Branching duct system of a salivary gland

We initiate the discussion with the general organization of a salivary gland, in particular its branching ducts (see Box 17-A).

The secretory product of an acinus is drained sequentially by the following (Figures 17-1 and 17-2):

Figure 17-1 Review of the general histologic organization of a compound gland

Figure 17-2 General organization of the salivary glands and pancreas

The parotid, submandibular (or submaxillary), and sublingual glands are classified as branched tubuloalveolar glands. Their excretory ducts open into the oral cavity.

Saliva is the major product of salivary glands

Saliva, amounting to a half-liter daily, contains proteins, glycoproteins (mucus), ions, water, and immunoglobulin A (IgA) (Figure 17-3). The submandibular gland produces about 70% of the saliva. The parotid gland contributes 25% and secretes an amylase-rich saliva. The production of saliva is under the control of the autonomic nervous system. Upon stimulation, the parasympathetic system induces the secretion of a water-rich saliva; the sympathetic system stimulates the release of a protein-rich saliva.

Figure 17-3 Functional aspects of a salivary gland

The mucus and water in saliva lubricate the mucosa of the tongue, cheeks, and lips during speech and swallowing, dissolve food for the function of the taste buds, and moisten food for easy swallowing. The protective function of the saliva depends on the antibacterial function of three constituents of saliva: (1) lysozyme, which attacks the walls of bacteria; (2) lactoferrin, which chelates iron necessary for bacterial growth; and (3) IgA, which neutralizes bacteria and viruses. The digestive function of saliva relies on (1) amylase (ptyalin), which initiates the digestion of carbohydrates (starch) in the oral cavity; and (2) lingual lipase, which participates in the hydrolysis of dietary lipids.

Clinical significance: Mumps, rabies, and tumors

In addition to its role in the production of saliva, the parotid gland is the primary target of the rabies and mumps virus transmitted in saliva containing the virus. The mumps virus causes transient swelling of the parotid gland and confers immunity.

Two complications of mumps are orchitis and meningitis. Bilateral orchitis caused by the mumps virus can result in sterility.

The parotid gland is the most frequent site for slow-growing benign salivary gland tumors. Its surgical removal is complicated by the need to protect the facial nerve running through the parotid gland.

Clinical significance: Carcinoma of the pancreas

The pancreatic duct–bile duct anatomic relationship is of clinical significance in carcinoma of the pancreas localized in the head region, because compression of the bile duct causes obstructive jaundice. The close association of the pancreas with large blood vessels, the extensive and diffuse abdominal drainage to lymph nodes, and the frequent spread of carcinoma cells to the liver via the portal vein are factors contributing to the ineffectiveness of surgical removal of pancreatic tumors.

Functions of the pancreatic acinus

The pancreatic acinus is lined by pyramidal cells joined to each other by apical junctional complexes (see Figure 17-8), which prevent the reflux of secreted products from the ducts into the intercellular spaces. The basal domain of an acinar pancreatic cell is associated with a basal lamina and contains the nucleus and a well-developed rough endoplasmic reticulum. The apical domain displays numerous zymogen granules (see Figure 17-8) and the Golgi apparatus.

The concentration of about 20 different pancreatic enzymes in the zymogen granules varies with the dietary intake. For example, an increase in the synthesis of proteases is associated with a protein-rich diet. A carbohydrate-rich diet results in the selective synthesis of amylases and a decrease in the synthesis of proteases. Amylase gene expression is regulated by insulin, an event that stresses the significance of the insuloacinar portal system.

The administration of a cholinergic drug or of the gastrointestinal hormones cholecystokinin and secretin increases the flow of pancreatic fluid (about 1.5 to 3.0 L/day).

The polypeptide hormone cholecystokinin, produced in enteroendocrine cells of the duodenal mucosa, binds to specific receptors of acinar cells and stimulates the release of zymogen (Figure 17-9).

Figure 17-9 Functions of the exocrine pancreas

Secretin is released when acid chyme enters the duodenum. Secretin is produced in the duodenum, binds to receptors on the surface of intercalated ductal cells, and triggers the release of bicarbonate ions and water into the pancreatic ducts. HCO₃⁻ ions and the alkaline secretion of Brunner’s glands, present in the submucosa of the duodenum, neutralize the acidic gastric chyme in the duodenal lumen and activate the pancreatic digestive enzymes.

