The structural organization of the liver highlights a significant clinical feature that deserves attention. The hepatic vein, hepatic artery, and bile ducts run parallel to each other in what is known as the hepatic triad. Hepatocytes located nearest to this triad are called periportal or zone 1 cells and receive the highest supply of oxygen and nutrients. Conversely, hepatocytes located closest to the hepatic vein branches are referred to as pericentral or zone 3 cells. These zone 3 cells are more vulnerable to ischemia, while zone 1 cells are more susceptible to oxidative injury. The location of damaged cells on biopsy can provide valuable clues about the cause of liver injury. Under normal circumstances, zone 1 cells are most active in detoxification functions. However, in cases of liver disease, zone 2 (intermediate between zones 1 and 3) and zone 3 cells can gradually be recruited. Zone 3 cells are believed to be most active in bile acid synthesis.

Bile, an excretory fluid produced by the liver, plays a crucial role in lipid digestion. Bile formation begins in hepatocytes, which actively transport solutes into bile canaliculi through their apical membranes. Bile is a micellar solution primarily composed of bile acids, phosphatidylcholine, and cholesterol in an approximate ratio of 10:3:1, respectively. The secretion of these solutes drives the movement of water and electrolytes across the tight junctions that connect adjacent hepatocytes, forming canalicular bile. The majority of bile flow is facilitated by the secretion of bile acids across the apical membrane of hepatocytes through a transporter called the bile salt export pump (BSEP). The resulting fluid's composition can be further modified as it passes through the biliary ductules (resulting in hepatic bile) and during storage in the gallbladder (gallbladder bile). Ultimately, bile becomes a concentrated solution of biological detergents that aids in solubilizing the products of lipid digestion in the aqueous environment of the intestinal lumen. This enhances the rate at which lipids are transferred to the absorptive epithelial surface and also facilitates the export of metabolic waste products from the body.

While rare, various familial syndromes characterized by progressive cholestasis have provided insights into the molecular nature of transporters involved in delivering bile constituents into the canaliculus. For instance, progressive familial intrahepatic cholestasis type II (PFIC II) has been linked to a mutation in BSEP, resulting in a near absence of bile acids in bile. Patients with this disorder develop cholestasis, but show little to no evidence of bile duct injury. On the other hand, type III PFIC is a more aggressive disease in which cholestasis is accompanied by early increases in circulating γ-glutamyltranspeptidase. The molecular culprit in this case is a mutation that abolishes the expression of multidrug resistance protein 3 (MDR3). Without this transporter, phosphatidylcholine is no longer able to enter bile, highlighting the crucial role of this lipid in protecting cholangiocytes from the harmful effects of bile acids, as mixed micelles cannot form in its absence.

Bile acids are the end products of cholesterol metabolism, produced by hepatocytes. Cholesterol is selectively metabolized through a series of enzymes to form bile acids.
One other feature of the structural organization of the liver bears emphasis because of its clinical significance. Branches of the hepatic vein, hepatic artery, and bile ducts run in parallel in the so-called hepatic triad. Hepatocytes lying closest to this triad are referred to as periportal, or zone 1, and have the greatest supply of oxygen and nutrients. In contrast, hepatocytes lying closest to branches of the hepatic vein are referred to as pericentral, or zone 3. The latter cells are more sensitive to ischemia, whereas the former are more sensitive to oxidative injury. Thus the location of damaged cells on biopsy may provide clues to the cause of a given case of liver injury. Zone 1 cells are most active in detoxification functions in normal circumstances, but •Fig. 32.4 Functionalanatomyofthebiliarysystem.Right and left hepatic ducts from liver Common hepatic duct Common bile duct Cystic duct Sphincter of Oddi Duodenum Gallbladder zone 2 (intermediate between zones 1 and 3) and zone 3 cells can progressively be recruited in cases of liver disease. Conversely, zone 3 cells are thought to be most active in bile acid synthesis.
Bile is the excretory fluid of the liver that plays an important role in lipid digestion. Bile formation begins in hepatocytes, which actively transport solutes into bile canaliculi across their apical membranes. Bile is a micellar solution in which the major solutes are bile acids, phosphatidylcholine, and cholesterol in an approximate ratio of 10:3:1, respectively. Secretion of these solutes drives concomitant movement of water and electrolytes across the tight junctions that link adjacent hepatocytes to form canalicular bile. The majority of bile flow is driven by the secretion of bile acids across the apical membrane of hepatocytes via an adenosine triphosphatase (ATPase) transporter known as the bile salt export pump (BSEP; see
Table 32.1 ). The composition of the resulting fluid can be modified further as it flows through the biliary ductules (resulting in hepatic bile) and still further on storage in the gallbladder (gallbladder bile). Ultimately bile becomes a concentrated solution of biological detergents that aids in solubilization of the products of lipid digestion in the aqueous environment of the intestinal lumen, thereby enhancing the rate at which lipids are transferred to the absorptive epithelial surface. It also serves as a medium in which metabolic waste products are exported from the body.
Thoughrare,avarietyoffamilialsyndromesthataremanifestedasprogressivecholestasishavetaughtusagreatdealaboutthemolecularnatureofthetransportersthatdeliverbileconstituentsintothecanaliculus.Forexample, (PFICII)hasbeenmappedtoamutationinBSEP thatresultsinanalmosttotalabsenceofbileacidsinbile.Cholestasisdevelopsinpatientswiththisdisorder,buttheyhaverelativelylittleifanyevidenceofbileductinjury.TypeIIIPFIContheotherhandisamuchmoreaggressivediseaseinwhichcholestasisisaccompaniedbyearlyincreasesincirculatingγ-glutamyltranspeptidase.Themolecularculpritisamutationthatabolishesexpressionofmultidrug resistance protein 3 (MDR3).Intheabsenceofthistransporter,phosphatidylcholineisnolongerabletoenterbile,thusillustratingtheimportanceofthislipidinprotectingcholangiocytesfromtheinjuriouseffectsofbileacids,becausemixedmicellescannotforminitsabsence.
Bile acids are produced by hepatocytes as end products of cholesterol metabolism. Cholesterol is selectively metabolized by a series of enzymes that result in formation of bile acid (