Stavra A. Xanthakos

High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitis†

Diets high in saturated fat and fructose have been implicated in the development of obesity and nonalcoholic steatohepatitis (NASH) in humans. We hypothesized that mice exposed to a similar diet would develop NASH with fibrosis associated with increased hepatic oxidative stress that would be further reflected by increased plasma levels of the respiratory chain component, oxidized coenzyme Q9 (oxCoQ9). Adult male C57Bl/6 mice were randomly assigned to chow, high‐fat (HF), or high‐fat high‐carbohydrate (HFHC) diets for 16 weeks. The chow and HF mice had free access to pure water, whereas the HFHC group received water with 55% fructose and 45% sucrose (wt/vol). The HFHC and HF groups had increased body weight, body fat mass, fasting glucose, and were insulin‐resistant compared with chow mice. HF and HFHC consumed similar calories. Hepatic triglyceride content, plasma alanine aminotransferase, and liver weight were significantly increased in HF and HFHC mice compared with chow mice. Plasma cholesterol (P < 0.001), histological hepatic fibrosis, liver hydroxyproline content (P = 0.006), collagen 1 messenger RNA (P = 0.003), CD11b‐F4/80+Gr1+ monocytes (P < 0.0001), transforming growth factor β1 mRNA (P = 0.04), and α‐smooth muscle actin messenger RNA (P = 0.001) levels were significantly increased in HFHC mice. Hepatic oxidative stress, as indicated by liver superoxide expression (P = 0.002), 4‐hydroxynonenal, and plasma oxCoQ9 (P < 0.001) levels, was highest in HFHC mice. Conclusion: These findings demonstrate that nongenetically modified mice maintained on an HFHC diet in addition to developing obesity have increased hepatic ROS and a NASH‐like phenotype with significant fibrosis. Plasma oxCoQ9 correlated with fibrosis progression. The mechanism of fibrosis may involve fructose inducing increased ROS associated with CD11b+F4/80+Gr1+ hepatic macrophage aggregation, resulting in transforming growth factor β1–signaled collagen deposition and histologically visible hepatic fibrosis. (HEPATOLOGY 2010)

Weight Loss and Health Status 3 Years after Bariatric Surgery in Adolescents

BACKGROUND Bariatric surgery is increasingly considered for the treatment of adolescents with severe obesity, but few prospective adolescent-specific studies examining the efficacy and safety of weight-loss surgery are available to support clinical decision making. METHODS We prospectively enrolled 242 adolescents undergoing weight-loss surgery at five U.S. centers. Patients undergoing Roux-en-Y gastric bypass (161 participants) or sleeve gastrectomy (67) were included in the analysis. Changes in body weight, coexisting conditions, cardiometabolic risk factors, and weight-related quality of life and postoperative complications were evaluated through 3 years after the procedure. RESULTS The mean (±SD) baseline age of the participants was 17±1.6 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 53; 75% of the participants were female, and 72% were white. At 3 years after the procedure, the mean weight had decreased by 27% (95% confidence interval [CI], 25 to 29) in the total cohort, by 28% (95% CI, 25 to 30) among participants who underwent gastric bypass, and by 26% (95% CI, 22 to 30) among those who underwent sleeve gastrectomy. By 3 years after the procedure, remission of type 2 diabetes occurred in 95% (95% CI, 85 to 100) of participants who had had the condition at baseline, remission of abnormal kidney function occurred in 86% (95% CI, 72 to 100), remission of prediabetes in 76% (95% CI, 56 to 97), remission of elevated blood pressure in 74% (95% CI, 64 to 84), and remission of dyslipidemia in 66% (95% CI, 57 to 74). Weight-related quality of life also improved significantly. However, at 3 years after the bariatric procedure, hypoferritinemia was found in 57% (95% CI, 50 to 65) of the participants, and 13% (95% CI, 9 to 18) of the participants had undergone one or more additional intraabdominal procedures. CONCLUSIONS In this multicenter, prospective study of bariatric surgery in adolescents, we found significant improvements in weight, cardiometabolic health, and weight-related quality of life at 3 years after the procedure. Risks associated with surgery included specific micronutrient deficiencies and the need for additional abdominal procedures. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; Teen-LABS ClinicalTrials.gov number, NCT00474318.).

