Non‐alcoholic fatty liver disease – histological scoring systems: a large cohort single‐center,evaluation study

Non‐alcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver disease. Till date, liver biopsy remains the gold standard for identification and quantification of the wide histological spectra of NAFLD. Histological scorings are very useful and widely applied for the diagnosis and management in clinical trials and follow‐up studies of non‐alcoholic steatohepatitis (NASH). However, in view of scarce published literature, there is a need to evaluate them in large cohort of NAFLD. This study was aimed to evaluate the two histological scoring systems (NAS‐CRN, SAF) in the diagnosis of NAFLD and to assess the role of histological characteristics as injury markers in NAFLD. Retrospective histological study of liver biopsies of 1000 patients diagnosed as NAFLD, between 2010 and 2016, was conducted. Histopathologic evaluation and semiquantiative scoring based on NAS‐CRN and SAF algorithm and their correlation with serum aminotransferase and fibrosis were performed. Liver biopsies were classified according to the NAS‐CRN scoring, as NAS <3 (not NASH) in 72 (7.2%), NAS 3–4 (borderline NASH) in 310 (31%), and NAS ≥5 (definite NASH) in 618 (61.8%), and SAF classified 117 (11.7%) not NASH and 883 (88.3%) definite NASH. There was excellent concordance for definite NASH and not NASH; however, 88.06% of borderline NASH was classified as NASH by SAF. 76.39% by NAS and 78.63% by SAF algorithm who were diagnosed as not NASH showed the presence of fibrosis; however, higher stages of fibrosis were significantly more prevalent in definite NASH, excluding burnt‐out cirrhosis. Serum ALT was significantly associated with increasing stages of fibrosis (p < 0.001) and the three categories (not NASH, borderline NASH, and definite NASH) when classified as with/without fibrosis (p < 0.001). Steatosis of higher grades, more ballooned cells, and more foci of Lobular Inflammation were found in significantly higher proportion of patients with NASH (p < 0.001), with higher fibrosis stages (p < 0.001) and higher serum ALT levels (p < 0.001). NAFLD classifications based on histological scoring NAS‐CRN and SAF algorithm are concordant for the category of definite NASH and not NASH, while borderline NASH shows discrepant interpretation. There was highly significant correlation between the NAS and SAF categories with high grades of histological characteristics, with serum ALT and with higher stages of fibrosis. Exclusion of fibrosis is a limitation with both scores.     

Hepatocellular carcinoma in a mouse model fed a choline‐deficient,L‐amino acid‐defined,high‐fat diet

Hepatocellular carcinoma (HCC) is a common cancer worldwide and represents the outcome of the natural history of chronic liver disease. The growing rates of HCC may be partially attributable to increased numbers of people with non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). However, details of the liver‐specific molecular mechanisms responsible for the NAFLD–NASH–HCC progression remain unclear, and mouse models that can be used to explore the exact factors that influence the progression of NAFLD/NASH to the more chronic stages of liver disease and subsequent HCC are not yet fully established. We have previously reported a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) as a dietary NASH model with rapidly progressive liver fibrosis in mice. The current study in C57BL/6J mice fed CDAHFD provided evidence for the chronic persistence of advanced hepatic fibrosis in NASH and disease progression towards HCC in a period of 36 weeks. When mice fed CDAHFD were switched back to a standard diet, hepatic steatosis was normalized and NAFLD activity score improved, but HCC incidence increased and the phenotype of fibrosis‐associated HCC development was observed. Moreover, when mice continued to be fed CDAHFD for 60 weeks, HCC further developed without severe body weight loss or carcinogenesis in other organs. The autochthonous tumours showed a variety of histological features and architectural patterns including trabecular, pseudoglandular and solid growth. The CDAHFD mouse model might be a useful tool for studying the development of HCC from NAFLD/NASH, and potentially useful for better understanding pathological changes during hepatocarcinogenesis.     

