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 This nosography tends to be outdated by the novel definition of metabolic associated fatty liver disease (MAFLD).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.

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Effect of cofactors on NAFLD/NASH and MAFLD. A paradigm illustrating the pathomechanics of organ dysfunction

Objective To evaluate the effect of Non-alcoholic fatty liver disease (NAFLD) status in the impact of lifestyle over Health-related quality of life (HRQoL) in patients with metabolic syndrome (MetS). Methods Baseline and 1 year follow up data from the PREDIMED-plus cohort (men and women, 55-75 years old with overweight/obesity and MetS) were studied. Adherence to an energy-restricted Mediterranean Diet (er-MeDiet) and Physical Activity (PA) were assessed with a validated screeners. Hepatic steatosis index (HSI) was implemented to evaluate NAFLD while the SF-36 questionnaire provided HRQoL evaluation. Statistical analyses were performed to evaluate the influence of baseline NAFLD on HRQoL as affected by lifestyle during 1 year of follow up. Results Data from 5205 patients with mean age of 65 years and a 48% of female participants. Adjusted linear multivariate mixed regression models showed that patients with lower probability of NAFLD (HSI < 36 points) were more responsive to er-MeDiet (β 0.64 vs β 0.05 per er-MeDiet adherence point, p< 0.01) and PA (β 0.05 vs β 0.01 per MET-h/week, p = 0.001) than those with high probability for NAFLD in terms Physical SF-36 summary in the 1 year follow up. 10 points of er-MeDiet adherence and 50 MET-h/week were thresholds for a beneficial effect of lifestyle on HRQoL physical domain in patients with lower probability of NAFLD. Conclusion The evaluation of NAFLD by the HSI index in patients with MetS might identify subjects with different prospective sensitivity to lifestyle changes in terms of physical HRQoL (http://www.isrctn.com/ISRCTN89898870).

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Role of NAFLD on the Health Related QoL Response to Lifestyle in Patients With Metabolic Syndrome: The PREDIMED Plus Cohort

Objective Insulin resistance (IR) is a major factor involved in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD). Triglyceride-glucose (TyG) index, an easily detected surrogate marker of IR, has not been explored sufficiently on its relationship with incident MAFLD risk. This study sought to investigate the association of baseline TyG index with the risk of MAFLD in a Chinese cohort. Methods This health check-up cohort was constructed with eligible 2056 Chinese from a community. The TyG index was calculated as ln (fasting triglyceride [mg/dL]×fasting glucose [mg/dL]/2). Cox proportion hazard models were used to evaluate the longitudinal association between baseline TyG index and the risk of MAFLD. Results During an average follow-up of 2.5 ± 0.5 years, about 12.8% of the subjects developed MAFLD, and the incidence of MAFLD trended to increase with the quartile TyG index (Ptrend < 0.05). After adjusting for all confounders, TyG index was independently correlated with the risk of incident MAFLD (HR = 1.784, 95% CI = 1.383–2.302, P < 0.001), and the risk of MAFLD in the highest quartile of TyG index was two times higher than that in the lowest quartile (95% CI = 1.377–2.992, P = 0.001). The restricted cubic spline analysis showed that the relationship between TyG index and the risk of MAFLD was linear in males (P for total < 0.001; P for non-linearity = 0.746), but nonlinear in females (P for non-linearity = 0.040). Conclusion A high baseline TyG index was independently associated with a high risk of incident MAFLD, and we might develop the strategy of MAFLD prevention based on the TyG index.

Association Between Triglyceride-Glucose Index and Risk of Metabolic Dysfunction-Associated Fatty Liver Disease: A Cohort Study

Nonalcoholic fatty liver disease (NAFLD) induced by obesity is a grave threat to human health. Phytic acid (PA) is a natural compound found in high-fiber diets, such as soybeans. This study investigated the effects and mechanisms of PA on obesity, hepatic lipid metabolism, and gut-liver axis homeostasis in high-fat diet (HFD)-fed mice. PA was observed to significantly inhibit obesity and alleviate liver steatosis in mice. PA improved HFD-induced liver inflammation, oxidative stress and fibrosis. Moreover, PA improved HFD-induced colonic inflammation, gut barrier damage and systemic inflammation in mice. Furthermore, PA effectively ameliorated the decreased diversity and gut microbiota composition in HFD-fed mice. Additionally, PA decreased the abundance of harmful bacteria Proteobacteria and Desulfovibrionaceae and increased the abundance of probiotic bacteria Muribaculaceae and Lachnospiraceae. Thus, PA is effective in restoring the homeostasis of the gut-liver axis. It further provides a theoretical basis for the prevention and treatment of NAFLD in patients with obesity by the rational intake of foods containing PA.

