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Main functions of these glands • Products of these organs facilitate transport and digestion of food within the gastrointestinal tract. • Salivary glands moisten and lubricate ingested food and the oral mucosa, to initiate the digestion of carbohydrates and lipids with amylase and lipase, and to secrete innate immune components such as lysozyme and lactoferrin• The pancreas secretes digestive enzymes that act in the small intestine and hormones important for the metabolism of the absorbed nutrients • Bile, whose components are necessary for digestion and absorption of fats, is made in the liver but stored and concentrated in the gallbladder • Liver also plays a major role in carbohydrate and protein metabolism, inactivates many toxic substances and drugs, and synthesizes most plasma proteins and factors necessary for blood coagulation SALIVARY GLANDS • There are 3 pairs of large salivary glands: • parotid, submandibular, and sublingual glands • Together produce about 90% of saliva • in addition numerous minor or intrinsic salivary glands located throughout most of the oral mucosa (Labial and buccal, Glossopalatine, Palatine, Lingual) which secrete about 10% of the total saliva volume Parotid salivary gland Sublingual salivary gland Submandibular salivary glandType of secretion • The secretion of each gland is either : • Serous, seromucous, or mucous • parotids is serous and watery • Submandibular and sublingual glands produce a seromucous secretion • Minor glands is mostly mucous except for the small serous glands at the bases of circumvallate papillaeThree epithelial cell types comprise the salivary secretory units • Serous cells : • are protein-secreting cells • usually pyramidal in shape, with basal round nuclei, well-stained RER, and apical secretory granules • Joined apically by tight and adherent junctions, • serous cells form a somewhat spherical unit called an acinus with a very small central lumen • Serous acini are intensely stained (pink-purple) due to their protein content( basal basophilic & apical acidophilic) • Serous acinar cells secrete enzymes such as alphaamylase, which catalyzes the hydrolysis of starch into simpler sugars like maltose • Mucous cells : • are more columnar in shape, with more compressed flat basal nuclei • Mucous cells contain apical granules with hydro philic mucins that provide lubricating properties • More weakly stains than serous acini • Cytoplasm appears pale, foamy • Stains like PAS (Periodic Acid-Schiff) or Alcian blue can highlight the carbohydrate-rich mucins in mucous acini, appearing reddish-pink or pale blue, respectively • Mucous cells are most often organized as cylindrical tubules rather than acini • mucous also acts as a barrier against pathogensStructural organization of salivary glandSerous demilune • Within the mixed units grouped serous cells occur distally on short mucous tubules and often assume a crescent-shaped arrangement called a serous demilune• Myoepithelial cells: • are found inside the basal lamina surrounding acini, tubules, and the proximal ends of the duct system • These cells are present between the basal lamina and the secretory or duct cells and are joined to the cells by desmosomes • They appear similar to smooth muscle but are derived from the epithelium • Have stellate-shaped, numerous branching processes with a flattened nucleus extend several contractile processes around the associated secretory unit or duct Function of myoepithelial cells • their activity is important for moving secretory products into and through the ducts • accelerate the initial flow of saliva from the acini, reduce luminal volume • support the underlying parenchyma, • reduce the back permeation of fluid • They secrete various tumor suppressor proteins such as protease inhibitors and antiangiogenesis factors which provide a barrier against invasive epithelial neoplasm.Duct system • It consists of hollow tubes that connect initially with the acinus (secretory end pieces) and extends to the oral cavity • it actively participates in the production and modification of saliva • On the basis of location, ducts are of two types: • Intralobular ducts: Those ducts which are within the lobule • intercalated • striated ducts • Interlobular ducts: Those ducts which lie within the connective tissue within the lobules of the gland • The excretory ductsIntercalated ducts • These are lined by single layer of cuboidal epithelium and are surrounded by myoepithelial cell bodies, • have centrally placed nuclei • A few secretory granules may be found in the apical cytoplasm, especially in the cells located near the endpieces • The apical cell surface has a few short microvilli projecting into the lumen • lateral surfaces are joined by junctional complexes • The macromolecule components, i.e., lysozyme and lactoferrin, are stored in the secretory granules of the intercalated duct and contribute to the saliva. – Lactoferrin binds iron, a vital nutrient for many microbes and disrupting microbial membranes – Lysozyme hydrolyzes the cell wallStriated ducts • Several of intercalated ducts join to form a striated duct • Striated ducts lined by columnar cells with a centrally placed large, spherical nucleus and pale, acidophilic cytoplasm. • By EM basal infoldings of the plasma membrane • a large amount of radially oriented mitochondria • The combination of infoldings and mitochondria accounts for the striations seen in the light microscopeFunction of striated ducts • their folded cell membranes present a large surface area with ion transporters, facilitating rapid ion transcytosis and making the secretion slightly hypotonic • These ducts are involved in active transport and are considered as site of electrolyte reabsorption especially of sodium and chloride and secretion of potassium and bicarbonate• A striated duct shows very faint striations in the basal half of the columnar cells, which represent mitochondria located in the folds of the lateral cell membrane Inter lobular excretory ducts • These ducts are located in the CT septa between the lobules of the gland • are larger in diameter than striated duct • The lining of these ducts is unusual, combining various epithelial types, including simple cuboidal or columnar, stratified cuboidal or columnar, and pseudostratified epithelia, distributed in no apparent pattern. • These atypical epithelia may reflect their composition of cells with many diverse functions, including cells for ion reabsorption, cells for secretion of mucin and other proteins, enteroendocrine cells, and basal stem cells• The main excretory duct may become stratified near the oral opening • Before emptying into the oral cavity, the main duct of each gland is lined with nonkeratinized stratified squamous epithelium • Tuft or brush cells found in the lining of epithelial tissues, including the duct system • These cells have long stiff microvilli and apical vesicles and are considered as chemoreceptor cells as they show nerve endings adjacent to the basal portion of the cell • Dendritic cells are found in various parts of the gland, including the ducts, acini, and interstitial tissues play an important role in immune surveillance (antigen presentation)Histology of serous glandHistology of mixed glandSaliva has protective function • Plasma cells in CT surrounding the intralobular ducts release IgA, which forms a complex with the secretory component synthesized by the epithelial cells of the serous acini and intralobular ducts. • The IgA complex released into the saliva provides defense against specific pathogens in the oral cavityThe functions of saliva are: Protection: – Lubricant – Mechanical washing • Buffering: _ Many bacteria need a specific pH for growth; saliva prevents potential pathogens from colonizing in the mouth by denying them optimal environmental conditions. – Plaque microorganisms can produce acids from sugars, which if not rapidly buffered and cleared by saliva can demineralize enamel. • Digestion: It provides taste acuity, neutralizes esophageal contents, and forms the food bolus. • Taste: It dissolves substances to be carried to taste buds and also contains a protein, called gustin, which is necessary for growth and maturation of taste buds.