Nonalcoholic fatty liver disease (NAFLD) has become globally prevalent and is the leading cause of chronic liver disease. Although NAFLD is reversible without medical intervention in the early stage, the condition could be sequentially worsened to nonalcoholic steatohepatitis (NASH) and, eventually, cirrhosis and hepatic cancer. The progression of NAFLD is related to various factors such as genetics, pre-disposed metabolic disorders, and immunologic factors. Thankfully, to date, there have been accumulating research efforts and, as a result, different classes of potent drug candidates have been discovered. In addition, there have also been various attempts to explore pharmaceutical strategies to improve the druggability of drug candidates. In this review, we provided a brief overview of the drug candidates that have undergone clinical trials. In the latter part, strategies for developing better drugs are discussed.

Pharmaceutical Strategies to Improve Druggability of Potential Drug Candidates in Nonalcoholic Fatty Liver Disease Therapy

Hepatic fat accumulation is the hallmark of non-alcoholic fatty liver disease (NAFLD). Our aim was to determine the plasma levels of oxylipins, free polyunsaturated fatty acids (PUFA) and markers of lipid peroxidation in patients with NAFLD in progressive stages of the pathology. Ninety 40–60-year-old adults diagnosed with metabolic syndrome were distributed in without, mild, moderate or severe NAFLD stages. The free PUFA and oxylipin plasma levels were determined by the UHPLC–MS/MS system. The plasma levels of oxylipins produced by cyclooxygenases, lipoxygenases and cytochrome P450, such as prostaglandin 2α (PGF2α), lipoxinB4 and maresin-1, were higher in severe NAFLD patients, pointing to the coexistence of both inflammation and resolution processes. The plasma levels of the saturated oxylipins 16-hydroxyl-palmitate and 3-hydroxyl-myristate were also higher in the severe NAFLD patients, suggesting a dysregulation of oxidation of fatty acids. The plasma 12-hydroxyl-estearate (12HEST) levels in severe NAFLD were higher than in the other stages, indicating that the hydroxylation of saturated fatty acid produced by reactive oxygen species is more present in this severe stage of NAFLD. The plasma levels of 12HEST and PGF2α are potential candidate biomarkers for diagnosing NAFLD vs. non-NAFLD. In conclusion, the NAFLD progression can be monitored by measuring the plasma levels of free PUFA and oxylipins characterizing the different NAFLD stages or the absence of this disease in metabolic syndrome patients.

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Polyunsaturated and Saturated Oxylipin Plasma Levels Allow Monitoring the Non-Alcoholic Fatty Liver Disease Progression to Severe Stages

Purpose The triglyceride-glucose (TyG) index is a new index of insulin resistance (IR), and its association with hyperuricemia (HUA) is unclear. The aim of this study was to investigate whether TyG is an independent risk factor for hyperuricemia (HUA) in patients with nonalcoholic fatty liver disease (NAFLD). Patients and Methods We retrospectively analyzed 461 patients with ultrasound-confirmed NAFLD and calculated the TyG index. Multivariate logistic regression was used to analyze the relationship between the TyG index and HUA in NAFLD patients. The correlation between the TyG index and HUA was further confirmed by a restricted cubic spline. Furthermore, the stability of the association between TyG index and HUA was examined using subgroup analysis. Receiver operating characteristic (ROC) curves were constructed to evaluate the predictive value of the TyG index on HUA. Multivariate linear regression was used to analyze the linear relationship between the TyG index and serum uric acid. Results A total of 166 HUA patients and 295 non-HUA patients were included in the study. The results of multivariate logistic regression analysis showed that after controlling the confounding risk factors, TyG was still an independent risk factor for HUA (OR = 2.00, 95% CI: 1.38 −2.91, p < 0.001). Restricted cubic splines showed that HUA risk increased linearly with TyG across the entire TyG range. The ROC curve showed that TyG index was better than triglyceride in predicting HUA in NAFLD patients, with AUC values of 0.62 and 0.59, respectively. Multiple linear regression analysis showed that TyG index was significantly positively correlated with blood uric acid (B = 1.37, 95% CI: 0.67–2.08, p < 0.001). Conclusion TyG index is an independent risk factor for HUA in patients with NAFLD. The increase of the TyG index level is closely related to the occurrence and development of HUA in patients with NAFLD.

