Understanding the Metabolic Pathology of Pediatric Obesity and NAFLD
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 100
- 试验地点
- 2
- 主要终点
- Gluconeogenesis
研究概览
简要总结
Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disease worldwide and affects nearly 40% of obese youth and up to 10% of the general pediatric population. Some features of NAFLD are similar in children and adults, yet fibrosis and inflammation are more common in the portal zone and occur earlier in pediatric NAFLD patients than adults. This portends a rapid progression to end-stage liver disease in early adulthood. For the majority of children with NAFLD, mechanisms driving the origin and rapid progression of disease remain unknown. Thus, there is a critical, unmet need to study the specific underlying patterns of metabolic and molecular changes in the liver underlying the development and progression unique to children with NAFLD.
This proposal will test the hypotheses that children with NAFLD have excess glucose and lipid produced by the liver, that those events are regulated by specific variations in the amount and location of RNAs and proteins in liver, and that the concentration of specific micro-RNAs in the blood can be used as a biomarker for NAFLD in pediatric patients.
详细描述
This project uses a cross-sectional design with a single testing period without a formal intervention (e.g., diet, drug, exercise) or natural follow-up period. Participants with nonalcoholic fatty liver disease (NAFLD), and age-matched control groups classified as either obese (Ob control) or normal weight (NW control) will complete all metabolic and descriptive tests, including blood analyses.
The NAFLD group will also have a liver biopsy as part of their standard clinical care; a portion of the biopsy will be used for the research testing. The Ob and NW control groups will not undergo liver biopsy. To provide a set of reference liver samples to compare with the NAFLD group, we will enroll a "liver control" group, consisting of age-matched patients who are scheduled to have a cholecystectomy with liver biopsy or are undergoing liver resection for tumor removal.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 10 Years 至 20 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age: All participants must be 10.0 to 20.9 years old at the time of enrollment.
- •Sex: Male and Female participants are eligible.
- •Race/Ethnicity: Participants of all racial/ethnic identities will be recruited.
- •Body mass index (BMI): Participants must be either in the normal weight (NW control group) or obese [Ob control, nonalcoholic fatty liver disease (NALFD) groups] range for BMI percentile. BMI percentile will be calculated from age- and sex-specific growth charts for children.
- •NAFLD status: The NAFLD group participants will be eligible if they are scheduled for liver biopsy for clinical reasons and their histopathology report confirms a diagnosis of NAFLD. NW control, and Ob control, and Liver control participants must not have diagnosed NAFLD.
排除标准
- •Chronic illness: Participants will not be able to participate if they have conditions that are likely to affect metabolic variables (either directly or due to required medications) or result in them being unable to complete the required tests. Such conditions could include, but are not limited to, untreated hypothyroidism or other endocrine disorders, rheumatoid arthritis requiring steroids or limiting mobility, cardiovascular disease, stroke, or cardiac failure, neurological disorders such as multiple sclerosis, cancer, liver diseases other than NAFLD (e.g., Wilson's disease), other organ disorders, or orthopedic conditions that limit physical activity.
- •Acute illness: Participants will not be able to participate if they develop acute conditions that are likely to affect metabolic outcomes (either directly or due to required medications) or result in them being unable to participate; e.g., respiratory illness, infectious disease, fever, accident resulting in bone fractures, myocardial infarction, major depression. If such conditions resolve and there are no longer risks or likelihood of adverse effect on the study outcomes, participants may be rescheduled for testing.
- •Medications and nutritional supplements: Medications, vitamins, or supplements that have known effects on the primary outcomes will be cause for exclusion. Examples include weight loss medications, glucocorticoids, or experimental medications used to correct a metabolic or hepatic condition. Medications used to control asthma, allergies, anxiety, depression, attention deficit disorder, menstrual cycle, hypothyroidism, gastric reflux, hypertension, and sleep will be allowed. Participants who are taking medications for treatment of acute illness or conditions such as cold, flu, injury, or infection will be rescheduled after they complete their treatment course.
- •Pregnancy: Evidence of pregnancy or intent to become pregnant during the study is cause for exclusion.
- •Smoking, alcohol abuse, or illicit drug abuse: Participants who smoke or have signs or symptoms of alcohol or substance abuse will be excluded.
结局指标
主要结局
Gluconeogenesis
时间窗: Day 1
Measurement of the rate newly synthesized glucose in circulation using labeled glycerol and deuterated water
Abundance of liver collagen
时间窗: Day 1
Abundance of collagen in liver biopsy sections, using Second Harmonic Generation microscopy
Insulin sensitivity
时间窗: Day 1
Calculated value of insulin sensitivity, using the oral minimal model and serial concentrations of glucose and insulin during an oral sugar tolerance test
Serum microRNA
时间窗: Day 1
Abundance of microRNAs in serum using a broad profiling platform and real-time quantitative polymerase chain reaction tests for confirming individual miRNAs
Liver mitochondrial flux
时间窗: Day 1
Reported as the fluorescent lifetime redox ratio (FLIRR), which is calculated from measurements of free and bound NADH and FAD in liver biopsy sections, using fluorescence lifetime imaging microscopy
De novo lipogenesis
时间窗: Day 1
Measurement of the rate of newly synthesized triglycerides in plasma using deuterated water
次要结局
- Targets of microRNA-122(Day 1)
- Liver transcriptomics(Day 1)