• Antimicrobial action: This occurs in various ways as: – Lactoferrin binds free iron deprives bacteria of its essential element – Lysozyme hydrolyzes the cell wall. – Histatin proteins with antibacterial property. – Immunoglobulin, secretory IgA, clumps or agglutinates microorganisms. • Maintenance of tooth integrity: Saliva is saturated with calcium and phosphate ions, and interaction with saliva results in postoperative maturation through diffusion of such ions. This maturation increases surface hardness, decreases permeability, and increases the resistance of enamel to caries. • Tissue repair: The rate of wound contraction is significantly increased in saliva due to the presence of peptides and proteins present in saliva.Saliva production • Parasympathetic stimulation, usually elicited through the smell or taste of food, provokes a copious watery secretion with relatively little organic content • Sympathetic stimulation inhibits such secretion and produces the potential for dry mouth often associated with anxietyMedical application • Inadequate saliva production, leading to dry mouth or xerostomia, can be caused by various factors affecting the major salivary glands, such as mumps viral infection, radiation of the glands, or the normal side effect of drugs such as antihistamines • Excessive saliva production, or sialorrhea, is associated with the autonomic activity of nausea, inflammation within the oral cavity, and rabies viral infectionParotid glands • located in each cheek near the ear • are branched acinar glands with exclusively serous acini • Serous cells secrete abundant α-amylase that initiates hydrolysis of carbohydrates and proline-rich proteins with antimicrobial and other protective propertiesMicrograph of a parotid gland shows densely packed serous acini (A) Secretory granules of serous cells as well as an intercalated duct (ID) striated duct (SD) Striations of a duct (SD) are better seen here, along with a septum (CT) and numerous serous acini (A). The connective tissue often includes adipocytesSubmandibular glands • produce two-thirds of all saliva • are branched tubuloacinar glands • having primarily serous acini, but with many mixed tubuloacinar secretory units • Within the mixed units grouped serous cells occur distally on short mucous tubules and often assume a crescent-shaped arrangement called a serous demilune • In addition to α-amylase and proline-rich proteins, serous cells of the submandibular gland secrete lysozyme for hydrolysis of bacterial wallsSublingual glands • The smallest of the major glands • are also branched tubuloacinar glands • secretory tubules of mucous cells predominate and the main product of the gland is mucus • The few serous cells present add amylase and lysozyme to the secretion.The submandibular gland is a mixed serous and mucous gland (serous cells redominate) The sublingual gland is a mixed but largely mucous glandPancreas • Is a mixed exocrine-endocrine gland that produces both digestive enzymes and hormones. • with a large head near the duodenum and more narrow body and tail regions that extend to the left • Has a thin capsule of CT from which septa extend to cover the larger vessels and ducts and to separate the parenchyma into lobules • The secretory acini are surrounded by a basal lamina that is supported only by a delicate sheath of reticular fibers with a rich capillary network. • somewhat resembles the parotid gland histologically, although the pancreas lacks striated ducts and the parotid glands lack islets of endocrine tissue • Each pancreatic acinus consists of several serous cells surrounding a very small lumen, without myoepithelial cells • The acinar cells have round basal nuclei, and numerous zymogen granules apically, typical of protein-secreting cells FUNCTION • Endocrine function involves smaller cells located in variously sized clusters called the pancreatic islets (islets of Langerhans) • Digestive enzymes are produced by cells of serous acini in the larger exocrine portion of the pancreas DUCT SYSTEM • Each acinus is drained by a short intercalated duct of simple squamous or low cuboidal epithelium • The initial cells of these small ducts extend into the lumen of the acinus as small pale-staining centroacinar cells that are unique to the pancreas• Under the influence of secretin, the centroacinar and intercalated duct cells of the intercalated ducts secrete a large volume of fluid, rich in HCO3 − (bicarbonate ions), which alkalinizes and transports hydrolytic enzymes produced in the acini• The intercalated ducts merge with intralobular ducts that lined with simple columnar epithelium • and larger interlobular ducts, which have increasingly columnar epithelia before joining the main pancreatic duct that runs the length of the gland lined with simple columnar epithelium • The ducts and blood vessels are located in connective tissueMicrograph of exocrine pancreas shows the serous, with very small lumens. Each acinus is drained by an intercalated duct with its initial cells, the centroacinar cells (arrow), inserted into the acinar lumen. (b) The diagram shows the arrangement of cells more clearly..Function of exocrine pancreas • Is a mixture of : • acinar secretion (proenzymes) • And duct secretion (bicarbonate) • The exocrine pancreas secretes approximately 1.5 L of alkaline pancreatic juice per day and delivers it directly into the duodenum where the HCO3− ions neutralize the acidic chyme entering there from the stomach and establish the pH for optimal activity of the pancreatic enzymes• These digestive enzymes include several proteases, α-amylase, lipases, and nucleases (DNAase and RNAase). • The proteases are secreted as inactive zymogens (trypsinogen, chymotrypsinogen, proelastase, and procarboxipeptidases). • Trypsinogen is cleaved and activated by enteropeptidases in the duodenum, generating trypsin that activates the other proteases in a cascade. Pancreatic tissue is protected against autodigestion by the following: • Storing the enzymes as inactive zymogen • Restricting protease activation to the duodenum • Trypsin inhibitor, which is copackaged in the secretory granules with trypsinogen • The higher pH in the acini and duct system due to HCO3− secreted by the centroacinar and intercalated duct cells, which helps keep all the enzymes inactiveRegulation of exocrine pancreatic secretion • Mainly through two polypeptide hormones produced by enteroendocrine cells of the small intestine in response to fatty acids & proteins:

1. Cholecystokinin (CCK) stimulates enzyme secretion by the acinar cells.
2. Secretin stimulate HCO3− secretion by the duct cells, reduces concentration of H ions & raising PH optimal for digestion • Autonomic (parasympathetic) nerve fibers also stimulate secretion from both acinar and duct cells.Medical application • Pancreatic cancer, which is usually a carcinoma of duct cells, can arise anywhere in the gland but occurs most often in the head of the organ near the duodenum. The tumor is usually asymptomatic until growth and metastasis are well advanced, leading to the low rate of early detection and subsequent high rate of mortality. • In acute pancreatitis, the proenzymes may be activated and digest pancreatic tissues, leading to very serious complications. Possible causes include infection, gallstones, alcoholism, drugs, and trauma. Chronic pancreatitis can produce progressive fibrosis and loss of pancreatic function. Liver • The liver is the largest internal organ, in adults averaging about 1.5 kg or 2% of the body weight. • Located in the right upper quadrant of the abdomen just below the diaphragm • Has major left and right lobes with two smaller inferior lobes, • most of which are covered by a thin capsule (Glisson'scapsule )and mesothelium of the visceral peritoneum • The capsule thickens at the hilum (or porta hepatis) on the inferior side, where the dual blood supply from the hepatic portal vein and hepatic artery enters the organ and where the hepatic vein, lymphatics, and common hepatic (bile) duct exit.Blood supply to the liver (hepatic circulation)Function of the liver • The main digestive function of the liver is production of bile, a complex substance required for the emulsification, hydrolysis, and uptake of fats in the duodenum. • The liver is also the major interface between the digestive system and the blood, as the organ in which nutrients absorbed in the small intestine are processed before distribution throughout the body. • About 75% of the blood entering the liver is nutrient-rich (but O2-poor) blood from the portal vein arising from the stomach, intestines, and spleen; the other 25% comes from the hepatic artery and supplies the organ’s O2.• In addition to secretion of bile components, hepatocytes and other liver cells process the contents of blood, with many specific functions: • Synthesis and secretion of the major plasma proteins, including albumins, fibrinogen, apolipoproteins, transferrin, and many others • Production of angiotensinogen important for salt conserving (renin-angiotensin-aldosterone system) • Breakdown (detoxification) and conjugation of ingested toxins, including many drugs • Amino acid deamination, producing urea removed from blood in kidneys• Conversion of amino acids into glucose (gluconeogenesis) • Storage of glucose in glycogen granules and triglycerides in small lipid droplets • Storage of vitamin A (in hepatic stellate cells) and other fat-soluble vitamins • Removal of effete erythrocytes (by specialized macrophages, or Kupffer cells) • Storage of iron in complexes with the protein ferritin. • Activation of vitamin D to 25,hydroxy D3(calcidiol) by 25,hydoxlase enzyme • calcidiol converted to calcitriol ( 1,25,hydroxy D3) in kidney by 1α hydroylase • Secret hormones : thrombopointin , hipicidin • Secret cholesterol and bilirubin Structure and function of liver • Abundant rough ER is focused on synthesis of plasma proteins and causes cytoplasmic basophilia • Abundant smooth ER, contains the enzyme systems for the inactivation or detoxification of substances in blood, which are then usually excreted with bile. • These include enzymes responsible