Clinical significance: Acute pancreatitis and cystic fibrosis

Zymogen granules contain inactive proenzymes that are activated within the duodenal environment. A premature activation of pancreatic enzymes, in particular trypsinogen to trypsin, and the inactivation of trypsin inhibitor (tightly bound to the active site of trypsin), result in the autodigestion of pancreatic acini. This condition—known to occur in acute hemorrhagic pancreatitis—usually follows heavy meals or excessive alcohol ingestion. The clinical features of acute pancreatitis (severe abdominal pain, nausea, and vomiting) and rapid elevation of amylase and lipase in serum (within 24 to 72 hours) are typical diagnostic features.

Cystic fibrosis is an inherited, autosomal recessive disease affecting the function of mucus-secreting tissues of the respiratory (see Chapter 13, Respiratory System), intestinal, and reproductive systems; the sweat glands of the skin (see Chapter 11, Integumentary System); and the exocrine pancreas in children and young adults. A thick sticky mucus obstructs the duct passages of the airways, pancreatic and biliary ducts, and intestine, followed by bacterial infections and damage of the functional tissues. A large number of patients (85%) have chronic pancreatitis characterized by a loss of acini and dilation of the pancreatic excretory ducts into cysts surrounded by extensive fibrosis (hence the designation cystic fibrosis of the pancreas). Insufficient exocrine pancreatic secretions cause the malabsorption of fat and protein, reflected by bulky and fatty stools (steatorrhea).

The lack of transport of Cl⁻ ions across epithelia is associated with a defective secretion of Na⁺ ions and water. A genetic defect in the chloride channel protein called cystic fibrosis transmembrane conductance regulator (CFTR) is responsible for cystic fibrosis. The disease is detected by the demonstration of increased concentration of NaCl in sweat. Children with cystic fibrosis “taste salty” after copious sweating.

Hepatic lobule

The structural and functional unit of the liver is the hepatic lobule. The hepatic lobule consists of anastomosing plates of hepatocytes limiting blood sinusoidal spaces (see Figure 17-12). A central venule (or vein) in the core of the hepatic lobule collects the sinusoidal blood containing a mixture of blood supplied by branches of the portal vein and the hepatic artery.

Branches of the hepatic artery and portal vein, together with a bile duct, form the classic portal triad found in the portal space surrounding the hexagonal-shaped hepatic lobule (Figure 17-11).

Figure 17-11 Histologic and functional classification of the hepatic lobule

Figure 17-12 Portal space and the bile ducts

Bile produced in the hepatocytes is secreted into narrow intercellular spaces, the bile canaliculi, located between the apposed surfaces of adjacent hepatocytes.

Bile flows in the opposite direction to the blood. Bile flows from the bile canaliculi into periportal bile ductules (cholangioles, or canals of Hering), and then into the bile ducts (or ductules) of the portal space after crossing the hepatic plate at the periphery of the hepatic lobule (Figure 17-12). Bile ductules converge at the intrahepatic bile ducts.

Functional view of the hepatic lobule

There are three conceptual interpretations of the architecture of the liver lobule (see Figure 17-11): (1) the classic concept of the hepatic lobule, based on structural parameters; (2) the portal lobule concept, based on the bile drainage pathway from adjacent lobules toward the same bile duct; and (3) the liver acinus concept, based on the gradient distribution of oxygen along the venous sinusoids of adjacent lobules.

The classic hepatic lobule is customarily described as a polyhedral structure, usually depicted as a hexagon with a central venule to which blood sinusoids converge (see Figure 17-11).

Components of the portal triad, constituting a branch of the portal vein and hepatic artery and a bile duct, are usually found at the angles of the hexagon. This geometric organization is poorly defined in humans because the limiting perilobular connective tissue is not abundant. However, recognition of the components of the portal triad is helpful in determining the boundaries of the human hepatic lobule.

In the portal lobule, the portal triad is the central axis, draining bile from the surrounding hepatic parenchyma.

