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Mechanobiology is a rapidly emerging field focused on the biological impact of physical forces at the molecular, cellular, and tissue level. Living cells perceive mechanical cues and transform them into biochemical signals through mechanotransduction. Mechanotransduction is a complex process that involves mechanosensors (which are located in the plasma membrane or within the cell) and mechanotransmission to the nucleus (which occurs either by physical connection between the mechanosensor and the nucleus or by mechanosignaling through biochemical pathways). Essential biological functions, including development, growth, motility, and metabolism, depend on the mechanoresponses generated by these events. Multiple lines of evidence indicate that disruption of mechanical homeostasis may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a highly prevalent metabolic disorder characterized by abnormal accumulation of lipid droplets in hepatocytes (steatosis) and often associated with inflammation and liver cell injury (steatohepatitis). While predicting individual predisposition to adverse outcomes in NAFLD remains a challenge, there is increasing evidence that steatosis and steatohepatitis trigger mechanoresponses that contribute to the early stages of pathogenesis in NAFLD and critically impact disease progression. Lipid accumulation and lipotoxicity modify liver viscoelasticity, alter the biomechanics of liver sinusoids, and initiate aberrant pathways of mechanotransduction in hepatocytes and non-parenchymal liver cells, such as sinusoidal endothelial cells and hepatic stellate cells. Interactions of these cells at mechanical interfaces with each other, with extracellular matrix, and with sinusoidal blood flow are profoundly altered by steatosis and steatohepatitis; such changes may promote a pro-angiogenic and pro-fibrotic milieu. A better understanding of liver mechanobiology may facilitate the identification of novel molecular and cellular targets in the management of NAFLD.Highlights● Cellular and molecular behavior is regulated by a variety of physical forces;● Viscoelastic properties of the liver are altered in non-alcoholic fatty liver disease (NAFLD);● Sinusoidal hemostasis is disrupted by early functional and structural changes in NAFLD;● Mechanical cues are likely to contribute to all aspects of NAFLD pathogenesis. LESS      Full article

Liver fibrosis is critical for liver-related outcomes and mortality in chronic liver disease, irrespective of etiology, including nonalcoholic fatty liver disease (NAFLD). NAFLD has been viewed as an independent correlate of cardiovascular risk. This review article briefly describes the cellular and molecular pathomechanisms underlying hepatic fibrosis. We then address noninvasive assessment of liver fibrosis. Finally, we discuss published evidence supporting fibrosis biomarkers’ role in assessing cardiovascular risk among patients with NAFLD. While histological assessment is the diagnostic standard of hepatic fibrosis, we specifically address noninvasive techniques, including equations based on anthropometric parameters, laboratory indices, and elastometry obtained with imaging techniques. The former group includes AST: ALT ratio, the Forns Index, the AST-to-platelet ratio index score, BARD (BMI, AAR, Diabetes) score, the fibrosis-4 index (FIB-4), the NAFLD fibrosis score, the gamma-glutamyl transferase-to-platelet ratio, and the Hepamet fibrosis score. The latter comprises elastographic techniques associated with ultrasonography or magnetic resonance. Our literature review identified numerous studies demonstrating that biomarkers of fibrosis (the most common being FIB-4) and elastographic techniques predict overall mortality and major cardiovascular events among NAFLD patients. The mechanisms accounting for this association are briefly reviewed. In addition to assessing hepatic fibrosis at baseline, during follow-up, and after therapeutic interventions in NAFLD patients, noninvasive assessment of hepatic fibrosis may predict cardiovascular events and overall mortality in these patients. LESS      Full article

Aim: The Global burden of nonalcoholic fatty liver disease (NAFLD) has significantly increased recently, with its prevalence mirroring increasing obesity and diabetes. However, population-specific evidence for young adults remains limited. Herein, we provide a 20-year trend analysis of NAFLD in young adults and examine factors associated with NAFLD and major adverse cardiovascular events (MACE) prevalence.Methods: This study uses data from the United States National Health and Nutrition Examination Survey (NHANES) 1999-2018. Fatty liver was examined with the fatty liver index (FLI) and United States-FLI (US-FLI), and advanced fibrosis was examined with the fibrosis-4 index. Clustered multivariate logistic regression analysis on the year of study was applied to obtain odds ratios (OR) for the estimation of events.Results: 13.31% (95%CI: 12.71% to 13.94%) of young adults had NAFLD. The prevalence increased from 9.98% in 1999 to 19.49% in 2018, with a statistically significant trend (P < 0.001). 9.52% and 5.29% of patients have clinically significant and advanced fibrosis, respectively. In multivariate analysis, diabetes (3.48, 95%CI: 2.37 to 5.11), hypertension (2.03, 95%CI: 1.62 to 2.55), elevated body mass index (1.22, 95%CI: 1.20 to 1.23, P < 0.001) significantly increases odds of NAFLD. The largest increase in odds was related to obesity (OR: 21.61, 95%CI: 16.95 to 27.55, P < 0.001). Young adults with NAFLD had a borderline non-significant increase in the prevalence of MACE compared to individuals without NAFLD (OR: 1.603, 95%CI: 0.949 to 2.708, P = 0.078).Conclusion: The rising prevalence of NAFLD in young adults depicts the changing landscape of NAFLD and its association with a significant increase in MACE. The challenge of effective risk stratification and education of these individuals remains. LESS      Full article

