Steatosis of indeterminate cause in a pediatric group: is it a primary mitochondrial hepatopathy?

Abstract

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. 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.reSUMO CONTEXTO E OBJETIVO: Em crianças, a esteatose hepática pode se relacionar a erros inatos do metabolismo (EIMs) ou à doença hepática gordurosa não-alcoólica (DHGNA). O objetivo deste estudo foi avaliar e caracterizar esteatose de causa indeterminada por meio de análises morfológica e morfométrica em tecido hepático. TIPO DE ESTUDO E LOCAL: Estudo transversal nos Departamentos de Patologia da Faculdade de Ciências Médicas da Universidade Estadual de Campinas (FCM-Unicamp) e Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (FMB-Unesp).MÉTODOS: Foram utilizadas 18 biópsias hepáticas consecutivas obtidas de 16 pacientes com idade variando de 3 meses a 12 anos e 9 meses, inseridas num banco de dados no período do estudo, que foram analisadas por microscopia óptica e eletrônica. Na microscopia eletrônica, foi realizada determinação da densidade mitocondrial e da área superficial média das mitocôndrias nos hepatócitos. Dez pacientes com idade variando de 1 a 14 anos foram usados como grupo controle. RESULTADOS: Foi detectada esteatose "pura", não acompanhada por fibrose ou outra alteração histoló-gica. Foi verificado que, na predominância de esteatose microvesicular, houve aumento significativo da área mitocondrial média. CONCLUSÃO: A esteatose microvesicular pode estar relacionada à hepatopatia mitocondrial primária, principalmente devido à redução na b-oxidação ou parcial estagnação da fosforilação oxidativa. Por essas razões, esta forma de esteatose (que não pode ser chamada de "pura") possivelmente represente uma fase inicial no...

Distinctive Features of Hepatic Steatosis in Children: Is It Primary or Secondary to Inborn Errors of Metabolism?

“…In particular, muscle involvement in type 3a and 11 GSD patients may lead to a gradual increase in AST levels. In our study, consistent with previous reports, 83.0% of patients had higher levels of ALT than AST in the NAFLD/NASH group, and this finding may be a useful diagnostic clue to clinical suspicion [ 2 7 ]. High TG and low HDL levels may also increase the risk of IEM, according to our data.…”

“…Hepatic steatosis, defined as lipid accumulation in the liver parenchyma, is considered an important cause of hepatopathy from infancy to adulthood because it may cause hepatic fibrosis and eventually cirrhosis when uncontrolled [ 1 ]. Children with hepatic steatosis may be asymptomatic or present with elevated transaminase levels or various symptoms related to underlying diseases [ 2 3 ].…”

Periportal steatosis in mice affects distinct parameters of pericentral drug metabolism

“…It is also observed in the context of drug-induced liver injury 30 . According to Silva, microvesicular steatosis may develop due to an impairment of the mitochondrial beta-oxidation of fatty acids, suggesting a mitochondrial disorder 31 potentially affecting metabolic function.…”

Indicators of mitochondrial disease

“…We read with great interest the article published by Silva et al entitled “Steatosis of indeterminate cause in pediatric group: is it a primary mitochondrial hepatopathy?”. 1 In the article, the authors hypothesize that hepatosteatosis with unknown etiology presented by group of pediatric patients may be mitochondrial disease. They attribute their idea to mitochondrial structural abnormalities detected through electron microscopy examination.…”

“… 2 Secondly, mitochondrial structural alterations do not provide strong enough evidence to indicate mitochondrial disease in the absence of other evidence, because many reasons other than mitochondrial disease can cause mitochondrial structural abnormalities. 3 , 4 Thirdly, indicators for mitochondrial disease, such as lactic acid levels in blood, muscle histochemistry or mitochondrial enzyme activity were not evaluated in the article by Silva et al 1 At least mitochondrial deoxyribonucleic acid (mtDNA) alterations should be analyzed, because almost all mitochondrial disease involves mtDNA deletion, mtDNA depletion, mtDNA point mutation or nuclear deoxyribonucleic acid (nDNA) alterations. 5 So, in our opinion, the evidence is not strong enough to hypothesize that this group of patients might have a mild form of primary mitochondrial hepatopathy.…”