S100A9: A Potential Biomarker for the Progression of Non-Alcoholic Fatty Liver Disease and the Diagnosis of Non-Alcoholic Steatohepatitis

Non-alcoholic fatty liver (NAFL) has the potential to progress to non-alcoholic steatohepatitis (NASH) or to promote type 2 diabetes mellitus (T2DM). However, NASH and T2DM do not always develop coordinately. Additionally, there are no definite noninvasive methods for NASH diagnosis currently. We established rat models of NAFL, NASH, and NAFL + T2DM to recapitulate different phenotypes associated with non-alcoholic fatty liver disease (NAFLD) and its progression. Histologic features of rat livers were scored according to criteria established by the Nonalcoholic Steatohepatitis Clinical Research Network. Microarray was performed to assess gene expression changes in rat livers. We find that gene expression of s100a9 was higher in NAFL group compared with control, and was increased in NASH groups and decreased in NAFL + T2DM group compared with NAFL. In contrast, srebf1, tbx21, and gimap4 only showed limited discriminating abilities in different groups. There is a significant positive correlation between serum levels of S100A9 and NAFLD Activity Score (NAS), the severity of hepatic steatosis, and lobular inflammation (r = 0.80, 0.64 and 0.86, P < 0.001). These findings suggest that S100A9 may be extremely useful in the diagnosis of NASH (AUROC: 0.947, CI: 0.845-1.049). Additionally, serum S100A9 levels displayed a strong correlation with ALT, AST and TBil (r = 0.81, 0.89 and 0.91, P < 0.001) but a weak correlation with FBG, HOMA-IR, TG, and TC (r = -0.41, -0.40, 0.47 and 0.49, P < 0.05). Conclusions: The results we provide here suggest that S100A9 may be useful as a biomarker for the hepatic and metabolic progression of NAFLD and the non-invasive diagnosis of NASH.     

Association Between Non-Alcoholic Fatty Liver Disease and Diabetes-Related Microvascular Complications: A Retrospective Cross-Sectional Study of Hospitalized Patients

ObjectiveOwing to limited research, the effect of nonalcoholic fatty liver disease (NAFLD) on type 2 diabetes outcomes remains unclear. This study aimed to investigate the association between NAFLD and microvascular complications in hospitalized patients with type 2 diabetes.MethodsWe included 1982 patients with type 2 diabetes. NAFLD was defined as hepatic steatosis detected by ultrasound without secondary causes of fat accumulation. The diagnosis of diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic neuropathy was based on clinical medical records. Risk for advanced liver fibrosis was categorized as “low risk,” “indeterminate risk,” and “high risk,” based on the NAFLD fibrosis score (NAFLD-FS). Logistic regression was used to test the association between NAFLD, risk for advanced fibrosis, and the presence of DR, DKD, and diabetic neuropathy.ResultsThe prevalence of NAFLD was 61.3%. The presence of DR and DKD was inversely associated with NAFLD, after adjusting for covariates. The presence of DR and DKD was higher in the “indeterminate risk” and “high risk” groups than in the “low risk” group, after adjusting for the same covariates. Only the presence of DKD significantly increased with high NAFLD-FS.ConclusionThe presence of DR and DKD was inversely associated with NAFLD among hospitalized patients with type 2 diabetes. DKD was closely associated with high NAFLD-FS among patients with NAFLD.     

Phenotype,Body Composition,and Prediction Equations (Indian Fatty Liver Index) for Non-Alcoholic Fatty Liver Disease in Non-Diabetic Asian Indians: A Case-Control Study

Objective

In this study, we have attempted comparison of detailed body composition phenotype of Asian Indians with non-alcoholic fatty liver disease (NAFLD) vs. those without, in a case controlled manner. We also aim to analyse prediction equations for NAFLD for non-diabetic Asian Indians, and compare performance of these with published prediction equations researched from other populations.

Methods

In this case-control study, 162 cases and 173 age-and sex-matched controls were recruited. Clinical, anthropometric, metabolic, and body composition profiles, and liver ultrasound were done. Fasting insulin levels, value of homeostasis model assessment of insulin resistance (HOMA-IR), and serum high sensitive C-reactive protein (hs-CRP) levels were evaluated. Multivariate logistic and linear regression analyses were used to arrive at prediction equations for fatty liver [Indian fatty liver index (IFLI)].

