The Genetics behind Sulfation: Impact on Airway Remodeling.

In COPD, chronic inflammation and exposure to irritants, such as cigarette smoke, lead to the thickening of bronchial walls. This results from increased deposition of collagen and other extracellular matrix components, contributing to the narrowing of airways. Nevertheless, it is widely recognized that COPD is an inflammatory disorder marked by partially reversible airflow limitation wherein genetic factors interact with the environment. In recent years, numerous investigations have substantiated the correlation between gene polymorphisms and COPD. SUMF1 has been implicated in diverse cellular processes, including lysosomal function and extracellular matrix maintenance, both of which play pivotal roles in respiratory health. The genetic variations in SUMF1 could lead to an imbalanced sulfation in the extracellular matrix of lung tissue, potentially playing a role in the onset of COPD. Recent studies have uncovered a potential link between dysregulation of SUMF1 and COPD progression, shedding light on its involvement in the abnormal sulfatase activity observed in COPD patients. Through a comprehensive review of current literature and experimental findings, this article aims to contribute to the growing body of knowledge surrounding the genetic intricacies concerning sulfation of airway remodeling and possible pharmacological applications in COPD and asthma management.

Circulating Ferritin in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

Objectives: To synthesize data on circulating ferritin between patients with histologically confirmed nonalcoholic fatty liver disease (NAFLD) and non-NAFLD controls. Methods: A systematic literature search was conducted in PubMed, Scopus, and the Cochrane Library. Thirty-one studies comprising data on 5631 individuals (2929 biopsy-proven NAFLD patients and 2702 controls) were included in the meta-analysis. Results: Higher circulating ferritin levels were observed in NAFLD patients than in controls [standardized mean difference (SMD) 1.14; 95% confidence interval (95% CI) 0.73-1.55], in patients with simple nonalcoholic fatty liver (NAFL) than in controls (SMD 0.57; 95% CI 0.34-0.80), in patients with nonalcoholic steatohepatitis (NASH) than in controls (SMD 0.95; 95% CI 0.69-1.22), and in NASH than in NAFL patients (SMD 0.62; 95% CI 0.25-0.99). There was moderate-to-high heterogeneity among studies in the above pairs of comparisons (I2 = 68-97%); no risk of publication bias was observed by Egger's test (P = 0.81, P = 0.72, P = 0.59, P = 0.42, respectively). The heterogeneity was reduced in the subgroup of biopsy-proven controls in all pairs of comparisons (I2 = 0-65%). The heterogeneity was also reduced after excluding studies with the Newcastle-Ottawa Scale (NOS) score <7 (n = 10) for the comparison of NAFLD patients vs. controls (I2 = 54%, P = 0.02). The meta-regression analysis revealed that the male ratio was positively associated with ferritin SMD in the comparison between NAFLD patients and controls and accounted for 32.7% (P = 0.002) of the heterogeneity in this pair of comparison. Conclusions: Circulating ferritin was higher in NAFLD (or NAFL or NASH) patients compared with controls. Higher levels of circulating ferritin were also associated with the severity of the disease, which, however, should be cautiously interpreted.PROSPERO registration ID: CRD42022354025.

Partial validation of a six-month high-fat diet and fructose-glucose drink combination as a mouse model of nonalcoholic fatty liver disease.

PURPOSE: The need to investigate the pathogenesis and treatment of nonalcoholic fatty liver disease (NAFLD) has led to the development of multiple mouse models. The aim of this study was to validate a fast food diet (FFD) mouse model that is introduced as being close to the human disease. METHODS: Eight to nine weeks old male and female C57BL/6 J mice were randomly allocated to a FFD group or to a chow diet (CD) group. Every four weeks, mice were weighed, and blood samples were collected for the measurement of glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TGs) and total cholesterol. After 25 weeks, mice were sacrificed, and liver tissue was histologically evaluated. RESULTS: FFD mice gained more weight (p = 0.049) and presented a higher liver-to-body weight ratio (p < 0.001) compared to CD mice. FFD group presented with greater steatosis, hepatocellular ballooning and NAFLD activity score (NAS), whereas lobular inflammation and fibrosis were not significantly different compared to CD. When stratified by sex, NAS was different between FFD and CD groups in both male and female mice. Group by time interaction was significant for weight, ALT and cholesterol, but not for glucose, AST and TGs. CONCLUSION: FFD mice presented with morphologic and biochemical features of NAFLD and with greater hepatic steatosis, hepatocellular ballooning and NAS, but not lobular inflammation and fibrosis, compared to CD mice. These results only partly validate the FFD mouse model for NAFLD, at least for a 6-month feeding period.

