Intralobular zonal heterogeneity and hepatic indicator dilution curves

Conventional interpretation of hepatic indicator dilution curves rests on the assumption, among others, that every hepatocyte operates with the same rate constants. When this assumption is false, owing to intralobular zonal variation in surface-to-volume ratios and/or to zonal differences in permeability, the apparent rate constants recoverable from outflow transients are wrong estimates of average liver performance. We develop the theoretical basis for this conclusion and illustrate by example how it can confuse the interpretation of experimental data. The analysis proceeds from vascular and extracellular reference curves recorded from perfused rat livers and from a simple model of intralobular architecture in which highly arborized periportal sinusoids have a larger surface-to-volume ratio than the less-branched vasculature around the central vein. The experimental data and the model, applied to a wide range of hypothetical solutes, are used to compare the true average rate constants for uptake, efflux, and intracellular removal with the apparent values recoverable from outflow curves. When zonal differences in surface-to-volume ratios are the sole source of heterogeneity, the wrong estimates prove of little practical importance. By contrast, assigning larger regional variations in permeability leads to substantial errors. The confusion arising from such errors may be qualitative as well as quantitative. The presence of heterogeneity and thus the risk of interpretive error appears unrecognizable from outflow curves.