The correct identification of patients at increased risk of non-alcoholic steatohepatitis (NASH) and advanced fibrosis is a critical step in the assessment of non-alcoholic fatty liver disease ...(NAFLD). Since liver biopsy is invasive, expensive and prone to sampling error, several clinical prediction rules and blood-based biomarkers have been developed as attractive and affordable alternatives for identification of patients at high risk of NASH and advanced fibrosis. Current biomarkers constitute predictive models (e.g. NAFLD fibrosis score, FIB-4 index and BARD score) or direct measures of inflammation (e.g. circulating keratin 18 fragments), or fibrosis (e.g. FibroTest®, ELF™ or Pro-C3 tests). In the clinical setting, biomarkers may discriminate between patients with NASH or advanced fibrosis, predict dynamic changes in NASH/fibrosis over time, and provide long-term prognostic information. Although clinically useful, current biomarker predictions may be influenced by hepatic and extrahepatic conditions (e.g. age, patient comorbidities, and fibrosis or NASH prevalence), which may lead to inaccurate estimates in small subsamples of patients. No highly sensitive and specific tests are available to differentiate NASH from simple steatosis. However, diagnostic accuracy can be improved by combining blood biomarkers. NAFLD fibrosis score and FIB-4 index are both cost-effective and highly sensitive tools to exclude patients with advanced fibrosis. Moreover, their higher scores may identify patients at higher risk of non-liver- and liver-related morbidity and mortality. More expensive tests such as FibroTest or ELF are more specific for detection of patients with significant and advanced fibrosis. Recent efforts have concentrated on “omics” approaches for developing and validating novel biomarkers. Herein, we describe currently available clinical prediction rules and blood-based biomarkers for identifying NASH and advanced fibrosis in patients with NAFLD, discussing their advantages and disadvantages, as well as their potential clinical utility for predicting dynamic changes over time and identifying patients at increased risk of adverse outcomes.
As the epidemics of obesity and type 2 diabetes mellitus increase worldwide, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing proportionately. The subtype of NAFLD which can ...be characterised as non-alcoholic steatohepatitis (NASH) is a potentially progressive liver disease that can lead to cirrhosis, hepatocellular carcinoma, liver transplantation, and death. NAFLD is also associated with extrahepatic manifestations such as chronic kidney disease, cardiovascular disease and sleep apnoea. NAFLD and NASH carry a large economic burden and create poor health-related quality of life. Despite this important burden, we are only beginning to understand its mechanisms of pathogenesis and the contribution of environmental and genetic factors to the risk of developing a progressive course of disease. Research is underway to identify appropriate non-invasive diagnostic methods and effective treatments. Although the risk of liver-related mortality is increased in patients with NAFLD and liver fibrosis stages F3 or F4, the leading cause of death is cardiovascular disease. Given the rapidly growing global burden of NAFLD and NASH, efforts must continue to find accurate non-invasive diagnostic and prognostic biomarkers, to develop effective treatments for individuals with advanced NASH and prevention methods for individuals at high risk of NAFLD and progressive liver disease.
Esculentin-2CHa(1–30) (‟ESC”) has been reported as a potent anti-diabetic peptide with little toxicity. However, its very short plasma residence time severely limits the therapeutic efficacy. To ...address this issue, we genetically engineered a fusion protein of tandem trimeric ESC with an albumin binding domain (ABD) and a fusion partner, SUMO (named ‟SUMO-3 × ESC-ABD”). The SUMO-3 × ESC-ABD, successfully produced from E. coli, showed low cellular and hemolytic toxicity while displaying potent activities for the amelioration of hyperglycemia as well as non-alcoholic fatty liver disease (NAFLD) in vitro. In animal studies, the estimated plasma half-life of SUMO-3 × ESC-ABD was markedly longer (427-fold) than that of the ESC peptide. In virtue of the extended plasma residence, the SUMO-3 × ESC-ABD could produce significant anti-hyperglycemic effects that lasted for >2 days, while both the ESC or ESC-ABD peptides elicited little effects. Further, twice-weekly treatment for 10 weeks, the SUMO-3 × ESC-ABD displayed significant improvement in blood glucose control with a reduction in body weight. Most importantly, a significant improvement in the conditions of NAFLD was observed in the SUMO-3 × ESC-ABD-treated mice. Along the systemic effects (by improved glucose tolerance and body weight reduction), direct inhibition of the hepatocyte lipid uptake was suggested as the major mechanism of the anti-NAFLD effects. Overall, this study demonstrated the utility of the long-acting SUMO-3 × ESC-ABD as a potent drug candidate for the treatment of NAFLD.
Display omitted
Short-term trials have shown a reduction in liver fat when saturated fatty acids (SFAs) are substituted with polyunsaturated fatty acids (PUFA), or with low-glycemic carbohydrates. However, few ...cohort studies have been conducted to investigate the associations of replacing SFA and SFA-rich foods with different macronutrients and foods in more severe stages of liver disease; nonalcoholic fatty liver disease (NAFLD) cirrhosis and hepatocellular carcinoma (HCC).
