Alternative Etiologies of Liver Disease in Children With Suspected NAFLD

Toshifumi Yodoshi, Sarah Orkin, Ana Catalina Arce-Clachar, Kristin Bramlage, Stavra A Xanthakos, Pamela L Valentino, Marialena Mouzaki, Toshifumi Yodoshi, Sarah Orkin, Ana Catalina Arce-Clachar, Kristin Bramlage, Stavra A Xanthakos, Pamela L Valentino, Marialena Mouzaki

Abstract

Objectives: To determine the prevalence of alternative causes of liver disease in a cohort of youth with overweight and obesity undergoing evaluation for suspected nonalcoholic fatty liver disease (NAFLD).

Methods: Multicenter, retrospective cohort study of patients aged ≤18 years with overweight and obesity and evidence of elevated serum aminotransferases and/or hepatic steatosis on imaging, referred for suspected NAFLD to Cincinnati Children's Hospital Medical Center (2009-2017) or Yale New Haven Children's Hospital (2012-2017). Testing was performed to exclude the following: autoimmune hepatitis (AIH), Wilson disease, viral hepatitis (B and C), thyroid dysfunction, celiac disease, α-1 antitrypsin deficiency, and hemochromatosis.

Results: A total of 900 children with overweight and obesity (63% boys, 26% Hispanic ethnicity) were referred, with a median age of 13 years (range: 2-18). Most had severe obesity (n = 666; 76%) with a median BMI z score of 2.45 (interquartile range [IQR]: 2.2-2.7). Median alanine aminotransferase level at presentation was 64 U/L (IQR: 42-95). A clinically indicated liver biopsy was performed in 358 children (40%) at a median of 6 months (IQR: 1-14) post initial visit; of those, 46% had confirmed nonalcoholic steatohepatitis. Positive autoantibodies were observed in 13% of the cohort, but none met criteria for AIH. Only 19 (2%) were found to have other causes of liver disease, with no cases of viral hepatitis or Wilson disease detected.

Conclusions: In a large, multicenter cohort, the vast majority of children with overweight and obesity with presumed or confirmed NAFLD tested negative for other causes of liver disease. In contrast to a previous pediatric report, no patient was diagnosed with AIH.

Conflict of interest statement

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Copyright © 2021 by the American Academy of Pediatrics.

Figures

FIGURE 1
FIGURE 1
The results of the exclusionary testing performed for patients referred for suspected NAFLD. CCHMC, Cincinnati Children’s Hospital Medical Center; HBsAb, Hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HCV Ab, hepatitis C virus antibody; HLH, hemophagocytic lymphohistiocytosis.

