To investigate the parenchymal units in the liver of the rat three-dimensionally, 15 micrometer cryosections were used for the demonstration of glucose-6-phosphatase (G6Pase) activity to visualize the borders of the individual units. Together with the supplying and draining vessels, they were traced through a sequence of 146 sections and reconstructed. A cone-shaped secondary unit with a height of 2.1 mm and a volume of 3.3 mm3 was reconstructed. It was "covered" by a continuous vascular surface, consisting of portal tracts and vascular septa, connecting the portal venular branches. The secondary unit was subdivided by portal tracts and vascular septa, and by branches of a draining central venular tree into 14 primary units. Most of them were tri- to heptahedral in shape. The height varied between 330 and 840 micrometer, and the volume varied between 0.094 and 0.621 mm3. The branches of the portal venular tree, with diameters from 28 +/- 5 micrometer to 61 +/- 14 micrometer, were oriented preferentially along the vertical axis of the units. Most of the primary units were drained by single branches of the central venular tree, located in the center and oriented along the vertical axis of the units. Vessel diameters ranged from 62 +/- 14 micrometer to 216 +/- 9 micrometer. The average length of the sinusoids was 355 +/- 3 micrometer. From the results of this reconstruction study, it was concluded that the concept of the liver acinus cannot be applied to the liver of the rat.

The morphological homogeneity of the liver parenchyma has represented a major obstacle in finding an acceptable definition of the structural/functional units of the liver. Concepts such as the "lobule," the "portal unit" and the "acinus" remain debatable. This study investigates the modular microarchitecture on the basis of the lobular concept. Using alkaline phosphatase activity as a histochemical marker, modules could be recognized clearly. In autopsy specimens of human liver, modules were traced through sequential cryosections, and a "secondary" module having a height of 1.9 mm, a surface of 14.7 mm 2 , and a volume of 5.1 mm 3 was reconstructed three-dimensionally. It was subdivided into 14 "primary" modules by portal tracts and vascular septa and by a common draining central venular tree. Primary modules were polyhedral, with seven to nine facets, having heights from 0.3 to 0.9 mm, surface areas from 1.7 to 5.0 mm 2 , and volumes from 0.1 to 0.9 mm 3 . Such variation in shape and size is considered an important part of the modular organization of the human liver. In conclusion, the findings on the three-dimensionality and microcirculation of liver modules support and extend the lobular concept and, at the same time, make apparent the shortcomings of the concepts of acinar and portal units. The results of this study should permit a better interpretation of histological sections of normal and pathological liver and provide a basis for understanding the metabolic heterogeneity of liver cells and their functional integration into parenchymal units. (HEPATOLOGY 2005;42:317-325.)

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To investigate intercellular compartmentation of liver metabolism, we have recently introduced new procedures for quantitative assessment of metabolic liver cell heterogeneity both along sinusoids of portal and septal origins as well as at the level of the parenchymal unit, and also for three-dimensional imaging of enzyme and metabolite distribution. As part of the evaluation of the role of metabolic liver cell heterogeneity for the regulation of net substrate flux in the glucose-6-phosphatase/glucokinase system, and for the reduction of of these antagonistic enzymes, these techniques were used on livers from male rats. They served to obtain distribution data on glucose-6-phosphatase (the hydrolytic component of the glucose-6-phosphatase/glucokinase system) and its substrate, glucose-6-P, during the postresorptive phase (i.e., a metabolic state of net glucose release). Glucose-6-phosphatase (Vmax) and glucose-6-P were shown to decrease along the sinusoidal axis, and values of both parameters were significantly higher along sinusoids of portal than septal origin. Distribution of in vivo rates of glucose-6-P hydrolysis indicates the importance of metabolite distribution for in vivo regulation of liver cell function, insofar as it considerably increases the degree of heterogeneity among hepatocytes over that maximal rates of glucose formation. Histo- and microchemical data support the concept of a "lobular parenchymal unit" composed of "primary lobules," and justify the conclusion that hepatocyte function, in addition to the hormonal and nutritional states of the animal, not only depends upon cell location along the sinusoidal axis, but also on the origin of sinusoids.