Abstract
Adapted fixation methods for electron microscopy allowed us to study liver cell fine structure in 217 biopsies of intact human livers over the course of 10 years. The following novel observations and concepts arose: single fat droplets in parenchymal cells can grow to a volume four times larger than the original cell, thereby extremely marginalizing the cytoplasm with all organelles. Necrosis of single parenchymal cells, still containing one huge fat droplet, suggests death by fat in a process of single-cell steatonecrosis. In a later stage of single-cell steatonecrosis, neutrophils and erythrocytes surround the single fat droplet, forming an inflammatory fat follicle indicating the apparent onset of inflammation. Also, fat droplets frequently incorporate masses of filamentous fragments and other material, most probably representing Mallory substance. No other structure or material was found that could possibly represent Mallory bodies. We regularly observe the extrusion of huge fat droplets, traversing the peripheral cytoplasm of parenchymal cells, the Disse space and the endothelium. These fat droplets fill the sinusoid as a sinusoidal lipid embolus. In conclusion, adapted methods of fixation applied to human liver tissue revealed that single, huge fat droplets cause necrosis and inflammation in single parenchymal cells. Fat droplets also collect Mallory substance and give rise to sinusoidal fat emboli. Therefore, degreasing of the liver seems to be an essential therapeutic first step in the self-repairing of non-alcoholic fatty liver disease. This might directly reduce single-cell steatotic necrosis and inflammation as elements in non-alcoholic steatohepatitis progression.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a worldwide health problem (Friedman et al 2018), possibly the most important liver disease in the developed world in the twenty-first century (Brenner 2009)
We studied a total of 217 biopsies of intact human liver, 16 patients were diagnosed with non-alcoholic steatohepatitis (NASH), 77 livers were steatotic and 84 were diagnosed with fibrosis
Still with one huge fat droplet inside, are testimony of a process that can be denominated as single-cell steatonecrosis (Fig. 2b)
Summary
Non-alcoholic fatty liver disease (NAFLD) is a worldwide health problem (Friedman et al 2018), possibly the most important liver disease in the developed world in the twenty-first century (Brenner 2009). The application of electron microscopy (EM) contributed to the knowledge of the fine structure and function of the parenchymal cell in normal and diseased liver (Novikoff and Essner 1960; Schaffner et al 1963a, b; Schaffner and Poper 1963). In both LM and EM studies, immersion fixation was routinely applied. This method preserves the parenchymal cells, but sinusoids collapse, and the fine structure of sinusoidal cells is almost completely lost. The early EM studies had difficulties in the distinction between endothelial and Kupffer cells, but concurrently described the space of Disse, the endothelial lining without a basal lamina and the capillarization of sinusoids in steatosis (Ito and Nemoto 1952; Schaffner et al 1963a; Schaffner and Poper 1963)
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