Year: 2017
Type: article
Abstract: In a cohort of obese Latino and African American children, 9 days of isocaloric restriction decreased liver fat, visceral fat, and de novo lipogenesis, and improved insulin kinetics. In children, high dietary sugar consumption is associated with nonalcoholic fatty liver disease. Fructose has been shown to stimulate hepatic de novo lipogenesis, which may drive the accumulation of liver and visceral fat. In a previous study of weight-stable healthy men, a high fructose diet for 9 days was associated with higher de novo lipogenesis and liver fat compared with an isocaloric diet in which starch was substituted for fructose. In this issue of Gastroenterology, Schwarz et al (with an editorial by Miriam Vos and Michael Goran) report the results of dietary fructose restriction in 26 Latino and 15 African American obese children (15 male and 26 female) of median age 13 years (range, 9-18), body mass index z-score of 2.3 (range, 1.9-3.2), and 48.6% body fat (range, 35.3%-55.9%). Children were fed diets that featured isocaloric substitution of starch for most sugar, resulting in a reduction of total sugar content from 28% to 10% and fructose from 12% to 4% of total energy intake over 9 days. At baseline and on day 10, the children underwent isotope tracer and feeding studies, magnetic resonance imaging and spectroscopy, and measurements of circulating lipoproteins, lipids, insulin, and glucose. After the intervention, liver fat decreased from a median of 7.1% to 3.8% (P < .001) and visceral fat decreased from 123 cm3 to 110 cm3 (P < .001); subcutaneous adipose tissue did not change significantly. Fractional de novo lipogenesis also decreased, and there were increases in measures of insulin sensitivity, secretion, and clearance. Although there was a small but significant decrease in weight (0.9 kg) in the overall cohort, the improvements in each of these outcome measures were consistent even among the subgroup that did not lose weight, as well as across subgroups defined by baseline liver fat content, sex, or race/ethnicity. These results suggest that long-term reductions in fructose intake may be a promising strategy to prevent or reverse nonalcoholic fatty liver disease. See page 743; editorial on page 642. In a secondary analysis of a phase II trial of obeticholic acid in adults with nonalcoholic steatohepatitis, magnetic resonance imaging–estimated proton density fat fraction accurately classifies grades and changes in hepatic steatosis compared with histology. The gold standard for diagnosis of hepatic steatosis, a central feature of nonalcoholic steatohepatitis, is liver biopsy for histologic evaluation. Magnetic resonance imaging (MRI)–estimated proton density fat fraction has been shown to be a promising noninvasive biomarker of hepatic steatosis based on single-center cross-sectional studies and small longitudinal treatment trials. However, an assessment of the diagnostic performance of proton density fat fraction within a prospective multicenter treatment trial would provide important additional validation. In this issue of Gastroenterology, Middleton et al report their analysis of data from nonalcoholic steatohepatitis patients enrolled in FLINT (Farnesoid X Receptor Ligand Obeticholic Acid Trial), a multicenter, randomized, double-blinded, placebo-controlled phase IIb clinical trial of obeticholic acid. Among 283 patients enrolled in the trial, 77 patients underwent assessment of hepatic steatosis by both a centrally read liver biopsy and MRI at baseline and after 72 weeks of treatment with obeticholic acid or placebo. Proton density fat fraction correlated well with histologic hepatic steatosis grade cross-sectionally. At baseline, proton density fat fraction classified grade 0 or 1 steatosis versus grade 2 or 3 steatosis with an area under the receiver operating curve of 0.95 (95% CI, 0.91-0.98) and grade 0 to 2 steatosis versus grade 3 steatosis with an area under the receiver operating curve of 0.96 (95% CI, 0.93-0.99). Change in proton density fat fraction also correlated well with longitudinal change in histologic hepatic steatosis grade. After 72 weeks of treatment with either obeticholic acid or placebo, proton density fat fraction accurately identified participants in which steatosis grade decreased with an area under the receiver operating curve of 0.81 (95% CI, 0.71-0.91) and participants in whom steatosis grade increased with an area under the receiver operating curve of 0.81 (95% CI, 0.63-0.99; Figure 1). These findings demonstrate that, despite using MRI with 2 different field strengths across multiple study sites, proton density fat fraction showed high agreement with histologic steatosis grade. These results support the use of MRI-estimated proton density fat fraction as a noninvasive biomarker of steatosis in either cross-sectional assessments or over longitudinal follow-up. See page 753. T cells isolated from very early diagnosed pediatric and adult celiac disease patients are responsive to a diverse array of gluten antigens. Both demonstrate preferential reactivity toward deamidated gluten. Comparison between populations suggest that T-cell responses are stabilized early in disease development. Celiac disease is an autoimmune disease of the small intestine owing to an autoreactive immune process directed at gluten. Most clinicians are familiar with the clinical manifestations of this disease, including diarrhea, malabsorption, and more commonly in adult populations, iron deficiency anemia, chronic fatigue, neurologic sequela, and vague abdominal pain. Celiac disease has a strong genetic association, in particular with HLA class II allotype HLA-DQ2.5. CD4+ gluten-reactive T cells can be isolated from the intestine of those affected with the disease. Transglutaminase 2 modifies gluten peptides, deamidating them, and it is this deamidated form that the gluten-reactive T cells