Mandel H, Hartman C, Berkowitz D, Elpeleg O N, Manov I, Iancu T C
Metabolic Disease Unit, Rambam Medical Center, Israel.
Hepatology. 2001 Oct;34(4 Pt 1):776-84. doi: 10.1053/jhep.2001.27664.
Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood. In some patients, the levels of mitochondrial DNA are markedly reduced, a condition referred to as mtDNA depletion syndrome (MDS). We report here on the ultrastructural changes in the livers of 10 infants with the hepatic form of this syndrome. All patients displayed progressive liver failure, neurological abnormalities, hypoglycemia, and lactic acidosis that warranted investigation of respiratory chain disorder in liver tissue, specifically expressing the disease. Decreased activity of respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, IV) was shown in 5 patients. Mitochondrial DNA depletion was confirmed by Southern blot analysis in the livers of 6 patients. We found hepatocytes filled with mitochondria having aspects of "oncocytic transformation," associated with numerous changes in shape, size, cristae, and matrix. The changes were virtually identical in all specimens. In many hepatocytes, microvesicular steatosis was the salient feature. Additional findings included cholestasis and focal cytoplasmic biliary necrosis (CBN), as well as cytosiderosis in hepatocytes and sinusoidal cells. In some hepatocytes the damage appeared extreme, but fibrosis was identified only in the few patients who died beyond 6 months of age. Although individual ultrastructural findings are not specific, when taken together, they show a diagnostic pattern highly suggestive of a respiratory chain disorder. In the appropriate clinical context, these findings can direct the clinician towards the diagnosis of hepatic MDS.
线粒体呼吸链疾病是幼儿期肝衰竭的既定病因。在一些患者中，线粒体DNA水平显著降低，这种情况被称为线粒体DNA耗竭综合征（MDS）。我们在此报告10例患有该综合征肝脏型的婴儿肝脏的超微结构变化。所有患者均表现出进行性肝衰竭、神经异常、低血糖和乳酸酸中毒，这使得有必要对肝脏组织中的呼吸链疾病进行调查，特别是明确表达该疾病。5例患者显示含有线粒体DNA编码亚基的呼吸链复合物（复合物I、III、IV）活性降低。通过Southern印迹分析在6例患者的肝脏中证实了线粒体DNA耗竭。我们发现肝细胞充满了具有“嗜酸性细胞转化”特征的线粒体，伴有形状、大小、嵴和基质的众多变化。所有标本中的变化几乎相同。在许多肝细胞中，微泡性脂肪变性是突出特征。其他发现包括胆汁淤积和局灶性细胞质胆汁坏死（CBN），以及肝细胞和窦状细胞中的含铁血黄素沉着。在一些肝细胞中，损伤似乎很严重，但仅在6个月龄后死亡的少数患者中发现了纤维化。尽管单个超微结构发现并不具有特异性，但综合起来，它们显示出一种高度提示呼吸链疾病的诊断模式。在适当的临床背景下，这些发现可指导临床医生诊断肝脏MDS。