for oxidation, methylation, and conjugation of steroids, barbiturates, antihistamines, and other drugs. • Other SER enzymes (glucuronosyl transferases) conjugate bilirubin to glucuronate, rendering it more soluble and facilitating its excretion in bile• Glycogen granules and small lipid droplets in hepatocytes, and very small electron-dense ferritin complexes (hemosiderin) primarily in the Kupffer cells, respectively mediate temporary storage of glucose, triglycerides, and iron. • Liver glycogen is depot of glucose and is mobilized if blood glucose falls bellow normal • Hepatocyte peroxisomes are also abundant and important for oxidation of excess fatty acids and conversion of excess purines to uric acid • Many Golgi complexes are also present, involved in synthesis of both plasma proteins and bile components. • The numerous mitochondria provide energy for all these activities Hepatocytes & Hepatic Lobules • Hepatocytes are large cuboidal or polyhedral epithelial cells, with large, round central nuclei and eosinophilic cytoplasm rich in mitochondria. • The cells are frequently binucleated and about 50% of them are polyploid, with two to eight times the normal chromosome number • The liver parenchyma is organized as thousands of small (~0.7 × 2 mm) hepatic lobules in which hepatocytes form hundreds of irregular plates arranged radially around a small central vein • The hepatocyte plates are supported by a delicate stroma of reticulin fibershepatic lobules are polygonal units showing plates of epithelial cells called hepatocytes radiating from a central venule (C). (b) peripheral CT of portal areas contains the portal triad: small bile ductules (D), venule (V) branches of the portal vein, and arteriole (A) branches of the hepatic artery.(a) Hepatocytes (H) are polygonal epithelial cells, which form branching, irregular plates separated by venous sinusoids (S) Reticulin (collagen type III) fibers (R) running along the plates of hepatocytes (H) Most CT in the liver is found in the septa and portal tractsPortal area • Peripherally each lobule has 3 to 6 portal areas with more fibrous CT, each of which contains 3 interlobular structures that comprise the portal triad: • A venule branch of the portal vein, with blood rich in nutrients but low in O2. • An arteriole branch of the hepatic artery, which supplies O2. • One or two small bile ductules of cuboidal epithelium, branches of the bile conducting system. • Most of the peripheral portal areas also contain lymphatics and nerve fibersMedical application • In the normal liver most dense connective tissue is found only in the portal areas, surrounding the blood vessels and bile ductule. • In liver cirrhosis, which occurs late in chronic liver disease, fibrosis and proliferation of fibroblasts and hepatic stellate cells occur beyond the portal areas. The excessive connective tissue may disrupt the normal hepatic architecture and interfere with liver functionvascular sinusoids • Between all of the anastomosing plates of hepatocytes of a hepatic lobule • Emerge from the peripheral branches of the portal vein and hepatic artery and converge on the lobule’s central vein • The venous and arterial blood mixes in these irregular hepatic sinusoids • The anastomosing sinusoids have thin, discontinuous linings of fenestrated endothelial cells surrounded by sparse basal lamina and reticular fibersSpace of Disse • The discontinuities and fenestrations allow plasma to fill a narrow perisinusoidal space (or space of Disse) and directly bathe the many irregular microvilli projecting from the hepatocytes into this space • This direct contact between hepatocytes and plasma facilitates most key hepatocyte functions involving uptake and release of nutrients, proteins, and potential toxins • The fenestrae and discontinuity of endothelium allow the free flow of plasma but not of cellular elements into the space of DisseOther cells • are found with the sinusoids of hepatic lobules:
3. stellate macrophages, usually called Kupffer cells, are found on the luminal surface of the endothelial cells, within the sinusoids • These cells recognize and phagocytose aged erythrocytes, freeing heme and iron for reuse or storage in ferritin complexes • Kupffer cells are also antigen-presenting cells and remove any bacteria or debris present in the portal blood2. Hepatic stellate cells (or Ito cells) are found In the perisinusoidal space have small lipid droplets, which store vitamin A and other fat-soluble vitamins These mesenchymal cells, which are difficult to see in routine preparations, also produce extracellular matrix (ECM) components (becoming myofibroblasts after liver injury) and produce cytokines that help regulate Kupffer cell activityBlood circulation in liver • The endothelium of the central vein in the middle of each hepatic lobule is supported by a very thin layer of fibrous CT • Central venules from each lobule converge into larger veins, which eventually form two or more large hepatic veins that empty into the inferior vena cava. • Blood always flows from the periphery to the center of each hepatic lobule. • Consequently, oxygen and metabolites, as well as all other toxic or nontoxic substances absorbed in the intestines, reach the lobule’s peripheral cells first and then the more central cells. Bile secretion • The smaller apical surfaces of the hepatocytes form bile canaliculi and are involved in exocrine secretion of bile • Hepatocytes adhere firmly with desmosomes and junctional complexes. • The apical surfaces of two adherent hepatocytes are grooved and juxtaposed to form the canaliculus, sealed by tight junctions, into which bile components are secreted • These canaliculi are elongated spaces with large surface areas due to the many short microvilli from the constituent hepatocytes • The bile canaliculi form a complex anastomosing network of channels through the hepatocyte plates that end near the portal tracts• The bile flow therefore progresses in a direction opposite to that of the blood, that is, from the center of the lobule to its periphery • Bile canaliculi are the smallest branches of the biliary tree or bile conducting system • They empty into bile canals of Hering composed of cuboidal epithelial cells called cholangiocytes • The short bile canals quickly merge in the portal areas with the bile ductules lined by cuboidal or columnar cholangiocytes and with a distinct CT sheath. • Bile ductules gradually merge, enlarge, and form right and left hepatic ducts leaving the liver.Near the periphery of each hepatic lobule, many bile canaliculi join with the much larger bile canals of Hering, which are lined by cuboidal epithelial cells called cholangiocytes. These canals soon join the bile ductules in the portal areas and drain into the biliary tree.• Into the canaliculi hepatocytes continuously secrete bile, a mixture of : • bile acids (organic acids such as cholic acid) • bile salts (the deprotonated forms of bile acids), • electrolytes, fatty acids, phospholipids, cholesterol, and bilirubin • Some bile components are synthesized in hepatocyte SER, but most are taken up from the perisinusoidal space • all are quickly secreted into the bile canaliculi• Bile acids/salts have an important function in emulsifying the lipids in the duodenum, promoting their digestion and absorption. • Bilirubin is a pigmented breakdown product of heme that is released from splenic macrophages primarily, but also from Kupffer cells, and carried to hepatocytes bound to albumen. Released into the duodenum with bile, bilirubin is converted by intestinal bacteria into other pigmented products, some of which are absorbed in the intestinal mucosa to be processed and excreted again in the liver or excreted into urine by the kidneys. These bilirubinrelated compounds give feces and urine their characteristic colors.Medical application • An important function of hepatocyte SER is the conjugation of hydrophobic (water-insoluble), yellow bilirubin by glucuronosyl transferases to form watersoluble, nontoxic bilirubin glucuronide, which is excreted into the bile canaliculi. When bilirubin glucuronide is not formed or excreted properly, various diseases characterized by jaundice can result. • A frequent cause of jaundice in newborns is an underdeveloped state of the hepatocyte SER (neonatal hyperbilirubinemia). • A treatment in these cases is exposure to blue light from ordinary fluorescent tubes, which transforms unconjugated bilirubin into a water-soluble photoisomer that can be excreted by the kidneys.(1) RER is primarily engaged in synthesis of plasma proteins for release into the perisinusoidal space. (2) Potentially toxic compounds, bilirubin (bound to albumin) and bile acids are taken up from the perisinusoidal space, processed by enzymes in the tubulovesicular system of the SER, and secreted into the bile canaliculi. (3) Glucose is taken up from the perisinusoidal space and stored in glycogen granules, with the process reversed when glucose is needed.Hepatic lobules
4. The classic hepatic lobule with blood flowing past hepatocytes from the portal areas to a central venule, emphasizes the endocrine function of the structure producing factors for uptake by plasma.