Results

As compared to those without fatty liver, those with fatty liver exhibited the following; Excess dorsocervical fat (‘Buffalo hump’), skin tags, xanthelasma, ‘double chin’, arcus; excess total, abdominal and subcutaneous adiposity, and high blood pressure, blood glucose, measures of insulin resistance (fasting insulin and HOMA-IR values), lipids and hs-CRP levels. Two prediction equations were developed; Clinical [Indian Fatty Liver Index-Clinical; IFLI-C]: 1(double chin) +15.5 (systolic blood pressure) +13.8 (buffalo hump); and IFLI-Clinical and Biochemical (CB): serum triglycerides+12 (insulin)+1(systolic blood pressure) +18 (buffalo hump). On ROC Curve analysis, IFLI performed better than all published prediction equations, except one.

Conclusion

Non-diabetic Asian Indians with NAFLD researched by us were overweight/obese, had excess abdominal and subcutaneous fat, multiple other phenotypic markers, had higher insulin resistance, glycemia, dyslipidemia and subclinical inflammation than those without. Prediction score developed by us for NAFLD; IFLI-C and IFLI-CB, should be useful for clinicians and researchers.     

Association between Dietary Vitamin C Intake and Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study among Middle-Aged and Older Adults

Background

Non-alcoholic fatty liver disease (NAFLD) has become one of the most prevalent chronic liver disease all over the world. The objective of this study was to evaluate the association between dietary vitamin C intake and NAFLD.

Method

Subjects were diagnosed with NAFLD by abdominal ultrasound examination and the consumption of alcohol was less than 40g/day for men or less than 20g/day for women. Vitamin C intake was classified into four categories according to the quartile distribution in the study population: ≤74.80 mg/day, 74.81–110.15 mg/day, 110.16–146.06 mg/day, and ≥146.07 mg/day. The energy and multi-variable adjusted odds ratio (OR), as well as their corresponding 95% confidence interval (CI), were used to determine the relationship between dietary vitamin C intake and NAFLD through logistic regression.

Result

The present cross-sectional study included 3471 subjects. A significant inverse association between dietary vitamin C intake and NAFLD was observed in the energy-adjusted and the multivariable model. The multivariable adjusted ORs (95%CI) for NAFLD were 0.69 (95%CI: 0.54–0.89), 0.93 (95%CI: 0.72–1.20), and 0.71 (95%CI: 0.53–0.95) in the second, third and fourth dietary vitamin C intake quartiles, respectively, compared with the lowest (first) quartile. The relative odds of NAFLD was decreased by 0.71 times in the fourth quartile of dietary vitamin C intake compared with the lowest quartile. After stratifying data by sex or the status of obesity, the inverse association remained valid in the male population or non-obesity population, but not in the female population or obesity population.

Conclusion

There might be a moderate inverse association between dietary vitamin C intake and NAFLD in middle-aged and older adults, especially for the male population and non-obesity population.     

Non-Alcoholic Fatty Liver Disease Is Closely Associated with Sub-Clinical Inflammation: A Case-Control Study on Asian Indians in North India

Objectives

Association between sub-clinical inflammation and non-alcoholic fatty liver disease (NAFLD) has not been studied in Asian Indians. In this case-control study, we aimed to analyse association of NAFLD with the sub-clinical inflammation and metabolic profile in Asian Indians in north India.

Methods

Ultrasound diagnosed 120 cases of NAFLD were compared to 152 healthy controls without NAFLD. Anthropometric profile [body mass index (BMI), waist circumference (WC), hip circumference (HC)], high-sensitivity C-reactive protein (hs-CRP), metabolic profile [fasting blood glucose (FBG), lipid profile] and hepatic function tests [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] were recorded.

Results

Metabolic parameters [FBG, total cholesterol (TC), serum triglycerides (TG),low-density lipoprotein (LDL-c)], hs-CRP and prevalence of the metabolic syndrome were higher in cases as compared to controls (p-value<0.05 for all). The median (range) of hs-CRP (mg/L) for cases [2.6(0.2–13.4)] were significantly higher than in controls [1.4(0.03–11.4), p = 0.01]. Similarly, higher values of hs-CRP were obtained when subgroups of cases with obesity, abdominal obesity and the metabolic syndrome were compared to controls [2.75 (0.03–14.3) vs. 1.52 (0.04–14.3), p = 0.0010; 2.8 (0.03–14.3) vs. 1.5 (0.06–14.3), p = 0.0014 and 2.7 (0.5–14.3) vs. 1.6 (0.06–8.5), p = 0.0013, respectively. On multivariate logistic regression analysis BMI (p = 0.001), WC (p = 0.001), FBG (p = 0.002), TC (p = 0.008), TG (p = 0.002), blood pressure (p = 0.005), metabolic syndrome (p = 0.001) and hs-CRP (p = 0.003) were significantly and independently associated with NAFLD. After adjusting for significant variables, the association between high hs-CRP and NAFLD remained large and statistically significant [adjusted OR = 1.17, 95% confidence interval (CI) = 1.05–1.29]. An increase in 1 mg/dl of hs-CRP level calculated to increase the risk of developing NAFLD by 1.7 times as compared to controls after adjusting for significant variables associated with NAFLD.

