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Purpose <p>Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is increasingly prevalent in pediatric populations, especially among children with obesity. Genetic risk variants for MASLD- particularly the 148M allele of the patatin-like phospholipase domain-containing 3 (<i>PNPLA3</i>) gene - have been linked to various clinical outcomes and have recently led to the identification of a “liver-specific” MASLD subtype, distinct from the classical cardiometabolic MASLD phenotype. While adult evidence shows divergent effects of this gene especially on extrahepatic outcomes, similar pediatric data in the context of MASLD remain limited.</p> Methods <p>A total of 629 children with obesity and ultrasound-detected MASLD were evaluated. Patients were classified according to the presence/absence of the 148M allele of <i>PNPLA3</i> gene. Kidney damage (KD) was defined as reduced estimated glomerular filtration rate (eGFR &lt; 90mL/min/1.73m2), while subclinical hypothyroidism (SH) was defined by thyroid stimulating hormone (TSH) &gt; 4.5µUI/ml with normal free triiodothyronine and free thyroxine levels. Hepatic fibrosis was estimated through an indirect measure such as Pediatric NAFLD Fibrosis Index (PNFI). Prediabetes was defined according to diagnostic criteria.</p> Results <p>The 148M allele of <i>PNPLA3</i> was associated with lower eGFR and higher TSH, glycaemia, and PNFI values (all <i>p</i> &lt; 0.05). Carriers showed an adjusted odds ratio of 1.67 for fibrosis, 2.24 for SH, 3.74 for KD, and 1.09 for prediabetes, respectively (all <i>p</i> &lt; 0.05).</p> Conclusion <p>The 148M allele of <i>PNPLA3</i> influences hepatic and extrahepatic outcomes in children with MASLD. Although preliminary, these data suggest that genetic stratification could enhance risk prediction and guide personalized monitoring and treatment strategies in pediatric MASLD.</p>

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Influence of genetics on clinical trajectories in children with MASLD: role of the PNPLA3 I148M polymorphism

  • 期刊论文

  • 发表日期：

    2026年2月7日

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  • Anna Di Sessa,
  • Gianmario Forcina,
  • Grazia Cirillo,
  • Giuseppina Rosaria Umano,
  • Gelsomina De Luca,
  • Pierluigi Marzuillo,
  • Emanuele Miraglia del Giudice

摘要

Purpose

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is increasingly prevalent in pediatric populations, especially among children with obesity. Genetic risk variants for MASLD- particularly the 148M allele of the patatin-like phospholipase domain-containing 3 (PNPLA3) gene - have been linked to various clinical outcomes and have recently led to the identification of a “liver-specific” MASLD subtype, distinct from the classical cardiometabolic MASLD phenotype. While adult evidence shows divergent effects of this gene especially on extrahepatic outcomes, similar pediatric data in the context of MASLD remain limited.

Methods

A total of 629 children with obesity and ultrasound-detected MASLD were evaluated. Patients were classified according to the presence/absence of the 148M allele of PNPLA3 gene. Kidney damage (KD) was defined as reduced estimated glomerular filtration rate (eGFR < 90mL/min/1.73m2), while subclinical hypothyroidism (SH) was defined by thyroid stimulating hormone (TSH) > 4.5µUI/ml with normal free triiodothyronine and free thyroxine levels. Hepatic fibrosis was estimated through an indirect measure such as Pediatric NAFLD Fibrosis Index (PNFI). Prediabetes was defined according to diagnostic criteria.

Results

The 148M allele of PNPLA3 was associated with lower eGFR and higher TSH, glycaemia, and PNFI values (all p < 0.05). Carriers showed an adjusted odds ratio of 1.67 for fibrosis, 2.24 for SH, 3.74 for KD, and 1.09 for prediabetes, respectively (all p < 0.05).

Conclusion

The 148M allele of PNPLA3 influences hepatic and extrahepatic outcomes in children with MASLD. Although preliminary, these data suggest that genetic stratification could enhance risk prediction and guide personalized monitoring and treatment strategies in pediatric MASLD.