5. The concept of portal lobules of hepatocytes is more useful when considering the exocrine function of these cells, that is, bile secretion • The portal area has the bile ductule at the center, and bile, moving in the opposite direction as the blood, flows toward it from all the surrounding hepatocytes • The tissue draining bile into each portal area duct is roughly triangular in shape, with the central veins of three classic lobules at its angles3. The hepatic acinus, a third way of viewing liver cells, emphasizes the nature of the blood supply to the hepatocytes and the oxygen gradient from the hepatic artery branch to the central vein • In a liver acinus hepatocytes make up an irregular oval or diamond-shaped area extending from two portal triads to the two closest central veins • The direction of blood flow partly explains why the properties and function of the periportal hepatocytes differ from those of the centrolobular cells • Periportal hepatocytes, comprising zone I in the acinus, get the most oxygen and nutrients and can most readily carry out functions requiring oxidative metabolism such as protein synthesis. • Hepatocytes in zone III, near the central vein, get the least oxygen and nutrients. They are the preferential sites of glycolysis, lipid formation, and drug biotransformations and are the first hepatocytes to undergo fatty accumulation and ischemic necrosis • In the intervening zone II, hepatocytes have an intermediate range of metabolic functions between those in zones I and IIIConcepts of structure-function relationships in liverLiver regeneration • Unlike the salivary glands and pancreas, the liver has a strong capacity for regeneration despite its normal slow rate of cell renewal. • Hepatocyte loss from the action of toxic substances triggers mitosis in the remaining healthy hepatocytes in a process of compensatory hyperplasia that maintains the original tissue mass. • Surgical removal of a liver portion produces a similar response in the hepatocytes of the remaining lobe • The regenerated liver tissue is usually well organized, with the typical lobular arrangement, and replaces the functions of the destroyed tissue. • This regenerative capacity is important clinically because one major liver lobe can sometimes be donated by a living relative for surgical transplant and full liver function restored in both donor and recipient. • Besides proliferation of existing hepatocytes, a role for liver stem cells in regeneration has been shown in some experimental models. Such cells, often called oval cells, are present among cholangiocytes of the bile canals near portal areas and produce progenitor cells for both hepatocytes and cholangiocytes.• Liver regeneration following partial hepatectomy occurs in three phases including : • (a) initiation or priming phase • (b) proliferation phase • (c) termination phase• Priming phase occurs within 5 hours of hepatectomy and involves activation and over expression of multiple specific genes to prepare the hepatocytes for replication. The regulatory mechanisms prepare hepatocytes to enter the cell cycle. • The proliferation phase involves activation of various growth factors, During this phase, hepatocytes undergo a series of cell division cycles and expansion • ]Termination phase is coordinated by TGF-β (transforming growth factor beta) that is responsible for stopping the regenerative process and preventing liver overgrowthMedical application • Fatty liver disease is a reversible condition in which large lipid droplets containing triglycerides accumulate abnormally in hepatocytes via the process called steatosis (fat buildup). • This disorder has multiple causes, but it occurs most commonly in individuals with alcoholism or obesity. Accumulation of fat in hepatocytes may produce a progressive inflammation of the liver, or hepatitis, in this case called steatohepatitisBiliary tree and gall bladder • The bile produced by the hepatocytes flows through the bile canaliculi, bile ductules, and bile ducts. These structures gradually merge, forming a converging network that ultimately forms the common hepatic duct, which joins the cystic duct from the gallbladder and continues to the duodenum as the common bile duct• The hepatic, cystic, and common bile ducts are lined with a mucous membrane having a simple columnar epithelium of cholangiocytes. • The lamina propria and submucosa are relatively thin, with mucous glands in some areas of the cystic duct, and surrounded by a thin muscularis • This muscle layer becomes thicker near the duodenum and finally, in the duodenal papilla, forms a sphincter of Oddi that regulates bile flow into the small bowelGall bladder • The gallbladder is a hollow, pear-shaped organ • capable of storing 30-50 mL of bile that is concentrated during storage. • The wall of the gallbladder consists of : • a mucosa composed of simple columnar epithelium and lamina propria, a thin muscularis with bundles of muscle fibers oriented in several directions, and an external adventitia or serosa • The mucosa has numerous folds that are particularly evident when the gallbladder is emptyThe gallbladder is a saclike structure that stores and concentrates bile, and releases it into the duodenum after a meal. (a) Its wall consists largely of a highly folded mucosa, with a simple columnar epithelium (arrows) overlying a typical lamina propria (LP); a muscularis (M) with bundles of muscle fibers oriented in all directions to facilitate emptying of the organ; and an external adventitia (A) where it is against the liver and a serosa where it is exposedUltra structure of epithelial cells • The lining epithelial cells of the gallbladder are active transport have prominent mitochondria, microvilli, and large intercellular spaces • Actively transporting water, for concentrating bile • The mechanism for this includes activity of Na+ pumps in the basolateral membranes, followed by passive movement of water from the bile. •Release of bile • To move stored bile into the duodenum, contraction of the gallbladder muscularis is induced by cholecystokinin (CCK) released from enteroendocrine cells of the small intestine. • Release of CCK is, in turn, stimulated by the presence of ingested fats in the small intestine. • Gallbladder removal due to obstruction or chronic inflammation leads to the direct flow of bile from liver to gut, with few major consequences on digestion. Medical application • Reabsorption of water from bile in the gallbladder is involved in the formation of gallstones in the lumen of the gallbladder or biliary ducts, a condition called cholelithiasis • This disorder usually originates with bile that already contains excessive amounts of normal bile components. • Supersaturation of cholesterol in bile can lead to the formation of cholesterol stones, the most common form • Brown or black pigment stones can form when bile contains excessive amounts of unconjugated bilirubin, which can result from chronic hemolysis associated with disorders such as sickle cell anemia • Gallstones can lead to biliary obstruction or more commonly to inflammation in acute or chronic cholecystitis

Main functions of these glands
• Products of these organs facilitate transport and
digestion of food within the gastrointestinal
tract.
