Ingegneria delle tecnologie per la salute

Fondamenti di anatomia e istologia

aa. 2019-20

Lesson 7. Digestive system and peritoneum

Liver

• hepatic artery delivers oxygenated blood from heart to , hepatic portal delivers partially deoxygenated blood containing nutrients (+ drugs and toxins) absorbed from the small intestine and actually supplies more oxygen to liver than do much smaller hepatic arteries; after processing bloodborne nutrients and toxins, liver releases nutrients needed by other cells back into the blood, which drains into central vein and then through hepatic vein to inferior vena cava. • hepatic portal circulation = all blood from alimentary canal passes through liver (explaining liver most common site for alimentary canal cancers metastasis) Liver: Histology = 3 main components:

1 [liver’s main cell type, accounting for around 80% of liver's volume, playing a role in a wide variety of secretory, metabolic, and endocrine functions; plates of hepatocytes called hepatic laminae radiate outward from portal vein in each hepatic lobule] = from their central position, hepatocytes process nutrients, toxins, and waste materials carried by blood: materials such as bilirubin processed and excreted into bile canaliculi, other materials including proteins, lipids, and carbohydrates processed and secreted into sinusoids or just stored in cells until called upon. Liver: Histology = 3 main components:

2 bile canaliculi [grooves in cell membranes between adjacent hepatocytes accumulating bile produced by hepatocytes: from here, bile flows first into bile ductules and then into bile ducts, uniting to form larger right and left hepatic ducts, which themselves merge and exit liver as , that joins with from , forming common through which bile flows into small intestine] Liver: Histology = 3 main components:

3 hepatic sinusoids [open, porous blood space formed by fenestrated from nutrient-rich hepatic portal and oxygen-rich hepatic arteries, where hepatocytes are tightly packed around, giving them easy access to the blood] = combine and send blood to a central vein and then through hepatic vein into inferior vena cava (this means that blood and bile flow in opposite directions); also contain star-shaped reticuloendothelial cells (Kupffer cells), phagocytes removing dead red and white blood cells, , and other foreign material that enter sinusoids Liver: Histology Liver: Histology Liver: Histology Liver: Histology Liver: Histology portal triad = distinctive arrangement around perimeter of hepatic lobules, consisting of 3 basic structures: a bile duct, a hepatic artery branch, and a hepatic portal vein branch. Liver: Histology portal triad Liver: Histology portal triad

Blood flow

Bile flow Liver: Histology Liver: Histology Liver: Histology Liver: Histology Liver: Histology Liver: Histology Liver: Histology Liver: Histology Liver: Histology Liver: Bile

• lipids are hydrophobic (= do not dissolve in water), before they can be digested in watery environment of small intestine, large lipid globules must be broken down into smaller lipid globules (= emulsification) • Bile = yellow-brown or yellow-green alkaline solution (pH 7.6 to 8.6) mixture of water, bile salts, bile pigments, phospholipids (such as lecithin), electrolytes, cholesterol, and triglycerides secreted (about liter each day) by liver to accomplish emulsification of lipids in small intestine. • bile salts and phospholipids = components most critical to emulsification having a nonpolar (hydrophobic) region as well as a polar (hydrophilic) region [hydrophobic region interacts with large lipid molecules, whereas hydrophilic region interacts with watery chyme in intestine: large lipid globules being pulled apart into many tiny lipid fragments of about 1 μm , dramatically increasing surface area available for lipid-digesting enzyme activity] Liver: Bile

• While most constituents of bile are eliminated in feces, bile salts are reclaimed by enterohepatic circulation: once bile salts reach ileum, they are absorbed and returned to liver in hepatic portal blood; hepatocytes then excrete bile salts into newly formed bile. • bilirubin = main bile pigment [waste product produced when spleen removes old or damaged red blood cells from circulation, including proteins, iron, and toxic bilirubin, transported to liver via splenic vein of : proteins and iron recycled, whereas bilirubin excreted in bile, accounting for green color of bile, and transformed by intestinal bacteria into stercobilin (= brown pigment giving stool its characteristic color: in some disease states, bile does not enter intestine, resulting in white (‘acholic’) stool with a high fat content, since virtually no fats are broken down or absorbed)] Liver: Bile

