Miriam B. Vos

Nonalcoholic Fatty Liver Disease: Pathology and Pathogenesis

Nonalcoholic fatty liver disease (NAFLD) is recognized as the leading cause of chronic liver disease in adults and children. NAFLD encompasses a spectrum of liver injuries ranging from steatosis to steatohepatitis with or without fibrosis. Fibrosis may progress to cirrhosis and complications including hepatocellular carcinoma. Histologic findings represent the complexity of pathophysiology. NAFLD is closely associated with obesity and is most closely linked with insulin resistance; the current Western diet, high in saturated fats and fructose, plays a significant role. There are several mechanisms by which excess triglycerides are acquired and accumulate in hepatocytes. Formation of steatotic droplets may be disordered in NAFLD. Visceral adipose tissue dysfunction in obesity and insulin resistance results in aberrant cytokine expression; many cytokines have a role in liver injury in NAFLD. Cellular stress and immune reactions, as well as the endocannabinoid system, have been implicated in animal models and in some human studies.

Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: Role of endotoxin

BACKGROUND/AIMS Consumption of refined carbohydrates in soft drinks has been postulated to be a key factor in the development of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to test the effects of ad libitum access to different sugars consumed in drinking water on hepatic fat accumulation. METHODS For 8 weeks, C57BL/J6 mice had free access to solutions containing 30% glucose, fructose, sucrose, or water sweetened with artificial sweetener (AS) or plain water. Body weight, caloric intake, hepatic steatosis and lipid peroxidation were assessed. RESULTS Total caloric intake and weight gain were highest in mice exposed to glucose. In contrast, hepatic lipid accumulation was significantly higher in mice consuming fructose compared to all other groups. Moreover, endotoxin levels in portal blood and lipid peroxidation as well as TNFalpha expression were significantly higher in fructose fed mice than in all other groups. Concomitant treatment of fructose fed mice with antibiotics (e.g., polymyxin B and neomycin) markedly reduced hepatic lipid accumulation in fructose fed mice. CONCLUSIONS These data support the hypothesis that high fructose consumption may not only lead to liver damage through overfeeding but also may be directly pro-inflammatory by increasing intestinal translocation of endotoxin.

Consumption of added sugars is decreasing in the United States

BACKGROUND The consumption of added sugars (caloric sweeteners) has been linked to obesity, diabetes, and heart disease. Little is known about recent consumption trends in the United States or how intakes compare with current guidelines. OBJECTIVE We examined trends in intakes of added sugars in the United States over the past decade. DESIGN A cross-sectional study of US residents ≥2 y of age (n = 42,316) was conducted by using dietary data from NHANES 1999-2008 (five 2-y cycles) and data for added-sugar contents from the MyPyramid Equivalents Database. Mean intakes of added sugars (grams and percentage of total energy intake) were weighted to obtain national estimates over time across age, sex, and race-ethnic groups. Linear trends were tested by using Walds F tests. RESULTS Between 1999-2000 and 2007-2008, the absolute intake of added sugars decreased from a mean (95% CI) of 100.1 g/d (92.8, 107.3 g/d) to 76.7 g/d (71.6, 81.9 g/d); two-thirds of this decrease, from 37.4 g/d (32.6, 42.1 g/d) to 22.8 g/d (18.4, 27.3 g/d), resulted from decreased soda consumption (P-linear trend <0.001 for both). Energy drinks were the only source of added sugars to increase over the study period (P-linear trend = 0.003), although the peak consumption reached only 0.15 g/d (0.08, 0.22 g/d). The percentage of total energy from added sugars also decreased from 18.1% (16.9%, 19.3%) to 14.6% (13.7%, 15.5%) (P-linear trend <0.001). CONCLUSION Although the consumption of added sugars in the United States decreased between 1999-2000 and 2007-2008, primarily because of a reduction in soda consumption, mean intakes continue to exceed recommended limits.

