Mechanisms of hepatic bile formation.

It should be evident from this review of recent investigations that we are still very far from a consistent description of bile formation, much less a satisfactory understanding. Nevertheless certain broad conclusions emerge. Four distinct kinds of active solute transport can be identified, and because bile always has nearly the same osmotic pressure as plasma, each of them is a determinant of bile flow. 1. Concentrative transport of water-soluble organic constituents, of which bile acids are quantitatively most important, occurs in the canaliculi accompanied by the passive flow of water and inorganic electrolytes. Owing to micelle formation the osmotic force for this flow is largely attributable to Na+ ions that accompany the bile acids anions. 2. The canalicular flow obligated by the excretion of bile acids is supplemented by the entry of additional fluid, the so-called bile acid-independent canalicular fraction. Because no organic component has been identified to account for this phenomenon, the active transport of one or more inorganic ions is probably responsible. The limited evidence available at present suggests that Na+ ions is the most likely candidate. 3. The extralobular biliary epithelium can modify the flow and composition of bile by the reabsorption of inorganic ions--a process which resembles reabsorption from the gallbladder in the sense that bile in the lumen remains iso-osmotic with plasma while bile acids and the other organic constituents are concentrated. 4. Under the influence of secretin, and to a lesser degree other intestinal hormones, the ducts or ductules can secrete additional fluid in which HCO3- is concentrated with respect to plasma. A fifth component of bile is generated by the canalicular excretion of phospholipid and cholesterol, but these are insoluble in water and are incorporated into micelles, and, therefore exert no osmotic force. The existence of these processes is inferred from studies of many different species, and it should be emphasized that the picture is a composite one. For example, distal fluid reabsorption has been convincingly demonstrated only in dogs and monkeys, and secretin is not a choleretic in rats or rabbits. It should also be clear that the actual mechanisms of solute transport remain poorly defined. Thus the term active transport in the present context should be thought of in its general thermodynamic sense rather than as denoting any particular transport mechanism. For the future, the most pressing problems are methodologic. To mention only three that seem especially important: ways must be found to sample bile closer to its origin; the proper interpretation of studies with isolated liver cell membranes will require unambiguous methods to certify their source; and descriptions of transport kinetics must somehow be refined to reflect the effective intracellular concentration of solutes as well as their distribution within the liver lobule.