Importance Nonalcoholic fatty liver disease (NAFLD) affects about 25% of adults worldwide and is associated with obesity. Weight loss may improve biomarkers of liver disease, but its implications have not been systematically reviewed and quantified. Objective To estimate the association of weight loss interventions with biomarkers of liver disease in NAFLD. Data Sources MEDLINE, Embase, PsycINFO, CINAHL, Cochrane, and Web of Science databases along with 3 trial registries were searched from inception through January 2019. Study Selection Randomized clinical trials of people with NAFLD were included if they compared any intervention aiming to reduce weight (behavioral weight loss programs [BWLPs], pharmacotherapy, and surgical procedures) with no or lower-intensity weight loss intervention. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Data Extraction and Synthesis Two independent reviewers screened the studies, extracted the data, and assessed the risk of bias using the Cochrane tool. Pooled mean differences or odds ratios (ORs) were obtained from random-effects meta-analyses. Main Outcomes and Measures Blood, radiologic, and histologic biomarkers of liver disease. Results Twenty-two studies with 2588 participants (with a mean [SD] age of 45 [14] years and with approximately 66% male) were included. Fifteen studies tested BWLPs, 6 tested pharmacotherapy, and 1 tested a surgical procedure. The median (interquartile range) intervention duration was 6 (3-8) months. Compared with no or lower-intensity weight loss interventions, more-intensive weight loss interventions were statistically significantly associated with greater weight change (–3.61 kg; 95% CI, –5.11 to –2.12;I2 = 95%). Weight loss interventions were statistically significantly associated with improvements in biomarkers, including alanine aminotransferase (–9.81 U/L; 95% CI, –13.12 to –6.50;I2 = 97%), histologically or radiologically measured liver steatosis (standardized mean difference: –1.48; 95% CI, –2.27 to –0.70;I2 = 94%), histologic NAFLD activity score (–0.92; 95% CI, –1.75 to –0.09;I2 = 95%), and presence of nonalcoholic steatohepatitis (OR, 0.14; 95% CI, 0.04-0.49;I2 = 0%). No statistically significant change in histologic liver fibrosis was found (–0.13; 95% CI, –0.54 to 0.27;I2 = 68%). Twelve studies were at high risk of bias in at least 1 domain. In a sensitivity analysis of the 3 trials at low risk of bias, the estimates and precision of most outcomes did not materially change. Conclusions and Relevance The trials, despite some heterogeneity, consistently showed evidence of the association between weight loss interventions and improved biomarkers of liver disease in NAFLD in the short to medium term, although evidence on long-term health outcomes was limited. These findings appear to support the need to change the clinical guidelines and to recommend formal weight loss programs for people with NAFLD.

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Association of Weight Loss Interventions With Changes in Biomarkers of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

Preamble
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing rapidly worldwide as the obese and diabetic populations increase, and it has been estimated to be 20–30% in Korea. Considering the increased popularity of a westernized diet and lifestyle, lack of exercise, and the resulting increase in obesity and diabetes, NAFLD is predicted to become more prevalent in the future and to become a major cause of chronic liver disease. In some patients, NAFLD progresses to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma (HCC), and it is an independent cardiovascular risk factor.

In 2013, the Korean Association for the Study of the Liver (KASL) enacted a clinical practice guideline for the diagnosis and treatment of NAFLD to improve understanding of the disease and provide useful clinical information and direction for healthcare providers. The research results that have accumulated since then necessitate a revision. Accordingly, the clinical practice guidelines committee began revising the guidelines to reflect the results of Korean and international research and develop new recommendations based on a systematic approach that reflects evidencebased medicine and expert opinions. However, evidence remains insufficient, and many studies are currently being conducted. As medical evidence and new findings accumulate in the future, these guidelines will require ongoing supplementation and revision.

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KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease

https://www.gastrojournal.org/article/S0016-5085(20)30222-5/pdf

Therapeutic Landscape for NAFLD in 2020

Fructose is one of the key dietary catalysts in the development of non-alcoholic fatty liver disease (NAFLD). NAFLD comprises a complex disease spectrum, including steatosis (fatty liver), non-alcoholic steatohepatitis (NASH), hepatocyte injury, inflammation, and fibrosis. It is also the hepatic manifestation of the metabolic syndrome, which covers abdominal obesity, insulin resistance, dyslipidemia, glucose intolerance or type 2 diabetes mellitus. Commensal bacteria modulate the host immune system, protect against exogenous pathogens, and are gatekeepers in intestinal barrier function and maturation. Dysbalanced intestinal microbiota composition influences a variety of NAFLD-associated clinical conditions. Conversely, nutritional supplementation with probiotics and preobiotics impacting composition of gut microbiota can improve the outcome of NAFLD. In crosstalk with the host immune system, the gut microbiota is able to modulate inflammation, insulin resistance, and intestinal permeability. Moreover, the composition of microbiota of an individual is a kind of fingerprint highly influenced by diet. In addition, not only the microbiota itself, but also its metabolites influence the metabolism and host immune system. The gut microbiota can produce vitamins and a variety of nutrients including short-chain fatty acids. Holding a healthy balance of the microbiota is therefore highly important. In the present review, we discuss the impact of long-term intake of fructose on the composition of the intestinal microbiota and its biological consequences in regard to liver homeostasis and disease. In particular, we will refer about fructose-induced alterations of the tight junction proteins affecting the gut permeability, leading to the translocation of bacteria and bacterial endotoxins into the blood circulation.