Phytic Acid Improves Hepatic Steatosis, Inflammation, and Oxidative Stress in High-Fat Diet (HFD)-Fed Mice by Modulating the Gut-Liver Axis.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease with a wide spectrum of liver conditions ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The prevalence of NAFLD varies across populations, and different ethnicities have specific risks for the disease. NAFLD is a multi-factorial disease where the genetics, metabolic, and environmental factors interplay and modulate the disease’s development and progression. Several genetic polymorphisms have been identified and are associated with the disease risk. This mini-review discussed the NAFLD’s genetic polymorphisms and focusing on the differences in the findings between the populations (diversity), including of those reports that did not show any significant association. The challenges of genetic diversity are also summarized. Understanding the genetic contribution of NAFLD will allow for better diagnosis and management explicitly tailored for the various populations.

https://www.mdpi.com/2227-9059/11/1/106/pdf?version=1672400810

Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review

Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is the most prevalent liver disorder worldwide. Historically, its diagnosis required biopsy, even though the procedure has a variable degree of error. Therefore, new non-invasive strategies are needed. Consequently, this article presents a thorough review of biopsy-free scoring systems proposed for the diagnosis of MAFLD. Similarly, it compares the severity of the disease, ranging from hepatic steatosis (HS) and nonalcoholic steatohepatitis (NASH) to fibrosis, by contrasting the corresponding serum markers, clinical associations, and performance metrics of these biopsy-free scoring systems. In this regard, defining MAFLD in conjunction with non-invasive tests can accurately identify patients with fatty liver at risk of fibrosis and its complications. Nonetheless, several biopsy-free scoring systems have been assessed only in certain cohorts; thus, further validation studies in different populations are required, with adjustment for variables, such as body mass index (BMI), clinical settings, concomitant diseases, and ethnic backgrounds. Hence, comprehensive studies on the effects of age, morbid obesity, and prevalence of MAFLD and advanced fibrosis in the target population are required. Nevertheless, the current clinical practice is urged to incorporate biopsy-free scoring systems that demonstrate adequate performance metrics for the accurate detection of patients with MAFLD and underlying conditions or those with contraindications of biopsy.

MAFLD/NAFLD Biopsy-Free Scoring Systems for Hepatic Steatosis, NASH, and Fibrosis Diagnosis

Congenital heart disease is one of the most common causes of death derived from malformations. Historically, its treatment has depended on timely diagnosis and early pharmacological and surgical interventions. Survival rates for patients with this disease have increased, primarily due to advancements in therapeutic choices, but mortality remains high. Since this disease is a time-sensitive pathology, pharmacological interventions are needed to improve clinical outcomes. Therefore, we analyzed the applications, dosage, and side effects of drugs currently used for treating congenital heart disease. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and potassium-sparing diuretics have shown a mortality benefit in most patients. Other therapies, such as endothelin receptor antagonists, phosphodiesterase-5 inhibitors, prostaglandins, and soluble guanylyl cyclase stimulators, have benefited patients with pulmonary artery hypertension. Likewise, the adjunctive symptomatic treatment of these patients has further improved the outcomes, since antiarrhythmics, digoxin, and non-steroidal anti-inflammatory drugs have shown their benefits in these cases. Conclusively, these drugs also carry the risk of troublesome adverse effects, such as electrolyte imbalances and hemodynamic compromise. However, their benefits for survival, symptom improvement, and stabilization outweigh the possible complications from their use. Thus, cases must be assessed individually to accurately identify interventions that would be most beneficial for patients.

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Congenital Heart Disease: The State-of-the-Art on Its Pharmacological Therapeutics

Breast implant illness refers to a combination of different symptoms related to breast implant surgery, including fatigue, brain fog, and arthralgias. This malaise occurs after cosmetic and reconstructive breast surgeries, although it has not been proven to be a disease. Even recent studies have reported concluding statements of the etiology, diagnosis, and treatment as unclear and widely unknown. Therefore, this review aimed to determine the associations between the manifestations of breast implant illness in surgery and breast reconstruction, as well as the autoimmune responses involved. Complications associated with breast implants include breast pain, capsular contracture, infections, as well as other manifestations specific to breast reconstruction. Moreover, patients with implants may present with new-onset systemic sclerosis, Sjögren’s syndrome, and connective tissue diseases. However, the incidence of capsular contracture has steadily decreased with each generation of implants, particularly since the development of textured implants, as well as with the use of antibiotics and antiseptic pocket irrigation. However, the incidence of anaplastic large cell lymphoma has increased with the use of textured implants. Remarkably, the autoimmune response to these implants remains unclear. Therefore, close follow-up, careful observation of any symptom presentation, and evidence-based treatment decisions are necessary for patients with breast implants.

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Breast Implant Illness: Surgical, Autoimmune, and Breast Reconstruction Associations

Cancer is currently considered one of the most threatening diseases worldwide. Diet could be one of the factors that can be enhanced to comprehensively address a cancer patient’s condition. Unfortunately, most molecules capable of targeting cancer cells are found in uncommon food sources. Among them, depsipeptides have emerged as one of the most reliable choices for cancer treatment. These cyclic amino acid oligomers, with one or more subunits replaced by a hydroxylated carboxylic acid resulting in one lactone bond in a core ring, have broadly proven their cancer-targeting efficacy, some even reaching clinical trials and being commercialized as “anticancer” drugs. This review aimed to describe these depsipeptides, their reported amino acid sequences, determined structure, and the specific mechanism by which they target tumor cells including apoptosis, oncosis, and elastase inhibition, among others. Furthermore, we have delved into state-of-the-art in vivo and clinical trials, current methods for purification and synthesis, and the recognized disadvantages of these molecules. The information collated in this review can help researchers decide whether these molecules should be incorporated into functional foods in the near future.

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Carlos Daniel Varela-Chinchilla

Papers

MAFLD/NAFLD Biopsy-Free Scoring Systems for Hepatic Steatosis, NASH, and Fibrosis Diagnosis

Congenital Heart Disease: The State-of-the-Art on Its Pharmacological Therapeutics

Breast Implant Illness: Surgical, Autoimmune, and Breast Reconstruction Associations

Depsipeptides Targeting Tumor Cells: Milestones from In Vitro to Clinical Trials