• Salivary glands moisten and lubricate ingested
food and the oral mucosa, to initiate the
digestion of carbohydrates and lipids with
amylase and lipase, and to secrete innate
immune components such as lysozyme and
lactoferrin• The pancreas secretes digestive enzymes that act
in the small intestine and hormones important for
the metabolism of the absorbed nutrients
• Bile, whose components are necessary for
digestion and absorption of fats, is made in the
liver but stored and concentrated in the
gallbladder
• Liver also plays a major role in carbohydrate and
protein metabolism, inactivates many toxic
substances and drugs, and synthesizes most
plasma proteins and factors necessary for blood
coagulation SALIVARY GLANDS
• There are 3 pairs of
large salivary glands:
• parotid, submandibular,
and sublingual glands
• Together produce about
90% of saliva
• in addition numerous
minor or intrinsic
salivary glands located
throughout most of the
oral mucosa (Labial and
buccal, Glossopalatine,
Palatine, Lingual)
which secrete about 10%
of the total saliva volume
Parotid salivary gland
Sublingual salivary gland
Submandibular salivary glandType of secretion
• The secretion of each gland is either :
• Serous, seromucous, or mucous
• parotids is serous and watery
• Submandibular and sublingual glands produce
a seromucous secretion
• Minor glands is mostly mucous except for the
small serous glands at the bases of
circumvallate papillaeThree epithelial cell types comprise
the salivary secretory units
• Serous cells :
• are protein-secreting cells
• usually pyramidal in shape, with basal round nuclei,
well-stained RER, and apical secretory granules
• Joined apically by tight and adherent junctions,
• serous cells form a somewhat spherical unit called an
acinus with a very small central lumen
• Serous acini are intensely stained (pink-purple) due
to their protein content( basal basophilic & apical
acidophilic)
• Serous acinar cells secrete enzymes such as alphaamylase, which catalyzes the hydrolysis of starch into
simpler sugars like maltose • Mucous cells :
• are more columnar in shape, with more
compressed flat basal nuclei
• Mucous cells contain apical granules with hydro
philic mucins that provide lubricating properties
• More weakly stains than serous acini
• Cytoplasm appears pale, foamy
• Stains like PAS (Periodic Acid-Schiff) or Alcian blue
can highlight the carbohydrate-rich mucins in
mucous acini, appearing reddish-pink or pale blue,
respectively
• Mucous cells are most often organized as
cylindrical tubules rather than acini
• mucous also acts as a barrier against pathogensStructural organization of salivary glandSerous demilune
• Within the mixed
units grouped
serous cells occur
distally on short
mucous tubules
and often assume a
crescent-shaped
arrangement called
a serous demilune• Myoepithelial cells:
• are found inside the basal lamina surrounding
acini, tubules, and the proximal ends of the duct
system
• These cells are present between the basal
lamina and the secretory or duct cells and are
joined to the cells by desmosomes
• They appear similar to smooth muscle but are
derived from the epithelium
• Have stellate-shaped, numerous branching
processes with a flattened nucleus extend
several contractile processes around the
associated secretory unit or duct Function of myoepithelial cells
• their activity is important for moving secretory
products into and through the ducts
• accelerate the initial flow of saliva from the acini,
reduce luminal volume
• support the underlying parenchyma,
• reduce the back permeation of fluid
• They secrete various tumor suppressor proteins
such as protease inhibitors and antiangiogenesis
factors which provide a barrier against invasive
epithelial neoplasm.Duct system
• It consists of hollow tubes that connect initially with the
acinus (secretory end pieces) and extends to the oral
cavity
• it actively participates in the production and modification
of saliva
• On the basis of location, ducts are of two types:
• Intralobular ducts: Those ducts which are within the
lobule
• intercalated
• striated ducts
• Interlobular ducts: Those ducts which lie within the
connective tissue within the lobules of the gland
• The excretory ductsIntercalated ducts
• These are lined by single layer of cuboidal epithelium
and are surrounded by myoepithelial cell bodies,
• have centrally placed nuclei
• A few secretory granules may be found in the apical
cytoplasm, especially in the cells located near the
endpieces
• The apical cell surface has a few short microvilli
projecting into the lumen
• lateral surfaces are joined by junctional complexes
• The macromolecule components, i.e., lysozyme and
lactoferrin, are stored in the secretory granules of the
intercalated duct and contribute to the saliva.
– Lactoferrin binds iron, a vital nutrient for many microbes and
disrupting microbial membranes
– Lysozyme hydrolyzes the cell wallStriated ducts
• Several of intercalated ducts join to form a
striated duct
• Striated ducts lined by columnar cells with a
centrally placed large, spherical nucleus and pale,
acidophilic cytoplasm.
• By EM basal infoldings of the plasma membrane
• a large amount of radially oriented mitochondria
• The combination of infoldings and mitochondria
accounts for the striations seen in the light
microscopeFunction of striated ducts
• their folded cell membranes present a large
surface area with ion transporters, facilitating
rapid ion transcytosis and making the secretion
slightly hypotonic
• These ducts are involved in active transport and
are considered as site of electrolyte reabsorption
especially of sodium and chloride and secretion
of potassium and bicarbonate• A striated duct
shows very faint
striations in the
basal half of the
columnar cells,
which represent
mitochondria
located in the
folds of the lateral
cell membrane Inter lobular excretory ducts
• These ducts are located in the CT septa between the
lobules of the gland
• are larger in diameter than striated duct
• The lining of these ducts is unusual, combining
various epithelial types, including simple cuboidal or
columnar, stratified cuboidal or columnar, and
pseudostratified epithelia, distributed in no apparent
pattern.
• These atypical epithelia may reflect their
composition of cells with many diverse functions,
including cells for ion reabsorption, cells for
secretion of mucin and other proteins,
enteroendocrine cells, and basal stem cells• The main excretory duct may become stratified near the
oral opening
• Before emptying into the oral cavity, the main duct of each
gland is lined with nonkeratinized stratified squamous
epithelium
• Tuft or brush cells found in the lining of epithelial tissues,
including the duct system
• These cells have long stiff microvilli and apical vesicles and
are considered as chemoreceptor cells as they show nerve
endings adjacent to the basal portion of the cell
• Dendritic cells are found in various parts of the gland,
including the ducts, acini, and interstitial tissues play an
important role in immune surveillance (antigen
presentation)Histology of serous glandHistology of mixed glandSaliva has protective function
• Plasma cells in CT surrounding the intralobular
ducts release IgA, which forms a complex with
the secretory component synthesized by the
epithelial cells of the serous acini and
intralobular ducts.
• The IgA complex released into the saliva
provides defense against specific pathogens in
the oral cavityThe functions of saliva are:
Protection:
– Lubricant
– Mechanical washing
• Buffering:
_ Many bacteria need a specific pH for growth; saliva prevents
potential pathogens from colonizing in the mouth by denying them
optimal environmental conditions.
– Plaque microorganisms can produce acids from sugars, which if
not rapidly buffered and cleared by saliva can demineralize
enamel.
• Digestion: It provides taste acuity, neutralizes esophageal contents,
and forms the food bolus.
• Taste: It dissolves substances to be carried to taste buds and also
contains a protein, called gustin, which is necessary for growth and
maturation of taste buds.• Antimicrobial action: This occurs in various ways as:
– Lactoferrin binds free iron deprives bacteria of its essential
element
– Lysozyme hydrolyzes the cell wall.
– Histatin proteins with antibacterial property.
– Immunoglobulin, secretory IgA, clumps or agglutinates
microorganisms.
• Maintenance of tooth integrity: Saliva is saturated with
calcium and phosphate ions, and interaction with saliva
results in postoperative maturation through diffusion of
such ions. This maturation increases surface hardness,
decreases permeability, and increases the resistance of
enamel to caries.
• Tissue repair: The rate of wound contraction is
significantly increased in saliva due to the presence of
peptides and proteins present in saliva.Saliva production
• Parasympathetic stimulation, usually elicited
through the smell or taste of food, provokes a
copious watery secretion with relatively little
organic content
• Sympathetic stimulation inhibits such secretion
and produces the potential for dry mouth often
associated with anxietyMedical application
• Inadequate saliva production, leading to dry
mouth or xerostomia, can be caused by various
factors affecting the major salivary glands, such
as mumps viral infection, radiation of the glands,
or the normal side effect of drugs such as
antihistamines
• Excessive saliva production, or sialorrhea, is
associated with the autonomic activity of nausea,
inflammation within the oral cavity, and rabies
viral infectionParotid glands
• located in each cheek near the ear
• are branched acinar glands with exclusively
serous acini
• Serous cells secrete abundant α-amylase that
initiates hydrolysis of carbohydrates and
proline-rich proteins with antimicrobial and
other protective propertiesMicrograph of a parotid gland shows densely
packed serous acini (A) Secretory granules of
serous cells as well as an intercalated duct (ID)
striated duct (SD)
Striations of a duct (SD) are better seen here,
along with a septum (CT) and numerous serous
acini (A). The connective tissue often includes
adipocytesSubmandibular glands
• produce two-thirds of all saliva
• are branched tubuloacinar glands
• having primarily serous acini, but with many
mixed tubuloacinar secretory units
• Within the mixed units grouped serous cells occur
distally on short mucous tubules and often
assume a crescent-shaped arrangement called a
serous demilune
• In addition to α-amylase and proline-rich proteins,
serous cells of the submandibular gland secrete
lysozyme for hydrolysis of bacterial wallsSublingual glands
• The smallest of the major glands
• are also branched tubuloacinar glands
• secretory tubules of mucous cells
predominate and the main product of the
gland is mucus
• The few serous cells present add amylase and
lysozyme to the secretion.The submandibular gland is a mixed
serous and mucous gland (serous cells
redominate)
The sublingual gland is a mixed but largely
mucous glandPancreas
• Is a mixed exocrine-endocrine gland that
produces both digestive enzymes and hormones.