Conclusions

In this cohort of Asian Indians in North India, presence of NAFLD showed independent relationships with sub-clinical inflammation.     

Non-Alcoholic Fatty Liver Disease Is Associated with an Increased Incidence of Atrial Fibrillation in Patients with Type 2 Diabetes

Background

The relationship between non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) in type 2 diabetes is currently unknown. We examined the relationship between NAFLD and risk of incident AF in people with type 2 diabetes.

Methods and Results

We prospectively followed for 10 years a random sample of 400 patients with type 2 diabetes, who were free from AF at baseline. A standard 12-lead electrocardiogram was undertaken annually and a diagnosis of incident AF was confirmed in affected participants by a single cardiologist. At baseline, NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other liver diseases. During the 10 years of follow-up, there were 42 (10.5%) incident AF cases. NAFLD was associated with an increased risk of incident AF (odds ratio [OR] 4.49, 95% CI 1.6–12.9, p<0.005). Adjustments for age, sex, hypertension and electrocardiographic features (left ventricular hypertrophy and PR interval) did not attenuate the association between NAFLD and incident AF (adjusted-OR 6.38, 95% CI 1.7–24.2, p = 0.005). Further adjustment for variables that were included in the 10-year Framingham Heart Study-derived AF risk score did not appreciably weaken this association. Other independent predictors of AF were older age, longer PR interval and left ventricular hypertrophy.

Conclusions

Our results indicate that ultrasound-diagnosed NAFLD is strongly associated with an increased incidence of AF in patients with type 2 diabetes even after adjustment for important clinical risk factors for AF.     

A Prospective Study of Fatty Liver Index and Incident Hypertension: The KoGES-ARIRANG Study

Background

Although non-alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, its influence on hypertension development is poorly understood. We investigated whether fatty liver disease, as assessed by the fatty liver index, could predict the development of hypertension independently of systemic insulin resistance, inflammatory status and adipokine levels.

Methods

Prospective cohort study of 1,521 adults (484 men and 1037 women) aged 40 to 70 years without baseline hypertension examined. An equation was used to calculate fatty liver index and classify patients as follows: fatty liver index <30, no non-alcoholic fatty liver disease; fatty liver index ≥60, non-alcoholic fatty liver disease; and 30≤ fatty liver index <60, intermediate fatty liver index.

Results

During an average of 2.6 years of follow-up, 153 subjects (10.06%) developed hypertension. Fatty liver index was positively associated with baseline blood pressure, homeostasis model assessment of insulin resistance, urinary albumin/creatinine excretion, and high sensitivity C-reactive protein. After adjustment for confounding factors, including markers of insulin resistance, systemic inflammation and adiponectin levels, the odds ratio [95% confidence interval] for the incident hypertension increased in a graded manner with fatty liver index (<30 vs. 30–59 vs. ≥60 = 1 vs. 1.83 [1.16~2.88] vs. 2.09 [1.08~4.055], respectively).

Conclusions

Non-alcoholic fatty liver disease assessed by fatty liver index was an independent risk factor for hypertension. Our findings suggest that fatty liver index, a simple surrogate indicator of fatty liver disease, might be useful for identifying subjects at high risk for incident hypertension in clinical practice.     

Prediction of Metabolic Syndrome by Non-Alcoholic Fatty Liver Disease in Northern Urban Han Chinese Population: A Prospective Cohort Study

Objectives

To explore the relationship between non-alcoholic fatty liver disease (NAFLD) and the metabolic syndrome (MetS), and evaluate the value of NAFLD as a marker for predicting the risk of MetS in a large scale prospective cohort from northern urban Han Chinese population.

