The liver in pediatric obesity : risks and consequences of increased transaminases and steatotic liver disease

More than 175 million children are living with obesity today. The rise in childhood obesity leads to the increased prevalence of metabolic dysfunction associated steatotic liver disease (MASLD), whose previous term was non-alcoholic fatty liver disease. Yet, the evidence of the risk and long-term consequences of MASLD in pediatric obesity remains limited. This thesis sought to (1) investigate children with obesity at the greatest risk of MASLD, (2) assess the effect of MASLD in pediatric obesity on the development of type 2 diabetes and severe liver disease, and (3) determine the effect of obesity treatment response on the risk of MASLD and type 2 diabetes.

This thesis consists of five studies. In all the studies, the main population was children and adolescents undergoing obesity treatment across Sweden enrolled in the Swedish Childhood Obesity Treatment Register (BORIS, https://www.e- boris.se/in-english/). BORIS was linked with several national registers containing medical data. Matched comparators for individuals in BORIS were obtained from the Total Population Register. In addition, Study II also included children with obesity in Germany, Austria, and Switzerland enrolled in the Adiposity Patients Registry (APV).

In Study I - III, factors associated with pediatric MASLD were identified.

Study I was a cross-sectional study of children with obesity who had alanine aminotransferase (ALT) data in BORIS. Of them, 38% had mildly increased ALT and additionally 11% had markedly increased ALT. Using ALT as a proxy for MASLD, a sex-age interaction in pediatric MASLD was observed; increasing age strengthened the odds of increased ALT among boys, whereas the odds tended to be static among girls. Moreover, increased ALT was more likely to be found in children with higher degree of obesity, dyslipidemia, and impaired fasting glycemia in a dose-response manner.

Study II was a cohort study of children with overweight or obesity in BORIS and APV registers. Those children born small for gestational age had 20% higher odds for elevated ALT. In addition, they were more likely to have elevated glycated hemoglobin and elevated blood pressure than their peers born appropriate for gestational age.

Study III was a nested case-control study on clinical determinants of MASLD diagnosis. We found that higher degree of obesity, impaired fasting glycemia, and hypertriglyceridemia were associated with a higher risk of MASLD. On the other hand, body mass index standard deviation score (BMI SDS) reduction of at least 0.25 units was associated with at least 44% relative risk reduction of MASLD.

Study IV assessed the effect of MASLD in pediatric obesity on type 2 diabetes, whereas Study V assessed the effect of pediatric obesity on severe liver disease.

Study IV was a cohort study, with the main exposure being ALT-based and diagnosis code-based MASLD, separately. MASLD in pediatric obesity was associated with at least doubled risk of developing young-onset type 2 diabetes. The risk was particularly prominent before age 20. Synergistic effect of MASLD and intermediate hyperglycemia on the risk of type 2 diabetes was observed (attributable proportion due to the synergistic effect: 67%). In addition, optimal response in obesity treatment was associated with 77% relative risk reduction of type 2 diabetes, irrespective of the MASLD status.

Study V was a cohort study, with severe liver disease during adolescence and young adulthood as the main outcome. Pediatric obesity was associated with a two times higher risk for severe liver disease. Moreover, the risk seems to be even higher in individuals with obesity in childhood who develop alcohol use disorder during follow-up. Nevertheless, only a small proportion of children with obesity were affected by severe liver disease (1.1% of individuals in the obesity cohort had severe liver disease diagnosis by age 40).

To conclude, factors associated with increased risk of MASLD in pediatric obesity include boys of older age, born small for gestational age, higher degree of obesity, impaired fasting glycemia, and hypertriglyceridemia. Further, MASLD increases the risk of young-onset type 2 diabetes. Moreover, pediatric obesity is also associated with increased risk of severe liver disease in adolescence and young adulthood. Obtaining optimal response in pediatric obesity treatment is important to prevent MASLD and reduce the risk of young-onset type 2 diabetes.

List of scientific papers

I. Putri, R. R., Casswall, T., & Hagman, E. (2021). Prevalence of increased transaminases and its association with sex, age, and metabolic parameters in children and adolescents with obesity - a nationwide cross-sectional cohort study. BMC pediatrics, 21(1), 271. https://doi.org/10.1186/s12887-021-02747-4

II. Prinz, N .* , Putri, R. R .* , Reinehr, T., Danielsson, P., Weghuber, D., Norman, M., Rochow, N., Marcus, C., Holl, R. W., & Hagman, E. (2023). The association between perinatal factors and cardiometabolic risk factors in children and adolescents with overweight or obesity: A retrospective two-cohort study. PLoS medicine, 20(1), e1004165. https://doi.org/10.1371/journal.pmed.1004165 (*shared first authorship)

III. Putri, R. R., Casswall, T., & Hagman, E. (2022). Risk and protective factors of non-alcoholic fatty liver disease in paediatric obesity: A nationwide nested case-control study. Clinical obesity, 12(2), e12502. https://doi.org/10.1111/cob.12502

IV. Putri, R. R., Casswall, T., Danielsson, P., Marcus, C., & Hagman, E. (2024). Steatotic Liver Disease in Pediatric Obesity and Increased Risk for Youth-Onset Type 2 Diabetes. Diabetes care, dc241236. Advance online publication. https://doi.org/10.2337/dc24-1236

V. Putri R. R., Caswall T., Danielsson P., Marcus C., Hagman E. Childhood obesity and increased risk for severe liver disease in adolescence and young adulthood. [Manuscript]