Triglyceride-Glucose Index is Significantly Associated with the Risk of Hyperuricemia in Patients with Nonalcoholic Fatty Liver Disease

Abstract Purpose Retinol-binding protein 4 (RBP4) has been considered to be related to metabolic related diseases, such as hyperuricemia, obesity, and diabetes mellitus. However, whether nonalcoholic fatty liver disease (NAFLD) is related to RBP4 is unclear. Previous studies on the relationship between NAFLD and RBP4 levels have yielded inconsistent results. Hence, this meta-analysis was aimed to clarify whether circulating RBP4 levels are in relation to the risk of NAFLD. Methods A meta-analysis was performed by applying observational studies to evaluate circulating RBP4 levels and NAFLD. Eligible studies published up to September 23, 2022, were searched in Embase, PubMed, and Cochrane databases. Results In this study, 17 cross-sectional studies involving 8423 participants were included. Results from a random effects model showed that circulating RBP4 levels were higher in NAFLD patients than non-NAFLD (standardized mean difference (SMD) 0.28; 95% confidence intervals (CI): 0.11–0.46, I 2 : 89.8%). This association was confirmed in the Yellow race. However, no significant association was noted in the Caucasian race. After excluding the morbidly obese Population from the weight loss study ( n = 2), the results of the comparison remained largely unchanged (SMD 0.28; 95% CI: 0.10–0.47, I 2 : 90.8%). Remarkable publication bias was not found. Although considerable heterogeneity was observed among the studies, no potential sources of heterogeneity were found in the subgroup analysis. Diagnostic methods for NAFLD were determined to be a potential source of statistical heterogeneity in meta-regression. Conclusion The findings provide evidence that NAFLD patients exhibit higher levels of circulating RBP4 compared with controls, but high heterogeneity was observed. Thus, a high RBP4 level is probably a potential risk factor for NAFLD. To confirm the causal link between NAFLD and RBP4 level of causality, further prospective cohort studies are needed. 

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The relationship between NAFLD and retinol-binding protein 4 - an updated systematic review and meta-analysis

Purpose Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are frequently co-occurring diseases. Liver fibrosis (LF), with increasing incidence, has a prognostic value for NAFLD mortality. Our study aimed to investigate the relevant factors for FL in T2DM individuals with NAFLD. Patients and Methods A total of 565 T2DM patients with NAFLD from Hebei General Hospital participated in the study. Patients underwent an abdominal ultrasound, a questionnaire and laboratory tests. The fibrosis-4 index (FIB-4) was used to evaluate LF, with FIB ≥1.3 indicating LF and FIB ≥2.67 indicating F3-4 fibrosis. Results Compared with NLF group, LF group had higher levels of systolic blood pressure (SBP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transpeptidase (GGT). The glomerular filtration rate (GFR), low-density lipoprotein cholesterol (LDL), glycated hemoglobin (HbA1c), and platelets (PLT) in LF patients were lower than those without LF. Patients with LF were older than those without LF. ALT, AST, and GGT in patients with severe LF were higher than those with mild LF, while platelet was lower. Age, SBP, duration of diabetes, ALT, AST, and GGT were positively correlated with FIB-4, while eGFR, TC, LDL, and HbA1c were negatively correlated with FIB-4. Logistic regression showed that age, SBP, ALT, GGT, LDL, and PLT were independently associated with LF. Conclusion For T2DM patients combined with NAFLD, older age, higher SBP, higher ALT, higher GGT, lower LDL, and lower PLT were relevant factors for LF.

Factors Associated with Liver Fibrosis in Chinese Patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease

Purpose The triglyceride–glucose index (TyG) is positively correlated with serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM). However, whether this relationship exists in non-obese T2DM patients remains unknown. The study investigated the relationship between TyG and SUA in Chinese non-obese T2DM patients and examined the prognostic value of TyG in hyperuricemia (HUA). Patients and Methods In total, 719 T2DM patients who were not obese were enrolled from among those who visited the Hebei General Hospital. The patients were categorized into groups according to their SUA levels. The relationship between TyG and clinical parameters was examined through correlation analysis. To consider covariates and examine the independent impact of TyG on HUA, logistic regression was performed. The receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of TyG and homeostasis model assessment of insulin resistance (HOMA-IR) for HUA. Results The HUA prevalence was 12.10%. TyG was statistically different among the four SUA groups, with lower TyG levels in the Q1, Q2, and Q3 groups than that in the Q4 group. TyG was positively correlated with SUA (r = 0.176, P < 0.001). Logistic regression exhibited that TyG and SUA were independently correlated (OR = 2.427, 95% CI = 1.134-5.195, P = 0.022) even after adjustment for confounding factors. The ROC curve showed that the predictive value of TyG for HUA was higher than that of HOMA-IR (AUROC = 0.613, P = 0.001). Conclusion TyG was positively correlated with SUA in non-obese T2DM patients. TyG may better predict HUA in non-obese T2DM patients than HOMA-IR.