• Hepatocytes work non-stop, but bile production increases when fatty chyme enters duodenum and stimulates secretion of gut hormone secretin. Between meals, bile is produced but conserved. The valve-like hepatopancreatic ampulla closes, allowing bile to divert to gallbladder, where it is concentrated and stored until next meal. Liver & Pancreas

= soft, oblong, glandular organ lying transversely in retroperitoneum behind stomach: head nestled into “c-shaped” curvature of duodenum with body extending to left about 15.2 cm (6 in) and ending as a tapering tail in hilum of spleen [curious mix of exocrine (secreting digestive enzymes) and endocrine (releasing hormones into blood) functions] Pancreas

• exocrine part = arises as little grape-like cell clusters, each called an acinus (plural = acini), located at terminal ends of pancreatic ducts, secreting enzyme-rich pancreatic juice into tiny merging ducts that form 2 dominant ducts [larger duct, Wirsung, fuses with (carrying bile from liver and gallbladder) just before entering the duodenum via a common opening (hepatopancreatic ampulla)]; smooth muscle sphincter of hepatopancreatic ampulla controls release of pancreatic juice and bile into small intestine; second and smaller , the accessory duct (duct of Santorini), runs from pancreas directly into duodenum, approximately 1 inch above hepatopancreatic ampulla.

• Scattered through sea of exocrine acini are small islands of endocrine cells, islets of Langerhans, producing hormones pancreatic polypeptide, insulin, glucagon, and somatostatin PANCREAS ANATOMY

esophagus

stomach

ductus choledocus pancreas

duodenum

duct of Santorini duct of Wirsung Pancreas PANCREATIC SECRETIONS

1. PROTEASES (70%) Endopeptidases (trypsin, chymotrypsin, elastases) Exopeptidases (carboxypeptidases)

trypsinogen trypsin activates all other precursors

enterokinase (duct walls)

2. NUCLEASES (DNAase, RNAase)

3. PANCREATIC AMYLASE (hydrolyse starch and gl;ycogen)

4. PANCREATIC LIPASE (triglycerides fatty acids and glycerol) REGULATION OF SECRETION

1. SECRETIN food in release of release of secretin secretion of alkaline pH stomach stomach acid into blood by bicarbonate (ideal for into duodenum duodenal cells by duct cells pancreatic enzymes)

2. PANCREOZYMIN (cholecystokinen)

amino acids and release of pancreozymin relase of pancreatic enzymes fats in intestine by intestinal mucosa into the intestine into blood

3. GASTRIN food in stomach gastrin secretion release of pancreatic enzymes by stomach mucosa into the intestine

4. AUTONOMIC INNERVATION (vagus nerve) Pancreas: Histology Pancreas: Histology

islet of Langerhans pancreatic acini

islet of pancreatic lobe Langerhans

BV Pancreas: Histology

LARGE SECRETORY DUCT INTERLOBULAR DUCT PANCREATIC SECRETORY DUCTS

simple cuboidal epithelium

acinus simple columnar epithelium Exocrine Pancreas: Histology

pyramidal secretory acinus basal basophilia cell (rough ER)

merocrine secretion (exocytosis)

zymogen granules centro- condensing acinar golgi vacuoles cells blood vesicles vessel intercalated duct

rough nerve endoplasmic golgi reticulum apparatus interlobular zymogen duct granules Pancreas: Histology