To investigate associations between the substitution of SFA and SFA-rich foods with other macronutrients and foods and NAFLD cirrhosis and HCC in a middle-aged to elderly Swedish population of n = 77,059 males and females.
Time-to-event analyses were performed to investigate associations between the food and macronutrient substitutions and NAFLD cirrhosis and HCC. Multivariable Cox regression models were constructed to estimate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). Statistical isocaloric and equal-mass substitutions were performed using the leave-one-out method. Prespecified nutrient and food substitutions of interest were SFA with carbohydrates, SFA with fiber, SFA with PUFA, butter with margarine and vegetable oils, unprocessed red meat with fish, and milk with fermented milk.
Over a median follow-up of 24 y, 566 cases of NAFLD cirrhosis and 205 cases of HCC were registered. Overall, dietary substitutions showed no clear associations with either NAFLD cirrhosis or HCC. Substituting SFA with carbohydrates showed an HR of 0.87 (95% CI: 0.74, 1.02) for HCC and 1.00 (95% CI: 0.89, 1.11) for NAFLD cirrhosis. Substituting milk with fermented milk showed an HR of 0.93 (95% CI: 0.85, 1.01) for HCC and 0.97 (95% CI: 0.92, 1.03) for NAFLD cirrhosis.
No clear associations were observed between diet and NAFLD cirrhosis or HCC. Although accompanied by low precision, possible lowered risks of HCC by substituting SFA with carbohydrates or milk with fermented milk might be of interest, but needs replication in other cohorts.
The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and ...metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.
Unraveling the inherent association between diseases and hypochlorous acid (HOCl), within the microenvironments of lipid droplets (LD) remains a formidable task due to the scarcity of research on ...multiple disease models. Intracellular HOCl and microenvironments (such as viscosity and polarity), are crucial in upholding redox balance, orchestrating diffusion, transportation and signal transduction within living cells. Nevertheless, the simultaneous visualization of HOCl alongside viscosity and polarity within the milieu of ferroptosis, inflammation, and neoplasia remains unachieved due to the absence of appropriate analytical tools. In response to this pressing need, we have developed an innovative, multifunctional near infrared (NIR) fluorescent probe, termed NCN, capable of simultaneously monitoring HOCl, viscosity, and polarity within lipid droplets. NCN is characterized by its heightened sensitivity to increased viscosity and decreased polarity, which allows it to target LDs with high specificity. Furthermore, the combined application of HOCl, viscosity, and polarity as diagnostic markers for cancer has been triumphantly demonstrated, encompassing cellular and tissue strata as well as in vivo tumor-bearing mouse models. Therefore, our probe offers a reliable means for understanding LD microenvironments and proposes a promising approach for the diagnostic evaluation of diseases.
Display omitted
•Three novel fluorescent probes were judiciously designed and proposed.•NCN can simultaneously monitor viscosity, polarity, and HOCl in zebrafish.•NCN enables the multifunctional detection of NAFLD, cancer, and inflammation models.
The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content ...experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms “nonalcoholic” and “fatty” were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction–associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction–associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction–associated steatotic liver disease, who consume greater amounts of alcohol per week (140–350 g/wk and 210–420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is common worldwide. Genes and proteins contributing to drug disposition may show altered expression as MASLD progresses. To assess ...this further, we undertook transcriptomic and proteomic analysis of 137 pharmacogenes in liver biopsies from a large MASLD cohort.
We performed sequencing on RNA from 216 liver biopsies (206 MASLD and 10 controls). Untargeted mass spectrometry proteomics was performed on a 103 biopsy subgroup. Selected RNA sequencing signals were replicated with an additional 187 biopsies.
Comparison of advanced MASLD (fibrosis score 3/4) with milder disease (fibrosis score 0–2) by RNA sequencing showed significant alterations in expression of certain phase I, phase II and ABC transporters. For cytochromes P450, CYP2C19 showed the most significant decreased expression (30 % of that in mild disease) but significant decreased expression of other CYPs (including CYP2C8 and CYP2E1) also occurred. CYP2C19 also showed a significant decrease comparing the inflammatory form of MASLD (MASH) with non-MASH biopsies. Findings for CYP2C19 were confirmed in the replication cohort. Proteomics on the original discovery cohort confirmed decreased levels of several CYPs as MASLD advanced but this decrease was greatest for CYP2C19 where levels fell to 40 % control. This decrease may result in decreased CYP2C19 activity that could be problematic for prescription of drugs activated or metabolized by CYP2C19 as MASLD advances. More limited decreases for other P450s suggest fewer issues with non-CYP2C19 drug substrates. Negative correlations at RNA level between CYP2C19 and several cytokine genes provided initial insights into the mechanism underlying decreased expression.
PDF
