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.
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.
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.
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.
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.
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.