Risk of Obstructive Sleep Apnea with Daytime Sleepiness Is Associated with Liver Damage in Non-Morbidly Obese Patients with Nonalcoholic Fatty Liver Disease

Background

A high prevalence of obstructive sleep apnea syndrome (OSAS) has been reported in severely obese patients with nonalcoholic fatty liver disease (NAFLD), but few studies have evaluated OSAS in non-morbidly obese NAFLD patients.

Aims

To determine the prevalence of risk for OSAS with or without daytime sleepiness in non-morbidly obese patients with NAFLD and evaluate the association with the severity of liver damage.

Methods

We considered 159 consecutive patients with histological NAFLD and body mass index (BMI) <35 Kg/m², and 80 controls without ultrasonographic steatosis matched for age, sex, and BMI. OSAS risk was determined by positivity for Berlin questionnaire (BQ), and daytime sleepiness by the Sleepness Epworth Scale (ESS). Liver damage was evaluated according to the NAFLD activity score.

Results

In NAFLD patients, BQ alone was positive in 39 (25%), ESS in 8 (5%), and both in 13 (8%, OSAS with sleepines); p = ns vs. controls without steatosis. In NAFLD patients at risk for OSAS with (but not in those without) sleepiness, we observed a higher prevalence of nonalcoholic steatohepatitis (NASH; 11/13, 85% vs. 72/146, 49%; p = 0.018), and of clinically significant fibrosis (stage>1; 9/13, 69% vs. 39/146, 27%; p = 0.003). At multivariate logistic regression analysis, OSAS with sleepiness was strongly associated with NASH and fibrosis>1 independently of known clinical risk factors such as age, gender, BMI, diabetes, and ALT levels (OR 7.1, 95% c.i. 1.7–51, p = 0.005 and OR 14.0, 95% c.i. 3.5–70, p = 0.0002, respectively).

Conclusions

A proportion of NAFLD patients without severe obesity is at risk for OSAS with daytime sleepiness, which is associated with the severity of liver damage independently of body mass and other cofactors.     

High Dietary Sodium Intake Assessed by Estimated 24-h Urinary Sodium Excretion Is Associated with NAFLD and Hepatic Fibrosis

Background

Although high sodium intake is associated with obesity and hypertension, few studies have investigated the relationship between sodium intake and non-alcoholic fatty liver disease (NAFLD). We evaluated the association between sodium intake assessed by estimated 24-h urinary sodium excretion and NAFLD in healthy Koreans.

Methods

We analyzed data from 27,433 participants in the Korea National Health and Nutrition Examination Surveys (2008–2010). The total amount of sodium excretion in 24-h urine was estimated using Tanaka’s equations from spot urine specimens. Subjects were defined as having NAFLD when they had high scores in previously validated NAFLD prediction models such as the hepatic steatosis index (HSI) and fatty liver index (FLI). BARD scores and FIB-4 were used to define advanced fibrosis in subjects with NAFLD.

Results

The participants were classified into three groups according to estimated 24-h urinary excretion tertiles. The prevalence of NAFLD as assessed by both FLI and HSI was significantly higher in the highest estimated 24-h urinary sodium excretion tertile group. Even after adjustment for confounding factors including body fat and hypertension, the association between higher estimated 24-h urinary sodium excretion and NAFLD remained significant (Odds ratios (OR) 1.39, 95% confidence interval (CI) 1.26–1.55, in HSI; OR 1.75, CI 1.39–2.20, in FLI, both P < 0.001). Further, subjects with hepatic fibrosis as assessed by BARD score and FIB-4 in NAFLD patients had higher estimated 24-h urinary sodium values.

Conclusions

High sodium intake was independently associated with an increased risk of NAFLD and advanced liver fibrosis.     

NIKEI: A New Inexpensive and Non-Invasive Scoring System to Exclude Advanced Fibrosis in Patients with NAFLD

Aims

To develop, validate and compare a non-invasive fibrosis scoring system for non-alcoholic fatty liver disease (NAFLD) derived from routinely obtained clinical and biochemical parameters.