References

    1. Vos MB, Abrams SH, Barlow SE, et al. . 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). J Pediatr Gastroenterol Nutr. 2017;64(2):319–334
    1. Doycheva I, Issa D, Watt KD, Lopez R, Rifai G, Alkhouri N. Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in young adults in the United States. J Clin Gastroenterol. 2018;52(4):339–346
    1. Anderson EL, Howe LD, Jones HE, Higgins JPT, Lawlor DA, Fraser A. The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis. PLoS One. 2015;10(10):e0140908.
    1. Mouzaki M, Trout AT, Arce-Clachar AC, et al. . Assessment of nonalcoholic fatty liver disease progression in children using magnetic resonance imaging. J Pediatr. 2018;201:86–92
    1. Goyal NP, Schwimmer JB. The progression and natural history of pediatric nonalcoholic fatty liver disease. Clin Liver Dis. 2016;20(2):325–338
    1. Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut. 2009;58(11):1538–1544
    1. Molleston JP, White F, Teckman J, Fitzgerald JF. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol. 2002;97(9):2460–2462
    1. A-Kader HH, Henderson J, Vanhoesen K, Ghishan F, Bhattacharyya A. Nonalcoholic fatty liver disease in children: a single center experience. Clin Gastroenterol Hepatol. 2008;6(7):799–802
    1. Mouzaki M, Yodoshi T, Arce-Clachar AC, et al. . Psychotropic medications are associated with increased liver disease severity in pediatric nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2019;69(3):339–343
    1. Burgert TS, Taksali SE, Dziura J, et al. . Alanine aminotransferase levels and fatty liver in childhood obesity: associations with insulin resistance, adiponectin, and visceral fat. J Clin Endocrinol Metab. 2006;91(11):4287–4294
    1. Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE. Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. J Pediatr. 2003;143(4):500–505
    1. Carter-Kent C, Yerian LM, Brunt EM, et al. . Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology. 2009;50(4):1113–1120
    1. Yodoshi T, Arce-Clachar AC, Sun Q, et al. . Glomerular hyperfiltration is associated with liver disease severity in children with nonalcoholic fatty liver disease. J Pediatr. 2020;222:127–133
    1. Schwimmer JB, Zepeda A, Newton KP, et al. .; Nonalcoholic Steatohepatitis Clinical Research Network . Longitudinal assessment of high blood pressure in children with nonalcoholic fatty liver disease. PLoS One. 2014;9(11):e112569.
    1. Cali AMG, Zern TL, Taksali SE, et al. . Intrahepatic fat accumulation and alterations in lipoprotein composition in obese adolescents: a perfect proatherogenic state. Diabetes Care. 2007;30(12):3093–3098
    1. Corey KE, Vuppalanchi R, Vos M, et al. .; Nonalcoholic Steatohepatitis Clinical Research Network . Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr. 2015;60(3):360–367
    1. Manco M, Bedogni G, Monti L, Morino G, Natali G, Nobili V. Intima-media thickness and liver histology in obese children and adolescents with non-alcoholic fatty liver disease. Atherosclerosis. 2010;209(2):463–468
    1. Sundaram SS, Sokol RJ, Capocelli KE, et al. . Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in pediatric nonalcoholic fatty liver disease. J Pediatr. 2014;164(4):699–706.e1
    1. Schwimmer JB, Newton KP, Awai HI, et al. . Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2013;38(10):1267–1277
    1. Mayer-Davis EJ, Kahkoska AR, Jefferies C, et al. . ISPAD Clinical Practice Consensus Guidelines 2018: definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes. 2018;19(suppl 27):7–19
    1. Trout AT, Anupindi SA, Gee MS, et al. . Normal liver stiffness measured with MR elastography in children. Radiology. 2020;297(3):663–669
    1. Schwimmer JB, Dunn W, Norman GJ, et al. . SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. Gastroenterology. 2010;138(4):1357–1364, 1364.e1–1364.e2
    1. Krebs NF, Himes JH, Jacobson D, Nicklas TA, Guilday P, Styne D. Assessment of child and adolescent overweight and obesity. Pediatrics. 2007;120(suppl 4):S193–S228
    1. Yodoshi T, Orkin S, Arce-Clachar AC, et al. . Identifying predictors of response to vitamin E for the treatment of pediatric nonalcoholic steatohepatitis. JPEN J Parenter Enteral Nutr. 2020;44(7):1301–1307
    1. Mack CL, Adams D, Assis DN, et al. . Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American association for the study of liver diseases. Hepatology. 2020;72(2):671–722
    1. Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD) . Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089–2111
    1. Garber JR, Cobin RH, Gharib H, et al. .; American Association Of Clinical Endocrinologists and American Thyroid Association Taskforce On Hypothyroidism In Adults . Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. [published corrections appear in Thyroid. 2013;23(2):251 and Thyroid. 2013;23(1):129]. Thyroid. 2012;22(12):1200–1235
    1. Bahn Chair RS, Burch HB, Cooper DS, et al. .; American Thyroid Association; American Association of Clinical Endocrinologists . Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. [published corrections appears in Thyroid. 2011;21(10):1169 and Thyroid. 2012;22(11):1195]. Thyroid. 2011;21(6):593–646
    1. Hill ID, Fasano A, Guandalini S, et al. . NASPGHAN clinical report on the diagnosis and treatment of gluten-related disorders. J Pediatr Gastroenterol Nutr. 2016;63(1):156–165