Functional considerations have modified the classic view and a liver acinus concept has gained ground in pathophysiology. In the liver acinus, the boundaries are determined by a terminal branch of the hepatic artery. The flow of arterial blood within the venous sinusoids creates gradients of oxygen and nutrients classified as zones I, II, and III. Zone I is the richest in oxygen and nutrients. Zone III, closer to the central vein, is oxygen-poor. Zone II is intermediate in oxygen and nutrients (see Figure 17-11).

Although pathologic changes in the liver are usually described in relation to the classic lobule, the liver acinus concept is convenient for understanding liver regeneration patterns, liver metabolic activities, and the development of cirrhosis.

Hepatocyte

The hepatocyte is the functional exocrine and endocrine cell of the hepatic lobule. Hepatocytes form anastomosing one-cell-thick plates limiting the sinusoidal spaces. The perisinusoidal space of Disse separates the hepatocytes from the blood sinusoidal space (Figure 17-13).

Figure 17-13 Organization of the hepatic lobule

The components of the portal triad, embedded in connective tissue, are separated from the hepatic lobule by a limiting plate of hepatocytes (see Figure 17-12). Blood from the portal vein and hepatic artery flows into the sinusoids and is drained by the central venule. Recall that bile flows in the opposite direction, from the hepatocytes to the bile duct in the portal space (see Figure 17-13).

A hepatocyte has two cellular domains: (1) a basolateral domain and (2) an apical domain (Figures 17-14 to 17-16):

Figure 17-14 Endoplasmic reticulum in hepatocytes

Figure 17-15 Apical and basolateral domains of hepatocytes

Figure 17-16 Hepatic sinusoids and bile canaliculi

The basolateral domain contains abundant microvilli and faces the space of Disse. Excess fluid in the space of Disse is collected in the space of Mall, located at the periphery of the hepatic lobule. Lymphatic vessels piercing the limiting plate drain the fluid of the space of Mall. Gap junctions on the lateral surfaces of adjacent hepatocytes enable intercellular functional coupling.

The basolateral domain participates in the absorption of blood-borne substances and in the secretion of plasma proteins (such as albumin, fibrinogen, prothrombin, and coagulation factors V, VII, and IX). Note that hepatocytes synthesize several plasma proteins required for blood clotting (see Chapter 6, Blood and Hematopoiesis). Blood coagulation disorders are associated with liver disease.

The apical domain borders the bile canaliculus, a trenchlike depression lined by microvilli and sealed at the sides by occluding junctions to prevent leakage of bile, the exocrine product of the hepatocyte (see Figure 17-15).

The hepatocyte contains a rough endoplasmic reticulum (see Figure 17-14), involved in the synthesis of plasma proteins, and a highly developed smooth endoplasmic reticulum, associated with the synthesis of glycogen, lipid, and detoxification mechanisms (Figure 17-17).

Figure 17-17 Ethanol metabolism in hepatocytes

Enzymes inserted in the membrane of the smooth endoplasmic reticulum are involved in the following functions: (1) the synthesis of cholesterol and bile salts; (2) the glucuronide conjugation of bilirubin, steroids, and drugs; (3) the breakdown of glycogen into glucose; (4) the esterification of free fatty acids to triglycerides; (5) the removal of iodine from the thyroid hormones triiodothyronine (T₃) and thyroxine (T₄); and (6) the detoxification of lipid-soluble drugs such as phenobarbital, during which the smooth endoplasmic reticulum is significantly developed.

The Golgi apparatus contributes to glycosylation of secretory proteins and the sorting of lysosomal enzymes. Lysosomes degrade aged plasma glycoproteins internalized at the basolateral domain by a hepatic lectin membrane receptor—the asialoglycoprotein receptor—with binding affinity to terminal galactose after the removal of sialic acid. Lysosomes in hepatocytes store iron, which can exist as soluble ferritin and insoluble hemosiderin, the degradation product of ferritin.

Peroxisomes

Peroxisomes are membrane-bound organelles with a high content of oxidases that generate hydrogen peroxide (Figure 17-18). Because hydrogen peroxide is a toxic metabolite, the enzyme catalase degrades this product into oxygen and water. This catalytic event occurs in hepatocytes and cells of the kidneys.

Figure 17-18 Peroxisome

Peroxisomes derive from preexisting peroxisomes by a budding process. Then, the organelle imports peroxisomal matrix proteins. A peroxisome contains about 50 enzymes involved in various metabolic pathways. The biogenesis of peroxisomes and their role in inherited disorders are outlined in Figure 17-18 and in Chapter 2, Epithelial Glands.