Animal studies on glucagon-like peptide-1 receptor agonists and related polyagonists in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic liver disease closely associated with the epidemics of obesity and type 2 diabetes mellitus (T2DM), but without licensed pharmacological treatment to date. As glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved anti-diabetic and anti-obesity medications, they were also considered a potential therapeutic option for NAFLD. Preclinical studies suggest that GLP-1RAs have a beneficial effect on major NAFLD histological outcomes, i.e., hepatic steatosis and inflammation, through multiple intrahepatic mechanisms, including increased fatty acid ß-oxidation, activation of autophagy, suppression of inflammation, and oxidative stress. Data on hepatic fibrosis are limited or inconclusive, although some studies reported improvement in indices of fibrosis or prevention of fibrosis initiation or reduction of collagen deposition. Whether the positive impact of GLP-1RAs on hepatic histology is indirect, i.e., through their action on extrahepatic tissues, or whether their action is direct, i.e., through activating GLP-1R on the hepatocytes, is still a controversial issue. Alongside GLP-1RAs, newly emerging peptide polyagonists (i.e., synthetic molecules that combine the amino acid sequences of more than one peptide, thus having the ability to bind more than one receptor) are now being investigated in NAFLD with high expectations. This review summarizes the existing knowledge derived from animal studies on the effects of GLP-1RAs and GLP-1RA related peptide polyagonists on NAFLD in an attempt to illuminate areas of uncertainty and provide the groundwork for future animal and clinical research in the field.

The role of glucagon-like peptide-1 receptor agonists in nonalcoholic fatty liver disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease, associated with obesity, type 2 diabetes mellitus and dyslipidemia, which can lead to liver cirrhosis and hepatocellular carcinoma in some patients. Apart from lifestyle modifications, which are the cornerstone for its management, several drugs are under evaluation, including glucagon-like peptide-1 receptor agonists (GLP-R1RAs). In this review, we summarized major clinical data concerning the effects of GLP-1RAs on NAFLD, trying to highlight existing knowledge and to elucidate areas of uncertainty, thus providing clues to potential clinical implications and research. AREAS COVERED: Selected clinical studies on GLP-R1As in NAFLD are presented in this narrative review. EXPERT OPINION: There is evidence that treatment with GLP-R1As in NAFLD has beneficial effects on NAFLD, i.e. improvement in liver function tests and histological improvement in hepatic steatosis and inflammation, but not fibrosis. Further research is required toward the early use of GLP-R1Αs, i.e. in NAFLD patients without fibrosis to evaluate whether they may prevent the progression to fibrosis, or in patients with advanced disease in combination with other medications, which may have additive or even synergistic effects on NAFLD.

Staphylococcus aureus enterotoxin A- and B-specific IgE in chronic obstructive pulmonary disease.

Sensitization to Staphylococcus aureus enterotoxins A (SEA) and B (SEB) has been associated with asthma severity, exacerbations, and disease control. Our study aimed to investigate if there are differences in serum SEA-IgE and SEB-IgE levels between patients with chronic obstructive pulmonary disease (COPD), asthma, and controls, and to assess the association between SE sensitization and COPD clinical parameters and Th2 inflammation biomarkers in two well-defined COPD cohorts. Our findings suggest that COPD patients do not exhibit higher SEA and SEB sensitization compared to asthma patients and controls. However, in COPD patients, the presence of atopy and allergy is associated with positivity for SEA-IgE and SEB-IgE. Consequently, these allergens may aid in identifying atopic or allergic subgroups within the COPD population, but they are not directly associated with the diagnosis of COPD, elevated circulating blood eosinophils, or fractional exhaled nitric oxide (FENO) levels.

Individualized heparin monitoring and management reduces protamine requirements in cardiac surgery on minimal invasive extracorporeal circulation; A prospective randomized study.