Caloric Sweetener Consumption and Dyslipidemia Among US Adults

CONTEXT Dietary carbohydrates have been associated with dyslipidemia, a lipid profile known to increase cardiovascular disease risk. Added sugars (caloric sweeteners used as ingredients in processed or prepared foods) are an increasing and potentially modifiable component in the US diet. No known studies have examined the association between the consumption of added sugars and lipid measures. OBJECTIVE To assess the association between consumption of added sugars and blood lipid levels in US adults. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study among US adults (n = 6113) from the National Health and Nutrition Examination Survey (NHANES) 1999-2006. Respondents were grouped by intake of added sugars using limits specified in dietary recommendations (< 5% [reference group], 5%-<10%, 10%-<17.5%, 17.5%-<25%, and > or = 25% of total calories). Linear regression was used to estimate adjusted mean lipid levels. Logistic regression was used to determine adjusted odds ratios of dyslipidemia. Interactions between added sugars and sex were evaluated. MAIN OUTCOME MEASURES Adjusted mean high-density lipoprotein cholesterol (HDL-C), geometric mean triglycerides, and mean low-density lipoprotein cholesterol (LDL-C) levels and adjusted odds ratios of dyslipidemia, including low HDL-C levels (< 40 mg/dL for men; < 50 mg/dL for women), high triglyceride levels (> or = 150 mg/dL), high LDL-C levels (> or = 130 mg/dL), or high ratio of triglycerides to HDL-C (> 3.8). Results were weighted to be representative of the US population. RESULTS A mean of 15.8% of consumed calories was from added sugars. Among participants consuming less than 5%, 5% to less than 17.5%, 17.5% to less than 25%, and 25% or greater of total energy as added sugars, adjusted mean HDL-C levels were, respectively, 58.7, 57.5, 53.7, 51.0, and 47.7 mg/dL (P < .001 for linear trend), geometric mean triglyceride levels were 105, 102, 111, 113, and 114 mg/dL (P < .001 for linear trend), and LDL-C levels modified by sex were 116, 115, 118, 121, and 123 mg/dL among women (P = .047 for linear trend). There were no significant trends in LDL-C levels among men. Among higher consumers (> or = 10% added sugars) the odds of low HDL-C levels were 50% to more than 300% greater compared with the reference group (< 5% added sugars). CONCLUSION In this study, there was a statistically significant correlation between dietary added sugars and blood lipid levels among US adults.

Dietary fructose in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in adults and children. A number of genetic and environmental factors are known to predispose individuals to NAFLD. Certain dietary sugars, particularly fructose, are suspected to contribute to the development of NAFLD and its progression. The increasing quantity of fructose in the diet comes from sugar additives (most commonly sucrose and high fructose corn syrup) in beverages and processed foods. Substantial links have been demonstrated between increased fructose consumption and obesity, dyslipidemia, and insulin resistance. Growing evidence suggests that fructose contributes to the development and severity of NAFLD. In human studies, fructose is associated with increasing hepatic fat, inflammation, and possibly fibrosis. Whether fructose alone can cause NAFLD or if it serves only as a contributor when consumed excessively in the setting of insulin resistance, positive energy balance, and sedentary lifestyle is unknown. Sufficient evidence exists to support clinical recommendations that fructose intake be limited through decreasing foods and drinks high in added (fructose‐containing) sugars. (HEPATOLOGY 2013;57:2525–2531)

Consumption of Added Sugars and Indicators of Cardiovascular Disease Risk Among US Adolescents

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among U.S. adults.1 While atherosclerosis and CVD occur later in life, their risk factors, including lipid disorders2, diabetes3, and obesity are increasingly being identified among adolescents and even children.4 Though CVD among children is rare,4 an increase in cardiometabolic risk factors at younger ages and their apparent tendency to track into adulthood5–7 highlights the need for early and effective prevention efforts. Lifestyle changes, including dietary change, have long been a central focus of efforts to reduce CVD risk. Since the 1950’s Americans have been advised to reduce their consumption of fats and cholesterol, and replace them with complex carbohydrates.8 It appears that, in part, Americans have followed this advice. But while food disappearance data suggests that fat consumption has decreased, it is refined rather than complex carbohydrates that have increased.9 While the overall health impact of this trend is unclear, several studies have shown a positive correlation between the consumption of carbohydrates – particularly some sugars - and the presence of CVD risk factors.10–12 A recent longitudinal study among women demonstrated that the incidence of CVD increased with higher consumption of sugar-sweetened beverages,13 the largest contributor of added sugars in the U.S. diet.14 Studies comparing the impact of different sugars have demonstrated that the monosaccharide fructose but not glucose, raises triglyceride levels and lowers HDL levels, suggesting that the metabolic impact may differ substantially by sugar type.12, 15 Added sugars are refined, calorie-containing sweeteners added to foods and beverages during processing or preparation. Consumption of these sugars has increased substantially in recent decades. Sugars used to sweeten soft drinks have become the largest single source of calories in the U.S. diet.16 In 1994–1996, Americans over the age of 2 y obtained nearly 16% of their total energy from added sugars; adolescents, the highest consumers, obtained more than 20% of their energy from sugars added to foods and beverages.17 Today in the U.S., the most commonly consumed added sugars are refined beet or cane sugar (sucrose) and high fructose corn syrup (HFCS),18 both of which contribute fructose and glucose, in approximately equal amounts, to the diet. Added sugars are estimated to contribute 74%–80% of the dietary fructose consumed.19, 20 Given the high consumption of added sugars among adolescents and the potential for long-term health risks associated with early diet, it is important to understand the impact of this dietary trend. The purpose of our study was to determine if there is an association between the consumption of added sugars and indicators of cardiometabolic health among U.S. adolescents.Background— Whereas increased carbohydrate and sugar consumption has been associated with higher cardiovascular disease risk among adults, little is known about the impact of high consumption of added sugars (caloric sweeteners) among US adolescents. Methods and Results— In a cross-sectional study of 2157 US adolescents in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004, dietary data from one 24-hour recall were merged with added sugar content data from the US Department of Agriculture MyPyramid Equivalents databases. Measures of cardiovascular disease risk were estimated by added sugar consumption level (<10%, 10 to <15%, 15 to <20%, 20 to <25%, 25 to <30%, and ≥30% of total energy). Multivariable means were weighted to be representative of US adolescents and variances adjusted for the complex sampling methods. Daily consumption of added sugars averaged 21.4% of total energy. Added sugars intake was inversely correlated with mean high-density lipoprotein cholesterol levels (mmol/L) which were 1.40 (95% confidence interval [CI] 1.36 to 1.44) among the lowest consumers and 1.28 (95% CI 1.23 to 1.33) among the highest (P trend =0.001). Added sugars were positively correlated with low-density lipoproteins (P trend =0.01) and geometric mean triglycerides (P trend =0.05). Among the lowest and highest consumers, respectively, low-density lipoproteins (mmol/L) were 2.24 (95% CI 2.12 to 2.37) and 2.44 (95% CI 2.34 to 2.53), and triglycerides (mmol/L) were 0.81 (95% CI 0.74, 0.88) and 0.89 (95% CI 0.83 to 0.96). Among those overweight/obese (≥85th percentile body-mass-index), added sugars were positively correlated with the homeostasis model assessment (P linear trend =0.004). Conclusion— Consumption of added sugars among US adolescents is positively associated with multiple measures known to increase cardiovascular disease risk.

Childhood Obesity: Update on Predisposing Factors and Prevention Strategies

Obesity is a global epidemic and children are affected in increasing numbers. Overweight children are at increased risk of becoming overweight adults with associated chronic diseases. In this update, we present key findings from a review of the current literature focused on potential causes and strategies for preventing childhood obesity. We highlight recent evidence regarding the role of genetics, maternal body mass index, postnatal influences, and environmental effects throughout childhood in predicting overweight. We also summarize the results of new research that examined the effectiveness of intervention strategies implemented in a variety of settings: home, school, community, and health care system. Statements recently released by the Centers for Disease Control and Prevention (CDC) and the US Department of Health and Human Services emphasize the need for effective policy and environmental change to promote healthy lifestyle change at the individual and population levels.

