Case Control Study
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World J Gastroenterol. Dec 7, 2014; 20(45): 17107-17114
Published online Dec 7, 2014. doi: 10.3748/wjg.v20.i45.17107
Increased circulating zonulin in children with biopsy-proven nonalcoholic fatty liver disease
Lucia Pacifico, Enea Bonci, Lidia Marandola, Sara Romaggioli, Stefano Bascetta, Claudio Chiesa
Lucia Pacifico, Sara Romaggioli, Stefano Bascetta, Department of Pediatrics and Child Neuropsychiatry, Sapienza University of Rome, 00161 Rome, Italy
Enea Bonci, Lidia Marandola, Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
Claudio Chiesa, Institute of Translational Pharmacology, National Research Council, 00133 Rome, Italy
Author contributions: Pacifico L, Bonci E and Chiesa C designed the study, analyzed the data and wrote the manuscript; Romaggioli S and Bascetta S collected the data; Marandola L performed the measurements and analyses; all the Authors participated in the critical review and in the final approval of the manuscript.
Correspondence to: Claudio Chiesa, MD, Institute of Translational Pharmacology, National Research Council, Via Fosso del Cavaliere 100, 00133 Rome, Italy. claudio.chiesa@ift.cnr.it
Telephone: +39-6-49979215 Fax: +39-6-49979216
Received: May 23, 2014
Revised: June 22, 2014
Accepted: July 16, 2014
Published online: December 7, 2014
Abstract

AIM: To investigate the potential association of circulating zonulin with the stage of liver disease in obese children with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD).

METHODS: A case-control study was performed. Cases were 40 obese children with NAFLD. The diagnosis of NAFLD was based on magnetic resonance imaging (MRI) with high hepatic fat fraction (HFF ≥ 5%), and confirmed by liver biopsy with ≥ 5% of hepatocytes containing macrovesicular fat. Controls were selected from obese children with normal levels of aminotransferases, and without MRI evidence of fatty liver as well as of other causes of chronic liver diseases. Controls were matched (1-to 1) with the cases on age, gender, pubertal stage and as closely as possible on body mass index- standard deviation score. All participants underwent clinical examination, laboratory tests including zonulin, inflammatory and metabolic parameters, and MRI for measurement of HFF and visceral adipose tissue.

RESULTS: Zonulin values were significantly greater in obese subjects with NAFLD than in those without NAFLD [median (interquartile range), 4.23 (3.18-5.89) vs 3.31 (2.05-4.63), P < 0.01]. In patients with NAFLD, zonulin concentrations increased significantly with the severity of steatosis and the Spearman’s coefficient revealed a positive correlation between zonulin values and steatosis (r = 0.372, P < 0.05); however, we did not find a significant correlation between zonulin and lobular inflammation (P = 0.23), ballooning (P = 0.10), fibrosis score (P = 0.18), or presence of nonalcoholic steatohepatitis (P = 0.17). Within the entire study population, zonulin levels were positively associated with gamma-glutamyl transferase, 2-h insulin, HFF, and negatively associated with whole-body insulin sensitivity index (WBISI), after adjustment for age, gender and pubertal status. When the associations were restricted to the group of NAFLD patients, 2-h insulin, hepatic fat, and WBISI retained statistical significance.

CONCLUSION: Circulating zonulin is increased in children and adolescents with NAFLD and correlates with the severity of steatosis.

Keywords: Zonulin, Intestinal permeability, Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, Children

Core tip: Alteration in gut microbiota followed by impairment of intestinal wall integrity may play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Zonulin is a mediator known to regulate intestinal permeability by modulating intracellular tight junctions. We showed that zonulin concentrations are increased in obese children with biopsy-proven NAFLD and correlate with the severity of steatosis, but not with the presence of nonalcoholic steatohepatitis (NASH), lobular inflammation or fibrosis score. These findings may well fit with the recent theory suggesting that simple steatosis and NASH are different and not necessarily inter-related diseases.