Methods

267 consecutive patients with biopsy proven fatty liver or non-alcoholic steatohepatitis were randomly assigned to the estimation (2/3) or validation (1/3) group to develop a model for the prediction of advanced fibrosis. Univariate statistics were performed to compare patients with and without advanced fibrosis, and following a multivariate logistic regression analysis a new scoring system was constructed. This non-invasive Koeln-Essen-index (NIKEI) was validated and compared to the FIB-4 index by calculating the area under the receiver operating characteristic curve (AUC). We evaluated a stepwise combination of both scoring systems for the precise prediction of advanced fibrosis. To set in contrast, we additionally tested the diagnostic accuracy of the AST/ALT ratio, BARD score and the NAFLD fibrosis score in our cohort.

Results

Age, AST, AST/ALT ratio, and total bilirubin were identified as significant predictors of advanced fibrosis and used to construct the NIKEI with an AUC of 0.968 [0.937; 0.998] compared to 0.929 [0.869; 0.989] for the FIB-4 index. The absence of advanced fibrosis could be confirmed with excellent accuracy (99–100%). The positive predictive value of the FIB-4 index was higher (100% vs. 60%), however, the false negative rate was also high (33%). With a stepwise combination of both indices 82%–84% of biopsies would have been avoidable without a single misclassification. The AUROC for AST/ALT ratio, the NAFLD fibrosis score, and the BARD score were 0.81 (95% CI, 0.72–0.90), 0.96 (95% CI 0.92–0.99), and 0.67 (95% CI 0.55–0.78), respectively.

Conclusion

The NIKEI can reliably exclude advanced fibrosis in subjects with NAFLD. In combination with the FIB-4 index misclassification with inadequate clinical management can be avoided while the need for liver biopsies can be reduced.     

Low Vitamin D Status Is Associated with Nonalcoholic Fatty Liver Disease Independent of Visceral Obesity in Korean Adults

Objective

To investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and nonalcoholic fatty liver disease (NAFLD) independent of visceral obesity in Koreans and to examine whether the associations differ according to the presence of diabetes or insulin resistance.

Research Design and Methods

A total of 1081 adults were enrolled from a population-based cohort in Ansan city. Serum 25(OH)D concentrations were measured in all subjects. Insulin resistance was measured by homeostasis model assessment of insulin resistance (HOMA-IR). Using computed tomography, NAFLD was diagnosed if the liver attenuation index (LAI, the difference between the mean hepatic and splenic attenuation) was <5 Hounsfield Units.

Results

In subjects with diabetes (n = 282), 25(OH)D levels were negatively associated with waist circumference, fasting insulin, HOMA-IR, triglyceride levels, and visceral abdominal fat, and were positively associated with LAI after adjusting for age, sex, season, exercise, and vitamin supplementation. In subjects without diabetes, only triglyceride level was negatively associated with 25(OH)D. The adjusted odds ratio (OR) for NAFLD increased sequentially across decreasing quartiles of 25(OH)D in subjects with diabetes even after adjusting for visceral fat [Q1 vs. Q4; OR for NAFLD 2.5 (95% CI:1.0–6.2)]. In contrast, no significant difference in OR was observed in subjects without diabetes. When we classified non-diabetic subjects by HOMA-IR, an increase in the OR for NAFLD across decreasing quartiles of 25(OH)D was observed in the high HOMA-IR (≥2.5) group [n = 207, Q1 vs. Q4; OR 3.8(1.4–10.3)], but not in the low HOMA-IR (<2.5) group [n = 592, OR 0.8 (0.3–1.9)].

Conclusions

Low vitamin D status is closely associated with NAFLD, independent of visceral obesity in subjects with diabetes or insulin resistance.     

Traditional but Not HIV-Related Factors Are Associated with Nonalcoholic Fatty Liver Disease in Asian Patients with HIV-1 Infection

Background

The prevalence and factors associated with nonalcoholic fatty liver disease (NAFLD) are largely unknown in HIV-1 monoinfected patients.

Methods

The present study elucidated the prevalence and factors associated with NAFLD among Asian patients with HIV-1 infection who underwent abdominal ultrasonography between January 2004 and March 2013. Diagnosis of NAFLD was based on the liver to kidney contrast and diffusion in hepatic echogenicity. Uni- and multi-variate logistic regression analyses were applied to estimate factors associated with NAFLD.