Aim: Metabolic liver diseases, including alcohol- and non-alcoholic fatty liver diseases (ALD/NAFLD), are characterized by inflammation and decreased ability to prevent infections. Patients with severe alcohol-associated hepatitis (sAH) are particularly susceptible to infections while undergoing treatment with steroids. Understanding the immunological mechanisms for these responses is critical to managing the treatment of patients with metabolic liver diseases. Cytotoxic NK cells and CD8 T cells, using cytolytic granules, serve an important immunological role by killing infected cells, including monocytes. However, patients with sAH have dysfunctional NK cells, which cannot kill target cells, though the mechanism is unknown.Method: We performed an exploratory study using single-cell RNA-seq (scRNA-seq) (n = 4) and multi-panel intracellular flow cytometry (n = 7-8 for all patient groups) on PBMCs isolated from patients with sAH and healthy controls (HC). Results: ScRNA-seq revealed receptors in NK cells and CD8 T cells required for cytotoxic cell recognition of activated monocytes were downregulated in patients with sAH compared to healthy controls. Granulysin was the most downregulated gene in both NK cells and effector CD8 T cells. In NK cells from HC, expression of granulysin, perforin, and granzymes A and B was highly correlated; however, in sAH, these genes lost coordinate expression, indicative of dysfunctional cytolytic granule formation. Finally, the expression of cytolytic granule proteins in NK cells was decreased from sAH, indicating reduced cytolytic granules.Conclusion: Together, these results suggest a loss of cytotoxic cell function in PBMCs from sAH that may contribute to a decreased ability to communicate with other immune cells, such as monocytes, and prevent the killing of infected cells, thus increasing the risk of infection. LESS      Full article

This concise review article critically examines the recent medical literature regarding gamma glutamyl transferase (GGT) with a special emphasis on newly proposed indications for GGT use, including cardiovascular risk assessment.GGT is a ubiquitous glycosylated protein embedded in the outer surface of cell membranes, which catalyzes the transfer of glutamyl groups from various substrates and plays a key role in the antioxidant/pro-oxidant balance. In the past, the enzyme was considered a non-specific liver test. Current evidence supports the role of GGT in the assessment of portal hypertension in cystic fibrosis, porto-sinusoidal vascular disease, malignant mesothelioma, and incident type 2 diabetes and as a biomarker of cardiometabolic risk and cardiovascular disease.Several specific points including the use of GGT in hepatology as a sensitive but poorly specific test and the association of GGT with metabolic syndrome, nonalcoholic fatty liver disease and its fibrotic stages, cardiometabolic risk, chronic kidney disease, neurodegenerative disorders and dementia, idiopathic pulmonary arterial hypertension, and Corona Virus Disease 2019 (COVID-19) are addressed based on the most recent research in these fields. Putative mechanisms linking GGT with increased metabolic stress and the effects of various therapeutic interventions on GGT values are also discussed. We conclude that GGT has evolved from an indiscriminate liver test and an index of alcohol consumption to a biomarker of cardiometabolic health. The proper interpretation of GGT values (i.e., of hepatic vs. extrahepatic origin) is deeply affected by the clinical and epidemiological context. We propose that GGT may be utilized in public health campaigns, in the research arena, and in clinical practice to identify those individuals who can benefit most from the proactive preventive and therapeutic approaches, given that they are at high cardiometabolic risk. LESS      Full article

Aim: Obesity and co-existing metabolic comorbidities are associated with increased cardiovascular (CV) morbidity and mortality risks, generally clustered to risk factors such as dyslipidemia. The aim of this study was to evaluate the lipid profile changes in subjects with severe obesity undergoing different procedures of bariatric and metabolic surgery (BMS), sleeve gastrectomy (SG), and Roux-en-Y gastric bypass (RYGB) in a real-world, clinical setting.Methods: A single-center, retrospective, observational clinical study was performed enrolling patients undergoing BMS. The primary outcome was the change in total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, and triglycerides.Results: In total, 123 patients were enrolled (males 25.2% and females 74.8%) with a mean age of 48.2 ± 7.9 years and a mean BMI of 47.0 ± 9.1 kg/m². All patients were evaluated until 16.9 ± 8.1 months after surgery. Total and HDL cholesterol did not change after surgery, while a significant reduction in triglyceride levels was recorded. Moreover, a rapid decline of both LDL and non-HDL cholesterol among follow-up visits was observed. In particular, significant inverse correlations were found between total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides and the number of months elapsed after bariatric surgery. Similarly, a direct correlation was found considering HDL cholesterol. Moreover, total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides significantly changed among visits after RYGB, while no changes were observed in the SG group. Finally, considering lipid-lowering therapies, the improvement in lipid asset was detected only in non-treated patients.Conclusion: This study corroborates the knowledge of the improvement in lipid profile with BMS in clinical practice. Together with sustained weight loss, the BMS approach efficiently corrects dyslipidemia, contributing to decreasing the CV risk. LESS      Full article

More than 100 years after the discovery of insulin, the exact etiology and pathophysiology of type 1 diabetes (T1D) remains elusive, but our knowledge is growing. This leads to louder calls to initiate a risk screening for T1D in the general population. This risk screening could be based on the genetic risk (in the general population or targeted HLA genotyping in family members of persons with T1D) or on the screening for autoantibodies in blood (e.g., antibodies against insulin, GAD, IA2, or ZnT8). The presence of autoantibodies is known to convey a clearly increased risk of progressing to T1D, particularly when two or more antibody types are present. It remains a point of discussion whether screening efforts are cost-effective. At present, in the absence of interventions capable of delaying the onset of disease, the only benefit of screening is the earlier diagnosis of T1D, thus avoiding life-threatening diabetic ketoacidosis (DKA). Nevertheless, large consortia (e.g., INNODIA and TrialNet) are currently focusing on not only disease biomarkers but also biomarkers of therapeutic effect of interventions. All hope is thus focused on the arrival of intervention strategies that could arrest the ongoing immune destruction of the beta cell and thus delay clinical disease onset. Thus far, attempts have focused on either protecting the beta cell or arresting the immune response, but the future seems to be one of combination therapy. Here, we perform a scoping review on the pathogenesis of T1D, discuss screening strategies, and present promising intervention strategies. LESS      Full article

