Common Liver-affecting Disorders in Children: Metabolic Dysfunction-Associated Steatotic Liver Disease and Celiac Disease

Alanine aminotransferase (ALT) is a hepatic enzyme used for the screening and follow-up of liver-affecting conditions. However, recommendations for ALT testing in children are scarce, and data on its measurement practices and common etiologies for abnormal values are limited. In Finland the widely used ALT upper limit <40 U/l may also be too high, and cutoffs of 22 U/l for girls and 26 U/l for boys were recently recommended according to one study from the United States. However, the generalizability and significance of these cutoffs for diagnostic outcomes remain obscure. Making the cutoffs even more relevant, a novel ALT-based diagnostic criterion for metabolic dysfunction-associated steatotic liver disease (MASLD) in those with excess adiposity or metabolic disturbances was recently proposed. The upsurge in obesity has likely made MASLD the most common chronic liver disease in children, but due to unclear definition, its prevalence and risk factors have scarcely been studied. Also, the increased prevalence of autoimmune diseases could give rise to liver morbidity. Untreated celiac disease in particular has been linked to elevated ALT values. However, the prevalence and associated factors, as well as the effect of gluten-free diet on elevated ALT in children with celiac disease remain obscure.

The aims of the present dissertation were I) to evaluate temporal changes in the measurement practices and prevalence of increased ALT, and common diagnoses associated with elevated ALT, II) to calculate novel ALT cutoffs for children, and to test the diagnostic performance of these novel and previously recommended cutoffs for screening and diagnosing MASLD, III) to ascertain the prevalence and associated factors for MASLD in children with overweight or obesity, and IV) to calculate the prevalence, associated factors, and effect of gluten-free diet on elevated ALT in celiac disease.

In Study I, 145,092 ALT measurements were collected from 28,118 1-16-yearold children investigated in Tampere University Hospital in the period 1992-2018. Testing increased fourfold while the prevalence of elevated ALT (≥40 U/l) fluctuated between 18 and 26%. In emergency care common causes associated with elevated ALT in the period 2008-2018 were infections (45%), whereas in outpatient departments autoimmune diseases (28%), psychiatric conditions (14%), and MASLD (10%) were commonly seen.

In Study II, ALT measurements from 6-17-year-old healthy children from the prospective Physical Activity and Nutrition in Children (PANIC) study (n=1,167) were used to calculate 95th percentile-based ALT upper limits of normal. The resulting cutoffs were 24-29 U/l for different aged girls and 29-32 U/l for boys. In a cohort of 6-16-year-old children with obesity (n=1,044), the respective prevalences of elevated ALT were 38% vs. 56% and those for MASLD 10% vs. 17% when the novel PANIC-based and previously recommended cutoffs were applied.

In Study III, data on 2-16-year-old children attending Tampere University Hospital or a primary healthcare unit due to overweight or obesity in the years 2002- 2020 were retrospectively collected (n=1000). Prevalence of MASLD varied between 14 and 20% during the study period, and the condition was associated with male sex and disturbances in glucose and lipid metabolism. In boys, an association was also seen with BMI, age, and puberty progression, whereas in girls the prevalence peaked at early puberty.

In Study IV, ALT levels at diagnosis were compared retrospectively between <17-year-old children with celiac disease (n=150), inflammatory bowel diseases (n=79), gastrointestinal reflux disease (n=37) or functional abdominal complaints (n=45), and with healthy controls from the PANIC cohort (n=500). Prevalence of elevated ALT (>30 U/l) was 15% in celiac disease, being less common than in other gastrointestinal diseases, but more prevalent than in population. Associated factors for elevated ALT in celiac disease were signs of malnutrition, severe villous atrophy, and higher autoantibody levels. ALT normalized in 81% on a gluten-free diet.

The present dissertation revealed increased ALT testing in children in the period 1992-2018, while the proportion of elevated values remained high and stable. This is probably due to increasing prevalence or better recognition of liver-affecting conditions. Besides acute infections, autoimmune conditions and MASLD were frequently associated with elevated ALT. However, ALT elevation caused by untreated celiac disease seemed to become rarer. Finnish population-based ALT upper limits were lower than the present laboratory cutoff, but higher than the recently recommended cutoffs. Using suboptimal cutoffs may have a marked impact on the prevalence of elevated ALT, thereby unnecessarily increasing the risk of downstream evaluations; future longitudinal studies on optimal cutoffs are needed. The use of a MASLD definition in clinical work still needs to be studied, and improved noninvasive diagnostic tests are called for. In light of these results, systematic MASLD screening could be recommended especially in those with metabolic risk factors, whereas frequent ALT testing in celiac disease seems unnecessary. All in all, evidence-based recommendations for ALT testing are needed.