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Fructose: A Dietary Sugar in Crosstalk with Microbiota Contributing to the Development and Progression of Non-Alcoholic Liver Disease.

High fat diet-triggered non-alcoholic fatty liver disease: A review of proposed mechanisms.

Background Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with prevalence above 30% in many adult populations. Strongly associated with obesity, weight loss through diet and physical activity is the mainstay of its management. Weight loss can be difficult to achieve and maintain however, and uncertainty exists as to which lifestyle changes are most effective. Objective The aim of this work was to systematically evaluate randomised controlled trials assessing diet, exercise or combination interventions aimed at reducing steatosis or markers of NAFLD activity. Design Medline, Scopus and Cochrane databases were searched from 1 January 1980 through to 31 July 2016, for intervention trials assessing the effects of diet, weight loss, exercise or any combination thereof, on NAFLD disease markers in human adults. Risk of publication bias and study quality was assessed using the American Dietetic Association Quality Criteria Checklist. Results From a total of...

https://bmjopengastro.bmj.com/content/bmjgast/4/1/e000139.full.pdf

Efficacy of dietary and physical activity intervention in non-alcoholic fatty liver disease: a systematic review

Estrogen is a vital hormone that regulates many biological functions within the body. These include roles in the development of the secondary sexual organs in both sexes, plus uterine angiogenesis and proliferation during the menstrual cycle and pregnancy in women. The varied biological roles of estrogens in human health also make them a therapeutic target for contraception, mitigation of the adverse effects of the menopause, and treatment of estrogen-responsive tumours. In addition, endogenous (e.g. genetic variation) and external (e.g. exposure to estrogen-like chemicals) factors are known to impact estrogen biology. To understand how these multiple factors interact to determine an individual’s response to therapy is complex, and may be best approached through a systems approach. We present a physiologically-based pharmacokinetic model (PBPK) of estradiol, and validate it against plasma kinetics in humans following intravenous and oral exposure. We extend this model by replacing the intrinsic clearance term with: a detailed kinetic model of estrogen metabolism in the liver; or, a genome-scale model of liver metabolism. Both models were validated by their ability to reproduce clinical data on estradiol exposure. We hypothesise that the enhanced mechanistic information contained within these models will lead to more robust predictions of the biological phenotype that emerges from the complex interactions between estrogens and the body. To demonstrate the utility of these models we examine the known drug-drug interactions between phenytoin and oral estradiol. We are able to reproduce the approximate 50% reduction in area under the concentration-time curve for estradiol associated with this interaction. Importantly, the inclusion of a genome-scale metabolic model allows the prediction of this interaction without directly specifying it within the model. In addition, we predict that PXR activation by drugs results in an enhanced ability of the liver to excrete glucose. This has important implications for the relationship between drug treatment and metabolic syndrome. We demonstrate how the novel coupling of PBPK models with genome-scale metabolic networks has the potential to aid prediction of drug action, including both drug-drug interactions and changes to the metabolic landscape that may predispose an individual to disease development.

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Linking physiologically-based pharmacokinetic and genome-scale metabolic networks to understand estradiol biology

Effects of oral lubrication on satiety, satiation and salivary biomarkers in model foods: A pilot study

Background

Ergothioneine is a naturally occurring metabolite of histidine found in many foods and in high amounts in mushrooms. In vivo, ergothioneine acts as an antioxidant and is widely distributed in most mammalian tissues. While ergothioneine is sold as a dietary supplement for its antioxidant and anti-inflammatory properties, to date there are no published intervention trials examining its health benefits in humans. The aim of this work was to develop a study protocol for a pilot interventional trial that will establish the primary and secondary outcomes, and the power required, for a definitive randomised controlled trial to test the hypothesis that ergothioneine supplementation is beneficial for people with metabolic syndrome.



Methods

We have designed the ErgMS study as a single-centre, randomised, double-blind, placebo-controlled, 3-arm parallel, pilot intervention trial, which aims to supplement participants with either placebo, 5 or 30 mg/day ergothioneine for 12 weeks. Measurements of metabolic syndrome risk factors, serum markers of oxidative stress (lipid peroxidation), inflammation, blood platelet function and liver function will take place at baseline, and after 6 weeks and 12 weeks of supplementation. In addition, we will examine if there are any changes in the serum metabolome in response to ergothioneine supplementation. Linear regression and two-way ANOVA will be utilised to analyse the association between ergothioneine and measured variables.



Discussion

The ErgMS study will be the first study to address the question does ergothioneine supplementation have health benefits for people with metabolic syndrome. Study results will provide preliminary data as to which dose may improve inflammatory markers in adults with metabolic syndrome and will inform dose and primary outcome selection for a definitive randomised controlled trial.



Trial registration

ISRCTN, ISRCTN25890011 Registered February 10th, 2021

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Joanna H. Sier

Papers

Efficacy of dietary and physical activity intervention in non-alcoholic fatty liver disease: a systematic review

Linking physiologically-based pharmacokinetic and genome-scale metabolic networks to understand estradiol biology

Effects of oral lubrication on satiety, satiation and salivary biomarkers in model foods: A pilot study

Ergothioneine supplementation in people with metabolic syndrome (ErgMS): protocol for a randomised, double-blind, placebo-controlled pilot study.

Does altering food texture influence appetite and the subsequent food intake?