Obesity, the metabolic syndrome, and metabolic dysfunction-associated fatty liver disease (MAFLD) can be portrayed as transmissible diseases. Indeed, they can be induced, in animal models, by cohabitation or by transplantation of fecal microbiota from other animals or humans with those diseases. As such, to get a 10,000-foot view, we need to see under the lens the microbes that populate our gut. Gut microbiota participates in the harvesting of energy from nutrients, it allows the digestion of otherwise indigestible nutrients such as fibers, and it also produces short chain fatty acids and some vitamins while emitting different compounds that can regulate whole-body metabolism and elicit proinflammatory responses. The metabolic syndrome and MAFLD share physiopathology and also patterns of gut dysbiota. Moreover, MAFLD also correlates with dysbiota patterns that are associated with direct steatogenic or fibrogenic effects. In the last decade, a tremendous effort has allowed a fair understanding of the dysbiota patterns associated with MAFLD. More recently, research is moving towards the delineation of microbiota-targeted therapies to manage metabolic dysfunction and MAFLD. This review provides in-depth insight into the state-of-the-art of gut dysbiosis in MAFLD, targeting clinical hepatologists. LESS      Full article

People with diabetes mellitus (DM) undergo more elective surgery than those without DM; however, up to half of the patients are undiagnosed when referred for surgery. This is an opportunity to intervene and instigate a management plan. Preoperative strategies may vary based on coexisting medical diseases such as obesity and the availability of resources with the aim of achieving glycaemic control while also treating coexisting conditions. In the context of obesity, there is substantial overlap in some of the treatment strategies. Guidelines, such as those from the UK Centre for Perioperative Medicine, suggest target glycated haemoglobin levels, preoperative fasting blood glucose levels, and when to defer an elective operation or instigate treatment to proceed if deemed safe. Preoperatively glycaemic control is often achieved pharmacologically, and newer agents, including glucagon-like peptide one receptor agonists (GLP1-RA) and sodium-glucose co-transporter 2 (SGLT2) inhibitors, are emphasised in the preoperative management of diabetes mellitus, particularly if obesity is also present. A very low-energy diet is an underutilised but well-evidenced method of achieving both glycaemic control and weight loss with a particularly dominant effect on liver fat which is helpful for people who are due to undergo abdominal surgery. Bariatric-metabolic procedures are of growing interest as bridging interventions to surgery and are more commonly used for obesity, but they also have a well-recognized impact on the improvement and remission of DM. This review gives an overview of the necessity of preoperative identification of DM and strategies for management. Intra-operative glycaemic control is also discussed, and the role of stress hyperglycaemia perioperatively. LESS      Full article

Primary nonalcoholic fatty liver disease (NAFLD) is bi-directionally associated with the metabolic syndrome and its constitutive features (“factors”: impaired glucose disposal, visceral obesity, arterial hypertension, and dyslipidemia). Secondary NAFLD occurs due to endocrinologic disturbances or other cofactors. This nosography tends to be outdated by the novel definition of metabolic associated fatty liver disease (MAFLD). Irrespective of nomenclature, this condition exhibits a remarkable pathogenic heterogeneity with unpredictable clinical outcomes which are heavily influenced by liver histology changes. Genetics and epigenetics, lifestyle habits [including diet and physical (in)activity] and immunity/infection appear to be major cofactors that modulate NAFLD/MAFLD outcomes, including organ dysfunction owing to liver cirrhosis and hepatocellular carcinoma, type 2 diabetes, chronic kidney disease, heart failure, and sarcopenia. The identification of cofactors for organ dysfunction that may help understand disease heterogeneity and reliably support inherently personalized medicine approaches is a research priority, thus paving the way for innovative treatment strategies. LESS      Full article

Aim: The optimal screening strategy for advanced liver fibrosis in overweight and obese patients is unknown. The aim of this study is to compare the performance of different strategies to select patients at high risk of advanced liver fibrosis for screening using non-invasive tools.Methods: All patients underwent: liver ¹H-MRS and percutaneous liver biopsy (in those with nonalcoholic fatty liver disease [NAFLD]). Unique selection strategies were compared to determine the best screening algorithm: (A) A "metabolic approach": selecting patients based on HOMA-IR ≥ 3; (B) A "diabetes approach": selecting only patients with type 2 diabetes; (C) An "imaging approach": selecting patients with hepatic steatosis based on ¹H-MRS; (D) A "liver biochemistry approach": selecting patients with elevated ALT (i.e., ≥ 30 IU/L for males and ≥ 19 IU/L for females); and (E) Universal screening of overweight and obese patients. FIB-4 index, NAFLD fibrosis score, and APRI were applied as screening strategies.Results: A total of 275 patients were included in the study. Patients with advanced fibrosis (n = 29) were matched for age, gender, ethnicity, and BMI. Selecting patients by ALT elevation provided the most effective strategy, limiting the false positive rate while maintaining the sensitivity compared to universal screening. Selecting patients by any other strategy did not contribute to increasing the sensitivity of the approach and resulted in more false positive results.Conclusion: Universal screening of overweight/obese patients for advanced fibrosis with non-invasive tools is unwarranted, as selection strategies based on elevated ALT levels lead to the same sensitivity with a lower false positive rate (i.e., fewer patients that would require a liver biopsy or referral to hepatology). LESS      Full article

