Overview of the Biliary System

Fig. 10.1 is a schematic illustration of the biliary system and the circulation of bile acids between the intestine and liver. Bile is continuously produced by the hepatocytes. The principal organic constituents of bile are the bile acids , which are synthesized by the hepatocytes. The secretion of bile acids carries water and electrolytes into the bile by osmotic filtration. Additional water and electrolytes, primarily sodium bicarbonate (NaHCO ₃ ), are added by cells lining the ducts. This latter component is stimulated by secretin and is essentially identical to the aqueous component of pancreatic secretion. The secretion of bile increases pressure in the hepatic ducts and causes the gallbladder to fill. Within the gallbladder, bile is stored and concentrated by the absorption of water and electrolytes. When a meal is eaten, the gallbladder is stimulated to contract by CCK and vagal stimulation. Within the lumen of the intestine bile participates in the emulsification, hydrolysis, and absorption of lipids. Most bile acids are absorbed either passively throughout the intestine or actively in the ileum. Bile acids lost in the feces are replaced by synthesis in the hepatocytes. The absorbed bile acids are returned to the liver via the portal circulation, where they are extracted actively from the blood. Together with newly synthesized bile acids, the returning bile acids are secreted into the bile canaliculi. Canalicular bile is secreted by ductule cells in response to the osmotic effects of anion transport. In humans, almost all bile formation is driven by bile acids and is therefore referred to as bile acid dependent . The portion of bile stimulated by secretin and contributed by the ducts is termed bile acid independent or ductular secretion .

Overview of the biliary system and the enterohepatic circulation of bile acids. Solid arrows indicate active transport processes. ACh , Acetylcholine; Ca ²⁺ , calcium; CCK , cholecystokinin; Cl ⁻ , chloride; H ⁺ , hydrogen ion; HCO ₃ – , bicarbonate; H ₂ O , water; K ⁺ , potassium; Na ⁺ , sodium.

From Johnson LR: Essential Medical Physiology , 3rd ed. Philadelphia, Academic Press, 2003, p 521.

Constituents of Bile

Bile is a complex mixture of organic and inorganic components. Taken separately, some of the components are insoluble and would precipitate out of an aqueous medium. Normally, however, bile is a homogeneous and stable solution whose stability depends on the physical behavior and interactions of its various components.

Bile acids, the major organic constituents of bile, account for approximately 50% of the solid components. Chemically, they are carboxylic acids with a cyclopentanoperhydrophenanthrene nucleus and a branched side chain of three to nine carbon atoms that ends in a carboxyl group ( Fig. 10.2 ). They are related structurally to cholesterol, from which they are synthesized by the liver. Indeed, the synthesis of bile acids is a major pathway for the elimination of cholesterol from the body. Conversion of cholesterol to bile acids occurs via two main synthetic pathways.

Principal organic constituents of bile. The two primary bile acids may be converted to secondary bile acids in the intestine. Each of the four bile acids may be conjugated to either glycine or taurine to form bile salts. The R-groups of lecithin represent fatty acids. pKa , Negative log of dissociation constant.

From Johnson LR: Essential Medical Physiology , 3rd ed. Philadelphia, Academic Press, 2003, p 522.

The major pathway begins with the rate-limiting step of 7α-hydroxylation of cholesterol by the hepatic enzyme 7α-hydroxylase. A secondary pathway begins with the conversion of cholesterol to 27-hydroxycholesterol, a reaction that takes place in many tissues. Four bile acids are present in bile, along with trace amounts of others that are modifications of the four. The liver synthesizes two bile acids, cholic acid and chenodeoxycholic acid . These are the primary bile acids (see Fig. 10.2 ). Within the lumen of the gut, a fraction of each acid is dehydroxylated by bacteria to form deoxycholic acid and lithocholic acid . These are called secondary bile acids. All four are returned to the liver in the portal blood and are secreted into the bile. Their relative amounts in bile are approximately four cholic to two chenodeoxycholic acid to one deoxycholic to only small amounts of lithocholic acid.