Nutritional Deficiencies in Obesity and After Bariatric Surgery

The presence of nutritional deficiencies in overweight and obesity may seem paradoxical in light of excess caloric intake, but several micronutrient deficiencies appear to be higher in prevalence in overweight and obese adults and children. Causes are multifactorial and include decreased consumption of fruits and vegetables, increased intake of high-calorie, but nutritionally poor-quality foods, and increased adiposity, which may influence the storage and availability of some nutrients. As the obesity epidemic continues unabated and the popularity of bariatric surgery rises for severely obese adults and adolescents, medical practitioners must be aware of pre-existing nutritional deficiencies in overweight and obese patients and appropriately recognize and treat common and rare nutritional deficiencies that may arise or worsen following bariatric surgery. This article reviews current knowledge of nutritional deficits in obese and overweight individuals and those that commonly present after bariatric surgery and summarizes current recommendations for screening and supplementation.

Nonalcoholic Steatohepatitis in Children: A Multicenter Clinicopathological Study

Nonalcoholic fatty liver disease (NAFLD) may have distinct histological features in children and adults, but to date limited data are available on the spectrum and significance of histological lesions in pediatric patients. We conducted a multicenter study of children with well‐characterized, biopsy‐proven NAFLD to (1) assess the presence and significance of a constellation of histological lesions and (2) identify clinical and laboratory predictors of disease severity. One hundred thirty children with NAFLD seen from 1995 to 2007 in five centers in the United States and Canada were studied. Clinical and laboratory data were collected. Slides stained with hematoxylin‐eosin and trichrome were evaluated by two liver pathologists. The NAFLD activity score (NAS) and the pattern of liver injury (type 1 or adult versus type 2 or pediatric nonalcoholic steatohepatitis [NASH]) were recorded. Fibrosis was staged using a published 7‐point scale. The median age was 12 years (range, 4‐18 years); 63% were boys, and 52% were Caucasian. Fibrosis was present in 87% of patients; of these, stage 3 (bridging fibrosis) was present in 20%. No patient had cirrhosis. The median NAS was 4. Overlapping features of both type 1 (adult pattern) and type 2 (pediatric pattern) NASH were found in 82% of patients. Compared with patients with no or mild fibrosis, those with significant fibrosis were more likely to have higher lobular and portal inflammation scores (P < 0.01), perisinusoidal fibrosis (P < 0.001), and NAS ≥5 (P < 0.005). Serum aspartate aminotransferase levels were the only clinical or laboratory data that independently predicted severity of fibrosis (P = 0.003). Conclusion: Our results highlight the limitations of published proposals to classify pediatric NAFLD, and identified histological lesions associated with progressive disease. (HEPATOLOGY 2009.)

Bariatric surgery for pediatric extreme obesity: now or later?

Obesity is a multifactorial disease of epidemic and global proportions that poses the most significant threat to the health of our younger generations. Those who are the most extremely affected bear the largest burden of health problems. In the US, extreme obesity affects approximately 9 million adults and 2 million children, and is associated with both immediate health problems and later health risk, including premature mortality. Present medical and behavioral interventions for extreme obesity in adults and children rarely result in the significant, durable weight loss necessary to improve health outcomes, prompting a search for more aggressive measures. Weight loss (bariatric) surgery has been advocated as an intervention for those with extreme obesity. In adults, bariatric surgery results in prolonged weight control and improvement in serious obesity comorbidities, namely type 2 diabetes, dyslipidemias, hypertension and obstructive sleep apnea syndrome. A surge in weight loss operations for adolescents has been observed recently, with a threefold increase in case volumes nationwide from 2000 to 2003. Current evidence suggests that after bariatric surgery, adolescents lose significant weight and serious obesity-related medical conditions and psychosocial status are improved. Thus it is reasonable to propose that bariatric surgery performed in the adolescent period may be more effective treatment for childhood-onset extreme obesity than delaying surgery for extremely obese youth until adulthood. This position has been echoed by a number of groups and an independent systematic review. Finally, it is conceivable that bariatric surgery performed in adulthood for childhood onset extreme obesity may not be as effective for comorbidity treatment as surgery performed earlier during adolescence.The purpose of this review is to examine the evidence, which supports early rather than later use of bariatric surgery in the treatment of extreme obesity, and to present this information in light of the medical and surgical risks of bariatric surgery.

Perioperative Outcomes of Adolescents Undergoing Bariatric Surgery: The Teen–Longitudinal Assessment of Bariatric Surgery (Teen-LABS) Study

IMPORTANCE Severe obesity in childhood is a major health problem with few effective treatments. Weight-loss surgery (WLS) is being used to treat severely obese adolescents, although with very limited data regarding surgical safety for currently used, minimally invasive procedures. OBJECTIVE To assess the preoperative clinical characteristics and perioperative safety outcomes of severely obese adolescents undergoing WLS. DESIGN, SETTING, AND PARTICIPANTS This prospective, multisite observational study enrolled patients from February 28, 2007, through December 30, 2011. Consecutive patients aged 19 years or younger who were approved to undergo WLS (n = 277) were offered enrollment into the study at 5 academic referral centers in the United States; 13 declined participation and 22 did not undergo surgery after enrollment, thus the final analysis cohort consisted of 242 individuals. There were no withdrawals. MAIN OUTCOMES AND MEASURES This analysis examined preoperative anthropometrics, comorbid conditions, and major and minor complications occurring within 30 days of operation. All data were collected in a standardized fashion. Reoperations and hospital readmissions were adjudicated by independent reviewers to assess relatedness to the WLS procedure. RESULTS The mean (SD) age of participants was 17.1 (1.6) years and the median body mass index (calculated as weight in kilograms divided by height in meters squared) was 50.5. Fifty-one percent demonstrated 4 or more major comorbid conditions. Laparoscopic Roux-en-Y gastric bypass, vertical sleeve gastrectomy, and adjustable gastric banding were performed in 66%, 28%, and 6% of patients, respectively. There were no deaths during the initial hospitalization or within 30 days of operation; major complications (eg, reoperation) were seen in 19 patients (8%). Minor complications (eg, readmission for dehydration) were noted in 36 patients (15%). All reoperations and 85% of readmissions were related to WLS. CONCLUSIONS AND RELEVANCE In this series, adolescents with severe obesity presented with abundant comorbid conditions. We observed a favorable short-term complication profile, supporting the early postoperative safety of WLS in select adolescents. Further longitudinal study of this cohort will permit accurate assessment of long-term outcomes for adolescents undergoing bariatric surgery. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00474318.

Prevalence and outcome of allergic colitis in healthy infants with rectal bleeding : A prospective cohort study

Objectives: Allergic colitis is often diagnosed clinically in healthy infants with rectal bleeding and often treated with costly hypoallergenic formula. The true prevalence of allergic colitis is unknown. We tested the hypothesis that allergic colitis is overdiagnosed in healthy infants with rectal bleeding. The authors also determined whether rectal bleeding in infants without allergic colitis would resolve without diet change. Methods: For the purposes of this study, allergic colitis was defined histologically as colonic mucosa with ≥ 6 eosinophils per high power field and/or eosinophils in colonic crypts or muscularis mucosae. We surveyed all 56 Ohio NASPGHAN members to determine standard practice regarding the evaluation of rectal bleeding in infants. In addition, infants ≤ 6 months old with rectal bleeding were recruited from the referral area of Cincinnati Childrens Hospital Medical Center. All infants underwent flexible sigmoidoscopy with biopsies at 5, 10 and 15 cm. Formula or maternal diet was changed only for infants with histologic findings of allergic colitis as defined. Study subjects were followed for 9 weeks. Results: In the survey of NASPGHAN members, 84% indicated they would empirically change the diet of an infant with rectal bleeding to treat presumed allergic colitis. In our study population, however, only 14 of 22 (64%; 95% confidence interval, 41-83) infants with rectal bleeding had allergic colitis. Five (23%) had normal biopsies and three (14%) had nonspecific colitis. Rectal bleeding in all infants with normal biopsies or nonspecific colitis resolved without diet change except for 1 infant subsequently diagnosed with infantile inflammatory bowel disease. Conclusion: A significant proportion of infants with rectal bleeding may not have allergic colitis and may undergo unnecessary, expensive formula or maternal diet changes that may discourage breast-feeding.