Results

435 Asian patients free of chronic hepatitis B or C virus infection and without excessive alcohol intake were analyzed. NAFLD was diagnosed in 135 (31%) patients. Obesity (BMI >30 kg/m²) was evident in 18 (4.1%) patients, and BMI was >25 kg/m² in 103 (24%). Multivariate analysis identified higher BMI (per 1 kg/m² increment, adjusted OR = 1.198; 95% CI, 1.112–1.290; p<0.001), dyslipidemia (adjusted OR = 2.045; 95% CI, 1.183–3.538; p = 0.010), and higher ALT to AST ratio (per 1 increment, adjusted OR = 3.557; 95% CI, 2.129–5.941; p<0.001) as significant factors associated with NAFLD. No HIV-specific variables, including treatment with dideoxynucleoside analogues (didanosine, stavudine, and zalcitabine) and cumulative duration of antiretroviral therapy (ART), were associated with NAFLD.

Conclusions

The incidence of NALFD among Asian patients with HIV-1 infection is similar to that in Western countries. NAFLD was associated with high BMI, dyslipidemia, and high ALT/AST ratio, but not with HIV-related factors. The results highlight the importance of early recognition and management of NAFLD and traditional factors associated with NAFLD for Asian patients with HIV-1 infection.     

Association between the PNPLA3 I148M Polymorphism and Non-Alcoholic Fatty Liver Disease in the Uygur and Han Ethnic Groups of Northwestern China

Objective

Multiple common gene variants play a role in non-alcoholic fatty liver disease (NAFLD) susceptibility. Our goal was to investigate the association between variants polymorphisms and NAFLD in the Uygur and Han from Northwestern China.

Methods

Eight tag single nucleotide polymorphisms (tSNPs) previously reported to be associated with NAFLD were characterized in 396 NAFLD individuals and 399 controls. The association of variants with NAFLD in the Uygur and Han was assessed using the chi-squared (χ²) test in different gene models. Unconditional logistic regression analysis was performed to obtain the odds ratios (ORs) for risk of NAFLD and their 95% confidence intervals (CI), adjusted for confounding factors. Finally, stratified analysis was used to explore the potential gene-environment interactions on the risk of NAFLD.

Results

In a recessive model, we found a potential association between rs738409 and NAFLD in both ethnic groups: Chinese Han (OR = 1.84, 95% CI: 1.03–3.27, p = 0.036), Uygur (OR = 2.25, 95% CI: 1.23–4.09, p = 0.006). The multiple logistic regression revealed that PNPLA3 rs738409 GG genotype may increase the risk of NAFLD by adjusting some confounding factors: Han (OR = 5.22, 95% CI: 1.94–14.04, p = 0.001), Uygur (OR = 4.29, 95% CI: 1.60–11.48, p = 0.004). Stratified analysis found that rs738409 polymorphism appeared to have interaction with sex, smoking status in Uygur, and have interaction with sex, age, BMI stage, lifestyle in Han.

Conclusion

Our data suggest the PNPLA3 I148M polymorphism influences susceptibility to NAFLD in the Han and Uygur of Northwestern China.     

PNPLA3 I148M Polymorphism,Clinical Presentation,and Survival in Patients with Hepatocellular Carcinoma

Background & Aims

Aim of this study was to evaluate whether the PNPLA3 I148M polymorphism, previously associated with hepatocellular carcinoma (HCC) risk, influences the clinical presentation of HCC and survival.

Methods

we considered 460 consecutive HCC patients referred to tertiary care centers in Northern Italy, 353 with follow-up data.

Results

Homozygosity for PNPLA3 148M at risk allele was enriched in HCC patients with alcoholic liver disease or nonalcoholic fatty liver disease (ALD&NAFLD: relative risk 5.9, 95% c.i. 3.5–9.9; other liver diseases: relative risk 1.9, 95% c.i. 1.1–3.4). In ALD&NAFLD patients, the PNPLA3 148M allele was associated with younger age, shorter history of cirrhosis, less advanced (Child A) cirrhosis at HCC diagnosis, and lower HCC differentiation grade (p<0.05). Homozygosity for PNPLA3 148M was associated with reduced survival in the overall series (p = 0.009), and with a higher number of HCC lesions at presentation (p = 0.007) and reduced survival in ALD&NAFLD patients (p = 0.003; median survival 30, 95% c.i. 20–39 vs. 45, 95% c.i. 38–52 months), but not in those with HCC related to other etiologies (p = 0.86; 48, 95% c.i. 32–64 vs. 55, 95% c.i. 43–67 months). At multivariate Cox regression analysis, homozygosity for PNPLA3 148M was the only negative predictor of survival in ALD&NAFLD patients (HR of death 1.57, 95% c.i. 1.12–2.78).