• with a large head near the duodenum and more
narrow body and tail regions that extend to the
left
• Has a thin capsule of CT from which septa extend
to cover the larger vessels and ducts and to
separate the parenchyma into lobules
• The secretory acini are surrounded by a basal
lamina that is supported only by a delicate sheath
of reticular fibers with a rich capillary network. • somewhat resembles the parotid gland
histologically, although the pancreas lacks
striated ducts and the parotid glands lack islets of
endocrine tissue
• Each pancreatic acinus consists of several serous
cells surrounding a very small lumen, without
myoepithelial cells
• The acinar cells have round basal nuclei, and
numerous zymogen granules apically, typical of
protein-secreting cells FUNCTION
• Endocrine function involves smaller cells located
in variously sized clusters called the pancreatic
islets (islets of Langerhans)
• Digestive enzymes are produced by cells of
serous acini in the larger exocrine portion of the
pancreas DUCT SYSTEM
• Each acinus is drained
by a short intercalated
duct of simple
squamous or low
cuboidal epithelium
• The initial cells of these
small ducts extend into
the lumen of the acinus
as small pale-staining
centroacinar cells that
are unique to the
pancreas• Under the influence of secretin, the
centroacinar and intercalated duct cells of the
intercalated ducts secrete a large volume of
fluid, rich in HCO3 − (bicarbonate ions), which
alkalinizes and transports hydrolytic enzymes
produced in the acini• The intercalated ducts merge with intralobular
ducts that lined with simple columnar epithelium
• and larger interlobular ducts, which have
increasingly columnar epithelia before joining the
main pancreatic duct that runs the length of the
gland lined with simple columnar epithelium
• The ducts and blood vessels are located in
connective tissueMicrograph of exocrine pancreas shows the serous, with very small
lumens. Each acinus is drained by an intercalated duct with its initial
cells, the centroacinar cells (arrow), inserted into the acinar lumen.
(b) The diagram shows the arrangement of cells more clearly..Function of exocrine pancreas
• Is a mixture of :
• acinar secretion (proenzymes)
• And duct secretion (bicarbonate)
• The exocrine pancreas secretes approximately 1.5
L of alkaline pancreatic juice per day and delivers
it directly into the duodenum where the HCO3−
ions neutralize the acidic chyme entering there
from the stomach and establish the pH for
optimal activity of the pancreatic enzymes• These digestive enzymes include several
proteases, α-amylase, lipases, and nucleases
(DNAase and RNAase).
• The proteases are secreted as inactive zymogens
(trypsinogen, chymotrypsinogen, proelastase,
and procarboxipeptidases).
• Trypsinogen is cleaved and activated by
enteropeptidases in the duodenum, generating
trypsin that activates the other proteases in a
cascade. Pancreatic tissue is protected against
autodigestion by the following:
• Storing the enzymes as inactive zymogen
• Restricting protease activation to the
duodenum
• Trypsin inhibitor, which is copackaged in the
secretory granules with trypsinogen
• The higher pH in the acini and duct system due
to HCO3− secreted by the centroacinar and
intercalated duct cells, which helps keep all the
enzymes inactiveRegulation of exocrine pancreatic
secretion
• Mainly through two polypeptide hormones
produced by enteroendocrine cells of the small
intestine in response to fatty acids & proteins:

1. Cholecystokinin (CCK) stimulates enzyme secretion
   by the acinar cells.


2. Secretin stimulate HCO3− secretion by the duct
   cells, reduces concentration of H ions & raising PH
   optimal for digestion
   • Autonomic (parasympathetic) nerve fibers also
   stimulate secretion from both acinar and duct cells.Medical application
   • Pancreatic cancer, which is usually a carcinoma of duct
   cells, can arise anywhere in the gland but occurs most
   often in the head of the organ near the duodenum. The
   tumor is usually asymptomatic until growth and metastasis
   are well advanced, leading to the low rate of early
   detection and subsequent high rate of mortality.
   • In acute pancreatitis, the proenzymes may be activated
   and digest pancreatic tissues, leading to very serious
   complications. Possible causes include infection, gallstones,
   alcoholism, drugs, and trauma. Chronic pancreatitis can
   produce progressive fibrosis and loss of pancreatic
   function. Liver
   • The liver is the largest internal organ, in adults averaging
   about 1.5 kg or 2% of the body weight.
   • Located in the right upper quadrant of the abdomen just
   below the diaphragm
   • Has major left and right lobes with two smaller inferior
   lobes,
   • most of which are covered by a thin capsule
   (Glisson'scapsule )and mesothelium of the visceral
   peritoneum
   • The capsule thickens at the hilum (or porta hepatis) on the
   inferior side, where the dual blood supply from the hepatic
   portal vein and hepatic artery enters the organ and where
   the hepatic vein, lymphatics, and common hepatic (bile)
   duct exit.Blood supply to the liver
   (hepatic circulation)Function of the liver
   • The main digestive function of the liver is production of
   bile, a complex substance required for the emulsification,
   hydrolysis, and uptake of fats in the duodenum.
   • The liver is also the major interface between the digestive
   system and the blood, as the organ in which nutrients
   absorbed in the small intestine are processed before
   distribution throughout the body.
   • About 75% of the blood entering the liver is nutrient-rich
   (but O2-poor) blood from the portal vein arising from the
   stomach, intestines, and spleen; the other 25% comes
   from the hepatic artery and supplies the organ’s O2.• In addition to secretion of bile components,
   hepatocytes and other liver cells process the
   contents of blood, with many specific functions:
   • Synthesis and secretion of the major plasma
   proteins, including albumins, fibrinogen,
   apolipoproteins, transferrin, and many others
   • Production of angiotensinogen important for salt
   conserving (renin-angiotensin-aldosterone
   system)
   • Breakdown (detoxification) and conjugation of
   ingested toxins, including many drugs
   • Amino acid deamination, producing urea
   removed from blood in kidneys• Conversion of amino acids into glucose
   (gluconeogenesis)
   • Storage of glucose in glycogen granules and
   triglycerides in small lipid droplets
   • Storage of vitamin A (in hepatic stellate cells)
   and other fat-soluble vitamins
   • Removal of effete erythrocytes (by specialized
   macrophages, or Kupffer cells)
   • Storage of iron in complexes with the protein
   ferritin. • Activation of vitamin D to 25,hydroxy D3(calcidiol)
   by 25,hydoxlase enzyme
   • calcidiol converted to calcitriol ( 1,25,hydroxy D3)
   in kidney by 1α hydroylase
   • Secret hormones : thrombopointin , hipicidin
   • Secret cholesterol and bilirubin Structure and function of liver
   • Abundant rough ER is focused on synthesis of plasma
   proteins and causes cytoplasmic basophilia
   • Abundant smooth ER, contains the enzyme systems
   for the inactivation or detoxification of substances in
   blood, which are then usually excreted with bile.
   • These include enzymes responsible for oxidation,
   methylation, and conjugation of steroids,
   barbiturates, antihistamines, and other drugs.
