carcinoma (HCC). These observations firmly link elevated levels of ETP to chronic liver disease.

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Red cell distribution width to lymphocyte ratio as a new biomarker in predicting prognosis in chronic liver disease patients with hepatocellular carcinoma

10.52768/jjgastro/1024 ◽

2021 ◽

Vol 1 (5) ◽

Author(s):

Yakup Ülger ◽

◽

Anıl Delik ◽

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Chronic Liver Disease ◽

Multivariate Logistic Regression Analysis ◽

Chronic Liver ◽

P Value ◽

Cell Distribution ◽

Distribution Width ◽

Alcoholic Fatty Liver ◽

Lymphocyte Ratio

Background: Hepatocellular Carcinoma (HCC), hepatitis B, hepatitis C, chronic alcoholism, non-alcoholic fatty liver disease, copper and iron deposition etiologies, together with various genetic factors, constitute a rather complex cancer group that includes chronic inflammation, chronic systemic inflammation triggered by oxidative stress. Therefore, an increase in the incidence and prevalence of liver cancer is expected in the future. Discovery of new biomarkers in HCC diagnosis, prognosis, prediction of treatment response and treatment follow-up is very important. The aim of our study was to retrospectively evaluate the clinical significance of the Red blood cell Distribution Width (RDW) to lymphocyte ratio (RLR) in patients with chronic liver disease with HCC. Materials and methods: Our study, which was designed retrospectively, included 200 patients who were followed up with the diagnosis of HCC. Liver function tests, hematological parameters, biochemical tests were analyzed in Çukurova University Balcalı hospital. Child Pugh Score (CTP) and RLR of the patients were calculated with the necessary equations. HCC patients were analyzed in two groups as alfa feto protein (AFP) negative (<20 ng/ml) and AFP positive (>20 ng/ml). All the obtained results were analyzed in SPSS program. Results: A total of 200 patients with HCC were included in this study. Half of the 200 HCC patients included in the study were found to be AFP negative, and the gender distribution in this group was found to be 24.2% for women and 75.8% for men. A significant increase in the rate of RLR was detected in the AFP positive group (AFP negative 13.54 ± 9.67, AFP positive 20.11 ± 27.38, and p value 0.03). According to Child Pugh score, RLR rates were found to be 11.72 ± 8.82 in CTP A, 15.96 ± 8.78 in CTP B, 27.47 ± 35.6 in CTP C, p value <0.001. In multivariate logistic regression analysis according to AFP group distribution, the OR value of RLR was determined as 0.95, 95% CI (0.90-1.00) and p value was 0.02. Conclusion: We think that RLR can be used as a new biomarker associated with poor prognosis in AFP positive HCC patients.

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Insulin Resistance and Hyperinsulinemia in Patients with Chronic Liver Disease and Hepatocellular Carcinoma

Clinical medicine Endocrinology and diabetes ◽

10.4137/cmed.s3116 ◽

2009 ◽

Vol 2 ◽

pp. CMED.S3116 ◽

Cited By ~ 1

Author(s):

Valter Donadon ◽

Massimiliano Balbi ◽

Antonio Perciaccante ◽

Pietro Casarin ◽

Giorgio Zanette

Keyword(s):