Conclusions

PNPLA3 148M is over-represented in ALD&NAFLD HCC patients, and is associated with occurrence at a less advanced stage of liver disease in ALD&NAFLD. In ALD&NAFLD, PNPLA3 148M is associated with more diffuse HCC at presentation, and with reduced survival.     

The Development of the Pediatric NAFLD Fibrosis Score (PNFS) to Predict the Presence of Advanced Fibrosis in Children with Nonalcoholic Fatty Liver Disease

Background

Noninvasive hepatic fibrosis scores that predict the presence of advanced fibrosis have been developed and validated in adult patients with NAFLD. The aims of our study were to assess the utility of commonly used adult fibrosis scores in pediatric NAFLD and to develop a pediatric specific fibrosis score that can predict advanced fibrosis.

Methods

Consecutive children with biopsy-proven NAFLD were included. Fibrosis was determined by an experienced pathologist (F0–4). Advanced fibrosis was defined as fibrosis stage ≥3. The following adult fibrosis scores were calculated for each child: AST/ALT ratio, AST/platelet ratio index (APRI), NAFLD fibrosis score (NFS), and FIB-4 Index. Multivariable logistic regression analysis was performed to build a new pediatric model for predicting advanced fibrosis.

Results

Our cohort consisted of 242 children with a mean age of 12.4±3.1 years and 63% were female. 36 (15%) subjects had advanced fibrosis. APRI and FIB-4 were higher in patients with advanced fibrosis compared to those with fibrosis stage 0–2; however, AST/ALT ratio and NFS were not different between the two groups. We used our data to develop a new model to predict advanced fibrosis which included: ALT, alkaline phosphatase, platelet counts and GGT. The multivariable logistic regression model (z) was defined as follows: z = 1.1+(0.34*sqrt(ALT))+(0.002*alkaline phosphatase) – (1.1*log(platelets) – (0.02*GGT). This value was then converted into a probability distribution (p) with a value between 0 to 100 by the following formula: p = 100×exp(z)/[1+exp(z)]. The AUCROC for this model was 0.74 (95% CI: 0.66, 0.82). This was found to be significantly better than APRI, NAFLD Fibrosis Score and FIB-4 Index.

Conclusion

Noninvasive hepatic fibrosis scores developed in adults had poor performance in diagnosing advanced fibrosis in children with NAFLD. We developed a new pediatric NAFLD fibrosis score with improved performance characteristics.     

Weight Loss in Nonalcoholic Fatty Liver Disease Patients in an Ambulatory Care Setting Is Largely Unsuccessful but Correlates with Frequency of Clinic Visits

Background and Aims

Nonalcoholic fatty liver disease (NALFD) is a leading cause of liver disease. Weight loss improves clinical features of NAFLD; however, maintenance of weight loss outside of investigational protocols is poor. The goals of this study were to characterize patterns and clinical predictors of long-term weight loss in ambulatory patients with NAFLD.

Methods

We retrospectively reviewed 924 non-cirrhotic patients with NAFLD presenting to a liver clinic from May 1^st 2007 to April 30^th 2013. Overweight and obese patients were counseled on lifestyle modifications for weight loss as per USPSTF guidelines. The primary outcome was percent weight change between the first and last recorded visits: % weight change  =  (weight^initial – weight^final)/(weight^initial). Baseline BMI and percent BMI change were secondary measures. Predictors of weight loss were determined using logistic regression.

Results

The mean baseline BMI was 33.3±6.6 kg/m², and the mean follow-up duration was 17.3±17.6 months. Most patients with NAFLD were in either overweight (26.1%) or class I obesity (30.5%) categories at baseline, while the prevalence of underweight and class III obesity was lower (0.2% and 15.4%, respectively). Overall, there was no change in mean weight or BMI during the follow-up period, and only 183 patients (19.8%) lost at least 5% body weight during the follow up period. Independent predictors of weight loss included number of clinic visits and baseline BMI, and patients with higher baseline BMI required more clinic visits to lose weight.

Conclusions

Weight loss is largely unsuccessful in NAFLD patients in the ambulatory care setting. Frequent clinical encounters are associated with weight reduction, especially among individuals with high baseline BMI. Future studies are required to define effective weight loss strategies in NAFLD patients.     