   • Other SER enzymes (glucuronosyl transferases)
   conjugate bilirubin to glucuronate, rendering it more
   soluble and facilitating its excretion in bile• Glycogen granules and small lipid droplets in
   hepatocytes, and very small electron-dense ferritin
   complexes (hemosiderin) primarily in the Kupffer cells,
   respectively mediate temporary storage of glucose,
   triglycerides, and iron.
   • Liver glycogen is depot of glucose and is mobilized if blood
   glucose falls bellow normal
   • Hepatocyte peroxisomes are also abundant and
   important for oxidation of excess fatty acids and
   conversion of excess purines to uric acid
   • Many Golgi complexes are also present, involved in
   synthesis of both plasma proteins and bile components.
   • The numerous mitochondria provide energy for all these
   activities Hepatocytes & Hepatic Lobules
   • Hepatocytes are large cuboidal or polyhedral epithelial
   cells, with large, round central nuclei and eosinophilic
   cytoplasm rich in mitochondria.
   • The cells are frequently binucleated and about 50% of
   them are polyploid, with two to eight times the normal
   chromosome number
   • The liver parenchyma is organized as thousands of
   small (~0.7 × 2 mm) hepatic lobules in which
   hepatocytes form hundreds of irregular plates
   arranged radially around a small central vein
   • The hepatocyte plates are supported by a delicate
   stroma of reticulin fibershepatic lobules are polygonal units
   showing plates of epithelial cells
   called hepatocytes radiating from a
   central venule (C).
   (b) peripheral CT of portal areas
   contains the portal triad: small bile
   ductules (D), venule (V) branches
   of the portal vein, and arteriole (A)
   branches of the hepatic artery.(a) Hepatocytes (H) are polygonal
   epithelial cells, which form
   branching, irregular plates
   separated by venous sinusoids (S)
   Reticulin (collagen type III) fibers
   (R) running along the plates of
   hepatocytes (H) Most CT in the
   liver is found in the septa and
   portal tractsPortal area
   • Peripherally each lobule has 3 to 6 portal areas
   with more fibrous CT, each of which contains 3
   interlobular structures that comprise the portal
   triad:
   • A venule branch of the portal vein, with blood rich
   in nutrients but low in O2.
   • An arteriole branch of the hepatic artery, which
   supplies O2.
   • One or two small bile ductules of cuboidal
   epithelium, branches of the bile conducting system.
   • Most of the peripheral portal areas also contain
   lymphatics and nerve fibersMedical application
   • In the normal liver most dense connective tissue
   is found only in the portal areas, surrounding the
   blood vessels and bile ductule.
   • In liver cirrhosis, which occurs late in chronic
   liver disease, fibrosis and proliferation of
   fibroblasts and hepatic stellate cells occur beyond
   the portal areas. The excessive connective tissue
   may disrupt the normal hepatic architecture and
   interfere with liver functionvascular sinusoids
   • Between all of the anastomosing
   plates of hepatocytes of a hepatic
   lobule
   • Emerge from the peripheral branches
   of the portal vein and hepatic artery
   and converge on the lobule’s central
   vein
   • The venous and arterial blood mixes in
   these irregular hepatic sinusoids
   • The anastomosing sinusoids have
   thin, discontinuous linings of
   fenestrated endothelial cells
   surrounded by sparse basal lamina
   and reticular fibersSpace of Disse
   • The discontinuities and fenestrations allow plasma to
   fill a narrow perisinusoidal space (or space of Disse)
   and directly bathe the many irregular microvilli
   projecting from the hepatocytes into this space
   • This direct contact between hepatocytes and plasma
   facilitates most key hepatocyte functions involving
   uptake and release of nutrients, proteins, and
   potential toxins
   • The fenestrae and discontinuity of endothelium allow
   the free flow of plasma but not of cellular elements
   into the space of DisseOther cells
   • are found with the sinusoids of hepatic lobules:


3. stellate macrophages, usually called Kupffer
   cells, are found on the luminal surface of the
   endothelial cells, within the sinusoids
   • These cells recognize and phagocytose aged
   erythrocytes, freeing heme and iron for reuse or
   storage in ferritin complexes
   • Kupffer cells are also antigen-presenting cells and
   remove any bacteria or debris present in the
   portal blood2. Hepatic stellate cells (or Ito cells) are found In the
   perisinusoidal space have small lipid droplets, which store
   vitamin A and other fat-soluble vitamins
   These mesenchymal cells, which are difficult to see in
   routine preparations, also produce extracellular matrix
   (ECM) components (becoming myofibroblasts after liver
   injury) and produce cytokines that help regulate Kupffer
   cell activityBlood circulation in liver
   • The endothelium of the central vein in the middle of
   each hepatic lobule is supported by a very thin layer
   of fibrous CT
   • Central venules from each lobule converge into
   larger veins, which eventually form two or more large
   hepatic veins that empty into the inferior vena cava.
   • Blood always flows from the periphery to the center
   of each hepatic lobule.
   • Consequently, oxygen and metabolites, as well as all
   other toxic or nontoxic substances absorbed in the
   intestines, reach the lobule’s peripheral cells first and
   then the more central cells. Bile secretion
   • The smaller apical surfaces of the hepatocytes form bile
   canaliculi and are involved in exocrine secretion of bile
   • Hepatocytes adhere firmly with desmosomes and junctional
   complexes.
   • The apical surfaces of two adherent hepatocytes are
   grooved and juxtaposed to form the canaliculus, sealed by
   tight junctions, into which bile components are secreted
   • These canaliculi are elongated spaces with large surface
   areas due to the many short microvilli from the constituent
   hepatocytes
   • The bile canaliculi form a complex anastomosing network of
   channels through the hepatocyte plates that end near the
   portal tracts• The bile flow therefore progresses in a direction
   opposite to that of the blood, that is, from the
   center of the lobule to its periphery
   • Bile canaliculi are the smallest branches of the
   biliary tree or bile conducting system
   • They empty into bile canals of Hering composed of
   cuboidal epithelial cells called cholangiocytes
   • The short bile canals quickly merge in the portal
   areas with the bile ductules lined by cuboidal or
   columnar cholangiocytes and with a distinct CT
   sheath.
   • Bile ductules gradually merge, enlarge, and form
   right and left hepatic ducts leaving the liver.Near the periphery of each hepatic lobule, many bile canaliculi
   join with the much larger bile canals of Hering, which are lined
   by cuboidal epithelial cells called cholangiocytes. These canals
   soon join the bile ductules in the portal areas and drain into the
   biliary tree.• Into the canaliculi hepatocytes continuously
   secrete bile, a mixture of :
   • bile acids (organic acids such as cholic acid)
   • bile salts (the deprotonated forms of bile acids),
   • electrolytes, fatty acids, phospholipids,
   cholesterol, and bilirubin
   • Some bile components are synthesized in
   hepatocyte SER, but most are taken up from the
   perisinusoidal space
   • all are quickly secreted into the bile canaliculi• Bile acids/salts have an important function in
   emulsifying the lipids in the duodenum, promoting
   their digestion and absorption.
   • Bilirubin is a pigmented breakdown product of heme
   that is released from splenic macrophages primarily,
   but also from Kupffer cells, and carried to
   hepatocytes bound to albumen. Released into the
   duodenum with bile, bilirubin is converted by
   intestinal bacteria into other pigmented products,
   some of which are absorbed in the intestinal mucosa
   to be processed and excreted again in the liver or
   excreted into urine by the kidneys. These bilirubinrelated compounds give feces and urine their
   characteristic colors.Medical application
   • An important function of hepatocyte SER is the
   conjugation of hydrophobic (water-insoluble), yellow
   bilirubin by glucuronosyl transferases to form watersoluble, nontoxic bilirubin glucuronide, which is
   excreted into the bile canaliculi. When bilirubin
   glucuronide is not formed or excreted properly, various
   diseases characterized by jaundice can result.
