Future therapeutic perspectives in nonalcoholic fatty liver disease: a focus on nuclear receptors, a promising therapeutic target.

Non-alcoholic fatty liver disease (NAFLD) is a major public health problem worldwide, with an increasing incidence, secondary to the increasing incidence of obesity and diabetes, from a very young age. It is associated with metabolic and cardiovascular disorders, as components of the metabolic syndrome (MS). NAFLD is the hepatic manifestation of MS. The pathogenesis of the disease is multifactorial and complex, involving genetic, metabolic, but also environmental factors. Currently, nuclear receptors (NRs) represent a promising therapeutic target in the treatment of non-alcoholic steatohepatitis (NASH). Of these, the most studied receptor was the liver X receptor (LXR), which would have great potential in the treatment of metabolic diseases, namely hypercholesterolemia, atherosclerosis, and NAFLD. However, the therapeutic use of NRs is restricted in medical practice for two reasons: limited knowledge of the structure of the receptor and its inability to modulate certain actions in the target organs and genes. One problem is the understanding of the function and structure of the N-terminal domain which has a major transcriptional activation function (AF1).

Vasculitis and infectious risk in a patient with type 2 diabetes mellitus: A case report.

The connection between vasculitis and infection is complex. The present study described a typical situation for a patient with unbalanced type 2 diabetes and chronic complications, in which a lack of adherence to the protection and care measures ultimately led to the appearance of some of the worst consequences of the condition, namely, ulceration, gangrene and amputation. In the context of an unstable condition with significant metabolic imbalance there was an impaired response to infections in the present patient, and the amputation resulted in wound persistence and ulcer development, followed by superinfection with methicillin-resistant Staphylococcus aureus according to the antibiogram performed. In this case, an episode of vasculitis was triggered without evidence of bacteraemia. The present case report highlighted the importance of proper hygiene and good metabolic control in patients with diabetes that suffer from amputations and conditions that expose them to certain complications, including vasculitis.

The therapeutic mechanisms and beneficial effects of ursodeoxycholic acid in the treatment of nonalcoholic fatty liver disease: a systematic review.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, with an increasing prevalence in all regions of the world. Its spectrum includes hepatic steatosis (HS) and non-alcoholic steatohepatitis (NASH) with progression to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD may represent the hepatic manifestation of the metabolic syndrome (MS), with a prevalence directly proportional to the prevalence of obesity and MS. The standard treatment for patients with NAFLD is lifestyle modification, which in medical practice has many limitations. To overcome them, numerous drugs with benefits in the prevention and treatment of the disease have been studied. Currently, the most used substances are vitamin E and Pioglitazone, with numerous benefits. Furthermore, new strategies and beneficial treatments are needed for the prevention of the disease, which is currently a priority in both the health and research fields. One of the most studied agents in the last decades has been ursodeoxycholic acid (UDCA), which is of great interest in the treatment of NAFLD due to its hepatoprotective effects.

Prothrombotic status in COVID­19 with diabetes mellitus (Review).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused an important social and health impact worldwide and the coronavirus disease-19 (COVID-19) has elicited devastating economy problems. The pathogenesis of SARS-CoV-2 infection is a complex mechanism and is considered to be the result of a challenging interaction, in which host and virus immune responses are the key elements. In this process, several inflammatory pathways are involved, and their initiation can have multiple consequences with a considerable impact on evolution, such as hyperinflammation and cytokine storm, thereby promoting activation of the coagulation system and fibrinolytic activity suppression. It is commonly recognized that COVID-19 severity involves multiple factors, including diabetes which increases the risk of developing different complications. This could be as a result of the low-grade inflammation as well as the innate and adaptive immune response dysfunction that is observed in patients with diabetes mellitus. In patients with diabetes, multiple metabolic disturbances which have a major impact in disturbing the balance between coagulation and fibrinolysis were discovered, thus the risk for thrombotic events is increased. Diabetes has been recognized as an important severity prognosis factor in COVID-19 cases and considering there is a significant association between diabetes and prothrombotic status, it could be responsible for the increased risk of thrombotic events with a worse prognosis.

A Study of Biomarkers Associated with Metabolic Dysfunction-Associated Fatty Liver Disease in Patients with Type 2 Diabetes.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new term that no longer excludes patients that consume alcohol or present other liver diseases, unlike nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the role of different biomarkers as predictors of MAFLD in patients with type 2 diabetes mellitus (T2DM). In this regard, a cross-sectional, non-interventional study was conducted over a period of 8 months in patients with T2DM. Liver steatosis displayed by abdominal ultrasound certified the MAFLD diagnosis. A percentage of 49.5% of the studied patients presented MAFLD. Through logistic regression adjusted for gender, age, T2DM duration, lipid-lowering therapy, smoking status, nutritional status, we demonstrated that elevated triglycerides (TG) levels, high non-high-density-lipoprotein (HDL)-cholesterol-to-HDL-cholesterol (non-HDL/HDL) ratio, high atherogenic index of plasma (AIP), and increased Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) had predictive value for MAFLD in patients with T2DM. Furthermore, we calculated the optimal cut-off values for these biomarkers (184 mg/dL for TG, 0.615 for AIP, 3.9 for the non-HDL/HDL ratio, and 2.01 for HOMA-IR) which can predict the presence of MAFLD in patients with T2DM. To our knowledge, this is the first study to assess the predictive value of the non-HDL/HDL ratio for MAFLD in patients with T2DM.

