Endoscopic duodenal mucosal resurfacing for nonalcoholic steatohepatitis (NASH): a pilot study
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SUBMITTER: Hadefi A
PROVIDER: S-EPMC8589546 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Insulin resistance is a core pathophysiological defect underscoring type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). Both conditions improve with duodenal exclusion surgery. Duodenal mucosal resurfacing (DMR) is an endoscopic intervention developed to treat metabolic disease which has been shown to improve glycaemia in patients with poorly controlled T2DM. Herein, we aimed to further analyse the effects of DMR on hepatic and metabolic parameters in this patient cohort. Methods:Eighty-five patients with T2DM who received endoscopic DMR treatment were enrolled from 5 centres and followed up for 6 months. We assessed safety in all patients. Efficacy was evaluated in patients who received at least 9 cm of duodenal ablation (n = 67). Endpoints included HbA1c, fasting plasma glucose, weight and aminotransferase levels. Metabolomic analysis was conducted in a subgroup (n = 14). Data were analysed using paired t test or ANOVA for repeated measures with Bonferroni correction and correction for initial weight loss if applicable. Results:The DMR procedure was completed with no intraprocedural complications in the entire cohort. HbA1c was lower 6 months after DMR than at baseline (7.9 ± 0.2% vs. 9.0 ± 0.2% [mean ± SE], p ?0.001). Fasting plasma glucose was also significantly lower 6 months after DMR compared to baseline (161 ± 7 mg/dl vs. 189 ± 6 mg/dl, p = 0.005). Body weight decreased slightly. At 6 months, alanine aminotransferase had decreased from 41 ± 3 IU/L to 29 ± 2 IU/L (p ?0.001) and aspartate aminotransferase had decreased from 30 ± 2 IU/L to 23 ± 1 IU/L (p ?0.001). Metabolomic analysis demonstrated that DMR had key lipid-lowering, insulin-sensitizing and anti-inflammatory effects, as well as increasing antioxidant capacity. Mean FIB-4 was also markedly decreased. Conclusion:Hydrothermal ablation of the duodenum by DMR elicits a beneficial metabolic response in patients with T2DM. DMR also improves hepatic indices, potentially through an insulin-sensitizing mechanism. These encouraging data deserve further evaluation in randomized controlled trials. Lay summary:Hydrothermal duodenal mucosal resurfacing (DMR) is an endoscopic technique designed to treat metabolic disease through ablation of the duodenal mucosa. DMR is a safe procedure which improves glycaemia and hepatic indices in patients with type 2 diabetes mellitus. DMR is an insulin-sensitizing intervention which can be complementary to lifestyle intervention approaches and pharmacological treatments aimed at preserving the pancreas and liver from failure. DMR is a potential therapeutic solution for patients with type 2 diabetes and fatty liver disease.
| S-EPMC7005649 | biostudies-literature
Project description: Not available
| S-EPMC5989132 | biostudies-literature
Project description:BackgroundThe duodenum has become a metabolic treatment target through bariatric surgery learnings and the specific observation that bypassing, excluding or altering duodenal nutrient exposure elicits favourable metabolic changes. Duodenal mucosal resurfacing (DMR) is a novel endoscopic procedure that has been shown to improve glycaemic control in people with type 2 diabetes mellitus (T2D) irrespective of body mass index (BMI) changes. DMR involves catheter-based circumferential mucosal lifting followed by hydrothermal ablation of duodenal mucosa. This multicentre study evaluates safety and feasibility of DMR and its effect on glycaemia at 24 weeks and 12 months.MethodsInternational multicentre, open-label study. Patients (BMI 24-40) with T2D (HbA1c 59-86 mmol/mol (7.5%-10.0%)) on stable oral glucose-lowering medication underwent DMR. Glucose-lowering medication was kept stable for at least 24 weeks post DMR. During follow-up, HbA1c, fasting plasma glucose (FPG), weight, hepatic transaminases, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), adverse events (AEs) and treatment satisfaction were determined and analysed using repeated measures analysis of variance with Bonferroni correction.ResultsForty-six patients were included of whom 37 (80%) underwent complete DMR and 36 were finally analysed; in remaining patients, mainly technical issues were observed. Twenty-four patients had at least one AE (52%) related to DMR. Of these, 81% were mild. One SAE and no unanticipated AEs were reported. Twenty-four weeks post DMR (n=36), HbA1c (-10±2 mmol/mol (-0.9%±0.2%), p<0.001), FPG (-1.7±0.5 mmol/L, p<0.001) and HOMA-IR improved (-2.9±1.1, p<0.001), weight was modestly reduced (-2.5±0.6 kg, p<0.001) and hepatic transaminase levels decreased. Effects were sustained at 12 months. Change in HbA1c did not correlate with modest weight loss. Diabetes treatment satisfaction scores improved significantly.ConclusionsIn this multicentre study, DMR was found to be a feasible and safe endoscopic procedure that elicited durable glycaemic improvement in suboptimally controlled T2D patients using oral glucose-lowering medication irrespective of weight loss. Effects on the liver are examined further.Trial registration numberNCT02413567.