The solubility of bile acids depends on the number of hydroxyl groups present and the state of the terminal carboxyl group. Cholic acid, with three hydroxyl groups, is the most soluble, whereas lithocholic, a monohydroxy acid, is least soluble. The dissociation constant (pK) of the bile acids is near the pH of the duodenal contents, so there are relatively equal amounts of protonated (insoluble) forms and ionic (soluble) forms. The liver, however, conjugates the bile acids to the amino acids glycine or taurine with a pKa of 3.7 and 1.5, respectively. Thus at the pH of duodenal contents, bile acids are largely ionized and water soluble. Conjugated bile acids exist as salts of various cations, primarily Na ⁺ , and are referred to as bile salts (see Fig. 10.2 ).

Several features are unique to the bile acids and account for their behavior in solution. Three-dimensionally, the hydroxyl and carboxyl groups are located on one side of the molecule. The bulk of the molecule is composed of the nucleus and several methyl groups ( Fig. 10.3 ). This structure renders bile acids amphipathic to the extent that the hydroxyl groups, the peptide bond of the side chain, and either the carbonyl or sulfonyl group of glycine or taurine are hydrophilic, and the cholesterol nucleus and methyl groupings are hydrophobic. In solution, the behavior of bile acids depends on their concentration. At low concentrations, little interaction occurs among bile acid molecules. As the concentration is increased, a point is reached at which aggregation of the molecules takes place. These aggregates are called micelles , and the point of formation is called the critical micellar concentration . Hydrophobic regions of the micelles interact with one another, and the hydrophilic regions interact with the water molecules (see Fig. 10.3 ).

Structures of components of micelles and micelles themselves. (A) Representations of bile salt, lecithin, and cholesterol molecules illustrating the separation of polar and nonpolar surfaces. (B) Cross section of a micelle showing the arrangement of these molecules and the principal products of fat digestion. Micelles are cylindrical disks whose outer curved surfaces are composed of bile salts. OH , Hydroxyl.

From Johnson LR: Essential Medical Physiology , 3rd ed. Philadelphia, Academic Press, 2003, p 523.

The second most abundant group of organic compounds in bile consists of the phospholipids , and the major ones are the lecithins (see Fig. 10.3 ). Phospholipids also are amphipathic, insofar as the phosphatidylcholine grouping is hydrophilic, whereas the fatty acid chains are hydrophobic. Although amphipathic, the phospholipids are not soluble in water but form liquid crystals that swell in solution. In the presence of bile salts, however, the liquid crystals are broken up and solubilized as a component of the micelles. Bile salts possess a large capacity to solubilize phospholipids; 2 moles (mol) of lecithin are solubilized by 1 mol of bile salts. The combination of bile salts and phospholipids also is better able to solubilize other lipids—mainly cholesterol and the products of fat digestion—than is a simple solution of bile salts.

A third organic component, cholesterol , is present in small amounts and contributes approximately 4% to the total solids of bile. Although present in small amounts, bile cholesterol is important because it may be excreted and therefore helps regulate body stores of cholesterol. Cholesterol appears mainly in the nonesterified form and is insoluble in water. In the presence of bile salts and phospholipids, however, it is solubilized as part of the micelle. Because it is a weakly polar substance, cholesterol is found in the interior of the micelle, where the hydrophobic portions of the bile salts, phospholipids, monoglycerides, and fatty acids interact (see Fig. 10.3 ). Within the liver, ducts, and gallbladder, bile is normally present as a micellar solution.

The fourth major group of organic compounds found in bile comprises the bile pigments . These constitute only 2% of the total solids, and bilirubin is the most important. Chemically, bile pigments are tetrapyrroles and are related to the porphyrins, from which they are derived. In their free form, bile pigments are insoluble in water. Normally, however, they are conjugated with glucuronic acid and are rendered soluble. Unlike the other organic compounds just mentioned, bile pigments do not take part in micellar formation. As their name implies, they are highly colored substances. Other than being responsible for the normal color of bile and feces, the pigment properties of these compounds are used to assess the level of function of the liver.

In addition to the organic compounds just discussed, many inorganic ions are found in bile. The predominant cation is Na ⁺ , accompanied by smaller amounts of potassium (K ⁺ ) and calcium (Ca ²⁺ ). The predominant inorganic anions are chloride (Cl ⁻ ) and <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='HCO3−’>HCO−3HCO3−
HCO 3 −
. Normally, the total number of inorganic cations exceeds the total number of inorganic anions. No anion deficit occurs, however, because the bile acids, which possess a net negative charge at the pH values found in bile, account for the difference. Bile is isosmotic even though the number of cations present is larger than expected. Because they are highly charged molecules, the bile acids attract a layer of cations that serve as counterions. These counterions are tightly associated with the micelles and thus exert little osmotic activity.

Bile Secretion

Functional Histology of the Liver

The functional organization of the liver is shown schematically in Fig. 10.4 . The liver is divided into lobules organized around a central vein that receives blood through separations surrounded by plates of hepatocytes. The separations are called sinusoids, and they in turn are supplied by blood from both the portal vein and the hepatic artery. The plates of hepatocytes are no more than two cells thick, so every hepatocyte is exposed to blood. Openings between the plates ensure that the blood is exposed to a large surface area. The hepatocytes remove substances from the blood and secrete them into the biliary canaliculi lying between the adjacent hepatocytes. The bile flows toward the periphery, countercurrent to the flow of the blood, and drains into bile ducts. This countercurrent relationship minimizes the concentration differences between substances in the blood and in the bile and contributes to the liver’s efficiency in extracting substances from the blood.

Schematic diagram of the relationship between blood vessels, hepatocytes, and bile canaliculi in the liver. Each hepatocyte is exposed to blood at one membrane surface and a bile canaliculus at the other.

From Johnson LR: Essential Medical Physiology , 3rd ed. Philadelphia, Academic Press, 2003, p 524.

Bile Acids and the Enterohepatic Circulation

The secretion of bile depends heavily on the secretion of bile acids by the liver. Once secreted, bile acids undergo an interesting journey (see Fig. 10.1 ). First, they may be stored in the gallbladder. Then they are propelled into and through the small intestine, where they take part in the digestion and absorption of lipids. Most of the bile acids themselves are absorbed from the intestine and travel via the portal blood to the liver, where they are taken up by the hepatocytes and resecreted. This process is termed the enterohepatic circulation .

Bile acids are secreted continuously by the liver. The rate of secretion, however, varies widely. Early experiments demonstrated that the rate of secretion depended on the amount of bile acids delivered to the liver via the blood; the more acids in the portal blood, the greater the secretion of bile. The amount of bile acids in the portal blood depends on the amount absorbed from the small intestine. The amount of bile acids in the intestine, in turn, depends on the digestive state of the individual. Between meals, most bile secreted by the liver is stored in the gallbladder, with only small amounts delivered intermittently to the small intestine. During a meal, the gallbladder empties its contents into the duodenum in a more continuous pattern. The ejected bile acids are then resorbed from the intestine and are secreted again by the liver.

Although many different bile acids are found in the bile, only cholic acid and chenodeoxycholic acid appear to be synthesized from cholesterol in significant amounts by human hepatocytes. For this reason, they are called “primary” bile acids. Their synthesis by the liver is a continuous but regulated process. The amount synthesized depends on the amount of bile acids returned to the liver in the enterohepatic circulation. When most of the bile acids secreted by the liver are returned, synthesis is low, but when the secreted acids are lost from the enterohepatic circulation, the rate of synthesis is high. Bile acids extracted from the portal blood act to feedback inhibit 7α-hydroxylase, the rate-limiting enzyme for the synthesis of bile acids from cholesterol. Normally, there are 2.5 g of bile salts in the enterohepatic circulation. If the absorptive processes in the intestine and liver are functioning properly, only approximately 0.5 g is lost daily. Synthesis is regulated to replenish this loss. If the enterohepatic circulation is interrupted (e.g., by a fistula draining bile to the outside), the rate of synthesis becomes maximal. In humans, this amounts to 3 to 5 g per day. In patients incapable of reabsorbing bile acids, the maximal rate of synthesis equals the total amount of bile acids secreted by the liver. Deoxycholic acid, lithocholic acid, and other “secondary” bile acids are produced in the intestine through the action of microorganisms on primary bile acids. These acids then are absorbed along with the primary bile acids, taken up by the hepatocytes, conjugated with taurine and glycine, and secreted in the bile. The bile acid pool may circulate through the enterohepatic circulation several times during the digestion of a meal, so that 15 to 30 g bile acids may enter the duodenum during a 24-hour period.

The enterohepatic circulation of bile acids is carried out by both active and passive transport processes ( Fig. 10.5 ). The more hydrophobic bile acids, which are those with fewer hydroxyl groups and those that have been deconjugated, are absorbed passively throughout the intestine. The more hydrophilic acids and the remaining hydrophobic acids are absorbed by an active process in the ileum. Uptake across the apical membrane of the enterocytes is mediated by a specific Na ⁺ -dependent transport protein. Cytoplasmic binding proteins transport the acids through the cell to the basolateral membrane. Transport across the basolateral membrane out of the cell is mediated by an Na ⁺ -independent anion exchange process that involves a carrier different from the one on the apical membrane. As stated previously, the ileal transport process is highly efficient, delivering more than 90% of the bile acids to the portal blood.

Enterohepatic circulation of bile acids. Bile acids are actively secreted by the liver. Once in the intestine they participate in the digestion and absorption of lipids. As they are propelled toward the distal small bowel, some of the “primary” acids are altered and become “secondary” acids. The more hydrophobic bile acids are absorbed passively throughout the intestine. The more hydrophilic acids are absorbed by a sodium-coupled active transport process that is localized to the ileum. A minor fraction of bile acids is not absorbed but is instead propelled into the colon. The absorbed bile acids are transported via the portal circulation to the liver, where they are extracted actively from the blood (at a rate of almost 100%) and resecreted. Synthesis of new primary acids from cholesterol occurs at a rate to compensate for the acids lost from the bowel. Solid arrows denote active absorption, secretion, and synthesis; open arrows denote passive absorption and propulsion of contents by contractions of the intestine.

In the liver, additional transport processes remove bile acids from the portal blood. Uptake across the basolateral or sinusoidal membrane of the enterocytes is mediated primarily by two types of systems. One group includes a specific Na ⁺ -coupled transporter protein, the Na ⁺ taurocholate cotransporting polypeptide ( NTCP ), which can transfer both conjugated and unconjugated bile acids. A group of Na ⁺ -independent transporters includes the organic anion transport proteins ( OATPs ), which can take up both bile acids and other organic anions. At the canaliculus, bile acids and other organic anions appear to be secreted by at least two adenosine triphosphate (ATP)-dependent processes. One of these is termed the bile salt excretory pump ( bsep ), and the other is the multidrug resistance protein 2 ( mrp2 ). The hepatic transport of bile acids also is highly efficient. Practically all bile acids contained in the portal blood are removed during one passage through the liver. The process does have a transport maximum, but this is seldom reached.

Bilirubin

The primary bile pigment in humans, bilirubin , is derived largely from the metabolic breakdown of hemoglobin ( Fig. 10.6 ). Most of the hemoglobin comes from aged red blood cells (RBCs) that are disposed of by cells of the reticuloendothelial (RE) system. In the RE cells, hemoglobin is split into hemin and globin. The hemin ring is opened and oxidized, and the iron is removed to form bilirubin, which is then transported via the blood from the cells of the RE system to the hepatocytes. In transit, bilirubin is tightly bound to plasma albumin; very little is free in the plasma. Hepatocytes can extract bilirubin from blood, conjugate it with glucuronic acid, and secrete the conjugated product into the bile. Bilirubin secretion into the bile by the hepatocytes is mediated by an active anion transport system. This system is different from the one for active transport of bile acids, but it is shared by certain other organic anions (e.g., sulfobromophthalein [Bromsulphalein, or BSP], various radiopaque dyes). Some evidence indicates that one of the OATPs participates in the transport of bilirubin.

Excretion of bile pigments. Bilirubin is produced by cells of the reticuloendothelial (RE) system from aged red blood cells (RBCs) . The unconjugated pigment is then carried, tightly bound to plasma albumin, to the liver. There it is actively taken up, conjugated with glucuronic acid, and secreted into the bile. The water-soluble conjugates are propelled along the intestine. In the distal small bowel and colon a portion of the conjugated pigment is acted on by bacteria and becomes unconjugated bilirubin and other pigments. Some of these pigments are absorbed passively into the blood and either returned to the liver and resecreted or passed through the liver and excreted by the kidneys. Most, however, pass through the colon and are excreted. Bold arrows indicate active absorption. H ₂ , Hydrogen.

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