Steatosis of indeterminate cause in a pediatric group
is it a primary mitochondrial hepatopathy?
Keywords:
Fatty liver, Mitochondria, liver, Anatomy, Infant, newborn, Metabolism, inborn errorsAbstract
CONTEXT AND OBJECTIVE: In children, hepatic steatosis may be related to inborn errors of metabolism (IEMs) or to non-alcoholic fatty liver disease (NAFLD). The aim of this study was to assess and characterize steatosis of indeterminate cause through morphological and morphometric analysis of liver tissue. DESIGN AND SETTING: Cross-sectional study at the Departments of Pathology of Faculdade de Ciências Médicas, Universidade Estadual de Campinas (FCM-Unicamp) and Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (FMB-Unesp). METHODS: Eighteen consecutive liver biopsies obtained from 16 patients of ages ranging from 3 months to 12 years and nine months that were inserted in a database in the study period were analyzed using optical microscopy and transmission electron microscopy. Through electron microscopy, the mitochondrial density and mean mitochondrial surface area were determined in hepatocytes. Ten patients ranging in age from 1 to 14 years were used as a control group. RESULTS: “Pure” steatosis was detected, unaccompanied by fibrosis or any other histological alteration. Microvesicular steatosis predominated, with a significant increase in mean mitochondrial surface area. CONCLUSION: Microvesicular steatosis may be related to primary mitochondrial hepatopathy, especially due to reduction of b-oxidation or partial stagnation of oxidative phosphorylation. For these reasons, this form of steatosis (which should not be called “pure”) is likely to represent an initial stage in the broad spectrum of NAFLD. We have drawn attention to cases of steatosis in the pediatric group, in which the microvesicular form predominates, since this may be associated with mitochondrial disorders.
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References
Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114(2):147-52.
Zafrani ES. Non-alcoholic fatty liver disease: an emerging pathological spectrum. Virchows Arch. 2004;444(1):3-12.
Nobili V, Marcellini M, Devito R, et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology. 2006;44(2):458-65.
Da Silva GH, Coelho KI, Coelho CA, Escanhoela CA. Mitochondrial alterations in nonalcoholic fatty liver disease. Pediatric case description of three submitted sequential biopsies. J Gastrointest Liver Dis. 2009;18(2):215-9.
Zhou YJ, Li YY, Nie YQ, et al. Prevalence of fatty liver disease and its risk factors in the population of South China. World J Gastroenterol. 2007;13(47):6419-24.
Imhof A, Kratzer W, Boehm B, et al. Prevalence of non-alcoholic fatty liver and characteristics in overweight adolescents in the general population. Eur J Epidemiol. 2007;22(12):889-97.
Sagi R, Reif S, Neuman G, et al. Nonalcoholic fatty liver disease in overweight children and adolescents. Acta Paediatr. 2007;96(8):1209- 13.
Ciba I, Widhalm K. The association between non-alcoholic fatty liver disease and insulin resistance in 20 obese children and adolescents. Acta Paediatr. 2007;96(1):109-12.
Radetti G, Kleon W, Stuefer J, Pittschieler K. Non-alcoholic fatty liver disease in obese children evaluated by magnetic resonance imaging. Acta Paediatr. 2006;95(7):833-7.
Zou CC, Liang L, Hong F, Fu JF, Zhao ZY. Serum adiponectin, resistin levels and non-alcoholic fatty liver disease in obese children. Endocr J. 2005;52(5):519-24.
Louthan MV, Theriot JA, Zimmerman E, Stutts JT, McClain CJ.
Decreased prevalence of nonalcoholic fatty liver disease in black obese children. J Pediatr Gastroenterol Nutr. 2005;41(4):426-9.
Fishbein M, Mogren J, Mogren C, Cox S, Jennings R. Undetected hepatomegaly in obese children by primary care physicians: a pitfall in the diagnosis of pediatric nonalcoholic fatty liver disease. Clin Pediatr (Phila). 2005;44(2):135-41.
Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42(3):641-9.
Marion AW, Baker AJ, Dhawan A. Fatty liver disease in children. Arch Dis Child. 2004;89(7):648-52.
Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr. 2000;30(1):48-53.
Molleston JP, White F, Teckman J, Fitzgerald JF. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol. 2002;97(9):2460-2.
Mandel H, Hartman C, Berkowitz D, et al. The hepatic mitochondrial DNA depletion syndrome: ultrastructural changes in liver biopsies. Hepatology. 2001;34(4 Pt 1):776-84.
Bioulac-Sage P, Parrot-Roulaud F, Mazat JP, et al. Fatal neonatal liver failure and mitochondrial cytopathy (oxidative phosphorylation deficiency): a light and electron microscopic study of the liver. Hepatology. 1993;18(4):839-46.
Ghadially FN. Ultrastuctural pathology of the cell and matrix. 4th ed. Boston: Butterworth-Heinemann; 1997.
Pérez-Carreras M, Del Hoyo P, Martín MA, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003;38(4):999-1007.
Morris AA. Mitochondrial respiratory chain disorders and the liver. Liver. 1999;19(5):357-68.
Hensley K, Kotake Y, Sang H, et al. Dietary choline restriction causes complex I dysfunction and increased H(2)O(2) generation in liver mitochondria. Carcinogenesis. 2000;21(5):983-9.
Pessayre D, Mansouri A, Haouzi D, Fromenty B. Hepatotoxicity due to mitochondrial dysfunction. Cell Biol Toxicol. 1999;15(6):367-73.
Oleszczuk A, Spannbauer M, Tannapfel A, et al. Regenerative capacity differs between micro- and macrovesicular hepatic steatosis. Exp Toxicol Pathol. 2007;59(3-4):205-13.
Reid AE. Nonalcoholic steatohepatitis. Gastroenterology. 2001;121(3):710-23.
Sanyal AJ; American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123(5):1705-25.
Sokol RJ, Treem WR. Mitochondria and childhood liver diseases. J Pediat Gastroenterol Nut. 1999;28(1):4-16.
Natarajan SK, Eapen CE, Pullimood AB, Balasubramanian KA. Oxidative stress in experimental liver microvesicular steatosis: role of mitochondria and peroxisomes. J Gastroenterol Hepatol. 2006;21(8):1240-9.
Fromenty B, Pessayre D. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol Ther. 1995;67(1):101-54.
Sherlock S, Dooley J. Nutritional and metabolic liver diseases. In: Sherlock S, Dooley J eds. Diseases of the liver and biliary system. 11th ed. Oxford: Blackwell Science; 2002. p. 423-52.
Sternlieb I, Berger JE. Optical diffraction studies of crystalline structures in electron micrographs. II. Crystalline inclusions in mitochondria of human hepatocytes. J Cell Biol. 1969;43(3):448-55.
Caldwell SH, Swerdlow RH, Khan EM, et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol. 1999;31(3):430-4.
Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120(5):1183-92.
Le TH, Caldwell SH, Redick JA, et al. The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis. Hepatology. 2004;39(5):1423-9.
Day CP, James OF. Steatohepatitis: a tale of two“hits”? Gastroenterology. 1998;114(4):842-5.
Gentile CL, Pagliassotti MJ. The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem. 2008;19(9):567-76.