Materials and Methods

A total of 17,920 MetS-free at baseline cohort members was included in the current study between 2005 and 2011. The baseline characteristics of the cohort were compared by NAFLD status at baseline, MetS status after follow-up. Cox proportional hazards models were used to estimate the unadjusted or adjusted hazard ratios (HRs) for NAFLD at baseline predicting the risk of MetS.

Results

2,183 (12.18%) new cases of MetS occurred between 2005 and 2011. In unadjusted model, HRs (95% CIs) for NAFLD predicting MetS was 3.65 (3.35, 3.97). After adjusting the confounding factors of age, gender, the metabolic factors, smoke and exercise, the HRs (95% CIs) was 1.70 (1.55, 1.87). Gender difference was observed, adjusted HRs (95% CIs) of NAFLD for predicting MetS were 2.06(1.72, 2.46) and 1.55(1.39, 1.72) in female and male population, respectively. Moreover, 163 participants developed MetS among participants without any MetS component at baseline, and its adjusted HRs was still significant, 1.87 (1.12, 3.13).

Conclusion

The present study indicates that NAFLD is an independent risk factor for predicting the risk of MetS in northern urban Han Chinese population, and the people with NAFLD should initiate weight and dietary control to prevent the occurrence of MetS.     

Body Mass Index Is Associated with Physical Performance in Suburb-Dwelling Older Chinese: A Cross-Sectional Study

Background

Physical performance is reported to have various beneficial effects on human health, especially in older individuals. Although such effects are associated with body mass index (BMI), the relationship between BMI and physical performance has not been clarified.

Design

We conducted a cross-sectional study of 966 suburb-dwelling Tianjin individuals aged ≥ 60 years (average age 67.5±6.02, men 435, women 531). Mobility, balance, and muscle strength were assessed by walking speed, timed up-and-go test (TUGT), and grip strength, respectively. The subjects were categorized into three groups based on BMI (kg/m²) as follows: normal weight, 18.5 ≤ BMI ≤ 23.9; overweight, 24.0 ≤ BMI ≤ 27.9; and obese, BMI ≥ 28.0.

Result

After adjusting for all other variables, relative grip strength decreased when BMI increased in both men and women (P for trend <0.001 and <0.001, respectively). BMI may be negatively associated with TUGT performance in the women only. There was no apparent association between walking speed and BMI in either sex, but after adjusting for age, walking speed was faster when BMI increased in women (P for trend= 0.0162).

Conclusion

This study suggests that in older individuals, higher BMI is associated with poor muscle strength in both sexes.     

The Prevalence of Non-Alcoholic Fatty Liver Disease in Children and Adolescents: A Systematic Review and Meta-Analysis

MethodsWe conducted a systematic review and meta-analysis of all studies reporting a prevalence of NAFLD based on any diagnostic method in participants 1–19 years old, regardless of whether assessing NAFLD prevalence was the main aim of the study.ResultsThe pooled mean prevalence of NAFLD in children from general population studies was 7.6% (95%CI: 5.5% to 10.3%) and 34.2% (95% CI: 27.8% to 41.2%) in studies based on child obesity clinics. In both populations there was marked heterogeneity between studies (I² = 98%). There was evidence that prevalence was generally higher in males compared with females and increased incrementally with greater BMI. There was evidence for differences between regions in clinical population studies, with estimated prevalence being highest in Asia. There was no evidence that prevalence changed over time. Prevalence estimates in studies of children/adolescents attending obesity clinics and in obese children/adolescents from the general population were substantially lower when elevated alanine aminotransferase (ALT) was used to assess NAFLD compared with biopsies, ultrasound scan (USS) or magnetic resonance imaging (MRI).ConclusionsOur review suggests the prevalence of NAFLD in young people is high, particularly in those who are obese and in males.     

Serum Complement C3f and Fibrinopeptide A Are Potential Novel Diagnostic Biomarkers for Non-Alcoholic Fatty Liver Disease: A Study in Qingdao Twins

Aims

To compare the different serum peptidome patterns between twins with and without non-alcoholic fatty liver disease (NAFLD) in order to help understand the pathogenesis of NAFLD and to identify potential diagnostic and therapeutic targets.

Methods

The peptidomics patterns of 63 cases with NAFLD were compared with their twin healthy controls in Qingdao, China. Peptides between 800Da and 3500Da were captured and concentrated using C18 reversed-phase columns, followed by MALDI-TOF mass spectrometry. The sequences of peptides associated with NAFLD were further identified by MALDI-TOF-TOF. Further validation studies were conducted. One hundred additional serum samples were detected by commercially available ELISA kits to calculate the concentrations of complement C3f and fibrinopeptide A, respectively. The differences of these two peptides in the NAFLD and control groups were compared using SPSS 17.0, respectively.