Nutritional consequences of bariatric surgery

Purpose of reviewBariatric surgery is being increasingly used to help treat morbidly obese adults and adolescents. As a greater percentage of this population faces a lifetime of living with surgically altered gastrointestinal anatomy and physiology, increased awareness of the nutritional consequences is critical for all health care practitioners, as many of these patients may be lost to follow-up and can present with significant nutritional complications years after surgery. Recent findingsNutritional deficiencies can occur after bariatric surgery, although to a lesser degree after restrictive procedures. Risk may increase over time, perhaps due to poor compliance with supplementation, continued inadequate intake and/or ongoing malabsorption. Adolescent patients may be at greater risk due to poor compliance and longer life span. Nutritional monitoring and supplementation among bariatric programs has been widely variable and few prospective studies of outcomes exist. SummaryBariatric surgery can carry significant risk of nutritional complications. Compliance with dietary recommendations should be monitored and encouraged, with annual screening for selected deficiencies. Prospective longitudinal research is needed to identify the true prevalence and significance of nutritional deficiency in these patients and to determine optimum dietary recommendations.

IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice

Inflammation plays a central pathogenic role in the pernicious metabolic and end‐organ sequelae of obesity. Among these sequelae, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the developed world. The twinned observations that obesity is associated with increased activation of the interleukin (IL)‐17 axis and that this axis can regulate liver damage in diverse contexts prompted us to address the role of IL‐17RA signaling in the progression of NAFLD. We further examined whether microbe‐driven IL‐17A regulated NAFLD development and progression. We show here that IL‐17RA−/− mice respond to high‐fat diet stress with significantly greater weight gain, visceral adiposity, and hepatic steatosis than wild‐type controls. However, obesity‐driven lipid accumulation was uncoupled from its end‐organ consequences in IL‐17RA−/− mice, which exhibited decreased steatohepatitis, nicotinamide adenine dinucleotide phosphate (NADPH)‐oxidase enzyme expression, and hepatocellular damage. Neutralization of IL‐17A significantly reduced obesity‐driven hepatocellular damage in wild‐type mice. Further, colonization of mice with segmented filamentous bacteria (SFB), a commensal that induces IL‐17A production, exacerbated obesity‐induced hepatocellular damage. In contrast, SFB depletion protected from obesity‐induced hepatocellular damage. Conclusion: These data indicate that obesity‐driven activation of the IL‐17 axis is central to the development and progression of NAFLD to steatohepatitis and identify the IL‐17 pathway as a novel therapeutic target in this condition. (Hepatology 2014;59:1830–1839)

Histologic Spectrum of Nonalcoholic Fatty Liver Disease in Morbidly Obese Adolescents

BACKGROUND & AIMS To characterize the spectrum of nonalcoholic fatty liver disease (NAFLD) in morbidly obese adolescents, we correlated liver histology with clinical features and compared findings with reported adult data. We hypothesized that NAFLD would be less severe as a result of younger age and shorter duration of obesity, but portal inflammation and fibrosis would be more prevalent. METHODS Cross-sectional study was made of 41 adolescent subjects, 13-19 years old (mean, 16 years), 61% female, 83% non-Hispanic white, mean body mass index 59 kg/m(2), undergoing gastric bypass with liver biopsy. Liver biopsies were graded and staged as proposed by the NASH Clinical Research Network. Data were analyzed by using descriptive statistics, analysis of variance, and Fisher exact tests. RESULTS Eighty-three percent had NAFLD: 24% steatosis alone, 7% isolated fibrosis with steatosis, 32% nonspecific inflammation and steatosis, and 20% nonalcoholic steatohepatitis (NASH). Twenty-nine percent had fibrosis; none had cirrhosis. Abnormal ALT (P = .05) and AST (P = .01) were more prevalent in NASH. Mean fasting glucose was significantly higher in NASH (P = .05), but prevalence of the metabolic syndrome was not significantly different. CONCLUSIONS NAFLD was very prevalent in morbidly obese adolescents, but severe NASH was uncommon. In contrast to morbidly obese adults, lobular inflammation, significant ballooning, and perisinusoidal fibrosis were rare, whereas portal inflammation and portal fibrosis were more prevalent, even in those who did not meet criteria for NASH. These findings might support use of a modified scoring system for pediatric NASH. Presence of the metabolic syndrome in morbidly obese adolescents did not distinguish NASH from steatosis alone.