   • A frequent cause of jaundice in newborns is an
   underdeveloped state of the hepatocyte SER (neonatal
   hyperbilirubinemia).
   • A treatment in these cases is exposure to blue light from
   ordinary fluorescent tubes, which transforms
   unconjugated bilirubin into a water-soluble
   photoisomer that can be excreted by the kidneys.(1) RER is primarily engaged
   in synthesis of plasma
   proteins for release into the
   perisinusoidal space.
   (2) Potentially toxic
   compounds, bilirubin
   (bound to albumin) and bile
   acids are taken up from the
   perisinusoidal space,
   processed by enzymes in the
   tubulovesicular system of
   the SER, and secreted into
   the bile canaliculi.
   (3) Glucose is taken up from
   the perisinusoidal space and
   stored in glycogen granules,
   with the process reversed
   when glucose is needed.Hepatic lobules


4. The classic hepatic lobule with blood flowing past
   hepatocytes from the portal areas to a central venule,
   emphasizes the endocrine function of the structure
   producing factors for uptake by plasma.


5. The concept of portal lobules of hepatocytes is more
   useful when considering the exocrine function of these
   cells, that is, bile secretion
   • The portal area has the bile ductule at the center, and
   bile, moving in the opposite direction as the blood,
   flows toward it from all the surrounding hepatocytes
   • The tissue draining bile into each portal area duct is
   roughly triangular in shape, with the central veins of
   three classic lobules at its angles3. The hepatic acinus, a third way of viewing liver
   cells, emphasizes the nature of the blood supply to
   the hepatocytes and the oxygen gradient from the
   hepatic artery branch to the central vein
   • In a liver acinus hepatocytes make up an irregular
   oval or diamond-shaped area extending from two
   portal triads to the two closest central veins
   • The direction of blood flow partly explains why the
   properties and function of the periportal
   hepatocytes differ from those of the centrolobular
   cells • Periportal hepatocytes, comprising zone I in the
   acinus, get the most oxygen and nutrients and can
   most readily carry out functions requiring
   oxidative metabolism such as protein synthesis.
   • Hepatocytes in zone III, near the central vein, get
   the least oxygen and nutrients. They are the
   preferential sites of glycolysis, lipid formation, and
   drug biotransformations and are the first
   hepatocytes to undergo fatty accumulation and
   ischemic necrosis
   • In the intervening zone II, hepatocytes have an
   intermediate range of metabolic functions
   between those in zones I and IIIConcepts of structure-function relationships in liverLiver regeneration
   • Unlike the salivary glands and pancreas, the liver has
   a strong capacity for regeneration despite its normal
   slow rate of cell renewal.
   • Hepatocyte loss from the action of toxic substances
   triggers mitosis in the remaining healthy hepatocytes
   in a process of compensatory hyperplasia that
   maintains the original tissue mass.
   • Surgical removal of a liver portion produces a similar
   response in the hepatocytes of the remaining lobe
   • The regenerated liver tissue is usually well organized,
   with the typical lobular arrangement, and replaces
   the functions of the destroyed tissue. • This regenerative capacity is important clinically
   because one major liver lobe can sometimes be
   donated by a living relative for surgical transplant
   and full liver function restored in both donor and
   recipient.
   • Besides proliferation of existing hepatocytes, a role
   for liver stem cells in regeneration has been shown
   in some experimental models. Such cells, often
   called oval cells, are present among cholangiocytes
   of the bile canals near portal areas and produce
   progenitor cells for both hepatocytes and
   cholangiocytes.• Liver regeneration following partial hepatectomy occurs
   in three phases including :
   • (a) initiation or priming phase
   • (b) proliferation phase
   • (c) termination phase• Priming phase occurs within 5 hours of hepatectomy
   and involves activation and over expression of multiple
   specific genes to prepare the hepatocytes for
   replication. The regulatory mechanisms prepare
   hepatocytes to enter the cell cycle.
   • The proliferation phase involves activation of various
   growth factors, During this phase, hepatocytes undergo
   a series of cell division cycles and expansion
   •
   ]Termination phase is coordinated by TGF-β
   (transforming growth factor beta) that is responsible for
   stopping the regenerative process and preventing liver
   overgrowthMedical application
   • Fatty liver disease is a reversible condition in
   which large lipid droplets containing triglycerides
   accumulate abnormally in hepatocytes via the
   process called steatosis (fat buildup).
   • This disorder has multiple causes, but it occurs
   most commonly in individuals with alcoholism or
   obesity. Accumulation of fat in hepatocytes may
   produce a progressive inflammation of the liver,
   or hepatitis, in this case called steatohepatitisBiliary tree and gall bladder
   • The bile produced by the hepatocytes flows
   through the bile canaliculi, bile ductules, and
   bile ducts. These structures gradually merge,
   forming a converging network that ultimately
   forms the common hepatic duct, which joins
   the cystic duct from the gallbladder and
   continues to the duodenum as the common
   bile duct• The hepatic, cystic, and common bile ducts are
   lined with a mucous membrane having a simple
   columnar epithelium of cholangiocytes.
   • The lamina propria and submucosa are relatively
   thin, with mucous glands in some areas of the
   cystic duct, and surrounded by a thin muscularis
   • This muscle layer becomes thicker near the
   duodenum and finally, in the duodenal papilla,
   forms a sphincter of Oddi that regulates bile flow
   into the small bowelGall bladder
   • The gallbladder is a hollow, pear-shaped organ
   • capable of storing 30-50 mL of bile that is
   concentrated during storage.
   • The wall of the gallbladder consists of :
   • a mucosa composed of simple columnar
   epithelium and lamina propria, a thin muscularis
   with bundles of muscle fibers oriented in several
   directions, and an external adventitia or serosa
   • The mucosa has numerous folds that are
   particularly evident when the gallbladder is
   emptyThe gallbladder is a saclike
   structure that stores and
   concentrates bile, and releases it
   into the duodenum after a meal.
   (a) Its wall consists largely of a
   highly folded mucosa, with a
   simple columnar epithelium
   (arrows) overlying a typical lamina
   propria (LP); a muscularis (M) with
   bundles of muscle fibers oriented
   in all directions to facilitate
   emptying of the organ; and an
   external adventitia (A) where it is
   against the liver and a serosa
   where it is exposedUltra structure of epithelial cells
   • The lining epithelial cells of the gallbladder are
   active transport have prominent mitochondria,
   microvilli, and large intercellular spaces
   • Actively transporting water, for concentrating
   bile
   • The mechanism for this includes activity of Na+
   pumps in the basolateral membranes, followed
   by passive movement of water from the bile.
   •Release of bile
   • To move stored bile into the duodenum,
   contraction of the gallbladder muscularis is induced
   by cholecystokinin (CCK) released from
   enteroendocrine cells of the small intestine.
   • Release of CCK is, in turn, stimulated by the
   presence of ingested fats in the small intestine.
   • Gallbladder removal due to obstruction or chronic
   inflammation leads to the direct flow of bile from
   liver to gut, with few major consequences on
   digestion. Medical application
   • Reabsorption of water from bile in the gallbladder is involved in the
   formation of gallstones in the lumen of the gallbladder or biliary
   ducts, a condition called cholelithiasis
   • This disorder usually originates with bile that already contains
   excessive amounts of normal bile components.
   • Supersaturation of cholesterol in bile can lead to the formation of
   cholesterol stones, the most common form
   • Brown or black pigment stones can form when bile contains
   excessive amounts of unconjugated bilirubin, which can result from
   chronic hemolysis associated with disorders such as sickle cell
   anemia
   • Gallstones can lead to biliary obstruction or more commonly to
   inflammation in acute or chronic cholecystitis