INTRODUCTION: Individualized heparin and protamine management is increasingly used as a strategy to reduce coagulation activation and bleeding complications. While it is associated with increased heparin requirements during Cardiopulmonary Bypass (CPB), the impact on protamine administration remains controversial. We aim to investigate the effect of heparin level-guided monitoring on protamine dosing during cardiac surgery where low-anticoagulation protocols are implemented. METHODS: This is a prospective, randomized, controlled trial. A total of 132 patients undergoing elective full-spectrum cardiac surgery with Minimal Invasive Extracorporeal Circulation (MiECC) were recruited. All patients were managed by the same anaesthetic, surgical and perfusion team. Patients were randomly allocated in two groups; the individualized heparin-protamine titration (IHPT) group and the conventional heparinization and reversal group by using ACT (cACT) with a 0.75:1, protamine: heparin ratio. Titration was accomplished with the Hepcon HMS Plus (Medtronic, Minneapolis, MN) system. The primary outcome of the study was the total protamine dose used. Secondary outcomes comprised of the total heparin dose, the percentage of patients achieving target ACT, 24-h transfusion requirements, postoperative bleeding, duration of mechanical ventilation, major morbidity and length of hospital stay. Patients in each group were divided in two subgroups according to the target ACT; those operated for coronary artery bypass grafting (CABG) using a target ACT >300 s and the rest (non-CABG) patients operated with a target ACT >400 s, respectively. RESULTS: Protamine requirements were significantly reduced when IHPT was implemented; CABG (118 ± 24 mg vs 163 ± 61 mg; p < 0.001) and non-CABG cases (151 ± 46 mg vs 197 ± 45 mg; p < 0.001). Moreover, heparin requirements were significantly higher in the non-CABG subgroup managed with IHPT (34,539 ± 7658 IU vs 29,893 ± 9037 IU; p = 0.02). In overall, no significant differences were detected with respect to postoperative bleeding, transfusion of RBC or other blood products. CONCLUSIONS: Individualized heparin monitoring and management reduces protamine requirements in cardiac surgery with MiECC implementing reduced anticoagulation strategy. TRIAL REGISTRATION: clinicaltrials.gov; NCT04215588.

Retinal Vascular Lesions in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Background: This systematic review and meta-analysis aimed to summarize and compare data on retinal vascular lesions between patients with nonalcoholic fatty liver disease (NAFLD) and individuals without the disease. Methods: Search was performed in PubMed, Scopus and Cochrane Library, complemented by handsearching (PROSPERO ID: CRD42022345558). Thirty-six studies comprising 24,985 individuals (12,387 NAFLD patients and 12,598 controls) were selected for the meta-analysis. Results: Apart from retinopathy, no study with a different type of retinal vascular lesion was retrieved. Overall, there was no significant difference in the presence of retinopathy in NAFLD patients compared to controls (Odds Ratio (OR) = 1.20; 95% Confidence Interval (CI): 0.91-1.59). Heterogeneity among studies was high (I2 = 93%; p < 0.00001), while Egger's test revealed no publication bias (p = 0.60). However, subgroup analysis showed positive association between retinopathy and NAFLD in type 1 diabetes mellitus (T1DM) (OR = 2.35; 95% CI: 1.53-3.60), but not in type 2 diabetes mellitus patients. Meta-regression analysis exploring potential confounders revealed no significant association. Conclusions: The presence of retinopathy was not overall different between individuals with and without NAFLD; however, T1DM patients with NAFLD had higher rates of retinopathy compared to T1DM patients without NAFLD, a finding warranting further research to show whether NAFLD may predict retinopathy in T1DM patients.

Effect of common OPRM1, COMT, SLC6A4, ABCB1, and CYP2B6 polymorphisms on perioperative analgesic and propofol demands on patients subjected to thyroidectomy surgery.