Results

Compared with healthy controls, eleven peaks (861.1, 877.07, 904.5, 1206.57, 1350.64, 1518.7, 1690.9, 1777.94, 2931.29, 3190.4, 3261.4) were up-regulated and 7 peaks (942.44, 1020.47, 1060.06, 1211.7, 1263.63, 1449.76, 2768.3) were down-regulated in the NAFLD group. Two peptides derived from complement C3f and fibrinopeptide A, respectively, had the highest ROC values indistinguishing NAFLD cases from their normal controls. In the validation group, the concentrations of complement C3f and fibrinopeptide A (1466.929±78.306 pg/ml, 4.189±0.326 ng/ml, respevtively) in NAFLD group was higher than in control group (complement C3f 1159.357±99.624 pg/ml, FPA 3.039±0.483 ng/ml; P<0.05).

Conclusions

In this study, we established apeptidomics pattern that could help distinguish NAFLD patients from their twin controls. The differently-regulated peptides identified in our study may be potential diagnostic markers or therapeutic targets for NAFLD.     

Risk of Advanced Neoplasia in First-Degree Relatives with Colorectal Cancer: A Large Multicenter Cross-Sectional Study

BackgroundFirst-degree relatives (FDR) of patients with colorectal cancer have a higher risk of developing colorectal cancer than the general population. For this reason, screening guidelines recommend colonoscopy every 5 or 10 y, starting at the age of 40, depending on whether colorectal cancer in the index-case is diagnosed at <60 or ≥60 y, respectively. However, studies on the risk of neoplastic lesions are inconclusive. The aim of this study was to determine the risk of advanced neoplasia (three or more non-advanced adenomas, advanced adenoma, or invasive cancer) in FDR of patients with colorectal cancer compared to average-risk individuals (i.e., asymptomatic adults 50 to 69 y of age with no family history of colorectal cancer).ConclusionsIndividuals having two FDR with colorectal cancer showed an increased risk of advanced neoplasia compared to those with average-risk for colorectal cancer. Men had over 2-fold higher risk of advanced neoplasia than women, independent of family history. These data suggest that screening colonoscopy guidelines should be revised in the familial-risk population.     

HbA1c Alone Is a Poor Indicator of Cardiometabolic Risk in Middle-Aged Subjects with Pre-Diabetes but Is Suitable for Type 2 Diabetes Diagnosis: A Cross-Sectional Study

Objectives

Glycated haemoglobin A_1c (HbA_1c) measurement is recommended as an alternative to fasting plasma glucose (FPG) for the diagnosis of pre-diabetes and type 2 diabetes. However, evidence suggests discordance between HbA_1c and FPG. In this study we examine a range of metabolic risk features, pro-inflammatory cytokines, acute-phase response proteins, coagulation factors and white blood cell counts to determine which assay more accurately identifies individuals at increased cardiometabolic risk.

Materials and Methods

This was a cross-sectional study involving a random sample of 2,047 men and women aged 46-73 years. Binary and multinomial logistic regression were employed to examine risk feature associations with pre-diabetes [either HbA_1c levels 5.7-6.4% (39-46 mmol/mol) or impaired FPG levels 5.6-6.9 mmol/l] and type 2 diabetes [either HbA_1c levels >6.5% (>48 mmol/mol) or FPG levels >7.0 mmol/l]. Receiver operating characteristic curve analysis was used to evaluate the ability of HbA_1c to discriminate pre-diabetes and diabetes defined by FPG.

Results

Stronger associations with diabetes-related phenotypes were observed in pre-diabetic subjects diagnosed by FPG compared to those detected by HbA_1c. Individuals with type 2 diabetes exhibited cardiometabolic profiles that were broadly similar according to diagnosis by either assay. Pre-diabetic participants classified by both assays displayed a more pro-inflammatory, pro-atherogenic, hypertensive and insulin resistant profile. Odds ratios of having three or more metabolic syndrome features were also noticeably increased (OR: 4.0, 95% CI: 2.8-5.8) when compared to subjects diagnosed by either HbA_1c (OR: 1.4, 95% CI: 1.2-1.8) or FPG (OR: 3.0, 95% CI: 1.7-5.1) separately.