INTERCALARY DUCTS AND CENTROACINAR CELLS intercalary duct

intercalary duct PANCREATIC EXOCRINE SECRETORY CELL

zymogen granules

centroacinar cell CELL BIOLOGY OF PANCREATIC SECRETION

1. SYNTHESIS 2. SEGREGATION 14C -leucine + tRNA mRNA for chymotrysinogen ribosomes

14C -amino-acyl tRNA ribosomes mRNA polypeptide chymotrysinogen

6. DISCHARGE RER cisterna

3. INTRACELLULAR TRANSPORT exocytosis RER

transitional elements

5. INTRACELLULAR 4. CONCENTRATION STORAGE

zymogen golgi granules H2O apparatus

H2O golgi vesicles condensing vacuoles ISLET OF LANGERHANS

alpha cell (glucagon) vascular pole (secretion by exocytosis) acinus beta cell

beta cell (insulin) alpha fenestrated cell blood capillary

INSULIN- increases membrane promotes glycogenesis decrease blood glucose levels permeability to glucose

GLUCAGON - promotes glycogenolysis increases blood glucose levels “ ANTAGONISTIC HORMONES” Pancreas: Histology Pancreas: Histology ISLET OF LANGERHANS Pancreas: Histology ISLET OF LANGERHANS - TEM STAINED ALPHA AND BETA CELLS

ALPHA CELLS BETA CELLS Pancreas: Histology

INTERCALARY DUCTS AND CENTROACINAR CELLS intercalary duct

centroacinar cell

intercalary duct Pancreas: Histology Gallbladder

= 8–10 cm (~3–4 in) long, nested in a shallow area on posterior aspect of right liver lobe , muscular sac storing, concentrating, and, when stimulated, propelling bile into duodenum via common bile duct, divided into 3 regions:

1.fundus = widest portion, tapering medially into 2.body, which in turn narrows to become 3.neck, angling slightly superiorly as it approaches hepatic duct;  cystic duct = 1–2 cm (less than 1 in) long, turning inferiorly as it bridges neck and hepatic duct. Gallbladder  simple columnar epithelium organized in rugae, similar to those of stomach, absorbing water and ions from bile and concentrating it by up to 10-fold: no submucosa in gallbladder wall and wall’s middle, muscular coat is made of smooth muscle fibers [when contracting, gallbladder’s contents ejected through cystic duct and into bile duct]  visceral peritoneum reflected from liver capsule holds gallbladder against liver and forms outer coat of the gallbladder. Gallbladder: Histology Gallbladder: Histology Liver, Pancreas, and Gallbladder Anatomy-Histology Correlate -The liver and gallbladder play important roles in digestion via the production and storage of bile. The liver is also the major organ for metabolism and detoxification. The pancreas also produces digestive enzymes to break down proteins, sugars, and fats. - The processes described above are the exocrine functions of the liver and gallbladder. But they also have endocrine roles, secreting compounds into the bloodstream. The hepatocytes produce albumin, fibrinogen, and thrombin, for example. The produce insulin, glucagon, and somatostatin. - The liver, gallbladder, and pancreas receive blood supply from the celiac trunk. One main branch is the common hepatic artery, leading to the hepatic artery proper that branches into left and right hepatic arteries to supply the liver. The right hepatic artery gives off the cystic artery to supply the gallbladder. - The pancreas is supplied by multiple vessels. The body and tail are supplied by the dorsal, inferior, and great pancreatic arteries, which all branch off the splenic artery (another main branch of the celiac trunk). The head, neck, and uncinate process are supplied by anastomoses of arteries branching off the celiac trunk and superior mesenteric artery. The gastroduodenal artery, from the common hepatic artery, divides into the anterior and posterior superior pancreaticoduodenal arteries. They anastomose with inferior branches of the inferior pancreatico- duodenal artery from the superior mesenteric artery. The same arteries supply the duodenum. -The liver has diaphragmatic and visceral surfaces which contact the diaphragm and abdominal viscera, respectively. Note the right triangular, left triangular, and coronary ligaments that attach to the diaphragm. Note also the bare area not covered by peritoneum. Anteriorly, there is a fold of peritoneum connecting the liver to the umbilicus called the falciform ligament, which contains the round ligament or ligamentum teres. It is the remnant of the that brought oxygenated blood from the placenta to the fetus heart. The is the remnant of the fetal that shunted blood from the umbilical vein to the inferior vena cava to bypass the liver. In the adult liver, the includes the hepatic arteries from the hepatic artery proper, the hepatic portal vein, and the hepatic and cystic ducts joining to form the common bile duct. - The portal vein brings nutrients and other compounds absorbed by the GI tract to be stored and/or processed. - Anatomical lobes: Note how the inferior vena cava, gallbladder, ligamentum teres, ligamentum venosum, and porta hepatis form an “H” shape on the visceral surface. It divides the liver into 4 anatomical lobes based on outer appearance – the right, left, caudate, and quadrate lobes. - Functional lobes: These are based on the distribution of the hepatic arteries, portal vein, and hepatic bile duct. The inferior vena cava and the gallbladder serve as the dividing line between the functional right and left lobes. - The liver is divided into many hepatic lobules. Inflow to the liver involves hepatic arteries, which bring oxygenated blood to hepatic tissue, and portal veins, which bring nutrients and other compounds absorbed by the GI tract to be processed and/or stored in the liver. Outflow also involves two routes – hepatic veins which drain into the inferior vena cava and the common hepatic duct which joins the cystic duct and empties bile into the duodenum. - Major characteristics of the liver are portal triads (labeled “portal” in bottom left and shown in the middle) and central veins (labeled in bottom left and shown in the right). Red arrows indicate direction of blood flow within blood sinusoids flanking cords of liver cells. - Note the portal triad contains 1) the portal vein, 2) the hepatic artery, and 3) the bile duct. Each has its typical appearance. The central vein is lined with endothelial cells, with perforations into which the sinusoids empty. - The central veins lead to sublobular veins, which reach collecting veins, hepatic veins, and finally the inferior vena cava. The venous outflow of the liver has no regard to the organization of the lobules. - The liver sinusoids are shown in higher magnification in the bottom left. They are dilated, capillary-like vessels lined by fenestrated, discontinuous epithelium (labeled “e”). Interspersed among the endothelial cells are Kupffer cells (labeled “k”), which are fixed macrophages within the hepatic tissue. They have distinct cytoplasm that may enter the sinusoidal lumen and function like other macrophages within the body. They also break down damaged red blood cell hemoglobin. - In the bottom middle panel, there are many spaces between the hepatocytes and sinusoidal epithelial cells marked by arrowheads. They are referred to the space of Disse where exchange between hepatocytes and blood flow takes place. - Once again, in the bottom right, we review the , endothelial cell of the liver sinusoid, and the space of Disse. - The liver lobules can be defined in 3 ways: - 1) Classic lobule – centered around the central vein with the portal triads at each corner. Shown below on the left, the classic lobule may not always be hexagonal in shape. - 2) Portal lobule (not shown) – centered on the portal triad, based on bile secretion, and approximately triangular in shape. - 3) Liver acinus of Rappaport – this is the most functionally important classification. Shown below on the right, the acinus is roughly oval in shape with 2 central veins and 2 portal triads on opposite ends. Based on the blood flow within hepatic tissue, the acinus is divided into 3 zones. Cells in different zones are specialized for different activity. Zone 1 cells, being closest to the portal triads and hence most oxygenated blood, have the most drug- metabolizing enzymatic activity. Following that same reasoning, zone 3 hepatocytes near the central veins are most susceptible to ischemia. - As mentioned earlier, the liver has both endocrine and exocrine functions. The various proteins that hepatocytes secrete enter the bloodstream via the liver sinusoids. The liver also secretes bile in the conventional exocrine fashion. - The hepatocytes secrete bile into sealed extracellular spaces called bile canaliculi. The typical “chicken-wire” appearance is more easily visualized with silver stain. - Once again, inflow to the liver involves oxygenated blood via hepatic arteries and absorbed nutrients and compounds from the GI tract via the hepatic portal veins. - All venous drainage from the GI tract and abdominal visceral organs enters the portal system back to the liver. The overall order is as following: arteries → capillaries → veins → portal vein → hepatic sinusoids → veins → vena cava → heart. - In contrast, the caval system is as following: arteries → capillaries → veins → vena cava → heart. Obviously, this is the circulatory system within the rest of the body. - The portal and caval system are not exclusive from each other. There are 4 sites of portocaval anastomoses: - 1) - 2) paraumbilical veins - 3) rectal veins - 4) retroperitoneal veins - If there is liver damage or cirrhosis – accumulation of fibrous tissue that constricts the sinusoids – there may be portal hypertension. This may lead to varicose veins at the 4 sites of anastomoses. - The gallbladder is found under the right lobe of the liver. Its function is to store bile produced by the liver, which leaves via the cystic duct. It also enters the gallbladder in the cystic duct, traveling retrograde when the bile is not needed for digestion. Note the fundus, body, neck, and infundibulum of the gallbladder. - Note the right and left hepatic ducts coming together as the common hepatic duct, joining the cystic duct to form the common bile duct. This descends to the 2nd part of the duodenum, is joined by the pancreatic duct, and empties its contents into the duodenal lumen via the major duodenal papilla. - The gallbladder is supplied by the cystic artery, which is extremely important to find during a cholecystectomy. In most people it branches off the right hepatic artery, but could also come off the left hepatic, proper hepatic, or gastroduodenal arteries. - Note the extensive folds of mucosa extending into the lumen, consisting of tall, simple columnar epithelium. The underlying connective tissue is comprised of lamina propria, with no distinctly defined submucosa. There are scattered bundles of smooth muscle in the muscularis. The adventitia has rather dense connective tissue connecting the gallbladder to the liver. - Finally, we will look at the pancreas. To review: The head of the pancreas and duodenum are supplied from both the celiac trunk and the superior mesenteric artery.