https://www.dovepress.com/getfile.php?fileID=85161

Association Between Triglyceride-Glucose Index and Serum Uric Acid Levels: A Biochemical Study on Anthropometry in Non-Obese Type 2 Diabetes Mellitus Patients

Background Consistent and effective self-management is a major challenge for people with diabetes and long-term effects can be difficult to sustain despite the many interventions. Interventions often fail to take patients’ perceptions of self-management into account from their perspective. Exploring the needs preferences and the influencing factors of self-management in patients can improve the effectiveness of self-management. Methods This study used a mixed research approach, exploring patient needs and preferences through web crawl methods and using qualitative interviews to explore the logic of preferences. 1605 data were obtained from 4 online health communities through web crawlers. Data were coded using grounded theory to analyze self-management needs. The codes were also coded for frequency statistics and ranked to explain the self-management preferences. The second phase explained the logic of the ranked distribution of preferences through one-on-one interviews with 22 patients. Results This study summarized six self-management needs of people with diabetes through web crawler data, among which medication management and conflict between disease and daily life were the most important concerns of patients. The reasons why patients are particularly concerned about these two needs were explored through qualitative interviews, and it was found that patients’ concerns about medication were mainly due to the following three aspects: the effect of drugs is direct and obvious, medication use makes life less complicated, and progressive side effects. The patients’ concerns about the conflict between disease and daily life are often caused by the following three aspects: diabetes impacts social roles, disease complicates life, and reducing the impact of the disease on life. Conclusion The self-management needs of Chinese diabetics have six themes. Medication management, conflict between disease and daily life, diet, diabetes knowledge, blood glucose monitoring and exerciseIn order of frequency of mention and possible preference: medication management, conflict between disease and daily life were the most frequent needs, while diet, knowledge about diabetes, blood glucose monitoring and exercise were their least frequent needs.Understanding the individual’s perception and understanding of diabetes self-management and the expression of the patient’s daily life situations can guide the medical team to optimize collaboration on personalized care plans.

A Mixed Methods Assessment of Self- Management Needs and Preferences of People with Type 2 Diabetes Mellitus in China

The prevalence of myopic macular degeneration (MMD) in the general population and patients with high myopia worldwide has not been fully investigated. Therefore, we screened all population-based studies that reported the prevalence of MMD, and pooled prevalence of MMD using a random-effect model. Subgroup analyses were performed to explore the differences in MMD prevalence in the general population and patients with high myopia according to ethnicity, region of residence (urban/rural), and grading system. Finally, 16 studies were included in this meta-analysis. Results obtained from 2,963 patients from seven countries on four continents indicated that the pooled prevalence of MMD in patients with high myopia was 49.0% (95% CI: 31.5%-66.7%). Results obtained from 71,052 participants from 10 countries on four continents suggested that the pooled prevalence of MMD in the general population was 1.7% (95% CI: 1.1%-2.6%). In the general population, living in urban areas and East Asians were associated with a high prevalence of MMD. Among patients with high myopia, only East Asians were at a higher risk of developing MMD. In conclusion, MMD was particularly prevalent in patients with high myopia. Compared with Europeans, East Asians (Chinese and Japanese) have a higher propensity of developing MMD, both in the general population and in patients with high myopia. It remains unclear whether the higher prevalence of MMD in patients with high myopia in East Asia is caused by differences in given age or given degree of myopia.Systematic review registration number: 202270014 (INPLASY.COM).

Xiaoyu He

Papers

The relationship between NAFLD and retinol-binding protein 4 - an updated systematic review and meta-analysis

Factors Associated with Liver Fibrosis in Chinese Patients with Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease

Association Between Triglyceride-Glucose Index and Serum Uric Acid Levels: A Biochemical Study on Anthropometry in Non-Obese Type 2 Diabetes Mellitus Patients

A Mixed Methods Assessment of Self- Management Needs and Preferences of People with Type 2 Diabetes Mellitus in China

Global prevalence of myopic macular degeneration in general population and patients with high myopia: A systematic review and meta-analysis.