Ultrastructural sequences during liver iron overload in genetic hemochromatosis
Ultrastructural sequences during liver iron overload in genetic hemochromatosis
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DOI：
10.1016/s0168-8278(97)80079-7
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发表时间：
1997-10-01
影响因子：
25.7
通讯作者：
Brissot, P
中科院分区：
文献类型：
--
作者：
Iancu, TC;Deugnier, Y;Brissot, P
背景/目的：铁在遗传性血色素沉着症中导致肝细胞损伤和肝硬化的途径尚不清楚。本研究的目的是描述该疾病不同阶段患者肝活检的超微结构变化，并将其与临床、组织病理学和生化数据联系起来。方法：对20例遗传性血色素沉着症患者的肝脏活检进行透射电镜检查。使用未染色的薄（60 nm）切片有助于识别和定位各种肝细胞中的电子不透明化合物铁蛋白和含铁血黄素。染色薄切片允许评估伴随的亚细胞损伤和胶原沉积。超微结构观察结果与组织病理学和生化数据相吻合。结果：所有患者均有肝铁超载，分为轻度、中度和重度。在轻度超载阶段（肝铁浓度HIC 93.5+/-23.3 μ mol/g，肝铁指数HII 2.3+/-0.7），门静脉周围肝细胞（腺泡区1）可见胞质铁蛋白和少见的环管溶酶体（铁色素体），没有细胞器损伤的证据，也没有窦状细胞铁色素沉着。在中度超载（HII为190.8+/-41.5 mu mol/g， HII为4.3+/-1.9）时，所有腺泡区肝细胞中均存在铁蛋白，且管周铁苷体丰富，尤其是在腺泡区1。单个肝细胞出现细胞器损伤，偶见窦细胞出现铁质沉着。在严重超载（HIC 308+/-49.0 mu mol/g和HII 7.5+/-1.7）时，所有腺泡区肝细胞充满了大的含含含铁血黄素的脂质体，线粒体、光滑和粗糙的内质网和细胞核发生了明显的变化。在这一阶段主要观察到明显的窦状细胞铁沉着和胶原沉积。结论：电镜显示，在“代偿性”遗传性血色素沉着病的长期潜伏阶段，肝细胞除了铁超载外，仅表现出极小的亚细胞变化。以广泛的亚细胞病理和局灶性坏死为特征的“失代偿性”负荷，发生在以下情况：1)肝细胞的铁苷沉着是全身性的（即超出肝细胞内铁苷体的管周极化和腺泡内的1区）；2)有证据表明窦细胞有大量的铁沉着。这些发现支持了肝铁浓度临界水平的概念，超过这个水平细胞器损伤明显，肝细胞损伤可能变得不可逆。
Background/Aims: The pathway through which iron contributes to liver cell damage and cirrhosis in genetic hemochromatosis is not clear. The objective of the present study was to describe the ultrastructural changes in liver biopsies of patients in various stages of this condition and to correlate these with clinical, histopathological and biochemical data.Methods: Liver biopsies from 20 patients with genetic hemochromatosis were examined by transmission electron microscopy. The use of unstained thin (60 nm) sections facilitated the identification and localization of the electron-opaque compounds ferritin and hemosiderin in various liver cells. Stained thin sections permitted evaluation of the concomitant subcellular damage and collagen deposition. The ultrastructural observations were corroborated with the histopathological findings and biochemical data.Results: All patients had liver iron overload, which was classified as mild, moderate or severe. In the stage of mild overload (hepatic iron concentration HIC 93.5+/-23.3 mu mol/g and hepatic iron index HII 2.3+/-0.7), cytosolic ferritin and scarce pericanalicular lysosomes (siderosomes) were seen in periportal hepatocytes (acinar zone 1), without evidence of organelle damage, and in the absence of sinusoidal cell siderosis. In moderate overload (HIC 190.8+/-41.5 mu mol/g and HII 4.3+/-1.9), ferritin was identified in hepatocytes of all acinar zones, and the pericanalicular siderosomes were abundant, especially in acinar zone 1. Single hepatocytes showed organelle damage and occasional sinusoidal cells showed siderosis. In severe overload (HIC 308+/-49.0 mu mol/g and HII 7.5+/-1.7), hepatocytes of all acinar zones were filled with large, hemosiderin-containing siderosomes, and changes in mitochondria, smooth and rough endoplasmic reticulum and nuclei were conspicuous. Marked sinusoidal cell siderosis and collagen deposition were observed predominantly in this stage.Conclusions: Electron microscopy has shown that during the long, latent stage of ''compensated'' genetic hemochromatosis, hepatocytes display only minimal subcellular changes, other than iron overload. ''Decompensated'' overload, characterized by extensive subcellular pathology and focal necrosis, is reached when 1) the hepatocytic siderosis is generalized (i.e. beyond pericanalicular polarization of siderosomes in hepatocytes, and beyond zone 1 in the acinus); and 2) there is evidence of massive siderosis of sinusoidal cells. These findings support the concept of a critical level of hepatic iron concentration beyond which organelle damage is conspicuous and liver cell injury may become irreversible.