THE HEPATIC CIRCULATION 



1397 



computed as that percentage of the blood volume. 

 And, finally, flow may be estimated from the extent 

 of dilution of a known quantity of some tracer by 

 total outflow during; a measured period of time. 

 Obviously, the validity of all measurements depends 

 upon a number of assumptions which are difficult 

 to verify. Nevertheless, suitable test substances have 

 been found and adequate evidence of reliability has 

 been forthcoming to warrant qualified acceptance 

 of much of the data set out in the literature. 



Clearance and extraction techniques. A variety of dye- 

 stuffs has been employed in the development of con- 

 stant infusion clearance and extraction techniques 

 beginning with bromosulfophthalein (BSP or Brom- 

 sulfalein) in 1945 (49), and more recently employing 

 tetrachlor-tetraiodo-fluorescein (rose bengal) (258), 

 and a tricarbocyanine dye, indocyanine green (238, 

 304). The hepatic removal of these substances can be 

 estimated with reasonable accuracy from the rate of 

 infusion if it may be assumed that a) disappearance 

 from the blood depends solely upon hepatic ex- 

 traction, and b) changes in plasma concentration 

 can be taken into account simply by multiplying 

 the change in concentration (AP) by the plasma vol- 

 ume (PV). Subtracting (rising level) or adding 

 (falling level) this product (in milligrams per min- 

 ute) and the infusion rate yields a value for hepatic 

 removal. The hepatic arteriovenous difference is 

 measured as the difference between concentrations 

 in samples of blood obtained from a peripheral artery 

 and an hepatic vein at the same time. As a rule these 

 values are derived by interpolation at the midpoint 

 between successive samples in order to allow for 

 simultaneous correction for changing levels. A 

 number of additional assumptions must be made in 

 accepting this procedure including c) that a sample 

 of blood from any hepatic vein is representative of 

 the total mixed hepatic venous drainage; and d) that 

 the presence of the catheter does not affect represent- 

 ative sampling. Numerous thoroughgoing investi- 

 gations have elucidated each step and in doing so 

 have contributed importantly to knowledge of hepa- 

 tocellular function. 



All these agents are apparently transferred from 

 blood to bile by fundamentally similar mechanisms. 

 The character of BSP removal has been the most in- 

 tensively studied but the data available on rose bengal 

 and indocyanine green suggest that they move by the 

 same pathways, since indocyanine green interferes 

 with hepatic uptake of BSP (304) and BSP with 

 uptake of rose bengal (177, 212). Considerable evi- 

 dence (45, 59, 75, 177, 212, 305, 306, 312) supports 



the view that BSP is removed from the blood by a 

 dual mechanism that involves a) accumulation or 

 "storage" of the dye within the polygonal cells in a 

 higher concentration than in the plasma, and b) 

 transfer by a limited transport system from plasma to 

 bile. Analysis of the biochemical mechanisms of 

 further subsidiary processes and of the physiological 

 concomitants is far from completion, but it seems not 

 unlikely that both storage and transfer require energy 

 expenditure and depend upon enzymatic catalysis. 

 Uptake into storage apparently proceeds only when 

 the plasma concentration is rising and for a period 

 after stabilization until equilibration is complete. 

 Whether BSP moves into the bile only from the so- 

 called "storage space," directly from the blood to the 

 bile canaliculi, or by both routes remains unsettled. 

 Rose bengal appears to be handled in much the same 

 fashion and may indeed be visualized by fluorescent 

 microscopy as it accumulates in high concentration 

 within the parenchymal cells. Intercellular accumula- 

 tion of indocyanine green has not been proved but 

 seems probable in view of the rapidity with which it 

 disappears from the blood relative to its output in 

 the bile (304). The limit imposed upon removal by 

 the transfer maximum or Tm- results in reduced 

 extraction by the liver as arterial plasma concentra- 

 tions rise and makes it preferable to maintain levels 

 close to 1 or 2 mg per cent in order to assure suffi- 

 ciently large differences between peripheral and 

 hepatic venous concentration for accurate measure- 

 ments. Even at higher levels, however, hepatic 

 removal accounts almost exclusively for the disap- 

 pearance of these substances from the blood. 



Considerable confusion has resulted from failure 

 to use such words as "removal," "extraction," and 

 "recovery" with precision. "Removal" may be 

 defined either as the amount of dye removed from 

 the blood each minute (the usage employed in this 



2 Unfortunately the term Lm has been applied by Mason 

 et al. (208) to maximal hepatic removal of BSP. Maximal 

 transfer is determined by liver mass and the abbreviation, 

 Lm, is, therefore, justified to some extent. Nevertheless, trans- 

 fer is a functional phenomenon that may be affected without 

 change in liver mass by substances competing for the same 

 system, by various inhibitors (such as deoxycholic acid or 

 Benemid in the case of BSP), and by fever or hepatic disorders 

 (74, 306). For this reason use of "Tm" to refer to the "transfer 

 maximum" seems preferable and in keeping with usage in 

 other fields (280). Of even greater importance is the fact that 

 Lm as determined by Mason (208) and others 6285, 295) 

 includes movements of dye into storage as well as transfer 

 from blood to bile. Hence in referring to a more discrete (albeit 

 complex and multifarious) activity Tm appears to be the more 

 suitable term. 