BACKGROUND: Perioperative anesthetic and/or analgesic demand present considerable variation, and part of that variation appears to be genetic in origin. Here we investigate the impact of common polymorphisms in OPRM1, COMT, SLC6A4, ABCB1, and CYP2B6 genes, on the intra-operative consumption of remifentanil and propofol, as well as the postoperative analgesic needs, in patients subjected to thyroidectomy surgery. METHODS: We conducted a prospective cohort study with 90 patients scheduled to undergo elective thyroidectomy, under total intravenous anesthesia achieved by target control infusion (TCI) of propofol and remifentanil. Postoperative analgesics were administered by protocol and on-demand by the individual patient. Genotyping was established by PCR-RFLP methods. Genotyping data, intra-operative hemodynamics, and total consumption of remifentanil and propofol, as well as postoperative analgesic needs and pain perception, were recorded for each individual. RESULTS: Patients with the ABCB1 3435TT genotype appeared to experience significantly less pain within one hour post-operatively, compared to C carriers [mean VAS (SD) = 0.86 (1.22) vs. 2.42 (1.75); p = 0.017], a finding limited to those seeking rescue analgesic treatment. Intra-operatively, homozygotes patients for the minor allele of OPRM1 A118G and CYP2B6 G516T appeared to consume less remifentanil [mean (SD) = 9.12 (1.01) vs. 13.53 (5.15), for OPRM1 118GG and A carriers] and propofol [median (range) = 14.95 (11.53, 1359.5) vs. 121.4 (1.43, 2349.4), for CYP2B6 516TT and G carriers, respectively] but the difference was not statistically significant in our sample. CONCLUSIONS: The ABCB1 C3435T polymorphism appears to affect the postoperative perception of surgical pain among patients with low pain threshold. The small number of minor allele homozygotes for the OPRM1 A118G and CYP2B6 G516T polymorphisms precludes a definitive conclusion regarding the inclusion of the latter in a TCI-programming algorithm, based on the results of this study. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12616001598471.

Association between hepatic steatosis and fibrosis indices and dietary habits, physical activity, and quality of life.

BACKGROUND AND STUDY AIMS: This cross-sectional study aimed to evaluate the association between hepatic steatosis and fibrosis indices and adherence to the Mediterranean diet (MD), physical activity (PA), and quality of life (QoL) in individuals unaware of the status of their liver. PATIENTS AND METHODS: Participants were asked to complete three questionnaires validated in Greek, namely: (1) the Chronic Liver Disease Questionnaire (CLDQ) for QoL assessment; (2) the semi-quantitative Food Frequency Questionnaire (FFQ), from which the MedDietScore was calculated; and (3) the International Physical Activity Questionnaire (IPAQ) for PA evaluation. Hepatic steatosis was evaluated using the Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), and Lipid Accumulation Product (LAP). Hepatic fibrosis was evaluated using the NAFLD Fibrosis Score (NFS), Fibrosis-4 (FIB-4), and AST-to-platelet ratio index (APRI). RESULTS: This study recruited 200 participants (90% men) aged 36 ± 6 years. Hepatic steatosis indices were not associated with MedDietScore and QoL. In terms of PA, univariable analysis showed that higher values of hepatic steatosis indices were associated with less intense activity. This association remained significant only for HSI during multivariable analysis (moderate activity vs. low activity: beta: -2.0, 95% confidence interval (CI): -3.5, -0.37, p = 0.016; and high activity vs. low activity: beta: -3.3, 95% CI: -5.03, -1.60, p < 0.001), after controlling for age, waist circumference, and the presence of metabolic syndrome. When using hepatic fibrosis indices, none of the participants had high probability of advanced hepatic fibrosis or cirrhosis (F3-F4). Consequently, we were unable to extensively evaluate the association between hepatic fibrosis indices and lifestyle characteristics or QoL. CONCLUSION: We showed that HSI, but not other steatosis indices, remained robustly associated with PA after adjusting for potential confounders in a population unaware of the presence of fatty liver.

Circulating adiponectin in patients with nonalcoholic fatty liver disease-related liver fibrosis: A systematic review and a meta-analysis.