合生元调整肠道微生态治疗大鼠NASH及其对TLR4的影响

目的探讨肠道菌群改变在非酒精性脂肪性肝炎(NASH)形成过程中的作用,进而探索通过合生元干预治疗NASH。方法以饲喂高脂饲料构建非酒精性脂肪性肝炎(NASH)模型,动态观察大鼠自主活动次数;全自动生化分析仪检测大鼠血清的三酰甘油(TG)、总胆固醇(TC)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、空腹血糖(FBS)及空腹胰岛素(FINS)的含量;用16S rRNA荧光定量PCR检测大鼠肠道主要菌群;常规HE染色观察肝组织病理学,计算非酒精性脂肪性肝病(NAFLD)活动度积分(NAS);用酶联免疫吸附试验和免疫组织化学法检测TLR4表达。在NASH建模第4,8及12周分别取10只大鼠,添加合生元配方饲养2周(BIO组),继续观察上述指标。结果 1)随着高脂饮食喂养时间的延长,肝细胞脂肪变程度明显加重,NAFLD评分显著增高(P0.01)。2)合生元干预2周后大鼠自主活动次数显著上调、血清学指标TG、TC、LDL、FBS和FINS水平显著下调(P0.05)。3)合生元干预2周后,可使双歧杆菌和乳酸杆菌的数量显著上调,肠球菌的数量显著下调。4)NASH模型组TLR4的表达逐渐增高(P0.05),经合生元干预2周后可显著下调大鼠TLR4的表达(P0.05)。结论肠道微生态改变与NASH的发生发展密切相关,合生元通过调整肠道微生态改善NASH鼠的生活质量与生化指标,其机制可能与TLR4蛋白水平回调有关。     

Nonalcoholic fatty liver disease and HIV infection

As persons with HIV live longer, chronic liver disease is increasingly important. Nonalcoholic fatty liver disease (NAFLD) is characterized by excess fat in hepatocytes in patients without significant alcohol use. It can progress from steatosis to nonalcoholic steatohepatitis (NASH) to cirrhosis. Visceral obesity and insulin resistance are integral to the pathogenesis of NAFLD. Patients with HIV are at greater risk of NAFLD due to antiretroviral therapy and viral hepatitis coinfection. Antiretroviral therapy can lead to patterns of injury that include steatosis and NASH. Coinfection with hepatitis C virus increases the risk of insulin resistance and hepatic steatosis, and co-existent features of NASH have also been reported. Histological-based, longitudinal studies are needed that address the interactions of NAFLD and HIV infection, the effects of antiretroviral therapy and hepatotropic virus coinfection, and inform better management strategies.     

利拉鲁肽对非酒精性脂肪肝大鼠脂联素及胰岛素抵抗的影响

 目的：观察利拉鲁肽（Lira）对非酒精性脂肪肝（NAFLD）大鼠血清和肝组织脂联素（ADP）及胰岛素抵抗的影响。方法：雄性SD大鼠30只,随机分为3组,分别予普通饮食（ND组）10只、高脂饮食（HFD组）10只和高脂饮食加利拉鲁肽腹腔注射（Lira组）10只。高脂饮食12周建立大鼠NAFLD模型,建模成功后Lira组予利拉鲁肽腹腔注射治疗4周。16周末处死各组大鼠,生物化学法检测丙氨酸氨基转移酶（ALT）、空腹血糖（FBG）、甘油三酯（TG）及总胆固醇（TC）,分光光度计测定游离脂肪酸（FFAs）,酶联免疫吸附法测定胰岛素和ADP。结果：与HFD组比较,Lira组大鼠体质量、肝指数、胰岛素抵抗指数、血清TG、TC、ALT、FBG及肝匀浆TG、TC、FFAs显著下降（均P<0.05）,血清及肝组织ADP明显升高（P＜0.05）,肝脏脂肪变性程度明显减少至恢复正常（P<0.05）,肝组织ADP含量与肝脏FFAs含量呈负相关。结论:利拉鲁肽改善胰岛素抵抗和肝脏脂肪变的可能机制之一与其升高血清及肝组织脂联素水平有关。     

Elevated systemic monocyte chemoattractrant protein-1 in hepatic steatosis without significant hepatic inflammation

