Metabolic Pathology of Pediatric NAFLD

March 4, 2024 updated by: University of Oklahoma

Understanding the Metabolic Pathology of Pediatric Obesity and NAFLD

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed 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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
100

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • United States
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Recruiting
        • University of Oklahoma Health Sciences Center
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

10 years to 20 years (Child, Adult)

Accepts Healthy Volunteers

Yes

Study Population

Participants in the NAFLD and Liver control groups will be recruited from the OU Health pediatric clinics. Prospective patients will be identified from clinic records and during clinic visits. Participants in the Ob control and NW control groups will be recruited from the local community.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: NAFLD
Participants in the pediatric NAFLD clinic
Other: Oral sugar tolerance test
Measurement of glucose and insulin for calculation of insulin sensitivity
Other: De novo lipogenesis test
Oral consumption of deuterated water to measure incorporation of label into lipids
Other: Gluconeogenesis test
Oral consumption of 13C-labeled glycerol to measure incorporation into glucose
Experimental: Ob control
Participants with obesity, without NAFLD
Other: Oral sugar tolerance test
Measurement of glucose and insulin for calculation of insulin sensitivity
Other: De novo lipogenesis test
Oral consumption of deuterated water to measure incorporation of label into lipids
Other: Gluconeogenesis test
Oral consumption of 13C-labeled glycerol to measure incorporation into glucose
Experimental: NW control
Participants in the normal range for body weight, without NAFLD
Other: Oral sugar tolerance test
Measurement of glucose and insulin for calculation of insulin sensitivity
Other: De novo lipogenesis test
Oral consumption of deuterated water to measure incorporation of label into lipids
Other: Gluconeogenesis test
Oral consumption of 13C-labeled glycerol to measure incorporation into glucose
Experimental: Liver control
Participants undergoing liver biopsy or liver surgery, without NAFLD
Other: Oral sugar tolerance test
Measurement of glucose and insulin for calculation of insulin sensitivity
Other: De novo lipogenesis test
Oral consumption of deuterated water to measure incorporation of label into lipids
Other: Gluconeogenesis test
Oral consumption of 13C-labeled glycerol to measure incorporation into glucose

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
De novo lipogenesis
Time Frame: Day 1
Measurement of the rate of newly synthesized triglycerides in plasma using deuterated water
Day 1
Gluconeogenesis
Time Frame: Day 1
Measurement of the rate newly synthesized glucose in circulation using labeled glycerol and deuterated water
Day 1
Serum microRNA
Time Frame: Day 1
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
Time Frame: Day 1
Abundance of collagen in liver biopsy sections, using Second Harmonic Generation microscopy
Day 1
Insulin sensitivity
Time Frame: 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
Day 1
Liver mitochondrial flux
Time Frame: 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
Day 1

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Targets of microRNA-122
Time Frame: Day 1
Transcripts bound to microRNA-122, measured using high-throughput sequencing of cross- linked immunoprecipitates (HITS-CLIP)
Day 1
Liver transcriptomics
Time Frame: Day 1
Spatial distribution of messenger RNAs in liver biopsies
Day 1

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Blood pressure
Time Frame: Day 1
Brachial and central blood pressures
Day 1
Arterial stiffness
Time Frame: Day 1
Measured as carotid-femoral pulse wave velocity
Day 1
Body composition
Time Frame: Day 1
Whole body and regional lean and fat mass, measure with dual energy X-ray absorptiometry
Day 1
Cardiorespiratory fitness
Time Frame: Day 1
Peak oxygen consumption during bicycle ergometry test to volitional fatigue
Day 1
Blood DNA analysis
Time Frame: Day 1
Measurement of single-nucleotide polymorphisms associated with NAFLD risk
Day 1
Liver steatosis
Time Frame: Day 1
Use of Fibroscan to measure controlled attenuation parameter (measure of steatosis)
Day 1
Liver fibrosis
Time Frame: Day 1
Use of Fibroscan to measure elastic modulus (surrogate measure of fibrosis)
Day 1

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Oklahoma

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Kevin Short, PhD, University of Oklahoma

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 25, 2022

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 1, 2026

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 1, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 1, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 17, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 24, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 6, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 4, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 14018
  • 1R01DK129656-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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