Associations of Chronic Diabetes Complications and Cardiovascular Risk with the Risk of Obstructive Sleep Apnea in Patients with Type 2 Diabetes.

Background: Type 2 diabetes mellitus (T2DM) is associated with increased mortality and morbidity, including cardiovascular diseases and obstructive sleep apnea (OSA). The aim of this study was to assess the associations between cardiovascular risk, chronic diabetes complications and the risk of OSA in adult patients with T2DM. Methods: The study included 529 patients with T2DM in whom moderate-to-severe OSA risk was assessed using the STOP-Bang questionnaire, dividing the subjects into two groups: group 1: STOP-Bang score <5, and group 2: STOP-Bang score ≥5, respectively. In all the subjects, cardiovascular risk was assessed using the UKPDS risk engine. Statistical analysis was performed using SPSS 26.0, the results being statistically significant if p value was <0.05. Results: 59% of the subjects scored ≥5 on the STOP-Bang questionnaire. We recorded statistically significant differences between the two groups regarding diabetes duration, HbA1c, HOMA-IR, albuminuria, as well as cardiovascular risk at 10 years for both coronary heart disease (CHD) and stroke (p < 0.05). Furthermore, through logistic regression, adjusting for confounding factors, we demonstrated that the STOP-Bang score ≥ 5 is a risk factor for 10-year fatal and nonfatal CHD risk. Conclusions: It is extremely important to screen and diagnose OSA in patients with T2DM, in order to improve the primary and secondary prevention of cardiovascular events in these patients.

Triglyceride and Glucose Index as a Screening Tool for Nonalcoholic Liver Disease in Patients with Metabolic Syndrome.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is regarded as a component of metabolic syndrome, which involves insulin resistance (IR) as the primary physiopathological event. The aim of this study was to establish the association between IR, assessed using the triglyceride and glucose index (TyG), and histopathological features of NAFLD lesions. METHODS: The study included 113 patients with metabolic syndrome. Fasting plasma glucose (FPG), fasting lipid profiles and liver enzymes were measured. IR was assessed by the TyG index. Liver biopsy was performed for assessment steatosis and fibrosis. RESULTS: the TyG index had a mean value of 8.93 ± 1.45, with a higher value in the patients with overweight (p = 0.002) and obesity (p = 0.004) characteristics than in the patients with normal weight. The TyG index mean value was 8.78 ± 0.65 in subjects without NASH, 8.91 ± 0.57 in patients with borderline NASH and 9.13 ± 0.55 in patients with definite NASH. A significant difference was found between subjects without NASH and the ones with definite NASH (p = 0.004), as well as in patients with early fibrosis vs. those with significant fibrosis. The analysis of the area under the ROC curve proved that the TyG index is a predictor of NASH (p = 0.043). CONCLUSION: the TyG index is a facile tool that can be used to identify individuals at risk for NAFLD.

Maternal and Fetal Metabolites in Gestational Diabetes Mellitus: A Narrative Review.

Gestational diabetes mellitus (GDM) is a major public health issue of our century due to its increasing prevalence, affecting 5% to 20% of all pregnancies. The pathogenesis of GDM has not been completely elucidated to date. Increasing evidence suggests the association of environmental factors with genetic and epigenetic factors in the development of GDM. So far, several metabolomics studies have investigated metabolic disruptions associated with GDM. The aim of this review is to highlight the usefulness of maternal metabolites as diagnosis markers of GDM as well as the importance of both maternal and fetal metabolites as prognosis biomarkers for GDM and GDM's transition to type 2 diabetes mellitus T2DM.

New Challenges of Treatment for Locally Advanced Head and Neck Cancers in the Covid-19 Pandemic Era.