Conclusions

In middle-aged Caucasian-Europeans, HbA_1c alone is a poor indicator of cardiometabolic risk but is suitable for diagnosing diabetes. Combined use of HbA_1c and FPG may be of additional benefit for detecting individuals at highest odds of type 2 diabetes development.     

Association between Complement C3 and Prevalence of Fatty Liver Disease in an Adult Population: A Cross-Sectional Study from the Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIHealth) Cohort Study

Activation of the innate immune system plays a key role in the development of fatty liver disease (FLD). The complement system is a major humoral component of the innate immune response and complement C3 plays a central role, implying that C3 may be a powerful predictor or therapeutic target for FLD. However, few studies have assessed the association between C3 and FLD in a large population. Here we use a cross-sectional study to investigate the link between serum C3 levels and FLD. Participants were recruited from Tianjin Medical University’s General Hospital-Health Management Centre. Serum C3 was measured using immunoturbidimetry method and FLD was diagnosed by liver ultrasonography. Multiple logistic regression analysis was used to examine the association between quartiles of C3 and FLD prevalence. The overall prevalence of nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) were 37.3% and 10.1%, respectively. After adjusting for covariates, the odds ratio of having NAFLD or AFLD (only in males) in the fourth quartile of C3 compared with the first quartile was 4.13 times greater (95% confidence interval, 2.97-5.77) (trend P values < 0.0001) and 2.09 times greater (95% confidence interval, 1.08-4.18) (trend P values = 0.02). This is the first study to demonstrate that serum C3 levels are independently associated with a higher prevalence of NAFLD and AFLD (only in males) in an adult population. Further studies are needed to establish a causal link and determine the precise role of C3 in FLD.     

Nonalcoholic Fatty Liver Disease and Risk of Diabetes: A Prospective Study in China

Objective: We aimed to investigate whether liver steatosis severity affects the risk of developing diabetes in a large cohort study.Methods: We prospectively examined the association in 41,650 Chinese adults with negative hepatitis-B surface antigen who were free of alcohol consumption, diabetes, and liver cirrhosis at baseline. Cox proportional models were used to estimate the risk of diabetes after a mean of 3.6 years of follow-up. Nonalcoholic fatty liver disease (NAFLD) was assessed with hepatic ultrasonography. Elevated alanine transaminase (ALT) was defined as ALT concentrations >19 and >30 U/L in females and males, respectively. Diabetes was defined as a fasting glucose ³7.0 mmol/L or treatment with hypoglycemic medication.Results: Liver steatosis severity was significantly associated with higher risks of developing diabetes (adjusted hazard ratio [HR] for severe vs. without NAFLD = 2.66, 95% confidence interval [CI]: 2.17–3.25, P-trend<.001) and impaired fasting glucose (fasting glucose between 5.6 and 6.9 mmol/L, adjusted HR = 1.36, 95% CI: 1.16–1.59, P-trend<.001), as well as a faster increase rate of fasting glucose concentrations (P-trend<.001), during 3.6 years of follow-up. Elevated ALT was also associated with incident diabetes (HR = 1.12, 95% CI: 1.02–1.22), adjusting for NAFLD and other covariates.Conclusion: We observed a dose-response relationship between liver steatosis severity and increased diabetes risk, and ALT may predict incident diabetes independently of NAFLD.Abbreviations: ALT = alanine transaminase; BP = blood pressure; CI = confidence interval; HCV = hepatitis C virus; HR = hazard ratio; IFG = impaired fasting glucose; NAFLD = nonalcoholic fatty liver disease; ULN = upper limit of normal     

Susceptibility and Gene Interaction Study of the Angiotensin II Type 1 Receptor (AGTR1) Gene Polymorphisms with Non-Alcoholic Fatty Liver Disease in a Multi-Ethnic Population