recognized when presented by disease-associated HLA molecules. Most of these fundamental studies were performed in adult patients, and there are limited data on whether T cells recognize a different set of peptides in pediatric populations. In this issue of Gastroenterology, Ráki et al define immune responses in pediatric patients enrolled in the European PreventCD trial and adults with newly diagnosed celiac disease. This trial was designed to determine if an early gluten challenge could prevent celiac disease in high-risk pediatric populations. Children, 4 to 6 months of age, were randomized to gluten or lactose, blood samples were obtained, and IgA antibodies to transglutaminase 2 and gliadin were measured. Intestinal biopsies were obtained from children suspected of developing the disease. T cells were isolated, and then reactivity to various forms of gluten was evaluated. T cells from both populations had reactivity to a wide spectrum of gluten epitopes, and pediatric T cells lacked predilection for recognizing peptides with native sequences. Most T cells in both populations had preferential recognition for deamidated over native gluten antigen. Thus, T-cell preferences are defined early during disease development and remain stable, even when a diagnosis is made later in life. See page 787. Transcriptomic profiling of hepatocellular carcinoma identifies that approximately 25% of tumors have molecular features that suggest favorable treatment response to immunotherapy. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide. Clear associations predisposing the development of HCC exist, such as ongoing hepatic inflammation from chronic viral infections, alcohol use, and the metabolic syndrome. Recently, molecular features of HCC have been described that advance our understanding of the pathogenesis of this disease. Nevertheless, effective therapy is lacking, with the median life expectancy being <2 years. Recently, immunotherapy has shown remarkable efficacy against solid tumors such as melanoma and lung cancer, although subsets of patients do not respond, and it is thought that certain tumor and immune features may underlie this differential response. In comparison, the immunologic spectrum of HCC is relatively undefined. Sia et al, in this issue of Gastroenterology, identified an immune-specific subtype of HCC by analyzing gene expression data from almost one thousand HCC patients and using a non-negative matrix factorization algorithm to distinguish tumor, stromal, and immune cell signatures. Focusing on the immune signatures, they determined immune regulatory molecule expression patterns in a training set of 228 HCC samples, followed by analysis of a validation cohort of 728 tumor samples. They then determined that roughly one-quarter of HCCs have markers of inflammatory response and could be subdivided into 2 classes (Figure 2). The first, called the adaptive T-cell response group, had a high-level expression of PD-L1 and PD-1 and active interferon-γ signaling; the second, called the exhausted immune response group, was defined by transforming growth factor-β–regulated network activity. Thus, there exist subsets of HCC that may respond favorably to targeted immunotherapy, such as PD-L1, PD-1, or transforming growth factor-β inhibitors. See page 812. Effects of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis, and Insulin Kinetics in Children With ObesityGastroenterologyVol. 153Issue 3PreviewConsumption of sugar is associated with obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. The conversion of fructose to fat in liver (de novo lipogenesis [DNL]) may be a modifiable pathogenetic pathway. We determined the effect of 9 days of isocaloric fructose restriction on DNL, liver fat, visceral fat (VAT), subcutaneous fat, and insulin kinetics in obese Latino and African American children with habitual high sugar consumption (fructose intake >50 g/d). Full-Text PDF Sugar, Sugar . . . Not So Sweet for the LiverGastroenterologyVol. 153Issue 3PreviewIn this issue of Gastroenterology, Schwarz et al1 report on the “Impact of Dietary Fructose Restriction on Liver Fat, De Novo Lipogenesis and Insulin Kinetics in Children with Obesity.” There are 3 recent developments important to the context and impact of the study. First, nonalcoholic fatty liver disease (NAFLD) is highly prevalent in children and the prevalence seems to be increasing.2 NAFLD in children occurs in a setting of excess weight gain and insulin resistance, and it foretells ongoing metabolic decline including type 2 diabetes3 and future cardiovascular disease. Full-Text PDF Similar Responses of Intestinal T Cells From Untreated Children and Adults With Celiac Disease to Deamidated Gluten EpitopesGastroenterologyVol. 153Issue 3PreviewCeliac disease is a chronic small intestinal inflammatory disorder mediated by an immune response to gluten peptides in genetically susceptible individuals. Celiac disease is often diagnosed in early childhood, but some patients receive a diagnosis late in life. It is uncertain whether pediatric celiac disease is distinct from adult celiac disease. It has been proposed that gluten-reactive T cells in children recognize deamidated and native gluten epitopes, whereas T cells from adults only recognize deamidated gluten peptides. Full-Text PDF Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-Assigned Steatosis Grades of Liver Biopsies From Adults With Nonalcoholic SteatohepatitisGastroenterologyVol. 153Issue 3PreviewWe assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference. Full-Text PDF Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular FeaturesGastroenterologyVol. 153Issue 3PreviewAgents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors. Full-Text PDF
Source: Gastroenterology
Authors: Andrew T. Chan, Christopher S. Williams
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,180
OpenAlex ID: W4230422412