Low density lipoproteins (LDL) reduction remains the key goal for reducing the risk of atherosclerotic cardiovascular diseases (CVD) in people with high residual risk and metabolic complications including liver disease. Notwithstanding, epidemiological projections support a key role of liver-derived apolipoprotein B (ApoB) containing lipoproteins, namely very low density lipoproteins (VLDL) and their “remnants” (TG), undergoing the activity of lipases, in eliciting atherosclerotic inflammatory sequelae of a comparable order of magnitude to that of LDL. Disparate experimental evidence supports that triglycerides (TG), residual cholesterol content, or the large apolipoprotein set on the surface of these lipoproteins can elicit a number of plausible immune-inflammatory mechanisms that foster the vascular atherosclerotic process. Therapeutic options that convincingly lowered the plasma levels of liver-derived ApoB containing lipoproteins, either by reducing the hepatic synthesis or by improving the peripheral lipolysis of the lipid content, did not exert robust CVD risk reduction, and the effect on inflammation was questionable. Understanding the mechanisms linking liver-derived lipoproteins with chronic inflammation will provide pathophysiological insights for the identification of new therapeutic targets for people at high CVD risk and with metabolic complications. In this perspective, this topic is of immediate interest for the prevention of CVD in patients affected by non-alcoholic fatty liver disease (NAFLD) and, even more, for NAFLD patients with diabetes, insulin resistance, or other comorbidities (metabolic-associated fatty liver disease). This review resumes the principal physio-pathological insights regarding the metabolism of liver-derived lipoproteins and provides an update on the current pharmacological options that can be considered for improving CVD prevention in metabolic liver diseases. LESS      Full article

Metabolism and cancer intersect in multiple ways. Cancer has unique metabolic properties, including an inordinate reliance on anaerobic glycolysis (the Warburg effect). From an evolutionary standpoint, increased cancer incidence is associated with increased metabolic rates across species. Epidemiological data prove that a group of overlapping metabolic alterations, including obesity, type 2 diabetes Mellitus, nonalcoholic fatty liver disease, and metabolic syndrome, constitute predisposing risk factors for cancer development in multiple anatomical sites. The molecular pathways underpinning this association involve hyperinsulinemia, hyperglycemia, sex hormones, adipokines, chronic inflammation, oxidative stress, and altered immune response. LESS      Full article

Nonalcoholic fatty liver disease (NAFLD) represents one of the most diffuse liver diseases worldwide. It is a condition ranging from liver steatosis to non-alcoholic steatohepatitis (NASH) and NASH-related cirrhosis. Recently, the term metabolic dysfunction-associated fatty liver disease has been proposed in place of NAFLD, accenting the metabolic and cardiovascular risks that accompany hepatic disease. In the last decades, NASH and NASH-related cirrhosis have been the fastest growing indications for liver transplantation (LT), and they will probably overcome the other indications in next future. After LT, recipients show an important increase in body weight due to a greater caloric intake, partially because of the metabolic influence of immunosuppressant drugs, favoring the development of diabetes mellitus, dyslipidemias, and arterial hypertension. These metabolic complications will, in turn, elevate cardiovascular risk in this population. In this review, we analyze the main metabolic challenges of both pre-and post-LT periods. LESS      Full article

This perspective article aims at addressing the potential commonalities associated with chronic obstructive pulmonary disease (COPD) and the two metabolic fatty liver syndromes: nonalcoholic fatty liver disease (NAFLD) and metabolic (associated) fatty liver disease (MAFLD). To this end, we briefly review the definitions and burdens of COPD and NAFLD and highlight the differences in the diagnostic criteria of NAFLD and MAFLD. We also critically discuss the recent line of research trying to identify an association between COPD and NAFLD. Moreover, among the chief co-morbidities of COPD patients, we identify significant six that exert a major impact on the natural course of COPD: major cardiovascular events, cardiac arrhythmias, metabolic syndrome, obstructive sleep apnea, osteoporosis, and psychodepression. The potential role of NAFLD in each of these COPD co-morbidities is accurately examined based on published studies. We conclude that both COPD and NAFLD/MAFLD are heterogeneous systemic syndromes. While the complex mechanistic links underlying the association of NAFLD/MAFLD with COPD and its co-morbidities remain to be fully elucidated, we highlight that the diagnosis of metabolic fatty liver syndromes in patients with COPD might be clinically relevant, as it might allow identifying a subset of COPD individuals who, being at risk of severe clinical outcomes, would need more comprehensive treatment approaches. LESS      Full article

Hepatitis C virus (HCV) is still considered as a major public health problem because in 2015 around 71 million people were chronically infected worldwide. It is important to note that chronic HCV infection is a systemic disease that is associated with diverse extrahepatic disorders including insulin resistance and type 2 diabetes mellitus. The discovery of new direct-acting antiviral agents (DAAs) has become a huge advance in the treatment of HCV infection. The complex interplay between HCV and glucose metabolic pathways remains to be fully elucidated, but it is becoming clearer that elimination of chronic HCV infection halts the progression of liver disease, but more evidence is still needed to better understand how successful antiviral treatment influences insulin resistance and other abnormalities of glucose metabolism linked to HCV infection. This review provides a comprehensive overview of the glucose metabolism disturbances related to chronic HCV infection, highlighting the new insights into the molecular basis of insulin resistance induced by HCV and the mechanisms underlying the reversion of this metabolic disorder by DAAs. LESS      Full article

Nonalcoholic fatty liver disease (NAFLD) onset and its progression towards nonalcoholic steatohepatitis (NASH) features increased intestinal permeability and leaky gut, thereby favoring the escape of endotoxin [lipopolysaccharides (LPS)] from the gut to the liver. The aim of this study was to resemble the crosstalk between intestine and liver during NAFLD by using an in vitro model of co-culture system. Enterocytes (Caco-2) were seeded on Transwell filters (pore size: 0.4 μm) and cultured for 21 days to constitute a confluent monolayer, and then they were co-cultivated with hepatocytes (HepG2) for an additional 24 h. Caco-2 on the apical chamber were exposed to LPS and/or a mixture of palmitic and oleic acid (PAOA) for 24 h. FITC-4000 dextrans (FD4) permeability across Caco-2 monolayer was increased by the treatment of Caco-2 cells with PAOA and LPS, consistently with tight junction-associated proteins reduction. Caco-2 exposure to PAOA/LPS promoted ApoB, triglyceride (TG), and free fatty acid secretion in basolateral media. In turn, HepG2 co-cultured with Caco-2 exposed to LPS, PAOA, or both accumulated lipid droplets and increased intracellular TG content. Likewise, Caco-2 released pro-inflammatory cytokines in basolateral media. These events triggered endoplasmic reticulum (ER) and oxidative stress, enhancing reactive oxygen species (ROS), H₂O₂, aldehyde derivate production, and ROS-induced DNA damage in HepG2 cells. Hence, Caco-2/HepG2 co-culture system may faithfully reproduce the breach in the intestinal barrier integrity that occurs in NAFLD, thus resulting in the increased inflammatory response and ER and oxidative and stress, which promote the switch towards NASH. LESS      Full article

