Ursodeoxycholic acid as a means of preventing atherosclerosis,steatosis and liver fibrosis in patients with nonalcoholic fatty liver disease

BACKGROUNDAtherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD). Weight loss is a key factor for successful NAFLD and CVD therapy. Ursodeoxycholic acid (UDCA), which is one of the first-line therapeutic agents for treatment of NAFLD, is reported to have a beneficial effect on dyslipidemia and ASCVD risk because of antioxidant properties.AIMTo evaluate the effects of 6 mo of UDCA treatment on hepatic function tests, lipid profile, hepatic steatosis and fibrosis, atherogenesis, and ASCVD risk in men and women with NAFLD, as well as to assess the impact of > 5% weight reduction on these parameters.METHODSAn open-label, multicenter, international noncomparative trial was carried out at primary health care settings and included 174 patients with ultrasound-diagnosed NAFLD who received 15 mg/kg/d UDCA for 6 mo and were prescribed lifestyle modification with diet and exercise. The efficacy criteria were liver enzymes, lipid profile, fatty liver index (FLI), noninvasive liver fibrosis tests (nonalcoholic fatty liver disease fibrosis score and liver fibrosis index), carotid intima-media thickness (CIMT), and ASCVD risk score. To test statistical hypotheses, the Wilcoxon test, paired t-test, Fisher’s exact test, and Pearson''s chi-squared test were used. RESULTSThe alanine aminotransferase (ALT) level changed by -14.1 U/L (-31.0; -5.3) from baseline to 3 mo and by -6.5 U/L (-14.0; 0.1) from 3 to 6 mo. The magnitude of ALT, aspartate transaminase, and glutamyltransferase decrease was greater during the first 3 mo of treatment compared to the subsequent 3 mo (P < 0.001, P < 0.01, P < 0.001, respectively). At 6 mo, in the total sample, we observed a statistically significant decrease in body weight and levels of FLI: 84.9 ± 10.4 vs 72.3 ± 17.6, P < 0.001, total cholesterol: 6.03 ± 1.36 vs 5.76 ± 1.21, Р < 0.001, low-density lipoprotein: 3.86 ± 1.01 vs 3.66 ± 0.91, Р < 0.001, and triglyceride: 3.18 (2.00; 4.29) vs 2.04 (1.40; 3.16), Р < 0.001. No effect on nonalcoholic fatty liver disease fibrosis score or liver fibrosis index was found. The CIMT decreased significantly in the total sample (0.985 ± 0.243 vs 0.968 ± 0.237, P = 0.013), whereas the high-density lipoprotein (Р = 0.036) and 10-year ASCVD risk (Р = 0.003) improved significantly only in women. Fifty-four patients (31%) achieved > 5% weight loss. At the end of the study, the FLI decreased significantly in patients with (88.3 ± 10.2 vs 71.4 ± 19.6, P < 0.001) and without > 5% weight loss (83.5 ± 10.3 vs 72.8 ± 16.7, P < 0.001). The changes in ALT, aspartate transaminase, glutamyltransferase, total cholesterol, and low-density lipoprotein levels were similar between the subgroups.CONCLUSIONUDCA normalizes liver enzymes greatly within the first 3 mo of treatment, improves lipid profile and hepatic steatosis independent of weight loss, and has a positive effect on CIMT in the total sample and 10-year ASCVD risk in women after 6 mo of treatment.     

G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment

Nonalcoholic fatty liver disease(NAFLD)is a broad-spectrum disease,ranging from simple hepatic steatosis to nonalcoholic steatohepatitis,which can progress to cirrhosis and liver cancer.Abnormal hepatic lipid accumulation is the major manifestation of this disease,and lipotoxicity promotes NAFLD progression.In addition,intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins,resulting in progression of NAFLD to fibrosis and even cirrhosis.G protein-coupled receptors(GPCRs)have been shown to play essential roles in metabolic disorders,such as NAFLD and obesity,through their function as receptors for bile acids and free fatty acids.In addition,GPCRs link gut microbiota-mediated connections in a variety of diseases,such as intestinal diseases,hepatic steatosis,diabetes,and cardiovascular diseases.The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids.GPCR agonists,including peptides and natural products like docosahexaenoic acid,have been applied to investigate their role in liver diseases.Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome.This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment.Overall,understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.     