- The body and tail of the pancreas are mostly supplied by branches of the splenic artery, namely the dorsal, greater, and inferior pancreatic arteries. - Piece of advice: It can be very confusing when identifying these arteries. First orient yourself, note whether the duodenum is in anatomical position or reflected (as it is on the bottom left), and identify where the arteries branch from and where they lead. - The pancreas contains multiple ducts, but the main pancreatic duct runs from the tail to the head of the pancreas. There may be a smaller accessory pancreatic duct. They join the common bile duct to empty into the duodenum. The pancreas is retroperitoneal. - Histologically, we can see the septa (S) between pancreatic lobules with interlobular ducts (D). As mentioned above, the pancreas also has both exocrine and endocrine functions. Most of the bottom left panel is filled with exocrine pancreatic tissue. Secretory portions are called acini. The scattered endocrine islets of Langerhans (I) are paler staining. - An islet is magnified in the bottom right. It is a compact mass of epithelial cells that receive rich vascular supply (arrows). It is typically very difficult to identify the different cell types in the islets. Briefly, the alpha cells secrete glucagon, the beta cells secrete insulin, and the delta cells secrete somatostatin. -Once again, most of the pancreas contains exocrine acini. Pancreatic enzymes are very diverse, including extremely efficient proteases, lipases, and amylases. - Separate acini are shown in the left. The pancreatic acinar or secretory cells are polarized, meaning the basal portions are filled with basophilic rough ER. The apical regions are filled with zymogen granules that contain many stored pro-enzymes. - Centroacinar cells, with paler staining, can be seen in the middle of some acini and mark the beginning of the duct system (marked “A” in the middle panel). They converge at “B” to form intercalated ducts, marked as “C”. The intercalated duct cells may be hard to identify, but they actively pump water and bicarbonate into the duct lumen. Intercalated ducts empty into interlobular ducts, marked as “small duct” in the bottom right, which lead to the main pancreatic duct.

[email protected] [email protected]