Hepatocellular Carcinoma ◽

Insulin Resistance ◽

Liver Disease ◽

Chronic Liver Disease ◽

Healthy Subjects ◽

Chronic Liver ◽

Metabolic Factors ◽

Mean Values ◽

The Mean

Objectives To investigate the role of insulin resistance (IR) and insulin plasma levels (IRI) in patients with chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Methods We recruited the following patients: 125 with HCC, 128 with liver cirrhosis (LC) and 133 with chronic hepatitis C (CHC). IR was assessed by the HOMA-IR method. To define IR and hyperinsulinemia we selected as a cut-off level, the value of the 80th percentile for HOMA-IR (2.72) and IRI (11.18) in 113 healthy subjects. Results The mean levels of HOMA-IR and IRI increase progressively among CHC (2.7 ± 2.9 and 11.5 ± 10.5, respectively), LC (5.4 ± 4.5 and 17.6 ± 11.2) and HCC (6.4 ± 9.8 and 18.2 ± 18.8). In the upper quintiles for HOMA-IR and IRI, the frequency of patients in the LC and HCC groups was twice as much in CHC cases. HCC with DM2 have the greatest percentage above the 80th percentile of HOMA-IR, their quintiles distribution is inverted and HOMA-IR mean values are significantly higher in comparison with HCC without DM2 cases. Discussion Our study shows that the association between IR and CLD begins in the early stages of liver fibrosis. DM2 increases HOMA-IR and IRI mean levels in HCC patients and these metabolic factors could play a major role in the link between diabetes mellitus and hepatocarcinoma.

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Coffee Consumption and the Progression of NAFLD: A Systematic Review

Nutrients ◽

10.3390/nu13072381 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2381

Author(s):

Rebecca Sewter ◽

Susan Heaney ◽

Amanda Patterson

Keyword(s):

Systematic Review ◽

Liver Disease ◽

Chronic Liver Disease ◽

Coffee Consumption ◽

Developed Countries ◽

Chronic Liver ◽

Cochrane Library ◽

Coffee Intake ◽

Alcoholic Fatty Liver ◽

The Impact

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed countries. Coffee is one of the most consumed beverages in the world and has been shown to be beneficial in limiting progression in chronic liver disease in general. However, research surrounding the impact of coffee consumption on NAFLD progression is limited. This systematic review aimed to investigate the relationship between coffee consumption and the progression of liver disease, specifically for cases of NAFLD. MEDLINE, EMBASE, CINAHL, the Cochrane Library, and Scopus were searched for published studies that evaluated the effects of coffee consumption on the progression of NAFLD. The results are presented in a narrative synthesis with principal summary measures, including odds ratios, p-values, and differences in mean coffee intake in relation to severity of NAFLD. Five studies met the inclusion criteria and were included in this review. There was no trial evidence among NAFLD patients, rather all studies were of a cross-sectional design. Using the Academy of Nutrition and Dietetics Quality Criteria Checklist, four studies received a positive rating, with the remaining study receiving a neutral rating. Overall, four out of the five studies reported a statistically significant relationship between coffee consumption and the severity of fibrosis. Methods around capturing and defining coffee consumption were heterogeneous and therefore an effective dose could not be elucidated. Results suggest that higher coffee consumption is inversely associated with the severity of hepatic fibrosis in individuals with NAFLD. However, further research is required to elucidate the optimum quantity and form/preparation of coffee required to exert this hepatoprotective role.

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Role of glycine-N-methyl transferase in human and murine nonalcoholic steatohepatitis

10.1101/2021.12.03.470998 ◽

2021 ◽

Author(s):

Connor R. Quinn ◽

Mario C. Rico ◽

Carmen Merali ◽

Salim Merali

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Chronic Liver Disease ◽

Nonalcoholic Steatohepatitis ◽

Disease Process ◽

Chronic Liver ◽

Label Free ◽

Methyl Transferase ◽

Alcoholic Fatty Liver ◽

The Impact

AbstractNon-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide, mirroring the obesity epidemic. NAFLD is the number one cause of chronic liver disease worldwide, with 25% of these patients developing nonalcoholic steatohepatitis (NASH). This significantly increases the risk of cirrhosis and decompensated liver failure. Past studies in rodent models have shown that the knockout of glycine-N-methyltransferase (GNMT) is associated with steatosis, fibrosis, and hepatocellular carcinoma. However, the attenuation of GNMT in subjects with NASH and the molecular basis for its impact on the disease process have yet to be elucidated. To address this knowledge gap, we show the reduction of GNMT protein levels in the liver of NASH subjects compared to healthy controls. To gain insight into the impact of decreased GNMT in the disease process, we performed global label-free proteome studies on the livers from a murine Western diet-based model of NASH. We identified the differential expression of essential proteins involved in hallmark NASH pathogenesis, including lipid metabolism, inflammation, and fibrosis. Significantly, the downregulation of GNMT, the prominent regulator of S-adenosylmethionine (AdoMet), was identified as a contributing factor to these networks, increasing fourfold in AdoMet levels. AdoMet is an essential metabolite for transmethylation reactions and a substrate for polyamine synthesis, and its levels can impact polyamine flux and generate oxidative stress. Therefore, we performed targeted proteome and metabolomics studies to show a decrease in GNMT transmethylation, an increase in flux through the polyamine pathway, and increased oxidative stress.Abstract Figure