Impact of Waist Circumference and Body Mass Index on Risk of Cardiometabolic Disorder and Cardiovascular Disease in Chinese Adults: A National Diabetes and Metabolic Disorders Survey

Background

We updated the prevalence of obesity and evaluated the clinical utility of separate and combined waist circumference (WC) or body mass index (BMI) category increments in identifying cardiometabolic disorder (CMD) and cardiovascular disease (CVD) risk in Chinese adults.

Methods and Findings

46,024 participants aged ≥20 years, a nationally representative sample surveyed in 2007–2008, were included in this analysis. Taking the cutoffs recommended by the Chinese Joint Committee for Developing Chinese Guidelines (JCDCG) and the Working Group on Obesity in China (WGOC) into account, the participants were divided into four WC and four BMI groups in 0.5-SD increments around the mean, and 16 cross-tabulated combination groups of WC and BMI. 27.1%, 31.4%, and 12.2% of Chinese adults are centrally obese, overweight, or obese according to JCDCG and WGOC criteria. After adjustment for confounders, after a 1-SD increment, WC is associated with a 1.7-fold or 2.2-fold greater risk of having DM or DM plus dyslipidemia than BMI, while BMI was associated with a 2.3-fold or 1.7-fold higher hypertension or hypertension plus dyslipidemia risk than WC. The combination of WC and BMI categories had stronger association with CMD risk, i.e., the adjusted ORs (95% CI) of having DM, hypertension, and dyslipidemia for the combined and separate highest WC and BMI categories were 2.19 (1.96–2.44) vs 1.88 (1.67–2.12) and 1.12 (0.99–1.26); 5.70 (5.24–6.19) vs 1.51 (1.39–1.65) and 1.69 (1.57–1.82); and 3.73 (3.42–4.07) vs 2.16 (1.98–2.35) and 1.33 (1.25–1.40), respectively. The combination of WC and BMI categories was more likely to identify individuals with lower WC and lower BMI at CVD risk, even after the effects of CMD were controlled (all P<0.05).

Conclusion

Central obesity, overweight, and obesity are epidemic in Chinese adults. The combination of WC and BMI measures is superior to the separate indices in identifying CMD and CVD risk.     

Non–Laboratory-Based Self-Assessment Screening Score for Non-Alcoholic Fatty Liver Disease: Development,Validation and Comparison with Other Scores

Background

Non-alcoholic fatty liver disease (NAFLD) is a prevalent and rapidly increasing disease worldwide; however, no widely accepted screening models to assess the risk of NAFLD are available. Therefore, we aimed to develop and validate a self-assessment score for NAFLD in the general population using two independent cohorts.

Methods

The development cohort comprised 15676 subjects (8313 males and 7363 females) who visited the National Health Insurance Service Ilsan Hospital in Korea in 2008–2010. Anthropometric, clinical, and laboratory data were examined during regular health check-ups and fatty liver diagnosed by abdominal ultrasound. Logistic regression analysis was conducted to determine predictors of prevalent NAFLD and to derive risk scores/models. We validated our models and compared them with other existing methods using an external cohort (N = 66868).

Results

The simple self-assessment score consists of age, sex, waist circumference, body mass index, history of diabetes and dyslipidemia, alcohol intake, physical activity and menopause status, which are independently associated with NAFLD, and has a value of 0–15. A cut-off point of ≥8 defined 58% of males and 36% of females as being at high-risk of NAFLD, and yielded a sensitivity of 80% in men (77% in women), a specificity of 67% (81%), a positive predictive value of 72% (63%), a negative predictive value of 76% (89%) and an AUC of 0.82 (0.88). Comparable results were obtained using the validation dataset. The comprehensive NAFLD score, which includes additional laboratory parameters, has enhanced discrimination ability, with an AUC of 0.86 for males and 0.91 for females. Both simple and comprehensive NAFLD scores were significantly increased in subjects with higher fatty liver grades or severity of liver conditions (e.g., simple steatosis, steatohepatitis).

Conclusions

The new non–laboratory-based self-assessment score may be useful for identifying individuals at high-risk of NAFLD. Further studies are warranted to evaluate the utility and feasibility of the scores in various settings.     