Angiotensin II type 1 receptor (AGTR1) has been reported to play a fibrogenic role in non-alcoholic fatty liver disease (NAFLD). In this study, five variants of the AGTR1 gene (rs3772622, rs3772627, rs3772630, rs3772633, and rs2276736) were examined for their association with susceptibility to NAFLD. Subjects made up of 144 biopsy-proven NAFLD patients and 198 controls were genotyped using TaqMan assays. The liver biopsy specimens were histologically graded and scored according to the method of Brunt. Single locus analysis in pooled subjects revealed no association between each of the five variants with susceptibility to NAFLD. In the Indian ethnic group, the rs2276736, rs3772630 and rs3772627 appear to be protective against NAFLD (p = 0.010, p = 0.016 and p = 0.026, respectively). Haplotype ACGCA is shown to be protective against NAFLD for the Indian ethnic subgroup (p = 0.03). Gene-gene interaction between the AGTR1 gene and the patatin-like phospholipase domain-containing 3 (PNPLA3) gene, which we previously reported as associated with NAFLD in this sample, showed a strong interaction between AGTR1 (rs3772627), AGTRI (rs3772630) and PNPLA3 (rs738409) polymorphisms on NAFLD susceptibility (p = 0.007). Further analysis of the NAFLD patients revealed that the G allele of the AGTR1 rs3772622 is associated with increased fibrosis score (p = 0.003). This is the first study that replicates an association between AGTR1 polymorphism and NAFLD, with further details in histological features of NAFLD. There is lack of evidence to suggest an association between any of the five variants of the AGTR1 gene and NAFLD in the Malays and Chinese. In the Indians, the rs2276736, rs3772630 and rs3772627 appear to protect against NAFLD. We report novel findings of an association between the G allele of the rs3772622 with occurrence of fibrosis and of the gene-gene interaction between AGTR1gene and the much-studied PNPLA3 gene.     

Hypertriglyceridemia Is Independently Associated with Renal,but Not Retinal Complications in Subjects with Type 2 Diabetes: A Cross-Sectional Analysis of the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study

Objective

Atherogenic dyslipidemia seems to play a major role in microvascular complications and in residual microvascular risk after statin therapy, which reduces triglycerides up to 40%. We assessed whether raised TG levels are associated with an increased burden from microvascular complications in patients with type 2 diabetes.

Methods

Subjects from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study (n=15,773) were divided in 4 groups depending on whether they had plasma triglycerides below (NTG, 67.8%) or above (HTG, 32.2%) 1.7 mmol/L and were (42.4%) or not on (57.6%) statin therapy. Estimated GFR (eGFR) was calculated from serum creatinine, albuminuria was measured by immunonephelometry or immunoturbidimetry, and retinopathy was evaluated by fundus examination.

Results

HTG subjects, either with or without statin, had higher prevalence of albuminuria, reduced eGFR and chronic kidney disease (CKD), especially the albuminuric forms, but not of retinopathy, than NTG subjects. In contrast, cardiovascular disease and advanced DR were more prevalent in subjects on statin than in those not, independently of triglyceride levels. Logistic regression analysis confirmed that HTG, without or with statin, was independently associated with micro and macroalbuminuria, mildly to severely reduced eGFR, and all CKD phenotypes, but not with retinopathy. The adjusted odd ratios for CKD increased linearly for every 0.26 mmol/L increase (approximately one decile) in triglyceride levels. The increase was higher with increasing severity of albuminuria, eGFR loss and CKD phenotype as well as in subjects receiving than in those not receiving statin treatment.

Conclusions

Triglycerides are associated with CKD, but not retinopathy in subjects with type 2 diabetes, independently of statin treatment. These data point to a possible role of hypertriglyceridemia in the development of CKD, though it remains to be demonstrated that diabetic individuals might benefit from triglyceride reduction with statins and eventually with combination therapy with fibrates.

Trial Registration

www.ClinicalTrials.gov NCT00715481     

Association between Soluble (Pro)Renin Receptor Concentration in Cord Blood and Small for Gestational Age Birth: A Cross-Sectional Study

Objective

The (pro)renin receptor [(P)RR] has been recognized as a multifunctional receptor. The purpose of this study was to assess the association between plasma soluble (P)RR [s(P)RR] concentration in human cord blood (i.e., neonatal blood at birth) and small for gestational age (SGA) birth.

Methods

Participants were women with a singleton pregnancy who delivered at the National Center for Child Health and Development between January 2010 and December 2011. Inclusion criteria were availability of maternal pre-pregnancy and paternal body mass index, and the absence of structural anomalies in neonates. s(P)RR concentration in cord blood was measured in 621 neonates. The 621 pairs of mothers and neonates were categorized into four groups based on quartiles of s(P)RR concentrations in cord blood. SGA was defined as a birth weight below the 10^th percentile for gestational age. Logistic regression analysis was performed to assess the association between cord plasma s(P)RR concentration (quartiles) and incidence of SGA births.

