Non-Invasive Diagnostic Panel for MASLD in Children With Obesity

Официальное название

A Non-Invasive Diagnostic Panel for MASLD in Children With Obesity: Evaluation of a Multiparametric Biomarker Panel and Genetic Risk Score Using LASSO-Regularized Logistic Regression - The PedMASLD-MultiOmics Pilot Study

Обзор

This prospective, single-center, two-group observational study evaluates a non-invasive multi-parameter diagnostic panel for metabolic dysfunction-associated steatotic liver disease (MASLD) in children with obesity. A total of 180 children aged 8 to 18 years with a body mass index at or above the 85th percentile for age and sex are planned for enrollment at a single tertiary pediatric center. Each participant attends a single study visit comprising a fasting venous blood sample for serum biomarkers (cytokeratin-18 M30 and M65, fibroblast growth factor 21, retinol-binding protein 4, insulin-like growth factor binding protein 7, adiponectin, leptin, insulin, and routine biochemistry), abdominal ultrasonography with two-dimensional shear wave elastography, and genotyping of three MASLD-associated variants (PNPLA3 rs738409, TM6SF2 rs58542926, HSD17B13 rs72613567). Participants are classified as MASLD-positive or MASLD-negative according to a guideline-based composite reference standard consisting of ultrasonographic steatosis grading and cardiometabolic risk factor criteria, assessed independently of the candidate index tests. The primary objective is to determine the discriminative performance, expressed as the area under the receiver operating characteristic curve, of a LASSO-regularized logistic regression model combining biomarker, elastography, and genetic predictors. No therapeutic intervention is assigned by the study protocol. Reporting will follow the STARD 2015 statement.

Подробное описание

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease of childhood and is closely associated with obesity. Liver biopsy, the histological reference standard, is not ethically acceptable as a routine screening tool in children because it requires general anaesthesia and carries procedural risk and sampling error. The currently used non-invasive screening tools, alanine aminotransferase and ultrasonography, have limited diagnostic accuracy when used alone. An accurate, non-invasive diagnostic approach for pediatric MASLD is therefore needed.

This single-center, prospective, two-group, exploratory pilot diagnostic classification study is conducted at Kayseri City Hospital, Kayseri, Türkiye. Children aged 8 to 18 years with a body mass index at or above the 85th percentile for age and sex, according to Turkish national growth references, are screened consecutively in the pediatric endocrinology outpatient clinic. Enrollment of 180 participants is planned, balanced by sex.

Each participant attends a single study visit of approximately three hours. After a 12-hour fast, a single venous blood sample is obtained for routine biochemistry, insulin, and the serum biomarker panel; serum and plasma aliquots are stored at -80 °C until batched analysis by enzyme-linked immunosorbent assay in duplicate with blinded internal controls. Abdominal ultrasonography is performed for hepatic steatosis grading, and liver stiffness is measured by two-dimensional shear wave elastography. A separate whole-blood sample is used for DNA isolation and genotyping of three MASLD-associated variants, from which a three-variant polygenic risk score is derived. Anthropometric measurements including waist circumference percentile, blood pressure, pubertal staging, and questionnaire-based nutritional and physical activity assessment are recorded at the same visit. No therapeutic intervention is assigned by the study protocol.

Participants are classified as MASLD-positive or MASLD-negative using a composite reference standard based on ultrasonographic steatosis grading together with cardiometabolic risk factor criteria, in accordance with current pediatric guidelines. To avoid incorporation bias, two-dimensional shear wave elastography is used only as a candidate predictor and does not contribute to the reference standard; reference standard assessment is performed blinded to biomarker and genotype results.

The analysis develops a LASSO-regularized logistic regression model combining serum biomarkers, liver stiffness, and the polygenic risk score, with internal validation by bootstrap resampling. Model discrimination is compared with alanine aminotransferase alone and with ultrasonography alone. Reporting will follow the STARD 2015 statement.

Вмешательства

• Диагностический тест Non-Invasive Multi-Parameter Diagnostic Panel
  All participants undergo the same set of index tests at a single study visit: a fasting venous blood sample for serum cytokeratin-18 M30 and M65, fibroblast growth factor 21, retinol-binding protein 4, insulin-like growth factor binding protein 7, adiponectin, leptin, insulin and routine biochemistry measured by enzyme-linked immunosorbent assay and standard laboratory methods; abdominal ultrasonography with two-dimensional shear wave elastography for liver stiffness; and genotyping of PNPLA3 rs

Первичные конечные точки

• Diagnostic Performance of the LASSO-Regularized Multi-Parameter Panel for MASLD [Срок оценки: Through study completion, an average of 12 months]

