Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with a prevalence that is increasing in parallel with the global rise in obesity and type 2 diabetes mellitus. The pathogenesis of NAFLD is complex and multifactorial, involving environmental, genetic and metabolic factors. The role of the diet and the gut microbiome is gaining interest as a significant factor in NAFLD pathogenesis. Dietary factors induce alterations in the composition of the gut microbiome (dysbiosis), commonly reflected by a reduction of the beneficial species and an increase in pathogenic microbiota. Due to the close relationship between the gut and liver, altering the gut microbiome can affect liver functions; promoting hepatic steatosis and inflammation. This review summarises the current evidence supporting an association between NAFLD and the gut microbiome and dietary factors. The review also explores potential underlying mechanisms underpinning these associations and whether manipulation of the gut microbiome is a potential therapeutic strategy to prevent or treat NAFLD.

In the last 20 years, noninvasive serum biomarkers to identify liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) have been developed, validated against liver biopsy (the gold standard for determining the presence of liver fibrosis) and made available for clinicians to use to identify ≥F3 liver fibrosis. The aim of this review is firstly to focus on the current use of widely available biomarkers and their performance for identifying ≥F3. Secondly, we discuss whether noninvasive biomarkers have a role in identifying F2, a stage of fibrosis that is now known to be a risk factor for cirrhosis and overall mortality. We also consider whether machine learning algorithms offer a better alternative for identifying individuals with ≥F2 fibrosis. Thirdly, we summarise the utility of noninvasive serum biomarkers for predicting liver related outcomes (e.g., ascites and hepatocellular carcinoma) and non-liver related outcomes (e.g., cardiovascular-related mortality and extra hepatic cancers). Finally, we examine whether serial measurement of biomarkers can be used to monitor liver disease, and whether the use of noninvasive biomarkers in drug trials for non-alcoholic steatohepatitis can accurately, compared to liver histology, monitor liver fibrosis progression/regression. We conclude by offering our perspective on the future of serum biomarkers for the detection and monitoring of liver fibrosis in NAFLD.

INTRODUCTIONThis study investigated the responses of plasma endotoxin and pro- and antiinflammatory cytokines during a 21-km road race in warm and humid conditions. The influence of carbohydrate-electrolyte (CE)-water (WA) drink mix ingested on leukocyte subset responses and the association between plasma lipopolysaccharide (LPS) concentration and fluid balance, exercise intensity, and body core temperature (Tc) were also studied.

MATERIALS AND METHODSThirty runners provided blood samples before and after the half-marathon for leukocyte, LPS and cytokine analyses. Tc was measured by the ingestible telemetric temperature sensor and fluid intake and split-times were recorded at 3 km intervals. Exercise intensity was determined by matching running speed and heart rate during the race with the corresponding speed-oxygen uptake relationship and heart rate measured in the laboratory 2 to 6 weeks before the race.

RESULTSPlasma LPS concentration increased from 1.9 +/- 1.9 pg/mL before, to 2.5 +/- 1.9 pg/mL after running (P <0.05). Peak plasma LPS concentration was 7.5 pg/mL. Plasma IL-1beta and TNF-concentration did not change significantly, whereas significant increases in IL-10 (50%), IL-1ra (23.2%) and IL-6 (65.2%) were observed after the race. No significant correlation between plasma LPS concentration and exercise intensity, hydration and Tc was observed.

CONCLUSIONLeukocyte subset responses were not related to the ratio of CE and water drink mix ingested. Running a half-marathon can induce mild endotoxaemia, which is not related to exercise intensity, fluid balance, and Tc responses. Mixing CE drink with water did not mitigate postexercise leukocytosis and lymphopenia.

Adult ; Beverages ; Cytokines ; immunology ; Endotoxins ; blood ; immunology ; Fluid Therapy ; Hot Temperature ; Humans ; Humidity ; Leukocytes ; immunology ; Lipopolysaccharides ; immunology ; Male ; Physical Exertion ; physiology ; Running ; physiology

Non-alcoholic fatty liver disease occurring in non-obese subjects (the so-called non-obese NAFLD) is a highly prevalent but neglected liver condition, which is closely associated with metabolic disorders and suboptimal lifestyles. Landmark studies have shown that lifestyle interventions are potentially beneficial in decreasing the risk of developing non-obese NAFLD and in ameliorating NAFLD in non-obese individuals with pre-existing NAFLD. Lifestyle interventions usually refer to changes in eating habits and physical activity, both of which have a powerful effect on non-obese NAFLD and on risk factors for non-obese NAFLD. However, to date, patients and health-care professionals have a poor awareness and understanding of non-obese NAFLD and the beneficial effects of lifestyle interventions in this patient population. The aim of this narrative review is to briefly discuss the evidence for the effects of lifestyle changes and what changes are needed amongst medical personnel and other stakeholders in order to raise awareness of non-obese NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease with a global prevalence of about 55% in people with type 2 diabetes mellitus (T2DM). T2DM, obesity and NAFLD are three closely inter-related pathological conditions. In addition, T2DM is one of the strongest clinical risk factors for the faster progression of NAFLD to non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. Increasing evidence suggests that newer classes of glucose-lowering drugs, such as peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter-2 inhibitors, could reduce the rates of NAFLD progression. This narrative review aims to briefly summarize the recent results from randomized controlled trials testing the efficacy and safety of old and new glucose-lowering drugs for the treatment of NAFLD or NASH in adults both with and without coexisting T2DM.

Biopsy ; Humans ; Liver/pathology* ; Liver Cirrhosis/pathology* ; Non-alcoholic Fatty Liver Disease/pathology*

BACKGROUND: Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH. METHODS: Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL). RESULTS: A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P  < 0.001, P  = 0.026 and P  = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal. CONCLUSION This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.
Humans ; Non-alcoholic Fatty Liver Disease/diagnosis* ; Keratin-18 ; Biomarkers ; Biopsy ; Hepatocytes/pathology* ; Apoptosis ; Liver/pathology*