Aims: Prior evidence demonstrates an association between non-alcoholic fatty liver disease (NAFLD) and colorectal adenomas (CRA) risk. However, information using the new definition of the disease [i.e., metabolic dysfunction-associated fatty liver disease (MAFLD)] is scarce. We aimed to assess the relationship between MAFLD and CRA risk.Methods: We conducted a cross-sectional study including patients from three university centers in Chile who underwent a colonoscopy for colorectal cancer screening and abdominal imaging study. We obtained sociodemographic and clinical data, and we performed univariate and multivariable regression analyses.Results: In total, 895 patients were included; 42% were male, the mean age was 59.9 ± 9.3 years, and 37.8% (338) had CRA. Patients harboring polyps were predominantly males (48.2% vs. 38.2%, P = 0.002), older (61.6 ± 8.7 years vs. 58.9 ± 9.5 years, P < 0.001), and exhibited a higher body weight than controls [75 (66-88) kg vs. 72 (63-82.3) kg, P = 0.002]. Fifty-six percent of patients showed hepatic steatosis in imaging studies and 54.4% met MAFLD diagnostic criteria. The adenoma detection rate was higher in the MAFLD group compared to controls (46.4% vs. 27.5%, P < 0.001). In the multivariable analysis, MAFLD was significantly associated with the presence of CRA (odds ratio = 2.32; 95%CI: 1.68-3.19, P < 0.0001). There were no statistically significant differences of histopathological characteristics of the adenomas according to the presence of MAFLD.Conclusion: The present study shows that, in Chilean Hispanic subjects, MAFLD is associated with an increased risk of CRA. This information may be useful to design specific screening colonoscopy recommendations in MAFLD patients. LESS      Full article

Nonalcoholic fatty liver is a worldwide common problem with more prevalence in non-Asian populations that is closely correlated with the muscle-related disorder sarcopenia. The incidence of both health issues has been observed to be strongly interlinked where presence of one exacerbates the other. Nonalcoholic fatty liver disease (NAFLD) pathophysiology increases the muscle loss, while the onset of NAFLD in sarcopenic patients aggravates the liver problems as compared to non-sarcopenic patients. Scarcity of research on the subject provides very little evidence about the cause and effect of disorders. No FDA approved drugs are available to date for NAFLD and sarcopenia. Research is underway to understand the complex biochemical pathways involved in the development of both disorders. This review is a small contribution toward understanding sarcopenia in the setting of NAFLD that provides insight on the common pathophysiological profile of sarcopenia and NAFLD and portrays a novel way of delving into the subject by introducing the concept of cortisol crosstalk with the muscle-liver axis. Sarcopenia and NAFLD are considered metabolism-related problems, and cortisol, being a glucocorticoid, plays an important role in metabolism of fats, carbohydrates, and proteins. Cushing’s syndrome, characterized by abnormally elevated concentrations of blood cortisol/enhanced intracellular activity, shares many pathologic conditions (such as insulin resistance, metabolic syndrome, abnormal levels of specific cytokines, and obesity) with NAFLD and sarcopenia. Hence, cortisol can be a potential biomarker in sarcopenia and NAFLD. As cortisol activity at cellular level is controlled by 11β-hydroxysteroid dehydrogenase type 1 and 2 (11β-HSD1/2) enzymes that convert inactive steroid precursor into active cortisol, these enzymes can be targeted for the study of sarcopenia and NAFLD. Combined studies on NAFLD and sarcopenia with respect to cortisol open a new avenue of research in the understanding of both disorders. LESS      Full article

Colorectal cancer is usually considered a disease of the elderly; however, in a small fraction of patients (2%-3% of all affected individuals), colorectal malignancies may develop earlier. The reasons whereby some individuals develop colorectal cancer at a young age are poorly understood. In a 12-year-old girl, a malignancy was diagnosed in the ascending colon. There was no familial history of Lynch syndrome or familial adenomatous polyposis. The metabolic profile of the patient revealed hypertriglyceridemia and low high-density lipoprotein cholesterol levels at nine years, then diagnosed as familial hypertriglyceridemia due to a constitutional mutation in the APOA5 gene (c.427delC). Moreover, variants possibly increasing the risk of cancer were detected in MSH6 (c.3438+11_3438+14delCTTA, intron 5) and APC (I1307K). The patient showed a rather unusual dietary pattern, since her basic alimentation from weaning consisted almost exclusively of meat homogenates and, subsequently, roasted meat or cutlets. Other foods, including fish, vegetables, sweets, and pasta, were refused. In this case, genetic and environmental factors could have acted in a particularly accelerated manner. Indeed, the genetic background of the patient (familial hypertriglyceridemia and polymorphisms predisposing to colorectal cancer) may have favored a dietary-driven colorectal carcinogenesis, resulting in an extremely early onset development of malignancy. LESS      Full article