Results

Among 621 neonates, 55 (8.9%) were diagnosed as SGA (SGA group) and 566 (91.1%) were not (non-SGA group). Average s(P)RR concentration in cord blood was 66.1±12.6 ng/ml (mean±standard deviation). There were 155 pairs in the first plasma s(P)RR concentration quartile (Q1: <58.2 ng/ml), 153 pairs in the second quartile (Q2: 58.2–65.1 ng/ml), 157 pairs in the third quartile (Q3: 65.1–73.1 ng/ml) and 156 pairs in the fourth quartile (Q4: >73.1 ng/ml). The distribution of SGA births was 18 (11.6%) in Q1, 14 (9.2%) in Q2, 16 (10.2%) in Q3 and 7 (4.5%) in Q4, respectively. The odds ratio of SGA births was 0.24 (95% confidence interval: 0.08–0.71) for the fourth quartile compared to the first quartile in multivariate models. The P-value for trend was also significant (P = 0.020).

Conclusion

High s(P)RR concentration is associated with a lower SGA birth likelihood.     

Anthropometric and Micronutrient Status of School-Children in an Urban West Africa Setting: A Cross-Sectional Study in Dakar (Senegal)

Background

Urban areas in West Africa are not immune to undernutrition with recent urbanization and high food prices being important factors. School children often have a poor nutritional status, potentially affecting their health and schooling performance. Yet, generally school children do not benefit from nutrition programs. The objective of the study was to assess the anthropometric and micronutrient status of children from state schools in the Dakar area.

Methods

School children (n = 604) aged from 5 to 17 y (52.5% girls, 47.5% ≥10 y) were selected through a two-stage random cluster sample of children attending urban primary state schools in the Dakar area (30 schools × 20 children). The prevalence of stunting (height-for-age<−2 z-scores) and thinness (BMI-for-age<−2 z-scores, WHO 2006, and three grades of thinness corresponding to BMI of 18.5, 17.0 and 16.0 kg/m2 in adults) were calculated from weight and height. Hemoglobin, plasma concentrations of ferritin (FER), transferrin receptors (TfR), retinol binding protein (RBP), and zinc, and urinary iodine concentrations were measured. Correction factors were used for FER and RBP in subjects with inflammation determined with C-reactive protein and α1-acid-glycoprotein.

Results

4.9% of children were stunted, 18.4% were thin, 5.6% had severe thinness (BMI-for-age<−3 z-scores). Only one child had a BMI-for-age>2 z-scores. Prevalence of anemia, iron deficiency and iron deficiency anemia was 14.4%, 39.1% and 10.6% respectively. 3.0% had vitamin A deficiency, 35.9% a marginal vitamin A status, and 25.9% zinc deficiency. Urinary iodine was <50 µg/L in 7.3% of children and ≥200 µg/L in 22.3%. The prevalence of marginal vitamin A, zinc deficiency, high TfR was significantly higher in boys than in girls (P<0.05). Height-for-age and retinol were significantly lower in participants ≥10 y and <10 y respectively.

Conclusion

Undernutrition, especially thinness, iron and zinc deficiencies in school children in the Dakar area requires special targeted nutrition interventions.     

Relationship between Urinary Level of Phytate and Valvular Calcification in an Elderly Population: A Cross-Sectional Study

Pathological calcification generally consists of the formation of solid deposits of hydroxyapatite (calcium phosphate) in soft tissues. Supersaturation is the thermodynamic driving force for crystallization, so it is believed that higher blood levels of calcium and phosphate increase the risk of cardiovascular calcification. However several factors can promote or inhibit the natural process of pathological calcification. This cross-sectional study evaluated the relationship between physiological levels of urinary phytate and heart valve calcification in a population of elderly out subjects. A population of 188 elderly subjects (mean age: 68 years) was studied. Valve calcification was measured by echocardiography. Phytate determination was performed from a urine sample and data on blood chemistry, end-systolic volume, concomitant diseases, cardiovascular risk factors, medication usage and food were obtained. The study population was classified in three tertiles according to level of urinary phytate: low (<0.610 μM), intermediate (0.61–1.21 μM), and high (>1.21 μM). Subjects with higher levels of urinary phytate had less mitral annulus calcification and were less likely to have diabetes and hypercholesterolemia. In the multivariate analysis, age, serum phosphorous, leukocytes total count and urinary phytate excretion appeared as independent factors predictive of presence of mitral annulus calcification. There was an inverse correlation between urinary phytate content and mitral annulus calcification in our population of elderly out subjects. These results suggest that consumption of phytate-rich foods may help to prevent cardiovascular calcification evolution.