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and the metabolic syndrome. It encompasses a clinico-pathologic spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The latter develops upon pro-inflammatory cell infiltration and is widely considered as the first relevant pathophysiological step in NAFLD-progression. The chemokine monocyte chemoattractant protein 1 (MCP-1) plays an important role in the progression of hepatic inflammation and fibrosis, and both increased hepatic expression and circulating serum levels have been described in NASH. Here, we aimed to investigate MCP-1 expression in simple hepatic steatosis. Upon feeding a high-fat diet mice developed hepatic steatosis in the absence of significant hepatic inflammation, but elevated hepatic MCP-1 expression compared to control mice fed a standard chow. Interestingly, high-fat diet fed mice had significantly higher MCP-1 serum levels, and MCP-1 mRNA expression was significantly increased in visceral adipose tissue. Furthermore, MCP-1 serum levels were also elevated in patients with ultrasound-diagnosed NAFLD and correlated with the body-mass index and fasting glucose. In conclusion, our data indicate both the liver and adipose tissue as cellular sources of elevated circulating MCP-1 levels already in the early phase of hepatic steatosis. Since MCP-1 derived from visceral adipose tissue reaches the liver via portal circulation at high concentrations it may significantly contribute to the progression of simple steatosis to NASH.     

Vitamin D Status and Bone Mineral Density in Obese Children with Nonalcoholic Fatty Liver Disease

Whether nonalcoholic fatty liver disease (NAFLD) is related to vitamin D and bone health in obese children is unknown. The aim of this study was to evaluate vitamin D status and bone mineral density (BMD) in obese children according to their condition within the NAFLD spectrum. Anthropometric data, laboratory tests, and abdominal ultrasonography were obtained from 94 obese children. The subjects were divided into three groups according to NAFLD spectrum: normal liver, simple steatosis, and nonalcoholic steatohepatitis (NASH). Although there were no differences in vitamin D levels between the three groups, these groups showed significant differences in highly sensitive C-reactive protein (P=0.044), homeostasis model assessment of insulin resistance (HOMA-IR) (P=0.02), hepatic fibrosis scores (P<0.05), and trunk fat percentage (P=0.025). Although there were significant differences in BMDs, the age-matched BMD z-scores were not significantly different between the three groups. Serum vitamin D levels were negatively correlated with age (r=-0.368, P=0.023), serum uric acid levels (r=-0.371, P=0.022), fibrosis 4 (FIB4) (r=-0.406, P=0.011), and HOMA-IR (r=-0.530, P=0.001) in obese children with NASH. Multiple regression analysis for vitamin D in the NASH group revealed age and HOMA-IR as significant factors. In conclusion, inflammatory markers, hepatic fibrosis scores, trunk fat, and insulin resistance may reflect the spectrum of NAFLD in obese children, whereas vitamin D levels and BMD may not. In patients with NASH, however, low serum vitamin D is associated with hepatic fibrosis and insulin resistance, but not with bone health status.     

Clinicopathological correlations in a series of adult patients with non‐alcoholic fatty liver disease

Possible correlations among clinical data, serum aminotransferase levels and histological features were assessed in a series of 37 adult patients with non‐alcoholic fatty liver disease (NAFLD), consisting of nine patients with fatty liver (FL) and 28 with non‐alcoholic steatohepatitis (NASH). In each liver biopsy, the NAFLD activity score (NAS) and the stage of fibrosis were determined. Additionally, the number of Kupffer cell aggregates (microgranulomas) per centimeter of biopsy length (MG/cm ratio) was assessed on immunohistochemical stains for CD68 antigen. Definite NASH (NAS ≥ 5) was strongly correlated with serum aspartate aminotransferase (AST) level (P= 0.003), stage of fibrosis (P= 0.003) and age (P= 0.014). On multivariate analysis, age >46 years and AST level above normal values were found to be independent clinical predictors of established NASH. The MG/cm ratio increased from control liver to FL to NASH (P < 0.001), and was correlated with the NAS (P= 0.003) and with the stage of fibrosis (P= 0.004), but not with the serum aminotransferase levels. In conclusion, persistent AST elevation in patients with suspected NAFLD should be an indication for liver biopsy, in order to determine the severity of necroinflammatory activity and the stage of fibrosis. Microgranuloma counting may represent a useful complementary marker of necroinflammatory activity in patients with NAFLD.     

Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease

Mechanisms associated with the progression of simple steatosis to non-alcoholic fatty liver disease (NAFLD) remain undefined. Regulatory T cells (T(regs)) play a critical role in regulating inflammatory processes in non-alcoholic steatohepatitis (NASH) and because T helper type 17 (Th17) functionally oppose T(reg)-mediated responses, this study focused on characterizing the role of Th17 cells using a NAFLD mouse model. C57BL/6 mice were fed either a normal diet (ND) or high fat (HF) diet for 8 weeks. Mice in the HF group had a significantly higher frequency of liver Th17 cells compared to ND-fed mice. Neutralization of interleukin (IL)-17 in HF mice ameliorated lipopolysaccharide (LPS)-induced liver injury reflected by decreased serum alanine aminotransferase (ALT) levels and reduced inflammatory cell infiltrates in the liver. In vitro, HepG2 cells cultured in the presence of free fatty acids (FFA; oleic acid and palmitic acid) for 24 h and IL-17 developed steatosis via insulin-signalling pathway interference. IL-17 and FFAs synergized to induce IL-6 production by HepG2 cells and murine primary hepatocytes which, in combination with transforming growth factor (TGF-β), expanded Th17 cells. It is likely that a similar process occurs in NASH patients, as there were significant levels of IL-17(+) cell infiltrates in NASH patient livers. The hepatic expression of Th17 cell-related genes [retinoid-related orphan receptor gamma (ROR)γt, IL-17, IL-21 and IL-23] was also increased significantly in NASH patients compared to healthy controls. Th17 cells and IL-17 were associated with hepatic steatosis and proinflammatory response in NAFLD and facilitated the transition from simple steatosis to steatohepatitis. Strategies designed to alter the balance between Th17 cells and T(regs) should be explored as a means of preventing progression to NASH and advanced liver diseases in NAFLD patients.     

Serum lipocalin-2 is a potential biomarker for the clinical diagnosis of nonalcoholic steatohepatitis

Background/AimsNonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis. We aimed to investigate the usefulness of a key biomarker, lipocalin-2 (LCN2), for the detection of NASH progression.MethodsA mouse NASH model was established using a high-fat diet and a high-sugar drinking water. Gene expression profile of the NASH model was analyzed using RNA sequencing. Moreover, 360 NAFLD patients (steatosis, 83; NASH, 277), 40 healthy individuals, and 87 patients with alcoholic fatty liver disease were recruited.ResultsInflammatory infiltration, focal necrosis in the leaflets, steatosis, and fibrosis were documented in the mouse liver. In total, 504 genes were differentially expressed in the livers of NASH mice, and showed significant functional enrichment in the inflammation-related category. Upregulated liver LCN2 was found to be significantly interactive with various interleukins and toll-like receptors. Serum LCN2 levels were significantly increased in NAFLD patients. Serum LCN2 levels were correlated with steatosis, intralobular inflammation, semiquantitative fibrosis score, and nonalcoholic fatty liver disease activity score. The area under the curve of serum LCN2 was 0.987 with a specificity of 100% and a sensitivity of 93.5% for NASH diagnosis, and 0.977 with almost the same specificity and sensitivity for steatosis.ConclusionsLCN2 might be involved in the transition from NAFL to NASH by mediating inflammation. Serum LCN2 levels might be a novel biomarker for the diagnosis of NASH.     

Lipid and carbohydrate parameters in children with chronic hepatitis C

PurposeHCV chronic infection still presents a very serious epidemiological and clinical problem. Apart from its cytopathic effect on liver parenchyma, its detrimental effect on lipid and carbohydrate metabolism has recently been emphasized. The aim of the study was to assess lipid and carbohydrate parameters in children with chronic HCV-related hepatitis.Material/MethodsThe study comprised 41 children with chronic hepatitis C (CHC) aged between 7 and 18 years, and 30 healthy controls. The anthropometric measurements of the subjects were taken, and, after overnight fasting, serum glucose, insulin, total bilirubin, AST, ALT, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride levels were investigated. The HOMA IR insulin resistance index was also calculated.ResultsThe values for mean body mass index (BMI), glucose, insulin, bilirubin, LDL-cholesterol, HDL-cholesterol, triglycerides, HDL/C index and HOMA IR levels did not differ significantly between the two groups. AST and ALT were significantly higher in the control group. The serum levels of cholesterol and LDL-cholesterol showed a tendency toward lower values in the control group. We found positive correlation between serum levels of insulin and HOMA IR with staging (respectively r=0.336, P < 0.04 and r=0.386, P < 0.02).ConclusionsIn children with CHC and a relatively short duration of the disease, lipid and glucose disorders are not observed. Correlations between insulin and HOMA IR with staging suggest the ability of HCV to contribute to fibrosis through interference with glucose metabolism.     