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The impact of diabetes on HCC.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4029 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4029-4029

Author(s):

Suzanne Graef ◽

Sarah Berhane ◽

Mabel Joey Teng ◽

Anna Skowronska ◽

Philip James Johnson

Keyword(s):

Multivariate Analysis ◽

Risk Factor ◽

Liver Disease ◽

Chronic Liver Disease ◽

Independent Risk Factor ◽

Chronic Liver ◽

Diabetic Patients ◽

Alcoholic Fatty Liver ◽

Treatment Of Diabetes ◽

The Impact

4029 Background: The incidence of hepatocellular carcinoma (HCC) in the UK has increased by 40% over the last 20 years, with a corresponding increase in mortality rate. The rising incidence of obesity and type II diabetes are believed to be contributing factors due to the association with non-alcoholic fatty liver and steatohepatitis. We aimed to examine if diabetes was as an independent risk factor for the development of HCC and to assess the impact of diabetes on overall survival (OS). Methods: Data from 724 patients with HCC and a control group comprising 340 patients with chronic liver disease were collected prospectively between 2007 and 2012. The odds ratio (OR) for HCC in diabetic versus non-diabetic patients was calculated. Univariate and multivariate analysis was performed using logistic regression. Cox proportional hazards analysis was used to estimate hazard ratio (HR) for death for HCC patients, with and without diabetes and for the impact of variation in diabetic treatments. Results: The prevalence of diabetes was 39% within the HCC population and 10.3% within the chronic liver disease group. Univariate analysis demonstrated increased risk of HCC associated with age, sex, diabetes, haemochromatosis, cirrhosis, alcohol abuse and Child’s score. In patients with diabetes OR for HCC was 5.74 (CI 3.9-8.3; p<0.001). Age, sex, cirrhosis, Child’s score, diabetes and diabetes treatment with insulin, retained significance as independent risk factors in multivariate analysis. There was no survival difference for HCC patients with and without diabetes. In diabetic patients with HCC, treatment of diabetes with metformin, compared against other diabetic treatment options, was associated with a significantly longer OS (31 versus 24 months, p = 0.016; HR 0.74, p = 0.027). Conclusions: This study has demonstrated that diabetes is an independent risk factor for the development of HCC in a high risk population and that treatment with insulin appears to confer further independent risk. Diabetes has no effect on survival following the development of HCC but treatment of diabetes with metformin is associated with prolonged survival. In considering the optimal treatment for diabetes in chronic liver disease the beneficial effects of metformin on OS, if HCC develops, should be taken into account.

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TFCP2 Genetic Polymorphism Is Associated with Predisposition to and Transplant Prognosis of Hepatocellular Carcinoma

Gastroenterology Research and Practice ◽

10.1155/2017/6353248 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Zhikun Liu ◽

Feng Gao ◽

Zhou Shao ◽

Haiyang Xie ◽

Lin Zhou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Genetic Polymorphism ◽