Clinical significance: Liver storage diseases

Severe liver diseases can result from the excessive storage of iron and copper. Hereditary hemochromatosis is an example of a disease characterized by increased iron absorption and accumulation in lysosomal hepatocytes. Cirrhosis and cancer of the liver are complications of hemochromatosis.

Wilson’s disease (hepatolenticular degeneration) is a hereditary disorder of copper metabolism in which excessive deposits of copper in liver and brain lysosomes produce chronic hepatitis and cirrhosis.

Clinical significance: Alcoholism and fatty liver (alcoholic steato-hepatitis)

After absorption in the stomach, most ethanol is transported to the liver, where it is metabolized to acetaldehyde and acetate in the hepatocytes. Ethanol is mainly oxidized by alcohol dehydrogenase, an NADH (reduced form of nicotinamide adenine dinucleotide)–dependent enzyme. This mechanism is known as the alcohol dehydrogenase (ADH) pathway. An additional metabolic pathway is the microsomal ethanol-oxidizing system (MEOS), present in the smooth endoplasmic reticulum. The two pathways are summarized in Figure 17-17.

Long-term consumption of ethanol results in fatty liver (a reversible process if ethanol consumption is discontinued), steatohepatitis (fatty liver accompanied by an inflammatory reaction), cirrhosis (collagen proliferation or fibrosis), and hepatocellular carcinoma (malignant transformation of hepatocytes).

The production of tumor necrosis factor–α (TNF-α) is one of the initial events in liver injury. TNF-α triggers the production of other cytokines. TNF-α, regarded as a proinflammatory cytokine, recruits inflammatory cells that cause hepatocyte injury and promote the production of type I collagen fibers by perisinusoidal cells of Ito (a process known as fibrogenesis) as a healing response.

Injury of hepatocytes results in programmed cell death, or apoptosis, caused by the activation of caspases (see Chapter 3, Cell Signaling). TNF-α participates in a number of inflammatory processes such as in the articular joints (Chapter 5, Osteogenesis) and the extravasation of inflammatory cells (Chapter 10, Immune-Lymphatic System).

Ethanol, viruses, or toxins induce Kupffer cells to synthesize TNF-α as well as transforming growth factor-β (TGF-β) and interleukin-6 (Figure 17-19). TGF-β stimulates the production of type I collagen by perisinusoidal cells, which increase in number. TNF-α acts on biliary ducts to interfere with the flow of bile (cholestasis).

Figure 17-19 Cytokines in chronic liver disease

Clinical significance: Perisinusoidal cells

Perisinusoidal cells (of Ito; also called hepatic stellate cells) are found in the space of Disse in proximity to the hepatic sinusoids. These cells are of mesenchymal origin, contain fat, and are involved in (1) the storage and release of retinoids; (2) production and turnover of extracellular matrix; and (3) regulation of blood flow in the sinusoids. Perisinusoidal cells remain in a quiescent, nonproliferative state, but can proliferate when activated by Kupffer cells and hepatocytes. Activation occurs after partial hepatectomy, focal hepatic lesions, and in different conditions that lead to fibrosis (Figure 17-20).

Figure 17-20 Perisinusoidal cells

In pathologic conditions, perisinusoidal cells change into collagen-producing cells. In addition to the synthesis and secretion of type I collagen, perisinusoidal cells secrete laminin, proteoglycans, and growth factors. The deposit of collagen and extracellular matrix components increases, leading to a progressive fibrosis of the liver, which is typical of cirrhosis.

TGF-β, produced by Kupffer cells and hepatocytes (see Figures 17-19 and 17-20), stimulates collagen production by perisinusoidal cells. An increased deposit of collagen fibers and extracellular matrix within the space of Disse is followed by a loss of fenestrations and gaps of sinusoidal endothelial cells.

As the fibrotic process advances, perisinusoidal cells change into myofibroblasts constricting the lumen of the sinusoids and increasing vascular resistance. An increase in resistance to the flow of portal venous blood in the hepatic sinusoids leads to portal hypertension in cirrhosis.