BACKGROUND AND AIM: There are conflicting data on adiponectin concentrations in nonalcoholic fatty liver disease (NAFLD). The main aim was to compare circulating total adiponectin concentrations in NAFLD patients with versus without liver fibrosis. METHODS: A systematic search was performed in PubMed, Scopus, and Cochrane Library. Twenty-two studies comprising 1753 biopsy-proven NAFLD individuals (1290 with and 463 without fibrosis) were included in the meta-analysis. RESULTS: There was no difference in adiponectin concentration between NAFLD patients with versus without fibrosis (standardized mean difference [SMD]: -0.15; 95% confidence interval [95% CI]: -0.35 to 0.05). Heterogeneity was moderate among studies (Ι2 : 60%, P < 0.001); no risk of publication bias was observed (Egger's test; P = 0.37). The sensitivity analysis, performed after the exclusion of studies with (i) children/adolescents and morbidly obese patients (n = 3) and (ii) adiponectin measurement with other methods than enzyme-linked immunosorbent assay (ELISA) (n = 9), revealed significantly lower adiponectin concentrations in NAFLD patients with fibrosis (i) SMD: -0.23, 95% CI: -0.41 to -0.04; (ii) SMD: -0.30, 95% CI: -0.55 to -0.04, respectively). Meta-regression analysis revealed no significant association of adiponectin SMD with age, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl-transferase, homeostasis model assessment insulin resistance and the proportion of men. CONCLUSIONS: Overall, patients with NAFLD and fibrosis had similar adiponectin concentrations with patients with NAFLD without fibrosis. However, adiponectin concentration was lower in NAFLD patients with fibrosis than those without fibrosis within the adult patients without morbid obesity and in studies in which adiponectin was measured with the same method (ELISA).

Anti-obesity Medications for the Management of Nonalcoholic Fatty Liver Disease.

PURPOSE OF REVIEW: Obesity is closely associated with nonalcoholic fatty liver disease (NAFLD), a highly prevalent disease without any approved medication. The aim of this review was to summarize the evidence on the effect of anti-obesity medications on NAFLD, especially focusing on hepatic histology. RECENT FINDINGS: Orlistat and some glucagon-like peptide-1 receptor analogs, including liraglutide and semaglutide, have beneficial effects on hepatic steatosis and inflammation, but not fibrosis. Other anti-obesity medications, including lorcaserin, setmelanotide, phentermine hydrochloric, phentermine/topiramate, and naltrexone/bupropion, have been minimally investigated in NAFLD. Furthermore, medications like sodium-glucose cotransporter-2 inhibitors and farnesoid X receptor have shown beneficial effects in both NAFLD and obesity, but they have not been licensed for either disease. Liraglutide, semaglutide, and orlistat may be currently used in selected patients with obesity and NAFLD. Further research is warranted, since targeting obesity may provide additional benefits on its comorbidities, including NAFLD.

Nonalcoholic fatty liver disease and osteoporosis: A potential association with therapeutic implications.

Nonalcoholic fatty liver disease (NAFLD) and osteoporosis are two highly prevalent metabolic diseases. Increasing experimental evidence supports a pathophysiological link between NAFLD and osteoporosis. A key feature could be chronic, low-grade inflammation, which characterizes NAFLD and possibly affects bone metabolism. In this context, several factors, including but not limited to receptor activator of nuclear factor kappa-B ligand, osteoprotegerin, osteopontin and osteocalcin, may serve as mediators. In the clinical setting, most but not all epidemiological evidence indicates that NAFLD is associated with lower bone mineral density or osteoporosis in adults. Although an association between NAFLD and osteoporosis has not yet been established, and thus remains speculative, pharmacological considerations already exist. Some of the current and emerging pharmacological options for NAFLD have shown possible anti-osteoporotic properties (eg, vitamin E, obeticholic acid, semaglutide), while others (eg, pioglitazone, canagliflozin) have been associated with increased risk of fractures and may be avoided in patients with NAFLD and concomitant osteoporosis, especially those at high fracture risk. Conversely, some anti-osteoporotic medications (denosumab) might benefit NAFLD, while others (raloxifene) might adversely affect it and, consequently, may be avoided in patients with osteoporosis and NAFLD. If an association between NAFLD and osteoporosis is established, a medication that could target both diseases would be a great advancement. This review summarizes the main experimental and clinical evidence on the potential association between NAFLD and osteoporosis and focuses on treatment considerations derived from this potential association.

Inflammatory Bowel Disease-associated Fatty Liver Disease: the Potential Effect of Biologic Agents.