| S-EPMC6984054 | biostudies-literature
Project description:The proportion of obese or diabetic population has been anticipated to increase in the upcoming decades, which rises the prevalence of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). Recent evidence indicates that NASH is the main cause of chronic liver diseases and it is an important risk factor for development of hepatocellular carcinoma (HCC). Although the literature addressing NASH-HCC is growing rapidly, limited data is available about the etiology of NASH-related HCC. Experimental studies on the molecular mechanism of HCC development in NASH reveal that the carcinogenesis is relevant to complex changes in signaling pathways that mediate cell proliferation and energy metabolism. Genetic or epigenetic modifications and alterations in metabolic, immunologic, and endocrine pathways have been shown to be closely related to inflammation, liver injury, and fibrosis in NASH along with its subsequent progression to HCC. In this review, we provide an overview on the current knowledge of NASH-related HCC development and emphasize molecular signaling pathways regarding their mechanism of action in NASH-derived HCC.
| S-EPMC6136489 | biostudies-literature
Project description:Nonalcoholic steatohepatitis (NASH) is a key step in the progression of nonalcoholic fatty liver (NAFL) to cirrhosis. However, the molecular mechanisms of the NAFL-to-NASH transition are largely unknown. Here, we identify methyltransferase like 3 (METTL3) as a key negative regulator of NASH pathogenesis. Hepatocyte-specific deletion of Mettl3 drives NAFL-to-NASH progression by increasing CD36-mediated hepatic free fatty acid uptake and CCL2-induced inflammation, which is due to increased chromatin accessibility in the promoter region of Cd36 and Ccl2. Antibody blockade of CD36 and CCL2 ameliorates NASH progression in hepatic Mettl3 knockout mice. Hepatic overexpression of Mettl3 protects against NASH progression by inhibiting the expression of CD36 and CCL2. Mechanistically, METTL3 directly binds to the promoters of the Cd36 and Ccl2 genes and recruits HDAC1/2 to induce deacetylation of H3K9 and H3K27 in their promoters, thus suppressing Cd36 and Ccl2 transcription. Furthermore, METTL3 is translocated from the nucleus to the cytosol in NASH, which is associated with CDK9-mediated phosphorylation of METTL3. Our data reveal a mechanism by which METTL3 negatively regulates hepatic Cd36 and Ccl2 gene transcription via a histone modification pathway for protection against NASH progression.
| S-EPMC8664922 | biostudies-literature
Project description:Tumor necrosis factor-alpha (TNF-alpha) is implicated in non-alcoholic steatohepatitis (NASH). Pentoxifylline inhibits TNF-alpha. We wanted to evaluate the efficacy of Pentoxifylline on NASH patients.Patients with biopsy proven NASH and persistently elevated alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal were randomized to 3 months of treatment with a step 1 American Heart Association diet and daily exercise with Pentoxifylline or placebo. Liver function tests, serum lipids and TNF-alpha, Interleukin 6 (IL-6), and plasma hyaluronic acid were measured at baseline, at weeks 6 and 12. Categorical data were analyzed by Fisher's exact test while independent sample t-test and Mann-Whitney test were used for continuous data.Eleven patients were randomized into the Pentoxifylline and nine to the placebo group. After 3 months of treatment body mass index (BMI), ALT and aspartate aminotransferase (AST) decreased significantly in both groups. There was no difference between the two groups in reduction of BMI (P = 0.897). There was significantly greater reduction in AST in the Pentoxifylline group (P = 0.038). There was a trend toward lower ALT level (P = 0.065) in the Pentoxifylline group. TNF-alpha and IL-6 decreased significantly in both groups after treatment, but there was no significant difference between the two groups.Three months of Pentoxifylline treatment in combination with diet and exercise results in significantly greater reduction in AST levels in patients with NASH as compared with controls.
