Pathogenetic role of inflammation and insulin resistance in non-alcoholic fatty liver disease in obese children

Authors

DOI:

https://doi.org/10.14739/2310-1210.2022.5.257288

Keywords:

fatty liver, insulin resistance, inflammation, obesity, children

Abstract

The hypothesis of primacy between insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) remains debatable, which requires additional research.

Aim. To examine the differences between cytokine profile and IR markers in children with NAFLD depending on liver damage degree compared to children with normal weight and obesity without NAFLD and to study their association with anthropometric and instrumental parameters.

Materials and methods. 170 patients aged 6–17 years (mean 12.15 ± 2.51 years) were included. Hepatic steatosis was determined by transient elastography. Patients were divided into 4 groups according to the presence of hepatic steatosis, non-alcoholic steatohepatitis (NASH) and obesity: group 1 – 37 obese patients with NASH; group 2 – 53 obese patients with simple steatosis; group 3 – 65 obese patients without NAFLD; group 4 (control) – 15 patients with normal weight without NAFLD. Anthropometric parameters, carbohydrate metabolism with the HOMA-IR calculation, and cytokine profile were examined.

Results. An increase in serum IL-6 and TNFα levels in NAFLD children compared to the control group (P ˂ 0.05), a decrease in IL-10 level in NAFLD children (P ˂ 0.05), and an increase in TNFα/IL-10 ratio (P ˂ 0.05) in NASH children compared to obese children without steatosis were demonstrated. In NAFLD children, a progressive increase in HOMA-IR was found compared to the control group and obese children without steatosis (P ˂ 0.05). The serum IL-6, TNFα levels, TNFα/IL-10 ratio, and HOMA-IR were positively correlated with obesity degree, adipose tissue distribution parameters, hepatic steatosis degree, CAP, while IL-10 level was negatively correlated with the hepatic steatosis degree.

Conclusions. In obese NAFLD children, a significant increase in HOMA-IR, IL-6, TNFα is correlated with excessive fat accumulation, adipose tissue distribution parameters, hepatic steatosis degree, and CAP that may be useful for early diagnosis of NAFLD in children. A significant increase in the TNFα/IL-10 ratio in NASH children allows to consider this indicator as a probable marker for diagnosis of different NAFLD forms in pediatric clinical practice.

Author Biographies

Yu. M. Stepanov, SI “Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine”, Dnipro

MD, PhD, DSc, Professor, Director of the SI “Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine”, Dnipro, Corresponding member of the National Academy of Medical Sciences of Ukraine, Chief Specialist of the National Academy of Medical Sciences of Ukraine in Gastroenterology and Dietetics, Honored Doctor of Ukraine

N. Yu. Zavhorodnia, SI “Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine”, Dnipro

MD, PhD, Head of the Department of Pediatric Gastroenterology

O. M. Tatarchuk, SI “Institute Gastroenterology of the National Academy of Medical Sciences of Ukraine”, Dnipro

PhD, Senior Researcher of the Department of Scientific Researches

I. A. Klenina, SI “Institute Gastroenterology of the National Academy of Medical Sciences of Ukraine”, Dnipro

PhD, Head of the Research Department

I. S. Konenko, SI “Institute Gastroenterology of the National Academy of Medical Sciences of Ukraine”, Dnipro

MD, PhD, Head of the Minimally Invasive Endoscopic Interventions and Instrumental Diagnostics Department

O. P. Petishko, SI “Institute Gastroenterology of the National Academy of Medical Sciences of Ukraine”, Dnipro

Researcher of the Department of Scientific-Organizational, Methodological Work and Information Technologies

References

Wells J. (2019). The diabesity epidemic in the light of evolution: insights from the capacity-load model. Diabetologia, 62(10), 1740-1750. https://doi.org/10.1007/s00125-019-4944-8

Nobili, V., Mantovani, A., Cianfarani, S., Alisi, A., Mosca, A., Sartorelli, M. R., Maffeis, C., Loomba, R., Byrne, C. D., & Targher, G. (2019). Prevalence of prediabetes and diabetes in children and adolescents with biopsy-proven non-alcoholic fatty liver disease. Journal of hepatology, 71(4), 802-810. https://doi.org/10.1016/j.jhep.2019.06.023

Schwimmer, J. B., Deutsch, R., Kahen, T., Lavine, J. E., Stanley, C., & Behling, C. (2006). Prevalence of fatty liver in children and adolescents. Pediatrics, 118(4), 1388-1393. https://doi.org/10.1542/peds.2006-1212