Non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD), also referred to as metabolic associated fatty liver disease (MAFLD), is the commonest form of chronic liver disorder arising from metabolic dysregulation. It encompasses a wide spectrum of fatty liver phenotypes including isolated steatosis to non-alcoholic steatohepatitis (NASH). NASH is considered more likely to lead to grave clinical consequences such as cirrhosis and hepatocellular carcinoma, compared to simple steatosis. NASH is characterised by steatosis, inflammation, and damage to hepatocytes. Here, we present a case of a middle-aged gentleman with a background of infectious hepatitis who presented with NASH, with emphasis on terminology and histological assessment criteria of NAFLD and NASH. Reflection on and consistent effort to standardise terminology and assessment criteria will aid in addressing the scientific and clinical needs of NAFLD and NASH.     

Role of serum adiponectin level in the development of liver cirrhosis in patients with hepatitis C virus

Adiponectin possesses anti-inflammatory and insulin-sensitizing properties. Little is known about the role of adiponectin in hepatitis-C-related liver disease. The aim of our study was to find a relationship between serum adiponectin levels and different grades of steatohepatitis in HCV-infected patients and to correlate it with the severity of liver disease. Sixty HCV-infected patients were divided into two groups according to the presence/absence of steatosis proofed by abdominal ultrasonography and liver biopsy was selected. We evaluated the biochemical parameters for all patients including: ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, serum albumin, prothrombin time, CBC, lipid profile, fasting blood glucose, fasting insulin, and serum adiponectin; HOMA-IR was calculated as [fasting insulin (mIU/l) × fasting glucose (mmol/l)]/22.5. We found that adiponectin was significantly lower in HCV-infected patients with steatosis than in those without steatosis. BMI, fasting blood glucose and HOMA-IR were significantly higher in HCV-infected patients with steatosis than in those without steatosis. Furthermore, it was found that steatosis correlates directly with fibrosis index, BMI, HOMA-IR, fasting blood glucose and ALT. Serum adiponectin levels inversely correlates with the grade of steatosis, histological activity index and the stage of fibrosis.     

Effect of serum interleukin 21 on the development of coronary artery disease

There has been more and more evidence to confirm the essential role of inflammatory processes in the development of coronary artery disease (CAD). Interleukin‐21 (IL‐21), the most recently discovered CD132‐dependent cytokine, plays a key role in regulating inflammation. The aim of the study was to understand the effect of peripheral IL‐21 on the pathogenesis and progression of CAD. Serum level of IL‐21 in 92 CAD patients and 73 controls was measured by the enzyme‐linked immunosorbent assay. Data showed that IL‐21 expression was significantly increased in CAD than in controls (p < 0.001). Interestingly, when comparing IL‐21 level with different genders, male subjects revealed higher IL‐21 than female subjects (p = 0.024). Also, we observed that patients with hypertension had upregulated level of serum IL‐21 (p = 0.002). Moreover, serum level of IL‐21 was positively correlated with total cholesterol level (p = 0.015) or low‐density lipoprotein cholesterol (p = 0.0009) of CAD cases. In addition, we analyzed IL‐21 level with the severity of CAD, and identified that cases with 3‐vessel affected had significantly elevated level of IL‐21 than those with 1‐vessel or 2‐vessel affected. These data suggested that serum level of IL‐21 may be closely associated with the development and progression of CAD.     