| S-EPMC2716847 | biostudies-other
Project description:BackgroundThere is limited data on the comparative economic and humanistic burden of non-alcoholic steatohepatitis (NASH) in the United States. The objective was to examine the burden of disease comparing NASH to a representative sample of the general population and separately to a type 2 diabetes mellitus (T2DM) cohort by assessing health-related quality of life (HRQoL) measures, healthcare resource use (HRU) and work productivity and activity impairment (WPAI).MethodsData came from the 2016 National Health and Wellness Survey, a nationally representative patient-reported outcomes survey conducted in the United States. Respondents with physician-diagnosed NASH, physician-diagnosed T2DM, and respondents from the general population were compared. Humanistic burden was examined with mental (MCS) and physical (PCS) component summary scores from the Short-Form (SF)-36v2, concomitant diagnosis of anxiety, depression, and sleep difficulties. Economic burden was analysed based on healthcare professional (HCP) and emergency room (ER) visits, hospitalizations in the past six months; absenteeism, presenteeism, overall work impairment, and activity impairment scores on WPAI questionnaire. Bivariate and multivariable analysis were conducted for each outcome and matched comparative group.ResultsAfter adjusting for baseline demographics and characteristics, NASH (N = 136) compared to the matched general population cohort (N = 544), reported significantly lower (worse) mental (MCS 43.19 vs. 46.22, p = 0.010) and physical (PCS 42.04 vs. 47.10, p < 0.001) status, higher % with anxiety (37.5% vs 25.5%, p = 0.006) and depression (43.4% vs 30.1%, p = 0.004), more HCP visits (8.43 vs. 5.17), ER visits (0.73 vs. 0.38), and hospitalizations (0.43 vs. 0.2) all p's < 0.05, and higher WPAI scores (e.g. overall work impairment 39.64% vs. 26.19%, p = 0.011). NASH cohort did not differ from matched T2DM cohort (N = 272) on mental or work-related WPAI scores, but had significantly worse physical status (PCS 40.52 vs. 44.58, p = 0.001), higher % with anxiety (39.9% vs 27.8%, p = 0.043), more HCP visits (8.63 vs. 5.68, p = 0.003) and greater activity impairment (47.14% vs. 36.07%, p = 0.010).ConclusionThis real-world study suggests that burden of disease is higher for all outcomes assessed among NASH compared to matched general controls. When comparing to T2DM, NASH cohort has comparable mental and work-related impairment but worse physical status, daily activities impairment and more HRU.
| S-EPMC10077759 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries with almost 25% affected adults worldwide. The growing public health burden is getting evident when considering that NAFLD-related liver transplantations are predicted to almost double within the next 20 years. Typically, hepatic alterations start with simple steatosis, which easily progresses to more advanced stages such as nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. This course of disease finally leads to end-stage liver disease such as hepatocellular carcinoma, which is associated with increased morbidity and mortality. Although clinical trials show promising results, there is actually no pharmacological agent approved to treat NASH. Another important problem associated with NASH is that presently the liver biopsy is still the gold standard in diagnosis and for disease staging and grading. Because of its invasiveness, this technique is not well accepted by patients and the method is prone to sampling error. Therefore, an urgent need exists to find reliable, accurate and noninvasive biomarkers discriminating between different disease stages or to develop innovative imaging techniques to quantify steatosis.
| S-EPMC6721710 | biostudies-literature
Project description:Background and aimsNonalcoholic steatohepatitis (NASH) is considered as a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression, given that it paves the way for severe liver injuries such as fibrosis and cirrhosis. The etiology of human NASH is multifactorial, and identifying reliable molecular players and/or biomarkers has proven difficult. Together with the inappropriate consideration of risk factors revealed by epidemiological studies (altered glucose homeostasis, obesity, ethnicity, sex, etc.), the limited availability of representative NASH cohorts with associated liver biopsies, the gold standard for NASH diagnosis, probably explains the poor overlap between published "omics"-defined NASH signatures.Approach and resultsHere, we have explored transcriptomic profiles of livers starting from a 910-obese-patient cohort, which was further stratified based on stringent histological characterization, to define "NoNASH" and "NASH" patients. Sex was identified as the main factor for data heterogeneity in this cohort. Using powerful bootstrapping and random forest (RF) approaches, we identified reliably differentially expressed genes participating in distinct biological processes in NASH as a function of sex. RF-calculated gene signatures identified NASH patients in independent cohorts with high accuracy.ConclusionsThis large-scale analysis of transcriptomic profiles from human livers emphasized the sexually dimorphic nature of NASH and its link with fibrosis, calling for the integration of sex as a major determinant of liver responses to NASH progression and responses to drugs.
| S-EPMC8048532 | biostudies-literature
Project description:To investigate the role of hepatic CYP2B in diet-induced nonalcoholic steatohepatitis (NASH), a Cyp2b triple knockout mouse lacking Cyp2b9, Cyp2b10, and Cyp2b13 was developed using CRISPER/Cas9. Wildtype (WT) and Cyp2b-null mice were fed a normal diet (ND) or a choline-deficient, L-amino acid-defined high-fat diet (CDAHFD), containing 0.1% methionine and 62% fat for 8 weeks. RNA was extracted from the livers of female and male mice from all treatment groups and used for RNA seqencing. RNAseq data demonstrated that a lack of Cyp2b was protective in female but more harmful in male mice. Hepatic gene expression revealed a higher number of phase I-III xenobiotic metabolism and inflammatory response genes were down-regulated in CDAHFD-fed WT female and Cyp2b-null male mice.
2019-12-31 | GSE137449 | GEO