Low-calorie sweetener consumption is increasing in the United States

BACKGROUND Low-calorie and no-calorie sweeteners (LCSs) have emerged as alternatives to added sugars. Research suggests that consumption among all Americans is increasing, yet it is unknown whether consumption trends differ among population subgroups. OBJECTIVE Our study aimed to assess recent national trends in LCS consumption among children and other demographic subgroups in the United States. DESIGN We used NHANES data collected in five 2-y cycles from 1999-2000 to 2007-2008. Consumption of foods and beverages with LCSs was estimated by using one 24-h dietary recall. Estimates of the proportion of the population consuming foods and beverages containing LCSs (prevalence of consumption) were weighted to obtain nationally representative results. Trends in prevalence of LCS consumption and mean intake of beverages sweetened with LCSs were tested by using chi-square tests for trend and F tests. RESULTS In 2007-2008, the percentage of children and adults consuming foods and beverages containing LCSs increased. The prevalence of consuming beverages with LCSs increased from 6.1% to 12.5% among children (P-trend < 0.0001) and from 18.7% to 24.1% among adults (P < 0.001). Increases in the prevalence of consumption of calorie-containing beverages with LCSs were observed among all weight, age, socioeconomic, and race-ethnicity subgroups in both children and adults. However, little change in consumption of no-calorie beverages with LCSs or LCS-containing foods was found. CONCLUSIONS The consumption of LCS-containing beverages has doubled among US children over the past decade. Further research is needed to understand the health effects of this trend.

Measurement of hepatic lipid: high-speed T2-corrected multiecho acquisition at 1H MR spectroscopy--a rapid and accurate technique.

PURPOSE To evaluate the feasibility, accuracy, and reproducibility of a fast breath-hold magnetic resonance (MR) spectroscopic method for T2-corrected hepatic lipid measurement in phantoms and in humans. MATERIALS AND METHODS All experiments were institutional review board approved and HIPAA compliant; informed consent was obtained from all subjects. The 15-second breath-hold high-speed T2-corrected multiecho (HISTO) MR spectroscopic technique was developed to acquire multiple echoes in a single acquisition, which enables the quantification of water and lipid T2, and subsequently to provide a corrected measure of hepatic lipid fraction. The accuracy of T2-corrected MR spectroscopy was evaluated in eight lipid phantoms doped with iron to simulate variable T2 effects. The mean absolute error of the HISTO technique with the known lipid amounts, as well as with uncorrected MR spectroscopic measures, was evaluated. The HISTO sequence was performed in 25 male subjects (mean age, 23.0 years +/- 19.2 [standard deviation]) to evaluate measurement bias with conventional, uncorrected MR spectroscopy. Three additional male subjects (mean age, 30.0 years +/- 1.0) were examined to assess reproducibility by using analysis of variance testing within subject and between separate imaging sessions. RESULTS The absolute error in quantifying lipid fraction by using iron-doped lipid phantoms was less than 11% for the HISTO technique, compared with more than 50% for uncorrected MR spectroscopy. In the 25 human subjects, hepatic lipid measured by using HISTO differed significantly from that by using uncorrected MR spectroscopic methods by 5.1% +/- 2.6. Analysis of variance of three separate imaging sessions with the HISTO technique indicated no significant variance (P = .13) in three subjects. CONCLUSION HISTO is an accurate, reproducible MR spectroscopic sequence for quantifying hepatic lipid noninvasively. Evidence has shown this method to be feasible in vivo for clinical use.

Correlation of vitamin E, uric acid, and diet composition with histologic features of pediatric NAFLD

Objectives: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children in the United States. Although changes in diet are often recommended to improve NAFLD, little is known regarding the influence of diet on histologic features of the disease. Subjects and Methods: This was a prospective, cross-sectional registry-based study. Children (n = 149) enrolled in the multicenter nonalcoholic steatohepatitis (NASH) Clinical Research Network had demographic, anthropometric, clinical, laboratory, and histology data obtained, including the Block Brief Food Questionnaire. Subjects were grouped by presence or absence of steatohepatitis and grades of histologic features according to NASH Clinical Research Network criteria. Results: No significant differences were found between children with steatosis compared with steatohepatitis for fraction of energy from fat, carbohydrates, and protein. Sugar-sweetened beverage consumption was low and did not correlate with histologic features, although uric acid, a surrogate marker for fructose intake, was significantly increased in those with definite NASH (P = 0.008). For all groups, vitamin E consumption was insufficient compared with the recommended daily allowance. Median consumption of vitamin E was lower in children with higher grade of steatosis (8.4 vs 6.1 vs 6.9 for grades I, II, and III, respectively, P = 0.05). Those consuming less vitamin C had increased ballooning degeneration (P = 0.05). Conclusions: Children with NAFLD have a diet that is insufficient in vitamin E and this may contribute to the pathophysiology of NAFLD. In children with NAFLD, reported sugar-sweetened beverage consumption is low; however, uric acid, which may reflect total fructose consumption, was significantly associated with NASH and should be further evaluated.