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and is characterized by a high burden of metabolic alterations. It exposes patients to increased morbidity and mortality, mostly driven by cardiovascular (CV) complications. Despite its large use, the nomenclature NAFLD has some limitations, due to the exclusion of patients with hepatic fat and concomitant other liver diseases or moderate alcohol consumption possibly contributing to hepatic damage. Therefore, a new and more inclusive definition of fatty liver has recently been proposed, namely metabolic associated fatty liver disease (MAFLD). It comprises patients with hepatic steatosis and associated metabolic comorbidities, without exclusion of other liver diseases. As for the nature of the new definition of MAFLD, it could be speculated that an increased risk of cardiovascular complications should be expected. Therefore, our review aims at answering the question about possible differences in cardiovascular risk and mortality in patients with NAFLD compared to MAFLD. We selected 8 studies out of 1130 by searching in the PubMed database. Data from literature seem to report an increased risk of CV events and mortality in patients affected by MAFLD compared to NAFLD, possibly due to the metabolic burden and coexistence of other liver diseases typical of MAFLD. However, further prospective studies are warranted to confirm this preliminary hypothesis. LESS      Full article

Aim: The association between type 2 diabetes mellitus (T2DM) and male hypogonadism has been largely demonstrated. Testosterone (T) serum levels are often lower in men with T2DM compared to the general population, and, conversely, men with higher T serum levels have shown lower risk of T2DM. On the contrary, the association between pre-diabetes and male hypogonadism has been less investigated thus far. Pre-diabetes is a common clinical condition preceding T2DM and has been recognized as a potential risk factor for other metabolic disorders and cardiovascular diseases. Therefore, the aims of this review are to investigate the association between pre-diabetes and male hypogonadism and to evaluate the potential effect of T treatment on glucose metabolism and anti-diabetic therapy on T serum levels.Methods: We conducted this systematic review developing different literature searches, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocol.Results: In our analysis, male hypogonadism has a prevalence of around 24%-35% in pre-diabetic men. Moreover, we observed improvement of metabolic parameters in pre-diabetes with T treatment. On the contrary, anti-diabetic therapy seems to have no particular effects on T serum levels.Conclusion: Overall, we demonstrated that, although T administration could be considered in pre-diabetic men, pre-diabetes-related treatments should be confined to the control glucose metabolism, since no evidence for a positive effect on total T serum levels is available. Future research should be oriented to study the role of new anti-diabetic drugs in the sex hormonal status in hypogonadal men. LESS      Full article

The Fatty Liver Index (FLI) is a non-invasive biomarker proposed, in 2006, by Bedogni’s group, to aid in identifying patients with suspected nonalcoholic fatty liver disease (NAFLD) to be submitted to liver ultrasonography to confirm steatosis. Criteria of Assessment of Narrative Review Articles, a scale for the assessment of quality of narrative review articles, inspired our review article, which aims at evaluating the scope of published articles on FLI issued over the last 15-year period. The analysis of retrieved data identified the following conclusions. First, given that FLI and NAFLD share the same risk factors, FLI can be used to identify NAFLD among populations at risk to be submitted to screening. Second, FLI is able to identify the hazard of atherosclerosis, both at a subclinical stage and as an overt disease. Third, FLI detects incident diabetes and chronic kidney disease. However, evidence supporting the notion that FLI also predicts the metabolic syndrome, some endocrine disorders, certain tumor types, and overall and cause-specific mortality appears to be more limited. In conclusion, 15 years after its first publication, FLI has been validated as a robust biomarker of both steatosis and NAFLD. Moreover, the scope of FLI has been expanded to previously unexpected areas. Finally, we discuss FLI limitations and a research agenda aimed at further improving the accuracy of FLI scores in predicting liver-related outcomes, endocrine-metabolic disorders, cancer risk, and survival. LESS      Full article

In a time of food abundance and waste, and when sedentarism is the norm, metabolic-associated fatty liver disease (MAFLD) has become a major health threat in the Western world. While research is committed to finding a pharmacological treatment for MAFLD, it is time to go back to the basis and address the behavioral pathogenesis of MAFLD. All patients with MAFLD, irrespective of body weight, should be submitted to thorough dietary counseling. Diet is a learned behavior and should be addressed holistically and in a personalized fashion. The benefits of a suitable diet surpass an improvement of liver disease, having the potential to improve cardiovascular- and cancer-related mortality, in patients with MAFLD. This review summarizes the current state of the art of diet on MAFLD, presenting straightforward recommendations for everyday practice. LESS      Full article

Aim: Takeda G-protein-coupled receptor 5 (TGR5) is a functional receptor which mediates a variety of metabolic and immune processes and is involved in the regulation of adipocyte pathophysiology. Data on TGR5 in human adipose tissue are very limited. Therefore, the aims of this study were to investigate TGR5 expression in visceral adipose tissue (VAT) and explore its association with signs of VAT dysfunction and overt metabolic disease in individuals with obesity. Methods: Fifty obese candidates to bariatric surgery were recruited at Sapienza University, Rome, Italy. The expression of TGR5 and markers of VAT dysfunction were assessed by rt-PCR in omental fragments obtained intraoperatively.Results: Individuals with higher VAT TGR5 levels (high-TGR5) had greater fasting glucose (P = 0.027) and worse lipid profile (total-cholesterol, P = 0.014; LDL-cholesterol, P = 0.022) than those with lower TGR5 (low-TGR5) expression. High-TGR5 subjects showed significantly higher expression of markers of AT-specific inflammation and insulin resistance, such as tissue metallopeptidase inhibitor 1 (TIMP1; P = 0.011), poly[ADP-ribose]polymerase 1 (PARP1, P = 0.034), and WNT1-inducible-signaling pathway protein 1 (WISP1, P = 0.05), apoptosis (caspase 7, P = 0.031), and lipid trafficking (ANGPTL4, P < 0.001), compared to low-TGR5 patients. High VAT TGR5 expression predicted the presence of abnormal glucose metabolism with AUROC = 0.925 (95%CI: 0.827-1.00, P = 0.001) for the age-, sex-, and waist circumference-adjusted ROC curve.Conclusion: Our data show that increased VAT TGR5 is associated with VAT dysfunction and impaired lipid trafficking and predicts the presence of metabolic disorders in human obesity, overall adding novel insights to the understanding of TGR5-mediated pathways in the clinical setting. LESS      Full article