Genetic Variation and Insulin Resistance in Middle‐Aged Chinese Men

We investigated the effect of variants in the first three genes in the insulin signaling pathway and genes identified from genome wide association studies (GWAS) of T2D quantitative traits with IR (fasting insulin and the homeostasis model assessment of IR, HOMA‐IR) and evaluated gene–environment interactions with IR traits among 1879 nondiabetic middle‐aged men from a population‐based study conducted in Shanghai, China. One candidate gene, IGF1, was associated with fasting insulin and HOMA‐IR. We observed four BMI–gene interactions (P < 0.05) with HOMA‐IR (INRS rs7254060, INRS rs7254358, GLU4 rs2113050, and GLU4 rs7713127) and seven BMI–gene interactions with fasting insulin (INRS rs7254060, INRS rs7254358, INRS rs10417205, INRS rs1799817, GLU4 rs12054720 GLU4 rs2113050, and GLU4 rs7713127). There were four WHR–gene interactions with HOMA‐IR (INRS rs10417205, INRS rs12971499, INRS rs7254060, and INRS rs7254358), five WHR–gene interactions with fasting insulin (INRS rs10417205, INRS rs7254060, INRS rs7254358, GLU4 rs2113050, and GLU4 rs7713127), eight physical activity–gene interactions with HOMA‐IR (INRS rs10411676, INRS rs11671297, INRS rs2229431, INRS rs12461909, INRS rs6510950, INRS rs10420382, IRS2 rs913949, and IRS2 rs2241745) and five physical activity–gene interactions with fasting insulin (INRS rs2229431, INRS rs12461909, INRS rs10420382, IRS2 rs913949, and IRS2 rs2241745). Our results suggest that BMI, WHR and physical activity may modify IR‐associated variants.     

非酒精性脂肪肝患者肝脏固醇调节元件结合蛋白1c的表达及意义

目的 观察非酒精性脂肪性肝病（NAFLD）患者肝组织固醇调节元件结合蛋白（SREBP1c）的表达变化,探讨其在NAFLD病理变化形成中的作用.方法 研究对象为NAFLD患者20例,20例年龄性别匹配的同期住院行肝活检无活动肝病组织学证据且肝脂肪变＜5％的慢性HBV携带者（ASC）设为对照组.免疫组织化学染色检测两组患者肝组织SREBP1c的表达,并比较血脂（TG、CHO）、空腹血糖（FBG）、空腹胰岛素（FINS）和血清肝脏酶谱（AST、ALT、GGT）等的组间差异.结果 与对照组患者比较,NAFLD组肝组织呈不同程度的弥漫性肝细胞脂肪变性,肝组织SREBP1c表达明显升高（P＜0.05）,与此一致,血清ALT、AST、TG、CHO、FBG、FINS水平升高（P均＜0.05）.结论 NAFLD患者肝组织SREBP1 c表达增高,在人NAFLD脂肪变形成过程中起重要作用.     

Molecular mechanisms involved in NAFLD progression

Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic-related disorder characterized by fatty infiltration of the liver in the absence of alcohol consumption. NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which might progress to end-stage liver disease. This progression is related to the insulin resistance, which is strongly linked to the metabolic syndrome consisting of central obesity, diabetes mellitus, and hypertension. Earlier, the increased concentration of intracellular fatty acids within hepatocytes leads to steatosis. Subsequently, multifactorial complex interactions between nutritional factors, lifestyle, and genetic determinants promote necrosis, inflammation, fibrosis, and hepatocellular damage. Up to now, many studies have revealed the mechanism associated with insulin resistance, whereas the mechanisms related to the molecular components have been incompletely characterized. This review aims to assess the potential molecular mediators initiating and supporting the progression of NASH to establish precocious diagnosis and to plan more specific treatment for this disease.     

Non-alcoholic fatty liver disease: a narrative review of genetics

Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver diseases worldwide. It encompasses a spectrum of disorders ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. One of the key challenges in NAFLD is identifying which patients will progress. Epidemiological and genetic studies indicate a strong pattern of heritability that may explain some of the variability in NAFLD phenotype and risk of progression. To date, at least three common genetic variants in the PNPLA3, TM6SF2, and GCKR genes have been robustly linked to NAFLD in the population. The function of these genes revealed novel pathways implicated in both the development and progression of NAFLD. In addition, candidate genes previously implicated in NAFLD pathogenesis have also been identified as determinants or modulators of NAFLD phenotype including genes involved in hepatocellular lipid handling, insulin resistance, inflammation, and fibrogenesis. This article will review the current understanding of the genetics underpinning the development of hepatic steatosis and the progression of NASH. These newly acquired insights may transform our strategy to risk-stratify patients with NAFLD and to identify new potential therapeutic targets.     