Burrows, R., Correa-Burrows, P., Bunout, D., Barrera, G., Rogan, J., Kim, E., Blanco, E., & Gahagan, S. (2021). Obesity and impairment of pancreatic β-cell function in early adulthood, independent of obesity age of onset: The Santiago Longitudinal Study. Diabetes/metabolism research and reviews, 37(2), e3371. https://doi.org/10.1002/dmrr.3371

Stefan, N., Häring, H. U., & Cusi, K. (2019). Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. The lancet. Diabetes & endocrinology, 7(4), 313-324. https://doi.org/10.1016/S2213-8587(18)30154-2

Tanase, D. M., Gosav, E. M., Costea, C. F., Ciocoiu, M., Lacatusu, C. M., Maranduca, M. A., Ouatu, A., & Floria, M. (2020). The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD). Journal of diabetes research, 2020, 3920196. https://doi.org/10.1155/2020/3920196

Scapaticci, S., D'Adamo, E., Mohn, A., Chiarelli, F., & Giannini, C. (2021). Non-Alcoholic Fatty Liver Disease in Obese Youth With Insulin Resistance and Type 2 Diabetes. Frontiers in endocrinology, 12, 639548. https://doi.org/10.3389/fendo.2021.639548

Dongiovanni, P., Stender, S., Pietrelli, A., Mancina, R. M., Cespiati, A., Petta, S., Pelusi, S., Pingitore, P., Badiali, S., Maggioni, M., Mannisto, V., Grimaudo, S., Pipitone, R. M., Pihlajamaki, J., Craxi, A., Taube, M., Carlsson, L., Fargion, S., Romeo, S., Kozlitina, J., … Valenti, L. (2018). Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. Journal of internal medicine, 283(4), 356-370. https://doi.org/10.1111/joim.12719

Liu, Z., Zhang, Y., Graham, S., Wang, X., Cai, D., Huang, M., Pique-Regi, R., Dong, X. C., Chen, Y. E., Willer, C., & Liu, W. (2020). Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. Journal of hepatology, 73(2), 263-276. https://doi.org/10.1016/j.jhep.2020.03.006

Morandi, A., Di Sessa, A., Zusi, C., Umano, G. R., El Mazloum, D., Fornari, E., Miraglia Del Giudice, E., Targher, G., & Maffeis, C. (2020). Nonalcoholic Fatty Liver Disease and Estimated Insulin Resistance in Obese Youth: A Mendelian Randomization Analysis. The Journal of clinical endocrinology and metabolism, 105(11), dgaa583. https://doi.org/10.1210/clinem/dgaa583

Tricò, D., Galderisi, A., Mari, A., Polidori, D., Galuppo, B., Pierpont, B., Samuels, S., Santoro, N., & Caprio, S. (2020). Intrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: A cross-sectional and longitudinal study from the Yale Pediatric NAFLD cohort. Diabetes, obesity & metabolism, 22(9), 1628-1638. https://doi.org/10.1111/dom.14076

Knorr, J., Wree, A., Tacke, F., & Feldstein, A. E. (2020). The NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis. Seminars in liver disease, 40(3), 298-306. https://doi.org/10.1055/s-0040-1708540

Vos, M. B., Abrams, S. H., Barlow, S. E., Caprio, S., Daniels, S. R., Kohli, R., Mouzaki, M., Sathya, P., Schwimmer, J. B., Sundaram, S. S., & Xanthakos, S. A. (2017). NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). Journal of pediatric gastroenterology and nutrition, 64(2), 319-334. https://doi.org/10.1097/MPG.0000000000001482

Vajro, P., Lenta, S., Socha, P., Dhawan, A., McKiernan, P., Baumann, U., Durmaz, O., Lacaille, F., McLin, V., & Nobili, V. (2012). Diagnosis of nonalcoholic fatty liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. Journal of pediatric gastroenterology and nutrition, 54(5), 700-713. https://doi.org/10.1097/MPG.0b013e318252a13f

De Lédinghen, V., Vergniol, J., Foucher, J., Merrouche, W., & le Bail, B. (2012). Non-invasive diagnosis of liver steatosis using controlled attenuation parameter (CAP) and transient elastography. Liver international, 32(6), 911-918. https://doi.org/10.1111/j.1478-3231.2012.02820.x