Aim: We examined the diagnostic accuracy of ultrasonography to detect any HS (defined as steatotic hepatocytes ≥ 5% on histology) and moderate-severe HS (defined as steatotic hepatocytes ≥ 30% on histology) by performing a systematic review and meta-analysis.Methods: We systematically searched PubMed, Web of Science, and Scopus databases, from January 2011 to February 2021, to identify studies conducted in adults investigating the diagnostic accuracy of ultrasonography vs. histology for detecting either ≥ 5% histologically defined HS or moderate-severe HS (≥ 30%). Meta-analysis was performed using random-effects modeling.Results: Twelve studies were included involving a total of 2921 individuals, 1710 (58.5%) of whom had HS ≥ 5% by histology. The overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of ultrasonography for the detection of ≥ 5% histologically defined HS, compared to histology, were 82% (95% confidence interval 76%-86%), 80% (72%-86%), 4.0 (2.90-5.70), and 0.23 (0.18-0.30), respectively. Based on the pooled analysis of seven studies, the overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of ultrasonography for the detection of ≥ 30% histologically defined HS were 85% (72%-92%), 85% (73%-93%), 5.72 (3.06-10.7), and 0.18 (0.10-0.33) , respectively. Funnel plots did not reveal any significant publication bias.Conclusion: Conventional ultrasonography allows for reliable and accurate detection of ≥ 5% histologically defined HS compared to histology. These findings call for an extensive use of conventional ultrasonography in the clinical arena. LESS      Full article

Sentiment analysis is a technique for exploring a piece of text with the aim to investigate sentiments hidden within it. The use of sentiment analysis in health care could assist in understanding how individuals discuss and feel about a specific topic. Currently, there are scarce data regarding the use of sentiment analysis related to nonalcoholic fatty liver disease (NAFLD), which is the most common chronic liver disease worldwide and is associated with hepatic and extra-hepatic complications. Hence, the aim of this report was to assess the sentiments of NAFLD expressed in messages posted on Twitter, one of the most popular social media platforms worldwide. We chose the hashtags #FattyLiver, #NAFLD, #NASH, and #MAFLD as terms to identify the messages related to NAFLD on Twitter. Messages containing at least one of these hashtags were collected using the standard Application Programming Interface provided by Twitter. The sentiment analysis revealed that sentiments hidden within messages related to NAFLD were substantially neutral and that “breastcancer” and “cancer” were two of the most common words used, suggesting that a large part of messages focused on the relationship between NAFLD and extra-hepatic cancers. Conversely, the association between NAFLD and cardiovascular disease seems to be less relevant for Twitter community. These observations might be useful for developing better public health strategies and for promoting a constructive attitude among subjects that read and discuss about NAFLD (and its complications) on social media. LESS      Full article

Nonalcoholic fatty liver disease (NAFLD) is emerging as the most common etiology for chronic liver disease. Despite this, our understanding of this illness is lacking. The previous paradigm is that central adiposity, hyperlipidemia, hypertension, and insulin resistance, also known as metabolic syndrome, lead to NAFLD, and this relationship is unidirectional. However, recent evidence clearly shows that the clinical burden of this illness extends well beyond liver-related morbidity and mortality and is associated with multiple extrahepatic complications, particularly metabolic consequences. Due to this, the professional consensus has proposed using the term metabolic associated fatty liver disease (MAFLD) to more accurately reflect pathogenesis and help in patient stratification for management. This review discusses the shared pathophysiological mechanisms that link these diseases and how this can be leveraged to prevent these complications in individuals with NAFLD/MAFLD. LESS      Full article

In this review, we discuss selected topics which are relevant to implementing precision medicine in metabolic disorders. Personalization of diet and exercise may help in preventing obesity and type 2 diabetes (T2D). Weight loss should be personalized based on age, sex, ethnicity, and coexisting comorbidities. Advances in our understanding of the pathophysiology, genetics, and epigenetics of obesity promise to offer tailored management options. Careful risk assessment is necessary prior to intervention. Risk may be underestimated, e.g., in women, in different ethnic groups, and in people with T2D. More personalized approaches could be useful among persons who failed to respond to traditional risk factor management, such as pharmacological treatment for dyslipidemia and arterial hypertension. Nonalcoholic fatty liver disease/metabolic-associated fatty liver disease (NAFLD/MAFLD) is both a cause and an effect of altered glucose and lipid metabolism. Personalized medicine approaches could be key to identify more effective pharmacological strategies as well as to reverse this common and burdensome metabolic liver disease. Finally, metabolomics could be used to identify relevant biomarkers for cancer diagnosis, staging, and prognostication. Cancers of the colon and rectum, breast, prostate, thyroid, and ovaries illustrate the notion that cancer cell metabolic derangements may be utilized in clinical practice. A true personalization of pharmacotherapies should be pursued especially in obese patients with cancer. LESS      Full article

Interpretation of diagnostic and surveillance laboratory results and imaging in liver disease is fraught with misinterpretation and/or uncertainty. Nonalcoholic fatty liver disease (NAFLD) represents an ever-growing proportion of liver disease cases but presents unique challenges for the clinician. Given the necessity of excluding other etiologies of liver disease, NAFLD can at times represent a challenging diagnosis as non-invasive assessment and biopsy are imperfect tests with important limitations. Similarly, cautious review of laboratory reports is necessary to avoid missing abnormal pathophysiology. The presence of lab values within the standard reference range may be concerning in the setting of chronic liver disease (“abnormally normal”) and conversely results flagged as abnormal may not necessarily be of great concern (“normally abnormal”). This review provides a framework for the clinician to review common diagnostic challenges in NAFLD and enhance patient care. LESS      Full article