Inflammatory bowel diseases [IBD] exhibit intestinal and systemic manifestations. Nonalcoholic fatty liver disease [NAFLD] is a common co-existing condition, possibly contributing to the cardio-metabolic burden and overall morbidity. Εmerging therapeutic choices of biologic agents have modified the clinical course of IBD; however, their impact on IBD-associated NAFLD has not been extensively evaluated. The prevalence of NAFLD varies among IBD patients, but it appears higher than in the general population in the majority of quality studies. In terms of pathogenetic and risk factors of NAFLD, they may vary with IBD activity. Dysbiosis, mucosal damage, and cytokine release have been implicated in the pathogenesis during the relapses, whereas metabolic risk factors seem to play a dominant role during the remissions of IBD. Considering biologics, although quality data are scarce, agents suppressing tumour necrosis factor may offer potential benefits in IBD-associated NAFLD, whereas anti-integrins do not appear to confer any therapeutic advantage. In conclusion, IBD-associated NAFLD possibly follows two different patterns, one manifested during the relapses and one during the remissions of IBD. Some, but not all, biologics may benefit NAFLD in patients with IBD. Further mechanistic and prospective cohort studies are warranted to illuminate the effects of various biologics on NAFLD.

Nonalcoholic fatty liver disease: lifestyle and quality of life.

Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder whose current rapidly expanding prevalence is causing it to develop into a major global health concern. NAFLD is closely linked to the modern, unhealthy lifestyle. The Western diet, characterized by excessive energy intake, frequent consumption of red meat, processed meat and foods, soft drinks, and sugar-sweetened beverages (SSBs), irregular meal distribution throughout the day, and unhealthy ways of cooking, predisposes to development of NAFLD. Low levels of physical activity and prolonged sedentary time are additional lifestyle risk factors for NAFLD. Given the present lack of effective pharmacological treatment, lifestyle modifications are regarded as the cornerstone of NAFLD management. Reducing daily calorie intake together with following the Mediterranean diet (MD) is an increasingly accepted approach. Furthermore, increasing the level of physical activity and limiting sedentary behavior are additional measures proposed to improve the outcomes of the disease. Apart from being affected by lifestyle, NAFLD may also affect patients' quality of life (QoL), mostly in the domain of physical function. In this regard, while the early and more benign form of the disease, i.e., simple hepatic steatosis, may not affect QoL, there is evidence, though conflicting, of the impact of nonalcoholic steatohepatitis (NASH) on this index, with, however, most studies showing that QoL is consistently affected in advanced disease, i.e., hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Considering all the above, appropriate management of lifestyle is likely to attenuate the severity of the disease and improve the QoL of NAFLD patients.

Adult hypophosphatasia treated with reduced frequency of teriparatide dosing.

We report a 41-year-old man diagnosed with the adult form of hypophosphatasia (HPP) and treated for 4 years with less frequent than conventional daily doses of teriparatide (TPTD). He presented with a history of three low-energy fractures and low bone mineral density (BMD) ineffectively treated with bisphosphonate. We identified within ALPL, the gene that encodes the homodimeric "tissue-nonspecific" isoenzyme of alkaline phosphatase (ALP) and underlies HPP, a heterozygous missense mutation (c.455 G>A→R135H). Characteristic painful periarticular calcification removed at a shoulder did not recur. However, access to medical treatment with asfotase alfa (AA) was denied. After he sustained a low-energy metatarsal fracture, we administered TPTD subcutaneously "off-label" at 20 µg/d. An elbow fracture occurred two months later. Five months afterwards, due to his limited number of approved TPTD doses, TPTD treatment was extended using alternate-day dosing. Although his serum ALP activity did not increase (33-48 U/l; reference range 40-120) with 4 years of TPTD treatment, his BMD improved 15% in the lumbar spine and 6% in the femoral neck with no further fractures. Our experience represents success overcoming two prescription deadlocks; AA was denied for adult HPP, and TPTD was not to be administered daily for more than two years.

