Intensive Lifestyle Management Improves Steatosis and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease Reply

We read with great interest the study by Lefere et al,1Lefere S. et al.Clin Gastroenterol Hepatol. 2022; 20: 2317-2326Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar which reported that accompanied with significant weight loss, an intensive multidisciplinary lifestyle management program not only improves liver steatosis but also fibrosis in children with nonalcoholic fatty liver disease (NAFLD), and more importantly, these changes were maintained and consolidated over the 1-year period of follow-up. It is well known that the severity of liver fibrosis is strongly correlated with liver-related morbidity and mortality and that a healthy lifestyle and weight reduction are crucial for the prevention and management of NAFLD.2Powell E.E. et al.Lancet. 2021; 397: 2212-2224Abstract Full Text Full Text PDF PubMed Scopus (683) Google Scholar We are concerned about whether the change in liver stiffness measurement (LSM) value reflects the regression of fibrosis in this study by Lefere et al,1Lefere S. et al.Clin Gastroenterol Hepatol. 2022; 20: 2317-2326Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar because it is widely acknowledged that the diagnostic accuracy of LSM for fibrosis/cirrhosis can be influenced by the presence of active liver necroinflammation.3Arena U. et al.Hepatology. 2008; 47: 380-384Crossref PubMed Scopus (619) Google Scholar Indeed, Ji et al4Ji D. et al.Am J Gastroenterol. 2021; 116: 1676-1685Crossref PubMed Scopus (15) Google Scholar recently reported that the decline in the LSM value may not accurately reflect the regression of fibrosis in patients with fibrotic chronic hepatitis B after undergoing short-term antiviral treatment, but the cause of such a decline in the LSM value remains unclear. Recently, we observed a correlation between LSM and liver necroinflammatory activity in patients with chronic liver disease with various causes, particularly among patients with NAFLD (r = 0.517, P < .001).5Wang L. et al.J Clin Transl Hepatol. 2019; 7: 313-321Crossref PubMed Scopus (14) Google Scholar To explore whether the increase in LSM values correlated linearly with the activity of liver necroinflammation, a longitudinal cohort of 14 patients with chronic hepatitis B who underwent antiviral treatment and had two liver biopsies were enrolled, and the dynamic changes in LSM were analyzed. The mean LSM values decreased from 9.2 kPa at baseline to 7.0 kPa at 26 weeks after treatment initiation and then remained almost unchanged thereafter at 78 weeks. Interestingly, a similar rapid decline in alanine aminotransferase (ALT) during the first 26 weeks was also observed. We then speculated that the sharp drop in LSM at the early phase after the initiation of treatment likely reflected the improvement of liver necroinflammation because the liver microenvironmental necroinflammation severity grade (according to the Scheuer system) declined significantly from 2.79 ± 0.89 at baseline to 1.86 ± 0.77 (P < .001) at 78 weeks, in contrast to the almost unchanged fibrosis scores (2.36 ± 0.75 vs 2.14 ± 0.95) at the same time period.5Wang L. et al.J Clin Transl Hepatol. 2019; 7: 313-321Crossref PubMed Scopus (14) Google Scholar In their study, Lefere et al1Lefere S. et al.Clin Gastroenterol Hepatol. 2022; 20: 2317-2326Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar described that 73.7% of patients with baseline F2 (LSM, 7–8.9 kPa) regressed to F0 or to F1 (LSM, <7 kPa) after 6 months of intensive multidisciplinary lifestyle management. Additionally, 72.2% of patients with baseline F3 to F4 (LSM, >9 kPa) regressed to F2 or to F0, as determined mainly by the decline in LSM. The authors mention in their paper that the relief of hepatic inflammation was probably not a major contributor to LSM changes in most patients, given the relatively low ALT values across the cohort and the lack of association between fibrosis stage improvement and ΔALTs at Month 6 (resolution group: ΔALT, -13; ΔAST, -7; no resolution group: ΔALT, -28; ΔAST, -19).1Lefere S. et al.Clin Gastroenterol Hepatol. 2022; 20: 2317-2326Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar However, an alternative explanation could not be excluded. In their study, patients with severe fibrosis (F3 to F4; LSM, >9 kPa) always had higher baseline ALT levels (F3 to F4, 37 [28–59] IU/mL) than patients with F2 (26 [20–39] IU/mL) and F0 to F1 (24 [17–32] IU/mL), and the regression of fibrosis was determined solely by the decrease in the LSM value. Moreover, the increase in LSM values correlated positively with the activity of liver necroinflammation. Therefore, it is rational to speculate that the decline in the LSM value most likely reflected the relief of inflammatory damage after 6 months of intensive multidisciplinary lifestyle management, particularly in those patients with a sharp decline in the LSM value accompanied by a significant decline in ALT activity after a short-term intervention. It might also suggest that some patients had possibly incorrect F3 to F4 scores. Moreover, the LSM measured at the moment after inflammation relief might reflect the true fibrosis stage. In conclusion, the reported decrease in the LSM value caused by a short period of intervention could mainly be caused by the relief of liver necroinflammation, which reminds us that the diagnostic accuracy of fibrosis would be more reliable after controlling for inflammation. NAFLD has become the most prevalent pediatric liver disease, with a 7.40% (95% confidence interval, 4.17–12.81) overall global prevalence.2Powell E.E. et al.Lancet. 2021; 397: 2212-2224Abstract Full Text Full Text PDF PubMed Scopus (683) Google Scholar In the absence of effective medications, intensive multidisciplinary lifestyle management can be beneficial to patients with NAFLD and should be promoted. Intensive Lifestyle Management Improves Steatosis and Fibrosis in Pediatric Nonalcoholic Fatty Liver DiseaseClinical Gastroenterology and HepatologyVol. 20Issue 10PreviewChildhood obesity, with associated comorbidities such as nonalcoholic fatty liver disease (NAFLD), is an increasing global health problem. Although lifestyle management is the mainstay of treatment, its efficacy on liver fibrosis has not yet been established. Full-Text PDF ReplyClinical Gastroenterology and HepatologyVol. 21Issue 10PreviewWe would like to thank Yao and Lu for commenting1 on our study “Intensive lifestyle management improves steatosis and fibrosis in pediatric nonalcoholic fatty liver disease.”2 Full-Text PDF