Locally advanced head and neck cancer is a unique challenge for cancer management in the Covid-19 situation. The negative consequences of delaying radio-chemotherapy treatment make it necessary to prioritize these patients, the continuation of radiotherapy being indicated even if SARS-CoV-2 infection is confirmed in the case of patients with moderate and mild symptoms. For an early scenario, the standard chemo-radiotherapy using simultaneous integrated boost (SIB) technique is the preferred option, because it reduces the overall treatment time. For a late scenario with limited resources, hypo-fractionated treatment, with possible omission of chemotherapy for elderly patients and for those who have comorbidities, is recommended. Concurrent chemotherapy is controversial for dose values >2.4 Gy per fraction. The implementation of hypo-fractionated regimens should be based on a careful assessment of dose-volume constraints for organs at risks (OARs), using recommendations from clinical trials or dose conversion based on the linear-quadratic (LQ) model. Induction chemotherapy is not considered the optimal solution in this situation because of the risk of immunosuppression even though in selected groups of patients TPF regimen may bring benefits. Although the MACH-NC meta-analysis of chemotherapy in head and neck cancers did not demonstrate the superiority of induction chemotherapy over concurrent chemoradiotherapy, an induction regimen could be considered for cases with an increased risk of metastasis even in the case of a possible Covid-19 pandemic scenario.

Systemic and adipose tissue inflammation in NASH: correlations with histopathological aspects.

INTRODUCTION: Non-alcoholic steatohepatitis (NASH) is a progressive form of liver steatosis that involves a risk of progression towards fibrosis, cirrhosis, and end-stage liver disease. Low-grade inflammation is recognized to be involved in non-alcoholic fatty liver disease (NAFLD) pathogeny. Additionally, adipose tissue dysfunction plays an important role in the development of metabolic diseases. PATIENTS, MATERIALS AND METHODS: We conducted a study on 68 patients with liver steatosis confirmed through liver biopsy during the surgery. In all the patients, we recorded anthropometric parameters and we performed blood tests for systemic inflammation [high-sensitivity C-reactive protein (hs-CRP), fibrinogen] and serum adipokines related to adipose tissue inflammation (leptin, adiponectin). Additional to histopathological examination, we also performed the immunohistochemical study of inflammatory mononuclear cells. RESULTS: The 68 patients had a mean age of 56.57±4.94 years old, had a mean value of hs-CRP of 2.30±0.91 mg∕L, a mean value of leptin of 14.02±17.02 ng∕mL and a mean value of adiponectin of 7.54±0.38 mg∕L. In all the cases studied by liver biopsy, the steatosis exceeded 5% of hepatocytes, but the frequency of NASH was 26.47%. Cluster of differentiation (CD)45-positive, CD4-positive, and CD8-positive T-lymphocytes predominated in the studied cases. We obtained a statistically significant high association between definite NASH and the values of hs-CRP, serum adiponectin and leptin∕adiponectin ratio (p<0.0001). CONCLUSIONS: Systemic and adipose tissue inflammation was statistically significant associated with histological lesions of steatosis and NASH, suggesting that the determination of hs-CRP and serum adipokines in dynamics in patients with NAFLD is predictive for the progression of the disease.

Triglyceride and glucose index: a useful tool for non-alcoholic liver disease assessed by liver biopsy in patients with metabolic syndrome?

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is associated with metabolic impairments, being a component of metabolic syndrome. Considering the involvement of fat accumulation and insulin resistance in NAFLD, triglyceride and glucose (TyG) index was proposed as a marker of NAFLD progression. The "gold standard" for the evaluation of liver lesions characteristic for NAFLD remains the liver biopsy. The aim of this study was to establish the links between TyG index, assessing insulin resistance, and histopathological lesions of liver samples obtained by liver biopsy in patients with metabolic syndrome. PATIENTS, MATERIALS AND METHODS: We conducted a study over a period of three years, including 113 adult patients with metabolic syndrome in whom hepatic disorders were assessed by liver biopsy and insulin resistance was evaluated by TyG index. RESULTS AND DISCUSSIONS: In our study, steatosis had a frequency of 92.03%, being identified 26 cases with mild steatosis, 48 with moderate steatosis and 31 with severe steatosis. Regarding non-alcoholic steatohepatitis (NASH), the frequency of this disorder in our study group was 29.2% in the subjects with liver steatosis, while liver fibrosis had a frequency of 53.09%. When we analyzed the relationships between TyG index and the presence of each type of lesion necessary for NASH diagnosis, we obtained statistically significant differences for the presence of hepatocyte ballooning (p=0.01) and a high statistically significance for the NAFLD activity score (NAS) (p<0.0001). CONCLUSIONS: TyG index is a facile tool that can be used to identify patients at risk for advanced NAFLD lesions evaluated by liver biopsy.

Prevalence of diabetes mellitus and prediabetes in the adult Romanian population: PREDATORR study.