The association of serum C-reactive protein, uric acid and magnesium with insulin resistance in Chinese postmenopausal women with prediabetes or early untreated diabetes

Objectives

This study aimed to evaluate the association of serum inflammatory markers (C-reactive protein (CRP) and uric acid (UA)), magnesium and other CVD risk factors with insulin resistance (IR) among Chinese postmenopausal women with prediabetes.

Study design and main outcomes measures

This is a cross-sectional analysis of baseline data among 180 postmenopausal women with prediabetes or early untreated diabetes. Major anthropometric and biochemical measures included body mass index (BMI), waist to hip ratio (WHR), fasting and postload glucose and insulin, serum CRP, UA, lipids profile, and magnesium. IR was estimated using fasting glucose and insulin by homeostasis model assessment (HOMA).

Results

Multivariate linear regression analyses indicated that Lg CRP, WHR, serum triglycerides (TGs) and magnesium were the major predictors of HOMA-IR. A multivariate logistic analyses showed that a CRP level above 3.0 mg/l was significantly associated with a 2.8-fold risk of having higher HOMA-IR (>2.52). BMI plays a key role in mediating the relationship of CRP and IR. Elevated serum TG (>1.71 mmol/l), WHR (>0.88), UA (>357 mmol/l) and lower serum magnesium (<0.78 mg/l) were associated with 5.26 (95%CI: 2.52–10.98, P < 0.05), 3.02 (95%CI: 1.64–5.55, P < 0.05), 1.97 (95%CI: 1.02–3.83, P = 0.05) and 0.51 (95%CI: 0.28–0.81) folds risk of higher HOMA-IR, respectively in the unadjusted model. Serum magnesium, but not UA was an independent risk factor of HOMA-IR.

Conclusion

The present study in prediabetic or early untreated diabetic Chinese postmenopausal women indicated that IR is significantly associated with increased inflammation (CRP and UA), serum TG, WHR and lower serum magnesium.     

Severity of non-alcoholic fatty liver disease is associated with high systemic levels of tumor necrosis factor alpha and low serum interleukin 10 in morbidly obese patients

Morbid obesity has been shown to increase the risk to develop hepatic steatosis, also referred to as non-alcoholic fatty liver disease (NAFLD). Emerging evidence suggests that the severity of NAFLD may associate with increased serum levels of inflammatory markers as well as decreased concentration of mediators with anti-inflammatory actions, such as tumor necrosis factor alpha (TNF-α) and interleukin (IL) 10, respectively. We thus examined the serum levels of TNF-α and IL-10 in 102 morbidly obese women and men (body mass index > 40 kg/m²), exhibiting different grades of NAFLD. Blood glucose, glycated hemoglobin, insulin, the homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol, triglycerides, high- and low-density lipoproteins, parameters of liver function, TNF-α, and IL-10 were measured in each subject. The stage of NAFLD was estimated by abdominal ultrasound imaging. In comparison with morbidly obese subjects without steatosis, morbidly obese patients with NAFLD showed increased age (39.23 ± 9.80 years), HOMA-IR (6.74 ± 1.62), total cholesterol (219.7 ± 9.58 mg/dl), aspartate aminotransferase (36.25 ± 3.24 UI/l), gamma-glutamyl transpeptidase (37.12 ± 3.41 UI/l), and TNF-α (37.41 ± 1.72 pg/ml) as well as decreased serum levels of IL-10 (61.05 ± 2.43 pg/ml). Interestingly, the systemic levels of TNF-α increased, while IL-10 decreased in accordance with the severity of NAFLD, which supports a role for systemic inflammatory mediators in promoting steatosis progression. Further clinical prospective studies need to be addressed to elucidate the role of TNF-α and IL-10 in the development of NAFLD while also establishing their clinical utility in the assessment of morbidly obese patients at higher risk to develop severe steatosis.