Aim: We examined the diagnostic accuracy of ultrasonography to detect any HS (defined as steatotic hepatocytes ≥ 5% on histology) and moderate-severe HS (defined as steatotic hepatocytes ≥ 30% on histology) by performing a systematic review and meta-analysis.Methods: We systematically searched PubMed, Web of Science, and Scopus databases, from January 2011 to February 2021, to identify studies conducted in adults investigating the diagnostic accuracy of ultrasonography vs. histology for detecting either ≥ 5% histologically defined HS or moderate-severe HS (≥ 30%). Meta-analysis was performed using random-effects modeling.Results: Twelve studies were included involving a total of 2921 individuals, 1710 (58.5%) of whom had HS ≥ 5% by histology. The overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of ultrasonography for the detection of ≥ 5% histologically defined HS, compared to histology, were 82% (95% confidence interval 76%-86%), 80% (72%-86%), 4.0 (2.90-5.70), and 0.23 (0.18-0.30), respectively. Based on the pooled analysis of seven studies, the overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of ultrasonography for the detection of ≥ 30% histologically defined HS were 85% (72%-92%), 85% (73%-93%), 5.72 (3.06-10.7), and 0.18 (0.10-0.33) , respectively. Funnel plots did not reveal any significant publication bias.Conclusion: Conventional ultrasonography allows for reliable and accurate detection of ≥ 5% histologically defined HS compared to histology. These findings call for an extensive use of conventional ultrasonography in the clinical arena. LESS      Full article

In this review, we discuss selected topics which are relevant to implementing precision medicine in metabolic disorders. Personalization of diet and exercise may help in preventing obesity and type 2 diabetes (T2D). Weight loss should be personalized based on age, sex, ethnicity, and coexisting comorbidities. Advances in our understanding of the pathophysiology, genetics, and epigenetics of obesity promise to offer tailored management options. Careful risk assessment is necessary prior to intervention. Risk may be underestimated, e.g., in women, in different ethnic groups, and in people with T2D. More personalized approaches could be useful among persons who failed to respond to traditional risk factor management, such as pharmacological treatment for dyslipidemia and arterial hypertension. Nonalcoholic fatty liver disease/metabolic-associated fatty liver disease (NAFLD/MAFLD) is both a cause and an effect of altered glucose and lipid metabolism. Personalized medicine approaches could be key to identify more effective pharmacological strategies as well as to reverse this common and burdensome metabolic liver disease. Finally, metabolomics could be used to identify relevant biomarkers for cancer diagnosis, staging, and prognostication. Cancers of the colon and rectum, breast, prostate, thyroid, and ovaries illustrate the notion that cancer cell metabolic derangements may be utilized in clinical practice. A true personalization of pharmacotherapies should be pursued especially in obese patients with cancer. LESS      Full article

The Fatty Liver Index (FLI) is a non-invasive biomarker proposed, in 2006, by Bedogni’s group, to aid in identifying patients with suspected nonalcoholic fatty liver disease (NAFLD) to be submitted to liver ultrasonography to confirm steatosis. Criteria of Assessment of Narrative Review Articles, a scale for the assessment of quality of narrative review articles, inspired our review article, which aims at evaluating the scope of published articles on FLI issued over the last 15-year period. The analysis of retrieved data identified the following conclusions. First, given that FLI and NAFLD share the same risk factors, FLI can be used to identify NAFLD among populations at risk to be submitted to screening. Second, FLI is able to identify the hazard of atherosclerosis, both at a subclinical stage and as an overt disease. Third, FLI detects incident diabetes and chronic kidney disease. However, evidence supporting the notion that FLI also predicts the metabolic syndrome, some endocrine disorders, certain tumor types, and overall and cause-specific mortality appears to be more limited. In conclusion, 15 years after its first publication, FLI has been validated as a robust biomarker of both steatosis and NAFLD. Moreover, the scope of FLI has been expanded to previously unexpected areas. Finally, we discuss FLI limitations and a research agenda aimed at further improving the accuracy of FLI scores in predicting liver-related outcomes, endocrine-metabolic disorders, cancer risk, and survival. LESS      Full article

Aim: The Global burden of nonalcoholic fatty liver disease (NAFLD) has significantly increased recently, with its prevalence mirroring increasing obesity and diabetes. However, population-specific evidence for young adults remains limited. Herein, we provide a 20-year trend analysis of NAFLD in young adults and examine factors associated with NAFLD and major adverse cardiovascular events (MACE) prevalence.Methods: This study uses data from the United States National Health and Nutrition Examination Survey (NHANES) 1999-2018. Fatty liver was examined with the fatty liver index (FLI) and United States-FLI (US-FLI), and advanced fibrosis was examined with the fibrosis-4 index. Clustered multivariate logistic regression analysis on the year of study was applied to obtain odds ratios (OR) for the estimation of events.Results: 13.31% (95%CI: 12.71% to 13.94%) of young adults had NAFLD. The prevalence increased from 9.98% in 1999 to 19.49% in 2018, with a statistically significant trend (P < 0.001). 9.52% and 5.29% of patients have clinically significant and advanced fibrosis, respectively. In multivariate analysis, diabetes (3.48, 95%CI: 2.37 to 5.11), hypertension (2.03, 95%CI: 1.62 to 2.55), elevated body mass index (1.22, 95%CI: 1.20 to 1.23, P < 0.001) significantly increases odds of NAFLD. The largest increase in odds was related to obesity (OR: 21.61, 95%CI: 16.95 to 27.55, P < 0.001). Young adults with NAFLD had a borderline non-significant increase in the prevalence of MACE compared to individuals without NAFLD (OR: 1.603, 95%CI: 0.949 to 2.708, P = 0.078).Conclusion: The rising prevalence of NAFLD in young adults depicts the changing landscape of NAFLD and its association with a significant increase in MACE. The challenge of effective risk stratification and education of these individuals remains. LESS      Full article