A natural history study of paediatric non-alcoholic fatty liver disease over 10 years.

Background & Aims: The long-term outcome of paediatric non-alcoholic fatty liver disease (NAFLD) has not been well established. Between 2008 and 2012, an unselected cohort of 133 children with severe obesity was screened for NAFLD. The aim of this study was to determine the 10-year natural history of NAFLD in this cohort. Methods: All 133 participants of the original study were approached. Proton magnetic resonance spectroscopy (1H-MRS) and the Enhanced Liver Fibrosis® (ELF) test were used to assess longitudinal changes in steatosis and fibrosis, respectively. Risk factors for disease progression were explored. Results: Fifty-one of the 133 participants (38%) from the original cohort were included. The mean follow-up time was 10.3 years (range 7-13 years), 65% were female and 92% had persistent obesity. The proportion of participants with steatosis remained unchanged (47%). Nine individuals developed steatosis and in nine individuals steatosis resolved. Predefined relevant individual changes in 1H-MRS were seen in 38% of the participants. The mean ELF test did not change significantly (8.70 ± 0.58 vs. 8.51 ± 0.71, p = 0.22). However, 16% had a relevant increase in ELF test and 6% of those with NAFLD developed advanced fibrosis at follow-up. Changes in steatosis correlated with changes in established metabolic risk factors, alanine aminotransferase, and bariatric surgery. A change in the ELF test was associated with a change in triglycerides. Conclusions: This 10-year follow-up study shows that one-third of the young adults who had childhood obesity develop steatosis and in one-third steatosis resolves. Six percent of those with NAFLD had developed advanced fibrosis at follow-up. These data underscore the importance of screening for NAFLD and monitoring for progression to advanced NAFLD in young people with obesity. Impact and implications: Childhood obesity accompanied by fat accumulation in the liver persists into young adulthood in the vast majority, and 6% develop serious liver injury. Worsening of metabolic disturbances increases the risk of liver injury.

Dexamethasone-associated metabolic effects in male mice are partially caused by depletion of endogenous corticosterone.

Synthetic glucocorticoids are clinically used to treat auto-immune and inflammatory disease. Despite the high efficacy, glucocorticoid treatments causes side effects such as obesity and insulin resistance in many patients. Via their pharmacological target, the glucocorticoid receptor (GR), glucocorticoids suppress endogenous glucocorticoid secretion. Endogenous, but not synthetic, glucocorticoids activate the mineralocorticoid receptor (MR) and side effects of synthetic glucocorticoids may thus not only result from GR hyperactivation but also from MR hypoactivation. Here, we tested the hypothesis that reactivation of MR with corticosterone add-on treatment can attenuate the metabolic effects of the synthetic glucocorticoid dexamethasone. Male 8-week-old C57Bl/6J mice received a high-fat diet supplemented with dexamethasone or vehicle, and were subcutaneously implanted with low-dose corticosterone- or vehicle-containing pellets. Dexamethasone strongly reduced body weight and fat mass gain, while corticosterone add-on partially normalized this. Dexamethasone-induced hyperglycemia and hyperinsulinemia were exacerbated by corticosterone add-on, which was prevented by MR antagonism. In subcutaneous white adipose tissue, corticosterone add-on prevented the dexamethasone-induced expression of intracellular lipolysis genes. In brown adipose tissue, dexamethasone also upregulated gene expression of brown adipose tissue identity markers, lipid transporters and lipolysis enzymes, which was prevented by corticosterone add-on. In conclusion, corticosterone add-on treatment prevents several, while exacerbating other metabolic effects of dexamethasone. While the exact role of MR remains elusive, this study suggests that corticosterone suppression by dexamethasone contributes to its effects in mice.

Evaluation of the feasibility of screening for paediatric non-alcoholic fatty liver disease.

AIM: To evaluate the feasibility of screening for non-alcoholic fatty liver disease (NAFLD) in clinical practice and the acceptance of a screening strategy, and to identify factors that determine compliance. METHODS: A screening protocol, based on alanine aminotransferase measurement and introduced to healthcare workers of Dutch outpatient obesity clinics in 2017, was evaluated. Medical files of children who visited the largest outpatient obesity clinic between 2017 and 2020 were evaluated. Focus group discussions (FGDs) were conducted with 14 healthcare workers who had been using the screening protocol. RESULTS: Screening for NAFLD was performed in 477/571 (84%) of the children. Loss of follow-up was the major reason for inadequate screening. Follow-up was performed in 81/134 children with an abnormal screening result (61%). The FGDs indicated 13 barriers for screening, regarding guideline- and knowledge-related issues. CONCLUSION: Screening for NAFLD was performed in the vast majority of the children. However, adherence to the guideline after an abnormal initial screening result needs to be improved. This can be achieved by improving the loss of follow-up of patients' and physicians' awareness of the relevance of mildly elevated ALT levels.