Metabolic Pathology of Pediatric NAFLD

Obesity Clinical Trial

Official title:

Understanding the Metabolic Pathology of Pediatric Obesity and NAFLD

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05430178
• Other study ID #: 14018
• Secondary ID: 1R01DK129656-01A
• Status: Recruiting
• Phase: N/A
• Start date: May 25, 2022
• Est. completion date: June 2026

Study information

• Verified date: March 2024
• Source: University of Oklahoma
• Contact: Kevin Short, PhD
• Phone: 405-271-8001
• Email: kevin-short[@]ouhsc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: June 2026
• Est. primary completion date: February 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 10 Years to 20 Years

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Fatty Liver
• Non-alcoholic Fatty Liver Disease
• Nonalcoholic Fatty Liver
• Nonalcoholic Steatohepatitis
• Obesity

Intervention

Other:
• Oral sugar tolerance test
Measurement of glucose and insulin for calculation of insulin sensitivity
• De novo lipogenesis test
Oral consumption of deuterated water to measure incorporation of label into lipids
• Gluconeogenesis test
Oral consumption of 13C-labeled glycerol to measure incorporation into glucose

Locations

Country	Name	City	State
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma

Sponsors (2)

Lead Sponsor	Collaborator
University of Oklahoma	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Blood pressure	Brachial and central blood pressures	Day 1
Other	Arterial stiffness	Measured as carotid-femoral pulse wave velocity	Day 1
Other	Body composition	Whole body and regional lean and fat mass, measure with dual energy X-ray absorptiometry	Day 1
Other	Cardiorespiratory fitness	Peak oxygen consumption during bicycle ergometry test to volitional fatigue	Day 1
Other	Blood DNA analysis	Measurement of single-nucleotide polymorphisms associated with NAFLD risk	Day 1
Other	Liver steatosis	Use of Fibroscan to measure controlled attenuation parameter (measure of steatosis)	Day 1
Other	Liver fibrosis	Use of Fibroscan to measure elastic modulus (surrogate measure of fibrosis)	Day 1
Primary	De novo lipogenesis	Measurement of the rate of newly synthesized triglycerides in plasma using deuterated water	Day 1
Primary	Gluconeogenesis	Measurement of the rate newly synthesized glucose in circulation using labeled glycerol and deuterated water	Day 1
Primary	Serum microRNA	Abundance of microRNAs in serum using a broad profiling platform and real-time quantitative polymerase chain reaction tests for confirming individual miRNAs	Day 1
Primary	Abundance of liver collagen	Abundance of collagen in liver biopsy sections, using Second Harmonic Generation microscopy	Day 1
Primary	Liver mitochondrial flux	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	Day 1
Primary	Insulin sensitivity	Calculated value of insulin sensitivity, using the oral minimal model and serial concentrations of glucose and insulin during an oral sugar tolerance test	Day 1
Secondary	Targets of microRNA-122	Transcripts bound to microRNA-122, measured using high-throughput sequencing of cross- linked immunoprecipitates (HITS-CLIP)	Day 1
Secondary	Liver transcriptomics	Spatial distribution of messenger RNAs in liver biopsies	Day 1