Consuming More of Daily Caloric Intake at Dinner Predisposes to Obesity. A 6-Year Population-Based Prospective Cohort Study

Background/Objectives

It has been hypothesized that assuming most of the caloric intake later in the day leads to metabolic disadvantages, but few studies are available on this topic. Aim of our study was to prospectively examine whether eating more of the daily caloric intake at dinner leads to an increased risk of obesity, hyperglycemia, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD).

Subjects/Methods

1245 non-obese, non-diabetic middle-aged adults from a population-based cohort underwent a 3-day food record questionnaire at enrollment. Anthropometric values, blood pressure, blood metabolic variables, and estimated liver fat were measured at baseline and at 6-year follow-up.

Design

Prospective cohort study.

Results

Subjects were divided according to tertiles of percent daily caloric intake at dinner. A significant increase in the incidence rate of obesity (from 4.7 to 11.4%), metabolic syndrome (from 11.1 to 16.1%), and estimated NAFLD (from 16.5 to 23.8%) was observed from the lower to higher tertile. In a multiple logistic regression model adjusted for multiple covariates, subjects in the highest tertile showed an increased risk of developing obesity (OR = 2.33; 95% CI 1.17–4.65; p = 0.02), metabolic syndrome (OR = 1.52; 95% CI 1.01–2.30; p = 0.04), and NAFLD (OR = 1.56; 95% CI 1.10–2.22; p = 0.01).

Conclusions

Consuming more of the daily energy intake at dinner is associated with an increased risk of obesity, metabolic syndrome, and NAFLD.     

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.     

Associations between Longer Habitual Day Napping and Non-Alcoholic Fatty Liver Disease in an Elderly Chinese Population

Context

Both longer habitual day napping and Non-Alcoholic Fatty Liver Disease (NAFLD) are associated with diabetes and inflammation, but the association between day napping and NAFLD remains unexplored.

Objective

To investigate the association between the duration of habitual day napping and NAFLD in an elderly Chinese population and to gain insight into the role of inflammatory cytokines in this association.

Design and Setting

We conducted a series of cross-sectional studies of the community population in Chongqing, China, from 2011 to 2012.

Participants

Among 6998 participants aged 40 to 75 years, 6438 eligible participants were included in the first study and analyzed to observe the association between day napping duration and NAFLD. In a separate study, 80 non-nappers and 90 nappers were selected to identify the role of inflammatory cytokines in this association. Logistic regression models were used to examine the odds ratios (ORs) of day nap duration with NAFLD.

Results

Day nappers had a significantly higher prevalence of NAFLD (P<0.001). Longer day napping duration was associated in a dose-dependent manner with NAFLD (P trend <0.001). After adjustment for potential confounders, the ORs were 1.67 (95% CI 1.13–2.46) for those reporting 0.5–1 h and 1.49 (95% CI 1.01–2.19) for those reporting >1 h of day napping compared with individuals who did not take day naps (all P<0.05). Longer-duration day nappers had higher levels of IL-6 and progranulin (PGRN) but lower levels of Secreted frizzled-related protein-5 (SFRP5, all P trend <0.001). After adjusting for IL-6, PGRN, and SFRP5, the association between day napping duration and NAFLD disappeared (all P>0.05).

Conclusion

Longer day napping duration is associated with a higher prevalence of NAFLD, and inflammatory cytokines may be an essential link between day napping and NAFLD.     

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.     

Differences in the Acute Effects of Aerobic and Resistance Exercise in Subjects with Type 2 Diabetes: Results from the RAED2 Randomized Trial

Objective

Both aerobic (AER) and resistance (RES) training, if maintained over a period of several months, reduce HbA1c levels in type 2 diabetes subjects. However, it is still unknown whether the short-term effects of these types of exercise on blood glucose are similar. Our objective was to assess whether there may be a difference in acute blood glucose changes after a single bout of AER or RES exercise.

Study Design

Twenty-five patients participating in the RAED2 Study, a RCT comparing AER and RES training in diabetic subjects, were submitted to continuous glucose monitoring during a 60-min exercise session and over the following 47 h. These measurements were performed after 10.9+0.4 weeks of training. Glucose concentration areas under the curve (AUC) during exercise, the subsequent night, and the 24-h period following exercise, as well as the corresponding periods of the non-exercise day, were assessed. Moreover, the low (LBGI) and high (HBGI) blood glucose indices, which summarize the duration and extent of hypoglycaemia or hyperglycaemia, respectively, were measured.