BACKGROUND: The PREDATORR (PREvalence of DiAbeTes mellitus, prediabetes, overweight, Obesity, dyslipidemia, hyperuricemia and chronic kidney disease in Romania) study is the first national study analyzing the prevalence of diabetes mellitus (DM) and prediabetes, and their association with cardiometabolic, sociodemographic, and lifestyle risk factors in the Romanian population aged 20-79 years. METHODS: This was an epidemiological study with a stratified, cross-sectional, cluster random sampling design. Sociodemographic, lifestyle, and anamnestic data were collected through self- and interviewer-administered questionnaires, and biochemical assays and oral glucose tolerance tests were performed. RESULTS: In all, 2728 participants from 101 clinics of general practitioners were randomly selected, with a probability proportional to population size according to the 2002 Romanian Census. The participation rate was 99.6%. Impaired glucose regulation (prediabetes, known and unknown DM) was found in 28.1% of the study population. The overall age- and sex-adjusted prevalence of DM was 11.6% (95% CI 9.6%-13.6%), of which 2.4% (95% CI 1.7%-3.1%) had unknown DM. The prevalence of DM increased with age and was higher in men than in women. The age- and sex-adjusted prevalence of prediabetes was 16.5% (95%CI 14.8%-18.2%), with the highest percentage in the 60-79 year age group and in women. Obesity, abdominal obesity, dyslipidemia, low education level, and a family history of diabetes were associated with glucose metabolism disorders. CONCLUSIONS: The PREDATORR study shows a high prevalence of impaired glucose regulation in the adult Romanian population, providing data on the prevalence of DM and prediabetes and their association with several risk factors.

Prevalence of chronic kidney disease and its association with cardio-metabolic risk factors in the adult Romanian population: the PREDATORR study.

PURPOSE: PREDATORR is the first national study analyzing the prevalence of chronic kidney disease and its prognosis and association with socio-demographic, cardio-metabolic and lifestyle risk factors in the adult Romanian population. METHODS: Chronic kidney disease was defined according to the KDIGO 2012 criteria as an estimated glomerular filtration rate <60 mL/min/1.73 m(2) and/or urinary albumin-to-creatinine ratio ≥30 mg/g. The socio-demographic, lifestyle and anamnestic data were collected through interviewer-administered questionnaires. Physical examination and biochemical assays were also performed. RESULTS: This cross-sectional study conducted between December 2012 and February 2014 in Romania included 2717 adults. The overall age- and sex-adjusted prevalence of chronic kidney disease was 6.74 % (95 %CI 5.60-7.88 %), of which 3.31 % (2.50-4.13 %) had only reduced kidney function (estimated glomerular filtration rate <60 mL/min/1.73 m(2)), 2.98 % (2.21-3.76 %) had only albuminuria, and 0.45 % (0.14-0.74 %) had both. The prevalence of chronic kidney disease increased with age and was similar in women and in men. Age, hyperuricemia, impaired glucose regulation (diabetes/prediabetes), hypertriglyceridemia and a family history of renal disease were independent risk factors for the presence of chronic kidney disease. CONCLUSIONS: The PREDATORR study showed a high prevalence of chronic kidney disease in the adult Romanian population providing data on its prognosis and association with several cardio-metabolic risk factors.

Pitfalls in diagnosing a pancreatic neuroendocrine tumor: a case report.

Pancreatic neuroendocrine tumors are a rare subset of pancreatic neoplasms. We report the case of a 33-year-old female patient who was admitted to the Diabetes Clinic of Craiova, Romania, due to a two-year history of episodic neuroglycopenic hyperinsulinemic hypoglycemic symptoms, suggestive for insulinoma associated with facial and upper trunk flushing characteristic to carcinoid syndrome. During these episodes, the laboratory investigations showed hypoglycemia (38 mg/dL), hyperinsulinemia (54.72 µU/mL) and normal values of beta-hydroxybutyrate, chromogranin A, serotonin, anti-insulin antibodies and urinary levels of 5-hydroxyindoleacetic acid. Endoscopic ultrasound with SonoVue and 3T MRI revealed an 18.3/16.3 mm hypervascular tissular mass situated in the uncinate process of the pancreatic head in close contact with the superior mesenteric vein without invasion and no other detectable secondary lesions in the pancreas or any other abdominal viscera. Patient underwent enucleation of pancreatic tumor. The histological and immunohistochemical findings indicated a functional well-differentiated pancreatic neuroendocrine tumor, G1 category according to the World Health Organization (WHO) criteria, with uncertain behavior (Ki67 index was 3%), confined to the pancreas, but with tumoral invasion of the delimiting conjunctive capsule. No evidence of tumoral CK19 staining, mitoses and necrosis, angioinvasion or extra-pancreatic invasion was observed. A post-operative nine-month follow-up showed resolution of hypoglycemic symptoms, normalized blood glucose and insulin levels and no evidence of recurrence. Our case report highlights the pitfalls in diagnosing a functional pancreatic neuroendocrine tumor due to atypical symptoms, the difficulty of identification and precise location of the small-size tumor and uncertain histopathological and immunohistochemical behavior.