Metabolic Pathology of Pediatric NAFLD

NCT05430178 | Recruiting

• 2 other identifiers: 140181R01DK129656-01A1
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Nonalcoholic Fatty Liver; Nonalcoholic Steatohepatitis; Obesity

Outcome Measures

Primary Outcomes (6)

• De novo lipogenesis

  Measurement of the rate of newly synthesized triglycerides in plasma using deuterated water

  Day 1

• Gluconeogenesis

  Measurement of the rate newly synthesized glucose in circulation using labeled glycerol and deuterated water

  Day 1

• 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

• Abundance of liver collagen

  Abundance of collagen in liver biopsy sections, using Second Harmonic Generation microscopy

  Day 1

• 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

• 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 Outcomes (2)

• Targets of microRNA-122

  Day 1

• Liver transcriptomics

  Day 1

Other Outcomes (7)

• Blood pressure

  Day 1

• Arterial stiffness

  Day 1

• Body composition

  Day 1

Study Arms (4)

NAFLD

EXPERIMENTAL

Participants in the pediatric NAFLD clinic

Other: Oral sugar tolerance test; Other: De novo lipogenesis test; Other: Gluconeogenesis test

Ob control

EXPERIMENTAL

Participants with obesity, without NAFLD

Other: Oral sugar tolerance test; Other: De novo lipogenesis test; Other: Gluconeogenesis test

NW control

EXPERIMENTAL

Participants in the normal range for body weight, without NAFLD

Other: Oral sugar tolerance test; Other: De novo lipogenesis test; Other: Gluconeogenesis test

Liver control

EXPERIMENTAL

Participants undergoing liver biopsy or liver surgery, without NAFLD

Other: Oral sugar tolerance test; Other: De novo lipogenesis test; Other: Gluconeogenesis test

Interventions

Oral sugar tolerance test OTHER

Measurement of glucose and insulin for calculation of insulin sensitivity

Liver control; NAFLD; NW control; Ob control

De novo lipogenesis test OTHER

Oral consumption of deuterated water to measure incorporation of label into lipids

Liver control; NAFLD; NW control; Ob control

Gluconeogenesis test OTHER

Oral consumption of 13C-labeled glycerol to measure incorporation into glucose

Liver control; NAFLD; NW control; Ob control

Eligibility Criteria

• Age: 10 Years - 20 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Smoking, alcohol abuse, or illicit drug abuse: Participants who smoke or have signs or symptoms of alcohol or substance abuse will be excluded.

Sponsors & Collaborators

• University of Oklahoma: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

RECRUITING

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Obesity

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Kevin Short, PhD

  University of Oklahoma

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kevin Short, PhD

CONTACT

405-271-8001; kevin-short@ouhsc.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Cross-sectional design in which all participants receive all interventions in the form of short-term observations following oral consumption of test materials.

Study Record Dates

• First Submitted: June 1, 2022
• First Posted: June 24, 2022
• Study Start: May 25, 2022
• Primary Completion: February 1, 2026
• Study Completion: June 1, 2026
• Last Updated: March 6, 2024

Record last verified: 2024-03

Locations

US (1)