    1. Regev A, Guaqueta C, Molina EG, et al. . Does the heterozygous state of alpha-1 antitrypsin deficiency have a role in chronic liver diseases? Interim results of a large case-control study. J Pediatr Gastroenterol Nutr. 2006;43(suppl 1):S30–S35
    1. Feldman A, Sokol RJ. Alpha-1-antitrypsin deficiency: an important cause of pediatric liver disease. Lung Health Prof Mag. 2013;4(2):8–11
    1. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS; American Association for the Study of Liver Diseases . Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(1):328–343
    1. Kleiner DE, Brunt EM, Van Natta M, et al. .; Nonalcoholic Steatohepatitis Clinical Research Network . Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–1321
    1. Brown GT, Kleiner DE. Histopathology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Metabolism. 2016;65(8):1080–1086
    1. Mieli-Vergani G, Vergani D, Baumann U, et al. . Diagnosis and management of pediatric autoimmune liver disease: ESPGHAN hepatology committee position statement. J Pediatr Gastroenterol Nutr. 2018;66(2):345–360
    1. Huster D. Wilson disease. Best Pract Res Clin Gastroenterol. 2010;24(5):531–539
    1. Stättermayer AF, Traussnigg S, Dienes HP, et al. . Hepatic steatosis in Wilson disease–Role of copper and PNPLA3 mutations. J Hepatol. 2015;63(1):156–163
    1. Fernando M, van Mourik I, Wassmer E, Kelly D. Wilson disease in children and adolescents. Arch Dis Child. 2020;105(5):499–505
    1. Yodoshi T, Orkin S, Arce-Clachar AC, et al. . Vitamin D deficiency: prevalence and association with liver disease severity in pediatric nonalcoholic fatty liver disease. Eur J Clin Nutr. 2020;74(3):427–435
    1. Gujral N, Freeman HJ, Thomson AB. Celiac disease: prevalence, diagnosis, pathogenesis and treatment. World J Gastroenterol. 2012;18(42):6036–6059
    1. Reilly NR, Lebwohl B, Hultcrantz R, Green PHR, Ludvigsson JF. Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease. J Hepatol. 2015;62(6):1405–1411
    1. Gatselis NK, Zachou K, Norman GL, et al. . IgA antibodies against deamidated gliadin peptides in patients with chronic liver diseases. Clin Chim Acta. 2012;413(19–20):1683–1688
    1. Lo Iacono O, Petta S, Venezia G, et al. . Anti-tissue transglutaminase antibodies in patients with abnormal liver tests: is it always coeliac disease? Am J Gastroenterol. 2005;100(11):2472–2477
    1. Rahimi AR, Daryani NE, Ghofrani H, et al. . The prevalence of celiac disease among patients with non-alcoholic fatty liver disease in Iran. Turk J Gastroenterol. 2011;22(3):300–304
    1. Rudolph B, Rivas Y, Kulak S, et al. . Yield of diagnostic tests in obese children with an elevated alanine aminotransferase. Acta Paediatr. 2015;104(12):e557–e563
    1. Niranjan U, Wright NP. Should we treat subclinical hypothyroidism in obese children? BMJ. 2016;352:i941.
    1. Reinehr T. Thyroid function in the nutritionally obese child and adolescent. Curr Opin Pediatr. 2011;23(4):415–420
    1. van Hulsteijn LT, Pasquali R, Casanueva F, et al. . Prevalence of endocrine disorders in obese patients: systematic review and meta-analysis. Eur J Endocrinol. 2020;182(1):11–21
    1. Lonardo A, Ballestri S, Mantovani A, Nascimbeni F, Lugari S, Targher G. Pathogenesis of hypothyroidism-induced NAFLD: evidence for a distinct disease entity? Dig Liver Dis. 2019;51(4):462–470
    1. Pacifico L, Bonci E, Ferraro F, Andreoli G, Bascetta S, Chiesa C. Hepatic steatosis and thyroid function tests in overweight and obese children. Int J Endocrinol. 2013;2013:381014.
    1. Kaltenbach TEM, Graeter T, Oeztuerk S, et al. . Thyroid dysfunction and hepatic steatosis in overweight children and adolescents. Pediatr Obes. 2017;12(1):67–74
    1. Liu L, Yu Y, Zhao M, et al. . Benefits of levothyroxine replacement therapy on nonalcoholic fatty liver disease in subclinical hypothyroidism patients. Int J Endocrinol. 2017;2017:5753039.
    1. Bruinstroop E, Dalan R, Cao Y, et al. . Low-dose levothyroxine reduces intrahepatic lipid content in patients with type 2 diabetes mellitus and NAFLD. J Clin Endocrinol Metab. 2018;103(7):2698–2706
    1. Harrison S, Moussa S, Bashir M, et al. . MGL-3196, a selective thyroid hormone receptor-beta agonist, significantly decreases hepatic fat in NASH patients at 12 weeks, the primary endpoint in a 36 week serial liver biopsy study. J Hepatol. 2018;68(suppl 1):S38
    1. Strange C, Moseley MA, Jones Y, Schwarz L, Xie L, Brantly ML. Genetic testing of minors for alpha1-antitrypsin deficiency. Arch Pediatr Adolesc Med. 2006;160(5):531–534
    1. Strnad P, Buch S, Hamesch K, et al. . Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis. Gut. 2019;68(6):1099–1107
    1. Strnad P, McElvaney NG, Lomas DA. Alpha1-antitrypsin deficiency. N Engl J Med. 2020;382(15):1443–1455
    1. El-Rayah EGA, Twomey PJ, Wallace EM, McCormick PA. Both α-1-antitrypsin Z phenotypes and low caeruloplasmin levels are over-represented in alcohol and nonalcoholic fatty liver disease cirrhotic patients undergoing liver transplant in Ireland. Eur J Gastroenterol Hepatol. 2018;30(4):364–367
    1. Newton KP, Hou J, Crimmins NA, et al. .; Nonalcoholic Steatohepatitis Clinical Research Network . Prevalence of prediabetes and type 2 diabetes in children with nonalcoholic fatty liver disease. JAMA Pediatr. 2016;170(10):e161971.
    1. Molleston JP, Schwimmer JB, Yates KP, et al. .; NASH Clinical Research Network . Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J Pediatr. 2014;164(4):707–713.e3

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere