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18. 1 Introduction




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It is important that trypsinogen is not activated within the acinar cells or as it passes along the ducts. Activation is normally prevented by the maintenance of an acid environment within the zymogen granules (probably through the action of a proton pump) and by the presence of trypsin inhibitor in the pancreatic juice. The latter binds to any active trypsin which may be present, to form an inactive complex. Acute necrotizing pan­creatitis is a life-threatening disorder often caused by the reflux of bile into the pancreas, or as a result of alcoholism. It is charac­terized by autodigestion of the pancreatic tissue with inflamma­tion and tissue damage caused by the escape of activated enzymes from the pancreas.

^ Pancreatic amylase

Although salivary amylase may initiate the digestion of starch in the mouth and possibly the stomach, pancreatic a-amylase is responsible for the majority of starch digestion in the duo­denum. This enzyme is secreted in its active form and is stable between pH 4 and 11, although its optimal pH is 6.9. Like salivary amylase, it splits the a-l,4-glycosidic bond (see Chapter 2), but unlike the salivary enzyme it is able to attack uncooked as well as cooked starch. Within 10 minutes or so of entering the small intestine, starch is entirely converted to various oligo-saccharides, chiefly maltose and maltriose. The intestinal brush-border disaccharidases then hydrolyze them into their constituent monosaccharides. Leakage of pancreatic amylase into the blood is a diagnostic index of tissue injury.

^ Lipolytic enzymes of the pancreas

Pancreatic juice contains several lipases, secreted in the form of inactive zymogens, among the most important of which are colipase, cholesterol esterase, and phopholipase A2. These are activated by trypsin in the duodenal lumen. Pancreatic lipase (triacylglycerol hydrolase) is believed to be secreted in its active form and hydrolyzes water-insoluble triglycerides to release free fatty acids and monoglycerides. Colipase anchors the lipase close to the oil : water interface so that it is able to act more effect­ively. Phospholipasc A2 digests phospholipids to release free fatty acids and lysolecithin. The role of bile in the digestion and absorption of fats is discussed in Section 18.11.

The regulation of pancreatic secretion

Like gastric secretion, pancreatic secretion is regulated by both the activity of the vagus nerves and by hormones. However, the endocrine control of pancreatic secretion is the more important. A list of the chief modulators of exocrine pancreatic secretion is given in Table 18.3. As for the stomach, the process of secretion may be considered in three phases: cephalic, gastric, and intes­tinal. The cephalic phase is under nervous control while the gastric and intestinal phases are controlled chiefly by hormones.

^ The cephalic phase of pancreatic secretion

The acinar cells and the smooth muscle cells of the ducts and blood vessels are innervated by parasympathetic vagal efferent fibers. Stimulation of these fibers causes the release of zymogen granules from the acinar cells into the ducts and an increase in blood flow. The blood vessels also receive some sympathetic vasoconstrictor fibers whose activity causes a reduction in blood flow.

Parasympathetic vagal activity is enhanced by the sight, smell, and taste of food. The neurotransmitters acetylcholine and VIP are released and seem to act synergistically to bring about increases in blood flow and the secretion of pancreatic juice. In addition to the direct action of vagal efferents, a small part of the pancreatic secretion of the cephalic phase is mediated by gastrin released from the antral cells in response to vagal stimulation.

^ The gastric phase of pancreatic secretion

Gastrin is chiefly responsible for this, relatively small, com­ponent of pancreatic secretion. Gastrin is secreted in response to distension of the stomach and in response to the presence of amino acids and peptides in the antrum. Distension also elicits secretion via a vago-vagal gastro-pancreatic reflex.

^ The intestinal phase of pancreatic secretion

This phase accounts for more than 70 per cent of total secretion by the exocrine pancreas. It occurs in response to cholecystokinin (CCK) and secretin secreted by the upper intestinal mucosa when its surface is bathed in monoglycerides, fatty acids, pep­tides, amino acids (especially tryptophan and phenylalanine),

Table 18.3 Chemical regulators of exocrine pancreatic secretion



Agents Action on pancreas

Cholecystokinin (CCK) "] Gastrin 1 Increased secretion of pancreatic enzymes and chloride-rich fluid by acinar cells Acetylcholine Substance P '

Secretin Vasoactive intestinal polypeptide (VIP) \ Increased secretion of bicarbonate-rich fluid from duct cells Peptide histidine-isoleucine (PHI) j

Insulin Increased enzyme synthesis and secretion, trophic effects Insulin-like growth factors (IGFs)

Somatostatin Inhibits secretion from acinar and duct cells

^ 416

18 The gut and nutrition


and acid. CCK stimulates the production of an enzyme-rich fluid from the acinar cells, while secretin increases the rate of flow of bicarbonate-rich fluid from the ductal cells. Furthermore, CCK appears to potentiate the secretory effects of secretin.

Summary

  1. The exocrine portion of the pancreas consists of acinar cells which
    secrete enzymes and fluid into a system of tiny ducts lined _with
    epithelial cells, which secrete alkaline fluid and modify the primary
    acinar secretion.

  2. All the major enzymes required to complete the digestion of fats, car­
    bohydrates, and proteins are contained within the pancreatic juice.
    The ionic composition of the pancreatic juice depends upon its rate of
    secretion. At high rates of secretion the bicarbonate content of the
    juice is higher than at lower rates.

  3. Most of the proteolytic enzymes (trypsins) are stored in the acinar
    cells as inactive precursors (zymogen granules), to avoid self-
    digestion. Activation of these enzymes takes place in. the duodenum.

  4. Pancreatic Ctf-amylase is responsible for starch digestion to oligosac-
    charides in the duodenum. It is secreted in its active form.

  5. Several Upases are present in pancreatic juice. They hydrolyze water-
    insoluble triglycerides to release free fatty acids and monoglycerides.
    Bile salts are important in this process as they form a stable emulsion
    on which the lipases can act.

  6. Control of exocrine pancreatic secretion is chiefly hormonal, although
    the initial cephalic phase of secretion is under the control of para-
    sympathetic nerves. Gastrin contributes to the gastric phase of secre­
    tion, but about 70 per cent of secretion occurs during the intestinal
    phase in response to CCK and secretin. These hormones are released
    by the upper intestinal mucosa in response to the products of fat and
    protein digestion.

18.11 The role of the liver and gallbladder in the function of the gastrointestinal tract

The liver and gallbladder are accessory organs associated with the small intestine. The liver is the largest abdominal organ, weigh­ing an average of 1.3 kg. It receives and processes the nutrient-rich venous blood reaching it from the GI tract and performs many vital metabolic and homeostatic functions, which are sum­marized briefly here (see also Section 31.5). The liver plays an extremely important role in energy metabolism. It stores glucose as glycogen, converts certain amino acids to glucose, and degrades lipids. It is also important in biosynthesis. It synthesizes all the plasma proteins except for the immunoglobulins, including com­plement and clotting factors. It also manufactures carrier proteins for cholesterol and the triacylglycerols. The liver secretes bile, which contains bile salts which are crucial for the emulsification of fats prior to their digestion and absorption. Finally, the liver converts ammonia to the much less toxic urea and adds polar groups to many drugs, some hormones, and certain metabolites so that they may be excreted in the urine or the bile.

Structure of the liver

Situated in the upper right quadrant of the abdominal cavity (see Fig. 18.1) the liver consists of four lobes surrounded by a tough fibroelastic capsule called Glisson's capsule. The falciform liga­ment, which attaches the liver to the diaphragm and anterior abdominal wall, separates the major right and left lobes. The smaller visceral and caudate lobes are on the ventral surface of the liver. A dorsal mesentery, the lesser omentum, attaches the liver to the lesser curvature of the stomach. The gallbladder rests in a recess on the inferior surface of the right lobe of the liver. Bile leaves the liver through terminal bile ducts which fuse to form the large common hepatic duct. As this duct passes towards the duo­denum it fuses with the cystic duct draining the gallbladder to form the bile duct. Separating the bile duct from the duodenum is the sphincter of Oddi, a ring of muscle that prevents the reflux of bile. Microscopically, the liver consists of between 50 000 and 100 000 lobules, separated by septa. These are roughly hexagonal structures, 1-2 mm in diameter, which form the functional units of the organ. Each lobule consists of a central vein which empties into the hepatic vein, from which single columns of hepatocytes (liver cells) radiate towards the surrounding layer of thin con­nective tissue. Between the hepatocytes lie small bile canaliculi that empty into the bile ducts and then the terminal bile ducts. At each of the six corners of a lobule lies a portal triad, so called because three structures are always present there. These are: a branch of the hepatic artery, a branch of the portal vein, and a bile duct. A simplified view of the structure of a liver lobule is shown in Fig. 18.19-

Hepatic circulation

The liver normally receives about 25 per cent of the cardiac output. It is unique among the abdominal organs in having a dual blood supply: the hepatic artery, carrying about 400 ml min"1, and the portal vein, supplying about 1000 ml min^1 of nutrient-rich blood. Small portal venules lying in the septa between lobules receive blood from the portal veins. From the venules, blood flows into branching sinusoids between the columns of hepatocytes. The sinusoids essentially form a leaky capillary network and from these blood flows into the central vein of the lobule. Deoxygenated blood from the central veins empties into the hepatic veins which join the inferior vena cava just below the level of the diaphragm. The pressure in the portal vein is about 1.3 kPa (lOmmHg), while that in the hepatic vein is only slightly lower (about 0.6 kPa or 5 mmHg). Consequently, 200—400 ml of blood are stored within the capacitance vessels of the liver. This blood may be shunted back into the systemic circulation during periods of hypovolemia or shock.

The interlobular septa also contain hepatic arterioles derived from branches of the hepatic'artery, many of which drain directly into the sinusoids supplying blood fully saturated with oxygen.

The sinusoids are lined with two types of cells: typical endo-thelial cells and phagocytic Kupffer cells. The endothelial cells

18.11 The role of the liver and gallbladder

417





Fig. 18.19 The basic histologic structure of a liver lobule.

present almost no barrier to the exchange (between the sinusoids and the hepatocytes) of materials of Mr up to 250 000. There is no basal lamina and the cytoplasm of the endothelium is fenes-trated. Microvilli on the area of hepatocyte membrane facing the sinusoids increase the surface area for exchange. The space between the hepatocytes and the sinusoidal wall is called the space of Disse (see Fig. 18.19). This contains a system of supporting collagen fibers.

The production of bile

The hepatocytes secrete a fluid known as hepatic bile into the bile canaliculi. This is an isotonic fluid with a pH between 7 and 8 that resembles plasma in its ionic composition. It also contains bile salts, bile pigments, cholesterol, lecithin, and mucus. As it passes along the bile ducts, the ductal epithelial cells modify this primary secretion by secreting a watery, bicarbonate-rich fluid. This adds considerably to the volume of the bile so that overall the liver produces 500-1000 ml of bile each day. The bile may be continuously discharged into the duodenum or stored in the gallbladder, during which time its composition changes (see below).

The chemical nature of bile acids and bile salts

The bile acids are derived from the metabolism of cholesterol. Cholic acid and chenodeoxycholic acid are formed in the hepato­cytes themselves and are known as the primary bile acids. In the intestine, the secondary bile acids, deoxycholic acid and litho-cholic acid, are formed in small amounts from the primary acids by the dehydroxylating action of bacteria. The primary bile acids are conjugated (by means of a peptide linkage) to amino acids such as glycine and taurine in a complex with sodium, to form water-soluble bile salts prior to secretion into the bile.

Figure 18.20 illustrates the structures of the primary bile acids and the conjugation of cholic acid with glycine.

Bile salts are amphipathic, that is they have both hydro-phobic and hydrophilic regions. The bile salts form aggregates called micelles when they reach a certain concentration in the bile. (This is known as the critical micellar concentration.) The micelles are organized so that the hydrophilic groups of the bile salts face the aqueous medium while the hydrophobic groups face each other to form a core. This chemical characteristic of the bile salts is of key importance to their role in the absorption of fats.

Bile acid-dependent and bile

acid-independent components of bile

secretion

Two distinct secretory mechanisms are involved in the elab­oration of bile by the liver, giving rise to the so-called bile acid-dependent and bile acid-independent components of bile:

  • The rate at which bile salts are actively secreted into the
    canaliculi depends upon the rate at which bile acids are
    returned from the small intestine to the hepatocytes via
    the enterohepatic circulation. This component of bile secre­
    tion is therefore referred to as the bile acid-dependent
    fraction.

  • The bile acid-independent fraction of bile secretion refers
    to the secretion of water and electrolytes by the hepato­
    cytes and the ductal epithelial cells. Sodium is transported
    actively into the bile canaliculi and is followed by the
    passive movement of chloride ions and water. Bicarbonate
    ions are actively secreted into the bile by the ductal cells
    and are followed by the passive movement of sodium and
    water. The processes involved in the formation of hepatic
    bile are summarized in Fig. 18.21.

418

18 The gut and nutrition



Fig. 18.20 A diagrammatic representation of the structure of the bile acids and their formation from cholesterol (a), and the conjugation of cholic acid with glycine to form the bile salt glycocholic acid (b).

The enterohepatic circulation

About 94 per cent of the bile salts that enter the intestine in the bile are reabsorbed into the portal circulation by active transport from the distal ileum. Many of the bile salts return to the liver unaltered and are recycled. Some are first deconjugated in the gut lumen and returned to the liver for reconjugation and recy­cling. A small number are deconjugated and then undergo modification by intestinal bacteria to secondary bile acids. Some of these, particularly lithocholic acid, are relatively insoluble and are excreted in the feces. It is estimated that bile acids may be recycled up to 20 times before finally being excreted in the feces. A schematic illustration of the enterohepatic circulation of the primary bile acids is shown in Fig. 18.22.

The regulation of bile secretion

Substances that increase the rate of bile secretion are called choleretics. Cholagogues ate substances such as cholecystokinin (CCK) that increase the flow of bile by stimulating the emptying of the gall bladder. The major factor in the production of hepatic bile is the return of bile salts to the hepatocytes via the enterohepatic cir­culation. This produces the driving force for fluid transport into the biliary system. Although the production of hepatic bile is not under hormonal control, the secretion of bicarbonate-rich watery fluid by the ductal epithelial cells is enhanced by secretin, and to a lesser extent, glucagon and gastrin. A further stimulus to hepatic production of bile is thought to be the increase in liver blood flow which follows a meal. A meal will also result in an increase in the

^ 18.11 The role of the liver and gallbladder j 419





Fig. 18.21 The processes involved in the formation of bile by the hepatocytes. БА, bile salt; 1, bile acid-dependent fraction; 2, bile acid-independent fraction.





Fig. 18.22 The enterohepatic circulation. Only the recirculation of the primary bile acids are illustrated. The transport of conjugated bile salts is shown by the solid red line and that of the deconjugated bile salts by the broken red line.

rate of reabsorption of bile salts via the enterohepatic circulation. This, in turn, will stimulate the bile acid-dependent fraction of bile secretion.

Other important constituents of bile

include phospholipids, cholesterol, and

bile pigments

Bile is the major route for the excretion of cholesterol from the body. Phospholipids, especially lecithin, are also secreted into

the bile. Both are secreted as lipid vesicles which then form micelles. The cholesterol partitions into the hydrophobic core while the lecithin, which is amphipathic, lies partly in the core and partly near the outer surface of the micelle. If excess choles­terol is present and cannot be solubilized into micelles, it may form crystals in the bile. These may contribute to the formation of cholesterol gallstones in the hepatic ducts or the gallbladder, by acting as nuclei for the deposition of calcium and phosphate salts. If the common bile duct becomes blocked by a gallstone, bile cannot entet the duodenum. There is distension and a build up of pressure within the gallbladder which can result in severe pain (biliary colic) and jaundice.

Bile is a vehicle for the elimination of bile pigments and other waste products, particularly less polar molecules of high molecular weight that are not excreted by the kidneys. Bile pigments are the excretory products of heme and are responsible for the characteristic colors of both bile and feces. They form about 0.2 per cent of the total bile composition and are fotmed from the breakdown of old red blood cells in the spleen. The major bile pigment is bilirubin, which is relatively insoluble and is carried to the liver mainly in combination with plasma albumin. In the hepatocytes, about 80 per cent of the bilirubin is conjugated with glucuronic acid, in the presence of an enzyme, glucuronyl transferase, to form bilirubin diglucuronide. This is water soluble and enters the bile, giving it its charac­teristic greeny-yellow color. The remaining bilirubin is con­jugated with sulfate to form bilirubin sulfate, or with a variety of other hydrophilic agents.

In the intestine, particularly the colon, bilirubin diglu­curonide is hydrolyzed by bacteria to form urobilinogen which is extremely water soluble and colorless, as well as stercobilin and urobilin which give the feces their characteristic brown color. Some of the urobilinogen is reabsorbed from the intestine into the blood. From there it is either re-secreted back into the bile

420

18 The gut and nutrition




Fig. 18.23 The processes of bilimbin formation, circulation, and elimination.

by the liver, or excreted by the kidneys into the urine. The processes of bilirubin formation, circulation, and elimination are shown diagrammatically in Fig. 18.23.

Accumulation of bilirubin in the blood causes jaundice

Jaundice (icterus) is due to an abnormal level of bilirubin in the blood (hyperbilirubinemia). It is characterized by yellow dis­coloration of the skin, sclera of the eyes, and deep tissues. There are many causes of jaundice, the most important of which are: excessive hemolysis of red cells, impaired uptake of bilirubin by

hepatocytes, and obstruction of bile flow either through the bile canaliculi or the bile ducts. Excessive hemolysis may occur following a poorly matched blood transfusion or in certain hereditary disorders. Jaundice is also seen in newborns whose fetal red cells are hemolysing more quickly than the immature liver can process the bilirubin.

Jaundice resulting from a failure of the liver to take up or conjugate bilirubin is known as hepatic jaundice. Hepatitis and cirrhosis are the most common causes of this disorder.

Obstructive jaundice occurs if bile is prevented from flowing from the liver to the intestine. Gallstones, strictures, or tumors of the bile duct and pancreatic tumors are common causes. Pruritus (itching) often accompanies this type of jaundice which is caused by the accumulation of bile salts in the blood. The feces are pale in colour due to the absence of bilirubin in the bile and often contain fatty streaks due to the lowered absorption of dietary fat. The urine, however, is darker than normal due to the increased excretion of bilirubin via the kidneys.

The role of the gallbladder

The gallbladder is a green, thin-walled muscular sac, 10 cm long, protruding from the inferior margin of the liver (see Fig. 18.1). It stores bile that is not required immediately for digestion, and concentrates it by absorbing water and elec­trolytes. The mucosa of the gallbladder, like that of the stomach, is thrown into folds when the organ is empty. These can expand to accommodate up to 60 ml of bile during the period between meals.

Between meals, most of the bile produced by the liver is diverted into the gallbladder because of the relatively high level of tone in the sphincter of Oddi. The gallbladder concentrates the bile by absorbing sodium, chloride, bicarbonate, and water from it. As a result, the bile salts present in the bile may be concentrated as much as twentyfold. Active transport of sodium by the mucosa from the lumen to the blood is the primary mechanism involved in the concentration of the bile. The anions chloride and bicarbonate are absorbed to maintain electroneutrality, and water follows passively. Potassium con­centrations rise as water is absorbed but then fall as potassium diffuses passively down the concentration gradient established. Table 18.4 shows the solute concentration ratios for gallbladder and hepatic bile resulting from absorptive processes occurring in the gallbladder.

Water moves out of the gallbladder to maintain iosotonicity despite the fact that the mucosa is not highly permeable to water. This is thought to be made possible by the physical nature of the mucosal layer of the gallbladder. The mucosa con­sists of a single layer of tall, columnar epithelial cells bound at their apical regions by tight junctions so that long lateral chan­nels form between the cellsT As salts are transported into these channels, local regions of high osmotic pressure are created, with tonicity highest at the apical regions of the channel. This is known as a standing osmotic gradient and permits the continuous

] 8.12 Absorption in the small intestine
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