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Metabolic Pathology of Pediatric NAFLD

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ClinicalTrials.gov Identifier: NCT05430178
Recruitment Status : Recruiting
First Posted : June 24, 2022
Last Update Posted : July 5, 2022
Sponsor:
Collaborator:
National Institutes of Health (NIH)
Information provided by (Responsible Party):
University of Oklahoma

Study Description
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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.


Condition or disease Intervention/treatment
Nonalcoholic Fatty Liver Nonalcoholic Steatohepatitis Obesity Other: Cardiometabolic testing

Detailed Description:

This project uses a cross-sectional design with a single testing period without an intervention or 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 will be enrolled.

Study Design
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Study Type : Observational
Estimated Enrollment : 100 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Understanding the Metabolic Pathology of Pediatric Obesity and NAFLD
Actual Study Start Date : May 25, 2022
Estimated Primary Completion Date : February 2026
Estimated Study Completion Date : June 2026

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
NAFLD
Participants in the pediatric NAFLD clinic
 Other: Cardiometabolic testing
Measurement of glucose and lipid metabolism, insulin sensitivity, exercise capacity, blood pressure, and arterial stiffness
Ob control
Participants with obesity, without NAFLD
 Other: Cardiometabolic testing
Measurement of glucose and lipid metabolism, insulin sensitivity, exercise capacity, blood pressure, and arterial stiffness
NW control
Participants in the normal range for body weight, without NAFLD
Liver control
Participants undergoing liver biopsy or liver surgery, without NAFLD


Outcome Measures
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Primary Outcome Measures :
  1. De novo lipogenesis [ Time Frame: Day 1 ]
    Measurement of the rate of newly synthesized triglycerides in plasma using deuterated water

  2. Gluconeogenesis [ Time Frame: Day 1 ]
    Measurement of the rate newly synthesized glucose in circulation using labeled glycerol and deuterated water

  3. 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

  4. Abundance of liver collagen [ Time Frame: Day 1 ]
    Abundance of collagen in liver biopsy sections, using Second Harmonic Generation microscopy

  5. Liver energetics [ Time Frame: Day 1 ]
    Assessment of mitochondrial and glycolytic flux in liver biopsy sections, using fluorescence lifetime imaging microscopy

  6. 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


Secondary Outcome Measures :
  1. Targets of microRNA-122 [ Time Frame: Day 1 ]
    Transcripts bound to microRNA-122, measured using high-throughput sequencing of cross- linked immunoprecipitates (HITS-CLIP)

  2. Liver transcriptomics [ Time Frame: Day 1 ]
    Spatial distribution of messenger RNAs in liver biopsies


Other Outcome Measures:
  1. Blood pressure [ Time Frame: Day 1 ]
    Brachial and central blood pressures

  2. Arterial stiffness [ Time Frame: Day 1 ]
    Measured as carotid-femoral pulse wave velocity

  3. Body composition [ Time Frame: Day 1 ]
    Whole body and regional lean and fat mass, measure with dual energy X-ray absorptiometry

  4. Cardiorespiratory fitness [ Time Frame: Day 1 ]
    Peak oxygen consumption during bicycle ergometry test to volitional fatigue

  5. Blood DNA analysis [ Time Frame: Day 1 ]
    Measurement of single-nucleotide polymorphisms associated with NAFLD risk

  6. Liver steatosis and fibrosis [ Time Frame: Day 1 ]
    Use of Fibroscan to measure controlled attenuation parameter (measure of steatosis) and elastic modulus (surrogate measure of fibrosis)

  7. Blood biochemistry [ Time Frame: Day 1 ]
    Glucose, insulin, lipids, liver enzymes, and related clinical tests


Biospecimen Retention:   Samples With DNA
Blood: serum, plasma, cells for DNA analysis Liver: specimens from patients undergoing biopsy for NAFLD confirmation or liver surgery

Eligibility Criteria
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Ages Eligible for Study:   10 Years to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
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.
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05430178


Contacts
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Contact: Kevin Short, PhD 405-271-8001 ext 43094 kevin-short@ouhsc.edu

Locations
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United States, Oklahoma
University of Oklahoma Health Sciences Center Recruiting
Oklahoma City, Oklahoma, United States, 73104
Contact: Kevin Short, PhD    405-271-8001 ext 43094    kevin-short@ouhsc.edu   
Sponsors and Collaborators
University of Oklahoma
National Institutes of Health (NIH)
Investigators
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Principal Investigator: Kevin Short, PhD University of Oklahoma
More Information
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Responsible Party: University of Oklahoma
ClinicalTrials.gov Identifier: NCT05430178    
Other Study ID Numbers: 14018
1R01DK129656-01A1 ( U.S. NIH Grant/Contract )
First Posted: June 24, 2022    Key Record Dates
Last Update Posted: July 5, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fatty Liver
Non-alcoholic Fatty Liver Disease
Obesity
Overnutrition
Nutrition Disorders
 Overweight
Body Weight
Liver Diseases
Digestive System Diseases