Sodium-glucose co-transporter 2 inhibitors in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is considered the most prevalent chronic hepatic disease, as it has been estimated that one of four individuals in the general population has been affected by NAFLD. The evolution of the referred entity, which includes nonalcoholic steatohepatitis (NASH) and hepatic fibrosis, may have crucial and even fatal consequences, leading to cirrhosis and hepatocellular carcinoma. Although NAFLD has also been linked with cardiovascular and renal diseases, and all-cause mortality increment, pharmacological therapy is as yet an unfulfilled demand. Since NAFLD is closely associated with type 2 diabetes mellitus (T2DM), a variety of anti-diabetic drugs have been investigated for their effectiveness towards NAFLD. Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) improve blood glucose levels through increasing renal glucose excretion and they are recommended as one of standard therapeutic categories for T2DM patients. Based on preclinical animal studies, SGLT-2i have shown a beneficial effect on NAFLD, inducing histologically proven amelioration of hepatic steatosis, inflammation and fibrosis. Promising data have been also derived by clinical trials, which have indicated a potentially beneficial effect of SGLT-2i on NAFLD, at least in terms of liver function tests and imaging. Thus, it is not strange that there are many ongoing trials on the effect of various SGLT-2i in NAFLD. In conclusion, current evidence concerning the effect of SGLT-2i on NAFLD is encouraging; however, data from ongoing clinical trials with histological endpoints are awaited.

A Study of Blood Fatty Acids Profile in Hyperlipidemic and Normolipidemic Subjects in Association with Common PNPLA3 and ABCB1 Polymorphisms.

Adiponutrin (patatin-like phospholipase domain-containing 3; PNPLA3), encoded in humans by the PNPLA3 gene, is a protein associated with lipid droplet and endoplasmic reticulum membranes, where it is apparently involved in fatty acid redistribution between triglycerides and phospholipids. A common polymorphism of PNPLA3 (I148M, rs738409), linked to increased PNPLA3 presence on lipid droplets, is a strong genetic determinant of non-alcoholic fatty liver disease (NAFLD) and of its progression. P-glycoprotein (Pgp, MDR1, ABCB1), encoded by the ABCB1 gene, is another membrane protein implicated in lipid homeostasis and steatosis. In the past, common ABCB1 polymorphisms have been associated with the distribution of serum lipids but not with fatty acids (FA) profiles. Similarly, data on the effect of PNPLA3 I148M polymorphism on blood FAs are scarce. In this study, a gas chromatography-flame ionization detection (GC-FID) method was optimized, allowing us to analyze twenty FAs (C14: 0, C15: 0, C15: 1, C16: 0, C16: 1, C17: 0, C17: 1, C18: 0, C18: 1cis, C18: 2cis, C20: 0, C20: 1n9, C20: 2, C20: 3n6, C20: 4n6, C20: 5, C23: 0, C24: 0, C24: 1 and C22: 6) in whole blood, based on the indirect determination of the fatty acids methyl esters (FAMES), in 62 hyperlipidemic patients and 42 normolipidemic controls. FA concentrations were then compared between the different genotypes of the rs738409 and rs2032582 (ABCB1 G2677T) polymorphisms, within and between the hyperlipidemic and normolipidemic groups. The rs738409 polymorphism appears to exert a significant effect on the distribution of blood fatty acids, in a lipidemic and fatty acid saturation state-depending manner. The effect of rs2032582 was less pronounced, but the polymorphism did appear to affect the relative distribution of blood fatty acids between hyperlipidemic patients and normolipidemic controls.

Epidemiology, Pathogenesis, Diagnosis and Emerging Treatment of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with an estimated rising prevalence, in concert with the epidemics of obesity and type 2 diabetes. The pathogenesis of NAFLD is not fully elucidated. Besides weight gain and insulin resistance, many other factors seem to contribute, including adipokines, gut microbiota and genetic predisposition. The disease starts as hepatic steatosis, which may proceed to nonalcoholic steatohepatitis (NASH); if fibrosis is added, the risk of cirrhosis and/or hepatocellular carcinoma is augmented. Liver biopsy is considered the gold standard for the diagnosis and staging of NAFLD; the early use of reliable and easily applied diagnostic tools, such as noninvasive biomarkers, is needed to identify patients at different-preferably early-stages of disease however. Whilst lifestyle modification is the first step to manage NAFLD, there is poor compliance, leading to the need of drug therapy. Accordingly, a variety of medications is under investigation. Given the multifaceted pathophysiology of NAFLD, probably, a combination of approaches in an individualized basis may be a more appropriate management. This review summarizes evidence on the epidemiology, pathogenesis, diagnosis and treatment of NAFLD.