Chronic Liver Disease ◽

Significant Risk ◽

Chronic Liver ◽

Free Survival ◽

Tumor Number ◽

The Impact ◽

Control Study

TFCP2 is an oncogene and plays crucial roles in the incidence and progression of hepatocellular carcinoma (HCC). However, no reports are available on the impact of TFCP2 genetic polymorphism on the susceptibility to and the transplant prognosis of HCC. Here, we genotyped 7 SNPs of TFCP2 in a case-control study of 119 patients with HCC and 200 patients with chronic liver disease. Of the 7 SNPs in TFCP2, rs7959378 distributed differentially between patients with versus patients without HCC. The patients with the CA (OR = 0.58, 95% CI = 0.35–0.96), the CC (OR = 0.39, 95% CI = 0.20–0.76), and the CA/CC (OR = 0.52, 95% CI = 0.32–0.83) genotypes had significantly decreased risk for HCC compared with those carrying the rs7959378 AA genotype. After adjusting for confounding factors, rs7959378 still conferred significant risk for HCC. Furthermore, the patients who carried rs7959378 AC/CC had a higher overall survival and lower relapse-free survival than those with the rs7959378 AA genotype. Similar results were found in the multivariate analysis adjusted by AFP, tumor size and tumor number, and differentiation. These findings indicate that rs7959378 is associated with the risk of HCC in patient with chronic liver disease and prognosis of HCC patients after liver transplantation.

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Expression of the type 3 InsP3 receptor is a final common event in the development of hepatocellular carcinoma

Gut ◽

10.1136/gutjnl-2018-317811 ◽

2019 ◽

Vol 68 (9) ◽

pp. 1676-1687 ◽

Cited By ~ 17

Author(s):

Mateus T Guerra ◽

Rodrigo M Florentino ◽

Andressa Franca ◽

Antonio C Lima Filho ◽

Marcone L dos Santos ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Liver Cancer ◽

Mouse Model ◽

Cancer Cells ◽

Chronic Liver Disease ◽

De Novo ◽

Chronic Liver ◽

Liver Cancer Cells ◽

Type 3

Background & objectivesHepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Several types of chronic liver disease predispose to HCC, and several different signalling pathways have been implicated in its pathogenesis, but no common molecular event has been identified. Ca2+ signalling regulates the proliferation of both normal hepatocytes and liver cancer cells, so we investigated the role of intracellular Ca2+ release channels in HCC.DesignExpression analyses of the type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR3) in human liver samples, liver cancer cells and mouse liver were combined with an evaluation of DNA methylation profiles of ITPR3 promoter in HCC and characterisation of the effects of ITPR3 expression on cellular proliferation and apoptosis. The effects of de novo ITPR3 expression on hepatocyte calcium signalling and liver growth were evaluated in mice.ResultsITPR3 was absent or expressed in low amounts in hepatocytes from normal liver, but was expressed in HCC specimens from three independent patient cohorts, regardless of the underlying cause of chronic liver disease, and its increased expression level was associated with poorer survival. The ITPR3 gene was heavily methylated in control liver specimens but was demethylated at multiple sites in specimens of patient with HCC. Administration of a demethylating agent in a mouse model resulted in ITPR3 expression in discrete areas of the liver, and Ca2+ signalling was enhanced in these regions. In addition, cell proliferation and liver regeneration were enhanced in the mouse model, and deletion of ITPR3 from human HCC cells enhanced apoptosis.ConclusionsThese results provide evidence that de novo expression of ITPR3 typically occurs in HCC and may play a role in its pathogenesis.

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Possible unrecognised liver injury is associated with mortality in critically ill COVID-19 patients

Therapeutic Advances in Gastroenterology ◽

10.1177/17562848211023410 ◽

2021 ◽

Vol 14 ◽

pp. 175628482110234

Author(s):

Mario Romero-Cristóbal ◽

Ana Clemente-Sánchez ◽

Patricia Piñeiro ◽

Jamil Cedeño ◽

Laura Rayón ◽

...