Bile: Mechanism of secretion

Bile is a complex mixture of organic and inorganic substances produced by the hepatocyte, transported by the bile canaliculus, an extracellular canal between adjacent hepatocytes (Figure 17-21). The bile canaliculus defines the apical domain of the hepatocyte. The basolateral domain faces the sinusoidal space. Tight junctions between adjacent hepatocytes seal the biliary canalicular compartment.

Figure 17-21 Bile canaliculus and the polarity of the hepatocyte

The primary organic components of bile are conjugated bile acids (called bile salts), glycine, and taurine N-acyl amidated derivatives of bile acids derived from cholesterol.

Bile has five major functions:

The transport of bile and other organic substances from the hepatocyte to the lumen of the bile canaliculus is an adenosine triphosphate (ATP)–mediated process. Four ATP-dependent transporters, present in the canalicular plasma membrane, participate in transport mechanisms of the bile (Figure 17-22).

Figure 17-22 Transport of bile into the bile canaliculus

These ATP transporters belong to the family of ABC transporters characterized by highly conserved ATP-binding domains, or ATP binding cassettes. The first ABC transporter was discovered as the product of the gene mdr (for multiple drug resistance). The mdr gene is highly expressed in cancer cells and the encoded product, MDR transporter, pumps drugs out of cells, making cancer cells resistant to cancer treatment with chemotherapeutic agents (see Cell Nucleus in Chapter 1, Epithelium).

The secretion of bile acids generates the osmotic gradient necessary for osmotic water flow into the bile canaliculus. In addition, an ion exchanger enables the passage of HCO₃⁻ and Cl⁻ ions. Finally, hydrolytic enzymes associated with the plasma membrane (ectoenzymes) of the bile canaliculus and bile duct produce nucleoside and amino acid breakdown products, which are reabsorbed by ductular epithelial cells.

A genetic defect in MDR2 causes focal hepatocyte necrosis, proliferation of bile ductules, and an inflammatory reaction in the portal space. Very low levels of phospholipids are detected in the bile of MDR2 mutants.

Metabolism of bilirubin

Bilirubin is the end product of heme catabolism and about 85% originates from senescent red blood cells destroyed mainly in the spleen by macrophages (Figure 17-23).

Figure 17-23 Metabolism of bilirubin

Bilirubin is released into the circulation, where it is bound to albumin and transported to the liver. Unlike albumin-bound bilirubin, free bilirubin is toxic to the brain. Recall from our discussion of erythroblastosis fetalis (see Chapter 6, Blood and Hematopoiesis) that an antibody-induced hemolytic disease in the newborn is caused by blood group incompatibility between the mother and fetus. The hemolytic process results in hyperbilirubinemia caused by elevated amounts of free bilirubin, which causes irreversible damage to the central nervous system (kernicterus).

When albumin-conjugated bilirubin reaches the hepatic sinusoids, the albumin-bilirubin complex dissociates, and bilirubin is transported across the plasma membrane of hepatocytes after binding to a plasma membrane receptor. Inside the hepatocyte, bilirubin binds to ligandin, a protein that prevents bilirubin reflux into the circulation. The bilirubin-ligandin complex is transported to the smooth endoplasmic reticulum, where bilirubin is conjugated to glucuronic acid by the uridine diphosphate (UDP)–glucuronyl transferase system. This reaction results in the formation of a water-soluble bilirubin diglucuronide, which diffuses through the cytosol into the bile canaliculus, where it is secreted into the bile.

In the small intestine, conjugated bilirubin in bile remains intact until it reaches the distal portion of the small intestine and colon, where free bilirubin is generated by the intestinal bacterial flora.

Unconjugated bilirubin is then reduced to urobilinogen. Most urobilinogen is excreted in the feces. A small portion returns to the liver following absorption by a process known as enterohepatic bile circulation. Another small fraction is excreted in the urine.

Composition of the bile

The human liver produces about 600 mL of bile per day. The bile consists of organic components (such as bile acids, the major component; phospholipids, mainly lecithins; cholesterol; and bile pigments, bilirubin) and inorganic components (predominantly Na⁺ and Cl⁻ ions).

Bile acids (cholic acid, chenodeoxycholic acid, deoxycholic acid, and lithocholic acid) are synthesized by the hepatocytes. Cholic and chenodeoxycholic acids are synthesized from cholesterol as a precursor and are called primary bile acids. Deoxycholic and lithocholic acids are called secondary bile acids because they are produced in the intestinal lumen by the action of intestinal bacteria on the primary bile acids.