Results

AER and RES training similarly reduced HbA1c. Forty-eight hour glucose AUC was similar in both groups. However, a comparison of glucose AUC during the 60-min exercise period and the corresponding period of the non-exercise day showed that glucose levels were lower during exercise in the AER but not in the RES group (time-by-group interaction p = 0.04). Similar differences were observed in the nocturnal periods (time-by-group interaction p = 0.02). Accordingly, nocturnal LBGI was higher in the exercise day than in the non-exercise day in the AER (p = 0.012) but not in the RES group (p = 0.62).

Conclusions

Although AER and RES training have similar long-term metabolic effects in diabetic subjects, the acute effects of single bouts of these exercise types differ, with a potential increase in late-onset hypoglycaemia risk after AER exercise.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01182948","term_id":"NCT01182948"}}NCT01182948     

Continuous Grading of Early Fibrosis in NAFLD Using Label-Free Imaging: A Proof-of-Concept Study

Background and Aims

Early detection of fibrosis is important in identifying individuals at risk for advanced liver disease in non-alcoholic fatty liver disease (NAFLD). We tested whether second-harmonic generation (SHG) and coherent anti-Stokes Raman scattering (CARS) microscopy, detecting fibrillar collagen and fat in a label-free manner, might allow automated and sensitive quantification of early fibrosis in NAFLD.

Methods

We analyzed 32 surgical biopsies from patients covering histological fibrosis stages 0–4, using multimodal label-free microscopy. Native samples were visualized by SHG and CARS imaging for detecting fibrillar collagen and fat. Furthermore, we developed a method for quantitative assessment of early fibrosis using automated analysis of SHG signals.

Results

We found that the SHG mean signal intensity correlated well with fibrosis stage and the mean CARS signal intensity with liver fat. Little overlap in SHG signal intensities between fibrosis stages 0 and 1 was observed. A specific fibrillar SHG signal was detected in the liver parenchyma outside portal areas in all samples histologically classified as having no fibrosis. This signal correlated with immunohistochemical location of fibrillar collagens I and III.

Conclusions

This study demonstrates that label-free SHG imaging detects fibrillar collagen deposition in NAFLD more sensitively than routine histological staging and enables observer-independent quantification of early fibrosis in NAFLD with continuous grading.     

Maternal Overweight and Obesity and Risks of Severe Birth-Asphyxia-Related Complications in Term Infants: A Population-Based Cohort Study in Sweden

Background

Maternal overweight and obesity increase risks of pregnancy and delivery complications and neonatal mortality, but the mechanisms are unclear. The objective of the study was to investigate associations between maternal body mass index (BMI) in early pregnancy and severe asphyxia-related outcomes in infants delivered at term (≥37 weeks).

Methods and Findings

A nation-wide Swedish cohort study based on data from the Medical Birth Register included all live singleton term births in Sweden between 1992 and 2010. Logistic regression analyses were used to obtain odds ratios (ORs) with 95% CIs for Apgar scores between 0 and 3 at 5 and 10 minutes, meconium aspiration syndrome, and neonatal seizures, adjusted for maternal height, maternal age, parity, mother''s smoking habits, education, country of birth, and year of infant birth. Among 1,764,403 term births, 86% had data on early pregnancy BMI and Apgar scores. There were 1,380 infants who had Apgar score 0–3 at 5 minutes (absolute risk  = 0.8 per 1,000) and 894 had Apgar score 0–3 at 10 minutes (absolute risk  = 0.5 per 1,000). Compared with infants of mothers with normal BMI (18.5–24.9), the adjusted ORs (95% CI) for Apgar scores 0–3 at 10 minutes were as follows: BMI 25–29.9: 1.32 (1.10–1.58); BMI 30–34.9: 1.57 (1.20–2.07); BMI 35–39.9: 1.80 (1.15–2.82); and BMI ≥40: 3.41 (1.91–6.09). The ORs for Apgar scores 0–3 at 5 minutes, meconium aspiration, and neonatal seizures increased similarly with maternal BMI. A study limitation was lack of data on effects of obstetric interventions and neonatal resuscitation efforts.