参泽舒肝胶囊联合多烯磷脂酰胆碱胶囊治疗非酒精性脂肪肝的临床研究

目的 研究参泽舒肝胶囊联合多烯磷脂酰胆碱胶囊治疗非酒精性脂肪肝的疗效。方法 将南方医科大学珠江医院2017年12月-2019年12月收治的非酒精性脂肪肝患者184例纳入本次研究,并以随机数表法将其分为试验组与对照组,每组92例。予以对照组患者多烯磷脂酰胆碱胶囊治疗,予以试验组患者多烯磷脂酰胆碱胶囊＋参泽舒肝胶囊治疗。比较两组患者治疗后临床疗效、治疗前后肝功能指标及血脂水平、血清学指标水平变化、肝脏B超评分与肝脾CT比值指标、用药不良反应情况等指标。结果 治疗后,试验组患者临床有效率（95.65%）高于对照组（86.96%）（P<0.05）;治疗前,两组患者谷丙转氨酶(aLanine aminotransferase,ALT)、谷草转氨酶(aspartate transaminase,AST)、高密度脂蛋白胆固醇（high density liptein cholesterol,HDL-C）、谷氨酰转肽酶(glutamyl transpeptidase,GGT)、总胆固醇(totalCholesterol,TC)、甘油三酯(triGlyceride,TG)、血清超氧化物歧化酶(superOxide dismutase,SOD)、丙二醛(malondialdehyde ,MDA)和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、B超评分与肝脾CT比值等指标比较,差异无统计学意义（P>0.05）;治疗后,两组患者ALT、AST、GGT水平降低,且试验组降低较明显（P<0.05）;两组TC及TG水平降低,HDL-C水平升高（P<0.05）;且试验组改善较明显（P<0.05）;两组患者SOD升高,MDA和TNF-α水平降低（P<0.05）;且试验组改善较明显（P<0.05）;两组患者治疗后B超评分均下降,肝脾CT比值均提升,试验组治疗后B超评分低于对照组,肝脾CT比值高于对照组（P<0.05）。两组患者均无不良反应。结论 参泽舒肝胶囊联合多烯磷脂酰胆碱胶囊治疗非酒精性脂肪肝疗效显著,且安全可行。     

甲氰咪胍在非酒精性脂肪性肝炎进展过程中对肝纤维化的影响

目的研究甲氰咪胍对金属蛋白酶组织抑制因子（TIMP）、基质金属蛋白酶（MMP）等纤维化相关指标的作用，探讨甲氰咪胍对NASH大鼠肝纤维化进展的影响。方法26只雄性SD大鼠随机分为正常饮食对照组（n=6）、高脂饮食模型组（n=10）和甲氰咪胍治疗组（n=10），实验时间12周。生化法检测血清AST、ALT、ALP、TBIL、肝组织1℃，放免法检测HA，RT-PCR法检测TIMP-1、TIMP-2、MMP2、MMP13 mRNA的表达。病理切片检查和Ⅰ型胶原免疫组化染色观察组织学改变。结果与模型组比较，治疗组大鼠肝功改善，HA水平下降，TIMP-1、TIMP-2、MMP2表达降低，但仍高于对照组，与模型组无显著差异，MMP13表达无降低。治疗组肝组织脂肪变改善，炎症减轻，Ⅰ型胶原沉积减少。结论甲氰咪胍具有一定抗纤维化的作用。     

Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease

AIM: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD), and progresses to the end stage of liver disease. Biochemical markers of liver fibrosis are strongly associated with the degree of histological liver fibrosis in patients with chronic liver disease. However, data are few on the usefulness of markers in NAFLD patients. The aim of this study was to identify better noninvasive predictors of hepatic fibrosis, with special focus on markers of liver fibrosis, type VI collagen 7S domain and hyaluronic acid. METHODS: One hundred and twelve patients with histologically proven NAFLD were studied. RESULTS: The histological stage of NAFLD correlated with several clinical and biochemical variables, the extent of hepatic fibrosis and the markers of liver fibrosis were relatively strong associated. The best cutoff values to detect NASH were assessed by using receiver operating characteristic analysis: type VI collagen 75 domain ≥5.0 ng/mL, hyaluronic acid ≥43 ng/mL. Both markers had a high positive predictive value: type VI collagen 7S domain, 86% and hyaluronic acid, 92%. Diagnostic accuracies of these markers were evaluated to detect severe fibrosis. Both markers showed high negative predictive values: type VI collagen 7S domain (≥5.0 ng/mL), 84% and hyaluronic acid (≥50 ng/mL), 78%, and were significantly and independently associated with the presence of NASH or severe fibrosis by logistic regression analysis. CONCLUSION: Both markers of liver fibrosis are useful in discriminating NASH from fatty liver alone or patients with severe fibrosis from patients with non-severe fibrosis.     

糖尿病合并非酒精性脂肪性肝病的治疗进展

随着生活水平的提高和生活方式的改变,糖尿病合并非酒精性脂肪性肝病(NAFLD)的发病率不断升高.虽有多种方法治疗糖尿病合并NAFLD,如生活方式的改变、增加胰岛素敏感性、抗氧化、调节血脂紊乱以及对一些风险因素的防治等,但由于其病因和发病机制尚未完全明了,仍缺乏更为有效的治疗方法.本文就近年来对糖尿病合并NAFLD的治疗进展作一综述.     

Nonalcoholic fatty liver disease and cardiovascular concerns: The time for hepatologist and cardiologist close collaboration

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver cell damage worldwide. It is strongly associated with an increased risk of cardiovascular disease (CVD). There are not enough recommendations for screening subjects with nonalcoholic steatohepatitis cirrhosis, who are not candidates for liver transplantation, nor who are asymptomatic with NAFLD without cirrhosis. In the current comprehensive narrative review, we aimed to evaluate the associations between CVD and NAFLD. Distinguishing the mechanisms linking these two disorders offers the opportunity to develop targeted therapies. Moreover, we will discuss screening approaches (whom and how-to) and treatment modalities proposed to reduce cardiovascular risk in patients with NAFLD.     

A PNPLA3 Polymorphism Confers Lower Susceptibility to Incident Diabetes Mellitus in Subjects With Nonalcoholic Fatty Liver Disease

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Impact of hypothyroidism on the development of non-alcoholic fatty liver disease: A 4-year retrospective cohort study

Background/Aims

Hypothyroidism is reported to contribute to the development of nonalcoholic fatty liver disease (NAFLD). We compared the risk of the development of NAFLD among three groups with different thyroid hormonal statuses (control, subclinical hypothyroidism, and overt hypothyroidism) in a 4-year retrospective cohort of Korean subjects.

Methods

Apparently healthy Korean subjects without NAFLD and aged 20-65 years were recruited (n=18,544) at health checkups performed in 2008. Annual health checkups were applied to the cohort for 4 consecutive years until December 2012. Based on their initial serum-free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels, they were classified into control, subclinical hypothyroidism (TSH >4.2 mIU/L, normal fT4), and overt hypothyroidism (TSH >4.2 mIU/L, fT4 <0.97 ng/dL) groups. NAFLD was diagnosed on the basis of ultrasonography findings.

Results

NAFLD developed in 2,348 of the 18,544 subjects, representing an overall incidence of 12.7%: 12.8%, 11.0%, 12.7% in the control, subclinical hypothyroidism, and overt hypothyroidism groups, respectively. The incidence of NAFLD did not differ significantly with the baseline thyroid hormonal status, even after multivariate adjustment (subclinical hypothyroidism group: hazard ratio [HR]=0.965, 95% confidence interval [CI]=0.814-1.143, P=0.67; overt hypothyroidism group: HR=1.255, 95% CI=0.830-1.899, P=0.28).

Conclusions

Our results suggest that the subclinical and overt types of hypothyroidism are not related to an increased incidence of NAFLD.