The synthetic bile acid pathway is the major mechanism of elimination of cholesterol from the body. Micelles are formed by the aggregation of bile acid molecules conjugated to taurine or glycine. Cholesterol is located inside the micelles. Bile pigments are not components of the micelles.

Bile secreted by the liver is stored in the gallbladder and released into the duodenum during a meal to facilitate the breakdown and absorption of fats (see Figure 16-9 in Chapter 16, Lower Digestive Segment). About 90% of both primary and secondary bile acids is absorbed from the intestinal lumen by enterocytes and transported back to the liver through the portal vein. This process is known as the enterohepatic circulation. The absorption of bile acids by the enterocyte is mediated at the apical plasma membrane by an Na⁺-dependent transporter protein and released through the basolateral plasma membrane by an Na⁺-independent anion exchanger.

Bilirubin is not absorbed in the intestine. Bilirubin is reduced to urobilinogen by bacteria in the distal small intestine and colon (see Figure 17-23). Urobilinogen is partially secreted in the feces, part returns to the liver through the portal vein, and some is excreted in urine as urobilin, the oxidized form of urobilinogen.

Bile acids establish an osmotic gradient that mobilizes water and electrolytes into the bile canaliculus. HCO₃⁻ ions, secreted by epithelial cells lining the bile ducts, are added to the bile, which becomes alkaline as Na⁺ and Cl⁻ ions and water are absorbed. Secretin increases the active transport of HCO₃⁻ into the bile.

The flow of bile into the duodenum depends on (1) the secretory pressure generated by the actively bile-secreting hepatocytes and (2) the flow resistance in the bile duct and sphincter of Oddi.

The sphincter of Oddi is a thickening of the circular muscle layer of the bile duct at the duodenal junction. During fasting, the sphincter of Oddi is closed and bile flows into the gallbladder. The gallbladder’s ability to concentrate bile 5 to 20 times compensates for the limited storage capacity of the gallbladder (20 to 50 mL of fluid) and the continuous production of bile by the liver.

Bile secretion during meal digestion is initiated by the cholecystokinin-induced contraction of the muscularis of the gallbladder in response to lipids in the intestinal lumen, assisted by the muscular activities of the common bile duct, the sphincter of Oddi, and the duodenum. Cholecystokinin stimulates the relaxation of the sphincter of Oddi, enabling bile to enter the duodenum. Note that cholecystokinin has opposite effects: it stimulates muscle contraction of the gallbladder and induces muscle relaxation of the sphincter of Oddi.

Clinical significance: Pathologic conditions affecting bile secretion

Because bile secretion involves the hepatocytes, bile ducts, gallbladder, and intestine, any perturbation along this pathway can result in a pathologic condition. For example, destruction of hepatocytes by viral infection (viral hepatitis) and toxins can lead to a decrease in bile production as well as an increase in bilirubin in blood (jaundice).

Obstruction of the passages by gallstones, infection, or tumors can block the flow of bile, with bile reflux to the liver and then to the systemic circulation.

Clinical significance: Hyperbilirubinemia

Several diseases occur when one or more of the metabolic steps of bilirubin formation are disrupted. A characteristic feature is hyperbilirubinemia—an increase in the concentration of bilirubin in the blood (more than 0.1 mg/mL).

Gilbert’s syndrome is the most common inborn error of metabolism causing moderate hyperbilirubinemia. Elevated levels of unconjugated bilirubin, with no serious health consequences, are detected in the bloodstream. The cause is the reduced activity of the enzyme glucuronyl transferase, which conjugates bilirubin (see Figure 17-23).

An inherited defect in the UDP–glucuronyl transferase system, known as Crigler-Najjar disease, results in failure to conjugate bilirubin in hepatocytes and the absence of conjugated bilirubin diglucuronide in bile. Infants with this disease develop bilirubin encephalopathy.

The Dubin-Johnson syndrome is a familial disease caused by a defect in the transport of conjugated bilirubin to the bile canaliculus. In addition to the transport of conjugated bilirubin, there is a general defect in the transport and excretion of organic anions in these patients.