Desai, N. K., Harney, S., Raza, R., Al-Ibraheemi, A., Shillingford, N., Mitchell, P. D., & Jonas, M. M. (2016). Comparison of Controlled Attenuation Parameter and Liver Biopsy to Assess Hepatic Steatosis in Pediatric Patients. The Journal of pediatrics, 173, 160-164.e1. https://doi.org/10.1016/j.jpeds.2016.03.021

Li, D. K., Khan, M. R., Wang, Z., Chongsrisawat, V., Swangsak, P., Teufel-Schäfer, U., Engelmann, G., Goldschmidt, I., Baumann, U., Tokuhara, D., Cho, Y., Rowland, M., Mjelle, A. B., Ramm, G. A., Lewindon, P. J., Witters, P., Cassiman, D., Ciuca, I. M., Prokop, L. D., Haffar, S., … Bazerbachi, F. (2020). Normal liver stiffness and influencing factors in healthy children: An individual participant data meta-analysis. Liver international, 40(11), 2602-2611. https://doi.org/10.1111/liv.14658

Alkhouri, N., Sedki, E., Alisi, A., Lopez, R., Pinzani, M., Feldstein, A. E., & Nobili, V. (2013). Combined paediatric NAFLD fibrosis index and transient elastography to predict clinically significant fibrosis in children with fatty liver disease. Liver international, 33(1), 79-85. https://doi.org/10.1111/liv.12024

World Health Organization. (n.d.). BMI-for-age (5-19 years). WHO http://www.who.int/growthref/who2007_bmi_for_age/en/

Fernández, J. R., Redden, D. T., Pietrobelli, A., & Allison, D. B. (2004). Waist circumference percentiles in nationally representative samples of African-American, European-American, and Mexican-American children and adolescents. The Journal of pediatrics, 145(4), 439-444. https://doi.org/10.1016/j.jpeds.2004.06.044

Gungor, N., Saad, R., Janosky, J., & Arslanian, S. (2004). Validation of surrogate estimates of insulin sensitivity and insulin secretion in children and adolescents. The Journal of pediatrics, 144(1), 47-55. https://doi.org/10.1016/j.jpeds.2003.09.045

Shashaj, B., Luciano, R., Contoli, B., Morino, G. S., Spreghini, M. R., Rustico, C., Sforza, R. W., Dallapiccola, B., & Manco, M. (2016). Reference ranges of HOMA-IR in normal-weight and obese young Caucasians. Acta diabetologica, 53(2), 251-260. https://doi.org/10.1007/s00592-015-0782-4

Abaturov, O., & Nіkulіna, A. (2020). Fenotypy ozhyrinnia u ditei, klinichni proiavy y henetychni asotsiatsii [Phenotypes of obesity in children, clinical manifestations and genetic associations]. Zdorovia dytyny, 15(4), 49-62. [in Ukrainian]. https://doi.org/http://dx.doi.org/10.22141/2224-0551.15.4.2020.208476

El Amrousy, D., & El-Afify, D. (2020). Osteocalcin and osteoprotegerin levels and their relationship with adipokines and proinflammatory cytokines in children with nonalcoholic fatty liver disease. Cytokine, 135, 155215. https://doi.org/10.1016/j.cyto.2020.155215

Prokopowicz, Z., Malecka-Tendera, E., & Matusik, P. (2018). Predictive Value of Adiposity Level, Metabolic Syndrome, and Insulin Resistance for the Risk of Nonalcoholic Fatty Liver Disease Diagnosis in Obese Children. Canadian journal of gastroenterology & hepatology, 2018, 9465784. https://doi.org/10.1155/2018/9465784

Shi, J. Q., Shen, W. X., Wang, X. Z., Huang, K., & Zou, C. C. (2017). Relationship Between Immune Parameters and Non-alcoholic Fatty Liver Disease in Obese Children. Indian pediatrics, 54(10), 825-829. https://doi.org/10.1007/s13312-017-1143-x

Bocsan, I. C., Milaciu, M. V., Pop, R. M., Vesa, S. C., Ciumarnean, L., Matei, D. M., & Buzoianu, A. D. (2017). Cytokines Genotype-Phenotype Correlation in Nonalcoholic Steatohepatitis. Oxidative medicine and cellular longevity, 2017, 4297206. https://doi.org/10.1155/2017/4297206

Wan, X., Zhu, X., Wang, H., Feng, Y., Zhou, W., Liu, P., Shen, W., Zhang, L., Liu, L., Li, T., Diao, D., Yang, F., Zhao, Q., Chen, L., Ren, J., Yan, S., Li, J., Yu, C., & Ju, Z. (2020). PGC1α protects against hepatic steatosis and insulin resistance via enhancing IL10-mediated anti-inflammatory response. FASEB journal, 34(8), 10751-10761. https://doi.org/10.1096/fj.201902476R

Kim, H. I., Yun, S. W., Han, M. J., Jang, S. E., & Kim, D. H. (2020). IL-10 Expression-Inducing Gut Bacteria Alleviate High-Fat Diet-Induced Obesity and Hyperlipidemia in Mice. Journal of microbiology and biotechnology, 30(4), 599-603. https://doi.org/10.4014/jmb.1912.12014

Tutunchi, H., Ostadrahimi, A., Saghafi-Asl, M., Roshanravan, N., Shakeri-Bavil, A., Asghari-Jafarabadi, M., Farrin, N., & Mobasseri, M. (2021). Expression of NF-κB, IL-6, and IL-10 genes, body composition, and hepatic fibrosis in obese patients with NAFLD-Combined effects of oleoylethanolamide supplementation and calorie restriction: A triple-blind randomized controlled clinical trial. Journal of cellular physiology, 236(1), 417-426. https://doi.org/10.1002/jcp.29870

Zhao, K., Ju, H., & Wang, H. (2019). Metabolic characteristics of obese children with fatty liver: A STROBE-compliant article. Medicine, 98(16), e14939. https://doi.org/10.1097/MD.0000000000014939

Wasilewska, N., Bobrus-Chociej, A., Harasim-Symbor, E., Tarasów, E., Wojtkowska, M., Chabowski, A., & Lebensztejn, D. M. (2018). Increased serum concentration of ceramides in obese children with nonalcoholic fatty liver disease. Lipids in health and disease, 17(1), 216. https://doi.org/10.1186/s12944-018-0855-9

Chen, Z., Yu, R., Xiong, Y., Du, F., & Zhu, S. (2017). A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease. Lipids in health and disease, 16(1), 203. https://doi.org/10.1186/s12944-017-0572-9

Yaribeygi, H., Farrokhi, F. R., Butler, A. E., & Sahebkar, A. (2019). Insulin resistance: Review of the underlying molecular mechanisms. Journal of cellular physiology, 234(6), 8152-8161. https://doi.org/10.1002/jcp.27603

Bessone, F., Razori, M. V., & Roma, M. G. (2019). Molecular pathways of nonalcoholic fatty liver disease development and progression. Cellular and molecular life sciences: CMLS, 76(1), 99-128. https://doi.org/10.1007/s00018-018-2947-0

Parrinello, C. M., Rudolph, B. J., Lazo, M., Gallo, L. C., Thyagarajan, B., Cotler, S. J., Qi, Q., Seeherunvong, T., Vidot, D. C., Strickler, H. D., Kaplan, R. C., & Isasi, C. R. (2019). Associations of Insulin Resistance and Glycemia With Liver Enzymes in Hispanic/Latino Youths: Results From the Hispanic Community Children's Health Study/Study of Latino Youth (SOL Youth). Journal of clinical gastroenterology, 53(2), e46-e53. https://doi.org/10.1097/MCG.0000000000000946

Park, B. H., Yoon, J. M., Kim, J. H., Moon, J. H., Lee, Y. H., Jang, S. M., & Kim, Y. J. (2017). Pathologic Impact of Insulin Resistance and Sensitivity on the Severity of Liver Histopathology in Pediatric Non-Alcoholic Steatohepatitis. Yonsei medical journal, 58(4), 756-762. https://doi.org/10.3349/ymj.2017.58.4.756

Fu, J. F., Shi, H. B., Liu, L. R., Jiang, P., Liang, L., Wang, C. L., & Liu, X. Y. (2011). Non-alcoholic fatty liver disease: An early mediator predicting metabolic syndrome in obese children? World journal of gastroenterology, 17(6), 735-742. https://doi.org/10.3748/wjg.v17.i6.735

Published

2022-10-22

How to Cite

1.
Stepanov YM, Zavhorodnia NY, Tatarchuk OM, Klenina IA, Konenko IS, Petishko OP. Pathogenetic role of inflammation and insulin resistance in non-alcoholic fatty liver disease in obese children. Zaporozhye Medical Journal [Internet]. 2022Oct.22 [cited 2024Nov.25];24(5):538-46. Available from: http://zmj.zsmu.edu.ua/article/view/257288

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Original research