Conclusion

Risks of severe asphyxia-related outcomes in term infants increase with maternal overweight and obesity. Given the high prevalence of the exposure and the severity of the outcomes studied, the results are of potential public health relevance and should be confirmed in other populations. Prevention of overweight and obesity in women of reproductive age is important to improve perinatal health. Please see later in the article for the Editors'' Summary     

Mild Obesity,Physical Activity,Calorie Intake,and the Risks of Cervical Intraepithelial Neoplasia and Cervical Cancer

Objective

We investigated whether obesity, physical activity, and calorie intake are associated with the risks of cervical intraepithelial neoplasia (CIN) and cervical cancer.

Methods

We enrolled 1125 women (age, 18–65 years) into a human papillomavirus cohort study established from 2006 to 2012. Multinomial logistic regression models were used to estimate crude and multivariate odds ratios (ORs) and the corresponding 95% confidence intervals (95% CIs), and to assess whether body mass index (BMI), height, weight, total calorie intake, and physical activity were associated with the risks of CIN and cervical cancer.

Results

Cervical cancer risk was positively associated with BMI and inversely associated with physical activity. When compared with women with a normal BMI (18.5–23 kg/m²), the multivariate ORs (95% CIs) for those overweight (23–25 kg/m²) and mild obesity (≥25 kg/m²) were 1.25 (0.79–2.00) and 1.70 (1.10–2.63), respectively. When compared with women with the lowest tertile of physical activity (<38.5 MET-hours/week), the ORs (95% CIs) for cervical cancer were 0.95 (0.61–1.48) and 0.61 (0.38–0.98) for women with medium physical activity (38.5–71.9 MET-hours/week) and those with high physical activity (72 MET-hours/week), respectively (p for linear trend  = 0.03). The CIN2/3 risk was inversely associated with physical activity after adjustment for confounders. Compared with women with low physical activity (< 38.5 MET-hours/week), the ORs (95% CIs) for CIN2/3 were 0.64 (0.40–1.01) and 0.58 (0.36–0.93) for the medium and high physical activity groups, respectively (p for linear trend  = 0.02). Total calorie intake was not statistically associated with the risks of CIN and cervical cancer after adjustment for confounders.

Conclusion

Our results indicate that in addition to screening for and treatment of CIN, recommendations on the maintenance of an appropriate BMI with an emphasis on physical activity could be an important preventive strategy against the development of cervical cancer.     

Establishment of a General NAFLD Scoring System for Rodent Models and Comparison to Human Liver Pathology

Background and aims

The recently developed histological scoring system for non-alcoholic fatty liver disease (NAFLD) by the NASH Clinical Research Network (NASH-CRN) has been widely used in clinical settings, but is increasingly employed in preclinical research as well. However, it has not been systematically analyzed whether the human scoring system can directly be converted to preclinical rodent models. To analyze this, we systematically compared human NAFLD liver pathology, using human liver biopsies, with liver pathology of several NAFLD mouse models. Based upon the features pertaining to mouse NAFLD, we aimed at establishing a modified generic scoring system that is applicable to broad spectrum of rodent models.

Methods

The histopathology of NAFLD was analyzed in several different mouse models of NAFLD to define generic criteria for histological assessment (preclinical scoring system). For validation of this scoring system, 36 slides of mouse livers, covering the whole spectrum of NAFLD, were blindly analyzed by ten observers. Additionally, the livers were blindly scored by one observer during two separate assessments longer than 3 months apart.

Results

The criteria macrovesicular steatosis, microvesicular steatosis, hepatocellular hypertrophy, inflammation and fibrosis were generally applicable to rodent NAFLD. The inter-observer reproducibility (evaluated using the Intraclass Correlation Coefficient) between the ten observers was high for the analysis of macrovesicular steatosis and microvesicular steatosis (ICC = 0.784 and 0.776, all p<0.001, respectively) and moderate for the analysis of hypertrophy and inflammation (ICC = 0.685 and 0.650, all p<0.001, respectively). The intra-observer reproducibility between the different observations of one observer was high for the analysis of macrovesicular steatosis, microvesicular steatosis and hypertrophy (ICC = 0.871, 0.871 and 0.896, all p<0.001, respectively) and very high for the analysis of inflammation (ICC = 0.931, p<0.001).

Conclusions

We established a simple NAFLD scoring system with high reproducibility that is applicable for different rodent models and for all stages of NAFLD etiology.