Keyword(s):

Liver Disease ◽

Liver Fibrosis ◽

Liver Injury ◽

Chronic Liver Disease ◽

Critically Ill ◽

Cox Regression ◽

Chronic Liver ◽

Cox Regression Analysis ◽

Risk Of Death ◽

The Impact

Background: Coronavirus disease (COVID-19) with acute respiratory distress syndrome is a life-threatening condition. A previous diagnosis of chronic liver disease is associated with poorer outcomes. Nevertheless, the impact of silent liver injury has not been investigated. We aimed to explore the association of pre-admission liver fibrosis indices with the prognosis of critically ill COVID-19 patients. Methods: The work presented was an observational study in 214 patients with COVID-19 consecutively admitted to the intensive care unit (ICU). Pre-admission liver fibrosis indices were calculated. In-hospital mortality and predictive factors were explored with Kaplan–Meier and Cox regression analysis. Results: The mean age was 59.58 (13.79) years; 16 patients (7.48%) had previously recognised chronic liver disease. Up to 78.84% of patients according to Forns, and 45.76% according to FIB-4, had more than minimal fibrosis. Fibrosis indices were higher in non-survivors [Forns: 6.04 (1.42) versus 4.99 (1.58), p < 0.001; FIB-4: 1.77 (1.17) versus 1.41 (0.91), p = 0.020)], but no differences were found in liver biochemistry parameters. Patients with any degree of fibrosis either by Forns or FIB-4 had a higher mortality, which increased according to the severity of fibrosis ( p < 0.05 for both indexes). Both Forns [HR 1.41 (1.11–1.81); p = 0.006] and FIB-4 [HR 1.31 (0.99–1.72); p = 0.051] were independently related to survival after adjusting for the Charlson comorbidity index, APACHE II, and ferritin. Conclusion: Unrecognised liver fibrosis, assessed by serological tests prior to admission, is independently associated with a higher risk of death in patients with severe COVID-19 admitted to the ICU.

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Two Metabolomics Phenotypes of Human Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease According to Fibrosis Severity

Metabolites ◽

10.3390/metabo11010054 ◽

2021 ◽

Vol 11 (1) ◽

pp. 54

Author(s):

Benjamin Buchard ◽

Camille Teilhet ◽

Natali Abeywickrama Samarakoon ◽

Sylvie Massoulier ◽

Juliette Joubert-Zakeyh ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Monounsaturated Fatty Acids ◽

Metabolic Reprogramming ◽

Resonance Spectroscopy ◽

Alcoholic Fatty Liver ◽

The Impact ◽

Alcoholic Fatty Liver Disease

Non-Alcoholic Fatty Liver Disease (NAFLD) is considered as the forthcoming predominant cause for hepatocellular carcinoma (HCC). NAFLD-HCC may rise in non-cirrhotic livers in 40 to 50% of patients. The aim of this study was to identify different metabolic pathways of HCC according to fibrosis level (F0F1 vs. F3F4). A non-targeted metabolomics strategy was applied. We analyzed 52 pairs of human HCC and adjacent non-tumoral tissues which included 26 HCC developed in severe fibrosis or cirrhosis (F3F4) and 26 in no or mild fibrosis (F0F1). Tissue extracts were analyzed using 1H-Nuclear Magnetic Resonance spectroscopy. An optimization evolutionary method based on genetic algorithm was used to identify discriminant metabolites. We identified 34 metabolites differentiating the two groups of NAFLD-HCC according to fibrosis level, allowing us to propose two metabolomics phenotypes of NAFLD-HCC. We showed that HCC-F0F1 mainly overexpressed choline derivatives and glutamine, whereas HCC-F3F4 were characterized by a decreased content of monounsaturated fatty acids (FA), an increase of saturated FA and an accumulation of branched amino acids. Comparing HCC-F0F1 and HCC-F3F4, differential expression levels of glucose, choline derivatives and phosphoethanolamine, monounsaturated FA, triacylglycerides were identified as specific signatures. Our metabolomics analysis of HCC tissues revealed for the first time two phenotypes of HCC developed in NAFLD according to fibrosis level. This study highlighted the impact of the underlying liver disease on metabolic reprogramming of the tumor.

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