Вторичные конечные точки (3)

• Comparative Discrimination of the Panel Versus Alanine Aminotransferase Alone and Ultrasonography Alone [Срок оценки: Through study completion, an average of 12 months]
• Serum Biomarker Concentrations in MASLD-Positive Versus MASLD-Negative Children With Obesity [Срок оценки: Day 1 (single study visit)]
• Incremental Discriminative Value of Serum IGFBP7 [Срок оценки: Through study completion, an average of 12 months]

Критерии участия

Критерии включения

• Age 8 to 18 years.
• Body mass index at or above the 85th percentile for age and sex according to Turkish national growth references.
• Hepatic steatosis of grade 1 or higher on abdominal ultrasonography and/or alanine aminotransferase at or above the biology-based upper limit of normal (26 U/L for boys; 22 U/L for girls), or persistent alanine aminotransferase elevation at or above twice the upper limit of normal (50 U/L for boys; 44 U/L for girls).
• At least one cardiometabolic risk factor.
• Written informed consent provided by a parent or legal guardian, with simplified assent for children aged 8 to 11 years and standard assent for children aged 12 years and older.

Критерии исключения

• Viral hepatitis.
• Autoimmune liver disease.
• Wilson disease, alpha-1 antitrypsin deficiency, or hereditary hemochromatosis.
• Use of hepatotoxic medication, including corticosteroids, methotrexate, valproate, amiodarone, or tamoxifen.
• Fasting duration shorter than 12 hours.
• Active infection, defined as C-reactive protein above 10 mg/L.
• Untreated thyroid disorder, defined as thyroid-stimulating hormone below 0.5 or above 5.
• Total parenteral nutrition.
• Diabetic ketoacidosis.
• Inability to obtain informed consent.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Turkey (Türkiye) · 1 центр

• Kayseri City Hospital — Kayseri

Публикации

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• Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig L, Lijmer JG, Moher D, Rennie D, de Vet HC, Kressel HY, Rifai N, Golub RM, Altman DG, Hooft L, Korevaar DA, Cohen JF; STARD Group. STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. BMJ. 2015 Oct 28;351:h5527. doi: 10.1136/bmj.h5527. PMID 26511519
• Lahtinen L, Hiltunen P, Vuorela N, Huhtala H, Kurppa K, Aitokari L. Screening and diagnosis of metabolic dysfunction-associated steatotic liver disease in children within public healthcare. Pediatr Res. 2025 Oct 30. doi: 10.1038/s41390-025-04540-w. Online ahead of print. PMID 41168404
• Schwimmer JB, Johnson JS, Angeles JE, Behling C, Belt PH, Borecki I, Bross C, Durelle J, Goyal NP, Hamilton G, Holtz ML, Lavine JE, Mitreva M, Newton KP, Pan A, Simpson PM, Sirlin CB, Sodergren E, Tyagi R, Yates KP, Weinstock GM, Salzman NH. Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease. Gastroenterology. 201 PMID 31255652
• Hahn JW, Lim JG, Lee KJ, Moon JS, Kim TH, Son Y, Yon DK, Lee YJ, Seo Y, Park J, Lee S, Kim D, Ko JS. Clinical and microbial correlates of response to lifestyle intervention in pediatric metabolic dysfunction-associated steatotic liver disease. Gut Pathog. 2026 Jan 18;18(1):6. doi: 10.1186/s13099-026-00798-5. PMID 41549262
• Yaser S, Yaser H, Mohammed HE, Nasser M, Darwish MK, Haseeb ME, Heiba AH, Ghonaim MM, Aboeldahab H, Bady Z. Efficacy of pharmacotherapies on pediatric patients with metabolic dysfunction-associated steatotic liver disease: a systematic review and network meta-analysis. BMC Gastroenterol. 2025 Dec 8;25(1):853. doi: 10.1186/s12876-025-04393-x. PMID 41361375
• Omana-Guzman I, Rosas-Diaz M, Martinez-Lopez YE, Perez-Navarro LM, Diaz-Badillo A, Alanis A, Bustamante A, Castillo-Ruiz O, Del Toro-Cisneros N, Esquivel-Hernandez DA, Garcia-Villalobos G, Garibay-Nieto N, Garcia-Oropesa EM, Hernandez-Martinez JC, Lopez-Sosa EB, Maldonado C, Martinez D, Membreno J, Moctezuma-Chavez OO, Munguia-Cisneros CX, Nava-Gonzalez EJ, Perales-Torres AL, Perez-Garcia A, River PMID 39574069

Идентификаторы

NCT: NCT07731360 · Etik C.D.No:1009(Kayseri CH) · TUSEB-2026-A4-U-55859

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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